HK1156533B - Controlled release corticosteroid compositions and methods for the treatment of otic disorders - Google Patents

Abstract

Disclosed herein are compositions and methods for the treatment of otic disorders with steroid, NSAID, and/or adenosine triphosphatase ("ATPase") modulator agents. In these methods, the steroidal, NSAID, and/or ATPase compositions and formulations are administered locally to an individual afflicted with an otic disorder, through direct application of these compositions and formulations onto or via perfusion into the targeted auris structure(s).

Description

Controlled release corticosteroid compositions and methods for treating otic disorders

Cross-referencing

The present application claims the following: U.S. provisional application No. 61/127,713, filed on 5/14/2008, U.S. provisional application No. 61/060,425, filed on 6/10/2008, U.S. provisional application No. 61/074,583, filed on 20/6/2008, U.S. provisional application No. 61/094,384, filed on 9/4/2008, U.S. provisional application No. 61/101,112, filed on 9/29/2008, U.S. provisional application No. 61/140,033, filed on 22/12/2008, U.S. provisional application No. 61/095,248, filed on 9/8/2008, U.S. provisional application No. 61/087,940, filed on 11/2008, 7/21/2008, U.K. provisional application No. 61/082,450, filed on 12/22/2008, uk application No. 0823378.5, each of which is incorporated herein by reference in its entirety.

Background

The vertebrate has a pair of ears symmetrically located on opposite sides of the head. The ear serves as a sense organ for detecting sound and an organ for maintaining balance and posture. The ear is generally divided into three parts: the outer ear (outer ear), the middle ear (aurimedia/middle ear), and the inner ear (auris interran/inner ear).

Disclosure of Invention

Described herein are compositions, formulations, methods of manufacture, methods of treatment, uses, kits and delivery devices for the controlled release of at least one corticosteroid to at least one structure or region of the ear. Disclosed herein are controlled release formulations for delivering corticosteroids to the ear. In some embodiments, the target portion of the ear is the middle ear. In some embodiments, the target portion of the ear is the inner ear. In other embodiments, the target portions of the ears are the middle and inner ears. In some embodiments, the controlled release formulation further comprises a quick release or immediate release component for delivering the corticosteroid to the targeted ear structure. All formulations included an otically acceptable excipient.

Also disclosed herein are methods, compositions, and devices for treating otic disorders by administering a controlled release formulation comprising a corticosteroid. In some embodiments, the otic disorder is Meniere's disease, Meniere's syndrome, or sensorineural hearing loss. In other embodiments, the otic disorder is an Autoimmune Inner Ear Disorder (AIED). Also disclosed herein are local delivery controlled release steroid compositions and formulations to inhibit or ameliorate hearing and vestibular damage caused by AIED, which may be caused by other autoimmune conditions, including Ankylosing Spondylitis (alkylspondylitis), Systemic Lupus Erythematosus (SLE), sjogren's syndrome (sqeul Syndrome), galamina's disease (Cogan's), ulcerative colitis, Wegener's granulomatosis, rheumatoid arthritis, scleroderma, and Behcet's disease (also known as behet's disease/adaminata). In other embodiments, the otic disorder is otitis media. In other embodiments, the otic disorder is vestibular neuronitis, positional vertigo, lammikynren's Syndrome (herpes zoster infection), syphilis infection, drug induced inner ear injury, acoustic nerve tumor, presbycusis, otosclerosis, or temporomandibular joint disease.

Described herein are controlled release compositions and devices for treating otic disorders comprising a therapeutically effective amount of a corticosteroid, an otically acceptable controlled release excipient, and an otically acceptable controlled release vehicle. In one aspect, the otoacceptable controlled release excipient is selected from an otoacceptable polymer, an otoacceptable viscosity enhancing agent, an otoacceptable gel, an otoacceptable hydrogel, an otoacceptable thermoreversible gel, or a combination thereof.

In some embodiments, the pH and the practical osmolality and/or osmolality of the composition are formulated to ensure that internal stability of the targeted ear structure is maintained. Suitable osmolarity/osmolarity for perilymph is the practical/deliverable osmolarity/osmolarity that maintains the homeostasis of the target ear structure during administration of the pharmaceutical formulation described herein.

For example, the osmolality of perilymph is between about 270-300mOsm/L, and the compositions described herein are optionally formulated to provide a practical osmolality of about 150 to about 1000 mOsm/L. In certain embodiments, the formulations described herein provide a practical and/or deliverable osmolality at the target site of action (e.g., inner ear and/or perilymph and/or endolymph) within about 150 to about 500 mOsm/L. In certain embodiments, the formulations described herein provide a practical osmolality at the target site of action (e.g., inner ear and/or perilymph and/or endolymph) within about 200 to about 400 mOsm/L. In certain embodiments, the formulations described herein provide a practical osmolality at the target site of action (e.g., inner ear and/or perilymph and/or endolymph) within about 250 to about 320 mOsm/L. In certain embodiments, the formulations described herein provide suitable osmolarity of the perilymph within about 150 to about 500mOsm/L, about 200 to about 400mOsm/L, or about 250 to about 320mOsm/L at the target site of action (e.g., inner ear and/or perilymph and/or endolymphatic). In certain embodiments, the formulations described herein provide a suitable osmolality of perilymph within about 150 to about 500mOsm/kg, about 200 to about 400mOsm/kg, or about 250 to about 320mOsm/kg at the target site of action (e.g., inner ear and/or perilymph and/or endolymphatic). Similarly, the pH of the perilymph is about 7.2-7.4, and the pH of the formulations of the present invention are formulated (e.g., by using a buffer) to provide a suitable pH of the perilymph of about 5.5 to about 9.0, about 6.0 to about 8.0, or about 7.0 to about 7.6. In certain embodiments, the pH of the formulation ranges from about 6.0 to about 7.6. In certain instances, the pH of the endolymph is about 7.2-7.9, and the pH of the formulations of the present invention is formulated (e.g., by using a buffer) in the range of about 5.5 to about 9.0, in the range of about 6.6 to about 8.0, or in the range of about 7.0 to about 7.6.

In some aspects, the otoacceptable controlled release excipient is biodegradable and/or bioeliminable (e.g., degraded and/or eliminated by urine, feces, or other route of elimination). In another aspect, the controlled release composition further comprises an otically acceptable mucoadhesive agent, an otically acceptable permeation enhancer, or an otically acceptable bioadhesive agent.

In one aspect, the controlled release composition is delivered using a drug delivery device that is a needle and syringe, a pump, a microinjection device, and an in situ forming sponge-like material, or a combination thereof. In some embodiments, the corticosteroid of the controlled release composition has limited or non-systemic release, is toxic when administered systemically, has a poor pK profile, or a combination thereof. In other aspects, the corticosteroid is dexamethasone (dexamethasone), betamethasone (betamethasone), prednisolone (prednisolone), methylprednisolone (methylprednisolone), deoxycorticosterone (deoxycorticosterone), 11-deoxycorticosterone, 18-hydroxy-11-deoxycorticosterone, beclomethasone (beclomethasone), triamcinolone (triamcinolone), or a combination thereof. In another aspect, the corticosteroid is a phosphate prodrug of a steroid. In another aspect, the corticosteroid is a salt of a steroid.

Also disclosed herein are methods of treating otic disorders, comprising administering the compositions and formulations disclosed herein as follows: at least once every 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days, at least once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks; or once a month, once every two months, once every three months, once every four months, once every five months, once every six months, once every seven months, once every eight months, once every nine months, once every ten months, once every eleven months, or once every twelve months. In particular embodiments, the controlled release formulations described herein provide a sustained dose of corticosteroid to the inner ear between subsequent doses of the controlled release formulation. That is, as just one example, if a new dose of a corticosteroid controlled release formulation is administered via intratympanic injection into the round window (round window) membrane every 10 days, the controlled release formulation provides an effective dose of the corticosteroid to the inner ear (e.g., through the round window membrane) during the 10 day period.

In another aspect, the composition is administered such that the composition contacts the round window film. In one aspect, the composition is administered by intratympanic injection.

Provided herein are pharmaceutical compositions or devices for treating otic diseases or conditions that are formulated to provide a therapeutically effective amount of dexamethasone, methylprednisolone, or prednisolone, the pharmaceutical compositions or devices comprising substantially low dexamethasone, methylprednisolone, or prednisolone degradation products, the pharmaceutical compositions or devices additionally comprising two or more features selected from:

(i) between about 0.1% to about 10% by weight of dexamethasone, methylprednisolone, or prednisolone, or a pharmaceutically acceptable prodrug or salt thereof;

(ii) between about 16 wt% to about 21 wt% of a polyoxyethylene-polyoxypropylene triblock copolymer having the general formula E106P 70E 106;

(iii) sterile water buffered to provide a pH of between about 5.5 and about 8.0;

(iv) multiparticulate dexamethasone, methylprednisolone or prednisolone;

(v) a gelling temperature between about 19 ℃ to about 42 ℃;

(vi) less than about 50 colony forming units (cfu) of microbial agent per gram of formulation, and

(vii) less than about 5 Endotoxin Units (EU) per kilogram body weight of the individual.

In some embodiments, a pharmaceutical composition or device described herein comprises:

(i) between about 0.1% to about 10% by weight of dexamethasone, methylprednisolone, or prednisolone, or a pharmaceutically acceptable prodrug or salt thereof;

(ii) Between about 16 wt% to about 21 wt% of a polyoxyethylene-polyoxypropylene triblock copolymer having the general formula E106P 70E 106; and

(iii) multiparticulate dexamethasone, methylprednisolone or prednisolone.

In some embodiments, a pharmaceutical composition or device described herein comprises:

(i) between about 0.1% to about 10% by weight of dexamethasone, methylprednisolone, or prednisolone, or a pharmaceutically acceptable prodrug or salt thereof;

(ii) between about 16 wt% to about 21 wt% of a polyoxyethylene-polyoxypropylene triblock copolymer having the general formula E106P 70E 106;

(iii) multiparticulate dexamethasone, methylprednisolone or prednisolone; and

(iv) a gelling temperature between about 19 ℃ and about 42 ℃.

In some embodiments, the pharmaceutical composition or device provides a practical osmolality of between about 150 and 500 mOsm/L. In some embodiments, the pharmaceutical composition or device provides a practical osmolality of between about 200 and 400 mOsm/L. In some embodiments, the pharmaceutical composition or device provides a practical osmolality of between about 250 and 320 mOsm/L.

In some embodiments, dexamethasone, methylprednisolone, or prednisolone is released from the pharmaceutical formulation or device described above for a period of at least 3 days. In some embodiments, dexamethasone, methylprednisolone, or prednisolone is released from the pharmaceutical formulation or device described above for a period of at least 5 days. In some embodiments, dexamethasone, methylprednisolone, or prednisolone is released from the pharmaceutical formulation or device described above for a period of at least 10 days. In some embodiments, dexamethasone, methylprednisolone, or prednisolone is released from the pharmaceutical formulation or device described above for a period of at least 14 days. In some embodiments, dexamethasone, methylprednisolone, or prednisolone is released from the above pharmaceutical formulation or device for a period of at least 1 month.

In some embodiments, the above pharmaceutical composition or device comprises dexamethasone, methylprednisolone or prednisolone in the form of a free acid, free alcohol, salt or prodrug. In some embodiments, the above pharmaceutical composition or device comprises dexamethasone, methylprednisolone or prednisolone in the form of a free acid, free alcohol, salt or prodrug, or a combination thereof.

In some embodiments, the above pharmaceutical composition or device comprises dexamethasone, methylprednisolone, or prednisolone in multiparticulate form. In some embodiments, the above pharmaceutical composition or device comprises dexamethasone, methylprednisolone, or prednisolone in the form of micron-sized particles. In some embodiments, the above pharmaceutical composition or device comprises dexamethasone, methylprednisolone, or prednisolone in the form of a micron-sized powder.

In some embodiments, the pH of the pharmaceutical composition or device is between about 5.5 and about 8.0. In some embodiments, the pH of the pharmaceutical composition or device is between about 6.0 and about 8.0. In some embodiments, the pH of the pharmaceutical composition or device is between about 6.0 and about 7.6.

In some embodiments, the above-described pharmaceutical compositions or devices contain less than 100 colony forming units (cfu) of microbial agent per gram of formulation. In some embodiments, the pharmaceutical composition or device contains less than 50 colony forming units (cfu) of microbial agent per gram of formulation. In some embodiments, the pharmaceutical composition or device contains less than 10 colony forming units (cfu) of microbial agent per gram of formulation.

In some embodiments, the pharmaceutical composition or device contains less than 5 Endotoxin Units (EU) per kilogram body weight of the individual. In some embodiments, the pharmaceutical composition or device contains less than 4 Endotoxin Units (EU) per kilogram body weight of the individual.

In some embodiments, the pharmaceutical composition or device provides a gelling temperature of between about 19 ℃ to about 42 ℃. In some embodiments, the pharmaceutical composition or device provides a gelling temperature of between about 19 ℃ to about 37 ℃. In some embodiments, the pharmaceutical composition or device provides a gelling temperature of between about 19 ℃ to about 30 ℃.

In some embodiments, the pharmaceutical composition or device is an otologically acceptable thermoreversible gel. In some embodiments, the polyoxyethylene-polyoxypropylene triblock copolymer is biodegradable and/or bioerodible (e.g., the copolymer is excluded from the body by a biodegradation process, such as in urine, feces, etc.). In some embodiments, the pharmaceutical compositions or devices described herein further comprise a mucoadhesive agent. In some embodiments, the pharmaceutical compositions or devices described herein additionally comprise a permeation enhancer. In some embodiments, the pharmaceutical compositions or devices described herein additionally comprise a thickening agent. In some embodiments, the pharmaceutical composition or device described herein additionally comprises a dye.

In some embodiments, the pharmaceutical compositions or devices described herein additionally comprise a drug delivery device selected from the group consisting of: a needle and syringe, a pump, a microinjection device, a wick, an in situ formed sponge material, or a combination thereof.

In some embodiments, the pharmaceutical compositions or devices described herein are those having limited or no systemic release, systemic toxicity, adverse PK profiles, or combinations thereof of dexamethasone, methylprednisolone, or prednisolone, or pharmaceutically acceptable salts thereof. In some embodiments of the pharmaceutical compositions or devices described herein, the dexamethasone, methylprednisolone, or prednisolone is in the form of a free base, a free acid, a salt, a prodrug, or a combination thereof. In some embodiments of the pharmaceutical compositions or devices described herein, the dexamethasone, methylprednisolone, or prednisolone are administered in the form of phosphate or ester prodrugs. In some embodiments of the pharmaceutical compositions or devices described herein, the steroid is dexamethasone phosphate or dexamethasone acetate. In some embodiments, the pharmaceutical compositions or devices described herein comprise dexamethasone, methylprednisolone, prednisolone, or pharmaceutically acceptable salts, prodrugs, or combinations thereof, as an immediate release agent.

In some embodiments, the pharmaceutical composition or device described herein is a pharmaceutical composition or device comprising multiparticulates of dexamethasone, methylprednisolone or prednisolone. In some embodiments, the pharmaceutical composition or device described herein is a pharmaceutical composition or device in which dexamethasone, methylprednisolone, or prednisolone are substantially in the form of micron-sized particles. In some embodiments of the pharmaceutical compositions or devices described herein, the dexamethasone is in the form of dexamethasone micropowder.

In some embodiments, the pharmaceutical compositions or devices described herein additionally comprise an additional therapeutic agent. In some embodiments, the additional therapeutic agent is a Na/KATPase modulator, chemotherapeutic agent, collagen, gamma globulin, interferon, antimicrobial agent, antibiotic, local-action anesthetic, platelet activating factor antagonist, otoprotectant (otoprotectants), nitric oxide synthase inhibitor, anti-vertigo agent, vasopressin (vasopressin) antagonist, antiviral agent, antiemetic agent, anti-TNF agent, vasopressin receptor modulator, methotrexate (methotrexate), cyclophosphamide (cyclophosphamide), immunosuppressive agent, macrolide, latanoprost (latanoprost), TNF convertase inhibitor, IKK inhibitor, glutamate receptor modulator, anti-apoptotic agent, neuroprotective agent, thalidomide (thalidomide), c-jun inhibitor compound, hyaluronidase (hyaluronidase), antioxidant, IL-1 beta modulator, ERR-beta antagonist, anti-TNF-converting enzyme, anti-TNF-converting enzyme, anti-TNF-beta modulator, anti-TNF-beta, anti-TNF-beta modulator, anti-TNF-gamma, and/alpha-gamma, IGF-1 modulators, Toll-like receptor (KCNQ channel modulators), neurotropin (neurotropin) modulators, ATOH modulators, or combinations thereof.

In some embodiments, the pharmaceutical composition or device described herein is one in which the pH of the pharmaceutical composition or device is between about 6.0 and about 7.6.

In some embodiments of the pharmaceutical compositions or devices described herein, the ratio of polyoxyethylene-polyoxypropylene triblock copolymer having general formula E106P 70E 106 to thickener is from about 40: 1 to about 5: 1. In some embodiments, the thickening agent is carboxymethyl cellulose, hydroxypropyl cellulose, or hydroxypropyl methyl cellulose.

In some embodiments, the otic disease or condition is meniere's disease, sudden sensorineural hearing loss, noise-induced hearing loss, age-related hearing loss, autoimmune otic disease, or tinnitus.

Also provided herein are methods of treating an otic disease or condition, the methods comprising administering to a subject in need thereof an intratympanic composition or device comprising a therapeutically effective amount of dexamethasone, methylprednisolone, or prednisolone, the composition or device comprising substantially low dexamethasone, methylprednisolone, or prednisolone degradation products, the composition or device additionally comprising two or more features selected from:

(i) Between about 0.1% to about 10% by weight of dexamethasone, methylprednisolone, or prednisolone, or a pharmaceutically acceptable prodrug or salt thereof;

(ii) between about 16 wt% to about 21 wt% of a polyoxyethylene-polyoxypropylene triblock copolymer having the general formula E106P 70E 106;

(iii) sterile water buffered to provide a pH of between about 5.5 and about 8.0;

(iv) multiparticulate dexamethasone, methylprednisolone or prednisolone;

(v) a gelling temperature between about 19 ℃ to about 42 ℃;

(vi) less than about 50 colony forming units (cfu) of microbial agent per gram of formulation, and

(vii) less than about 5 Endotoxin Units (EU) per kilogram body weight of the individual.

In some embodiments of the methods described herein, the dexamethasone, methylprednisolone, or prednisolone is released from the composition or device for a period of at least 3 days. In some embodiments of the methods described herein, the dexamethasone, methylprednisolone, or prednisolone is released from the composition or device for a period of at least 5 days. In some embodiments of the methods described herein, the dexamethasone, methylprednisolone, or prednisolone is released from the composition or device for a period of at least 10 days. In some embodiments of the above methods, the dexamethasone, methylprednisolone, or prednisolone is substantially in the form of micron-sized particles.

In some embodiments of the methods described herein, the composition is administered through a round window. In some embodiments of the methods described herein, the otic disease or condition is meniere's disease, sudden sensorineural hearing loss, noise-induced hearing loss, age-related hearing loss, autoimmune otic disease, or tinnitus.

Drawings

FIG. 1 illustrates the in vitro release profile of dexamethasone with various concentrations of Poloxamer 407(Poloxamer 407).

Figure 2 illustrates the relationship between Mean Dissolution Time (MDT) and P407 concentration for the formulation.

Figure 3 illustrates the release profile of various steroid formulations containing 17% P407.

Fig. 4 illustrates the correlation between Mean Dissolution Time (MDT) and apparent viscosity of the formulation.

FIG. 5 illustrates the effect of concentration on the viscosity of an aqueous solution of Valenones (Blanose) purified CMC.

FIG. 6 illustrates the effect of concentration on the viscosity of an aqueous solution of Methocel.

Figure 7 illustrates that the gel was left in the guinea pig ear for up to 5 days after intratympanic injection.

Figure 8 illustrates the gel exclusion time course for the formulations described herein.

FIG. 9 illustrates the release profile of the formulations described herein.

Detailed Description

Provided herein are controlled release corticosteroid compositions and formulations for the treatment of disorders of the ear, including meniere's disease and sensorineural hearing loss.

A few therapeutic products are available for the treatment of otic disorders such as AIED, however, systemic routes via oral, intravenous or intramuscular routes are currently used to deliver these therapeutic agents. Systemic drug administration may result in unequal drug concentration potentials, with higher circulating levels in serum and lower levels in target middle and inner ear organ structures. Thus, a significant amount of drug is required to overcome this inequality in order to deliver an adequate therapeutically effective amount to the inner ear. In addition, systemic drug administration may increase the likelihood of systemic toxicity and adverse side effects because high serum levels are required to achieve adequate local delivery to the target site. Systemic toxicity may also occur as a result of the therapeutic agent being broken down by the liver and processed to form toxic metabolites that effectively negate any benefit obtained by the administered therapeutic agent.

To overcome the toxicity and concomitant side effects of systemic delivery, disclosed herein are methods and compositions and devices for the local delivery of therapeutic agents to targeted otic structures. Access to, for example, the vestibule and cochlear organs will pass through the middle ear (including round window membrane), oval window/stapes footplate, annular ligament, and through the auditory capsule/temporal bone.

Accordingly, provided herein are controlled release corticosteroid formulations and compositions for the local treatment of a target ear structure, thereby avoiding side effects resulting from systemic administration of corticosteroid formulations and compositions. Topically applied corticosteroid formulations and compositions and devices are compatible with the target ear structure and are administered directly to the desired target ear structure, such as the cochlear region, the tympanic cavity, or the external ear, or to a structure in direct communication with the inner ear region, including (but not limited to) the round window membrane, the cochlear ridge, or the oval window membrane. By specifically targeting the ear structure, adverse side effects resulting from systemic treatment can be avoided. In addition, clinical studies have shown that long term exposure of the drug to the perilymph of the cochlea has benefits, such as improved clinical efficacy on sudden hearing loss when multiple administrations of the therapeutic agent are given. Thus, by providing a controlled release corticosteroid formulation or composition to treat an otic disorder, a constant, variable, and/or long-term source of corticosteroid can be provided to an individual or patient suffering from an otic disorder, thereby reducing or eliminating variability in treatment. Accordingly, one embodiment disclosed hereinIs to provide a formulation that enables the release of at least one corticosteroid at a therapeutically effective dose at a variable or constant rate, such as to ensure continuous release of at least one pharmaceutical agent. In some embodiments, the corticosteroids disclosed herein are administered in an immediate release formulation or composition. In other embodiments, the steroid and/or ATPase modulator is administered in a sustained release formulation or variant thereof that releases continuously, variably, or in a pulsatile manner. In still other embodiments, the corticosteroid formulation is administered as an immediate release and sustained release formulation that releases continuously, variably, or in a pulsatile manner, or a variant thereof. Release is optionally dependent on environmental or physiological conditions, e.g., external ionic environment (see, e.g., for Release System, Johnson corporation (Johnson)& Johnson))。

In addition, local treatment of the targeted ear structure can also be amenable to the use of therapeutic agents previously unsuitable for use, including therapeutic agents with poor pK characteristics, poor uptake, low systemic release, and/or toxicity issues. Since corticosteroid formulations and compositions and devices can target targets locally and there is a biological blood barrier in the inner ear, the risk of adverse effects from treatment with previously characterized toxic or ineffective corticosteroids will be reduced. Thus, the use of corticosteroids in the treatment of otic disorders that have previously been rejected by the practitioner due to their adverse effects or ineffectiveness is also contemplated within the scope of the embodiments herein.

Also included within embodiments disclosed herein are combinations of corticosteroid formulations and compositions and devices disclosed herein using other otocompatible agents. When used, these agents assist in the treatment of hearing or balance loss or dysfunction caused by autoimmune disorders, including vertigo, tinnitus, hearing loss, balance impairment, infection, or combinations thereof. Thus, the use of an agent that ameliorates or reduces the effects of vertigo, tinnitus, hearing loss, balance impairment, infection, inflammatory response, or a combination thereof is also contemplated in combination with: corticosteroids, including anti-TNF agents, antiemetics, chemotherapeutic agents, including cyclophosphamide (cytoxan), azathioprine (azathiprine), or methotrexate; treatment with: collagen, gamma globulin, interferon, copaxone, central nervous system agents, local-acting anesthetics, antibiotics, platelet-activating factor antagonists, nitric oxide synthase inhibitors, and combinations thereof.

In addition, the otoacceptable controlled release corticosteroid formulations and treatments described herein are provided to the targeted ear region (including the inner ear) of an individual in need thereof, and an oral dose of a corticosteroid is additionally administered to the individual in need thereof. In some embodiments, an oral dose of corticosteroid is administered prior to administration of the otoacceptable controlled release corticosteroid formulation, and the oral dose is then gradually reduced over a time period that provides an otoacceptable controlled release corticosteroid formulation. Alternatively, an oral dose of corticosteroid is administered during administration of the otoacceptable controlled release corticosteroid formulation, and then the oral dose is gradually reduced over a time period that provides an otoacceptable controlled release corticosteroid formulation. Alternatively, an oral dose of corticosteroid is administered after administration of the otoacceptable controlled release corticosteroid formulation has begun, and then the oral dose is gradually reduced over a time period that provides an otoacceptable controlled release corticosteroid formulation.

Additionally, corticosteroid pharmaceutical compositions or formulations or devices included herein also include carriers, adjuvants, such as preservatives, stabilizers, wetting or emulsifying agents, dissolution promoters, salts to adjust osmotic pressure, and/or buffers. Such carriers, adjuvants and other excipients should be compatible with the environment in which the targeted ear structure is located. Thus, carriers, adjuvants and excipients that are not or have minimal ototoxicity are specifically contemplated to allow effective treatment of the otic disorders contemplated herein with minimal side effects on the target area or region. To prevent ototoxicity, the corticosteroid pharmaceutical compositions or formulations or devices disclosed herein are optionally targeted to distinct regions of the targeted ear structure, including (but not limited to) the tympanic cavity, the vestibular bone labyrinth and membrane labyrinth, the cochlear bone labyrinth and membrane labyrinth, and other anatomical or physiological structures located in the inner ear.

Certain definitions

The term "otoacceptable" as used herein includes with respect to formulations, compositions or ingredients that do not have a sustained deleterious effect on the middle and inner ear of the treated individual. As used herein, "otic pharmaceutically acceptable" means that a substance, such as a carrier or diluent, does not abrogate the biological activity or properties of the compound for the middle and inner ear, and is relatively low or low in toxicity to the middle and inner ear, i.e., the substance is administered to a subject without causing undue biological effects or interacting in a deleterious manner with any of the components contained in the composition.

As used herein, ameliorating or alleviating a symptom of a particular otic disease, disorder or condition by administration of a particular compound or pharmaceutical composition refers to any reduction in severity, delay in onset, slowing of progression, or reduction in duration of action, whether permanent or temporary, sustained or transient, due to or caused by administration of the compound or composition.

"antioxidants" are otically acceptable antioxidants and include, for example, Butylated Hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium metabisulfite, and tocopherol. In certain embodiments, antioxidants enhance chemical stability when desired. Antioxidants are also useful in counteracting the ototoxic effects of certain therapeutic agents, including agents used in combination with the corticosteroids disclosed herein.

"inner ear" refers to the inner ear, including the cochlea and vestibular labyrinth and round window connecting the cochlea with the middle ear.

"otic bioavailability" or "inner ear bioavailability" or "middle ear bioavailability" or "outer ear bioavailability" refers to the percentage of an administered dose of a compound disclosed herein that is available in the targeted otic structure of the animal or human being under study.

By "middle ear" is meant the middle ear, including the tympanic cavity, the ossicles and the oval window connecting the middle ear with the inner ear.

"outer ear" refers to the external ear, including the pinna, the ear canal, and the tympanic membrane that connects the outer ear to the middle ear.

"plasma concentration" refers to the concentration of a compound provided herein in the plasma component of the blood of an individual.

A "carrier material" is an excipient that is compatible with the corticosteroid, the target ear structure, and the release profile properties of an otically acceptable pharmaceutical formulation. Such carrier materials include, for example, binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. "otic pharmaceutically compatible carrier materials" include, but are not limited to, acacia (acacia), gelatin, colloidal silica, calcium glycerophosphate, calcium lactate, maltodextrin, glycerol, magnesium silicate, polyvinylpyrrolidone (PVP), cholesterol esters, sodium caseinate, soy lecithin, taurocholic acid, phosphatidylcholine, sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose and cellulose conjugates, sodium stearoyl lactylate, carrageenan (carrageenans), monoglycerides, diglycerides, pregelatinized starch, and the like.

The term "diluent" refers to a compound used to dilute the corticosteroid prior to delivery and which is compatible with the targeted otic structure.

"dispersants" and/or "viscosity modifiers" are substances that control the diffusion and homogeneity of corticosteroids in liquid media. Examples of diffusion promoters/dispersants include, but are not limited to, hydrophilic polymers, electrolytes,60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as PVP)) And based on carbohydratesDispersants for compounds such as hydroxypropyl cellulose (e.g. HPC, HPC-SL and HPC-L), hydroxypropylmethyl cellulose (e.g. HPMC K100, HPMC K4M, HPMC K15M and HPMC K100M), sodium carboxymethylcellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate stearate (HPMCAS), amorphous cellulose, magnesium aluminium silicate, triethanolamine, polyvinyl alcohol (PVA), vinylpyrrolidone/vinyl acetate copolymer (S630), polymers of 4- (1, 1, 3, 3-tetramethylbutyl) -phenol with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g. poloxamers F127, poloxamers) Andwhich is a block copolymer of ethylene oxide and propylene oxide); and poloxamines (e.g., terfenac)Also known as poloxaminesWhich is a tetrafunctional block copolymer obtained by sequentially adding propylene oxide and ethylene oxide to ethylenediamine (basf corporation, pasippany, n.j.), polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25 or polyvinylpyrrolidone K30, polyvinylpyrrolidone/vinyl acetate copolymer (S-630), polyethylene glycol (for example, polyethylene glycol having a molecular weight of about 300 to about 6000 or about 3350 to about 4000 or about 7000 to about 5400), sodium carboxymethylcellulose, methylcellulose, polysorbate-80, sodium alginate, gums (such as tragacanth and acacia, guar gum, xanthans (including xanthans), sugars, celluloses (such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose), polysorbate-80, xanthan gum), xanthan gum, cellulose (such as sodium carboxymethylcellulose, sodium carboxymethylcellulose), polysorbate-80, sodium alginate, and mixtures thereof, Sodium alginate and polyEthoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone (povidone), carbomer (carbomer), polyvinyl alcohol (PVA), alginate, chitosan (chitosan), and combinations thereof. Plasticizers such as cellulose or triethylcellulose are also used as dispersants. Optional dispersants suitable for use in the liposomal dispersions and self-emulsifying dispersions of corticosteroids disclosed herein are dimyristoyl phosphatidylcholine, phosphatidylcholine (c8-c18), phosphatidylethanolamine (c8-c18), phosphatidylglycerol (c8-c18), native phosphatidylcholine from eggs or soybeans, native phosphatidylglycerol from eggs or soybeans, cholesterol, and isopropyl myristate.

"drug absorption" or "absorption" refers to the process of movement of a corticosteroid from the local site of administration (for example only, the round window membrane of the inner ear) and across the barrier (round window membrane, described below) into the inner ear or inner ear structure. The term "co-administration" or the like as used herein is intended to encompass the administration of a corticosteroid to a single patient, and is intended to encompass treatment regimens in which the corticosteroid is administered by the same or different routes of administration, or at the same or different times.

The term "effective amount" or "therapeutically effective amount" as used herein refers to an amount of corticosteroid that is expected to be administered sufficient to alleviate one or more symptoms of the disease or condition being treated to some extent. For example, the result of administration of a corticosteroid drug as disclosed herein is a reduction and/or alleviation of the signs, symptoms, or causes of AIED. For example, an "effective amount" for therapeutic use is the amount of corticosteroid (including the formulations disclosed herein) required to provide reduction or amelioration of disease symptoms without undue adverse side effects. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. An "effective amount" of a corticosteroid composition disclosed herein is an amount effective to achieve a desired pharmacological effect or therapeutic improvement without undue adverse side effects. It will be appreciated that in some embodiments, the "effective amount" or "therapeutically effective amount" varies from subject to subject as a function of the metabolism of the compound administered, the age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. It will also be appreciated that the "effective amount" in an extended release dosage format may be different from the "effective amount" in an immediate release dosage format, based on pharmacokinetic and pharmacodynamic considerations.

The term "enhance" refers to increasing or prolonging the efficacy or duration of the desired effect of the corticosteroid, or attenuating any adverse symptoms such as local pain that occur with administration of a therapeutic agent. Thus, in terms of enhancing the effect of the corticosteroids disclosed herein, the term "enhance" refers to the ability to increase or prolong the efficacy or duration of the effect of other therapeutic agents used in combination with the corticosteroids disclosed herein. As used herein, an "enhancing effective amount" refers to an amount of a corticosteroid or other therapeutic agent sufficient to enhance the effect of the other therapeutic agent or corticosteroid in a desired system. When used in a patient, an amount effective for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drug, and the judgment of the treating physician.

The term "inhibiting" includes preventing, slowing or reversing the progression of the condition (e.g., AIED) or the progression of the condition in a patient for which treatment is necessary.

The terms "kit" and "article of manufacture" are used synonymously.

"pharmacodynamics" refers to factors that determine the biological response observed at a desired site within the target otic structure relative to the concentration of the drug.

"pharmacokinetics" refers to the factors that determine the attainment and maintenance of an appropriate drug concentration at a desired site within the target otic structure.

In prophylactic applications, corticosteroid-containing compositions described herein are administered to patients susceptible to or otherwise at risk of a particular disease, disorder, or condition, such as meniere's disease, or patients suffering from a disease associated with AIED, including, by way of example only, ankylosing spondylitis, Systemic Lupus Erythematosus (SLE), schwann's syndrome, myristyl disease, ulcerative colitis, wegener's granulomatosis, inflammatory bowel disease, rheumatoid arthritis, scleroderma, and behcet's disease. Such an amount is defined as a "prophylactically effective amount or dose". In this use, the exact amount also depends on the health status, body weight, etc. of the patient.

As used herein, a "medical device" includes any of the compositions described herein that provide an accumulator for the extended release of an active agent described herein after administration to the ear.

By "prodrug" is meant a corticosteroid that is converted in vivo to the parent drug. In certain embodiments, the prodrug is enzymatically metabolized to the biologically, pharmaceutically, or therapeutically active form of the compound by one or more steps or processes. To make prodrugs, the pharmaceutically active compounds are modified so that the active compounds will be regenerated after in vivo administration. In one embodiment, the prodrug is designed to alter the metabolic stability or transport characteristics of the drug, mask side effects or toxicity, or alter other characteristics or properties of the drug. In some embodiments, the compounds provided herein are derivatized into suitable prodrugs.

A "round window membrane" is a membrane in humans that covers the cochlear window (also known as the round window, the right round window, or the round window). In humans, the thickness of the round window membrane is about 70 microns.

"solubilizer" means an otically acceptable compound such as triacetin, triethyl citrate, ethyl oleate, ethyl octanoate, sodium lauryl sulfate, sodium decanoate, sucrose esters, alkyl glycosides, sodium docusate (sodium docusate), vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcyclodextrin, ethanol, N-butanol, isopropanol, cholesterol, bile salts, polyethylene glycol 200-.

"stabilizer" refers to a compound that is compatible with the environment of the targeted ear structure, such as any antioxidant, buffer, acid, preservative, and the like. Stabilizers include, but are not limited to, agents that produce any of the following effects: (1) improving the compatibility of the excipient with the container or delivery system (including syringes or vials), (2) improving the stability of the composition components, or (3) improving the stability of the formulation.

As used herein, "steady state" refers to the generation of a steady or constant level of drug exposure within a target ear structure when the amount of drug administered to the target ear structure is equal to the amount of drug eliminated over one dosing interval.

The term "individual" as used herein is used to refer to an animal, preferably a mammal, including a human or a non-human. The terms patient and individual are used interchangeably.

"surfactant" means an otically acceptable compound such as sodium lauryl sulfate, docusate sodium, sodium lauryl sulfate, sodium docusate, sodium lauryl sulfate,60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, poloxamer, bile salts, glycerol monostearate, copolymers of ethylene oxide and propylene oxide, e.g.(BASF) and the like. Some other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers, such as octoxynol 10(octoxynol 10), octoxynol 40(octoxynol 40). In some embodiments, surfactants are included to enhance physical stability or for other purposes.

The term "treating" as used herein includes prophylactic and/or therapeutic alleviation, or amelioration of symptoms of a disease or condition, prevention of other symptoms, amelioration or prevention of the underlying metabolic etiology of a symptom, inhibition of a disease or condition (e.g., arresting the development of a disease or condition), alleviation of a disease or condition, regression of a disease or condition, alleviation of a condition caused by a disease or condition, or termination of symptoms of a disease or condition.

Anatomy of ear

As shown in the following figures, the outer ear is the external part of an organ and is composed of the pinna (pinna/auricle), the ear canal (external auditory canal), and the outward part of the tympanic membrane (also called eardrum). The pinna is the fleshy part of the outer ear, visible on the side of the head, which serves to collect and direct sound waves to the ear canal. Thus, the outer ear functions in part to collect and direct sound waves to the tympanic membrane and the middle ear.

The middle ear is an air-filled cavity, called the tympanic cavity, behind the tympanic membrane. The tympanic membrane, also known as the eardrum, is a membrane that separates the outer and middle ear. The middle ear is located in the temporal bone and includes three ear bones (ossicles) in this space; malleus, incus, and stapes. The ossicles are connected together via tiny ligaments forming a bridge across the tympanogram space. One end of the malleus is attached to the tympanic membrane, and its anterior end is attached to the incus, which in turn is attached to the stapes. The stapes is attached to the oval window, which is one of two windows located in the tympanic cavity. A fibrous tissue layer called the annulus ligament connects the stapes with the oval window. Sound waves from the outer ear first cause the tympanic membrane to vibrate. Vibrations travel via the ossicles and oval window to the cochlea, transferring motion to the fluid in the inner ear. Thus, the arrangement of the ossicles provides a mechanical linkage between the tympanic membrane and the oval window of the fluid-filled inner ear, wherein the sound is converted and converted to the inner ear for further processing. Loss of stiffness, rigidity or mobility of the ossicles, tympanic membrane or oval window leads to hearing loss, such as otosclerosis or stapedial stiffness.

The tympanic cavity is also connected to the throat via the eustachian tube. The eustachian tube is capable of equalizing the pressure between the outside air and the middle ear cavity. The round window is a component of the inner ear but is also accessible within the tympanic cavity, which leads to the cochlea of the inner ear. The round window is covered by a round window film, which consists of three layers: an outer or mucosal layer, an intermediate or fibrous layer, and an inner membrane in direct fluid communication with the cochlea. Thus, the round window communicates directly with the inner ear via the inner membrane.

The motion in the oval window and the round window are interconnected, i.e. when the stapes transmits the tympanic membrane motion to the oval window to move inwardly relative to the inner ear fluid, the round window (more precisely, the round window membrane) is correspondingly pushed out and away from the cochlear fluid. This movement of the round window moves fluid within the cochlea, which in turn causes movement of the intra-cochlear hair cells, thereby transducing the hearing signal. The round window membrane becomes stiff or stiff, resulting in hearing loss due to the inability to move cochlear fluids. Recent research has focused on implanting a mechanical transducer on the round window that bypasses the normal conduction path via the oval window and provides an amplified input to the cochlear cavity.

Auditory signal transduction occurs in the inner ear. The fluid-filled inner ear is composed of two main components: the cochlea and vestibular organs. The inner ear is partially located in a bony labyrinth, which is a complex series of passages in the cranio-temporal bone. The vestibular organ is the balancing organ and consists of three semicircular canals and the vestibule. The arrangement of the three semicircular canals relative to each other allows the movement of the head along three orthogonal planes in space to be detected by the movement of the fluid and the signals subsequently processed by the sense organs of the semicircular canals, known as the ampulla crest. The ampulla cristae contains hair cells and supporting cells and is covered with a dome-shaped gel material called the ampulla cap. The hair of the hair cells is embedded in the ampulla cap. The semicircular canal detects dynamic balance, i.e. the balance of a rotational or angular movement.

While the semicircular canal moves with the head when the head is rotated rapidly, the endolymphatic fluid located within the membrane semicircular canal tends to remain immobile. The interior lymph fluid pushes against the ampulla cap, which tilts to one side. When the ampulla cap is tilted, it bends some of the hair cells on the ampulla crest, which in turn triggers a sensory pulse. Because each semicircular canal lies on a different plane, the corresponding ampulla crest of each semicircular canal responds differently to the same movement of the head. This produces a chimeric impulse that propagates to the central nervous system on the vestibular branch of the vestibulocochlear nerve. The central nervous system interprets this information and elicits the appropriate responses to maintain balance. Important in the central nervous system is the cerebellum, which mediates sense and balance.

The vestibule is the central portion of the inner ear and contains mechanoreceptors with hair cells that ascertain the static balance or position of the head relative to gravity. Static balancing works when the head is stationary or moving in a straight line. The membranous labyrinth in the vestibulum is divided into two sac-like structures, the ellipsoidal sac and the balloon. Each structure also contains a small structure called a sac-spot, which is responsible for maintaining static equilibrium. The cystic plaque consists of sensory hair cells embedded in a gel mass (similar to the ampulla cap) covering the cystic plaque. Calcium carbonate particles called otoliths are embedded on the surface of the gel layer.

When the head is in an upright position, the hairs stand up along the capsular plaque. When the head is tilted, the gel material and otolith tilt accordingly, bending some of the hair on the follicle-coat cells. This bending action initiates signal impulses to the central nervous system that travel through the vestibular branch of the vestibulo-cochlear nerve, which in turn relays movement impulses to the appropriate muscles to maintain balance.

The cochlea is the portion of the inner ear that is relevant to hearing. The cochlea is a conical tube-like structure that curls into a snail-like shape. The intracochlear space is divided into three regions, which are further defined by the location of the vestibular and basilar membranes. The superior portion of the vestibular membrane is the scala vestibuli, which extends from the oval window to the apex of the cochlea and contains perilymph fluid, an aqueous liquid with low potassium content and high sodium content. The basement membrane defines the scala tympani region, which extends from the apex of the cochlea to the round window and contains the perilymph. The basement membrane contains thousands of rigid fibers that increase in length from the round window to the apex of the cochlea. The substrate film fibers vibrate when acoustically stimulated. The middle of the scala vestibuli and the scala tympani is the cochlear duct, and the cochlear duct takes the closed sac at the vertex of the cochlear duct as the tail end. Cochlear duct contains endolymph fluid similar to cerebrospinal fluid and high in potassium.

The organ of Corti (Corti) is the sensory organ for hearing, located on the basement membrane and extending up into the cochlear canal. The organ of coca contains hair cells having hair-like projections extending from their free surface and contacting a gelatinous surface called the apical membrane. Although the hair cell has no axons, it is surrounded by sensory nerve fibers that form the cochlear branch of the anterior cochlear nerve (cranial nerve VII).

As discussed, an oval window (also referred to as an elliptical window) communicates with the stapes to relay sound waves vibrating from the tympanic membrane. The vibration transferred to the oval window increases the pressure at which the fluid fills the inside of the cochlea via the perilymph and the scala vestibuli/scala tympani, which in turn causes the round window membrane to expand in response. The coordinated oval window squeezes inward/the round window expands outward allowing fluid movement within the cochlea without changing intracochlear pressure. However, as the vibrations travel through the perilymph in the scala vestibuli, they produce corresponding vibrations in the vestibular membrane. These corresponding vibrations travel through the endolymph of the cochlear canal and are transferred to the basement membrane. When the basement membrane is vibrated or moved up and down, the organ of coca moves along the basement membrane. Hair cell receptors in the organ of corti then move relative to the apical membrane, causing mechanical deformation of the apical membrane. This mechanical deformation induces nerve impulses that travel via the vestibular cochlear nerve to the central nervous system, mechanically propagating the received acoustic waves as signals that are then processed by the central nervous system.

Disease and disorder

Otic disorders, including inner ear, middle ear and outer ear disorders, produce symptoms including (but not limited to) the following: hearing loss, nystagmus, dizziness, tinnitus, inflammation, swelling, infection, and congestion. These disorders can have many etiologies, such as infection, injury, inflammation, tumor, and adverse reactions to drugs or other chemical agents. Several causes of hearing and/or balance impairment or inflammation may be attributed to autoimmune disorders and/or cytokine-mediated inflammatory responses. In one embodiment, the otic disorder is meniere's disease. In one embodiment, the otic disorder is sensorineural hearing loss. In one embodiment, the otic disorder is Autoimmune Inner Ear Disease (AIED). In one embodiment, the otic disorder is meniere's disease. In other embodiments, the otic disorder is Meniere's syndrome, vestibular neuronitis, postural vertigo, lammijhunter syndrome (herpes zoster infection), syphilis infection, drug-induced inner ear injury, acoustic nerve tumor, hearing loss due to excessive noise, presbycusis, otosclerosis, or temporomandibular joint disease.

The diseases presented herein, including the diseases presented below, can be treated using the steroid pharmaceutical compositions described herein.

Meniere's disease

Meniere's disease is an idiopathic condition characterized by sudden onset of vertigo, nausea and vomiting, which can last from 3 to 24 hours and can gradually resolve. The disease is accompanied over time by progressive hearing loss, tinnitus and pressure sensation in the ear. Although the cause of meniere's disease is unknown, it may be associated with an imbalance of stability in the fluid of the inner ear, including increased production or decreased resorption of fluid of the inner ear.

Surgical procedures that have been used to alleviate symptoms include disrupting vestibular and/or cochlear function to alleviate vertigo symptoms. These procedures are aimed at reducing the fluid pressure in the inner ear and/or disrupting the inner ear balance function. Endolymphatic shunt procedures to relieve fluid pressure can be performed in the inner ear to relieve symptoms of vestibular dysfunction. Other treatments include gentamicin (gentamicin) administration, which destroys sensory hair cell function when injected into the tympanic membrane, thereby eradicating inner ear balance function. Vestibular nerve cutting can also be used, which can control vertigo while preserving hearing.

The standard of care for meniere's disease requires individuals to follow a low salt diet. In some cases, the low salt diet is supplemented with antibiotic administration. In some cases, the low salt diet is supplemented with gentamicin administration. In some cases, the low salt diet is supplemented with oral steroid administration. In some cases, the low salt diet is supplemented with oral prednisone (prednisone) administration (25-50mg PO/IM/PR q4-6 h).

In one set of embodiments, patients who are being treated for meniere's disease using the standard of care presented above are instead treated using the otoaccessible controlled release corticosteroid formulations and methods described herein. In another set of embodiments, patients who are being treated for meniere's disease using the standard of care presented above but are refractory to, or unresponsive to, such treatment are treated instead using the otoacceptable controlled release corticosteroid formulations and methods described herein.

In some embodiments, mechanical or imaging devices are used to monitor or examine hearing, balance, or other ear conditions. For example, Magnetic Resonance Imaging (MRI) devices are specifically contemplated within the scope of the embodiments, wherein MRI devices (e.g., 3 tesla MRI devices) are capable of assessing meniere's disease progression and subsequent treatment of the pharmaceutical formulations disclosed herein. Also contemplated is the use of gadolinium-based dyes, iodine-based dyes, barium-based dyes, and the like with any of the otocompatible compositions or devices described herein and/or any of the mechanical or imaging devices described herein. In certain embodiments, gadolinium hydrate is used in combination with MRI and/or any pharmaceutical composition or device described herein to assess disease severity (e.g., scale of membranous labyrinth dropsy), penetration of the formulation into the inner ear, and/or therapeutic efficacy of the pharmaceutical formulation/device in otic diseases described herein (e.g., meniere's disease).

Meniere's syndrome

Meniere's syndrome shows similar symptoms to Meniere's disease, and is classified as a secondary condition to another disease process such as thyroid disease or inflammation of the inner ear due to syphilis infection. Thus, meniere's syndrome is a secondary effect of various processes that interfere with the normal production or resorption of endolymph, including endocrine abnormalities, electrolyte imbalance, autoimmune dysfunction, drug therapy, infection (e.g., parasitic infection), or hyperlipidemia. Treatment of patients suffering from meniere's syndrome is similar to meniere's disease.

Sensorineural hearing loss

Sensorineural hearing loss occurs when the inner ear component or the accompanying nerve component is affected, and may involve nerves (i.e., auditory nerves or auditory nerve pathways in the brain) or sensory components. Sensory hearing loss may be genetic, or it may be caused by acoustic injury (e.g., loud noise), viral infection, drug induction, or meniere's disease. The incidence of neural hearing loss may be caused by brain tumors, infections, or various brain and neurological disorders, such as stroke. Some genetic disorders, such as Refsum's disease (lack of accumulation of branched chain fatty acids), may also cause neurological disorders that affect hearing loss. Auditory nerve pathways may be impaired by demyelinating diseases such as idiopathic inflammatory demyelinating diseases (including multiple sclerosis), transverse myelitis, Devyward's disease, progressive multifocal leukoencephalopathy, Guriman-Bairy syndrome (Guillain-Barre syndrome), chronic inflammatory demyelinating polyneuropathy and anti-MAG peripheral neuropathy.

The incidence of sudden deafness or sensorineural hearing loss is about 1 per 5000 individuals and can be caused by viral or bacterial infections, such as mumps, measles, influenza, chickenpox, cytomegalovirus, syphilis or infectious mononucleosis, or physical damage to the inner ear organs. In some cases, no cause can be identified. Tinnitus and vertigo may be accompanied by sudden deafness, which gradually subsides. Oral corticosteroids may be prescribed to treat sensorineural hearing loss. In some cases, surgical intervention may be necessary.

The formulations and methods described herein include treating sensorineural hearing loss, including treating sudden sensorineural hearing loss, including idiopathic sudden sensorineural hearing loss. For SSHL, current treatment options include 2-week treatment with high doses of oral steroids (4-7 days course +7-10 days tapering off) plus dexamethasone (4-10mg/ml) or methylprednisolone (40-62.5 mg/ml). As illustrated herein, high doses of oral steroids lead to undesirable side effects and adverse events. Thus, the methods and formulations described herein, which are intended for sustained release of a local delivery of steroid into the inner ear, are expected to produce significantly fewer side effects than the use of oral/systemic steroids. In one embodiment, ISSHL is characterized by unilateral sensorineural hearing loss with an attack time of less than 72 hours, where HL is defined as greater than 30dB at least 3 adjacent test frequencies.

The standard of care for idiopathic paroxysmal sensorineural hearing loss (ISSHL) is treatment with high doses of oral steroids. In some cases, the individual is treated with a high dose oral steroid for about two weeks. In some cases, the individual is treated with the high dose oral steroid for about two weeks, followed by a gradual reduction of the oral steroid for about 7 to about 10 days. In some cases, the oral steroid is dexamethasone (4-10 mg/ml). In some cases, the oral steroid is methylprednisolone (40-62.5 mg/ml).

In one set of embodiments, patients who are using the standard of care treatment ISSHL presented above are changed to be treated using the otoaccessible controlled release corticosteroid formulations and methods described herein. In another set of embodiments, patients who are using the standard of care treatment ISSHL presented above but are refractory to, or unresponsive to, such treatment are instead treated using the acceptable controlled release corticosteroid ear formulations and methods described herein.

Hearing loss due to excessive noise

Hearing loss can also occur from prolonged exposure to loud noises, such as loud music, heavy equipment or machinery, airplanes, gunfire, or other human-based noises. Hearing loss occurs as a result of destruction of hair cell receptors in the inner ear. This hearing loss is often accompanied by tinnitus. Often diagnosed as a permanent hearing loss impairment.

Although there is currently no treatment for noise-induced hearing loss, several treatment regimens have been developed experimentally, including treatment with insulin-like growth factor 1 (IGF-1). Plum (Lee) et al, otology and neurootology (otol. neurotol.) (2007) 28: 976-981.

Presbycusis

Presbycusis or age-related hearing loss is a component of natural aging and is a result of degeneration of the sensory cells in the organ of the Cocotinib (Corti) helix in the inner ear. Other causes may also be attributed to a reduction in the number of nerve fibers in the vestibulo-cochlear nerve and a loss of flexibility of the cochlear basilar membrane. There is no known treatment for permanent hearing impairment caused by presbycusis or excessive noise.

Drug induced inner ear injury

Injuries caused by administration of drugs including certain antibiotics, diuretics (e.g., ethacrynic acid and furanilic acid), aspirin (aspirin), aspirin-like substances (e.g., salicylates) and quinine (quinine) include: impairment of kidney function resulting in reduced clearance of the affecting drug and its metabolites may accelerate the deterioration of inner ear organs. While drugs may affect hearing and balance, it is likely to affect hearing to a greater extent.

For example, neomycin (neomycin), kanamycin (kanamycin), and amikacin (amikacin) have a greater effect on hearing than on balance. The antibiotics erythromycin (viomycin), gentamicin and tobramycin (tobramycin) affect hearing and balance. Another commonly administered antibiotic, Streptomycin, induces vertigo more than a decrease in hearing and may lead to Dandy's syndrome in which walking in the dark becomes difficult and a sensation is induced in which each step is accompanied by environmental movement. Aspirin, when taken in extremely high doses, can also cause temporary hearing loss and tinnitus, a condition in which sound is perceived in the absence of external sounds. Similarly, quinine, ethacrynic acid and furoxanilide can cause temporary or permanent hearing loss.

Autoimmune inner ear disease

Autoimmune Inner Ear Disease (AIED) is one of the few reversible causes of sensorineural hearing loss. It is a rare condition that occurs in adults and children, often involving bilateral disorders of auditory and vestibular function of the inner ear. Although in many cases AIED occurs without systemic autoimmune symptoms, up to one third of patients also suffer from systemic autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis (muldin, L.) (2007), Hearing difficulties common in patients with rheumatoid arthritis (Hearing disorders with Hearing impairment arthritis), clinical rheumatology (Clin rhemato), 27 (5): 637-. Behcet's disease is a multisystemic disorder that also commonly has auditory vestibular problems. Although there is some evidence that food-related allergies are the cause of cochlear and vestibular autoimmunity, there is currently no agreement as to their importance in the etiology of the disease. A classification scheme for AIED has been developed (Harris and Keithley), (2002) Autoimmune inner ear disease (auto inner ear disease), otorhinolaryngological Head and neck surgery (Otorhinolaryngology Head and Necksurgery. 91, 18-32).

Treatment with corticosteroids reduces AIED symptoms. Oral administration of the corticosteroid prednisone (60 mg per day for four (4) weeks) showed significant improvement in pure tone and speech audiometry results. Modulation of the corticosteroid effect can be through the corticosteroid receptor or the mineralocorticoid receptor.

Inflammatory disorders

Inflammatory conditions of the ear include, but are not limited to, otitis media, otitis externa, mastoiditis, bullous myringitis, eustachian tube mucositis or eustachian tube inflammation, labyrintitis, and the like. Otitis Media (OM) includes, for example, Acute Otitis Media (AOM), otitis media with effusion (OME) and chronic otitis media, which are conditions affecting adults and children. OM susceptibility is multifactorial and complex, including environmental, microbial, and host factors. In some cases, an increase in cytokine production, including inflammatory cytokines (e.g., interleukins and TNF) has been observed in the effusion media of individuals suffering from OM. Treatment with anti-inflammatory steroids alleviates symptoms of ear inflammatory disorders (e.g., otitis media, eustachian tube mucositis, etc.). In some cases, bacterial infection is the cause of an inflammatory disorder (e.g., OM). In some cases, administration of antibiotics in combination with anti-inflammatory corticosteroids reduces the symptoms of OM.

Pharmaceutical agent

Provided herein are pharmaceutical compositions or formulations or devices comprising steroids that ameliorate or reduce otic disorders including meniere's disease, sensorineural hearing loss, and/or inflammatory disorders and their attendant symptoms including, but not limited to, hearing loss, nystagmus, dizziness, tinnitus, inflammation, swelling, infection, and congestion. Otic disorders, including AIED or Meniere's disease and/or inflammatory disorders, have etiologies and symptoms responsive to the pharmaceutical agents disclosed herein or other pharmaceutical agents. In particular embodiments, the steroid is a corticosteroid, including glucocorticosteroids and mineral corticosteroids. Any corticosteroid described herein (including free acids, free bases, free alcohols, salts, prodrugs, or any combination thereof) is compatible with the pharmaceutical compositions or devices described herein. Corticosteroids not specifically disclosed herein but suitable for ameliorating or eradicating otic disorders are expressly included within the scope of the presented embodiments and are intended to fall within the scope.

Furthermore, pharmaceutical agents that have previously been shown to be toxic, harmful, or ineffective during systemic or local administration to other organ systems, e.g., due to toxic metabolites formed after liver processing, toxicity of the drug in a particular organ, tissue, or system, high levels needed to achieve efficacy, inability to be released via systemic routes, or poor pK characteristics, are suitable for use in some embodiments herein. For example, side effects of dexamethasone include: sodium retention, excessive water retention, congestive heart failure in susceptible patients, hypertension, muscle weakness, muscle atrophy, osteoporosis, tendon rupture, peptic ulcers, ulcerative esophagitis, thinning of skin, skin reactions, disorders of wound healing, tics, dizziness, headache, psychological disorders, Cushing's syndrome, growth retardation in children, diabetes, hirsutism, cataracts, glaucoma, weight gain, increased appetite and nausea. Pharmaceutical agents (e.g., corticosteroids) with limited or no systemic release, systemic toxicity, poor pK profiles, or combinations thereof are expressly contemplated within the scope of the embodiments disclosed herein.

The corticosteroid formulations disclosed herein optionally target directly to an ear structure in need of treatment; for example, one contemplated embodiment is to apply the corticosteroid formulation disclosed herein directly onto the round window membrane or the cochlear crest (cristatenes cochlea) of the inner ear, thereby directly reaching and treating the inner ear or inner ear component. In other embodiments, the corticosteroid formulation disclosed herein is administered directly to the oval window. In yet other embodiments, direct access is achieved by direct microinjection into the inner ear, for example, using cochlear microinfusion. These embodiments also optionally include a drug delivery device, wherein the drug delivery device delivers the corticosteroid formulation by using a needle and syringe, a pump, a microinjection device, a sponge-like material formed in situ, or any combination thereof. In yet other embodiments, the administration of the corticosteroid formulation targets the middle ear by piercing the inner tympanic membrane and applying the corticosteroid formulation directly to the affected middle ear structures including the tympanic cavity wall or the ossicles. By doing so, the corticosteroid formulations disclosed herein will be localized to the targeted middle ear structure without loss, for example, by diffusion or leakage through the eustachian tube or the pierced tympanic membrane.

Corticosteroid/anti-inflammatory steroid

Corticosteroids are characterized by mineralocorticoid and glucocorticoid actions, depending on the pharmacology of the agent. Mineralocorticoids are characterized by their similarity to aldosterone and their effect on electrolyte content and water balance. Glucocorticoids such as the endogenous glucocorticoid cortisol control metabolism and diminish inflammation by preventing cytokine release. Many agents have some degree of mineralocorticoid and glucocorticoid activity. The following table shows the relative potency and activity of several synthetic glucocorticoids.

Steroids	Glucocorticoid potency	Mineralocorticoid potency
			Cortisol	1	0.054
Prednisone	4	0.002
			Prednisolone	1.7	0.013
Dexamethasone	21	0.0094
			Betamethasone	45	0.0038
Triamcinolone acetonide	0.35	0.0002
			Prednisolone	182	0.0011
Aldosterone	0.07	1.0

Systemic glucocorticoid therapy is a therapy currently used for autoimmune hearing loss. Typical treatment durations last for months, and side effects of systemic therapy may be substantial. For dexamethasone, side effects include: sodium retention, excessive water retention, congestive heart failure in susceptible patients, hypertension, muscle weakness, muscle atrophy, osteoporosis, tendon rupture, peptic ulcer, ulcerative esophagitis, thinning skin, skin reactions, disorders of wound healing, convulsions, dizziness, headache, psychological disorders, cushing's syndrome, growth retardation in children, diabetes, hirsutism, cataracts, glaucoma, weight gain, increased appetite, and nausea. One advantage of using the formulations described herein is a substantial reduction in systemic exposure to anti-inflammatory glucocorticoids.

Prednisolone is a corticosteroid drug that is dominated by glucocorticoids and has low mineralocorticoid activity. It is about 4-5 times more potent than endogenous cortisol. Which is an active metabolite of prednisone administered orally. Dexamethasone is a corticosteroid drug with glucocorticoid activity. It is about 25-30 times more potent than endogenous cortisol. Dexamethasone sodium phosphate is a water-soluble phosphate prodrug of dexamethasone. Methods for assaying dexamethasone phosphate in pericochlear lymph fluid have been disclosed (Liu) et al, J.of Chromatography B (2004), 805 (2): 255-60). Triamcinolone is a synthetic glucocorticoid drug that has been administered orally, by injection, inhalation, or in the form of a topical cream or ointment. Triamcinolone acetonide (Triamcinolone acetonide) is a more potent analog. Triamcinolone acetonide (triamcinolone hexacetonide) is the pivaloyl ester of triamcinolone acetonide. Beclomethasone dipropionate, also known as beclomethasone, is a very potent glucocorticoid drug. Clobetasol (Clobetasol) is a very potent corticosteroid used in topical formulations. It has anti-inflammatory, antipruritic, vasoconstrictive and immunomodulatory properties.

In one embodiment, the active pharmaceutical ingredient of the formulations described herein is prednisolone. In another embodiment, the active pharmaceutical ingredient of the formulations described herein is dexamethasone. In another embodiment, the active pharmaceutical ingredient of the formulations described herein is dexamethasone phosphate. In another embodiment, the active pharmaceutical ingredient of the formulations described herein is beclomethasone. In another embodiment, the active pharmaceutical ingredient of the formulations described herein is betamethasone. In another embodiment, the active pharmaceutical ingredient of the formulations described herein is triamcinolone. In another embodiment, the active pharmaceutical ingredient of the formulations described herein is triamcinolone acetonide. In another embodiment, the active pharmaceutical ingredient of the formulations described herein is clobetasol.

In another embodiment, the active pharmaceutical ingredient of the formulations described herein is a phosphate prodrug of a glucocorticoid. In another embodiment, the active pharmaceutical ingredient of the formulations described herein is an ester prodrug of a glucocorticoid. In some embodiments, the active pharmaceutical ingredient of the formulations described herein is selected from the group consisting of 21-acetoxypregnenolone (21-acetoxypregnenolone), alclometasone (alclometasone), algestone (algestone), amcinonide (amcinonide), beclomethasone, betamethasone, budesonide (budesonide), prednisolone (chloroprednisone), clobetasol, clobetasone (clobetasone), clocortolone (clocotolone), prednisolone (cloprednol), corticosterone (corticosterone), cortisone (cortiisone), fluxole (cortivazol), deflazacort (deflazacort), desonide (desonide), desoximone (desoximetone), dexamethasone, diflunisone (diflucortolone), diflucortolone (diflunisone), diflunisone (diflunisal), flunisolone (diflunisone), flunisole (diflunisone), fluocinonide (diflunisone), fluocinolone diflunisone (fluocinonide), fluocinolone acetonide (fluocinonide), fluocinonide (fluocinonide), fluocinolone acetonide (fluocinonide), fluocinonide (fluocinolone acetonide (fluocinonide), fluocinonide (fluocinolone acetonide (fluocinonide), fluocinonide (fluocinolone (fluocinonide), fluocortolone (fluocortolone), fluorometholone (fluometolone), fluperlone acetate (fluperolone acetate), fluprednidene acetate (fluprednidene acetate), fluprednidene (formocortal), halcinonide (halcinonide), clobetasol propionate (halobetasol propionate), halomethasone (halometasone), haloprednisolone acetate (halopredone acetate), hydrocortisone ester (hydrocortisone), hydrocortisone (hydrocortisone), loteprinosone (lotsone), loteprinonate (lotepredone), methylprednisolone (methylprednisolone), fluorometholone (triamcinolone acetonide), triamcinolone acetonide (triamcinolone acetonide), triamcinolone acetonide (triam, Prednisolone valerate (prednival), prednisone (prednylidene), rimexolone (rimexolone), tixocortol (tixocortol), triamcinolone acetonide or triamcinolone acetonide, or a phosphate prodrug or ester prodrug thereof.

In some embodiments, the concentration of the active pharmaceutical ingredient of the formulations described herein is between about 0.01% to about 20%, between about 0.01% to about 10%, between about 0.01% to about 8%, between about 0.05% to 6%, between about 0.1% to 5%, between about 0.2% to about 3%, or between about 0.1% to about 2% of the active ingredient, or a pharmaceutically acceptable prodrug or salt thereof, by weight of the formulation. In some embodiments, the concentration of the active pharmaceutical ingredient of the formulations described herein is between about 0.1mg/mL to about 70mg/mL, about 0.5mg/mL to about 50mg/mL, about 0.5mg/mL to about 20mg/mL, about 1mg/mL to about 70mg/mL, about 1mg/mL to about 50mg/mL, about 1mg/mL to about 20mg/mL, about 1mg/mL to about 10mg/mL, or about 1mg/mL to about 5mg/mL of the active agent or pharmaceutically acceptable prodrug or salt thereof, by volume of the formulation.

In some embodiments, the formulations described herein additionally comprise an antibiotic and are useful for treating an otic disease or condition described herein. Antibiotics include, but are not limited to amikacin, gentamicin, kanamycin, neomycin, netilmicin (netilmicin), streptomycin, tobramycin, paromomycin (paromomycin), geldanamycin (geldanmycin), herbimycin (herbimycin), chlorocephem (loracarbef), ertapenem (ertapenem), doripenem (doripenem), imipenem (imipenem), cilastatin (cilastatin), meropenem (meropenm), cefhydroxylamine (cefixime), cefazolin (cefazolin), cephalothin (cefalotin), cefotaxin (cefepime), cefotaxime (cefepime), cefaclor (cefixime), cefixime (cefepime), cefixime (cefixime), cefepime (cefepime), cefixime (cefepime), cefepime (cefepime), cefepime (cefepime), cefepime, Ceftizoxime (ceftizoxime), ceftriaxone (ceftriaxone), cefepime (cefepime), cephapirin (ceftobiprole), teicoplanin (teicoplanin), vancomycin (vancomycin), azithromycin (azithromycin), clarithromycin (clarithromycin), dirithromycin (dirithromycin), erythromycin (erythromycin), roxithromycin (roxithromycin), oleandomycin (troleucin), telithromycin (telithromycin), spectinomycin (spectinomycin), aztreonam (aztreonam), amoxicillin (amoxicilin), ampicillin (ampicilin), azlocillin (azlocillin), carbacillin (carbenicillin), cloxacillin (cloxacillin), methicillin (loxacillin), penicillin (loxacillin (mexilin), doxillin (loxacillin (mexilin), penicillin (loxacillin (mexillin), doxillin (mexilin (mexillin), mexillin (doxillin), mexillin (mexillin), mexillin (mexillin), mexillin (me, Ciprofloxacin (ciprofloxacin), enoxacin (enoxacin), gatifloxacin (gatifloxacin), levofloxacin (levofloxacin), lomefloxacin (lomefloxacin), moxifloxacin (moxifloxacin), norfloxacin (norfloxacin), ofloxacin (ofloxacin), trovafloxacin (trovafloxacin), mafenide (mafenide), azosulfilide (prothionamide), sulfacetamide (sulfacetamide), sulfamethizole (sulfamethidazole), sulfanilamide (sulfaninimimide), sulfasalazine (sulfazazine), sulfisoxazole (sulfadiminazole), trimethoprim (trimethoprim), demeclocycline (doxycycline), minocycline (minocycline), tetracycline (tetracycline), tetracycline (sulfadiazine), tetracycline (sulfadimicin), streptomycin (sulfadimicin), thiamethoxazole (sulfaclindamine), doxycycline (doxycycline), minocycline (doxycycline), tetracycline (sulfaclin (doxycycline), tetracycline (sulfadimicin), tetracycline (sulfadimicin (thiamine), thiamine (thiamethoxazole), streptomycin (thiamethoxine (thiamine), streptomycin (thiamethoxazole), streptomycin (thiamine), streptomycin (thiamine), thiamine (thiamine), thiamine (thiamine, Mupirocin (mupirocin), nitrofurantoin (nitrofuratoin), platenomycin (platensicin), pyrazinamide (pyrazinamide), quinupristin (quinupristin)/dalfopristin (dalfopristin), rifampin (rifampin), tinidazole (tinidazole), AL-15469A (Alconk Research), AL-38905 (Alconk Research), and the like, and combinations thereof.

General methods of Sterilization

Provided herein are otic compositions that ameliorate or reduce otic disorders described herein. Further provided herein are methods comprising administering the otic compositions. In some embodiments, the composition or device is sterilized. Embodiments disclosed herein include methods and processes for sterilizing a pharmaceutical composition or device disclosed herein for use in a human. The aim is to provide safe pharmaceutical products that are relatively free of infection-causing microorganisms. The united states food and drug administration (u.s.food and drug administration) in the publication "guide to industry: regulatory guidelines are provided in Sterile pharmaceutical Products (guidelines for Industry: Sterildrug Products by Aseptic Processing), available from http:// www.fda.gov/cd/guidelines/5882 fl. htm, which is incorporated herein by reference in its entirety.

As used herein, sterilization means a process for destroying or removing microorganisms present in a product or packaging. Any suitable method that can be used for sterilization of objects and compositions can be used. Methods that can be used to inactivate microorganisms include, but are not limited to, the application of extreme heat, lethal chemicals or gamma radiation. In some embodiments, is a process for preparing an otic treatment formulation comprising subjecting the formulation to a sterilization method selected from the group consisting of heat sterilization, chemical sterilization, radiation sterilization, or filter sterilization. The method used depends essentially on the nature of the device or composition to be sterilized. Detailed descriptions of many sterilization methods are provided in the Remington published by Riping Kort (Lippincott), Williams (Williams) and Wilkins (Wilkins): pharmaceutical Science and Practice (Remington: The Science and Practice of Pharmacy) chapter 40, and The subject matter is incorporated herein by reference.

Heat sterilization

Many methods can be used for sterilization by applying extreme heat. One method is by using a saturated steam autoclave. In this method, saturated steam having a temperature of at least 121 ℃ is brought into contact with the object to be sterilized. In the case of objects to be sterilized, heat is transferred directly to the microorganisms, or indirectly to the microorganisms in their entirety by heating the aqueous solution to be sterilized. This method is widely practiced because of its flexibility, safety and economy in the sterilization process.

Dry heat sterilization is a method for killing microorganisms and for depyrogenation at high temperatures. This process is carried out in an apparatus adapted to heat HEPA filtered microorganism-free air to a temperature of at least 130 ℃ - > 180 ℃ for the sterilization process and to a temperature of at least 230 ℃ - > 250 ℃ for the depyrogenation process. The water to reconstitute the concentrate or powder formulation is also sterilized with an autoclave. In some embodiments, the formulations described herein comprise a micron-sized pharmaceutical agent (e.g., a corticosteroid (e.g., dexamethasone)) sterilized by dry heating (e.g., heating at an internal powder temperature of 130 ℃. about.7-11 hours, or at an internal temperature of 150 ℃. about.180 ℃ for 1-2 hours).

Chemical sterilization

Chemical sterilization is an alternative to products that cannot withstand extreme heat sterilization. In this method, various gases and vapors with bactericidal properties (such as ethylene oxide, chlorine dioxide, formaldehyde or ozone) are used as anti-apoptotic agents. The bactericidal activity of ethylene oxide is due to, for example, its ability to act as a reactive alkylating agent. Thus, the sterilization process requires direct contact of the ethylene oxide vapor with the product to be sterilized.

Radiation sterilization

One advantage of radiation sterilization is the ability to sterilize many types of products without thermal degradation or other damage. The radiation usually employed being beta radiation or radiation from⁶⁰Gamma irradiation from a Co source. The permeability of gamma radiation allows it to be used for sterilization of many product types, including solutions, compositions, and heterogeneous mixtures. The germicidal action of irradiation results from the interaction of gamma radiation with biological macromolecules. This interaction generates charged species and free radicals. Subsequent chemical reactions such as rearrangement and cross-linking processes result in the loss of normal function of these biological macromolecules. The formulations described herein are also optionally sterilized using beta irradiation.

Filtration

Filter sterilization is a method for removing, but not destroying, microorganisms from a solution. Membrane filters are used to filter solutions that are sensitive to heat. The filter is a thin, strong, uniform polymer of Mixed Cellulose Ester (MCE), polyvinylidene fluoride (PVF; also known as PVDF), or Polytetrafluoroethylene (PTFE), and has a pore size in the range of 0.1 to 0.22 microns. Solutions with various characteristics are optionally filtered using different filtration membranes. For example, PVF and PTFE membranes are well suited for filtering organic solvents, while aqueous solutions are filtered through PVF or MCE membranes. The filter device can be used on many scales, from single-point use disposable filters attached to syringes to commercial scale filters for manufacturing plants. The membrane filter is sterilized using an autoclave or chemical sterilization. Validation of the Membrane filtration System was performed according to a standardized protocol (Microbiological Evaluation of Filters for Sterilizing Liquids), volume 4, phase 3, Washington D.C. (D.D.: Health industry manufacturers Association, 1981) and involves the use of known quantities (about 10) ⁷Per cm²) Such as Brevundimonas diminuta (ATCC 19146), a membrane filter.

The pharmaceutical composition is optionally sterilized by passage through a membrane filter. Formulations containing nanoparticles (U.S. Pat. No. 6,139,870) or multi-layered liposomes (Richard et al, International Journal of pharmacy (2006), 312 (1-2): 144-50) can be sterilized by filtration through a 0.22 micron filter without destroying their tissue structure.

In some embodiments, the methods disclosed herein comprise sterilizing the formulation (or components thereof) by means of filter sterilization. In another embodiment, an otoacceptable otic therapeutic formulation comprises particles, wherein the particle formulation is suitable for filter sterilization. In another embodiment, the particle formulation comprises particles less than 300nm in size, less than 200nm in size, and less than 100nm in size. In another embodiment, an otically acceptable formulation comprises a particle formulation, wherein sterility of the particles can be ensured by sterile filtration of the precursor component solution. In another embodiment, the otoacceptable formulation comprises a particle formulation, wherein sterility of the particle formulation is ensured by cryogenic sterile filtration. In another embodiment, the low temperature sterile filtration is performed at a temperature between 0 ℃ and 30 ℃, between 0 ℃ and 20 ℃, between 0 ℃ and 10 ℃, between 10 ℃ and 20 ℃, or between 20 ℃ and 30 ℃.

In another embodiment, a process for preparing an auris-acceptable particle formulation comprises: filtering an aqueous solution containing the particle formulation through a sterilizing filter at a low temperature; lyophilizing the sterile solution; and reconstituting the particle formulation with sterile water prior to administration. In some embodiments, the formulations described herein are manufactured as single vial formulations containing a micron-sized active pharmaceutical ingredient in suspension. Single vial formulations are prepared by aseptically mixing a sterile poloxamer solution with a sterile micron-sized active ingredient (e.g., dexamethasone) and transferring the formulation into a sterile pharmaceutical container. In some embodiments, prior to dispensing and/or administration, a single vial containing a formulation described herein in suspension is resuspended.

In particular embodiments, the filtration and/or filling procedure is performed at about 5 ℃ below the gelation temperature (tgel) of the formulations described herein and at a viscosity below the theoretical value of 100cP to allow filtration using a peristaltic pump within a reasonable time.

In another embodiment, an otically acceptable otic therapeutic formulation comprises a nanoparticle formulation, wherein the nanoparticle formulation is suitable for filter sterilization. In another embodiment, the nanoparticle formulation comprises nanoparticles less than 300nm in size, less than 200nm in size, or less than 100nm in size. In another embodiment, the otoacceptable formulation comprises a microsphere formulation, wherein sterility of the microspheres is ensured by sterile filtration of the precursor organic solution and the aqueous solution. In another embodiment, the otoacceptable formulation comprises a thermoreversible gel formulation, wherein sterility of the gel formulation is ensured by cryogenic sterile filtration. In another embodiment, the low temperature sterile filtration is performed at a temperature between 0 ℃ and 30 ℃, or between 0 ℃ and 20 ℃, or between 0 ℃ and 10 ℃, or between 10 ℃ and 20 ℃, or between 20 ℃ and 30 ℃. In another embodiment, a process for preparing an otoacceptable thermoreversible gel formulation comprises: filtering the aqueous solution containing the thermoreversible gel component through a sterile filter at low temperature; lyophilizing the sterile solution; and reconstituting the thermoreversible gel formulation with sterile water prior to administration.

In certain embodiments, the active ingredient is dissolved in a suitable vehicle (e.g., buffer) and separately sterilized (e.g., by heat treatment, filtration, gamma irradiation). In some cases, the active ingredients are sterilized separately in the dry state. In some cases, the active ingredient is sterilized in the form of a suspension or a colloidal suspension. In a further step the remaining excipients (e.g. the fluid gel component present in the otic formulation) are sterilized by a suitable method (e.g. filtration and/or irradiation of the cooled excipient mixture); the two solutions, which are separately sterilized, are then aseptically mixed to provide the final otic formulation. In some cases, the final sterile mixing is performed immediately prior to administration of the formulations described herein.

In some cases, commonly used sterilization methods (e.g., heat treatment (e.g., in an autoclave), gamma irradiation, filtration) result in irreversible degradation of the polymer component (e.g., thermoset, gelled, or mucoadhesive polymer component) and/or the active agent in the formulation. In some cases, it may not be possible to sterilize an otic formulation by membrane filtration (e.g., 0.2 micron membrane) if the formulation includes a thixotropic polymer that gels during filtration.

Accordingly, provided herein are methods of sterilizing otic formulations that prevent degradation of the polymeric component (e.g., thermoset and/or gelling and/or mucoadhesive polymeric component) and/or the active agent during sterilization. In some embodiments, degradation of an active agent (e.g., any of the otic therapeutic agents described herein) is reduced or eliminated by using a specific pH range of the buffer component and a specific ratio of gelling agent in the formulation. In some embodiments, selection of an appropriate gelling agent and/or thermosetting polymer allows for sterilization of the formulations described herein by filtration. In some embodiments, the use of a suitable thermosetting polymer and a suitable copolymer (e.g., gelling agent) in combination with a particular pH range of the formulation allows for the autoclaving of the formulation without substantial degradation of the therapeutic agent or polymeric excipient. An advantage of the sterilization process provided herein is that, in certain instances, the formulation is terminally sterilized via an autoclaving process without any loss of active agent and/or excipient and/or polymer components during the sterilization step, and the formulation becomes substantially free of microorganisms and/or pyrogens.

Microorganisms

Provided herein are otoacceptable compositions or devices that ameliorate or reduce an otic disorder described herein. Further provided herein are methods comprising administering the otic compositions. In some embodiments, the composition or device is substantially free of microorganisms. Acceptable sterility is based on applicable criteria defining a therapeutically acceptable otic composition, including, but not limited to, the United States Pharmacopeia Chapter <1111> and subsequent contents. For example, an acceptable level of sterility includes about 10 colony forming units (cfu) per gram of formulation, about 50cfu per gram of formulation, about 100cfu per gram of formulation, about 500cfu per gram of formulation, or about 1000cfu per gram of formulation. In some embodiments, an acceptable level of sterility for the formulation includes less than 10cfu/mL, less than 50cfu/mL, less than 500cfu/mL, or less than 1000cfu/mL of the microbial agent. In addition, acceptable levels of sterility include exclusion of designated harmful microbial agents. For example, specified harmful microbial agents include, but are not limited to, Escherichia coli (Escherichia coli/e.coli), Salmonella sp, Pseudomonas aeruginosa (Pseudomonas aeruginosa/p.aeruginosa), and/or other specific microbial agents.

The sterility of an otoacceptable otic therapeutic agent formulation is confirmed by sterility assurance procedures according to united states pharmacopeia chapters <61>, <62>, and <71 >. Sterility assurance the key component of the quality control, quality assurance and verification process is the method of sterility testing. By way of example only, sterility testing was performed using two methods. The first is direct inoculation, in which a sample of the composition to be tested is added to the growth medium and incubated for a period of up to 21 days. The turbidity of the growth medium indicates contamination. Disadvantages of this approach include the small sampling scale of the bulk material, which reduces sensitivity, and the detection of microbial growth based on visual inspection. An alternative method is membrane filtration sterility testing. In this method, a volume of product is passed through a small membrane filter paper. Then, filter paper was placed in the medium to promote microbial growth. This method has the advantage of higher sensitivity because the entire product is sampled. The assay is optionally performed by a membrane filtration sterility test using the commercially available Millipore (Millipore) Steritest sterility test system. For the filtration test of creams or ointments, the TLHVSL number 210 Steritest filtration system was used. For filtration testing of emulsions or viscous products, a TLAREM210 or TDAREM210 Steritest filtration system was used. For the filtration test of the pre-filled syringe, a TTHASY No. 210 Steritest filtration system was used. For filtration testing of materials dispensed as aerosols or foams, a TTHVA210 Steritest filtration system was used. For filtration testing of soluble powders in ampoules or vials, TTHADA210 or TTHADV210 number stertest filtration systems were used.

The tests for E.coli and Salmonella involve the use of lactose broth incubated at 30-35 ℃ for 24-72 hours, in MacConkey and/or EMB agar for 18-24 hours, and/or Lapaporter (Rappaport) medium. Tests for detecting pseudomonas aeruginosa include the use of NAC agar. Chapter <62> of the united states pharmacopeia additionally lists test procedures for the designation of harmful microorganisms.

In certain embodiments, any of the controlled release formulations described herein have less than about 60 Colony Forming Units (CFU), less than about 50 Colony Forming Units (CFU), less than about 40 Colony Forming Units (CFU), or less than about 30 CFU per gram of formulation. In certain embodiments, the otic formulations described herein are formulated to be isotonic with the endolymph and/or the perilymph.

Endotoxin

Provided herein are otic compositions that ameliorate or reduce otic disorders described herein. Further provided herein are methods comprising administering the otic compositions. In some embodiments, the composition or device is substantially free of endotoxin. Another aspect of the sterilization process is the killing of microorganisms (hereinafter referred to as "Product(s)") by-products are removed. The depyrogenation process removes pyrogens from the sample. Pyrogens are endotoxins or exotoxins that induce an immune response. An example of an endotoxin is the Lipopolysaccharide (LPS) molecule found in the cell wall of gram-negative bacteria. When bacteria are killed by a sterilization procedure such as autoclaving or treatment with ethylene oxide, the LPS residue elicits an inflammatory immune response, such as septic shock. Since the molecular size of endotoxin can vary widely, the presence of endotoxin is expressed in "endotoxin units" (EU). 1EU corresponds to 100 picograms of Escherichia coli LPS. Humans can respond to as little as 5EU per kilogram of body weight. Sterility is expressed in any unit recognized in the art. In certain embodiments, the otic compositions described herein have a lower endotoxin content (e.g., < 4EU per kilogram of individual body weight) as compared to a generally acceptable endotoxin content (e.g., 5EU per kilogram of individual body weight). In some embodiments, an otically acceptable otic therapeutic formulation has less than about 5EU per kilogram of the body weight of the individual. In other embodiments, an otically acceptable otic therapeutic formulation has less than about 4EU per kilogram of individual body weight. In other embodiments, an otically acceptable otic therapeutic formulation has less than about 3EU per kilogram of individual body weight. In other embodiments, an otically acceptable otic therapeutic formulation has less than about 2EU per kilogram of individual body weight.

In some embodiments, an otically acceptable otic therapeutic formulation or device has less than about 5EU per kilogram of formulation. In other embodiments, an otically acceptable otic therapeutic formulation has less than about 4EU per kilogram of the formulation. In other embodiments, an otically acceptable otic therapeutic formulation has less than about 3EU per kilogram of the formulation. In some embodiments, an otically acceptable otic therapeutic formulation has less than about 5EU per kilogram of product. In other embodiments, an otically acceptable otic therapeutic formulation has less than about 1EU per kilogram of product. In other embodiments, the otoacceptable otic therapeutic formulation has less than about 0.2EU per kilogram of product. In some embodiments, an otically acceptable otic therapeutic formulation has less than about 5EU per gram unit or product. In other embodiments, an otically acceptable otic therapeutic formulation has less than about 4EU per gram unit or product. In other embodiments, an otically acceptable otic therapeutic formulation has less than about 3EU per gram unit or product. In some embodiments, an otically acceptable otic therapeutic formulation has less than about 5EU per milligram unit or product. In other embodiments, an otically acceptable otic therapeutic formulation has less than about 4EU per milligram unit or product. In other embodiments, the otoacceptable otic therapeutic formulation has less than about 3EU per milligram unit or product. In certain embodiments, the otic compositions described herein contain from about 1 to about 5EU per ml of formulation. In certain embodiments, the otic compositions described herein contain from about 2 to about 5EU per ml of formulation, from about 3 to about 5EU per ml of formulation, or from about 4 to about 5EU per ml of formulation.

In certain embodiments, the otic compositions or devices described herein contain a lower endotoxin content (e.g., < 0.5EU per ml of formulation) as compared to a generally acceptable endotoxin content (e.g., 0.5EU per ml of formulation). In some embodiments, an otically acceptable otic therapeutic formulation or device has less than about 0.5EU per milliliter of formulation. In other embodiments, the otoacceptable otic therapeutic formulation has less than about 0.4EU per milliliter of formulation. In other embodiments, the otoacceptable otic therapeutic formulation has less than about 0.2EU per milliliter of formulation.

By way of example only, pyrogen detection is performed using several methods. Suitable Sterility Tests include those described in the United States Pharmacopoeia (USP) <71> Sterility test (steriliteity Tests) (23 rd edition, 1995). The rabbit pyrogen test and The Limulus amebocyte lysate test (Limulus amebocyte lysate test) are specified in detail in The United States pharmacopoeia chapters <85> and <151> (USP23/NF 18, Biological Tests (Biological Tests), The United States Pharmacopeial Convention), Rockwell, Md., and 1995). Alternative pyrogen assays have been developed based on monocyte activation-cytokine assays. Homogeneous cell lines suitable for quality control applications have been developed and have been shown to be able to detect pyrogenicity in samples that have passed the rabbit pyrogen test and the limulus amebocyte lysate test (Taktak et al, J.Pharm. Pharmacol.) (1990), 43: 578-82). In another embodiment, the otoacceptable otic therapeutic formulation is subjected to a depyrogenation procedure. In another embodiment, a process for manufacturing an otoacceptable otic therapeutic formulation comprises testing the formulation for pyrogenicity. In certain embodiments, the formulations described herein are substantially pyrogen free.

pH and practical osmolality

As used herein, "practical osmolality" means the osmolality of the formulation as measured by the inclusion of the active agent and all excipients except the gelling agent and/or thickening agent (e.g., polyoxyethylene-polyoxypropylene copolymer, carboxymethylcellulose, etc.). The practical osmolality of the formulations described herein is measured by any suitable method, such as the freezing point depression method described by Viga et al, J.Pharm, 1998, 160, 157-162. In some cases, the practical osmolality of a composition described herein is measured by vapor pressure osmometry (e.g., vapor pressure let-down) which allows for determination of the osmolality of the composition at higher temperatures. In some cases, the vapor pressure depression method allows for the determination of the osmolality of a formulation comprising a gelling agent (e.g., a thermoreversible polymer) at higher temperatures where the gelling agent is in the form of a gel. The otic formulation described herein has a practical osmolality of from about 100 to about 1000mOsm/kg, from about 200 to about 800mOsm/kg, from about 250 to about 500mOsm/kg, or from about 250 to about 320mOsm/kg, or from about 250 to about 350mOsm/kg, or from about 280 to about 320 mOsm/kg. In some embodiments, the formulations described herein have a practical osmolality of about 100 to about 1000mOsm/L, about 200 to about 800mOsm/L, about 250 to about 500mOsm/L, about 250 to about 350mOsm/L, about 250 to about 320mOsm/L, or about 280 to about 320 mOsm/L.

In some embodiments, the osmolality at the target site of action (e.g., perilymph) is about the same as the delivered osmolality (i.e., the osmolality of a substance that passes through or permeates the round window membrane) of any of the formulations described herein. In some embodiments, the formulations described herein have a deliverable capacity osmolality of about 150 to about 500, about 250 to about 350, about 280 to about 370, or about 250 to about 320 mOsm/L.

The main cation present in the Neilinba is potassium. In addition, endolymph has a high concentration of positively charged amino acids. The main cation present in perilymph is sodium. In some cases, the ionic composition of the endolymph and perilymph regulates the electrochemical pulsing of hair cells. In some cases, any change in the ionic balance of the endolymph or perilymph results in hearing loss due to changes in the conduction of electrochemical pulses along the ear hair cells. In some embodiments, the compositions disclosed herein do not disrupt the ionic balance of the perilymph. In some embodiments, the compositions disclosed herein have the same or substantially the same ionic balance as perilymph. In some embodiments, the compositions disclosed herein do not disrupt the ionic balance of the endolymph. In some embodiments, the compositions disclosed herein have the same or substantially the same ionic balance as the endolymph. In some embodiments, the otic formulations described herein are formulated to provide an ionic balance that is compatible with inner ear fluids (e.g., endolymph and/or perilymph).

The pH of the endolymph and perilymph is close to the physiological pH of blood. The pH of the endolymph ranges from about 7.2 to 7.9; the pH of perilymph ranges from about 7.2 to 7.4. The in situ pH of the proximal endolymph was about 7.4, while the pH of the distal endolymph was about 7.9.

In some embodiments, the pH of the compositions described herein is adjusted (e.g., by using a buffer) to a lynprophilic pH range of about 5.5 to 9.0. In particular embodiments, the pH of the compositions described herein is adjusted to a pH range suitable for perilymph of about 5.5 to about 9.0. In some embodiments, the pH of the compositions described herein is adjusted to a suitable range of perilymph of about 5.5 to about 8.0, about 6 to about 8.0, or about 6.6 to about 8.0. In some embodiments, the pH of the compositions described herein is adjusted to a pH range suitable for perilymph of about 7.0-7.6.

In some embodiments, suitable formulations also include one or more pH adjusting agents or buffers. Suitable pH adjusting agents or buffers include, but are not limited to, acetate, bicarbonate, ammonium chloride, citrate, phosphate, pharmaceutically acceptable salts thereof, and combinations or mixtures thereof.

In one embodiment, when one or more buffers are used in the present formulations, such as in combination with a pharmaceutically acceptable vehicle, the buffer is present in the final formulation in an amount ranging from about 0.1% to about 20%, about 0.5% to about 10%, for example. In certain embodiments of the present invention, the amount of buffer included in the gel formulation is such that the pH of the gel formulation does not interfere with the body's natural buffering system.

In one embodiment, a diluent is also used to stabilize the compound, as it may provide a more stable environment. Salts dissolved in buffered solutions (which may also provide pH control or maintenance) are used in the art as diluents, including, but not limited to, phosphate buffered saline solutions.

In some embodiments, the pH of any of the gel formulations described herein allows for sterilization of the gel formulation (e.g., by filtration or sterile mixing or heat treatment and/or autoclaving (e.g., terminal sterilization)) without degradation of the pharmaceutical agent (e.g., steroid) or the polymers comprising the gel. To reduce hydrolysis and/or degradation of the otic agent and/or gel polymer during sterilization, the pH of the buffer is designed to maintain the pH of the formulation within the range of 7-8 during sterilization (e.g., autoclaving).

In particular embodiments, the pH of any of the gel formulations described herein allows for terminal sterilization (e.g., by heat treatment and/or autoclaving) of the gel formulation without degradation of the pharmaceutical agent (e.g., corticosteroid) or the polymer comprising the gel. For example, to reduce hydrolysis and/or degradation of the otic agent and/or gel polymer during the autoclaving process, the pH of the buffer is designed to maintain the pH of the formulation in the range of 7-8 at elevated temperatures. Depending on the otic agent used in the formulation, any suitable buffer may be used. In some cases, because of the pK of TRIS_aDecreases with increasing temperature at about-0.03/° C, and the pK of PBS_aAutoclaving at about 0.003/° c increases with increasing temperature, so autoclaving at 250 ° F (121/° c) causes the pH of the TRIS buffer to shift significantly downward (i.e., more acidic), while the pH of the PBS buffer shifts upward to a relatively small degree, and thus the otic agent increases significantly more hydrolysis and/or degradation in TRIS than in PBS. Degradation of the otic agent is reduced by using a suitable combination of buffer and polymer additives (e.g., P407, CMC) as described herein.

In some embodiments, a formulation pH suitable for sterilization of an otic formulation described herein (e.g., by filtration or sterile mixing or heat treatment and/or autoclaving (e.g., terminal sterilization)) is between about 5.0 and about 9.0, between about 5.5 and about 8.5, between about 6.0 and about 7.6, between about 7 and about 7.8, between about 7.0 and about 7.6, between about 7.2 and 7.6, or between about 7.2 and about 7.4. In particular embodiments, a formulation suitable for sterilization (e.g., by filtration or aseptic mixing or heat treatment and/or autoclaving (e.g., terminal sterilization)) of any of the compositions described herein has a pH of about 6.0, about 6.5, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 7.6.

In some embodiments, the formulation has a pH as described herein and includes a thickener (e.g., a viscosity enhancing agent), such as a cellulose-based thickener described herein, as a non-limiting example. In some cases, the addition of a second polymer (e.g., a thickener) and the pH of the formulation as described herein allows for sterilization of the formulations described herein without any substantial degradation of the otic agent and/or polymer components in the otic formulation. In some embodiments, the ratio of thermoreversible poloxamer to thickener in a formulation having a pH as described herein is about 40: 1, about 35: 1, about 30: 1, about 25: 1, about 20: 1, about 15: 1, about 10: 1, or about 5: 1. For example, in certain embodiments, the sustained release and/or extended release formulations described herein comprise a combination of poloxamer 407 (poloxamine F127) and carboxymethylcellulose (CMC) in a ratio of about 40: 1, about 35: 1, about 30: 1, about 25: 1, about 20: 1, about 15: 1, about 10: 1, or about 5: 1. In some embodiments, the amount of thermoreversible polymer in any of the formulations described herein is about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40% of the total weight of the formulation. In some embodiments, the amount of thermoreversible polymer in any of the formulations described herein is about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% of the total weight of the formulation. In some embodiments, the amount of thickener (e.g., gelling agent) in any of the formulations described herein is about 1%, about 5%, about 10%, or about 15% of the total weight of the formulation. In some embodiments, the amount of thickener (e.g., gelling agent) in any of the formulations described herein is about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5% of the total weight of the formulation.

In some embodiments, the pharmaceutical formulations described herein are stable with respect to pH for any of the following periods: at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, or at least about 6 months. In other embodiments, the formulations described herein are stable with respect to pH over a period of at least about 1 week. Also described herein are formulations that are stable with respect to pH over a period of at least about 1 month.

Tension agent

Generally, the osmolality of the endolymph is higher than that of the perilymph. For example, the osmolality of endolymph is about 304mOsm/kg H₂O, and the osmolality of perilymph is about 294mOsm/kg H₂And O. In certain embodiments, an amount of tonicity agent is added to the formulations described herein to provide a practical osmolality of the otic formulation of about 100 to about 1000mOsm/kg, about 200 to about 800mOsm/kg, about 250 to about 500mOsm/kg, or about 250 to about 350mOsm/kg, or about 280 to about 320 mOsm/kg. In some embodiments, the formulations described herein have a practical osmolality of about 100 to about 1000mOsm/L, about 200 to about 800mOsm/L, about 250 to about 500mOsm/L, about 250 to about 350mOsm/L, about 280 to about 320mOsm/L, or about 250 to about 320 mOsm/L.

In some embodiments, the deliverable capacity osmolality of any of the formulations described herein is designed to be isotonic with the target ear structure (e.g., endolymph, perilymph, etc.). In particular embodiments, the otic compositions described herein are formulated to provide about 250 to about 320mOsm/L (about 250 to about 320mOsm/kg H) at the site of targeted action₂O osmolality) andpreferably about 270 to about 320mOsm/L (about 270 to about 320mOsm/kg H)₂O osmolality) of the perilymph is suitable. In particular embodiments, after delivery to the target site, the deliverable osmolality/osmolality of the formulation (i.e., the osmolality/osmolality of the formulation in the absence of a gelling agent or thickening agent (e.g., a thermoreversible gel polymer)) is adjusted, for example, by using an appropriate salt concentration (e.g., a potassium or sodium salt concentration) or using a tonicity agent that causes the formulation to become compatible with endolymphatic and/or perilymphatic (i.e., isotonic with endolymphatic and/or perilymph). Due to the correlation of different amounts of water with the monomer units of the polymer, the osmolality of the formulations comprising thermoreversible gel polymers is an unreliable measure. The practical osmolality of the formulation (i.e., the osmolality in the absence of a gelling agent or thickener (e.g., a thermoreversible gel polymer)) is a reliable measure and is measured by any suitable method (e.g., freezing point depression, vapor depression). In some cases, the formulations described herein provide deliverable osmolality (e.g., target site (e.g., perilymph)) that causes minimal interference with the internal ear environment and causes minimal discomfort (e.g., dizziness and/or nausea) in the mammal after administration.

In some embodiments, any of the formulations described herein are isotonic with perilymph and/or endolymph. The isotonic formulation is provided by the addition of a tonicity agent. Suitable tonicity agents include, but are not limited to, any pharmaceutically acceptable sugar, salt, or any combination or mixture thereof, such as, but not limited to, dextrose, glycerol, mannitol, sorbitol, sodium chloride, and other electrolytes.

Suitable otic compositions include one or more salts in an amount necessary to provide an osmolality of the composition within an acceptable range. The salts include salts having a sodium, potassium or ammonium cation and a chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anion; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

In some embodiments, the formulations described herein have a pH and/or a useful capacity osmolality as described herein, and the concentration of the active pharmaceutical ingredient is between about 1 μ M and about 10 μ M, between about 1mM and about 100mM, between about 0.1mM and about 100 nM. In some embodiments, the formulations described herein have a pH and/or a useful osmolality as described herein, and the concentration of the active pharmaceutical ingredient is between about 0.1 and about 20%, between about 0.1 and about 10%, between about 0.1 and about 7.5%, between about 0.1 and 6%, between about 0.1 and 5%, between about 0.2 and about 3%, between about 0.1 and about 2% of the active ingredient by weight of the formulation. In some embodiments, the formulations described herein have a pH and/or a useful capacity osmolality as described herein, and the concentration of the active pharmaceutical ingredient is between about 0.1 and about 70mg/mL, between about 1mg and about 50mg/mL, between about 1mg and about 20mg/mL, between about 1mg/mL and about 10mg/mL, between about 1mg/mL and about 5mg/mL, or between about 0.5mg/mL and about 5mg/mL of the active agent, by volume of the formulation.

Particle size

The size reduction is used to increase the surface area and/or adjust the dissolution properties of the formulation. It also serves to maintain a consistent mean Particle Size Distribution (PSD) (e.g., micron-sized particles, nano-sized particles, etc.) of any of the formulations described herein. In some embodiments, any of the formulations described herein comprise multiparticulates, i.e., a plurality of particle sizes (e.g., micron-sized particles, nano-sized particles, non-sized particles, colloidal particles); that is, the formulation is a multiparticulate formulation. In some embodiments, any of the formulations described herein comprise one or more multi-particulate (e.g., micron-sized) therapeutic agents. Micron sizing is a process of reducing the average diameter of particles of solid materials. Micron-sized particles refer to particles from about micron-sized in diameter to about nanometer-sized in diameter. In some embodiments, the average diameter of the particles in the micron-sized solid is from about 0.5 μm to about 500 μm. In some embodiments, the average diameter of the particles in the micron-sized solid is from about 1 μm to about 200 μm. In some embodiments, the average diameter of the particles in the micron-sized solid is from about 2 μm to about 100 μm. In some embodiments, the average diameter of the particles in the micron-sized solid is from about 3 μm to about 50 μm. In some embodiments, the particulate micron-sized solid comprises a particle size of less than about 5 microns, less than about 20 microns, and/or less than about 100 microns. In some embodiments, the use of corticosteroid particles (e.g., micron-sized particles) allows for the extended and/or sustained release of corticosteroid from any of the formulations described herein as compared to formulations comprising non-multiparticulate (e.g., non-micron-sized) corticosteroid. In some cases, a formulation containing multiparticulate (e.g., micron-sized) corticosteroid was ejected from a 1mL syringe fitted with a 27G needle without any blockage or obstruction.

In some cases, any particle in any of the formulations described herein is a coated particle (e.g., a coated micron-sized particle, a nanoparticle) and/or a microsphere and/or a liposome particle. Particle size reduction techniques include, for example, milling, grinding (e.g., air disk milling (jet milling), ball milling), coacervation, complex coacervation, high pressure homogenization, spray drying, and/or supercritical fluid crystallization. In some cases, the particles are sized by mechanical impact (e.g., hammer mill, ball mill, and/or pin mill). In some cases, the particles are sized via fluid energy (e.g., a spiral jet mill, a ring flow jet mill, and/or a fluidized bed jet mill). In some embodiments, the formulations described herein comprise crystalline particles and/or isotropic particles. In some embodiments, the formulations described herein comprise amorphous particles and/or anisotropic particles. In some embodiments, the formulations described herein comprise particles of a therapeutic agent, wherein the therapeutic agent is a free base, or a salt, or a prodrug of the therapeutic agent, or any combination thereof.

In some embodiments, the formulations described herein comprise one or more corticosteroids, wherein the corticosteroid comprises a nanoparticle. In some embodiments, the formulations described herein comprise corticosteroid beads (e.g., dexamethasone beads), optionally coated with a controlled release excipient. In some embodiments, the formulations described herein comprise a corticosteroid granulated and/or reduced in size and coated with a controlled release excipient; the granulated coated corticosteroid particles are then optionally micron sized and/or formulated in any of the compositions described herein.

In some cases, pulsatile release otic pharmaceutical formulations are prepared by using the procedures described herein using a corticosteroid in the free acid or free base form in combination with a corticosteroid salt. In some formulations, the pulsatile release otic drug formulations are prepared by using a combination of a micron-sized corticosteroid (and/or a salt or prodrug thereof) and coated particles (e.g., nanoparticles, liposomes, microspheres) using any of the procedures described herein. Alternatively, a pulsatile release profile is achieved by preparing a pulsatile release formulation by delivering up to 20% of the dose of a corticosteroid (e.g., a micron-sized corticosteroid, free alcohol, free acid or a salt or prodrug thereof; multiparticulate corticosteroid, free alcohol, free acid or a salt or prodrug thereof) with the aid of cyclodextrins, surfactants (e.g., poloxamer 407, 338, 188), tweens (80, 60, 20, 81), PEG-hydrogenated castor oil, co-solvents (e.g., N-methyl-2-pyrrolidone), and the like, and using any of the procedures described herein.

In particular embodiments, any otocompatible formulation described herein comprises one or more micron-sized pharmaceutical agents (e.g., steroids). In some such embodiments, the micron-sized pharmaceutical agent comprises micron-sized particles, coated (e.g., coated with an extended release coating), micron-sized particles, or a combination thereof. In some such embodiments, the micron-sized pharmaceutical agent comprising micron-sized particles, coated micron-sized particles, or a combination thereof comprises a corticosteroid in the form of a free acid, a free base, a salt thereof, a prodrug, or any combination thereof. In certain embodiments, the pharmaceutical compositions described herein comprise dexamethasone, methylprednisolone, or prednisolone in the form of a micron-sized powder. In certain embodiments, the pharmaceutical compositions described herein comprise dexamethasone in the form of dexamethasone micropowder.

The multiparticulate and/or micron-sized corticosteroid described herein is delivered to the otic structure (e.g., the inner ear) by means of any type of matrix, including solid, liquid, or gel matrices. In some embodiments, the multiparticulate and/or micron-sized corticosteroid described herein is delivered to an ear structure (e.g., the inner ear) via intratympanic injection with the aid of any type of matrix, including solid, liquid, or gel matrices.

Pharmaceutical formulations

Provided herein are pharmaceutical compositions or devices comprising at least one corticosteroid and a pharmaceutically acceptable diluent, excipient, or carrier. In some embodiments, the pharmaceutical composition includes other medicinal or pharmaceutical agents, carriers, adjuvants, such as preservatives, stabilizers, wetting or emulsifying agents, dissolution promoters, salts for regulating osmotic pressure, and/or buffers. In other embodiments, the pharmaceutical composition also contains other therapeutic substances.

In some embodiments, the compositions or devices described herein include a dye to help enhance the visualization of the gel upon application. In some embodiments, dyes compatible with the otoacceptable compositions or devices described herein include Evans blue (e.g., 0.5% of the total weight of the otic formulation), Methylene blue (e.g., 1% of the total weight of the otic formulation), isosulfur blue (Isosulfan blue) (e.g., 1% of the total weight of the otic formulation), Trypan blue (e.g., 0.15% of the total weight of the otic formulation), and/or indocyanine green (e.g., 25mg per vial). Other common dyes, such as FD & C red 40, FD & C red 3, FD & C yellow 5, FD & C yellow 6, FD & C blue 1, FD & C blue 2, FD & C green 3, fluorescent dyes (e.g., fluorescein isothiocyanate), rose bengal (rhodomine), Alexa Fluors, DyLight Fluors), and/or dyes that can be observed in conjunction with non-invasive imaging techniques such as MRI, CAT scan, PET scan, etc. Also contemplated is the use of gadolinium-based MRI dyes, iodine-based dyes, barium-based dyes, and the like with any of the otic formulations described herein. The Sigma-Aldrich catalog of dyes other dyes (included herein by reference with respect to the disclosure) that are compatible with any of the formulations or compositions described herein are listed under the dye entry.

Any of the pharmaceutical compositions or devices described herein are administered by contacting the composition or device with the cochleostomy crest, the round window, the tympanic cavity, the tympanic membrane, the middle ear, or the outer ear.

In one embodiment of the otoacceptable controlled release corticosteroid pharmaceutical formulations described herein, the corticosteroid is provided in a gel matrix, also referred to herein as an "otoacceptable gel formulation," "inner ear acceptable gel formulation," "middle ear acceptable gel formulation," "outer ear acceptable gel formulation," "otic gel formulation," or variations thereof. All components of the gel formulation must be compatible with the targeted ear structure. In addition, the gel formulation provides controlled release of the corticosteroid to a desired site of a target ear structure; in some embodiments, the gel formulation also has an immediate release or quick release component for delivering the corticosteroid to the desired target site. In other embodiments, the formulation has a sustained release component for delivery of the corticosteroid. In some embodiments, the gel formulation comprises a multiparticulate (e.g., micron-sized) corticosteroid. In some embodiments, the otic gel formulation is biodegradable. In other embodiments, the otic gel formulation includes a mucoadhesive excipient to allow adhesion to the outer mucosal layer of the round window membrane. In yet other embodiments, the otic gel formulation includes a permeation enhancer excipient; in other embodiments, the otic gel formulation contains sufficient viscosity enhancing agents to provide the following viscosities: between about 500 and 1,000,000 centipoise; between about 750 and 1,000,000 centipoise; between about 1000 and 1,000,000 centipoise; between about 1000 and 400,000 centipoise; between about 2000 and 100,000 centipoise; between about 3000 and 50,000 centipoise; between about 4000 and 25,000 centipoise; between about 5000 and 20,000 centipoise; or between about 6000 and 15,000 centipoise. In some embodiments, the otic gel formulation contains a viscosity enhancing agent sufficient to provide a viscosity between about 50,0000 and 1,000,000 centipoise.

In other or alternative embodiments, the otic gel formulation can be administered on or near the round window membrane via intratympanic injection. In other embodiments, the otic gel formulation is cast on or near the round or spiral window crest by entering into or near the round or spiral window crest area via retroauricular dissection and surgical manipulation. In addition, the otic gel formulation is administered via a syringe and needle, wherein the needle is inserted through the tympanic membrane and directed to the round window or the glabellar region. The otic gel formulation is then deposited on or near the round or spiral window crest for local treatment of autoimmune otic disorders. In other embodiments, the otic gel formulation is administered via a microcatheter implanted in the patient, and in still other embodiments, the formulation is administered via a pump device on or near the round window membrane. In still other embodiments, the otic gel formulation is applied on or near the round window membrane via a microinjection device. In yet other embodiments, the otic gel formulation is applied in the tympanic cavity. In some embodiments, the otic gel formulation is administered on the tympanic membrane. In yet other embodiments, the otic gel formulation is applied on or in the ear canal.

In other embodiments, any of the pharmaceutical compositions or devices described herein comprise a multiparticulate corticosteroid in a liquid base (e.g., a liquid composition for intratympanic injection or otic drops). In certain embodiments, any of the pharmaceutical compositions described herein comprise a multiparticulate corticosteroid in a solid matrix.

Controlled release formulations

In general, controlled release drug formulations control the site of release of the drug and the time of release in vivo. As discussed herein, controlled release refers to immediate release, delayed release, sustained release, extended release, variable release, pulsatile release, and bimodal release. Controlled release has a number of advantages. First, controlled release of the pharmaceutical agent allows for lower dosing frequency and thus minimizes repeat treatment. Second, controlled release therapy results in more efficient drug utilization and less compound remains as a residue. Third, controlled release offers the potential for localized drug delivery by placing the delivery device or formulation at the site of disease. In addition, controlled release offers the possibility of administering and releasing two or more different drugs each with a unique release profile, or the possibility of releasing the same drug at different rates or for different durations, by means of a single dosage unit.

Accordingly, it is an aspect of embodiments disclosed herein to provide an otically acceptable controlled release corticosteroid composition or device for the treatment of autoimmune and/or inflammatory disorders. The controlled release aspects of the compositions and/or formulations and/or devices disclosed herein are imparted by a variety of agents, including but not limited to excipients, agents or materials that may be accepted for use in the inner ear or other ear structures.

An auris-acceptable gel

Gels, sometimes referred to as gels (jellies), have been defined in a number of ways. For example, the united states pharmacopoeia defines a gel as a semi-solid system consisting of a suspension of small inorganic particles or large organic molecules interspersed with liquids. Gels include single phase or two phase systems. Single phase gels consist of organic macromolecules uniformly distributed throughout a liquid in such a way that no distinct boundaries exist between the dispersed macromolecules and the liquid. Some single phase gels are prepared from synthetic macromolecules (e.g., carbomer) or from natural gums (e.g., tragacanth). In some embodiments, while single phase gels are generally aqueous, alcohols and oils will also be used for preparation. Two-phase gels consist of a network of small individual particles.

Gels can also be classified as hydrophobic or hydrophilic. In certain embodiments, the matrix of the hydrophobic gel consists of liquid paraffin gelled with polyethylene, or fatty oil gelled with colloidal silica, or aluminum or zinc soap. In contrast, the matrix of hydrophobic gels usually consists of water, glycerol or propylene glycol gelled with suitable gelling agents (e.g., tragacanth, starch, cellulose derivatives, carboxyvinyl polymers and magnesium aluminum silicate). In certain embodiments, the rheology of the compositions or devices disclosed herein is pseudoplastic, plastic, thixotropic, or dilatant.

In one embodiment, the enhanced viscosity otoacceptable formulations described herein are not liquid at room temperature. In certain embodiments, the enhanced viscosity formulation is characterized by a phase transition between room temperature and body temperature (including individuals with severe fever, e.g., up to about 42 ℃). In some embodiments, the phase transition occurs at 1 ℃ below body temperature, 2 ℃ below body temperature, 3 ℃ below body temperature, 4 ℃ below body temperature, 6 ℃ below body temperature, 8 ℃ below body temperature, or 10 ℃ below body temperature. In some embodiments, the phase transition occurs at about 15 ℃ below body temperature, about 20 ℃ below body temperature, or about 25 ℃ below body temperature. In particular embodiments, the formulations described herein have a gelation temperature (tgel) of about 20 ℃, about 25 ℃, or about 30 ℃. In certain embodiments, the gelation temperature (tgel) of the formulations described herein is about 35 ℃ or about 40 ℃. In one embodiment, administration of any of the formulations described herein at approximately body temperature reduces or inhibits dizziness associated with intratympanic administration of the otic formulation. The definition of body temperature includes the body temperature of healthy individuals or unhealthy individuals including those with fever (up to about 42 ℃). In some embodiments, the pharmaceutical compositions or devices described herein are liquid at about room temperature and are administered at or about room temperature to reduce or ameliorate side effects such as vertigo.

Polymers composed of polyoxypropylene and polyoxyethylene form thermoreversible gels when incorporated into aqueous solutions. These polymers are capable of changing from a liquid to a gel state at temperatures approaching body temperature, resulting in a suitable formulation for application to a target ear structure. The phase change from liquid to gel depends on the polymer concentration and composition in the solution.

Poloxamer 407(PF-127) is a nonionic surfactant composed of a polyoxyethylene-polyoxypropylene copolymer. Other poloxamers include 188 (grade F-68), 237 (grade F-87), 338 (grade F-108). Aqueous solutions of poloxamers are stable in the presence of acids, alkali metals and metal ions. PF-127 is a commercially available polyoxyethylene-polyoxypropylene triblock copolymer having the general formula E106P 70E 106, with an average molar mass of 13,000. The polymer may additionally be purified using suitable methods that enhance the gelling properties of the polymer. It contains about 70% ethylene oxide, which is responsible for its hydrophilicity. It is one of a series of poloxamer ABA block copolymers, the poloxamer ABA block copolymer members sharing the chemical formula shown below.

PF-127 is of particular interest because concentrated solutions (> 20% w/w) of the copolymer transform from a low viscosity clear solution to a solid gel upon heating to body temperature. Thus, this phenomenon suggests that the gel formulation forms a semi-solid structure and a sustained release depot (depot) when in contact with the body. In addition, PF-127 has good solvency, low toxicity, and is therefore considered a good vehicle for drug delivery systems.

In an alternative embodiment, the thermo-sensitive gel (thermogel) is a PEG-PLGA-PEG triblock copolymer (Zheng (Jeong) et al, Nature (1997), 388: 860-2; Zheng (Jeong) et al, J.Control.Release) (2000), 63: 155-63; Zheng (Jeong) et al, advanced drug delivery reviews (adv. drug delivery Rev.) (2002), 54: 37-51). The polymer exhibits sol-gel behavior at a concentration of about 5% w/w to about 40% w/w. Depending on the desired properties, the lactide/glycolide molar ratio in the PLGA copolymer is in the range of about 1: 1 to about 20: 1. The resulting copolymer is soluble in water and forms a free-flowing liquid at room temperature, but a hydrogel at body temperature. A commercially available PEG-PLGA-PEG triblock copolymer is RESOMER RGP t50106 manufactured by Boehringer Vargham (Boehringer Ingelheim). This material consisted of a 50: 50 poly (DL-lactide-co-glycolide) PGLA copolymer containing 10% w/w PEG and having a molecular weight of about 6000.

Is the commercial name of a class of low molecular weight biodegradable block copolymers from maclo Incorporated having reverse thermal gelation properties as described in U.S. patent nos. 6,004,573, 6,117949, 6,201,072 and 6,287,588. It also includes biodegradable polymer drug carriers disclosed in U.S. patent application nos. 09/906,041, 09/559,799, and 10/919,603 of the application. The biodegradable drug carrier comprises an ABA-type or BAB-type triblock copolymer or mixture thereof, wherein the a block is relatively hydrophobic and comprises a biodegradable polyester or poly (orthoester), and the B block is relatively hydrophilic and comprises polyethylene glycol (PEG), the copolymer has a hydrophobic content between 50.1 to 83 wt% and a hydrophilic content between 17 to 49.9 wt%, and the total block copolymer molecular weight is between 2000 and 8000 daltons. The pharmaceutical carrier exhibits water solubility and undergoes reversible thermal gelation at temperatures below normal mammalian body temperature and thus exists in gel form at temperatures equal to physiological mammalian body temperature. The biodegradable hydrophobic a polymer block comprises a polyester or a poly (orthoester), wherein the polyester is synthesized from monomers selected from the group consisting of: d, L-lactide, D-lactide, L-lactide, D, L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid, epsilon-caprolactone, epsilon-hydroxycaproic acid, gamma-butyrolactone, gamma-hydroxybutyric acid, delta-valerolactone, delta-hydroxyvaleric acid, hydroxybutyric acid, malic acid and copolymers thereof, and having an average molecular weight between about 600 daltons and 3000 daltons. The hydrophilic B block segment is preferably polyethylene glycol (PEG) having an average molecular weight between about 500 daltons and 2200 daltons.

Other biodegradable thermoplastic polyesters include(provided by atlas laboratories, Inc.) and/or thermoplastic polyesters such as those disclosed in U.S. patent nos. 5,324,519, 4,938,763, 5,702,716, 5,744,153, and 5,990,194; among them suitable biodegradable thermoplastic polyesters are disclosed as thermoplastic polymers. Examples of suitable biodegradable thermoplastic polyesters include polylactic acid, polyglycolide, polycaprolactone, copolymers thereof, terpolymers thereof, and any combination thereof. In some such embodiments, suitable biodegradable thermoplastic polyesters are polylactic acid, polyglycolide, copolymers thereof, terpolymers thereof, or combinations thereof. In one embodiment, the biodegradable thermoplastic polyester is 50/50 poly (DL-lactide-co-glycolide) with carboxyl end groups; from about 30 wt.% to about 40 wt.% of the composition; and an average molecular weight of about 23,000 to about 45,000. Alternatively, in another embodiment, the biodegradable thermoplastic polyester is 75/25 poly (DL-lactide-co-glycolide) without carboxyl end groups; from about 40 wt.% to about 50 wt.% of the composition; and an average molecular weight of about 15,000 to about 24,000. In other or alternative embodiments, the terminal groups of the poly (DL-lactide-co-glycolide) are hydroxyl, carboxyl, or ester, depending on the polymerization method. Polycondensation of lactic acid or glycolic acid provides polymers containing terminal hydroxyl and carboxyl groups. The ring-opening polymerization of cyclic lactide or glycolide monomers with water, lactic acid or glycolic acid provides polymers with the same end groups. However, ring opening of cyclic monomers with monofunctional alcohols (such as methanol, ethanol or 1-dodecanol) provides polymers containing one hydroxyl group and one ester end group. Ring-opening polymerization of cyclic monomers with diols such as 1, 6-hexanediol or polyethylene glycol provides polymers containing only hydroxyl end groups.

Since the polymer system of the thermoreversible gel is more completely dissolved at low temperature, the dissolution method comprises adding the desired amount of polymer to the amount of water to be used at low temperature. Generally, after wetting the polymer by shaking, the mixture is covered and placed in a cold room or a thermostated container of about 0-10 ℃ to dissolve the polymer. Stirring or shaking the mixture to make the thermoreversible gel polymer fasterDissolve rapidly. The corticosteroid and various additives such as buffers, salts, and preservatives are then added and dissolved. In some cases, the corticosteroid and/or other pharmaceutically active agent is suspended if it is not soluble in water. The pH is adjusted by adding a suitable buffer. Optionally by incorporating in the composition a round window membrane mucoadhesive carbomer (such as934P) to impart thereto the characteristics of mucoadhesion of the round window membrane (Maxithiya (Majithiya) et al, Association of pharmaceutical scientists medical science and technology (AAPS PharmSciTech) (2006), 7(3), page E1; EP0551626, both incorporated herein by reference with respect to the disclosure).

One embodiment is an otically acceptable pharmaceutical gel formulation that does not require the use of added viscosity enhancers. These gel formulations incorporate at least one pharmaceutically acceptable buffer. One aspect is a gel formulation comprising a corticosteroid and a pharmaceutically acceptable buffer. In another embodiment, the pharmaceutically acceptable excipient or carrier is a gelling agent.

In other embodiments, a suitable otic acceptable pharmaceutical formulation of a corticosteroid also includes one or more pH adjusting agents or buffers to provide a pH suitable for endolymph or perilymph. Suitable pH adjusting agents or buffers include, but are not limited to, acetate, bicarbonate, ammonium chloride, citrate, phosphate, pharmaceutically acceptable salts thereof, and combinations or mixtures thereof. These pH adjusting and buffering agents are included in amounts necessary to maintain the pH of the composition between about pH 5 and about pH 9, in one embodiment between about 6.5 and about 7.5, and in yet another embodiment, the pH is about 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5. In one embodiment, when one or more buffers are used in the present formulations, such as in combination with a pharmaceutically acceptable vehicle, the buffer is present in the final formulation in an amount ranging from about 0.1% to about 20%, about 0.5% to about 10%, for example. In certain embodiments of the invention, the amount of buffer included in the gel formulation is such that the pH of the gel formulation does not interfere with the natural buffer system of the middle or inner ear or with the natural pH of the endolymph or perilymph: depending on where in the cochlea the corticosteroid formulation is targeted. In some embodiments, the buffer is present in the gel formulation at a concentration of about 10 μ M to about 200 mM. In certain embodiments, the buffer is present at a concentration of about 20mM to about 100 mM. One example is a buffer such as acetate or citrate at a slightly acidic pH. In one embodiment, the buffer is sodium acetate buffer having a pH of about 4.5 to about 6.5. In one embodiment, the buffer is a sodium citrate buffer having a pH of about 5.0 to about 8.0 or about 5.5 to about 7.0.

In alternative embodiments, the buffer used is tris (hydroxymethyl) aminomethane, bicarbonate, carbonate, or phosphate at a slightly basic pH. In one embodiment, the buffer is a sodium bicarbonate buffer having a pH of about 6.5 to about 8.5, or about 7.0 to about 8.0. In another embodiment, the buffer is a disodium phosphate buffer having a pH of about 6.0 to about 9.0.

Also described herein are controlled release formulations or devices comprising a corticosteroid and a viscosity enhancing agent. By way of example only, suitable viscosity enhancing agents include gelling agents and suspending agents. In one embodiment, the viscosity enhanced formulation does not include a buffer. In other embodiments, the viscosity-enhanced formulation includes a pharmaceutically acceptable buffer. If necessary, sodium chloride or other tonicity agents are optionally used to adjust tonicity.

By way of example only, an otically acceptable viscosity agent includes hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium chondroitin sulfate, sodium hyaluronate. Other viscosity enhancing agents compatible with the targeted ear structure include, but are not limited to, acacia, agar, magnesium aluminum silicate, sodium alginate, sodium stearate, fucus (bladderwrrack), bentonite, carbomer, carrageenan, Carbopol (Carbopol), yellow Raw gum, cellulose, microcrystalline cellulose (MCC), carob bean (ceratonia), chitin, carboxymethylated polyglucose, Chondrus crispus (chondrus), dextrose, furcellaran (furcellaran), gelatin, Ghatti gum (Ghatti gum), guar gum, hectorite (hectorite), lactose, sucrose, maltodextrin, mannitol, sorbitol, honey, corn starch, wheat starch, rice starch, potato starch, gelatin, sterculia gum, xanthan gum, tragacanth gum, ethyl cellulose, ethyl hydroxyethyl cellulose, ethyl methyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, poly (hydroxyethyl methacrylate), oxidized poly gelatin (oxypolygelatin), pectin, polygeline (polygeline), povidone, propylene carbonate, methyl vinyl ether/maleic anhydride copolymer (PVM/MA), Poly (methoxyethyl methacrylate), poly (methoxyethoxyethyl methacrylate), hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (CMC), silicon dioxide, polyvinylpyrrolidone (PVP: povidone),(dextrose, maltodextrin, and sucralose) or a combination thereof. In particular embodiments, the viscosity enhancing excipient is a combination of MCC and CMC. In another embodiment, the viscosity enhancing agent is carboxymethylated chitosan or a combination of chitin and alginate. The combination of chitin and alginate with the corticosteroids disclosed herein acts in a controlled release formulation, limiting diffusion of the corticosteroid from the formulation. In addition, a combination of carboxymethylated chitosan and alginate is optionally used to help increase the permeability of corticosteroids through round window membranes.

Some embodiments are viscosity-enhanced formulations comprising a corticosteroid of about 0.1mM and about 100mM, a pharmaceutically acceptable viscosity agent, and water for injection, the concentration of the viscosity agent in the water being sufficient to provide a viscosity-enhanced formulation having a final viscosity of about 100 to about 100,000 cP. In certain embodiments, the viscosity of the gel is in the range of about 100 to about 50,000cP, about 100cP to about 1,000cP, about 500cP to about 1500cP, about 1000cP to about 3000cP, about 2000cP to about 8,000cP, about 4,000cP to about 50,000cP, about 10,000cP to about 500,000cP, about 15,000cP to about 1,000,000 cP. In other embodiments, when an even more viscous medium is desired, the biocompatible gel comprises at least about 35%, at least about 45%, at least about 55%, at least about 65%, at least about 70%, at least about 75%, or even at least about 80% by weight of corticosteroid. In highly concentrated samples, the biocompatible viscosity enhancing formulation comprises at least about 25%, at least about 35%, at least about 45%, at least about 55%, at least about 65%, at least about 75%, at least about 85%, at least about 90%, or at least about 95% or more corticosteroid by weight.

In some embodiments, the viscosity of the gel formulations presented herein is measured by any of the described means. For example, in some embodiments, the viscosity of the gel formulations described herein is calculated using an LVDV-II + CP cone and plate viscometer and a cone and spindle CPE-40. In other embodiments, the viscosity of the gel formulations described herein is calculated using a boehringer (Brookfield) (spindle and cup) viscometer. In some embodiments, the viscosity ranges mentioned herein are measured at room temperature. In other embodiments, the viscosity ranges mentioned herein are measured at body temperature (e.g., average body temperature of a healthy human).

In one embodiment, a pharmaceutically acceptable viscosity-enhanced otically acceptable formulation comprises at least one corticosteroid and at least one gelling agent. Suitable gelling agents for preparing the gel formulation include, but are not limited to, cellulose derivatives, cellulose ethers (e.g., carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose), guar gum, xanthan gum, locust bean gum, alginates (e.g., alginic acid), silicates, starch, tragacanth, carboxyvinyl polymers, carrageenan, paraffin, petrolatum, and any combination or mixture thereof. In some other embodiments, hydroxypropyl methylcellulose is utilized As a gelling agent. In certain embodiments, the viscosity enhancing agents described herein are also utilized as gelling agents for the gel formulations presented herein.

In some embodiments, other gel formulations are also suitable depending on the particular corticosteroid, other pharmaceutical agents used, or excipients/additives, and thus are considered to be within the scope of the present invention. For example, other commercially available glycerol-based gels, glycerol-derived compounds, bound or cross-linked gels, matrices, hydrogels and polymers, as well as gelatins and derivatives thereof, alginates and alginate-based gels, and even various natural and synthetic hydrogels and hydrogel-derived compounds are all contemplated for use in the corticosteroid formulations described herein. In some embodiments, an otically acceptable gel includes, but is not limited to, alginate hydrogelsGel (convalescent (ConvaTec), Princeton, n.j.);hydrogels (convatect (ConvaTec)),(Johnson medicine)&Johnson Medical), Arlington, Tex, texas;(V) Acamenane Hydrogel (Acemannan Hydrogel) (Carrington laboratories, Inc.), Euro Texas, Texas (Irving, Tex.); glycerol gel Hydrogels (Swiss-American Products, Inc., Dallas, Tex) and sterile(Johnson)&Johnson)). In other embodiments, a biodegradable, biocompatible gel also refers to a compound present in an otoacceptable formulation as disclosed and described herein.

In some formulations developed for administration to mammals and for compositions formulated for administration to humans, the otically acceptable gel comprises substantially all of the weight of the composition. In other embodiments, the otoacceptable gel comprises up to about 98% or about 99% by weight of the composition. This is desirable when a substantially non-fluid or substantially viscous formulation is desired. In another embodiment, when a less viscous or more fluid otic acceptable pharmaceutical gel formulation is desired, the biocompatible gel portion of the formulation comprises at least about 50%, at least about 60%, at least about 70%, or even at least about 80% or 90% by weight of the compound. All intermediate integers falling within these ranges are within the present disclosure, and in some alternative embodiments, more flowable (and thus less viscous) auri-acceptable gel compositions are formulated, such as compositions in which the gel or matrix component of the mixture comprises no more than about 50%, no more than about 40%, no more than about 30%, or even no more than about 15% or about 20% by weight of the composition.

Round window film mucoadhesive agent

It is also within the scope of the embodiments to add round window membrane mucoadhesive agents to the corticosteroid formulations and compositions and devices disclosed herein. The term 'mucoadhesion' is used to refer to a substance that binds to the mucin layer of a biological membrane, such as the outer membrane of a three-layer round window membrane. For use as a round window membrane mucoadhesive polymer, the polymer has some general physiochemical characteristics, such as predominance of anionic hydrophilicity and a number of hydrogen bond forming groups, surface properties suitable for wetting mucus/mucosal tissue surfaces, or flexibility sufficient to penetrate the mucus network.

Can be connected with earThe round window membrane mucoadhesive agents used with the formulations include, but are not limited to, at least one soluble polyvinylpyrrolidone polymer (PVP); a water-swellable, water-insoluble, fibrous cross-linked carboxyl-functional polymer; crosslinked poly (acrylic acid) (e.g. poly (acrylic acid)) (947P); carbomer homopolymer; a carbomer copolymer; a hydrophilic polysaccharide gum, maltodextrin, a cross-linked alginate gum gel, a water dispersible polycarboxylated vinyl polymer, at least two particulate components selected from the group consisting of titanium dioxide, silica and clay, or mixtures thereof. The round window membrane mucoadhesive is optionally used in combination with an otically acceptable viscosity-increasing excipient, or alone, to increase the interaction of the composition with the targeted ear component of the mucosal layer. In one non-limiting example, the mucoadhesive agent is maltodextrin and/or alginate gel. When used, the round window membrane mucoadhesive characteristics imparted to the composition are at levels sufficient to deliver an effective amount of the corticosteroid composition to, for example, the mucosal layer or the cochlear ridge of the round window membrane in an amount that coats the mucosa and thereafter delivers the composition to the affected area (including, by way of example only, the inner ear vestibule and/or cochlear structure). One method of determining adequate mucoadhesion includes monitoring changes in the interaction of the composition with the mucosal layer, including (but not limited to) measuring changes in retention or residence time of the composition in the absence or presence of mucoadhesive excipients.

In one non-limiting example, the round window membrane mucoadhesive is maltodextrin. Maltodextrins are carbohydrates produced by the hydrolysis of starch, optionally derived from corn, potato, wheat or other plant products. Maltodextrin is optionally used alone or in combination with other round window membrane mucoadhesive agents to impart mucoadhesive characteristics to the compositions disclosed herein. In one embodiment, maltodextrin in combination with carbopol polymer is used to increase the round window membrane mucoadhesive characteristics of the compositions or devices disclosed herein.

In another embodiment, the round window membrane mucoadhesive is an alkyl-glycoside and/or a sugar alkyl ester. As used herein, "alkyl-glycoside" means that the compound comprises any hydrophilic sugar (e.g., sucrose, maltose, or glucose) attached to a hydrophobic alkyl group. In some embodiments, the round window membrane mucoadhesive is an alkyl-glycoside, wherein the alkyl-glycoside comprises a saccharide linked to a hydrophobic alkyl group (e.g., an alkyl group comprising from about 6 to about 25 carbon atoms) via an amide, amine, carbamate, ether, thioether, ester, thioester, glycosidic, thioglycosidic, and/or ureide linkage. In some embodiments, the round window membrane mucoadhesive is hexyl-, heptyl-, octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, tetradecyl-, pentadecyl-, hexadecyl-, heptadecyl-and octadecyl alpha-or beta-D-maltoside; hexyl-, heptyl-, octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, tetradecyl-, pentadecyl-, hexadecyl-, heptadecyl-and octadecyl alpha-or beta-D-glucosides; hexyl-, heptyl-, octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, tetradecyl-, pentadecyl-, hexadecyl-, heptadecyl-and octadecyl alpha-or beta-D-sucrose glycosides; hexyl-, heptyl-, octyl-, dodecyl-, tridecyl-and tetradecyl-beta-D-thiomaltoside; heptyl-or octyl-1-thio-alpha-or beta-D-glucopyranoside; alkyl thiogalactoside; alkyl maltotriosides; long chain aliphatic carbonic acid amides of sucrose beta-amino-alkyl ethers; a derivative in which palatinose (palatinose) or isomaltamine (isomaltamine) is linked to an alkyl chain via an amide bond and a derivative in which isomaltamine is linked to an alkyl chain via urea; long chain aliphatic carbonic acid ureides of sucrose beta-amino-alkyl ethers and long chain aliphatic carbonic acid amides of sucrose beta-amino-alkyl ethers. In some embodiments, the round window membrane mucoadhesive is an alkyl-glycoside, wherein the alkyl glycoside is maltose, sucrose, glucose, or a combination thereof, linked via a glycosidic bond to an alkyl chain having 9-16 carbon atoms (e.g., nonyl-, decyl-, dodecyl-, and tetradecyl succharides; nonyl-, decyl-, dodecyl-, and tetradecyl glucosides; and nonyl-, decyl-, dodecyl-, and tetradecyl maltosides). In some embodiments, the round window membrane mucoadhesive is an alkyl-glycoside, wherein the alkyl glycoside is dodecyl maltoside, tridecyl maltoside, and tetradecyl maltoside. In some embodiments, the otoacceptable penetration enhancer is a surfactant comprising an alkyl-glycoside, wherein the alkyl glycoside is tetradecyl-beta-D-maltoside. In some embodiments, the round window membrane mucoadhesive is an alkyl-glycoside, wherein the alkyl-glycoside is a disaccharide comprising at least one glucose. In some embodiments, the otoacceptable penetration enhancer is a surfactant comprising α -D-glucopyranoside- β -glucopyranoside, n-dodecyl-4-O- α -D-glucopyranoside- β -glucopyranoside, and/or n-tetradecyl-4-O- α -D-glucopyranoside- β -glucopyranoside. In some embodiments, the round window membrane mucoadhesive is an alkyl-glycoside, wherein the Critical Micelle Concentration (CMC) of the alkyl-glycoside in pure water or an aqueous solution is less than about 1 mM. In some embodiments, the round window membrane mucoadhesive is an alkyl-glycoside, wherein the oxygen atom within the alkyl-glycoside is substituted with a sulfur atom. In some embodiments, the round window membrane mucoadhesive is an alkyl-glycoside, wherein the alkyl glycoside is a β -anomer. In some embodiments, the round window membrane mucoadhesive is an alkyl-glycoside, wherein the alkyl glycoside comprises 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.5%, or 99.9% of a β -anomer.

Otoacceptable cyclodextrins and other stable formulations

In one embodiment, the otoacceptable formulation further comprises a cyclodextrin. Cyclodextrins are cyclic oligosaccharides containing 6, 7 or 8 glucopyranose units, called α -cyclodextrin, β -cyclodextrin or γ -cyclodextrin, respectively. Cyclodextrins have a hydrophilic exterior that enhances water solubility, and a hydrophobic interior that forms a cavity. In an aqueous environment, the hydrophobic portion of other molecules typically enter the hydrophobic cavity of the cyclodextrin to form an inclusion compound (inclusion). Additionally, cyclodextrins are also capable of other types of non-binding interactions with molecules that are not inside the hydrophobic cavity. Each glucopyranose unit of the cyclodextrin has three free hydroxyl groups, or α -cyclodextrin has 18 hydroxyl groups, β -cyclodextrin has 21 hydroxyl groups, and γ -cyclodextrin has 24 hydroxyl groups. One or more of these hydroxyl groups can be reacted with any of several reagents to form a variety of cyclodextrin derivatives, including hydroxypropyl ethers, sulfonates, and sulfoalkyl ethers. The structures of beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin (HP β CD) are shown below.

In some embodiments, cyclodextrins are used in the pharmaceutical compositions described herein to increase the solubility of the drug. In many cases of enhanced dissolution, inclusion compounds are involved; however, other interactions between the cyclodextrin and the insoluble compound also increase solubility. Hydroxypropyl-beta-cyclodextrin (HP β CD) is commercially available as a pyrogen-free product. It is a non-hygroscopic white powder that is readily soluble in water. HP β CD is thermostable and does not degrade at neutral pH. Thus, cyclodextrins increase the solubility of the therapeutic agent in the composition or formulation. Thus, in some embodiments, cyclodextrins are included to increase the solubility of an otoacceptable corticosteroid in the formulations described herein. In other embodiments, cyclodextrins are additionally used as controlled release excipients within the formulations described herein.

Useful cyclodextrin derivatives include, by way of example only, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxyethyl beta-cyclodextrin, hydroxypropyl gamma-cyclodextrin, sulfated beta-cyclodextrin, sulfated alpha-cyclodextrin, sulfobutyl ether beta-cyclodextrin.

The concentration of cyclodextrin used in the compositions and methods disclosed herein varies with physiochemical properties, pharmacokinetic properties, side effects or adverse events, formulation considerations, or other factors associated with the therapeutically active agent or salt or prodrug thereof, or the nature of other excipients in the composition. Thus, in certain instances, the concentration or amount of cyclodextrin used in accordance with the compositions and methods disclosed herein will vary as desired. When used, the amount of cyclodextrin required to increase the solubility of the corticosteroid and/or to act as a controlled release excipient in any of the formulations described herein is selected using the principles, examples, and teachings described herein.

Other stabilizers suitable for use in the otoacceptable formulations disclosed herein include, for example, fatty acids, fatty alcohols, long chain fatty acid esters, long chain ethers, hydrophilic derivatives of fatty acids, polyvinylpyrrolidone, polyvinyl ethers, polyvinyl alcohols, hydrocarbons, hydrophobic polymers, moisture absorbing polymers, and combinations thereof. In some embodiments, amide analogs of the stabilizers are also used. In other embodiments, the stabilizing agent is selected to alter the hydrophobicity of the formulation (e.g., oleic acid, wax), or to modify the mixing of various components in the formulation (e.g., ethanol), to control the moisture content of the formulation (e.g., PVP or polyvinylpyrrolidone), to control phase mobility (substances with melting points above room temperature, such as long chain fatty acids, alcohols, esters, ethers, amides, etc., or mixtures thereof; waxes), and/or to improve the compatibility of the formulation with the encapsulating material (e.g., oleic acid or waxes). In another embodiment, some of these stabilizers are used as a solvent/co-solvent (e.g., ethanol). In other embodiments, the stabilizer is present in an amount sufficient to inhibit degradation of the corticosteroid. Examples of such stabilizers include (but are not limited to): (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1mM to about 10mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) a combination thereof.

Other suitable otoacceptable corticosteroid formulations include one or more anti-aggregation additives to enhance the stability of the corticosteroid formulation by reducing the rate of protein aggregation. The anti-aggregation additive chosen will depend on the nature of the conditions to which the corticosteroid, e.g., corticosteroid antibody, is exposed. For example, certain formulations that are subjected to agitation and thermal stress require different anti-aggregation additives than formulations that are subjected to lyophilization and reconstitution. By way of example only, suitable anti-aggregation additives include urea, guanidinium chloride, simple amino acids such as glycine or arginine, sugars, polyols, polysorbates, polymers such as polyethylene glycol and dextran, alkyl sugars such as alkyl glycosides, and surfactants.

Other suitable formulations optionally include one or more otologically acceptable antioxidants to enhance chemical stability, if desired. By way of example only, suitable antioxidants include ascorbic acid, methionine, sodium thiosulfate, and sodium metabisulfite. In one embodiment, the antioxidant is selected from the group consisting of metal chelators, thiol-containing compounds, and other general stabilizers.

Other suitable compositions include one or more otically acceptable surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include, but are not limited to, polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers such as octoxynol 10, octoxynol 40.

In some embodiments, the otoacceptable pharmaceutical formulations described herein are stable with respect to compound degradation over any of the following periods: at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 3 months, at least about 4 months, at least about 5 months, or at least about 6 months. In other embodiments, the formulations described herein are stable with respect to compound degradation over a period of at least about 1 week. Also described herein are formulations that are stable with respect to compound degradation over a period of at least about 1 month.

In other embodiments, another surfactant (co-surfactant) and/orThe buffer is combined with one or more pharmaceutically acceptable vehicles as previously described herein so that the surfactant and/or buffer maintains the product at a pH that is optimal for stability. Suitable co-surfactants include (but are not limited to): a) natural and synthetic lipophilic agents, such as phospholipids, cholesterol and cholesterol fatty acid esters and derivatives thereof; b) nonionic surfactants include, for example, polyoxyethylene fatty alcohol esters, sorbitan fatty acid esters (Span), polyoxyethylene sorbitan fatty acid esters (e.g., polyoxyethylene (20) sorbitan monooleate (tween 80), polyoxyethylene (20) sorbitan monostearate (tween 60), polyoxyethylene (20) sorbitan monolaurate (tween 20) and other tweens, sorbitan esters, glyceryl esters, such as Myrj and glyceryl triacetate (glycotriteate/triacetin), polyethylene glycol, cetyl alcohol, cetyl stearyl alcohol, polysorbate 80, poloxamers, poloxamines, polyoxyethylene castor oil derivatives (e.g., poloxamers, poloxamines, polyoxyethylene castor oil derivatives) RH40、Cremphor A25、Cremphor A20、EL) and other Cremophor, sulfosuccinates, alkyl sulfates (SLS); PEG glyceryl fatty acid esters, such as PEG-8 glyceryl caprylate/caprate (Labrasol), PEG-4 glyceryl caprylate/caprate (Labrafac Hydro WL 1219), PEG-32 glyceryl laurate (Gelucire 444/14), PEG-6 glyceryl monooleate (Labrafil M1944 CS), PEG-6 glyceryl linoleate (Labrafil M2125 CS); propylene glycol mono-and di-fatty acid esters such as propylene glycol laurate, propylene glycol caprylate/caprate;700. ascorbyl-6-palmitate, stearylamine, sodium lauryl sulfate, glyceryl triricinoleate, and any combination or mixture thereof; c) anionic surfactants include, but are not limited to, calcium carboxymethylcellulose, carboxymethylSodium cellulose, dioctyl sodium sulfosuccinate, sodium alginate, alkyl polyoxyethylene sulfate, sodium lauryl sulfate, triethanolamine stearate, potassium laurate, bile salts, and any combinations or mixtures thereof; and d) cationic surfactants such as cetyltrimethylammonium bromide and dodecyldimethylbenzyl-ammonium chloride.

In another embodiment, when one or more co-surfactants are used in an otically acceptable formulation of the present invention, the co-surfactant is, for example, combined with a pharmaceutically acceptable vehicle and is present in the final formulation in an amount ranging, for example, from about 0.1% to about 20%, from about 0.5% to about 10%.

In one embodiment, a diluent is also used to stabilize the corticosteroid or other pharmaceutical compound as it provides a more stable environment. Salts dissolved in buffered solutions (which may also provide pH control or maintenance) are used as diluents, including, but not limited to, phosphate buffered saline solutions. In other embodiments, the gel formulation is isotonic with the endolymph or perilymph: depending on the portion of the cochlea targeted for the corticosteroid formulation. The isotonic formulation is provided by the addition of a tonicity agent. Suitable tonicity agents include, but are not limited to, any pharmaceutically acceptable sugar, salt, or any combination or mixture thereof, such as, but not limited to, dextrose and sodium chloride. As described herein, the amount of tonicity agent will depend on the target structure of the pharmaceutical formulation.

Suitable tonicity compositions also include one or more salts in an amount necessary to provide an osmolality of the composition within an acceptable range for perilymph or endolymphatic conditions. The salts include salts having a sodium, potassium or ammonium cation and a chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anion; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

In some embodiments, the otoacceptable gel formulations disclosed herein alternatively or additionally contain a preservative to prevent microbial growth. Suitable otically acceptable preservatives for use in the viscosity enhanced formulations described herein include, but are not limited to, benzoic acid, boric acid, parabens, alcohols, quaternary ammonium compounds, stabilized chlorine dioxide, mercurial agents (such as phenylmercuric nitrate and thimerosal), mixtures of the foregoing, and the like.

In another embodiment, by way of example only, within the otoacceptable formulations presented herein, the preservative is an antimicrobial agent. In one embodiment, the formulation includes preservatives, by way of example only, methylparaben, sodium bisulfite, sodium thiosulfate, ascorbic acid, chlorobutanol, thimerosal, parabens, benzyl alcohol, phenyl ethanol, and the like. In another embodiment, the concentration of methylparaben is from about 0.05% to about 1.0%, from about 0.1% to about 0.2%. In another embodiment, the gel is prepared by mixing water, methyl paraben, hydroxyethyl cellulose and sodium citrate. In another embodiment, the gel is prepared by mixing water, methyl paraben, hydroxyethyl cellulose and sodium acetate. In another embodiment, the mixture is sterilized by autoclaving at 120 ℃ for about 20 minutes and the pH, methylparaben concentration and viscosity are tested prior to mixing with an appropriate amount of the corticosteroid disclosed herein.

Suitable otologically acceptable water soluble preservatives for use in the drug delivery vehicle include sodium bisulfite, sodium thiosulfate, ascorbic acid, chlorobutanol, thimerosal, parabens, benzyl alcohol, Butylated Hydroxytoluene (BHT), phenyl ethanol, and the like. These agents are generally present in an amount of about 0.001% to about 5% by weight, and preferably present in an amount of about 0.01% to about 2% by weight. In some embodiments, the otocompatible formulations described herein are preservative-free.

Round window membrane permeation enhancer

In another embodiment, the formulation further comprises one or more round window membrane permeation enhancers. Permeation through the round window membrane is enhanced by the presence of the round window membrane permeation enhancer. Round (T-shaped)Window membrane permeation enhancers are chemical entities that facilitate the transport of co-administered substances through the round window membrane. Round window membrane permeation enhancers are grouped by chemical structure. Such as sodium lauryl sulfate, sodium laurate, polyoxyethylene-20-cetyl ether, lauryl alcohol-9, sodium dodecyl sulfate, dioctyl sodium sulfosuccinate, polyoxyethylene-9-lauryl ether (PLE),Ionic and nonionic surfactants such as nonylphenoxy polyethylene (NP-POE), polysorbates, and the like are used as the penetration enhancer for round window membranes. Bile salts (such as sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium taurochenofusdate, etc.), fatty acids and derivatives (such as oleic acid, caprylic acid, mono-and diglycerides, lauric acid, acylcholine, caprylic acid, acylcarnitine, sodium caprate, etc.), chelating agents (such as EDTA, citric acid, salicylates, etc.), sulfoxides (such as dimethyl sulfoxide (DMSO), dodecyl methyl sulfoxide, etc.), and alcohols (such as ethanol, isopropanol, glycerol, propylene glycol, etc.) may also be used as round window membrane permeation enhancers.

Round window membrane permeable liposome

Liposomes or lipid particles may also be employed to encapsulate the corticosteroid formulation or composition. Phospholipids dispersed in an aqueous medium are moderated to form multi-layered liposomes in which the regions entrapping the aqueous medium separate the lipid layers. These multilamellar liposomes are sonicated or turbulently agitated to form unilamellar liposomes, often referred to as liposomes, having a size of about 10-1000 nm. These liposomes have many advantages as carriers for corticosteroids or other pharmaceutical agents. It is biologically inert, biodegradable, non-toxic and non-antigenic. The liposomes formed are of various sizes and have different compositions and surface characteristics. In addition, it is capable of entrapping multiple agents and releasing the agents at the site of liposome collapse.

Suitable phospholipids for use herein in an otically acceptable liposome are, for example, phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine, sphingomyelin, cardiolipin, plasmalogen, phosphatidic acid and cerebroside, especially phospholipids that are soluble in non-toxic pharmaceutically acceptable organic solvents with the corticosteroids herein. Preferred phospholipids are e.g. phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, lysophosphatidylcholine, phosphatidylglycerol and the like and mixtures thereof, especially lecithin, e.g. soy lecithin. The amount of phospholipid used in the formulations of the present invention ranges from about 10% to about 30%, preferably from about 15% to about 25%, and especially about 20%.

It is preferred to selectively modify the characteristics of the liposomes with lipophilic additives. Examples of such additives include, by way of example only, stearylamine, phosphatidic acid, tocopherol, cholesterol succinic acid monoester, and lanolin extract. The amount of lipophilic additive used is in the range of 0.5% to 8%, preferably 1.5% to 4%, and especially about 2%. Generally, the ratio of the amount of lipophilic additive to the amount of phospholipid ranges from about 1: 8 to about 1: 12, and is especially about 1: 10. The phospholipids, lipophilic additives and corticosteroids and other pharmaceutical compounds are used in conjunction with a non-toxic pharmaceutically acceptable organic solvent system that solubilizes the ingredients. Not only must the solvent system completely dissolve the corticosteroid, it must also allow the formulation to have stable single bilayer liposomes. The solvent system comprises dimethyl isosorbide (dimethyl isosorbide) and tetraethylene glycol (glycofurol), i.e. glycofurol (tetrahydrofuryl alcohol polyethylene glycol ether), in amounts of about 8% to about 30%. The ratio of the amount of dimethyl isosorbide to the amount of tetraethylene glycol in the solvent system is in the range of about 2: 1 to about 1: 3, specifically about 1: 1 to about 1: 2.5, and preferably about 1: 2. Thus, the amount of tetraethylene glycol in the final composition varies from 5 to 20%, especially 5 to 15%, and preferably is about 10%. Thus, the amount of isosorbide dimethyl ether in the final composition is in the range of 3% to 10%, especially 3% to 7%, and preferably about 5%.

The term "organic component" as used hereinafter refers to a mixture comprising the phospholipid, lipophilic additive and organic solvent. The corticosteroid may be dissolved in the organic component or otherwise to maintain full activity of the agent. The amount of corticosteroid in the final formulation may range from 0.1% to 5.0%. In addition, other ingredients such as antioxidants may be added to the organic component. Examples include tocopherol, butylated hydroxyanisole, butylated hydroxytoluene, ascorbyl palmitate, ascorbyl oleate, and the like.

In other embodiments, the otoacceptable formulations (including gel formulations and viscosity-enhancing formulations) additionally include excipients, other medicinal or pharmaceutical agents, carriers, adjuvants, such as preservatives, stabilizers, wetting or emulsifying agents, dissolution promoters, salts, solubilizers, anti-foaming agents, antioxidants, dispersants, wetting agents, surfactants, and combinations thereof.

Suitable carriers for the otoacceptable formulations described herein include, but are not limited to, any pharmaceutically acceptable solvent that is compatible with the physiological environment of the targeted otic structure. In other embodiments, the substrate is a pharmaceutically acceptable surfactant in combination with a solvent.

In some embodiments, other excipients include sodium stearyl fumarate, diethanolamine cetyl sulfate, isostearate, polyoxyethylated castor oil, nonoxynol 10(nonoxyl 10), octoxynol 9, sodium lauryl sulfate, sorbitan esters (sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitan tristearate, sorbitan laurate, sorbitan oleate, sorbitan palmitate, sorbitan stearate, sorbitan dioleate, sorbitan sesquiisostearate, sorbitan sesquistearate, sorbitan triisostearate), lecithin, pharmaceutically acceptable salts thereof, and combinations or mixtures thereof.

In other embodiments, the carrier is a polysorbate. Polysorbates are nonionic surfactants of sorbitan esters. Suitable polysorbates for use in the present invention include, but are not limited to, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 (tween 80), and any combination or mixture thereof. In other embodiments, polysorbate 80 is utilized as a pharmaceutically acceptable carrier.

In one embodiment, a glycerin-based water soluble otically acceptable viscosity enhancing formulation for use in preparing a pharmaceutical delivery vehicle comprises at least one corticosteroid containing at least about 0.1% water soluble glycerin compounds or more. In some embodiments, the percentage of corticosteroid varies between about 1% and about 95%, between about 5% and about 80%, between about 10% and about 60%, or more, by weight or volume of the total pharmaceutical formulation. In some embodiments, the amount of compound in each therapeutically useful corticosteroid formulation is prepared such that a suitable dose will be obtained within any given unit dose of the compound. Factors such as solubility, bioavailability, biological half-life, route of administration, product shelf life, and other pharmacological considerations are contemplated herein.

The otically acceptable pharmaceutical gel also contains a co-solvent and a buffer, if necessary. Suitable otically acceptable water soluble buffers are alkali or alkaline earth metal carbonates, phosphates, bicarbonates, citrates, borates, acetates, succinates and the like, such as sodium phosphate, sodium citrate, sodium borate, sodium acetate, sodium bicarbonate, sodium carbonate and Tromethamine (TRIS). These agents are present in an amount sufficient to maintain the pH of the system at 7.4 ± 0.2 and preferably at 7.4. Thus, the buffer is up to 5% by weight of the total composition.

Cosolvents are used to enhance the solubility of corticosteroids, however, some corticosteroids or other pharmaceutical compounds are not soluble. They are typically suspended in a polymeric vehicle with the aid of suitable suspending or viscosity enhancing agents.

In addition, some pharmaceutical excipients, diluents or carriers may be ototoxic. For example, benzalkonium chloride, a common preservative, is ototoxic and thus may be harmful if introduced into the vestibule or cochlear structures. In formulating controlled release corticosteroid formulations, it is advisable to avoid or combine appropriate excipients, diluents or carriers to reduce or eliminate possible ototoxic components from the formulation or to reduce the amount of such excipients, diluents or carriers. The controlled release corticosteroid formulation optionally includes an otoprotectant such as an antioxidant, alpha lipoic acid, calcium, fosfomycin, or an iron chelator to counteract possible ototoxic effects that may result from the use of a particular therapeutic agent or excipient, diluent, or carrier.

Mode of treatment

Method and schedule of administration

Drugs delivered to the inner ear have been administered systemically by oral, intravenous or intramuscular routes. However, systemic administration for local pathologies in the inner ear increases the likelihood of systemic toxicity and adverse side effects, and produces a non-productive distribution of drug in which high levels of drug are seen in the serum and correspondingly lower levels are seen in the inner ear.

Intratympanic injection of a therapeutic agent is a technique in which the therapeutic agent is injected into the middle and/or inner ear behind the tympanic membrane. In one embodiment, the formulations described herein are administered directly onto the round window membrane via tympanogram. In another embodiment, the otoacceptable corticosteroid formulation described herein is administered onto the round window membrane via a non-transtympanic route to the inner ear. In other embodiments, the formulations described herein are administered onto the round window membrane via a surgical route to the round window membrane, including modifying the cochlear ridge.

In one embodiment, the delivery system is a syringe and needle device capable of piercing the tympanic membrane and reaching directly to the round window membrane or the cochlear crest of the inner ear. In some embodiments, the needle on the syringe is wider than the 18 gauge needle. In another embodiment, the needles are 18 gauge to 31 gauge. In another embodiment, the needles are 25 gauge to 30 gauge. Depending on the consistency or viscosity of the corticosteroid composition or formulation, the needle size of the syringe or hypodermic needle may vary accordingly.

In another embodiment, the needle is a hypodermic needle for immediate delivery of the gel formulation. Hypodermic needles may be single use needles or disposable needles. In some embodiments, a syringe may be used to deliver a pharmaceutically acceptable gel-based corticosteroid-containing composition as disclosed herein, wherein the syringe has a press-fit (Luer) or screw-on (Luer-lock) fitting. In one embodiment, the syringe is a hypodermic syringe. In another embodiment, the syringe is made of plastic or glass. In yet another embodiment, the hypodermic syringe is a single use syringe. In another embodiment, the glass syringe is capable of being sterilized. In yet another embodiment, sterilization is performed using an autoclave. In another embodiment, the syringe comprises a cylindrical syringe body in which the gel formulation is stored prior to use. In other embodiments, the syringe comprises a cylindrical syringe body in which a gel-based pharmaceutically acceptable corticosteroid composition as disclosed herein is stored prior to use, which allows for convenient mixing with a suitable pharmaceutically acceptable buffer. In other embodiments, the syringe may contain other excipients, stabilizers, suspending agents, diluents, or combinations thereof to stabilize or otherwise stably store the corticosteroid or other pharmaceutical compound contained therein.

In some embodiments, the syringe comprises a cylindrical syringe body, wherein the body is compartmentalized, each compartment capable of storing at least one component of an otically acceptable corticosteroid gel formulation. In another embodiment, a syringe with a compartmentalized body allows for mixing of the components prior to injection into the middle or inner ear. In other embodiments, the delivery system comprises a plurality of syringes, each syringe of the plurality of syringes containing at least one component of the gel formulation such that the components are pre-mixed prior to injection or mixed after injection. In another embodiment, the syringe disclosed herein comprises at least one reservoir, wherein the at least one reservoir comprises a corticosteroid or a pharmaceutically acceptable buffer or a viscosity enhancing agent (such as a gelling agent), or a combination thereof. Intratympanic injection is optionally performed using commercially available injection devices in their simplest form, such as a ready-to-use plastic syringe having a syringe barrel, a needle-containing needle assembly, a plunger with a plunger stem, and a mounting flange.

In some embodiments, the delivery device is a device designed for administration of a therapeutic agent to the middle and/or inner ear. By way of example only, Jiale medicine Gmbh (GYRUS Medical Gmbh) provides a micro-otoscope (micro-otoscope) that observes and delivers drugs to the round window niche; medical treatment devices for delivering fluid to inner ear structures have been described in U.S. patent nos. 5,421,818, 5,474,529, and 5,476,446 to Arenberg (Arenberg), each of which is incorporated herein by reference for the disclosure. U.S. patent application No. 08/874,208 (incorporated herein by reference with respect to the disclosure) describes a surgical method of implanting a fluid transfer catheter to deliver a therapeutic agent to the inner ear. U.S. patent application publication 2007/0167918 (incorporated herein by reference with respect to the disclosure) additionally describes a combined ear aspirator and drug dispenser for intratympanic fluid sampling and medicament administration.

The formulations and modes of administration thereof described herein are also suitable for use in methods of direct instillation or perfusion of the inner ear compartment. Thus, the formulations described herein are suitable for use in surgical procedures, including, by way of non-limiting example, cochlear incisions, labyrinotomies, mastoidectomies, stapedectomy, endolymphatic sacculotomy, and the like.

An otically acceptable composition or formulation containing a corticosteroid compound described herein can be administered for prophylactic and/or therapeutic treatment. In therapeutic applications, a corticosteroid composition is administered to a patient already suffering from an autoimmune disease, disorder, or condition in an amount sufficient to cure or at least partially arrest the symptoms of the disease, disorder, or condition. The amount effective for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drug, and the judgment of the treating physician.

In the event that the condition of the patient is not improved, the corticosteroid compound administration can be administered for an extended period of time, i.e., for an extended period of time, including the entire life span of the patient, at the discretion of the physician, to improve or otherwise control or limit the symptoms of the disease or condition in the patient.

In the case of an improvement in the patient's condition, the corticosteroid compound administration may be continued, based on the judgment of the physician; alternatively, the dose of drug administered may be temporarily reduced or temporarily suspended for a certain period of time (i.e., "drug holiday"). The length of the drug holiday varies from 2 days to 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, and 365 days. During a drug holiday, the dose reduction may be 10% -100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

Once the autoimmune condition of the patient is improved, a maintenance corticosteroid dose is administered as necessary. Then, optionally, the dosage or frequency of administration, or both, is reduced according to symptoms to a level that maintains an improvement in the disease, disorder, or condition. In certain embodiments, the patient is in need of chronic intermittent therapy after any recurrence of symptoms.

The amount of corticosteroid corresponding to this amount will vary depending on the following factors: such as the particular compound, the disease condition and its severity, the particular circumstances of case-related including, for example, the particular corticosteroid administered, the route of administration, the autoimmune condition being treated, the target area being treated, and the individual or host being treated. In general, however, the dosage for treatment of an adult human will generally be in the range of 0.02-50mg per administration, preferably 1-15mg per administration. The desired dose is provided in a single dose or in divided doses administered simultaneously (or over a short period of time) or at appropriate intervals.

In some embodiments, the initial administration is of a particular corticosteroid and the subsequent administration is of a different formulation or corticosteroid.

Pharmacokinetics of controlled release formulations

In one embodiment, the formulations disclosed herein additionally provide for immediate release of the corticosteroid from the formulation, or within 1 minute, or within 5 minutes, or within 10 minutes, or within 15 minutes, or within 30 minutes, or within 60 minutes, or within 90 minutes. In other embodiments, the therapeutically effective amount of the at least one corticosteroid is released from the formulation immediately, or within 1 minute, or within 5 minutes, or within 10 minutes, or within 15 minutes, or within 30 minutes, or within 60 minutes, or within 90 minutes. In certain embodiments, the formulation comprises an otic pharmaceutically acceptable gel formulation that provides immediate release of at least one corticosteroid. Other embodiments of the formulations may also include agents that enhance the viscosity of the formulations included herein.

In other or additional embodiments, the formulation provides an extended release formulation of at least one corticosteroid. In certain embodiments, the diffusion of the at least one corticosteroid from the formulation continues for a period of time greater than 5 minutes, or 15 minutes, or 30 minutes, or 1 hour, or 4 hours, or 6 hours, or 12 hours, or 18 hours, or 1 day, or 2 days, or 3 days, or 4 days, or 5 days, or 6 days, or 7 days, or 10 days, or 12 days, or 14 days, or 18 days, or 21 days, or 25 days, or 30 days, or 45 days, or 2 months, or 3 months, or 4 months, or 5 months, or 6 months, or 9 months, or 1 year. In other embodiments, the therapeutically effective amount of the at least one corticosteroid is released from the formulation for a duration of time that exceeds 5 minutes, or 15 minutes, or 30 minutes, or 1 hour, or 4 hours, or 6 hours, or 12 hours, or 18 hours, or 1 day, or 2 days, or 3 days, or 4 days, or 5 days, or 6 days, or 7 days, or 10 days, or 12 days, or 14 days, or 18 days, or 21 days, or 25 days, or 30 days, or 45 days, or 2 months, or 3 months, or 4 months, or 5 months, or 6 months, or 9 months, or 1 year.

In other embodiments, the formulation provides immediate release and extended release formulations of corticosteroids. In still other embodiments, the formulation contains an immediate release and an extended release formulation in a ratio of 0.25: 1, or a ratio of 0.5: 1, or a ratio of 1: 2, or a ratio of 1: 3, or a ratio of 1: 4, or a ratio of 1: 5, or a ratio of 1: 7, or a ratio of 1: 10, or a ratio of 1: 15, or a ratio of 1: 20. In another embodiment, the formulation provides immediate release of the first corticosteroid and extended release of the second corticosteroid or other therapeutic agent. In yet other embodiments, the formulation provides immediate release and extended release formulations of at least one corticosteroid and at least one therapeutic agent. In some embodiments, the formulation provides an immediate release formulation and an extended release formulation of the first corticosteroid and the second therapeutic agent in a ratio of 0.25: 1, or a ratio of 0.5: 1, or a ratio of 1: 2, or a ratio of 1: 3, or a ratio of 1: 4, or a ratio of 1: 5, or a ratio of 1: 7, or a ratio of 1: 10, or a ratio of 1: 15, or a ratio of 1: 20, respectively.

In one embodiment, the formulation provides a therapeutically effective amount of at least one corticosteroid at the site of disease, substantially without systemic exposure. In another embodiment, the formulation provides a therapeutically effective amount of at least one corticosteroid at the site of disease, with substantially no detectable systemic exposure. In other embodiments, the formulation provides a therapeutically effective amount of at least one corticosteroid at the site of disease with little or no detectable systemic exposure.

Combinations of immediate release, delayed release and/or extended release corticosteroid compositions or formulations may be combined with other pharmaceutical agents as well as excipients, diluents, stabilizers, tonicity agents and other components disclosed herein. Thus, depending on the corticosteroid used, the desired consistency or viscosity, or the selected mode of delivery, alternative aspects of the embodiments disclosed herein are combined with immediate release, delayed release, and/or extended release embodiments, respectively.

In certain embodiments, the pharmacokinetics of the corticosteroid formulations described herein are determined by injecting the formulation onto or near the round window membrane of a test animal (including, for example, guinea pigs or chinchillas). The test animals were euthanized and tested for 5mL perilymph fluid samples over a defined period (e.g., 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, and 7 days for testing the pharmacokinetics of the formulation over a 1 week period). The inner ear was removed and tested for the presence of corticosteroids. If necessary, the content of corticosteroid in other organs was measured. In addition, systemic levels of corticosteroids are measured by drawing blood samples from test animals. To determine whether the formulation impedes hearing, the test animal is optionally tested for hearing.

Alternatively, the inner ear is provided (removed from the test animal) and the migration of the corticosteroid is measured. As a further alternative, an in vitro model of the round window membrane is provided and the migration of corticosteroids is measured.

Kit/article of manufacture

Kits for preventing, treating, or ameliorating symptoms of a disease or disorder in a mammal are also provided. Such kits will generally comprise one or more corticosteroid controlled release compositions or devices disclosed herein and instructions for use of the kit. Also encompassed by the present disclosure is the use of one or more corticosteroid controlled release compositions for the manufacture of a medicament for treating, reducing or ameliorating a disease, dysfunction or symptom of a disorder in a mammal, such as a human, having, suspected of having or at risk of developing an inner ear disorder.

In some embodiments, the kit comprises a carrier, package, or container divided to hold one or more containers, such as vials, tubes, and the like, each comprising one of the individual elements used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In other embodiments, the container is formed from a variety of materials, such as glass or plastic.

The articles provided herein contain packaging materials. Also provided herein are packaging materials for packaging pharmaceutical products. See, for example, U.S. patent nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected formulation and predetermined mode of administration and treatment. The various corticosteroid formulation compositions provided herein are contemplated as various treatments for any disease, disorder or condition for which controlled release of a corticosteroid can be by administration into the inner ear.

In some embodiments, from the standpoint of commercial and user use of the formulations described herein, it is desirable for the kit to include one or more additional containers, each having one or more of a variety of materials (such as reagents, and/or devices, optionally in concentrated form). Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube label for listing contents and/or

Examples of the invention

Example 1-preparation of a thermoreversible gel dexamethasone formulation or device

Composition (I)	Amount (milligrams per gram of formulation)
		Dexamethasone	20.0
P-hydroxybenzoic acid methyl ester	1.0
		HPMC	10.0
Poloxamer 407	180.0
		TRIS HCl buffer (0.1M)	789.0

A 10g batch of gel formulation containing 2.0% dexamethasone was prepared by suspending 1.80g poloxamer 407 (BASF Corp.)) in 5.00g TRIS HCl buffer (0.1M) and mixing the components with stirring overnight at 4 ℃ to ensure complete dissolution. Dexamethasone (200.0mg), hydroxypropyl methylcellulose (100.0mg), methylparaben (10mg), and additional TRIS HCl buffer (0.1M) (2.89g) were added and stirred further until complete dissolution was observed. The mixture was maintained below room temperature until use.

Example 2-preparation of Mucosa-adhesive thermoreversible gel prednisolone formulation or device

Composition (I)	Amount (milligrams per gram of formulation)
		PrednisoneDragon with water storage device	30
P-hydroxybenzoic acid methyl ester	1.0
		HPMC	10.0
Carbopol 934P	2.0
		Poloxamer 407	180.0
TRIS HCl buffer (0.1M)	787.0

A 10g batch of mucoadhesive gel formulation containing 2.0% prednisolone was prepared by suspending 2.0mg carbopol 934P and 1.80g poloxamer 407 (BASF Corp.)) in 5.00g TRIS HCl buffer (0.1M), and mixing the components with stirring at 4 ℃ overnight to ensure complete dissolution. Prednisolone, hydroxypropyl methylcellulose (100.0mg), methylparaben (10mg), and additional TRIS HCl buffer (0.1M) (2.87g) were added and stirred further until complete dissolution was observed. The mixture was maintained below room temperature until use.

Example 3-preparation of Cyclodextrin-containing thermoreversible gel 2.5% dexamethasone formulation or device

Composition (I)	Amount (milligrams per gram of formulation)
		5% CD solution	500.0
P-hydroxybenzoic acid methyl ester	1.0
		Poloxamer 407	180.0
TRIS HCl buffer (0.1M)	317.0

Poloxamer 407 (BASF Corp.) was suspended in TRIS HCl buffer (0.1M) and the components were mixed overnight with stirring at 4 ℃ to ensure complete dissolution. The cyclodextrin solution and methylparaben were added and further stirred until complete dissolution was observed. The mixture was maintained below room temperature until use.

EXAMPLE 4 preparation of Cyclodextrin-containing mucoadhesive thermoreversible gel dexamethasone formulation or device

Composition (I)	Amount (milligrams per gram of formulation)
		5% CD solution	500.0
P-hydroxybenzoic acid methyl ester	1.0
		Poloxamer 407	180.0

Carbopol 934P	2.0
		TRIS HCl buffer (0.1M)	317.0

Carbopol 934P and poloxamer 407 (BASF Corp.)) were suspended in TRIS HCl buffer (0.1M) and the components were mixed with stirring overnight at 4 ℃ to ensure complete dissolution. The cyclodextrin solution and methylparaben were added and further stirred until complete dissolution was observed. The mixture was maintained below room temperature until use.

Example 5-preparation of a thermoreversible gel dexamethasone formulation or device containing micron-sized dexamethasone powder

Composition (I)	Amount (milligrams per gram of formulation)
		Dexamethasone	20.0
BHT	0.002
		Poloxamer 407	160.0
PBS buffer (0.1M)	9.0

A10 g batch of gel formulation containing 2.0% micron-sized dexamethasone, 13.8mg disodium phosphate dihydrate USP (Fisher Scientific.) +3.1mg monobasic sodium phosphate monohydrate USP (Fisher Scientific.) +74mg sodium chloride USP (Fisher Scientific.)) was dissolved with 8.2g sterile-filtered deionized water and the pH adjusted to 7.4 with 1M NaOH. The buffer solution was cooled and, with mixing, 1.6g of poloxamer 407 (BASF Corp.) containing about 100ppm BHT was sprinkled into the cooled PBS solution, mixing the solution until all poloxamer was dissolved. Poloxamer was sterile filtered using a 33mm PVDF 0.22 μm sterile syringe filter (Millipore Corp.) and transferred under sterile conditions into a 2mL sterile glass vial (Wheaton), the vial was closed with a sterile butyl rubber stopper (Kimble) and sealed with a 13mm aluminum seal (Kimble). 20mg of micron-sized dexamethasone (Spectrum chemicals) was placed in respective clean depyrogen vials, the vials were closed with sterile butyl rubber stoppers (Kimbles) and sealed with 13mm aluminum seals (Kimbles), and the vials were dry-heat sterilized (Feishel Scientific Isotemp oven) at 140 ℃ for 7 hours prior to administration for the experiments described herein using 1mL of a cold poloxamer solution connected to a 21-needle (Becton Dickinson) of a 1mL sterile syringe (Becton Dickinson), the suspension was thoroughly mixed by shaking to ensure homogeneity of the suspension, then the suspension was withdrawn with the 21-needle and the administration was changed to the 27-needle.

Example 6-preparation of thermoreversible gel micron-sized prednisone formulation or device containing permeation enhancer

Composition (I)	Amount (milligrams per gram of formulation)
		Prednisone	20.0
P-hydroxybenzoic acid methyl ester	1.0
		Dodecyl maltoside (A3)	1.0
HPMC	10.0
		Poloxamer 407	180.0
TRIS HCl buffer (0.1M)	789.0

A 10g batch of gel formulation containing 2.0% micron-sized prednisone was prepared by suspending 1.80g poloxamer 407 (BASF Corp.)) in 5.00g TRIS HCl buffer (0.1M) and mixing the components with stirring overnight at 4 ℃ to ensure complete dissolution. Prednisone (200.0mg), hydroxypropyl methylcellulose (100.0mg), methylparaben (10mg), and dodecyl maltoside (10mg) and additional TRISHCl buffer (0.1M) (2.89g) were added and stirred further until complete dissolution was observed. The mixture was maintained below room temperature until use.

Example 7-pH vs. autoclaved 17% Poloxamer 407 NF/2% dexamethasone phosphate (DSP) Effect of degradation products of PBS buffer

Stock solutions of 17% poloxamer 407/2% dexamethasone phosphate (DSP) were prepared by dissolving 351.4mg sodium chloride (Fisher Scientific), 302.1mg disodium phosphate anhydrous (Fisher Scientific), 122.1mg monosodium phosphate anhydrous (Fisher Scientific), and 2.062g dexamethasone phosphate (DSP) in 79.3g sterile filtered deionized water. The solution was cooled in an ice-cold water bath and then 17.05g of poloxamer 407NF (spectrummichemials) was sprinkled into the cold solution with mixing. The mixture was further mixed until the poloxamer was completely dissolved. The pH of this solution was measured.

PBS containing 17% poloxamer 407/2% dexamethasone phosphate (DSP), pH 5.3.

An aliquot of the above solution (about 30mL) was taken and the pH adjusted to 5.3 by the addition of 1M HCl.

PBS containing 17% poloxamer 407/2% dexamethasone phosphate (DSP), pH 8.0.

An aliquot (about 30mL) of the above stock solution was taken and the pH adjusted to 8.0 by the addition of 1M NaOH.

PBS buffer (pH 7.3) was prepared by dissolving 805.5mg of sodium chloride (Fisher Scientific), 606mg of anhydrous disodium phosphate (Fisher Scientific), 247mg of anhydrous monosodium phosphate (Fisher Scientific) in sterile filtered deionized water, and then making up to 200 g.

A2% solution of dexamethasone phosphate (DSP) in PBS (pH 7.3) was prepared by dissolving 206mg of dexamethasone phosphate (DSP) in PBS buffer and making up to 10g with PBS buffer.

1mL of the sample was individually placed in a 3mL screw-top glass vial (with rubber liner) and tightly closed. The vials were placed in a mackofoger (mark form) stereomatic autoclave (ambient, slow liquid) and sterilized at 250 ° F for 15 minutes. After autoclaving, the samples were cooled to room temperature and then placed in a refrigerator. The vials were mixed while cold and the samples were homogenized.

The appearance (e.g., discoloration and/or precipitation) was observed and recorded. PBS with 2% DSP alone showed discoloration (yellowish) and some precipitation, while the samples containing poloxamer showed no signs of discoloration. Precipitation was observed only for samples containing poloxamer, pH 5.3.

Using a solution equipped with Luna C18(2)3 μm,250X 4.6mm column) was subjected to HPLC analysis using a 30-80 acetonitrile gradient (1-10min) (water-acetonitrile mixture with 0.05% TFA) for a total operating time of 15 minutes. The main peaks are recorded in the table below. Samples were diluted by taking 30. mu.L of sample and dissolving with 1.5mL of a 1: 1 mixture of acetonitrile in water. The purity of the sample was consistently greater than 99% prior to autoclaving.

TABLE 1 Properties observed after autoclaving for samples containing Dexamethasone Sodium Phosphate (DSP)

All samples had a purity of 99 +%, prior to autoclaving.

Example 8-autoclaving of PBS containing 17% Poloxamer 407 NF/2% Phospholase Dexamethasone (DSP) Effect of Release Profile and viscosity

Aliquots of the samples of example 6 (autoclaved and non-autoclaved) were evaluated for release profile and viscosity measurements to assess the effect of heat sterilization on gel properties.

Dissolution was carried out in a snapwell (polycarbonate membrane of diameter 6.5mm with a pore size of 0.4 μm) at 37 ℃. 0.2mL of the gel was placed in a snapwell and allowed to harden, then 0.5mL was placed in a reservoir and shaken at 70rpm using a Yorlebo (Labline) orbital shaker. Samples were taken every hour (0.1 mL was withdrawn and replaced with warm buffer). Samples were analyzed for poloxamer concentration using UV at 624nm using the cobalt thiocyanate method against an external calibration standard curve. Briefly, 20. mu.L of the sample was mixed with 1980. mu.L of a 15mM cobalt thiocyanate solution and the absorbance was measured at 625nm using an Evolution 160UV/Vis spectrophotometer (Thermo Scientific).

Fitting the released dexamethasone phosphate (DSP) to the Cosmeier-Peppas equation (Korsmeyer-Peppasequo)

Wherein Q is the amount of otic agent released over time t, Q_aIs the total release of the otic agent, k is the release constant n times, n is a dimensionless number associated with the dissolution mechanism and b is the axis intercept, characterizing the release mechanism of the initial burst, where n ═ 1 characterizes the erosion control mechanism. The Mean Dissolution Time (MDT) is the sum of the drug molecules remaining in the matrix before release over different time periods divided by the total number of molecules and is calculated as follows:

The viscosity measurement was carried out using a temperature control unit equipped with a water jacket (temperature rise from 15 ℃ C. to 34 ℃ C. at 1.6 ℃ C./min) with a shear rate of 0.08rpm (0.31 s/shear rate)^-1) Brookfield viscometer (Brookfield viscometer) RVDV-II + P with a lower rotating CPE-51 spindle. Tgel is defined as the inflection point of the curve where the viscosity increase occurs due to the sol-gel transition.

TABLE 2 Effect of autoclaving on the Release Profile and viscosity of PBS containing 17% Poloxamer 407 NF/2% Dexamethasone Sodium Phosphate (DSP)

	MDT(hr)	T gel (. degree.C.)	Maximum viscosity (Pas)
				Not autoclaved	3.2	25	403
Autoclaving	3.2	26	341

*0.31s^-1Maximum apparent viscosity in gel state (up to 37 ℃) at shear rate

The results show that after autoclaving PBS containing 17% poloxamer 407 NF/2% Dexamethasone Sodium Phosphate (DSP), there is little effect on viscosity and release profile.

Example 9-addition of second Polymer to a solution containing 2% dexamethasone phosphate (DSP) and 17% Poloxamer 407NF Degradation products and effects of viscosity of the formulation after Heat Sterilization (autoclaving)

Solution A: a solution containing sodium carboxymethylcellulose (CMC) in PBS buffer (pH 7.0) was prepared by dissolving 178.35mg sodium chloride (Fisher Scientific), 300.5mg disodium phosphate anhydrous (Fisher Scientific), 126.6mg monosodium phosphate anhydrous (Fisher Scientific) in 78.4 sterile filtered deionized water, then sprinkling 1g Blanose 7M65 CMC (Hercules, 2% viscosity 5450cP) into the buffer solution and heating to aid dissolution, then cooling the solution.

A solution (pH 7.0) containing 17% poloxamer 407 NF/1% CMC/2% Dexamethasone Sodium Phosphate (DSP) in PBS buffer was prepared by cooling 8.1g of solution A in an ice-cold water bath, then adding 205mg Dexamethasone Sodium Phosphate (DSP), followed by mixing. With mixing, 1.74g of poloxamer 407NF (Spectrum Chemicals) was sprinkled into the cold solution. The mixture was further mixed until all poloxamer was completely dissolved.

2mL of the above sample was placed in a 3mL screw-top glass vial (with rubber liner) and tightly closed. The vials were placed in a mackofoger (mark form) stereomatic autoclave (ambient, slow liquid) and sterilized at 250 ° F for 25 minutes. After autoclaving, the samples were cooled to room temperature and then placed in a refrigerator. The vials were mixed while still cold and the samples were homogenized.

No precipitation or discoloration was observed after the autoclaving treatment. HPLC analysis was performed as described in example 6. Less than 1% degradation products were detected due to hydrolysis of the dexamethasone product, i.e., the formulation was stable to autoclaving.

Viscosity measurements were performed as described in example 7. The results show that the autoclaving treatment has little effect on the gel viscosity or tgel temperature. Less total impurities were observed in the poloxamer-containing formulations compared to the control sample (PBS with 2% DSP).

Dissolution testing was performed as described in example 7. The results show an MDT of 11.9hr compared to 3.2hr for the formulation without CMC. The addition of CMC or a second polymer introduces a diffusion barrier that reduces the rate of dexamethasone release (i.e., increases MDT).

Example 10 buffer type Heat Sterilization (autoclaving) of formulations containing Poloxamer 407NF Influence of later degradation products

TRIS buffer was prepared by dissolving 377.8mg of sodium chloride (Fisher Scientific) and 602.9mg of tromethamine (Sigma Chemical Co.) in sterile filtered deionized water, then made up to 100g, and the pH was adjusted to 7.4 with 1M HCl.

Stock solution of TRIS buffer solution containing 25% poloxamer 407:

45g of TRIS buffer was weighed, cooled in an ice-cold bath, and 15g of poloxamer 407NF (Spectrum Chemicals) was sprinkled into the buffer with mixing. The mixture was further mixed until all poloxamer was completely dissolved. Stock solution of PBS buffer solution containing 25% poloxamer 407 (pH 7.3):

704mg of sodium chloride (Fisher Scientific), 601.2mg of anhydrous disodium phosphate (Fisher Scientific), 242.7mg of anhydrous monosodium phosphate (Fisher Scientific) were dissolved in 140.4g of sterile filtered deionized water. The solution was cooled in an ice-cold water bath and then 50g of poloxamer 407NF (spectra CHEMICALS) was sprinkled into the cold solution with mixing. The mixture was further mixed until the poloxamer was completely dissolved and a clear translucent solution was obtained. The pH of this solution was found to be 7.3.

A series of formulations were prepared from the stock solutions described above. All experiments used dexamethasone phosphate (DSP) and micron-sized dexamethasone USP from stoichiomethyl chemicals.

1mL of the sample was individually placed in a 3mL screw-top glass vial (with rubber liner) and tightly closed. The vials were placed in a mackofoger (mark form) stereomatic autoclave (ambient, slow liquid) and sterilized at 250 ° F for 25 minutes. After autoclaving, the samples were cooled to room temperature. The vials were placed in a refrigerator and mixed while cold to homogenize the samples.

HPLC analysis was performed as described in example 6. The stability of the formulations was compared in TRIS buffer and PBS buffer.

TABLE 3 Effect of buffer type on degradation of formulations containing dexamethasone and dexamethasone phosphate

Viscosity measurements were performed as described in example 7.

The results show that to reduce hydrolysis during autoclaving, the buffer needs to maintain a pH in the range 7-8 at elevated temperatures. More drug hydrolysis was observed in TRIS buffer than in PBS (table 3). By using the polymer additives described in this application (e.g., P407), the occurrence of other degradation products is reduced. A reduction in degradation products was observed in the formulation containing 20% poloxamer 407 compared to the formulation without poloxamer 407 (table 7).

Formulations containing suspended micron-sized dexamethasone were more stable than their solution counterparts after autoclaving.

Example 11: pulsatile release otic formulations

Pulsed release formulations were prepared using a combination of dexamethasone and Dexamethasone Sodium Phosphate (DSP) in a 1: 1 ratio using the procedure described herein. A deliverable dose of dexamethasone was dissolved in the 17% poloxamer solution of example 7 with the help of beta-cyclodextrin. The remaining 80% of deliverable dexamethasone was then added to the mixture, and the final formulation was prepared using any of the procedures described herein.

Pulsed release formulations comprising dexamethasone were prepared according to the procedures and examples described herein and tested using the procedures described herein to determine the pulsed release profile.

Example 12: preparation of a composition containing 17% Poloxamer 407/2% DSP/78pPm Evans blue PBS

Stock solutions of evans blue (5.9mg/mL) in PBS buffer were prepared by dissolving 5.9mg of evans blue (Sigma Chemical Co) with 1mL of PBS buffer (from example 61).

A stock solution of the 25% poloxamer 407 containing PBS buffer solution of example 8 was used in this study. To the stock solution of example 8, an appropriate amount of DSP was added to prepare a formulation comprising 2% DSP (table 4).

Table 4 this study used a stock solution of the 25% poloxamer 407 containing PBS buffer solution of example 9.

The middle ear of guinea pigs was administered the above formulations by the procedures described herein and the ability of the formulations to gel after contact, and the location of the gel was identified after administration and 24 hours after administration.

Example 13: terminal sterilization of poloxamer 407 formulations with and without a visualizing dye

17% poloxamer 407/2% DSP/phosphate buffer, pH 7.3:709mg of sodium chloride (Fisher Scientific), 742mg of disodium phosphate dehydrate USP (Fisher Scientific), 251.1mg of monosodium phosphate monohydrate USP (Fisher Scientific) and the appropriate amount of DSP were dissolved in 158.1g of sterile filtered deionized water. The solution was cooled in an ice-cold water bath and then 34.13g of poloxamer 407NF (spectra chemicals) was sprinkled into the cold solution with mixing. The mixture was further mixed until the poloxamer was completely dissolved and a clear translucent solution was obtained. The pH of this solution was 7.3.

Phosphate buffer containing 17% poloxamer 407/2% DSP/59ppm evans blue:2mL of 17% Poloxamer 407/2% DSP/phosphate buffer was taken and 2mL of 5.9mg/mL Evans blue (Sigma-Aldrich chemical Co.) in PBS buffer was added.

25% poloxamer 407/2% DSP/phosphate buffer:330.5mg of sodium chloride (Fisher Scientific), 334.5mg of disodium phosphate dihydrate USP (Fisher Scientific), 125.9mg of monosodium phosphate monohydrate USP (Fisher Scientific) and 2.01g of dexamethasone sodium phosphate USP (Spectrum Chemicals) were dissolved in 70.5g of sterile filtered deionized water.

The solution was cooled in an ice-cold water bath and then 25.1g of poloxamer 407NF (spectra chemicals) was sprinkled into the cold solution with mixing. The mixture was further mixed until the poloxamer was completely dissolved and a clear translucent solution was obtained. The pH of this solution was 7.3.

Phosphate buffer containing 25% poloxamer 407/2% DSP/59ppm evans blue:2mL 25% Poloxamer 407/2% DSP/phosphate buffer was taken and 2mL 5.9mg/mL Evans blue (Sigma-Aldrich chemical Co.) in PBS buffer was added.

2mL of the formulation was placed in a 2mL glass vial (Wheaton serum glass vial) and sealed with 13mm butyl styrene (Kimbel stopper) and sealed with 13mm aluminum seal. The vials were placed in a mackofoger (mark form) stereomatic autoclave (ambient, slow liquid) and sterilized at 250 ° F for 25 minutes. After autoclaving, the samples were cooled to room temperature and then frozen for storage. The vials were placed in a refrigerator and mixed while cold to homogenize the samples. The discoloration or precipitation of the samples after the autoclaving treatment was recorded.

HPLC analysis was performed as described in example 6.

TABLE 5 Effect of autoclaving on the purity of dexamethasone sodium phosphate-containing formulations with and without the dye observed

Viscosity measurements were performed as described in example 7. The results show that autoclaving the formulation containing the visualizing dye does not affect the degradation products and the viscosity of the formulation.

The average dissolution time for the 25% poloxamer 407 formulation (the amount of dexamethasone phosphate released was measured using UV at 245nm, determined as described in example 7) was measured to be 5.6hr, and the 17% poloxamer 407 formulation showed 3.2 hr.

Example 14: in vitro comparison of Release profiles

Dissolution was performed in a snapwell (6.5 mm diameter polycarbonate membrane with a pore size of 0.4 μm) at 37 ℃, 0.2mL of the gel formulation described herein was placed in the snapwell and allowed to harden, then 0.5mL of buffer was placed in a reservoir and shaken at 70rpm using a ulibo (Labline) orbital shaker. Samples were taken every hour (0.1 mL was withdrawn and replaced with warm buffer). The samples were analyzed for dexamethasone concentration using a 245nm UV vs. external calibration standard curve. Polonik concentration was analyzed using cobalt thiocyanate method at 624 nm. The relative rank order of Mean Dissolution Time (MDT) as a function of% P407 was determined. A linear relationship between the Mean Dissolution Time (MDT) of the formulation and the P407 concentration indicates that dexamethasone was released due to polymer gel (poloxamer) erosion, rather than via diffusion. The non-linear relationship indicates a combined release of dexamethasone via diffusion and/or polymer gel degradation.

Alternatively, the use of the article of lie new (Li Xin-Yu) paper [ pharmaceutical science (Acta pharmaceutical Sinica)2008, 43 (2): 208-.

Figure 1 illustrates the in vitro release profile of dexamethasone formulations with different concentrations of poloxamer 407. FIG. 2 illustrates the approximately linear relationship (1: 1 correlation) between Mean Dissolution Time (MDT) and P407 concentration for the formulations. The results indicated that dexamethasone was released due to polymer gel (poloxamer) erosion, rather than via diffusion.

Example 15: in vitro comparison of gelation temperature

The effect of poloxamer 188 and dexamethasone on the gelling temperature and viscosity of poloxamer 407 formulations was evaluated for the purpose of manipulating the gelling temperature.

A stock solution of 25% poloxamer 407 in PBS buffer (example 9) and the PBS solution of example 6 were used. Poloxamer 188NF from BASF (BASF) was used.

TABLE 6 preparation of samples containing Poloxamer 407/Poloxamer 188

Sample (I)	25% P407 stock solution (g)	Poloxamer 188(mg)	PBS buffer (g)
				16％P407/10％P188	3.207	501	1.3036
17％P407/10％P188	3.4089	500	1.1056
				18％P407/10％P188	3.6156	502	0.9072
19％P407/10％P188	3.8183	500	0.7050
				20％P407/10％P188	4.008	501	0.5032
20％P407/5％P188	4.01	256	0.770

The average dissolution time (method described in example 7) for 20% poloxamer 407/10% poloxamer 188 was measured to be 2.2hr, while 20% poloxamer 407/5% poloxamer 188 was shown to be 2.6 hr. The viscosity was determined using the procedure described in example 7. Autoclaving did not affect the viscosity or tgel of the formulations containing poloxamer 188.

The data obtained were fit to an equation and this equation was used to estimate the gelation temperature of the F127/F68 mixture (17-20% F127 and 0-10% F68).

T_Gel＝-1.8(％F127)+1.3(％F68)+53

The data obtained were fit to an equation and the average dissolution time (hr) was estimated using this equation based on the gelation temperature of the F127/F68 mixture (17-25% F127 and 0-10% F68) using the results obtained in examples 12 and 14.

MDT＝-0.2(T_Gel)+8

Example 16: determination of the temperature range for sterile filtration

The viscosity at low temperatures was measured to help guide the temperature range over which sterile filtration was required to reduce the likelihood of clogging.

Viscosity measurements were performed using a Brookfield viscometer (Brookfield viscometer) RVDV-II + P with CPE-40 spindle rotating at 1, 5, and 10rpm (shear rates of 7.5, 37.5, and 75s-1) equipped with a water jacket temperature control unit (temperature ramping from 10 ℃ to 25 ℃ at 1.6 ℃/min).

The T gel of 17% polonix P407 was measured with increasing concentrations of otic drug. The increase in T gel for the 17% poloxamine formulation was estimated from the following formula:

ΔT_gel0.93%]

TABLE 7 viscosity of possible formulations under manufacturing/filtration conditions

^a37.5s^-1Viscosity measured at shear rate

The results show that sterile filtration of the formulations described herein can be performed at about 19 ℃.

Example 17: determining the manufacturing conditions

A 17% P407 placebo was manufactured for 8 liter batches to evaluate manufacturing/filtration conditions. A placebo was made by placing 6.4 liters of deionized water in a 3 gallon SS pressure vessel and cooling in a refrigerator overnight. The next morning, the water bath was taken out (5 ℃ C., room temperature 18 ℃ C.), and 48g of sodium chloride, 29.6g of disodium phosphate dehydrate and 10g of sodium dihydrogen phosphate monohydrate were added and dissolved with an overhead mixer (IKA RW20, 1720 rpm). Half an hour later, once the buffer had dissolved (solution temperature 8 ℃, room temperature 18 ℃), 1.36kg of poloxamer 407NF (span chemicals) was slowly sprinkled into the buffer solution over a 15 minute interval (solution temperature 12 ℃, room temperature 18 ℃) and then the speed was increased to 2430 rpm. After mixing for an additional 1 hour, the mixing rate was reduced to 1062rpm (complete dissolution).

Room temperature was maintained below 25 ℃ to maintain the solution temperature below 19 ℃. The solution temperature was maintained below 19 ℃ for up to 3 hours after the start of manufacture without the need for a freezing/cooling vessel.

The surface area was estimated to be 17.3cm at 20psi and 14 deg.C in the solution²Three different Sartoscale (Sartoscale) (sartostadi (Sartorius Stedim)) filters

1) Sartopore 2, 0.2 μm 5445307HS-FF (PES), flow rate: 16mL/min

2) Sartobran P, 0.2 μm 5235307HS-FF (cellulose ester), flow rate: 12mL/min

3) Sartopore 2XLI, 0.2 μm 5445307IS-FF (PES), flow rate: 15mL/min

Using a Sartopore 2 filter 5441307H4-SS, using a surface area of 0.015m²0.45, 0.2 μ M Stantopore 2150 sterile capsules (Sartorius Stedim) were filtered at solution temperature under 16psi pressure. The flow rate was measured to be about 100mL/min at 16psi, with no change in flow rate when the temperature was maintained in the range of 6.5-14 ℃. The decreasing pressure and increasing temperature of the solution causes the flow rate to decrease as the viscosity of the solution increases. The discoloration of the solution was monitored during this process.

TABLE 8.17% Poloxamer 407 placebo predicted filtration times at solution temperature range 6.5-14 deg.C using Sartopore 20.2 μm filter at 16psi pressure

Filter	Size (m)2)	Estimated flow Rate (mL/min)	Filtration time 8 liter (estimated value)
				Sartopore No. 2, 4	0.015	100mL/min	80min
Sartopore No. 2, 7	0.05	330mL/min	24min
				Sartopore No. 2, 8	0.1	670mL/min	12min

Before the filtration evaluation, the viscosity, Tgel and UV/Vis absorption were checked. Polonic UV/Vis spectra were obtained from Evolution 160UV/Vis (Thermo Scientific). The peak in the range of 250-300nm is due to the presence of a BHT stabilizer (poloxamer) in the starting material.

The above process was suitable for making 17% P407 formulations and included temperature analysis of room conditions. A temperature of about 19 c reduces the cost of cooling the container during manufacture. In some cases, the solution temperature is further controlled using a jacketed vessel to reduce manufacturing issues.

EXAMPLE 18 in vitro Release of dexamethasone from autoclaved micron-sized samples

TRIS buffer containing 17% poloxamer 407/1.5% dexamethasone: 250.8mg of sodium chloride (Fisher Scientific) and 302.4mg of tromethamine (Sigma Chemical Co.) were dissolved in 39.3g of sterile filtered deionized water and the pH adjusted to 7.4 with 1M HCl. 4.9g of the above solution was used, and 75.5mg of micron-sized dexamethasone USP (Spectrum Scientific) was well suspended and dispersed. 2mL of the formulation was transferred to a 2mL glass vial (Wheaton serum glass vial) and sealed with 13mm butyl styrene (Kimbel stopper) and sealed with 13mm aluminum seal. The vials were placed in a mackofoger (mark form) stereomatic autoclave (ambient, slow liquid) and sterilized at 250 ° F for 25 minutes. After autoclaving, the samples were cooled to room temperature. The vials were placed in a refrigerator and mixed while cold to homogenize the samples. The discoloration or precipitation of the samples after the autoclaving treatment was recorded.

Dissolution was carried out in a snapwell (6.5 mm diameter polycarbonate membrane with a pore size of 0.4 μm) at 37 ℃, 0.2mL of the gel was placed in the snapwell and allowed to harden, then 0.5mL of PBS buffer was placed in a reservoir and shaken at 70rpm using a ulibo (Labline) orbital shaker. Samples were taken every hour [ 0.1mL was withdrawn and replaced with warm PBS buffer containing 2% PEG-40 hydrogenated castor oil (BASF) to enhance dexamethasone solubility ]. The samples were analyzed for dexamethasone concentration by uv at 245nm against an external calibration standard curve. The release rate was compared to other formulations disclosed herein. The MDT time for each sample was calculated.

The dissolution of dexamethasone in the 17% poloxamer system was assessed by measuring the concentration of dexamethasone in the supernatant after centrifugation of the sample at 15,000rpm for 10 minutes using an ebpendorf (eppendorf) centrifuge 5424. The dexamethasone concentration in the supernatant was measured by UV at 245nm against an external calibration standard curve. Figure 3 illustrates the release profile of various steroid formulations containing 17% P407. Table 9 describes the dexamethasone solubility in TRIS buffer and 17% P407 solution.

TABLE 9 dexamethasone solubility in TRIS buffer and 17% P407 solution

Sample (I)	Dexamethasone concentration in supernatant (μ g/mL)
		17％P407/1.5％DEX/TRIS	580
TRIS buffer containing 2% DEX (example 4)	86
		Autoclaved TRIS buffer containing 2% DEX (example 4)	153

Example 19 Release Rate or MDT and viscosity of formulations containing sodium carboxymethylcellulose

17% poloxamer 407/2% DSP/1% CMC (Hercules) Blanose 7M): a PBS buffer solution (pH 7.0) of sodium carboxymethylcellulose (CMC) was prepared by dissolving 205.6mg of sodium chloride (Fisher Scientific), 372.1mg of disodium phosphate dihydrate (Fisher Scientific), 106.2mg of monosodium phosphate monohydrate (Fisher Scientific) in 78.1g of sterile filtered deionized water. 1g of Blankose 7M CMC (Hercules, viscosity 533cP at 2%) was sprinkled into the buffer solution and heated to a flowing solution, then the solution was cooled and 17.08g of Poloxamer 407NF (Spectrum Chemicals) was sprinkled into the cold solution with mixing. Formulations containing 17% poloxamer 407 NF/1% CMC/2% DSP in PBS buffer were prepared by adding/dissolving 205mg dexamethasone to 9.8g of the above solution and mixing until all dexamethasone was completely dissolved. The pH of this solution was 7.0.

17% poloxamer 407/2% DSP/0.5% CMC (Blanose 7M 65): a PBS buffer solution (pH 7.2) of sodium carboxymethylcellulose (CMC) was prepared by dissolving 257mg of sodium chloride (Fisher Scientific), 375mg of disodium phosphate dihydrate (Fisher Scientific), 108mg of monosodium phosphate monohydrate (Fisher Scientific) in 78.7g of sterile filtered deionized water. To the buffer solution 0.502g of Blanose 7M65CMC (Hercules, viscosity 5450cP at 2%) was sprinkled and heated to a flowing solution, then the solution was cooled and 17.06g of poloxamer 407NF (spectra Chemicals) was sprinkled to the cold solution with mixing. A PBS buffer solution of 17% poloxamer 407 NF/1% CMC/2% DSP was prepared by adding/dissolving 201mg DSP to 9.8g of the above solution and mixing until the DSP was completely dissolved. The pH of this solution was 7.2.

17% poloxamer 407/2% DSP/0.5% CMC (Blanose 7H 9): a PBS buffer solution of sodium carboxymethylcellulose (CMC) (pH 7.3) was prepared by dissolving 256.5mg sodium chloride (Fisher Scientific), 374mg disodium phosphate dihydrate (Fisher Scientific), 107mg monosodium phosphate monohydrate (Fisher Scientific) in 78.6g sterile filtered deionized water, then spraying 0.502g Blanose 7H9CMC (Hercules, 1% viscosity 5600cP) into the buffer solution and heating to a flowing solution, then cooling the solution, and spraying 17.03g poloxamer 407NF (scanty Chemicals) into the cold solution with mixing. A PBS buffer solution of 17% poloxamer 407 NF/1% CMC/2% DSP was prepared by adding/dissolving 203mg DSP to the above solution of 9.8 and mixing until the DSP was completely dissolved. The pH of this solution was 7.3.

Viscosity measurements were performed as described in example 7. Dissolution was carried out as described in example 7.

Fig. 4 illustrates the correlation between Mean Dissolution Time (MDT) and apparent viscosity of the formulation. The release rate is adjusted by the incorporation of a second polymer. The selection of the grade and concentration of the second polymer is aided by the use of the graphs shown in figures 5 and 6 for water soluble polymers as generally used below.

EXAMPLE 20 Dry Sterilization of dexamethasone micropowder

10 milligrams of micron-sized dexamethasone powder (shift batch XD0385) was charged into a 2mL glass vial and sealed with a 13mm butyl styrene rubber stopper (Kimble) and placed in an oven at various temperatures for 7-11 hours.

Using a solution equipped with Luna C18(2)3 μm,250 × 4.6mm column) was prepared using 30-95 solvent B (solvent a: 35% methanol, 35% water, 30% ethyl hydrochloric acid buffer, solvent B: HPLC analysis was carried out with 70% methanol: 30% ethanolic acid buffer, pH4, gradient (1-6min) and isocratic (95% solvent B) (11 min) for a total operating time of 22 min. The samples were dissolved in ethanol and analyzed. Dry heat sterilization of micron-sized dexamethasone at temperatures up to 138 ℃ did not affect the particle size distribution of micron-sized dexamethasone. HPLC analysis indicates dry Heat sterilized micron The purity of the sized dexamethasone was 99%.

Example 21 application of viscosity-enhanced corticosteroid formulation on round Window Membrane

The formulation of example 1 was prepared and loaded into a 5ml siliconized glass syringe connected to a 15 gauge luer lock (luer lock) disposable needle. Lidocaine (Lidocaine) is applied topically to the tympanic membrane, and a small incision is made to allow visualization of the middle ear cavity. The needle tip is introduced into position over the round window membrane and the anti-inflammatory corticosteroid formulation is applied directly onto the round window membrane.

Example 22 in vivo testing of intratympanic injection of corticosteroid formulation in guinea pigs

A cohort of 21 guinea pigs (Charles River, female, weight 200-. sub.300 g) were intratympanically injected with 20-120. mu.L of 2% DSP formulation. Figure 7 shows that the gel was left in the guinea pig ear for up to 5 days after intratympanic injection. For a 90 μ Ι _ injection volume, increasing injection volume increases gel retention. However, an injection volume of 120 μ L showed lower gel retention.

A cohort of 21 guinea pigs (Charles River, female, weight 200-. sup.300 g) were intratympanically injected with 50 μ L of the different P407-DSP formulations described herein containing 0 to 6% DSP. Fig. 8A and 8B show the gel exclusion time course for each formulation. The gel exclusion time course for the 6% DSP formulation was faster (mean dissolution time (MDT) lower) than for the other formulations containing lower concentrations of DSP (0%, 0.6% and 2%, respectively). In addition, faster gel exclusion was observed when the P407 concentration of the 6% DSP formulation (6% Dex-P (), increased from 17% to 19%, as shown in fig. 8A. Thus, the injection volume and the concentration of corticosteroid in the formulations described herein were tested to determine the optimal parameters for preclinical and clinical studies. It was observed that the intra-tympanic formulation containing a high concentration of DSP had a different release profile than the intra-tympanic formulation containing a lower concentration of DSP.

Example 23 in vivo extended Release kinetics

A cohort of 21 guinea pigs (Charles River, female, weight 200-. Animals were dosed on day 1. Figure 9 shows the release profile of the formulation based on the perilymph-based assay test. In the 1.5% dexamethasone regimen, the exposure level at days 7-10 was about 10% of Cmax, with a mean residence time of about 3.5 days. In the 4.5% dexamethasone regimen, exposure levels were maintained at levels similar to or higher than those seen on day 1 for at least 10 days, with a mean residence time designed to exceed 18 days.

Example 24-evaluation of corticosteroid formulations in AIED animal models

Method and material

Inducing an immune response

The Swiss mice (Swiss mice) weighing 20 to 24g of the female albino variant National Institutes of Health (Harland Sprague-Dawley Inc.), Indianapolis Inc. (Indianapolis, Inc.) were used. Keyhole limpet hemocyanin (KLH; Pacific Biomarine Supply Co., Inc., Venice, Calif.) was suspended in Phosphate Buffered Saline (PBS) (pH 6.4), aseptically dialyzed against PBS and centrifuged twice. The pellet (associated with KLH) was dissolved in PBS and injected subcutaneously in the back of the animals (0.2mg, emulsified in Freund's complete adjuvant). Fortifiers (Freund's incomplete adjuvant containing 0.2mg KLH followed by injection of 5 μ l PBS (pH 6.4) containing 0.1mg KLH) were administered via a fine hole drilled through the cochlear capsule. The cochlea is accessed using surgical microscopy and sterile techniques. A posterior auricular incision was made and a hole was drilled in the bulla to allow good visualization of the bulge of the cochlear fundus (cochlear basal turn), the stapedial artery and the round window niche. The stapedial artery was cauterized and removed, and a 25 μm hole was drilled into the cochlea sac into the scala tympani of the transverse fundoplication. KLH or PBS controls were injected slowly using a Hamilton syringe (Hamilton system) coupled through plastic tubing to a glass micropipette filled with antigen or control. After injection, the hole was sealed with bone wax and excess fluid was removed. Only one cochlea per animal was treated with KLH.

Treatment of

KLH and control mice were divided into two groups (n-10 per group). The corticosteroid formulation of example 1 containing dexamethasone was administered to the round window membrane of a group of animals. Control formulations without dexamethasone were administered to the second group. Dexamethasone and control formulation were administered again 3 days after the initial administration. On day seven of treatment, animals were sacrificed.

Analysis of results

Electrophysiological testing

The hearing threshold of auditory brainstem response threshold (ABR) to click stimulation was measured initially and 1 week after the experimental procedure in each ear of each animal. Animals were placed in a single wall sound booth (Industrial Acoustics Co, n.y., USA) on a hot plate. Subcutaneous electrodes (astra pharmaceutical company (Astro-Med, Inc.) glass instruments Division (Grass Instrument Division, West Warwick, RI, USA) were inserted on the apex (active electrode), mastoid (reference), and hind leg (ground)). The click stimulus (0.1 ms) was generated by the computer and delivered to a 200 ohm Beyer DT 48 speaker equipped with an ear speculum placed in the outer ear canal. The recorded ABR is amplified and digitized by a battery operated preamplifier and input into a computer controlled tack-Davis technology ABR recording system (tack-Davis technology, gainstville, FL, USA) that provides stimulation, recording and averaging functions. The animals were given stimuli with continuously decreasing amplitude in 5dB steps and the recorded stimuli-locked activity was averaged (n: 512) and displayed. The threshold is defined as the level of stimulation between recordings with no clearly detectable response and clearly identifiable response.

Histochemical analysis

Animals were anesthetized and sacrificed by intracardiac perfusion with warm normal saline heparinized saline and about 40ml periodate-lysine-trioxymethylene (4% trioxymethylene final concentration) fixative in sequence. The right temporal bone was immediately removed and decalcified with buffered 5% tetraethylethylenediamine (pH 7.2) for 14 days (4 ℃). Following decalcification, the temporal bone was sequentially immersed IN increasing concentrations (50%, 75%, 100%) of Optimal Cutting Temperature (OCT) compound (Tissue-Tek, Marl Inc. (Miles Inc.), Elkhart, IN, Ind), snap frozen (-70 ℃) and cryo-thermostated sections (4 μm) parallel to the modiolus axis. Sections were collected for hematoxylin and eosin (H & E) staining and immunohistochemical analysis.

The severity of inflammation was assessed by the amount of infiltration of the scala tympani cells, and fair scores were given to each cochlea. Score 0 indicates no inflammation and score 5 indicates that all cochlea returns have severe inflammatory cell infiltration.

Example 25 evaluation of corticosteroid formulations in animal models of otitis media

Induction of otitis media

These studies used healthy adult chinchillas (chincholla) weighing 400 to 600g with normal middle ear, ascertained by otoscopy and tympanometry. The eustachian tube was blocked 24 hours prior to inoculation to prevent the inoculum from flowing out of the eustachian tube. 1 ml of a 4-h-log phase, type 3 Streptococcus pneumoniae (S. pneumoconiae) strain containing approximately 40 Colony Forming Units (CFU) was placed directly in the lower tympanum bullae of Botrytis. Control mice were inoculated with 1 ml sterile PBS.

Treatment of

The s.pneumoniae vaccinated mice and the control mice were divided into two groups (n ═ 10 per group). The prednisolone formulation of example 2 was applied to the wall of the tympanic cavity of a group of animals. The control formulation without prednisolone was administered to the second group. Prednisolone and the control formulation were administered again 3 days after the initial administration. On day seven of treatment, animals were sacrificed.

Analysis of results

Ear Middle Ear Fluid (MEF) was sampled 1, 2, 6, 12, 24, 48 and 72 hours after streptococcus pneumoniae inoculation. Quantitative MEF cultures were performed on sheep blood agar with a quantitative threshold set at 50 CFU/ml. Inflammatory cells were quantified by hemacytometer and differentiated cells were counted using reiter's stain (Wright's staining).

EXAMPLE 26 AIED clinical trials Using dexamethasone formulations

10 adult patients who had previously responded to systemic dexamethasone therapy but had currently discontinued therapy due to adverse events were selected. The dexamethasone thermoreversible gel formulation of example 1 was administered to the round window membrane of each patient by puncturing the tympanic membrane. Dexamethasone gel formulation was re-administered 7 days after the initial administration and again at 2 and 3 weeks of treatment.

Each patient was subjected to a hearing assessment consisting of pure-tone audiometry (250-. The tests were performed prior to administration of the dexamethasone formulation and 1, 2, 3 and 4 weeks after the initial treatment.

Example 27-assessment of prednisolone in a Sonodynia-induced injury mouse model

Method and material

Induce ototoxicity

12 harrens pralago-Dawley (Harlan Sprague-Dawley) mice weighing 20 to 24g were used. Baseline Auditory Brainstem Response (ABR) was measured at 4-20 mHz. Mice were anesthetized and exposed to 6kHz continuous pure tone with a loudness of 120dB for 30 minutes.

Treatment of

After the acoustic injury, the control group (n-10) was administered with physiological saline. Following the acoustic injury, prednisolone (2.0 mg per kg body weight) as formulated in example 2 was administered to the experimental group (n ═ 10).

Electrophysiological testing

The hearing threshold of auditory brainstem response threshold (ABR) to click stimuli was measured initially and 1 week after the experimental procedure in each ear of each animal. Animals were placed in a single wall sound booth (industrial acoustics Co, n.y., USA) on a hot plate. Subcutaneous electrodes (astrotrichum pharmaceuticals (Astro-Med, Inc.) glass instruments Division (Grass Instrument Division, West Warwick, RI, USA) were inserted on the cranial apex (active electrode), mastoid (reference), and hind leg (ground). The click stimulus (0.1 ms) was generated by the computer and delivered to a 200 ohm Beyer DT 48 speaker equipped with an ear speculum placed in the outer ear canal. The recorded ABR is amplified and digitized by a battery operated preamplifier and input into a computer controlled tack-Davis Technology ABR recording system (tack-Davis Technology, gainsville, FL, USA) that provides stimulation, recording and averaging functions. The animals were given stimuli with continuously decreasing amplitude in 5dB steps and the recorded stimuli-locked activity was averaged (n: 512) and displayed. The threshold is defined as the level of stimulation between recordings with no clearly detectable response and clearly identifiable response.

EXAMPLE 28 clinical testing of dexamethasone in Meniere's disease patients

Object of study

The primary goal of this study will be to evaluate the safety and efficacy of dexamethasone versus placebo in improving tinnitus symptoms in patients with meniere's disease.

Design of research

This would be a phase 3 multicenter double-blind randomized placebo-controlled three-group study comparing JB004/a with placebo in tinnitus treatment. Approximately 250 individuals will participate in this study and will be randomly assigned (1: 1) to one of the 3 treatment groups based on the random assignment order established by the host. Each group will receive 300mg dexamethasone delivered in either a thermoreversible gel or a controlled release placebo formulation. The release of dexamethasone was controlled and was performed within 30 days. The route of administration will be intratympanic injection.

Measurement of primary outcome

Visual Analog Scale (VAS), measures the change in perceived loudness of tinnitus at a measurement time of 2 hours post-dose (or any other time point relative to pre-dose baseline). Alternatively, audiometry is used in healthy ears to match the tone of tinnitus in the affected ears.

Measurement of secondary outcome

VAS, measure tinnitus pitch (tinitus pitch), pain and anxiety. Pure tone audiometry and psychoacoustic assessment. Sleep and tinnitus questionnaires. Safety, tolerability and pharmacokinetics of the drug. [ time range: sensation at the measurement time 2 hours after dosing (or any other time point relative to pre-dose baseline).

Inclusion criteria

Patients may be enrolled if they meet any of the following criteria:

a male or female individual diagnosed with tinnitus.

Individuals who are willing to restrict alcohol intake.

Women with childhood potential who refrain from sexual intercourse or agree to control of fertility.

Women with no possibility of a young child.

Exclusion criteria

Patients may be excluded if they meet any of the following criteria:

intermittent or pulsatile tinnitus

Individuals with pathological levels of anxiety or depression.

Individuals without an audiogram deficiency and with normal hearing.

Individuals who did not respond to the lidocaine infusion test or showed large variability in pre-infusion values.

The presence of any surgical or medical condition that may interfere with drug PK.

Individuals with liver damage or a history of liver dysfunction.

Renal impaired individuals.

HIV, hepatitis C or hepatitis B positive individuals.

Individuals with abnormal laboratory, ECG or physical examination results.

Individuals with abnormal thyroid function.

Individuals with a history of liver, heart, kidney, nerve, cerebrovascular, metabolic or pulmonary disease.

Individuals who have had a myocardial infarction.

Individuals with a history of epileptic disorders.

Individuals with a history of cancer.

Individuals with a history of drugs or other allergies.

Individuals who are positive for drug use and/or have a history of substance abuse or dependence.

An individual who has taken a psychotropic or antidepressant agent over a specified time frame.

Drugs or foods known to interfere with liver enzymes (e.g., grapefruit or grapefruit juice).

Individuals who have recently used investigational drugs or recently participated in the trial.

Women positive for pregnancy test.

Female individuals intended to become pregnant or male individuals intended to become the father of the child within the next 4 weeks following the last study drug administration in the study.

Individuals who have donated 1 unit of blood or more in the last month or who are intended to donate blood within 1 month of completion of the study.

Example 29-evaluation of dexamethasone formulations in animal models of endolymphatic edema

This procedure was used to determine the efficacy of the dexamethasone formulations prepared in example 1.

Materials and methods

35 Hartley guinea pigs (Hartley Guinea pig) with a positive Preyer's reflex and weighing approximately 300g were used. 5 animals used as a control group (normal ear group) were fed for 5 weeks, neither manipulated nor treated, and the remaining 30 were used as experimental animals. All experimental animals received electrocautery of the endolymphatic sac (plum (Lee) et al, otorhinolaryngology (Acta Otolarynggol.) (1992) 112: 658-666; Wuta (Takeda) et al, equilibrium research (Equilib. Res.) (1993) 9: 139-143). 4 weeks after surgery, the animals were divided into 3 groups, i.e. non-infused edematous ears, vehicle-treated edematous ears and dexamethasone-treated edematous ears, each consisting of 10 animals. The ear group with non-infused edema received no treatment other than endolymphatic electrocautery. In the vehicle-treated edematous ear group and the dexamethasone-treated edematous ear group, the liposome formulations were applied to the round window membrane. 1 week after administration of the composition, all animals were sacrificed to assess changes in endolymphatic space. All animals were left undisturbed and free to move in individual cages located in quiet rooms throughout the period except during the experimental procedure.

To assess the changes in the endolymphatic space, all animals were perfused with a physiological saline solution via the heart under deep anesthesia with peritoneal injection of pentobarbital (pentobarbital) and fixed with 10% formalin (formalin). The left temporal bone was removed and post-fixed in 10% formaldehyde solution for 10 days or more. Thereafter, it was decalcified with 5% trichloroacetic acid for 12 days and dehydrated in a graded ethanol series. It was embedded in paraffin and collodion. The prepared blocks were cut horizontally into 6-micron slices. The sections were stained with hematoxylin and eosin (eosin) and observed under an optical microscope. Quantitative assessment of intra-lymphatic spatial changes was performed according to the methods of the Wuta (Takeda et al, Hearing Res. (2003) 182: 9-18).

Example 30 evaluation of intratympanic dexamethasone with Idiopathic Sudden Sensorineural Hearing Loss (ISSHL) Estimation of

Object of study

The main goal of this study will be to assess the safety and efficacy of oral steroid therapy or Intratympanic (IT) steroid therapy.

Measurement of primary outcome

Pure Tone hearing threshold Average (PTA) and Word Recognition (Word Recognition) as the equal weighted end points; for the speech discrimination score, a 50 vocabulary monosyllabic system would be employed; improvement in PTA or whole or partial frequencies is greater than 20dB, with defects greater than 30dB, and/or WDS improvement of 20% or higher; in addition to the absolute change, recovery relative to the contralateral ear will also be determined.

Full recovery-recovery to within 5% of the contralateral speech discrimination score point, or within 5dB of contralateral PTA.

Design of research

This would be a multicenter double-blind randomized placebo-controlled parallel group study comparing intratympanic dexamethasone to placebo in ISSHL treatment. Approximately 140 individuals will participate in this study and are randomly assigned (1: 1) to one of 3 treatment groups based on a random assignment order.

a. Individuals in group I will receive oral prednisone (1 mg/kg prednisone per day, 14 days; then the dose is reduced by 10mg per day until no steroid can be administered again)

b. Individuals in group II will receive IT dexamethasone sodium phosphate (1 injection of 0.3-0.5mL dexamethasone per mL vehicle, administered once a month, up to 3 injections) and oral prednisone (1 mg/kg prednisone per day, 14 days, followed by a daily dose reduction of 10mg until no steroid can be administered)

c. Individuals in group III will receive placebo IT injections (1 injection of 0.3-0.5mL vehicle administered once a month, up to 3 injections) and oral prednisone

Hearing assessment

The hearing assessment includes:

a. pure tone threshold means (500Hz, 1kHz and 2 kHz; 4kHz, 6kHz and 8 kHz).

i. Two PTA values will then be determined: low frequency values (500Hz-2kHz) and high frequency values (4-8 kHz).

b. Stapes reflex

c. Drum pressure measurement and tone attenuation

d. Speech recognition threshold

Hearing loss will be measured for each individual prior to initiation of treatment (twice before distribution into the study and once before random distribution). Hearing assessments were made 1, 2, 4 and 8 weeks, 4 and 6 months after initiation of treatment

Major inclusion criteria

Male or female patients between the ages of 18 and 75

Unilateral SHL (sensorineural hearing loss) that develops within 72 hours

The individual will have a hearing loss at any frequency of no more than 70 dB.

Exclusion criteria

Previously undergone oral steroid treatment for any reason for more than 10 days within the previous 30 days

Previous experiences with oral steroid treatment for ISSHL for 5 days or more than 5 days within the previous 14 days

History of hearing changes in either ear

EXAMPLE 31 evaluation of intratympanic dexamethasone with Meniere's disease

Object of study

The primary goal of this study will be to assess the safety and efficacy of Intratympanic (IT) dexamethasone treatment.

Measurement of primary outcome

Vertigo (vertigo)

a. A self-reporting system comprising the following scheme:

i. day-0 without dizziness;

day-1 of mild flare;

moderate severe attacks last more than 20 minutes-2;

a severe attack lasting 1 hour or more than 1 hour or accompanied by nausea or vomiting-3;

v. most severe seizure so far-4;

treatment failure is defined as vertigo divided by 50 or more than 50 per month for 2 consecutive months

Inclusion criteria

MD clinical diagnosis according to 1995AAO-HNS criteria:

b. at least two definite vertigo attacks

c. A definite small episode is spontaneous (rotational) vertigo lasting at least 20 minutes.

Exclusion criteria

Treatment with aminoglycoside or macrolide antibiotics;

treatment with antineoplastic agents

d. Platinum compounds

e. Difluoromethyl ornithine

Design of research

This would be a multicenter double-blind randomized placebo-controlled parallel group study comparing intratympanic dexamethasone to placebo in ISSHL treatment. Approximately 140 individuals will participate in this study and are randomly assigned (1: 1) to one of 3 treatment groups based on a random assignment order.

a. Individuals in group I will receive standard of care (1500 mg nmt sodium diet per day, throttling xanthine intake, and/or diuretics)

b. Individuals in group II will receive IT dexamethasone sodium phosphate (0.3-0.5 mL dexamethasone per mL vehicle at 1 injection, administered once a month, up to 3 injections) and standard of care

c. Individuals in group IV will receive placebo IT injections (1 injection of 0.3-0.5mL of vehicle administered once a month, up to 3 injections) and standard of care

Evaluation of

Before treatment begins, the severity of Meniere's disease will be measured for each individual (twice before distribution into the study and once before randomized distribution)

Meniere's disease assessment 1, 2, 4 and 8 weeks, 4 and 6 months after treatment initiation

Evaluation of

a. The date, frequency, duration and severity of the onset of vertigo and tinnitus;

b. reduction of ear pressure sensation, measurement using standard VAS questionnaire, and verification of rating scheme

c. Measurement of serum vasopressin

While preferred embodiments of the present invention have been shown and described herein, these embodiments are provided by way of example only. The invention is optionally practiced with various alternatives to the embodiments described herein. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims (10)

1. A pharmaceutical thermoreversible gel composition suitable for use in the treatment of otic disorders by intratympanic administration onto or near the round window membrane of the ear, comprising an otoacceptable thermoreversible gel comprising a polymer composed of polyoxypropylene and polyoxyethylene and a multiparticulate anti-inflammatory corticosteroid such that the anti-inflammatory corticosteroid is continuously released for a period of at least 5 days following a single administration.

2. The composition of claim 1, wherein the pH of the composition is between 7.0 and 8.0.

3. The composition of claim 1, for use in treating meniere's disease, formulated to provide sustained release of a therapeutically effective amount of dexamethasone for a period of at least 5 days, the composition comprising:

between 1mg/mL and 70mg/mL of multiparticulate dexamethasone or a pharmaceutically acceptable prodrug or salt thereof;

between 16% and 21% by weight of a polymer composed of polyoxypropylene and polyoxyethylene; and

wherein the pharmaceutical composition has an osmolality suitable for perilymph of between 250 and 320 mOsm/kg.

4. The composition of claim 1, for use in treating sudden sensorineural hearing loss, formulated to provide a sustained release of a therapeutically effective amount of dexamethasone for a period of at least 5 days, the composition comprising:

Multiparticulate dexamethasone between 1mg/mL and 70mg/mL or a pharmaceutically acceptable salt or prodrug thereof;

between 16% and 21% by weight of a polymer composed of polyoxypropylene and polyoxyethylene; and

wherein the pharmaceutical composition has an osmolality suitable for perilymph of between 250 and 320 mOsm/kg.

5. The composition for use in treating an otic disorder in accordance with claim 1, wherein the anti-inflammatory corticosteroid is dexamethasone.

6. The composition for use in treating an otic disorder according to any one of claims 1 to 5, wherein sustained release provides a period of at least 7 days.

7. The composition for use in treating an otic disorder according to any one of claims 1 to 5, wherein sustained release provides a period of at least 10 days.

8. The composition for use in treating an otic disorder according to any one of claims 1 to 5, wherein sustained release provides a period of at least 14 days.

9. The composition for use in treating an otic disorder in accordance with one of claims 1-5, wherein the dexamethasone is administered in the form of a phosphate or ester prodrug.

10. The composition for use in treating an otic disorder according to any one of claims 1 to 5, wherein the polymer composed of polyoxypropylene and polyoxyethylene is poloxamer 407.