HK1089676B - Formulations and methods for treating rhinosinusitis - Google Patents

Description

Formulations and methods for treating sinusitis

I. Related application

This application is a continuation-in-part of the application of nos. 10/414,682 and 10/414,756. Both applications were filed on 16/4/2003. Each of which is incorporated herein by reference in its entirety.

Field of the invention

The present invention relates to formulations and methods for treating sinusitis in mammals (e.g., humans), including but not limited to, fungal-induced sinusitis. The formulations of the present invention comprise a steroidal component, such as fluticasone or beclomethasone, wherein the steroidal component has a specific particle size distribution profile. The formulation may also comprise an antibiotic, antifungal or antiviral agent, or any combination thereof. Although the formulations of the present invention may take any form, preferably they are sterile aqueous suspensions or solutions capable of intranasal administration to the nasal-paranasal mucosa via a spray pump. Furthermore, the steroid component may be administered alone or in combination with an antifungal, antibiotic or antiviral agent.

Background of the invention

Sinusitis is generally described as inflammation of the nasal cavity and/or sinuses, involving the nasal mucosa. Chronic Rhinosinusitis (CRS) is diagnosed when signs or symptoms of inflammation persist for 8-12 weeks or more. One-seventh of americans are estimated to have chronic sinusitis (CRS). Symptoms of CRS include nasal congestion, loss of smell, nasal or retronasal discharge, nasal congestion and facial pain/pressure (usually in the affected sinus region).

CRS reduces normal physical and social functioning, and patients with CRS often have an overall reduced quality of life. Moreover, CRS is often associated with other co-pathogenic conditions, such as asthma, eczema, and other mediators. Asthma is seen in 20-35% of patients with CRS and in up to 75% of patients with moderate to severe asthma.

It is now known that sinusitis can be caused by fungi in the mucus. It is believed that some people develop an immune response to some fungi found in most, if not all, of the human mucus. This immune response results in the entry of activated leukocytes, eosinophils, into the mucus. Activated eosinophils release important basic toxic proteins into the mucus, attack and kill fungi, but also damage the nasal and sinus mucosa. Important basic proteins also damage the epithelium, which allows bacteria to infect tissues.

One type of fungal-induced sinusitis is Allergic Fungal Sinusitis (AFS). AFS is generally diagnosed as: (1) the presence of nasal polyps; (2) allergic mucin; (3) CT scan proves CRS; (4) positive in fungal culture or histology; and/or (5) allergic reaction to fungi as evidenced by history, skin test, or serology. AFS often causes or is associated with CRS.

Current treatments for fungus-induced rhinosinusitis include antifungal drug therapy to remove the antigenic burden. Local or systemic corticosteroids may also be used to control CRS-related mucosal tissue inflammation. This inflammation is thought to be due to tissue and bone destruction associated with CRS. Recently, it has been discovered that steroidal anti-inflammatory agents having specific particle size distribution characteristics, such as Fluticasone Propionate (FP) and Beclomethasone Dipropionate (BDP), provide increased bioavailability, increased efficacy and/or prolonged therapeutic effect when administered intranasally.

CRS may also be characterized by or associated with chronic bacterial infection of the sinuses (nasal-paranasal region), which often overlaps with self-perpetuating, eosinophil-rich inflammatory processes of the sinuses. Currently, antibiotic therapy is available for up to six weeks or more to treat and eliminate CRS-associated bacterial infections.

Summary of the invention

The present invention relates generally to formulations and methods for treating sinusitis in mammals (e.g., humans), including but not limited to, fungal-induced sinusitis. In one embodiment, the formulation of the invention comprises a steroid, either alone or in combination with an antifungal agent or an antibiotic. It is believed that treatment of a patient with an antifungal agent will be sufficient to reduce the biological level of fungi in the mucus of the patient such that one or more symptoms of sinusitis are prevented from progressing, or are reduced, or are prevented from worsening.

In one embodiment, the formulation comprises from about 4mg to about 30mg of the antifungal agent amphotericin β. In an alternative embodiment, the formulation of the invention comprises about 20 to about 70mg of the antifungal agent fluconazole or itraconazole.

The present invention is also based on the insight that when a patient or individual first seeks the assistance of a physician or by the time treatment is initiated, he or she may have developed one or more symptoms of sinusitis, possibly CRS. Thus, it would also be beneficial to provide an anti-inflammatory steroid to a patient to treat mucosal tissue inflammation associated with sinusitis, as such inflammation may cause or be attributed to tissue and bone destruction in the nasal-paranasal region.

It has recently been found that certain steroidal anti-inflammatory agents having specific particle size distribution characteristics provide increased bioavailability, increased efficacy or prolonged therapeutic effect when administered intranasally. In one embodiment, the formulation of the present invention comprises from about 25 to about 400 meg of a steroidal anti-inflammatory agent, including but not limited to fluticasone or a pharmaceutically acceptable derivative thereof, having the following particle size distribution profile: about 10% of the drug substance particles have a particle size of about 0.90 microns; about 25% of the drug substance particles have a particle size of less than 1.6 microns; about 50% of the drug substance particles have a particle size of less than 3.2 microns; about 75% of the drug substance particles have a particle size of less than 6.10 microns; about 90% of the drug substance particles have a particle size of less than 10.0 microns.

In an alternative embodiment, the formulation of the present invention comprises from about 0.2 to about 3mg of the steroidal anti-inflammatory agent beclomethasone or a pharmaceutically acceptable derivative thereof, having the following particle size distribution characteristics: about 10% of the drug substance particles have a particle size of about 0.75 microns; about 25% of the drug substance particles have a particle size of less than 1.5 microns; about 50% of the drug substance particles have a particle size of less than 2.0 microns; about 75% of the drug substance particles have a particle size of less than 3.5 microns; about 90% of the drug substance particles have a particle size of less than 5.0 microns; greater than 90% or about 100% of the drug substance particles have a particle size of less than 10 microns.

In many cases, fungus-induced rhinosinusitis may be accompanied by or associated with bacterial infection of the nasal-paranasal mucosa. In one embodiment, the formulation of the invention comprises an antibiotic. In an alternative embodiment, the formulation comprises from about 1 to about 800mg of the antibiotic neomycin sulfate.

The formulation of the invention may be in a form such that the formulation is in direct contact with the nasal-paranasal mucosa. In one embodiment, the formulation is a sterile aqueous solution or suspension. In an alternative embodiment, the formulation is located in a metered dose spray pump.

The present invention also relates generally to methods of treating sinusitis, including fungus-induced sinusitis. In an alternative embodiment, an individual suffering from sinusitis may be administered the steroid component of the invention, alone or in combination or association with an antifungal, antibiotic or antiviral agent. For example, the steroid component may be administered independently of the antifungal or antibiotic, or each of these components may be administered simultaneously (e.g., in a single formulation) or separately, concurrently, sequentially or subsequently, with respect to each other, or any combination thereof.

Detailed description of the invention

The present invention relates to formulations for treating one or more symptoms of sinusitis in an individual. Sinusitis occurs in the nasal-paranasal area. Symptoms of sinusitis include, without limitation, facial pain, compression, and/or distension; loss of olfaction; nasal obstruction or obstruction; nasal or paranasal discharge; rhinorrhea; hyposmia/ansomnia; generating heat; headache; halitosis; fatigue; toothache; cough; and ear pain, pressure and/or fullness. After examination, sinus inflammation is often indicated by the presence of thick mucus or macroscopic visual obstruction of the nose or paranasal area by mucus or polyps.

Nasal polyps may also be associated with or indicative of sinusitis. Nasal polyps are outgrowths of the nasal-paranasal mucosa, usually smooth, gelatinous, translucent, rounded or pear-shaped, and dull. Generally, nasal polyps are located on the lateral walls of the nose, usually in the middle meatus or along the middle and upper turbinate. Most nasal polyps are from the ethmoid sinus, but some are from the maxillary sphenoid sinus. Nasal polyp masses are composed mainly of edema fluid, containing sparse fibrous cells and some mucous glands. The surface epithelium of nasal and paranasal polyps typically shows squamous metaplasia. Eosinophils are usually present in polyps in moderate to large amounts, and nasal polyp fluids are now known to contain greater than normal concentrations of IgA, IgE, IgG and IgM antibodies, as well as abnormally high concentrations of IL-5, a cytokine that contributes to eosinophil activation and survival.

It is to be understood that the scope of the present invention relates to the treatment of sinusitis, including but not limited to any sinus inflammation, including but not limited to acute, sub-acute, recurrent acute and chronic sinusitis, and may be accompanied, exacerbated, associated with or caused (to a full or partial extent) by fungi, viruses or microorganisms in the mucosa. For example, sinusitis may include fungus-induced sinusitis, e.g., caused by an immune response to mucosal fungi or other microorganisms. In an alternative embodiment, the fungal-induced rhinosinusitis is allergic fungal rhinosinusitis or AFS.

Preparation

In an alternative embodiment, the present invention is directed to a formulation for treating sinusitis. In one embodiment, the formulation comprises a steroidal anti-inflammatory agent, either alone or in combination with an antifungal agent, an antibiotic, or an antiviral agent. As used herein, treatment refers to the prevention, or amelioration of, or any manner of beneficially altering, or preventing the worsening of, sinusitis or one or more symptoms associated therewith. As used herein, ameliorating means any alleviation of one or more symptoms of sinusitis, including but not limited to, fungus-induced sinusitis, whether permanent or temporary, sustained or temporary.

Antifungal agent

An antifungal agent for use herein includes any ingredient effective in the treatment of sinusitis, including fungus-induced sinusitis. Preferably, the antifungal agent of the formulation reduces the presence of fungal organisms in the mucus to a level such that the characteristic inflammatory response and resulting damage associated with fungal induced sinusitis is reduced, whether permanent or temporary, sustained or temporary, or is stopped, treated or prevented.

For example, in an alternative embodiment of the invention, an antifungal agent for use herein may include any ingredient that prevents the growth of or kills fungal organisms, such as antifungal polyene macrolides, tetraene macrolides, pentaene macrolides, fluorinated pyrimidines, imidazoles, triazoles, pyrroles, halogenated phenol ethers, thiocarbamates, allylamines, and the like. In addition, the antifungal agent may be a component that either tampers with the fungal cell wall component or acts as a sterol inhibitor. Specific antifungal agents within the scope of the present invention include, without limitation, amphotericin β, flucytosine, ketoconazole, miconazole, itraconazole, fluconazole, griseofulvin, clotrimazole, econazole, terconazole, butoconazole, oxiconazole, sulconazole, saperconazole, voriconazole, ciclopirox olamine, haloprogin, tolnaftate, naftifine, nystatin, natamycin, terbinafine hydrochloride, morpholine, butenafine undecenoate, whitefeld ointment, propionic acid, and caprylic acid, and those ingredients that can be identified as antifungal agents using methods well known in the art. Preferably, the antifungal agent of the formulation is amphotericin β or fluconazole.

It is noted that a particular patient may possess a fungal organism that acts as a causative agent, which is resistant to a particular antifungal agent. In such a case, embodiments of the invention involve treating the patient with an effective antifungal agent (e.g., an antifungal agent that prevents growth of or kills a fungal organism that acts as a pathogenic factor). Such fungal organisms that act as pathogenic agents can be identified using collection and culture methods known in the art.

In an alternative embodiment, the formulations of the present invention may comprise any amount of antifungal agent, so long as one or more symptoms associated with, or associated with, fungus-induced rhinosinusitis are reduced, prevented, or eliminated without significant toxicity. In one embodiment, an effective amount can be any Minimum Inhibitory Concentration (MIC) greater than or equal to the fungal organism or isolate present in the mucus of a particular individual that does not induce significant toxicity to the individual upon administration. Some antifungal agents may have a relatively large effective concentration range, while others may have a relatively narrow effective concentration range. In addition, the effective amount may vary for specific fungal organisms or isolates, as certain organisms and isolates are more or less sensitive to a particular antifungal agent. Such effective amounts of individual antifungal agents can be determined using generally available or readily ascertainable information relating to antifungal effective concentrations, animal toxicity concentrations, and tissue penetration ratios.

For example, a non-toxic antifungal agent may generally be administered directly or indirectly in any amount that exhibits antifungal activity within mucus. In addition, the antifungal agent that does not penetrate the mucosal epithelium may generally be administered directly to the mucus in any amount that exhibits antifungal activity within the mucus. Such effective amounts can also be determined by conventional in vitro or in vivo experimentation using the information provided herein. For example, a patient with fungus-induced rhinosinusitis may receive direct administration of an antifungal agent in an amount close to the MIC calculated from an in vitro assay. If the patient fails to respond, the amount administered may be increased, for example by ten times. After receiving such higher concentrations, the patient's responsiveness to treatment and toxicity symptoms can be monitored and adjusted accordingly.

In one embodiment, the formulation comprises from about 0.01ng to about 1000mg of the formulation per kg of mammalian body weight per administration, wherein the formulation is administered directly to the nasal-paranasal mucosa. Particularly suitable antifungal agents for administration are itraconazole, ketoconazole or voriconazole. The MIC values for voriconazole vary from about 0.003. mu.g/mL to about 4. mu.g/mL, depending on the particular fungal organism or isolate population tested. For fluconazole, MIC values range from about 0.25 μ g/mL to greater than about 64 μ g/mL.

There are a variety of factors that can influence the actual amount of antifungal agent in the formulations provided herein. For example, the frequency of administration of the formulation, the duration of treatment, the combination of other antifungal agents, the site of administration, the degree of inflammation, and the anatomy of the treatment area may require an increase or decrease in the actual amount of antifungal agent in the formulation.

Table 1 lists preferred ranges and dosages for the antifungal agents of the present invention.

TABLE 1

Antifungal agents and dosages

Common name

Name of trade mark

Categories

Preferred ranges

More preferred range

Most preferred range

Most preferred dosage

Amphotericin beta

Fungizone

Antifungal agent

0.5-150mg

4-30mg

7.5-15mg

10mg Q12H

Fluconazole

Diflucan

Antifungal agent

0.5-150mg

20-70mg

25-50mg

10mg Q12H

Itraconazole

Sporanox

Antifungal agent

0.5-150mg

20-70mg

25-50mg

30mg Q12H

Steroidal anti-inflammatory agents

Steroidal anti-inflammatory agents for use herein include fluticasone, beclomethasone, and pharmaceutically acceptable derivatives thereof, and any combination thereof. Pharmaceutically acceptable derivatives, as used herein, include any salt, ester, enol ether, enol ester, acid, base, solvate or hydrate thereof. Such derivatives can be prepared by those skilled in the art using methods known for such derivatization.

In an alternative embodiment, the steroidal anti-inflammatory agent has a specific particle size distribution profile. Particle size as used herein means the average particle size as measured by conventional particle size measurement techniques well known to those skilled in the art, such as sedimentation field flow fractionation, photon correlation spectroscopy, or ring centrifugation, among others.

Fluticasone

Preferably, the intranasal steroid of the formulation is fluticasone propionate. Fluticasone propionate is a synthetic corticosteroid having the empirical formula C₂₅H₃₁F₃O₅And S. Its chemical name is S- (fluoromethyl) 6 alpha, 9-difluoro-11 beta, 17-dihydroxy-16 alpha-methyl-3-oxoandrosta-1, 4-diene-17 beta-thiocarboxylate 17-propionate. The fluticasone propionate is white to off-white powder, and the molecular weight is 500.6; it is particularly insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol.

In one embodiment, the formulation of the present invention may comprise a corticosteroid anti-inflammatory agent (e.g., fluticasone propionate) having the following particle size distribution characteristics: about 10% or less of the steroid particles have a particle size of less than 0.90 microns; about 25% or less of the steroid particles have a particle size of less than 1.6 microns; about 50% or less of the steroid particles have a particle size of less than 3.2 microns; about 75% or less of the steroid particles have a particle size of less than 6.10 microns; about 90% or less of the steroid particles have a particle size of less than 10 microns.

In an alternative embodiment, the formulation of the present invention comprises a steroidal anti-inflammatory agent having the following particle size distribution behavior: about 10% of the steroid particles have a particle size of less than 0.70 micron; about 25% of the steroid particles have a particle size of less than 1.30 microns; about 50% of the steroid particles have a particle size of less than 2.5 microns; about 75% of the steroid particles have a particle size of less than 4.0 microns; about 90% of the steroid particles have a particle size of less than 6.0 microns; greater than 90% or about 100% of the steroid particles have a particle size of less than 10 microns. Preferably, the steroid is fluticasone propionate.

In a preferred embodiment, the formulation of the invention comprises steroids having the following particle size distribution behaviour: about 10% of the steroid particles have a particle size of less than 0.50 microns; about 25% of the steroid particles have a particle size of less than 0.90 microns; about 50% of the steroid particles have a particle size of less than 1.7 microns; about 75% of the steroid particles have a particle size of less than 3.5 microns; about 90% of the steroid particles have a particle size of less than 5.5 microns.

In another alternative embodiment, greater than 90% or about 100% of the steroid particles have a particle size of less than 15 microns, preferably less than 10 microns, more preferably less than 8 microns, and most preferably less than 7 microns.

Beclomethasone

Also preferably, the steroidal anti-inflammatory agent of the formulation is beclomethasone dipropionate or a monohydrate thereof. The chemical name of beclomethasone dipropionate is 9-chloro-11 b, 17, 21-trihydroxy-16 b-methyl pregna-1, 4-diene-3, 20-diketone 17, 21-dipropionate. The compound may be a white powder with a molecular weight of 521.25; only slightly soluble in water (Physicians' Desk Reference, RTM), readily soluble in chloroform, freely soluble in acetone and alcohol.

The formulations of the present invention may comprise a steroidal anti-inflammatory agent (e.g., beclomethasone dipropionate) having the following particle size distribution behavior: about 10% or less of the steroid particles have a particle size of less than 0.75 microns; about 25% or less of the steroid particles have a particle size of less than 1.5 microns; about 50% or less of the steroid particles have a particle size of less than 2.0 microns; about 75% or less of the steroid particles have a particle size of less than 3.5 microns; about 90% or less of the steroid particles have a particle size of less than 5.0 microns; greater than 90% or about 100% of the steroid particles have a particle size of less than 10 microns.

In an alternative embodiment, the formulation of the present invention comprises a steroidal anti-inflammatory agent having the following particle size distribution behavior: about 10% of the steroid particles have a particle size of less than 0.35 micron; about 25% of the steroid particles have a particle size of less than 0.70 microns; about 50% of the steroid particles have a particle size of less than 1.25 microns; about 75% of the steroid particles have a particle size of less than 2.0 microns; about 90% of the steroid particles have a particle size of less than 3.0 microns; greater than 90% or about 100% of the steroid particles have a particle size of less than 6.5 microns. Preferably, the steroid is beclometasone dipropionate.

In a preferred embodiment, the formulation of the invention comprises a steroidal anti-inflammatory agent with the following particle size distribution behaviour: about 10% of the steroid particles have a particle size of less than 0.40 microns; about 25% of the steroid particles have a particle size of less than 0.70 microns; about 50% of the steroid particles have a particle size of less than 1.3 microns; about 75% of the steroid particles have a particle size of less than 2.0 microns; about 90% of the steroid particles have a particle size of less than 3.0 microns; greater than 90% or about 100% of the steroid particles have a particle size of less than 6.0 microns.

In another alternative embodiment, the formulation of the present invention comprises a steroidal anti-inflammatory agent having the following particle size distribution behavior: about 10% of the steroid particles have a particle size of less than 0.60 microns; about 25% of the steroid particles have a particle size of less than 0.90 microns; about 50% of the steroid particles have a particle size of less than 1.5 microns; about 75% of the steroid particles have a particle size of less than 2.5 microns; about 90% of the steroid particles have a particle size of less than 3.5 microns; greater than 90% or about 100% of the steroid particles have a particle size of less than 6.0 microns.

In another alternative embodiment, greater than 90% or about 100% of the steroid particles have a particle size of less than 15 microns, preferably less than 10 microns, more preferably less than 8 microns, and most preferably less than 7 microns. In another preferred embodiment, greater than 90% or about 100% of the steroid particles have a particle size between 4 and 7 microns or between 5 and 6 microns. In another embodiment, greater than 90% or about 100% of the steroid particles have a particle size of less than 10 microns, preferably less than 7 microns, less than 6 microns, less than 5 microns or less than 4 microns.

The provision of steroidal anti-inflammatory agents according to the invention is believed to be a more effective way to provide drug therapy to the nasal-paranasal region, thereby increasing the bioavailability and efficacy of the steroid. It is to be understood that the particle size distribution characteristics described in each of the applications No.10/414,682 and 10/414,756 may be adapted for any of the anti-inflammatory agents described herein. Preferred anti-inflammatory agents are fluticasone and beclomethasone. Moreover, the dosages described in these applications may also be suitable for use in the present invention. Each of these applications is incorporated herein by reference in its entirety.

Additionally, the formulations of the present invention may comprise fluticasone or beclomethasone, alone or in combination with one or more other steroidal anti-inflammatory agents. Examples of steroidal anti-inflammatory agents for use herein include, but are not limited to, betamethasone, triamcinolone, dexamethasone, prednisone, mometasone, flunisolide, and budesonide. Other anti-inflammatory agents for use herein are listed in table 2 below.

TABLE 2

Steroidal anti-inflammatory agents and dosages

Common name

Name of trade mark

Categories

Preferred ranges

More preferred range

Most preferred range

Most preferred dosage

Acetylcysteine

Mucomist Mucosil

Mucolytic agent

125-500mg

150-450mg

200-400mg

300mg Q12H

Amikacin

Amikin

Aminoglycosides

50-500mg

75-300mg

100-200mg

166mg Q8-12H

Amphotericin

Fungizone

Antifungal agent

2.5-45mg

4-30mg

7.5-15mg

10mg Q12H

Atropine

Anticholinergic agents

10-700mcg

25-400mcg

75-30mcg

200mcg Q12H

Nitrogen is present inStatin-like substances

Astelin

Antihistaminic agent

137-1096mcg

204-822mcg

382-616mcg

411mcg Q12H

Azithromycin

Zithromax

Macrolides

50-400mg

75-300mg

150-200mg

167mg Q12H

Aztreonam

Azactam

Monolactams

250-1000mg

300-900mg

475-750mg

450mg Q8H

Beclomethasone

Vanceril Beclovent

Steroidal anti-inflammatory agents

0.1-4mg

0.2-3mg

0.2-2mg

0.8mg Q12H

Betamethasone

Celestone

Steroidal anti-inflammatory agents

0.1-4mg

0.2-3mg

0.2-2mg

0.8mg Q12H

Cefazolin

Ancef，Kefzol

Cephalosporin (I generation)

250-1000mg

300-900mg

575-700mg

650mg Q8H

Cefepime

Maxipime

Cephalosporin (IV generation)

125-1000mg

200-900mg

575-700mg

650mg Q12H

Cefonicid

Moniacid

Cephalosporin (generation II)

250-1000mg

300-900mg

575-700mg

600mg Q24H

Cefeprosan

Cefobid

Cephalosporin (III generation)

250-1000mg

300-900mg

575-700mg

600mg Q12H

Cefotaxime

Claforan

Cephalosporin (III generation)

250-1000mg

300-900mg

575-700mg

600mg Q8-12H

Cefotetan

Cefotan

Cephalosporin (cephamycin)

250-1000mg

300-900mg

575-700mg

600mg Q8-12H

Cefoxitin

Mefoxin

Cephalosporin (cephamycin)

250-1000mg

300-900mg

575-700mg

600mg Q12H

Ceftazidime

Fortaz，Ceptaz

Cephalosporin (III generation)

250-1000mg

300-900mg

475-750mg

550mg Q12H

Ceftizoxime

Cefizox

Cephalosporin (III generation)

250-1000mg

300-900mg

575-700mg

600mg Q8-12H

Ceftriaxone

Rocephin

Cephalosporin (III generation)

250-1000mg

300-900mg

575-700mg

650mg Q12H

Cefuroxime

Ceftin

Cephalosporin (generation II)

100-600mg

200-520mg

250-400mg

285mg Q8H

Cefapirin

Cefadyl

Cephalosporin (I generation)

250-1000mg

300-900mg

575-700mg

650mg Q12H

Ciprofloxacin

Cipro

Quinolones

25-200mg

50-175mg

75-110mg

90mg Q12H

Clindamycin

Cleocin

Lincose streptamide

50-600mg

75-500mg

125-300mg

225mg Q12H

Cromolyn sodium salt

Intal/Nasalcrom

Mast cell stabilizers

5-100mg

7.5-75mg

10-50mg

20mg Q12H

Dexamethasone

Decadron

Steroidal anti-inflammatory agents

0.1-4mg

0.2-3mg

0.2-2mg

0.8mg Q12H

Alpha-streptokinase

Pulmozyme

Mucolytic agent

0.5-5mg

1-4mg

2-3mg

1.5mg Q12H

Doxycycline

Vibramycin

Tetracycline derivatives

10-100mg

15-80mg

25-65mg

27mg Q12H

Erythromycin lactobionate

Erythrocin

Macrolides

50-600mg

60-350mg

100-300mg

150mg Q8H

Fluconazole

Diflucan

Antifungal agent

12.5-150mg

20-70mg

25-50mg

30mg Q12H

Fluniprole

Aerobid Nasalide

Steroidal anti-inflammatory agents

0.1-4mg

0.2-3mg

0.2-2mg

0.8mg Q12H

Flurbiprofen

Ocufen

Nonsteroidal anti-inflammatory agents

0.01-2mg

0.05-1mg

0.1-0.5mg

0.15mg Q12H

Fluticasone

Flonase

Steroidal anti-inflammatory agents

10-700mcg

25-400mcg

75-300mcg

200mcg Q24H

Gentamicin

Garamycin

Aminoglycosides

10-200mg

30-150mg

80-120mg

95mg Q8-12H

Ibuprofen

Motrin

Nonsteroidal anti-inflammatory agents

25-400mg

30-300mg

50-150mg

100mg Q12H

Ipratropium

Atrovent

Anticholinergic agents

10-700mcg

25-400mcg

75-300mcg

200mcg Q12H

Itraconazole

Sporanox

Antifungal agent

12.5-150mg

20-70mg

25-50mg

30mg Q12H

Ketorolac

Acular

Nonsteroidal anti-inflammatory agents

0.05-4mg

0.1-2mg

0.3-1mg

0.5mg Q12H

Levofloxacin

Levaquin

Quinolones

40-200mg

50-150mg

60-80mg

70mg Q12H

Linezolid

Zyvox

Multiple antibacterial agents

50-600mg

75-450mg

100-300ng

200mg Q12H

Loratadine

Claritin

Antihistaminic agent

0.5-10mg

1-7.5mg

1-5mg

2mg Q12H

Meropenem

Merrin

Carbapenem

200-75mg

250-700mg

300-500mg

33mg Q8H

Mezlocillin

Mezlin

Penicillin

300-1500mg

375-1000mg

750-950mg

833mg Q6H

Miconazole

Monistat

Antifungal agent

12.5-300mg

30-200mg

50-100mg

60mg Q12H

Montelukast

Singulair

Anti-leukotriene agents

0.5-15mg

2-25mg

3-15mg

10mg Q12H

Mupirocin

Bactroban

Antibacterial agent

1-25mg

1.5-20mg

2-15mg

10mg Q6-8H

Nafcillin

Unipen

Penicillin

250-1000mg

300-900mg

575-700mg

600mg Q8H

Nedocromil

Tilade

Mast cell stabilizers

1-25mg

3-15mg

5-12mg

7mg Q12H

Ofloxacin

Floxin

Quinolones

25-200mg

50-175mg

75-110mg

90mg Q12H

Oxacillin

Prostaphin

Penicillin

250-1000mg

300-900mg

575-700mg

600mg Q8H

Oxymetazoline

Afrin

Decongestant

0.05-0.5mg

0.075-0.4mg

0.1-0.3mg

0.2mg Q12H

Phenylephrine

Neo-Synephine

Decongestant

5-50mg

10-35mg

15-20mg

10mg Q12H

Piperacillin

Pipracil

Penicillin

100-1000mg

125-750mg

250-600mg

460mg Q6H

Potassium iodide

Preservative

30-200mg

40-150mg

50-80mg

60mg Q12H

Rifampicin

Rifadin

Multiple kinds of

500-5000mg

1000-4000mg

1500-3500mg

2250mg Q12H

Taurolidine

Taurolidine

Non-antibiotic antimicrobial agents

5-200mg

20-150mg

40-120mg

80mg Q12H

Tetralin azolin

Tizine

Decongestant

0.05-0.5mg

0.06-0.4mg

0.1-0.3mg

0.15mg Q12H

Ticarcillin + clavulanic acid

Timentin

Penicillin

500-5000mg

1000-4000mg

1500-3500mg

2250mg Q6-8H

Tobramycin

Nebcin

Aminoglycosides

10-200mg

30-150mg

80-120mg

95mg Q8-12H

Triamcinolone acetonide

Asthmacor Aristocort

Steroidal anti-inflammatory agents

0.05-3mg

0.2-2.5mg

0.5-2mg

0.6mg Q12H

Vancomycin

Vancocin

Multiple antibiotics

50-400mg

75-325mg

125-250mg

166mg Q6-8H

Xylometazoline

Otrivin

Decongestant

0.05-0.4mg

0.075-0.3mg

0.1-0.2mg

0.125mg Q12H

Zafirlukast

Accolate

Anti-leukotriene agents

2-60mg

4-50mg

6-30mg

20mg Q12H

Antibiotic

The formulation of the present invention may further comprise an antibiotic. In addition, since more than one bacterial organism may be associated with a bacterial infection in the nasal-paranasal region, the formulation may contain a broad spectrum antibiotic, such as amoxicillin, erythromycin or cefadroxil. Alternatively, combinations of antimicrobial agents having different activity profiles may be used. Examples of antibiotics for use in the present invention are shown in table 3.

TABLE 3

Antibiotics and dosages

Common name

Name of trade mark

Categories

Preferred ranges

More preferred range

Most preferred range

Most preferred dosage

Amikacin

Amikin

Aminoglycosides

1-800mg

5-500mg

50-300mg

150mg Q8H

Azithromycin

Zithromax

Macrolides

25-400mg

75-300mg

150-200mg

167mg Q12H

Aztreonam

Azactam

Single lactam compound

150-1000mg

300-900mg

475-750mg

450mg Q8H

Cefazolin

Ancef，Kefzol

Cephalosporin (I generation)

150-1000mg

300-900mg

575-700mg

650mg Q8H

Cefepime

Maxipime

Cephalosporin (IV generation)

75-1000mg

200-900mg

575-700mg

650mg Q12H

Cefonicid

Moniacid

Cephalosporin (generation II)

150-1000mg

300-900mg

575-700mg

600mg Q24H

Cefoperazone

Cefobid

Cephalosporin (III generation)

150-1000mg

300-900mg

575-700mg

600mg Q12H

Cefotaxime

Claforan

Cephalosporin (III generation)

150-1000mg

300-900mg

575-700mg

600mg Q8-12H

Cefotetan

Cefotetan

Cephalosporin (cephamycin)

150-1000mg

300-900mg

575-700mg

600mg Q8-12H

Cefoxitin

Mefoxin

Cephalosporin (cephamycin)

150-1000mg

300-900mg

575-700mg

600mg Q12H

Ceftazidime

Fortaz，Ceptaz

Cephalosporin (III generation)

150-1000mg

300-900mg

475-750mg

550mg Q12H

Ceftizoxime

Cefizox

Cephalosporin (III generation)

150-1000mg

300-900mg

575-700mg

600mg Q8-12H

Ceftriaxone

Rocephin

Cephalosporin (III generation)

150-1000mg

300-900mg

575-700mg

650mg Q12H

Cefuroxime

Ceftin

Cephalosporin (generation II)

50-600mg

200-520mg

250-400mg

285mg Q8H

Cefapirin

Cefadyl

Cephalosporin (I generation)

150-1000mg

300-900mg

575-700mg

650mg Q12H

Ciprofloxacin

Cipro

Quinolones

15-200mg

50-175mg

750110mg

90mg Q12H

Clindamycin

Cleocin

Lincose streptamide

25-600mg

75-500mg

125-300mg

225mg Q12H

Doxycycline

Vibramycin

Tetracycline derivatives

10-100mg

15-80mg

25-65mg

27mg Q12H

Erythromycin lactobionate

Erythrocin

Macrolides

25-600mg

60-350mg

100-300mg

150mg Q8H

Gentamicin

Garamycin

Aminoglycosides

1-800mg

5-500mg

50-300mg

150mg Q8H

Kanamycin

Kantrex

Aminoglycosides

1-800mg

5-500mg

50-300mg

150mg Q8H

Linezolid

Zyvox

Multiple antibacterial agents

25-600mg

75-450mg

100-300ng

200mg Q12H

Mezlocillin

Mezlin

Penicillin

100-1500mg

375-1000mg

750-950mg

833mg Q6H

Mupirocin

Bactroban

Antibacterial agent

1-25mg

1.5-20mg

2-15mg

10mg Q6-8H

Nafcillin

Unipen

Penicillin

150-1000mg

300-900mg

575-700mg

600mg Q8H

Netilmicin

Netromycin

Aminoglycosides

1-800mg

5-500mg

50-300mg

150mg Q8H

Neomycin

Mycifradin

Aminoglycosides

1-800mg

5-500mg

50-300mg

150mg Q8H

Oxacillin

Prostaphin

Penicillin

150-1000mg

300-900mg

575-700mg

600mg Q8H

Paromomycin

Humatin

Aminoglycosides

1-800mg

5-500mg

50-300mg

150mg Q8H

Piperacillin

Pipracil

Penicillin

50-1000mg

125-750mg

250-600mg

460mg Q6H

Streptomycin

Aminoglycosides

1-800mg

5-500mg

50-300mg

150mg Q8H

Ticarcillin + clavulanic acid

Timentin

Penicillin

200-5000mg

1000-4000mg

1500-3500mg

2250mg Q6-8H

Tobramycin

Aminoglycosides

1-800mg

5-500mg

50-300mg

150mg Q8H

Vancomycin

Vancocin

Multiple antibiotics

25-400mg

75-325mg

125.250mg

166mg Q6-8H

Antiviral agents

The formulations of the present invention may comprise a therapeutically effective amount of one or more antiviral agents. These drugs may be administered separately or simultaneously with the steroid of the invention. Antiviral agents may include acyclovir, famciclovir, valacyclovir, edexuridine, ganciclovir, foscarnet, cidofovir (cidovir) (vistide), ganciclovir intravitreal implant (vitristert), fomivirsen (Formivirsen), HPMPA (9- (3-hydroxy-2-phosphonomethoxypropyl) adenine), PMEA (9- (2-phosphonomethoxyethyl) adenine), HPMPG (9- (3-hydroxy-2- (phosphonomethoxy) propyl) guanine), PMEG (9- [2- (phosphonomethoxy) ethyl ] guanine), HPMPC (1- (2-phosphonomethoxy-3-hydroxypropyl) -cytosine), ribavirin, EICAR (5-ethynyl-1-beta-D-ribofuranosyl imidazole-4-methylamine), pyrazofurin (3- [ beta-D-ribofuranosyl ] -4-hydroxypyrazole-5-amide), 3-Deazaguanine, GR-92938X (1-beta-D-ribofuranosyl pyrazole-3, 4-diamide), LY253963(1, 3, 4-thiadiazol-2-yl-cyanamide), RD3-0028(1, 4-dihydro-2, 3-benzodiazepine), CL387626(4, 4 '-bis [4, 6-bis [ 3-aminophenyl-N, N-bis (2-carbamoylethyl) sulfoimino ] -1, 3, 5-triazin-2-ylaminobiphenyl-2, 2' -disulfonic acid disodium salt), BABIM (bis [ 5-amidino-2-benzimidazolyl ] methane) and NIH 351.

Other suitable dosages and treatment methods for the compositions described herein are described in US2001/0006944A1, published as 2001, 7/5, which is incorporated herein by reference in its entirety.

Other Components

The formulation of the present invention may be in any dosage form so long as the formulation is administered to a mammal in an amount, frequency, and duration effective to prevent, reduce, or eliminate one or more symptoms associated with sinusitis, including fungal-induced sinusitis. For example, formulations within the scope of the present invention may be in the form of solids, liquids and/or aerosols, including without limitation powders, crystals, gel pastes, ointments, salves, creams, solutions, suspensions, semi-liquids, sprays (spray), sprays (nebula), mists, nebulized vapors, tinctures, pills, capsules, tablets and gelcaps (gelcap). In addition, the formulation may contain cocktail reagents of other ingredients, particularly those described herein. For example, formulations within the scope of the present invention may contain, without limitation, one, two, three, four, five or more of the various antifungal, antibiotic, antiviral or other ingredients described herein. Furthermore, the preparations within the scope of the invention may contain additional ingredients

And include, without limitation, pharmaceutically acceptable aqueous carriers, pharmaceutically acceptable solid carriers, steroids, mucolytics, antimicrobials, anti-inflammatory agents, immunosuppressive agents, dilators, vasoconstrictors, decongestants, leukotriene inhibitors, anticholinergics, antihistamines, therapeutic compounds, and combinations thereof. Such antiviral agents may include IMPDH inhibitors, viral adsorption entry inhibitors, fusion with host cells inhibitors, antisense oligonucleotides, and nucleoside analogs.

In one embodiment, the formulation may be in any form suitable for intranasal administration. In another alternative embodiment, the formulation of the present invention is in the form of a solution or suspension suitable for intranasal administration.

In one embodiment, the formulation of the present invention may contain preservatives, suspending agents, wetting agents, tonicity agents and/or diluents. In one embodiment, the formulations provided herein may comprise from about 0.01% to about 95%, or from about 0.01% to about 50%, or from about 0.01% to about 25%, or from about 0.01% to about 10%, or from about 0.01% to about 5%, of one or more pharmacologically suitable suspending fluids, which are physiologically acceptable upon administration. Pharmacologically suitable fluids for use herein include, but are not limited to, polar solvents, including, but not limited to, compounds containing hydroxyl or other polar groups. Solvents include, but are not limited to, water or alcohols, such as ethanol, isopropanol, and polyols, including propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, glycerol, and polyoxyethylene alcohols. Polar solvents also include protic solvents including, but not limited to, water, aqueous salt solutions containing one or more pharmaceutically acceptable salts, alcohols, glycols, or mixtures thereof. In an alternative embodiment, the water used in the formulation should meet or exceed regulatory requirements for the drug.

In certain embodiments herein, the formulations of the present invention have a pH of about 2.0 to about 9.0. Optionally, the formulations of the present invention may contain a pH buffer. For example, the buffer may comprise any known pharmacologically suitable buffer which is physiologically acceptable following intranasal administration. The addition of a buffer can maintain the pH of the formulation between, for example, about 3.0 and about 7.0.

Sterile or substantially antimicrobial preservation may be provided as part of the formulation. Since certain formulations of the present invention are intended for intranasal administration, it is preferred that they be free of pathogenic organisms. The benefit of a sterile liquid suspension is that it reduces the likelihood of introducing contaminants into an individual when the suspension formulation is administered intranasally, thereby reducing the likelihood of opportunistic infections. It is contemplated that the process of achieving sterility may include any suitable sterilization step known in the art.

In one embodiment, the formulation of the present invention is produced under sterile conditions, the steroidal anti-inflammatory agent is micronized in a sterile environment, mixed under sterile conditions, and packaged. In an alternative embodiment, one or more of the ingredients of the formulation may be steam, gamma radiation sterilized, or prepared using or mixing sterile steroid powders and other sterile ingredients as appropriate. Moreover, the formulations may be prepared and disposed of under sterile conditions, or may be sterilized before or after packaging.

In addition to or as an alternative to sterilization, the formulations of the present invention may contain a pharmaceutically acceptable preservative to minimize the possibility of microbial contamination. In addition, pharmaceutically acceptable preservatives can be used in the formulation to increase the stability of the formulation. It should be noted, however, that any preservative must be selected for safety, as the tissue being treated may be sensitive to the stimulus. Preservatives suitable for use herein include, but are not limited to, those that protect the solution from contamination by pathogenic particles, including phenylethyl alcohol, benzalkonium chloride, benzoic acid, or benzoates, such as sodium benzoate. Preferably, the preservative used in the formulation is benzalkonium chloride or phenylethyl alcohol. In certain embodiments, the formulations herein comprise from about 0.01% to about 1.0% w/w benzalkonium chloride or from about 0.01% to about 1% v/w phenylethyl alcohol. Preservatives can also be present in amounts of about 0.01% to about 1%, preferably about 0.002% to about 0.02%, by total weight or volume of the composition.

The formulations provided herein may also comprise from about 0.01% to about 90%, or from about 0.01% to about 50%, or from about 0.01% to about 25%, or from about 0.01% to about 10%, or from about 0.01% to about 1% w/w of one or more emulsifying agents, wetting agents, or suspending agents. Such agents for use herein include, but are not limited to, polyoxyethylene sorbitan fatty esters or polysorbates, including, but not limited to, polyethylene sorbitan monooleate (polysorbate 80), polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 65 (polyoxyethylene (20) sorbitan tristearate), polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate; lecithin; alginic acid; sodium alginate; potassium alginate; ammonium alginate; calcium alginate; propylene-1, 2-glycol alginate; agar; carrageenan; locust bean gum; guar gum; gum tragacanth; acacia gum; xanthan gum; kara gum; pectin; amidated pectin; ammonium phosphatide; microcrystalline cellulose; methyl cellulose; hydroxypropyl cellulose; hydroxypropyl methylcellulose; ethyl methyl cellulose; a carboxymethyl cellulose; sodium, potassium and calcium salts of fatty acids; mono-and diglycerides of fatty acids; acetic acid esters of mono-and diglycerides of fatty acids; lactic acid esters of mono-and diglycerides of fatty acids; citric acid esters of mono-and diglycerides of fatty acids; tartaric acid esters of mono-and diglycerides of fatty acids; mono-and diacetyl tartaric acid esters of mono-and diglycerides of fatty acids; mixed acetic and tartaric esters of mono-and diglycerides of fatty acids; sucrose esters of fatty acids; sucrose glyceride; polyglycerol esters of fatty acids; polyglycerol esters of condensed fatty acids of castor oil; 1, 2-diol esters of fatty acids; sodium stearoyl-2 lactylate; calcium stearoyl-2-lactate; stearoyl tartrate; sorbitan monostearate; sorbitan tristearate; sorbitan monolaurate; sorbitan monooleate; sorbitan monopalmitate; quillaja saponaria extract; polyglycerol esters of dimerized fatty acids of soybean oil; oxidatively polymerizing soybean oil; and a pectin extract. In certain embodiments herein, the formulation comprises polysorbate 80, microcrystalline cellulose, sodium carboxymethylcellulose, and/or glucose.

The formulation may further comprise from about 0.01% to about 90%, or from about 0.01% to about 50%, or from about 0.01% to about 25%, or from about 0.01% to about 10%, or from about 0.01% to about 1% of one or more pharmacologically suitable excipients and additives. Excipients and additives generally have no pharmacological activity, or at least no undesirable pharmacological activity. Their concentration may vary depending on the agent selected, although the presence or absence of such agents or their concentration is not an essential feature of the invention. Excipients and additives may include, but are not limited to, surfactants, humectants, stabilizers, complexing agents, antioxidants, or other additives known in the art. Complexing agents include, but are not limited to, ethylenediaminetetraacetic acid (EDTA) or salts thereof, such as the disodium salt, citric acid, nitrilotriacetic acid, and salts thereof. In another embodiment, particularly in the suspension formulations provided herein, the complexing agent is sodium edetate. In one embodiment, the composition contains sodium edetate at a concentration of from about 0.05mg/mL to about 0.5mg/mL or from about 0.1mg/mL to about 0.2 mg/mL. Also for example, the formulations of the present invention may contain from about 0.001% to about 5% by weight of a humectant to inhibit mucosal drying and prevent irritation. Any of a variety of pharmaceutically acceptable humectants may be employed, including, for example, sorbitol, propylene glycol, polyethylene glycol, glycerol, or mixtures thereof.

The formulations provided herein may also comprise from about 0.01% to about 90%, or from about 0.01% to about 50%, or from about 0.01% to about 25%, or from about 0.01% to about 10% w/w of one or more solvents or co-solvents to increase the solubility of any component of the formulation. Solvents or co-solvents for use herein include, but are not limited to, hydroxylated solvents or other pharmaceutically acceptable polar solvents, such as alcohols, including isopropanol, glycols, such as propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, glycerol, and polyoxyethylene alcohols. In another embodiment, the formulation of the present invention may comprise one or more conventional diluents known in the art. The preferred diluent is purified water.

Tonicity agents may include, but are not limited to, sodium chloride, potassium chloride, zinc chloride, calcium chloride, and mixtures thereof. Other tonicity adjusting agents may also include, but are not limited to, mannitol, glycerol, and glucose or mixtures thereof. In alternative embodiments, the formulation may comprise from about 0.01% to about 10% w/w, or from about 1% to about 8% w/w, or from 1% to about 6% w/w, preferably about 5.0% w/w. The preferred tonicity agent is anhydrous dextrose.

In an alternative embodiment, the formulation of the invention is stable. As used herein, the stability of a formulation provided by the present invention means the length of time that greater than 80%, 85%, 90% or 95% of the initial amount of active ingredient is present in the formulation at a given temperature. For example, the formulations provided herein can be stored between about 15 ℃ and about 30 ℃ stable for at least 1, 2, 12, 18, 24, or 36 months. Moreover, the formulations may be stored at 25 ℃ for more than 1, 2, 12, 18, 24, or 36 months and still be suitable for administration to a patient in need thereof. Moreover, in another alternative embodiment, the formulation retains more than 80%, or more than 85%, or more than 90%, or more than 95% of the initial amount of the active ingredient after storage between about 15 ℃ and about 30 ℃ for more than 1, 2, 12, 18, 24, or 36 months using arrhenius kinetics.

The formulations of the present invention may be manufactured in any conventional manner known in the art or with minor adjustments to such means. For example, the formulations can be prepared by intimately mixing the ingredients described herein at ambient or elevated temperature, if appropriate to achieve solubility of the ingredients.

The preparation of steroidal anti-inflammatory agents of the present invention, such as fluticasone propionate and beclomethasone dipropionate, having specific particle size distribution characteristics may be obtained by any conventional means known in the art or by minor adjustments of such means. For example, suspensions of drug particles are susceptible to particle size reduction when subjected to the "jet milling" (high pressure particles in liquid milling) technique. Other known methods for reducing particle size to the micron range include mechanical milling, application of ultrasonic energy, and other techniques.

In addition, the formulation of the present invention may comprise any of the following components: (i) an antihistamine; (ii) a non-steroidal anti-inflammatory agent; (iii) a decongestant; (iv) a mucolytic agent; (v) an anticholinergic agent; or (vi) a mast cell stabilizer. Examples of such components are given in US 2002/0061281a1, published as 2002, 5/23. The entire disclosure of which is incorporated herein by reference.

In an alternative embodiment, the invention relates to a pharmaceutical composition that can be used for the treatment of sinusitis caused by the following fungi: alpha hemolytic streptococcus, beta hemolytic streptococcus, branhamella catarrhalis, Diptheroids, Haemophilus influenzae (beta-lactamase positive and negative), Moraxella, Pseudomonas aeruginosa, Pseudomonas maltophilia, Serratia marcescens, Staphylococcus aureus, Streptococcus pneumoniae, Aspergillus, Mucor, Candida albicans, Flusarium, Curvularia, Cryptococcus, Coccidioides and Histoplasma.

Mode of administration

The administration of the formulation may be of any type that allows the formulation to be brought into contact with the nasal-paranasal mucosa. Direct intranasal administration includes, without limitation, nasal irrigation, nasal spray, nasal inhalation, and nasal tamponade, e.g., with saturated gauze, so long as the administered ingredient comes into contact with the nasal-paranasal mucosa and then passes through the epithelium. Alternatively, injection into the paranasal-paranasal cavity, e.g. using a needle or catheter, is considered as a direct intranasal administration, provided that the administered composition contacts the paranasal-nasal mucosa and then passes through the epithelium after withdrawal of the needle or catheter. The formulation can be administered intranasally directly using any device, including without limitation, syringes, balloons, inhalers, canisters, spray cans, nebulizers, and face masks.

Indirect administration to the nasal-paranasal structure may include, without limitation, oral, intravenous, intradermal, and intraperitoneal administration, as long as the administered ingredient is in contact with the nasal-paranasal mucosa. In addition, any device may be used to indirectly administer the drug to the nasal-paranasal structure, including without limitation syringes and adjustable release capsules.

The formulations may be packaged in any convenient manner suitable for administration of the formulations of the invention. Spray delivery containers for various types of nasal formulations known in the past will be essentially equally suitable for the formulations of the present invention, provided that the container material is compatible with the formulation. In one embodiment, the formulation of the present invention is packaged in a container such that it may be aerosolized into each nostril. For example, the container may be made of a soft plastic material so that squeezing the sides of the bottle forces the spray through the nozzle and into the nasal cavity. Alternatively, pressing a small pump button may pump air into the container, causing the liquid aerosol to be sent to the return stroke.

In an alternative embodiment, the formulation of the invention may be packaged in a container pressurized with a gas that is inert to the user and the solution composition. The gas may be dissolved in the vessel under pressure, or may result from the dissolution or reaction of a solid material, producing the gas as a dissolved product or reaction product. Suitable inert gases that may be used include nitrogen, argon and carbon dioxide. Moreover, the formulations herein may be administered as a spray or aerosol, wherein the formulation is contained in a pressurized container containing a liquid propellant, such as dichlorodifluoromethane or chlorotrifluoroethylene, and the like.

Preferably, the formulation is packaged in a metered dose spray pump or a metered dose atomising pump so that a fixed volume of formulation (i.e. each spray unit) is delivered per actuation of the pump. For administration in drops or other topical dosage forms, the formulations herein may suitably be packaged in containers with conventional dropper/closure means, including pipettes and the like, preferably delivering a substantially fixed volume of the formulation.

Method of treatment

The invention also relates to methods of treating sinusitis, including fungi-induced sinusitis. In one embodiment, the method of treating sinusitis according to the present invention comprises the step of administering to a mammal in need thereof a therapeutically effective amount of a formulation of the present invention. The formulations may comprise the steroid of the invention alone or in combination with an antifungal, antibiotic or antiviral agent. The formulation is preferably administered intranasally. In one embodiment, the formulation is administered directly to the nasal-paranasal mucosa. In an alternative embodiment, the formulation is administered intranasally via a metered dose spray pump. In general, any individual course of treatment for any active ingredient described herein can be readily determined by his or her physician.

The methods of the present invention may further comprise administering the formulations of the present invention for a duration or frequency sufficient to treat one or more symptoms of sinusitis, including fungal-induced sinusitis. For example, the formulation may be administered from 1 to about 10 times a day for from about 1 to about 100 days or more, or until such fungi-induced rhinosinusitis is cured. In one embodiment, the method of the invention comprises intranasally administering a formulation comprising a therapeutically effective amount of an antifungal agent and a steroidal anti-inflammatory agent via a metered dose spray pump to a mammal diagnosed with fungal-induced sinusitis, one to three times daily for up to two weeks. In alternative embodiments, administration of the formulation may comprise administering 1, 2, 3, 4, 5, 6, 7, or 8 doses of the formulation to the nasal-paranasal mucosa, one, two, three, four, or five times daily.

In an alternative embodiment, the formulation of the method of the invention further comprises an antibiotic. However, when administering antibiotics, physicians must remember the incidence of drug-resistant bacteria in their populations and take into account the overall health status of the patient. Particular attention should be paid to diseases that may interfere with the normal recovery of the infection and/or that are predisposed to complications (e.g., diabetes, chronic lung disease, asthma, cystic fibrosis, and immunodeficiency). In addition, the physician should consider whether the patient is immune-free when selecting the antibiotic. In one embodiment, the antibiotic is administered for a period of 1 day to about 10 weeks. In an alternative embodiment, the antibiotic is administered for a period of about 1 day to about 28 days.

Accordingly, the present invention provides a method of treating fungal-induced rhinosinusitis associated with bacterial infection of the nasal-paranasal region, comprising the steps of: administering a formulation comprising an antifungal agent, a steroidal anti-inflammatory agent and an antibiotic until the bacterial infection is cured, and then administering a formulation comprising an antifungal agent and a steroidal anti-inflammatory agent.

In an alternative embodiment, the present invention provides a method of treating fungal-induced rhinosinusitis, comprising the steps of: the formulation comprising the steroidal anti-inflammatory agent is administered alone or in combination or association with an anti-fungal, antibiotic or anti-viral agent. For example, the steroid may be administered separately from the antifungal or antibiotic, or each component may be administered simultaneously (e.g., in a single formulation), concurrently, subsequently or sequentially. In another embodiment, each component is administered separately in its own formulation and according to a dosage regimen appropriate for that particular component. Dosage regimes suitable for steroid drugs, antifungal agents, antibiotics or antiviral agents are known to those skilled in the art.

V. examples

Examples 1-5 herein are prophetic examples, which are intended to illustrate, but not limit, the formulations and methods of the present invention. It will be appreciated that variations to the specific compositions may be made and may be required in order to obtain or optimise a formulation. Such adaptations of the following prophetic examples are normal and will be understood by those skilled in the art and should not be used to limit the invention, if desired.

It is believed that prophetic examples 1-5 will be suitable for nasal-paranasal mucosal administration to an individual suffering from fungal induced rhinosinusitis associated with bacterial infection. The formulation may be sterile. It will be appreciated that the steroids, antibiotics, antifungals, or other ingredients described herein may be administered in the same formulation, or may be administered alone, or any combination thereof.

Example 1

Amphotericin B	2.0-100.0mg/ml
		Neomycin sulfate	5.0-100.0mg/ml
Phenylethanolic acid	0.5-10.0mg/ml
		Fluticasone propionate	0.25-1.0mg/ml
Microcrystalline cellulose	5.0-15.0mg/ml
		Polysorbate 80	0.1-1.0mg/ml
Purified water	Proper amount of

Example 1 is one prophetic example of a formulation of the present invention, wherein about 10% of the fluticasone propionate particles have a particle size of less than 0.70 microns; about 25% of the fluticasone propionate particles have a particle size of less than 1.30 microns; about 50% of the fluticasone propionate particles have a particle size of less than 2.5 microns; about 75% of the fluticasone propionate particles have a particle size of less than 4.0 microns; about 90% of the fluticasone propionate particles have a particle size of less than 6.0 microns; greater than 90% or about 100% of the fluticasone propionate particles have a particle size of less than 10 microns. The solution of example 1 can be prepared by methods known to those of ordinary skill in the art.

Example 2

Fluconazole	1.0-20.0mg/ml
		Neomycin sulfate	5.0-100.0mg/ml
Phenylethanolic acid	0.5-10.0mg/ml
		Fluticasone propionate	0.25-1.0mg/ml
Microcrystalline cellulose	5.0-15.0mg/ml
		Polysorbate 80	0.1-1.0mg/ml
Purified water	Proper amount of

Example 2 is one prophetic example of a formulation of the present invention, wherein about 10% of the fluticasone propionate particles have a particle size of less than 0.70 microns; about 25% of the fluticasone propionate particles have a particle size of less than 1.30 microns; about 50% of the fluticasone propionate particles have a particle size of less than 2.5 microns; about 75% of the fluticasone propionate particles have a particle size of less than 4.0 microns; about 90% of the fluticasone propionate particles have a particle size of less than 6.0 microns; greater than 90% or about 100% of the fluticasone propionate particles have a particle size of less than 10 microns. The solution of example 2 can be prepared by methods known to those of ordinary skill in the art.

Example 3

Amphotericin B	2.0-100.0mg/ml
		Neomycin sulfate	5.0-100.0mg/ml
Benzalkonium chloride	0.1-0.5mg/ml
		Glucose	20.0-100.0
Phenylethanolic acid	0.5-10.0mg/ml
		Beclomethasone dipropionate	0.25-1.0mg/ml
Purified water	Proper amount of

Example 3 is a prophetic example of a formulation of the present invention, wherein about 10% of the beclometasone dipropionate particles have a particle size of less than 0.40 microns; about 25% of the beclomethasone dipropionate particles have a particle size of less than 0.70 microns; about 50% of the beclomethasone dipropionate particles have a particle size of less than 1.3 microns; about 75% of the beclomethasone dipropionate particles have a particle size of less than 2.0 microns; about 90% of the beclomethasone dipropionate particles have a particle size of less than 3.0 microns; greater than 90% or about 100% of the beclometasone dipropionate particles have a particle size of less than 6.0 microns. Example 3 can be prepared by methods known to those of ordinary skill in the art.

Example 4

Fluconazole	1.0-20.0mg/ml
		Neomycin sulfate	5.0-100.0mg/ml
Benzalkonium chloride	0.1-0.5mg/ml
		Glucose	20.0-100.0
Phenylethanolic acid	0.5-10.0mg/ml
		Beclomethasone dipropionate	0.25-1.0mg/ml
Purified water	Proper amount of

Example 4 is a prophetic example of a formulation of the present invention, wherein about 10% of the beclometasone dipropionate particles have a particle size of less than 0.40 microns; about 25% of the beclomethasone dipropionate particles have a particle size of less than 0.70 microns; about 50% of the beclomethasone dipropionate particles have a particle size of less than 1.3 microns; about 75% of the beclomethasone dipropionate particles have a particle size of less than 2.0 microns; about 90% of the beclomethasone dipropionate particles have a particle size of less than 3.0 microns; greater than 90% or about 100% of the beclometasone dipropionate particles have a particle size of less than 6.0 microns. Example 4 can be prepared by methods known to those of ordinary skill in the art.

Example 5

Fluconazole	1.0-20.0mg/ml
		Benzalkonium chloride	0.1-0.5mg/ml
Glucose	20.0-100.0
		Phenylethanolic acid	0.5-10.0mg/ml
Beclomethasone dipropionate	0.25-1.0mg/ml
		Purified water	Proper amount of

Example 5 is a prophetic example of a formulation of the present invention, wherein about 10% of the beclometasone dipropionate particles have a particle size of less than 0.40 microns; about 25% of the beclomethasone dipropionate particles have a particle size of less than 0.70 microns; about 50% of the beclomethasone dipropionate particles have a particle size of less than 1.3 microns; about 75% of the beclomethasone dipropionate particles have a particle size of less than 2.0 microns; about 90% of the beclomethasone dipropionate particles have a particle size of less than 3.0 microns; greater than 90% or about 100% of the beclometasone dipropionate particles have a particle size of less than 6.0 microns. Example 5 can be prepared by methods known to those of ordinary skill in the art.

The examples herein are for illustrative purposes only. They are not intended to limit the scope of the invention. Further, it should be understood that various changes and modifications to the preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present invention and without diminishing its attendant advantages. Such changes and modifications are therefore intended to be covered by the appended claims. Moreover, the invention may suitably comprise, consist of, or consist essentially of the elements or steps described herein. Further, the invention described herein suitably may comprise or be practiced in the absence of any element or step which is not specifically disclosed herein. Further, one or more steps described herein may be performed concurrently with another step.

Claims (36)

1. A nasal formulation for treating fungal-induced rhinosinusitis in a mammal, the formulation comprising an aqueous suspension comprising:

(a)1 to 700 meg of a suspended solid steroidal anti-inflammatory agent, wherein the steroidal anti-inflammatory agent is fluticasone or a pharmaceutically acceptable derivative thereof, said steroidal anti-inflammatory agent having the following particle size distribution profile:

i.10% of the steroidal anti-inflammatory agent particles have a particle size of less than 0.5 microns;

ii.25% of the steroidal anti-inflammatory agent particles have a particle size of less than 0.9 microns;

iii.50% of the steroidal anti-inflammatory agent particles have a particle size of less than 1.7 microns;

iv.75% of the steroidal anti-inflammatory agent particles have a particle size of less than 3.5 microns; and

v.90% of the steroidal anti-inflammatory agent particles have a particle size of less than 5.5 microns;

wherein the formulation is suitable for administration to the nasal-paranasal mucosa; and

(b) an antifungal agent, wherein the amount of antifungal agent is 0.5-150 mg; wherein the formulation is suitable for administration to the nasal-paranasal mucosa.

2. The nasal formulation of claim 1, wherein 100% of the particles have a particle size of less than 7.0 microns.

3. A nasal formulation for treating fungal-induced rhinosinusitis in a mammal, the formulation comprising an aqueous suspension comprising:

(a)1 to 700mcg of a suspended solid steroidal anti-inflammatory agent, wherein the steroidal anti-inflammatory agent is beclomethasone or a pharmaceutically acceptable derivative thereof, said steroidal anti-inflammatory agent having the following particle size distribution profile:

i.10% of the steroidal anti-inflammatory agent particles have a particle size of less than 0.35 microns;

ii.25% of the steroidal anti-inflammatory agent particles have a particle size of less than 0.7 microns;

iii.50% of the steroidal anti-inflammatory agent particles have a particle size of less than 1.25 microns;

iv.75% of the steroidal anti-inflammatory agent particles have a particle size of less than 2.0 microns;

v.90% of the steroidal anti-inflammatory agent particles have a particle size of less than 3.0 microns; and

vi greater than 90% or about 100% of the steroidal anti-inflammatory agent particles have a particle size of less than 6.5 microns; and

(b) an antifungal agent, wherein the amount of antifungal agent is 0.5-150 mg; wherein the formulation is suitable for administration to the nasal-paranasal mucosa.

4. A nasal formulation according to claim 3 wherein 100% of the particles have a particle size of less than 6.0 microns.

5. The nasal preparation according to claim 1 or 3, further comprising at least one complexing agent selected from the group consisting of ethylenediaminetetraacetic acid, citric acid, nitrilotriacetic acid and salts thereof, and sodium ethylenediaminetetraacetate.

6. The nasal formulation of claim 5, wherein the formulation comprises 7.5 to 15mg amphotericin β.

7. The nasal formulation of claim 5, wherein the formulation comprises 20 to 70mg of fluconazole or itraconazole.

8. The nasal formulation of claim 5, wherein the formulation comprises 30mg of fluconazole or itraconazole and a therapeutically effective amount of an antiviral agent selected from the group consisting essentially of acyclovir, famciclovir, valacyclovir, edexuridine, ganciclovir, foscarnet, cidofovir, ganciclovir intravitreal implant, and fomivirse.

9. A nasal formulation according to claim 1 comprising 25 to 400mcg of said steroidal anti-inflammatory agent.

10. A nasal formulation according to claim 3 containing 0.2 to 3mg of said steroidal anti-inflammatory agent.

11. The nasal formulation of claim 1, wherein the formulation is sterile.

12. The nasal formulation of claim 1, wherein the formulation further comprises a preservative.

13. The nasal formulation of claim 12, wherein the preservative is benzalkonium chloride.

14. The nasal formulation of claim 1, wherein the formulation is stable.

15. The nasal formulation of claim 5, wherein the formulation is in a metered dose spray pump bottle.

16. The nasal formulation of claim 5, further comprising 0.01% to 90% by weight of one or more of the following compounds, calculated on a dry weight basis:

(a) microcrystalline cellulose;

(b) sodium carboxymethylcellulose;

(c) glucose;

(d) benzalkonium chloride;

(e) polysorbate 80; and

(g) and (3) phenethyl alcohol.

17. The nasal formulation of claim 1, further comprising an antibiotic.

18. The nasal formulation of claim 17, wherein the antibiotic is one or more selected from the group consisting of: amikacin, azithromycin, aztreonam, ceftizole, cefepime, cefonicid, cefoperazone, cefotaxime, cefotetan, cefoxitin, ceftazidime, ceftizoxime, ceftriaxone, cefuroxime, cefapirin, ciprofloxacin, clindamycin, doxycycline, erythromycin lactobionate, gentamicin, kanamycin, linezolid, mezlocillin, mupirocin, nafcillin, netilmicin, neomycin, oxacillin, paromomycin, piperacillin, streptomycin, ticarcillin, tobramycin, and vancomycin.

19. The nasal formulation of claim 17, wherein the formulation comprises 1 to 800mg neomycin sulfate.

20. The nasal formulation of claim 17, wherein the formulation comprises 5 to 500mg neomycin sulfate.

21. The nasal formulation of claim 17, wherein the formulation comprises 50 to 300mg neomycin sulfate.

22. The nasal formulation of claim 17, wherein the formulation comprises 150 neomycin sulfate.

23. Use of a formulation in the manufacture of a medicament for treating fungal-induced rhinosinusitis in a mammal, the formulation comprising an aqueous suspension comprising:

(a)1 to 700 meg of a suspended solid steroidal anti-inflammatory agent, wherein the steroidal anti-inflammatory agent is fluticasone or a pharmaceutically acceptable derivative thereof, said steroidal anti-inflammatory agent having the following particle size distribution profile:

i.10% of the steroidal anti-inflammatory agent particles have a particle size of less than 0.5 microns;

ii.25% of the steroidal anti-inflammatory agent particles have a particle size of less than 0.9 microns;

iii.50% of the steroidal anti-inflammatory agent particles have a particle size of less than 1.7 microns;

iv.75% of the steroidal anti-inflammatory agent particles have a particle size of less than 3.5 microns; and

v.90% of the steroidal anti-inflammatory agent particles have a particle size of less than 5.5 microns; and

(b) an antifungal agent, wherein the amount of antifungal agent is 0.5-150 mg; wherein the formulation is suitable for administration to the nasal-paranasal mucosa.

24. The use of claim 23, wherein 100% of the particles have a particle size of less than 7.0 microns.

25. Use of a formulation in the manufacture of a medicament for treating fungal-induced rhinosinusitis in a mammal, the formulation comprising an aqueous suspension comprising:

(a)1 to 700mcg of a suspended solid steroidal anti-inflammatory agent, wherein the steroidal anti-inflammatory agent is beclomethasone or a pharmaceutically acceptable derivative thereof, said steroidal anti-inflammatory agent having the following particle size distribution profile:

i.10% of the steroidal anti-inflammatory agent particles have a particle size of less than 0.35 microns;

ii.25% of the steroidal anti-inflammatory agent particles have a particle size of less than 0.7 microns;

iii.50% of the steroidal anti-inflammatory agent particles have a particle size of less than 1.25 microns;

iv.75% of the steroidal anti-inflammatory agent particles have a particle size of less than 2.0 microns;

v.90% of the steroidal anti-inflammatory agent particles have a particle size of less than 3.0 microns; and

vi greater than 90% or about 100% of the steroidal anti-inflammatory agent particles have a particle size of less than 6.5 microns; and

(b) an antifungal agent, wherein the amount of antifungal agent is 0.5-150 mg; wherein the formulation is suitable for administration to the nasal-paranasal mucosa.

26. Use according to claim 25, wherein 100% of the particles have a particle size of less than 6.0 microns.

27. The use of claim 23 or 25, said formulation further comprising an antifungal agent selected from the group consisting of amphotericin β, fluconazole, and itraconazole.

28. The use of claim 27, wherein the formulation comprises 4mg to 30mg amphotericin β.

29. The use of claim 27, wherein the formulation comprises 20 to 70mg of fluconazole or itraconazole.

30. The use of claim 23, wherein said formulation comprises 25 to 400mcg of said steroidal anti-inflammatory agent.

31. The use of claim 27, wherein the formulation is in a metered dose spray pump bottle.

32. The use of claim 23 or 25, wherein the formulation is administered topically to the nasal-paranasal mucosa of the mammal from 1 to 10 times per day.

33. The use of claim 23 or 25, further comprising the step of administering an antibiotic to said mammal, wherein said mammal is diagnosed with a bacterial infection of the nasal-paranasal mucosa.

34. The use of claim 23 or 25, wherein the formulation further comprises an antibiotic.

35. The use of claim 34, wherein the formulation comprises 1 to 800mg neomycin sulfate.

36. The use of claim 34, wherein the formulation is a sterile aqueous suspension in a metered dose spray pump bottle, wherein the formulation is administered to said mammal by spraying in each nostril 1 to 10 times per day.