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WO2009058147A1 - Particules polymères chargeables pour une utilisation thérapeutique dans un dysfonctionnement érectile - Google Patents

Particules polymères chargeables pour une utilisation thérapeutique dans un dysfonctionnement érectile Download PDF

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Publication number
WO2009058147A1
WO2009058147A1 PCT/US2007/083216 US2007083216W WO2009058147A1 WO 2009058147 A1 WO2009058147 A1 WO 2009058147A1 US 2007083216 W US2007083216 W US 2007083216W WO 2009058147 A1 WO2009058147 A1 WO 2009058147A1
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WO
WIPO (PCT)
Prior art keywords
particles
phosphazene
bis
poly
polymeric particles
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Application number
PCT/US2007/083216
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English (en)
Inventor
Ulf Kritz
Olaf Fritz
Ronald Wojcik
Ralph E. Gaskins
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Celonova Biosciences, Inc.
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Priority to PCT/US2007/083216 priority Critical patent/WO2009058147A1/fr
Publication of WO2009058147A1 publication Critical patent/WO2009058147A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence

Definitions

  • microspheres and nanospheres have many medical uses in diagnostic and therapeutic procedures. In selected clinical applications, it may be advantageous to provide such microspheres and nanospheres to deliver active agents for the treatment of erectile dysfunction in mammals.
  • Erectile dysfunction (ED or (male) impotence) is a sexual dysfunction characterized by the inability to develop or maintain an erection of the penis.
  • ED Erectile dysfunction
  • erectile dysfunction may be physiological or psychological.
  • Physiologically erection is a hydraulic mechanism based upon blood entering and being retained in the penis, and there are various ways in which this can be impeded, most of which are amenable to treatment.
  • Psychological impotence is where erection or penetration fails due to thoughts or feelings (psychological reasons) rather than physical impossibility; this can often be helped. Notably in psychological impotence there is a very strong placebo effect.
  • Erectile dysfunction tied closely as it is to cultural notions of potency, success and masculinity, can have devastating psychological consequences including feelings of shame, loss or inadequacy; often unnecessary since in most cases the matter can be helped.
  • Peniie erection is managed by two different mechanisms. The first one is the reflex erection, which is achieved by directly touching the penile shaft. The second is the psychogenic erection, which is achieved by erotic or emotional stimuli.
  • the former uses the peripheral nerves and the lower parts of the spinal cord, whereas the latter uses the limbic system of the brain, In both conditions an intact neural system is required for a successful and complete erection.
  • Stimulation of penile shaft by the nervous system leads to the secretion of nitric oxide (NO), which causes the relaxation of smooth muscles of corpora cavernosa (the main erectile tissue of penis), and subsequently penile erection.
  • NO nitric oxide
  • Neurogenic Disorders spinal cord and brain injuries, nerve disorders such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, and stroke.
  • Hormonal Disorders pituitary gland tumor; low level of the hormone testosterone
  • Nonphysical causes Mental disorders (clinical depression, schizophrenia, substance abuse, panic disorder, generalized anxiety disorder, personality disorders or traits.), psychological problems, negative feelings. • Surgery (radiation therapy, surgery of the colon, prostate, bladder, or rectum may damage the nerves and blood vessels involved in erection. Prostate and bladder cancer surgery often require removing tissue and nerves surrounding a tumor, which increases the risk for impotence.) • Aging.
  • a few causes of impotence may be iatrogenic (medically caused).
  • Various antihypertensives (medications intended to control high blood pressure) and some drugs that modify central nervous system response may inhibit erection by denying blood supply or by altering nerve activity.
  • Surgical intervention for a number of different conditions may remove anatomical structures necessary to erection, damage nerves, or impair blood supply.
  • Complete removal of the prostate gland or external beam radiotherapy of the gland are common causes of impotence; both are treatments for advanced prostate cancer.
  • the following materials may be used: cationic, anionic or nonionic surfactants such as TweenTM 20, TweenTM 40, TweenTM 80, polyethylene glycols, sodium dodecyl sulfate, various naturally occurring proteins such as serum albumin, or any other macromolecular surfactants in the delivery formulation.
  • thickening agents can be used help prevent particles from settling by sedimentation and to increase solution viscosity, for example, polyvinyl alcohols, polyvinyl pyrrolidones, sugars or dextrins. Density additives may also be used to achieve buoyancy.
  • microparticles such as microspheres in one or more sizes.
  • it may also be of value to a user to provide each of such sizes of microspheres incorporated with color-coded associated dyes to indicate the microsphere size to the user.
  • the color-coded size of the microspheres could correspond to differing doses of active agents contained within the microspheres.
  • it may further be of value to provide sized and color-coded microspheres to a user in similarly color-coded syringes or other containers for transport and delivery to further aid a user in identifying the size of microspheres being used.
  • the invention includes a particle for use in a therapeutic and/or diagnostic procedure.
  • the particle comprises po!y[bis(trifluoroethoxy) phosphazene] and/or a derivative thereof.
  • the present invention further includes particles comprising poly[bis(trifluoroethoxy) phosphazene and/or a derivative thereof provided as microspheres provided in one or more specified sizes.
  • the present invention further includes particles comprising poly[bis(trifluoroethoxy) phosphazene and/or a derivative thereof provided as sized microspheres and further comprising a cotor-coded dye incorporated into or attached to the exterior of the microspheres to visually aid a user in identifying the size of microspheres in use.
  • Microspheres of the present invention may further be provided as sized microspheres further comprising a color-coded dye incorporated into or attached to the exterior of the microspheres and contained or delivered in a similarly color-coded syringe or other transport or delivery container to further visually aid a user in providing a visual confirmation of the specific size of microspheres in use.
  • Microspheres of the present invention may further be provided as sized microspheres further comprising a colored dye incorporated into or attached to the exterior of the microspheres and contained or delivered in a similarly color-coded syringe or other transport or delivery container to functionally serve to impart a desired color to mammalian tissues in use,
  • a method of delivering an active agent to a localized area within a body of a mammal comprising contacting the localized area with at least one of a particle comprising poly[bis(trifluoroethoxy) phosphazene] and/or a derivative thereof and an active agent, such that an effective amount of the active agent is exposed to the localized area.
  • a sustained release formulation of an active agent for oral administration comprising a polymer capsule and an active agent, wherein the polymeric capsule comprises poly[bis(trifluoroethoxy) phosphazene] and/or a derivative thereof.
  • the invention also includes a method of delivering an active agent to a localized area within the body of a mammal comprising contacting the localized area with at least one of a particle comprising poly[bis(trifluoroethoxy) phosphazene] and/or a derivative thereof and an active agent, such that an effective amount of the active agent is exposed to the localized area, wherein the particle comprises an agent to increase density.
  • a method for minimizing agglomeration of particles formed from acrylic- based polymers comprises providing barium sulfate to the core and/or surface of the particles.
  • FIG. 1 shows a schematic representation of a general cryoextraction scheme used to prepare particles according to one embodiment of the invention
  • Fig. 2 shows the manual dripping technique by which the polymer solution was supplied to liquid nitrogen in preparation of the microspheres of Example 1, herein;
  • FIG. 3A and Fig. 3B show unloaded polyphosphazene particles (microspheres) as prepared by one embodiment of the cryoextraction method as described herein.
  • Figure 3A shows a 4x optical microscope view and
  • Fig, 3B shows a 10Ox scanning electron microscope view;
  • FIG. 4 shows a particle (microsphere) formed according to one embodiment of the invention loaded with bovine insulin (20% (wt/wt)) at IQOx magnification SEM;
  • Fig. 5A and Fig. 5B show the surface morphology of unloaded polyphosphazene microspheres.
  • Fig. 5A is an image obtained using an atomic force microscope and
  • Fig. 5B is a scanning electron micrograph showing the surface of an unloaded polyphosphazene microsphere at 5000x magnification;
  • Figs. 6 and 7 show a cryoextraction setup for use in an embodiment of the invention wherein Fig. 6 is a cryoextraction vessel and Fig. 7 is a syringe pump;
  • FIG. 8 is a cross- sectional view of an apparatus for use in microcatheter testing of microparticles in Example 14 herein;
  • Figs 9A and 9B show an SEM at 1.0KX magnification of the surface of the Sample C microparticles just after the hydration/dehydration cycle and at a 50.00KX magnification of the film thickness of microparticles formed in accordance with Sample C of Example 12 used in the evaluation of Example 14, respectively;
  • Figs. 1OA, 1OB, 1 OC and 1OD are SEMs of microparticles made in accordance with Sample C of Example 12 used in the evaluation of Example 14 after passing through a catheter showing surface features (Figs. 1OA, 1OB and 10C) at 1.0KX magnification and at 5.0KX magnification (Fig. 10D); and
  • Figs. HA. t IB, HC and HD are SEMs of microparticles formed in accordance with Sample C of Example 12 after thermal stress testing in Example 14.
  • Fig. 1 IA is a 5OX magnification of a minor amount of delamination in the strong white contrast portion.
  • Fig. HB is a 200X magnification of the microparticles of Fig. HA.
  • Figs. HC and HD are, respectively, 200X and 1.0KX magnified SEMs of other Sample C microparticles showing only minor defects,
  • Figs. 12A-12G show yet another exemplary restorative application of the present invention used for erectile dysfunction.
  • Fig. 12A shows a sagittal view of a human penis.
  • Fig. 12B shows an axial view of the penis at the level indicated on Fig. 12A.
  • Figs. 12C and 12D are detailed views arising from Fig 12B, showing the penis at non-erect and erect stages, respectively.
  • Fig. 12E shows the axial view of Fig. 12B, with an injection needle in the corpora cavernosa.
  • Figs. 12F and 12G are detailed views arising from Fig 12E, showing the penis at non-erect and erect stages, respectively and the locations of microspheres injected therein in the corpora cavernosa.
  • particles that may be manufactured using poly[bis(trifluoroethoxy) phosphazene] and/or derivatives thereof, as well as methods of preparing such particles. Additionally, described herein are therapeutic methods and procedures which use the particles as described herein, including methods of delivery of an active agent using the particle locally to treat mammalian patients with erectile dysfunction.
  • sustained release drug delivery formulations for implantable or injectable administration including the particles for localized delivery of an active agent to the integument and/or systemic delivery of an active agent as well as a sustained release drug delivery formulation that can be injected subcutaneously or applied topically for localized delivery of an active agent for the treatment of erectile dysfunction.
  • Particle and “particles” as used herein mean a substantially spherical or ellipsoid article(s), hollow or solid, that may have any diameter suitable for use in the specific methods and applications described below, including a microsphere(s) and a nanosphere(s), beads and other bodies of a similar nature known in the art.
  • the preferred particles of the invention are composed, in whole or in part, the specific polyphosphazene polymer known as poiy[bis(trifluoroethoxy) phosphazene] or a derivative of poly[bis(trifluoroethoxy) phosphazene].
  • the specific polymer provides particles that are at least in part inorganic in that they include an inorganic polymer backbone and which are also biocompatible in that when introduced into a mammal (including humans and animals), they do not significantly induce a response of the specific or non-specific immune systems.
  • the scope of the invention also includes the use(s) of such particles as controlled drug delivery vehicles or tracer particles for targeted tissues and other organs.
  • the particles are useful in a variety of therapeutic and/or diagnostic procedures in part because they can be prepared in a variety of sizes and colors for various purposes. Additionally, owing to the biocompatible nature of the polymer, the particles facilitate avoidance or elimination of immunogenic reactions generally encountered when foreign bodies are introduced into a mammalian body, such as "implant rejection” or “allergic shock,” and other adverse reactions of the immune system. Moreover, it has been found that the particles of the invention may be provided in a form to exhibit reduced biodegradation in vivo, thereby increasing the long-term stability of the particle in the biological environment.
  • the products released from the degradation include only non-toxic concentrations of phosphorous, ammonia, and trifluoroethanol, which, advantageously, is known to promote anti-inflammatory responses when in contact with mammalian tissue.
  • Each of the particles in the invention is formed at least in part of the polymer, poly[bis(2,2,2-trifluoroethoxy) phosphazene] or a derivative thereof (referred to further herein as "poly[bis(trifluoroethoxy)phosphazene]".
  • poly[bis(2,2,2-trif!uoroethoxy)phosphazene] or derivatives thereof have chemical and biological qualities that distinguish this polymer from other know polymers in general, and from other know polyphosphazenes in particular.
  • the polyphosphazene is poly[bis(2,2,2-trifluoroethoxy) phosphazene] or derivatives thereof, such as other alkoxide, halogenated alkoxide, or fluorinated alkoxide substituted analogs thereof.
  • the preferred poly[bis(trifluoroethoxy)phosphazene] polymer is made up of repeating monomers represented by the formula (1) shown below:
  • R to R are all trifluoroethoxy (OCH 2 CF 3 ) groups, and wherein n may vary from at least about 40 to about 100,000, as disclosed herein.
  • n may vary from at least about 40 to about 100,000, as disclosed herein.
  • one may use derivatives of this polymer in the present invention.
  • derivatives is meant to refer to polymers made up of monomers having the structure of formula I but where one or more of the R 1 to R 6 functional group(s) is replaced by a different functional group(s), such as an unsubstituted alkoxide, a halogenated alkoxide, a fluorinated alkoxide, or any combination thereof, or where one or more of the R 1 to R 6 is replaced by any of the other functional group(s) disclosed herein, but where the biological inertness of the polymer is not substantially altered.
  • At least one of the substituents R s to R 6 can be an unsubstituted alkoxy substituent, such as methoxy (OCH 3 ), ethoxy (OCH 2 CH 3 ) or n-propoxy (OCH 2 CH 2 CH 3 ).
  • at least one of the substituents R 1 to R 6 is an alkoxy group substituted with at least one fluorine atom.
  • R 1 to R 6 examples include, but are not limited to OCF 3 , OCH 2 CF 3 , OCH 2 CH 2 CF 3 , OCH 2 CF 2 CF 3 , OCH(CF 3 ) 2 , OCCH 3 (CF 3 ) 2 , OCH 2 CF 2 CF 2 CF 3 , OCH 2 (CF 2 ) 3 CF 3 , OCH 2 (CF 2 ) 4 CF 3 , OCH 2 (CF 2 )SCF 3 , OCH 2 (CFJ) 6 CF 3 , OCH 2 (CF 2 ) 7 CF 3 , OCH 2 CF 2 CHF 2 , OCH 2 CF 2 CF 2 CHF 2 , OCH 2 (CF 2 ) 3 CHF 2!
  • examples of especially useful fluorinated alkoxide functional groups include, but are not limited to, 2,2,3,3,3-pentafluoropropyloxy (OCH 2 CF 2 CF 3 ), 2,2,2,2',2',2'-hexafluorotsopropyloxy (OCH(CF 3 ) 2 ), 2,2,3,3 A4 5 4-heptafluorobuty!oxy (OCH 2 CF 2 CF 2 CF 3 ), 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyloxy (OCH 2 (CF 2 ) 7 CF 3 ), 2,2,3,3,-tetrafluoropropyloxy (OCH 2 CF 2 CHF 2 ), 2,2,3,3,4,4-hexaftuorobutyloxy
  • 1% or less of the R 1 to R 6 groups may be alkenoxy groups, a feature that may assist in crosslinking to provide a more elastomeric phosphazene polymer.
  • alkenoxy groups include, but are not limited to,
  • OCH 2 CH CH 2 , OCH 2 CH 2 CH-CH 2 , allylphenoxy groups, and the like, including combinations thereof.
  • residues R 1 to R 6 are each independently variable and therefore can be the same or different.
  • n can be as large as ⁇ in formula I, it is intended to specify values of n that encompass poiyphosphazene polymers that can have an average molecular weight of up to about 75 million Daltons. For example, in one aspect, n can vary from at least about 40 to about 100,000. In another aspect, by indicating that n can be as large as oc in formula I, it is intended to specify values of n from about 4,000 to about 50,000, more preferably, n is about 7,000 to about 40,000 and most preferably n is about 13,000 to about 30,000.
  • the polymer used to prepare the polymers disclosed herein has a molecular weight based on the above formula, which can be a molecular weight of at least about 70,000 g/mol, more preferably at least about 1,000,000 g/mol, and still more preferably a molecular weight of at least about 3xlO 6 g/mol to about 2OxIO 6 g/mol. Most preferred are polymers having molecular weights of at least about 10,000,000 g/mol.
  • n is 2 to oo
  • R 1 to R 6 are groups which are each selected independently from alkyl, aminoalkyl, haloalkyl, thioalkyl, thioaryl, alkoxy, haloatkoxy, aryloxy, haloaryloxy, alkylthiolate, arylthiolate, alkylsulphonyl, alkylamino, dialkylamino, heterocycloalkyl comprising one or more heteroatoms selected from nitrogen, oxygen, sulfur, phosphorus, or a combination thereof, or heteroary!
  • the pendant side groups or moieties (also termed "residues") R ! to R 6 are each independently variable and therefore can be the same or different.
  • R 1 to R 6 can be substituted or unsubstituted
  • the alkyl groups or moieties within the alkoxy, alkylsulphonyl, dialkylamino, and other alkyl-containing groups can be, for example, straight or branched chain alkyl groups having from 1 to 20 carbon atoms, typically from 1 to 12 carbon atoms, it being possible for the alkyl groups to be further substituted, for example, by at least one halogen atom, such as a fluorine atom or other functional group such as those noted for the R 1 to R 6 groups above.
  • alky! groups such as propyl or butyl, it is intended to encompass any isomer of the particular alkyl group.
  • examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy groups, and the like, which can also be further substituted.
  • the alkoxy group can be substituted by at least one fluorine atom, with 2,2,2-trifluoroethoxy constituting a useful alkoxy group.
  • one or more of the alkoxy groups contains at least one fluorine atom.
  • the alkoxy group can contain at least two fluorine atoms or the alkoxy group can contain three fluorine atoms.
  • the polyphosphazene that is combined with the silicone can be poly[bis(2,2,2-trifluoroethoxy)phosphazene].
  • Alkoxy groups of the polymer can also be combinations of the aforementioned embodiments wherein one or more fluorine atoms are present on the poiyphosphazene in combination with other groups or atoms.
  • alkylsutphonyl substituents include, but are not limited to, methylsulphonyl, ethylsulphonyl, propyisulphonyl, and butylsulphonyl groups.
  • dialkylamino substituents include, but are not limited to, dimethyl-, diethyl-, dipropyl-, and dibutylamino groups. Again, by specifying alkyl groups such as propyl or butyl, it is intended to encompass any isomer of the particular alkyl group.
  • Exemplary aryloxy groups include, for example, compounds having one or more aromatic ring systems having at least one oxygen atom, non-oxygenated atom, and/or rings having alkoxy substituents, it being possible for the aryl group to be substituted for example by at least one alkyl or alkoxy substituent defined above.
  • Examples of aryloxy groups include, but are not limited to, phenoxy and naphthoxy groups, and derivatives thereof including, for example, substituted phenoxy and naphthoxy groups.
  • the heterocycloalkyl group can be, for example, a ring system which contains from 3 to 10 atoms, at least one ring atom being a nitrogen, oxygen, sulfur, phosphorus, or any combination of these heteroatoms.
  • the hetereocycloalkyl group can be substituted, for example, by at least one alkyl or alkoxy substituent as defined above.
  • Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperaz ⁇ nyl, pyrrolidinyl, and morphoiinyl groups, and substituted analogs thereof.
  • the heteroaryl group can be, for example, a compound having one or more aromatic ring systems, at least one ring atom being a nitrogen, an oxygen, a sulfur, a phosphorus, or any combination of these heteroatoms.
  • the heteroaryl group can be substituted for example by at least one alkyl or alkoxy substituent defined above.
  • heteroaryl groups include, but are not limited to, imidazoiyl, thiophene, furane, oxazolyl, pyrrolyl, pyridinyl, pyridinolyl, isoquinolinyl, and quinolinyl groups, and derivatives thereof, such as substituted groups.
  • the diameter of a particle formed according to the invention will necessarily vary depending on the end application in which the particle is to be used.
  • the diameter of such particles is preferably about 0.1 ⁇ m to about 5,000 ⁇ m, with a diameter of about 0.1 ⁇ m to about LOOO ⁇ m being most preferred.
  • Other preferred sizes include diameters of about 40 ⁇ m,
  • the particles may also include other compounds which function to enhance, alter or otherwise modify the behavior of the polymer or particle either during its preparation or in its therapeutic and/or diagnostic use.
  • active agents such as peptides, proteins, hormones, carbohydrates, polysaccharides, nucleic acids, lipids, vitamins, steroids and organic or inorganic drugs may be incorporated into the particle.
  • Excipients such as dextran, other sugars, polyethylene glycol, glucose, and various salts, including, for example, chitosan glutamate, may be included in the particle.
  • polymers other than the poly[bis(trifluoroethoxy) phosphazene] and/or its derivative may be included with in the particle.
  • examples of polymers may include poly(tactic acid). poly(lactic-co-glycolic acid), poly(caprolactone), polycarbonates, polyamides, polyanhydrides, polyamino acids, polyorthoesters, polyacetais, polycyanoacrylates, and polyurethanes.
  • polymers include polyacrylates, ethylene-vinyl acetate co-polymers, acyi substituted cellulose acetates and derivatives thereof, degradable or non-degradable polyurethanes, polystyrenes, polyvinylchloride, polyvinyl fluoride, poly(vinyl imidazole), chlorosulphonated polyolefins, and polyethylene oxide.
  • polyacrylates include, but are not limited to, acrylic acid, butyl acrylate, ethylhexyl acrylate, methyl acrylate, ethyl acrylate, acrylonitrile, methyl methacrytate, TMPTA (trimethylolpropane triacrylate), and the like.
  • the loaded or unloaded particle may be coated with an additional polymer layer or layers, including polymers such as those mentioned hereinabove.
  • poly[bis(trifluoroethoxy) phosphazene or its derivatives may be used to form such a coating on a particle formed of other suitable polymers or copolymers known or to be developed in the art that are used to form particles as described herein.
  • poly[bis(trifluoroethoxy) phosphazene is applied as a coating on a microparticie(s) formed of an acrylic-based polymer as set forth in further detail below.
  • Coatings are beneficial, for example, if the particle(s) are to be used in a sustained release, orally administered, drug delivery formulation (enteric coating) or if the particles are to be loaded with a potentially toxic contrast agent (non-biodegradable coating).
  • the microspheres may be prepared by any means known in the art that is suitable for the preparation of particles containing poly[bis(trifluoroethoxy) phosphazene].
  • a "polymer solution” is prepared by mixing one or more polymer solvent(s) and the poly[bis(trifluoroethoxy) phosphazene and/or a derivative thereof until the polymer is dissolved.
  • Suitable solvents for use in the preparation of the polymer solution include any in which the polymer poly[bis(trifluoroethoxy) phosphazene and/or its derivatives are soluble.
  • Exemplary solvents include, without limitation, ethyl-, propyl-, butyl-, pentyl-, octylacetate, acetone, methylethylketone, methylpropylketone, methylisobutylketone, tetrahydrofurane, cyclohexanone, dimethylacetamide, acetonitrile, dimethyl ether, hexafluorobenzene or combinations thereof.
  • the polymer solution contains the poly[bis(trifluoroethoxy) phosphazene and/or its derivative polymer in a concentration of about 1% by weight of polymer to 20% by weight of polymer, preferably about 5% to 10% by weight of polymer.
  • Other polymers as discussed above, may be present in the solution, or may be added to the vessel in the form of a second solution powder or other form, if one wishes to include such polymers in the final particle.
  • non-solvent any organic or inorganic solvents that do not substantially dissolve the poly[bis(trifluoroethoxy)phosphazene] polymer and which have a melting point that is lower relative to the melting point of the solvent in which the polymer is dissolved (“polymer solvent”), so that the non-solvent thaws before the solvent thaws in the course of the incubation step.
  • this difference between the melting point of the non-solvent and the polymer solvent is about 10° C, more preferably about 15° C, and most preferably, greater than about 20° C.
  • the structural integrity of the resultant particle may be enhanced if the difference of the melting points of the polymer solvent and of the non-solvent is greater than 15° C, However, it is sufficient that the non-solvent point is merely slightly lower than that of the polymer solvent.
  • the non-solvent/polymer solvent combination is incubated for approximately 1 to 5 days or until the polymer solvent has been completely removed from the particles. While not wishing to be bound by theory, it is hypothesized that during the incubation, the non-solvent functions to extract the polymer solvent from the microscopic polymer solution droplets from the particles such that the polymer is at least gelled. As the incubation period passes, the droplets will shrink and the solvent becomes further extracted, leading to a hardened outer polymeric shell containing a gelled polymer core, and finally, after completion of the incubation, a complete removal of the residual solvent.
  • the non-solvent temperature may stay below the melting point of the solvent during the cryoextraction process.
  • polymer solution droplets are shown being dispensed either with a syringe or other device at a controlled rate onto a top layer of liquid nitrogen.
  • the nitrogen layer is situated over a bottom layer consisting of the selected non-solvent, which will eventually serve to extract the solvent from the frozen polymer solution droplets.
  • the non-solvent layer has been previously frozen with liquid nitrogen prior to the dispensing of the polymer solution.
  • the vessel labeled (b) shows the onset of the dewing of the frozen nonsolvent, into which the frozen polymeric droplets will sink.
  • the vessel labeled (c) shows the cryoextraction procedure after approximately three days of incubation wherein the polymer solution droplets, incubated within the non-solvent, have been depleted of a substantial amount of solvent.
  • the result is a gelled, polymeric particle in the form of a bead having a hardened outer shell.
  • the non- solvent height within the vessel is slightly reduced due to some evaporation of the non-solvent.
  • the size of the beads will shrink quite substantially during this process depending on the initial concentration of the polymer in the polymer solution,
  • such particles can be formed using any way known or to be developed in the art.
  • Two exemplary preferred methods of accomplishing this include wherein (i) the non-solvent residing in the vessel in the method embodiment described above is cooled to close to its freezing point or to its freezing point prior to the addition of the polymer solution such that the polymer droplets freeze upon contact with the pre-cooled non-solvent; or (ii) the polymer droplets are frozen by contacting them with a liquefied gas such as nitrogen, which is placed over a bed of pre-frozen non-solvent (see, Fig.
  • particles that are hollow or substantially hollow or porous By modifying this general process, one may prepare particles that are hollow or substantially hollow or porous. For example, if the removal of the solvent from the bead is carried out quickly, e.g., by applying a vacuum during the final stage of incubation, porous beads will result.
  • the particles of the invention can be prepared in any size desired, "Microspheres" may be obtained by nebulizing the polymer solution into a polymer aerosol using either pneumatic or ultrasonic nozzles, such as, for example a Sonotek 8700-60ms or a Lechler US50 ultrasonic nozzle, each available from Sono[,tek] Corporation, Milton, New York, U.S.A. and Lechler GmbH, Metzingen, Germany. Larger particles may be obtained by dispensing the droplets into the non-solvent solution using a syringe or other drop-forming device. Moreover, as will be known to a person of skill in the art, the size of the particle may also be altered or modified by an increase or decrease of the initial concentration of the polymer in the polymer solution, as a higher concentration will lead to an increased sphere diameter,
  • the particles can include a standard and/or a preferred core based on an acrylic polymer or copolymer with a shell of poly[bis(trifluoroethoxy) phosphazene.
  • the acrylic polymer based polymers with poly[bis(trifluoroethoxy) phosphazene shell described herein provide a substantially spherical shape, mechanical flexibility and compressibility, improved specific gravity properties.
  • the core polymers may be formed using any acceptable technique known in the art, such as that described in B. Thanoo et a!., "Preparation of Hydrogel Beads from Crosslinked Poly(Methyl Methacrylate) Microspheres by Alkaline Hydrolysis," J. Appl.
  • acrylic-based polymers are preferably formed by polymerizing unhydrolyzed precursors, including, without limitation, methyl acrylate (MA), methyl methacrylate (MMA), ethylmethacrylate (EMA), hexamethyl (HMMA) or hydroxy ethyl methacryiate (HEMA), and derivatives, variants or copolymers of such acrylic acid derivatives. Most preferred is MMA.
  • the polymer should be present in the core in a hydrated or partially hydrate d (hydrogel) form.
  • Such polymers are preferably cross- linked in order to provide suitable hydrogel properties and structure, such as enhanced non- biodegradabi ⁇ ty, and to help retain the mechanical stability of the polymer structure by resisting dissolution by water.
  • the core prepolymers are formed by dispersion polymerization that may be of the suspension or emulsion polymerization type.
  • Emulsion polymerization results in substantially spherical particles of about 10 nm to about 10 microns.
  • Suspension polymerization results in similar particles but of larger sizes of about 50 to about 1200 microns.
  • Suspension polymerization may be initiated with a thermal initiator, which may be soiubilized in the aqueous or, more preferably, monomer phase.
  • Suitable initiators for use in the monomer phase composition include benzoyl peroxide, lauroyl peroxide or other similar peroxide-based initiators known or to be developed in the art, with the most preferred initiator being lauroyl peroxide.
  • the initiator is preferably present in an amount of about 0.1 to about 5 percent by weight based on the weight of the monomer, more preferably about 0.3 to about 1 percent by weight based on the weight of the monomer.
  • a cross-linking co- monomer is preferred for use in forming the hydrated polymer.
  • Suitable cross-linking co- monomers for use with the acrylic-based principle monomer(s) used in preparing a polymerized particle core include various glycol-based materials such as ethylene glycol dimethacrylate (EGDMA), diethylene glycol dimethacrylate (DEGDMA) or most preferably, triethylene glycol dimethacrylate (TEGMDA).
  • a chain transfer agent may also be provided if desired. Any suitable MA polymerization chain transfer agent may be used. In the preferred embodiment herein, dodecylmercaptane may be used as a chain transfer agent in amounts acceptable for the particular polymerization reaction.
  • the aqueous phase composition preferably includes a surfactant/dispersant as well as a complexing agent, and an optional buffer is necessary.
  • Surfactants/dispersants should be compatible with the monomers used herein, including Cyanamer® 370M, polyacrylic acid and partially hydrolyzed polyvinyl alcohol surfactants such as 4/88, 26/88, 40/88.
  • a dispersant should be present in an amount of about 0.1 to about 5 percent by weight based on the amount of water in the dispersion, more preferably about 0.2 to about 1 percent by weight based on the amount of water in the dispersion.
  • An optional buffer solution may be used if needed to maintain adequate pH.
  • a preferred buffer solution includes sodium phosphates (Na 2 HP(VNaH 2 PO 4 ).
  • a suitable complexing agent is ethylene diamine tetraacetic acid (EDTA), which may be added to the aqueous phase in a concentration of from about 10 to about 40 ppm EDTA, and more preferably about 20 to about 30 ppm. It is preferred that in the aqueous phase composition, the monomer to water ratio is about 1 :4 to about 1 :6.
  • EDTA ethylene diamine tetraacetic acid
  • the polymerization should take place at about ambient conditions, preferably from about 60° C to about 80° C with a time to gelation of about one to two hours. Stirring at rates of 100 to 500 rpm is preferred for particle formation, with lower rates applying to larger sized particles and higher rates applying to smaller sized particles.
  • PMMA particles such as microparticles
  • they are preferably subjected to hydrolysis conditions typical of those in the art, including use of about 1-10 molar excess of potassium hydroxide per mol of PMMA.
  • potassium hydroxide is provided in a concentration of about 1-15% potassium hydroxide in ethylene glycol.
  • the solution is then heated preferably at temperatures of about 150-185° C for several hours.
  • lesser amounts of potassium hydroxide be used which are less than about 5 molar excess of potassium hydroxide per mole of PMMA, more preferably about 3 molar excess or less.
  • a concentration of about 10-15% potassium hydroxide in ethylene glycol is aiso preferably used, and more preferably about 14% to about 15%. It will be understood by one skilled in the art, that heating conditions at higher temperatures may be used to decrease overall reaction times. Reaction times may be varied depending on the overall diameter of the resultant particles.
  • the following conditions are able to provide particles having about 35% compressibility and desired stability: for diameters of about 200-300 ⁇ m, the solution should be heated for about 7.5 to about 8.5 hours; for diameters of about 300-355 ⁇ m, about 9.5 to about 10.5 hours; for diameters of about 355-400 ⁇ m, about 11.5 to about 12.5 hours; and for about 400-455 ⁇ m, about 13.5 to about 14.5 hours, etc.
  • the particle size can be adjusted using variations in the polymerization process, for example, by varying the stirring speed and the ratio of the monomer to the aqueous phase. Further, smaller sizes can be achieved by increasing surfactant/dispersant ratio.
  • particles are separated from the reaction mixture and their pH may be adjusted to any range as suited for further processing steps or intended uses.
  • the pH of the particle core may be adjusted in from about 1.0 to about 9.4, preferably about 7.4 if intended for a physiological application. Since size, swelling ratio and elasticity of the hydrogel core material are dependent on pH value, the lower pH values may be used to have beneficial effects during drying to prevent particle agglomeration and/or structural damage.
  • Particles are preferably sieved into different size fractions according to intended use. Drying of particles preferably occurs using any standard drying process, including use of an oven at a temperature of about 40° -80° C for several hours up to about a day.
  • the surface of the hydrogel may be subjected to treatment with any suitable ionic or non-ionic surfactant, such as tetraalkylammonium salts, polyalcohols and similar materials.
  • any suitable ionic or non-ionic surfactant such as tetraalkylammonium salts, polyalcohols and similar materials.
  • a more permanent change in adhesion properties is brought about by rendering the surface of the particles hydrophobic by reaction of its polymethacrylic acid groups with a suitable reactant.
  • Suitable reactants include, but are not limited to, hydrophobic alcohols, amides and carboxylic acid derivatives, more preferably they include halogenated alcohols such as trifluoroethanol.
  • Such surface treatment also prevents delamination of the coating from the core once the coating is applied.
  • Preferred surface treatments may include, without limitation, an initial treatment with thionyl chloride followed by reaction with trifluoroethanol.
  • the surface may be treated by suspending the particles in a mixture of sulfuric acid and a hydrophobic alcohol, such as trifluoroethanol. Such treatments are preferred if the particles are to be coated in that they minimize any delamination of a coating.
  • the PMA core particles may be coated with a surface layer of and/or infused with barium sulfate.
  • the barium sulfate is radiopaque and aids in visualization of the finished particles when in use. It also provides enhanced fluidization properties to the particles such that it reduces agglomeration especially during drying and allows for fluid bed coating of the PMA particles with an outer coating of poly[bis(trifluoroethoxy) phosphazene, thereby providing improved adhesion between a poly[bis(trifluoroethoxy) phosphazene outer core and a polymeric acrylate core particles.
  • barium sulfate By allowing fluidization even when the core particles are swollen, barium sulfate also improves the overall coating and adhesion properties. By enabling the coating of the core particles even in a swollen state with poly[bis(trifluoroethoxy) phosphazene, barium sulfate also reduces the potential tendency of the poiy[bis(trif! ⁇ oroethoxy) phosphazene shells to crack or rupture in comparison with coating the particles in a dry state and then later exposing the particles to a suspension in which the core particles swell and exert force on the shell of poly[bis(trifiuoroethoxy) phosphazene.
  • a coating of barium sulfate on the core particles is preferably applied by adhesion of the barium sulfate in the form of an opaque coating on the hydrogel surface of the PMA beads.
  • Barium sulfate can further assist in reducing electrostatic effects that limit particle size. By allowing for absorption of additional humidity, the barium sulfate tends to counteract the electrostatic effects.
  • Barium sulfate crystals adhering only loosely to the PMA particles may be covalently crosslinked or chemically grafted to the particle surface by spraycoating a sufficient amount of an aminosilane adhesion promoter onto the PMA particle. This will help to effectively reduce barium sulfate particulate matter in solution after hydration of the particles.
  • Exemplary particles include 3-aminopropyl-trimethoxysilane and similar silane-based adhesion promoters.
  • a further alternative for improving visualization of and potential functionality of microparticles made as noted herein include the absorption of a water soluble organic dye inside the hydrogel core particles.
  • exemplary dyes are preferably those FDA dyes approved for human use and which are known or to be developed for safe, non-toxic use in the body and which are capable of providing acceptable contrast.
  • Organic dyes may include dyes such as D&C Violet no. 2 and others preferably approved for medical device uses, such as for contact lenses and resorbable sutures.
  • barium sulfate operates as an inorganic filler and finely dispersed pigment that makes the particles visible by light diffraction due to small crystal size, the dyes when impregnated in the particles absorb the complementary part of the visible color spectrum.
  • Water soluble organic dyes in various embodiments of the present invention may be provided in colors that approximate various shades of human flesh or other tissue tones for improved cosmesis.
  • Yet another alternative embodiment of the present invention relates to the use of custom color dyes for inclusion in the microspheres for patient-specific applications. These applications include, but are not limited to, situations in which such microspheres are to be introduced and left within thin or superficial tissue, where the presence of the microspheres might otherwise be visible to an observer.
  • a user would first provide a quantitative analysis of a desired tissue using a hand-held spectrophotometer or other device to records data from a desired area of a mammalian patient's skin is used in conjunction with a computerized color formulation system. Based on this color measurement, a color formula will be calculated by the computer, and appropriate dyes will be mixed to produce pigmented microspheres to match the color of the desired target skin.
  • Particles, including microparticles made in accordance with the foregoing process for forming a core hydrogel polymer are then coated with poly[bis(trifluoroethoxy) phosphazene] and/or its derivatives.
  • Any suitable coating process may be used, including solvent fluidized bed and/or spraying techniques. However, preferred results may be achieved using fluidized bed techniques in which the particles pass through an air stream and are coated through spraying while they spin within the air stream.
  • the poiy[bis(trifluoroethoxy) phosphazene] or derivative polymer is provided in dilute solution for spraying to avoid clogging of the nozzle.
  • Exemplary solvents for use in such solutions include ethyl acetate, acetone, hexafluorbenzene, methyl ethyl ketone and similar solvents and mixtures and combinations thereof, most preferred is ethyl acetate alone or in combination with isoamyl acetate.
  • Typical preferred concentrations include about 0.01 to about 0.3 weight percent poly[bis(trifluoroethoxy) phosphazene] or its derivative in solution, more preferably about 0.02 to 0.2 weight percent poly[bis(trifluoroethoxy) phosphazene], and most preferably about 0.075 to about 0.2 weight percent.
  • hydrogel core can be varied as can the technique for coating a particle, however it is preferred that a core which is useful in the treatment techniques and applications described herein is formed and subsequently coated with poly[bis(trifluoroethoxy) phosphazene] and/or its derivatives as described herein.
  • D 2 O deuterium oxide
  • particles of pH 1 can be neutralized with cesium hydroxide and/or the final neutralized particles can be equilibrated with cesium chloride.
  • Such compounds diffuse cesium into the particles, such that either the cesium salt of polymethacrylic acid is formed or polyrnethacrylic acid is diffused and thereby enriched with cesium chloride.
  • the cesium increases the density of the particles, thereby increasing the ability to add higher amounts of contrast agent.
  • Typical buoyancy levels can be adjusted using the cesium technique such that about 45 to about 50% contrast agent may be added to the delivery medium as is desired for embolization.
  • Cesium salts are non-toxic and render the particles visible using fluoroscopy.
  • Cesium's atomic weight of 132.9 g/mol is slightly higher than that of iodine providing beneficial effects including increase in overall density and enhancement of X-ray contrast visibility even without a contrast agent.
  • active agent can be used as an alternative cesium source rendering the particles buoyant in an embolic solution as well as able to be used as an active treatment source,
  • barium sulfate may be used between the core particles and the preferred poly[bis(trifluoroethoxy) phosphazene] coating or introduced into the interior of the core particles using any technique known or to be developed in the art.
  • organic dyes may similarly be included in the particle core.
  • These materials, particularly the barium sulfate also contribute to an increase in density as well as providing radiopacity.
  • the barium sulfate allows this benefit even upon substantial and/or JFuIl hydration, allowing particles in suspension to remain isotonic.
  • a barium sulfate powder coating can provide an inert precipitate having no effect on physiological osmolarity.
  • the invention also includes methods of delivering an active agent to a localized area within the body of a mammal.
  • the method includes contacting the localized area with at least one of the particles of the invention as described above, such that an effective amount of the active agent is released locally to the area.
  • Diseases or pathologies that may be treated by this method include any wherein the localized or topical application of the active agent achieves some benefit in contrast to the systemic absorption of the drug.
  • Suitable active agents include NSAIDS, steroids, hormones, and nucleic acids,
  • the particle formulated for delivery of an active agent to a localized area is about 1 to about 1,000 ⁇ m in diameter
  • the drug loaded microspheres can be applied to localized areas within the mammalian body using syringes and/or catheters as a delivery device, without causing inadvertent occlusions.
  • a catheter can be inserted into the groin artery and its movement monitored until it has reached the area where the localized administration is desired.
  • a dispersion of the particles in a suitable injection medium can be injected through the catheter, guaranteeing only a specific area of the body will be subjected to treatment with drug loaded beads (particles).
  • injection mediums include any pharmaceutically acceptable mediums that are known or to be developed in the art, such as, e.g., saline, PBS or any other suitable physiological medium.
  • the invention may include an injectable dispersion including particles and a contrasting agent which particles are substantially dispersed in the solution.
  • the particles are also detectible through fluoroscopy or other imaging modalities.
  • the polymeric particles of the invention may be used to prepare a sustained release formulation of an active agent for local administration.
  • the formulation comprises a particle, as described above, loaded with an active agent.
  • the polymeric particle utilized may be hollow, substantially hollow or solid.
  • the particle can be loaded with the active agent either by dispersion or solvation of the active agent in the polymer solution prior to the production of micro-sized particles through spray droplets, pastillation of a polymer melt or carrying out of a cryoextraction process.
  • an unloaded polymer particle can be prepared and subsequently immersed in solutions containing active agents. The particles are then incubated in these solutions for a sufficient amount of time for the active agent to diffuse into the matrix of the polymer. After drying the particles, the active agent will be retained in the polymer particle.
  • drug loading can be controlled by adjusting drug concentrations of the incubation medium and removing the particles from the incubation medium when an equilibrium condition has been attained.
  • Penile erection is managed by two different mechanisms.
  • the first mechanism is the reflex erection, which is achieved by touch sensation involving the penile shaft.
  • the second mechanism is the psychogenic erection, which is achieved by erotic or emotional stimuli.
  • the former uses the peripheral nerves and the lower parts of the spinal cord, whereas the latter uses the limbic system of the brain. In both conditions an intact neural system is required for a successful and complete erection.
  • Stimulation of penile shaft by the nervous system leads to the secretion of nitric oxide (NO), which causes the relaxation of smooth muscles of corpora cavernosa (the main erectile tissue of penis), and subsequently penile erection.
  • NO nitric oxide
  • Active agents for use with microspheres of the present invention in the treatment of erectile dysfunction include, but are not limited to, testosterone, alprostadil, minoxidil, sildenafil, varenafil, tadafil, other phosphodiesterase inhibitors, dopamine receptor agonists, naltrexone, bremelanotide, Melanotan H, other melanocortin receptor agonists, hMaxiK therapy, and derivatives, metabolites, and/or combinations thereof,
  • Active agents for use with microspheres of the present invention in the treatment of erectile dysfunction further include, but are not limited to nitric oxide, nitrous oxide, inorganic or organic inorganic or organic nitrates, nitrites, nitroglycerine, amyl nitrate, other nitrogen compounds, endothelium-derived relaxing factor or ⁇ DRF, nitric oxide synthase (NOS) enzymes, or other agents capable of increasing intravascular levels of nitric oxide.
  • nitric oxide nitrous oxide
  • inorganic or organic inorganic or organic nitrates nitrites
  • nitroglycerine nitroglycerine
  • amyl nitrate other nitrogen compounds
  • endothelium-derived relaxing factor or ⁇ DRF endothelium-derived relaxing factor or ⁇ DRF
  • NOS nitric oxide synthase
  • microspheres according to the present invention when loaded with active agent and used for treatment of erectile dysfunction, may be provided with a biodegradable poly[bis(trifluoroethoxy)phosphazene] shell, surrounding a hydrogel core that may be provided with a time release mechanism to dispense the active agent(s) therein.
  • microspheres according to the present invention when loaded with active agent and used for treatment of erectile dysfunction, may comprise an active agent reieasably bound to poly[bis(trifluoroethoxy)phosphazene], or a core of active agent surrounded by a biodegradable poly[bis(trifluoroethoxy)phosphazene] shell.
  • active agents may be provided in a chemical state at the time of their initial injection or delivery into a patient's tissues, but may be subsequently released as a reaction to naturally-occurring or artificially induced or enhanced releasing stimuli.
  • releasing stimuli may be produced by osmotically driven pumps, matrices with controllable swelling, diffusion, or erosion rates, non-uniform drug loading profiles, and multi-layered matrices.
  • active agent release may be achieved by the controlled delivery oft herapeutic molecules or protein in a pulsatile or triggered fashion. This may involve fabrication of a delivery system that releases its active agent payload at a predetermined time or in pulses of a predetermined sequence.
  • microspheres loaded with active agent for the treatment of erectile dysfunction may be injected or otherwise delivered into the skin, subcutaneous tissues, or into bodily organs for release of active agent and subsequent affect on erectile function.
  • Microspheres of the present invention may also be provided for topical use for topical delivery alone, or in conjunction with lubricants, spermicides, or other topical preparations.
  • Microspheres of the present invention provided for topical use may be used in association with a condom, or applied directly to the desired skin surface.
  • a drug delivery system may respond to changes in the local environment.
  • Such systems may alter their rate of drug delivery in response to internal or externa! stimuli including pH (acid or base), presence or absence of a specific activating molecule, magnetic fields, ultrasound, electric fields, heat or a change in temperature, light, and mechanical forces, or any combination thereof.
  • Such systems are suitable for release of therapeutics that benefit from nonconstant plasma concentrations.
  • active agent such as a drug complex may be attached by formation of a covalent bond to the hydrogel core of microspheres of the invention by providing to the core a reactive surface anchoring group, specifically designed to react independently with both the hydrogei core and with the drug complex.
  • This reactive surface anchoring group can be a molecular, macromolecular or polymeric entity.
  • the reactive surface anchoring group may be grafted to the hydrogel core by means of covalent reaction with the carboxylic acid functionality of the core, such as by creating a carboxylic ester or an amide bond. Other mechanisms may also be employed.
  • the surface reactive group is covalently reacted with the drug complex or other active agent, by any potential means given by the intrinsic identity of the drug complex or other active agent.
  • the drug complex contains an amine functionality, it can be coupled to a carboxylic acid group using a carbodiimide such as l-ethyl-3-(3-dimethyiaminopropyl) carbodiimide hydrochloride (EDC) or HN'-dicyclohexylcarbodiimide (DCC). (This provides the simplest means of attachment, as no surface anchoring group is necessary.) If the drug complex contains a carboxylic acid group, a diamine can be coupled to the core and the drug using EDC.
  • a drug complex may alternately be bound by strong electrostatic interaction to the core or the poly[bis(trif!uoroethoxy)phosphazene] shell of microspheres of the present invention by providing drug complexes and surface reactive anchoring groups that are capable of forming Lewis-acid-base complexes, such as the Lewis acidic trifluoroethoxy groups of poly[bis(trifluoroethoxy)phosphazene] can interact with basic functionalities such as amines in general.
  • Any multivalent metal ion may be complexed to the hydrogel core of microspheres of the present invention through means of ionic crosslinking. This is, for example, possible with the platinum cytostatics, or with agents such as Mn, Fe, Sa, Eu, and their related compounds. Similarly, multivalent anions may be complexed to an ionically crosslinked core.
  • the present invention includes a variety of potential mechanisms of active agent release from loaded microspheres. These include thermal induction (by means of a sol-gel transition), radiation induction (such as cleavage of the bonds attached to active agent/drug or hydrogel via ionizing or other electromagnetic radiation including light) resulting tn release of active agent/drug from the microspheres), enzymatic triggering release (bonds between drug and hydrogel core may be biodegradable by certain enzymes), pH induced (as described above), or ionic strength induced (based on change of osmolarity, such that diffusion of drugs is achieved by an applied osmolarity gradient, where the drug is loaded in the core and released when in a lower osmoiarity environment.)
  • an alkyl substituent or group can have from 1 to 20 carbon atoms
  • Applicants intent is to recite that the alkyl group have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms.
  • microspheres have a diameter of approximately 500 to 600 ⁇ m
  • Applicants include within this disclosure the recitation that the microspheres have a diameter of approximately 500 ⁇ m, approximately 510 ⁇ m, approximately 520 ⁇ m, approximately 530 ⁇ m, approximately 540 ⁇ m, approximately 550 ⁇ m, approximately 560 ⁇ m, approximately 570 ⁇ m, approximately 580 ⁇ m, approximately 590 ⁇ m, and/or approximately 600 ⁇ m, including any range or sub-range encompassed therein.
  • Applicants reserve the right to proviso out or exclude any individual members of such a group, including any sub-ranges or combinations of sub-ranges within the group, that can be claimed according to a range or in any similar manner, if for any reason Applicants choose to claim less than the full measure of the disclosure, for example, to account for a reference that Applicants are unaware of at the time of the filing of the application.
  • Microspheres having a diameter of approximately 500 to 600 ⁇ m were prepared.
  • a polymer solution was prepared by dissolving poly[bis(trifluoroethoxy)phosphazene] polymer of a molecular weight 3x10 6 g/mol in the polymer solvent ethyl acetate to obtain a 2% (wt/v) polymer solution.
  • Four milliliters of this polymer solution was manually dripped into liquid nitrogen using a 5 ml syringe. This dispersion was dispensed onto a frozen layer of 150 milliliters of pentane. (See Fig. 2.) The cryoextraction was allowed to proceed for three days. Subsequently, polymeric particles were retrieved from the reaction vessel, and were air dried at 21° C.
  • Microspheres having a diameter of approximately 350 to 450 ⁇ m were prepared.
  • a polymer solution was prepared by dissolving poly[bis(trifluoroethoxy)phosphazene] polymer of a molecular weight 3x10 6 g/mol in ethyl acetate to obtain a 1% (wt/v) polymer solution.
  • Four milliliters of this polymer solution was manually dripped into liquid nitrogen using a 5 ml syringe. This dispersion was dispensed onto a frozen layer of 150 milliliters of pentane. (See Fig. 2.) The cryoextraction was allowed to proceed for three days. Subsequently, polymeric particles were retrieved from the reaction vessel and were air dried at 21° C.
  • Microspheres having a diameter of approximately 500 to 600 ⁇ m were prepared.
  • a polymer solution was prepared by dissolving poly[bis(trifluoroethoxy)phosphazene] polymer of a molecular weight 12x10 6 g/mol in methylisobutylketone to obtain a 2% (wt/v) polymer solution.
  • Four milliliters of this polymer solution was manually dripped into liquid nitrogen using a 5 ml syringe. This dispersion was dispensed onto a frozen layer of 150 milliliters of a 1 :9 (v/v) ethanol/pentane mixture (See Fig. 2.). The cryoextraction was allowed to proceed for three days. Subsequently, polymeric particles were retrieved from the reaction vessel, and dried under reduced pressure at 21 ° C.
  • Microspheres having a diameter of approximately 500 to 600 ⁇ m were prepared.
  • a polymer solution was prepared by dissolving poly[bis(trifluoroethoxy)phosphazene] polymer of a molecular weight 9xlO 6 g/mol in isoamylketone to obtain a 2% (wt/v) polymer solution.
  • Four milliliters of this polymer solution was manually dripped into liquid nitrogen using a 5 ml syringe. This dispersion was dispensed onto a frozen layer of 150 milliliters of pentane. (See Fig. 2.) The cryoextraction was allowed to proceed for three days. Subsequently, polymeric polymers were retrieved from the reaction vessel and dried under reduced pressure at 21° C.
  • Microspheres having a diameter of approximately 500 to 600 ⁇ m were prepared.
  • a polymer solution was prepared by dissolving poly[bis(trifluoroethoxy)phosphazene] polymer of a molecular weight 16x10 6 g/mol in cyclohexanone to obtain a 2% (wt/v) polymer solution.
  • Four milliliters of this polymer solution was manually dropped into liquid nitrogen using a 5 ml syringe. This dispersion was dispensed onto a frozen layer of 150 milliliters of a 1 :1 (v/v) ethanol/diethyl ether mixture. (See Fig. 2.) The cryoextraction was allowed to proceed for three days. Subsequently, polymeric particles were retrieved from the reaction vessel and dried under reduced pressure at 21° C.
  • Microspheres having a diameter of approximately 500 to 600 ⁇ m were prepared.
  • a polymer solution was prepared by dissolving poly[bis(trifluoroethoxy)phosphazene] polymer of a molecular weight 3x10 6 g/mol in ethyl acetate to obtain a 2% (wt/v) polymer solution.
  • Four milliliters of this polymer solution was manually dripped into liquid nitrogen using a 5 mi syringe. This dispersion was dispensed onto a frozen layer of 150 milliliters of hexane. (See Fig. 2.) The cryoextraction was allowed to proceed for three days. Subsequently, polymeric particles were retrieved from the reaction vessel and air dried at 21° C.
  • Microspheres having a diameter of approximately 500 to 600 ⁇ m were prepared.
  • a polymer solution was prepared by dissolving poly[bis(trifluoroethoxy)phosphazene] polymer of a molecular weight 3x10 6 g/mol in ethyl acetate to obtain a 2% (wt/v) polymer solution.
  • Four milliliters of this polymer solution was manually dripped into liquid nitrogen using a 5 ml syringe. This dispersion was dispensed onto a frozen layer of 150 milliliters of ethanol. (See Fig. 2.) The cryoextraction was allowed to proceed for three days. Subsequently, polymeric particles were retrieved from the reaction vessel and air dried at 21° C. The particles were noticeably gel-like and after drying were ellipsoid in shape.
  • Microspheres having a diameter of approximately 500 to 600 ⁇ m were prepared.
  • a polymer solution was prepared by dissolving poly[bis(trifluoroethoxy)phosphazene] polymer of a molecular weight 3x10 6 g/mol in ethyl acetate to obtain a 2% (wt/v) polymer solution.
  • Four milliliters of this polymer solution was manually dripped into liquid nitrogen using a 5 ml syringe. This dispersion was dispensed onto a frozen layer of 150 milliliters of diethylether. (See Fig. 2.) The cryoextraction was allowed to proceed for three days. Subsequently, polymeric particles were retrieved from the reaction vessel and air dried at 21° C. The resultant particles were, after drying, compact and uniformly spherical.
  • a two liter cryovessel as shown in Fig. 6 was filled with 100 milliliters of diethyl ether as a non-solvent. Liquid nitrogen was slowly added until the non-solvent froze. The vessel was then filled with additional liquid nitrogen, until the amount of liquid nitrogen rose approximately 5 to 10 cm when measured vertically above the non-solvent layer. The vessel was closed with an insulated lid, and a syringe needle connected via Teflon tubing to a syringe pump was inserted through a small opening in the lid.
  • a Teflon ® cylinder with one inlet and one to eight outlets is used to distribute the dispensed volumes into several vessels in parallel. (It is preferable that the ratio of solvent to non-solvent volume stays below 10% (v/v). Otherwise the particles may adhere to one another.)
  • the needle tips used for dispensing are small, such as the G33 size. Additionally, the dropping distance should be more than 5 cm, so that the droplets aided by gravity immediately sink into the liquid nitrogen upon hitting the surface.
  • Figs. 3A and 3B show the microspheres as they appear using an optical microscope at 4x magnification.
  • Fig. 3B shows a microsphere as it appears using a scanning electron microscope at 10Ox magnification.
  • Hydrogel micropart teles formed in accordance with the procedures described herein were evaluated for buoyancy and suspension properties for use in embolization applications.
  • the microparticies included a sample using unmodified polymethacrylic acid potassium salt hydrogel particles (Sample A); a sample using trifluoroethyl esterified polymethacrylic acid potassium salt hydrogels (Sample B); and a sample using the same hydrogel as Sample B, but wherein the particles were coated with poly[bis(trifluoroethoxy) phosphazene (Sample C).
  • An isotonic phosphate buffered sa ⁇ ne solution of pH 7.4 having 0.05 volume % TweenTM 20 was prepared by dissolving 5 phosphate buffered saline tablets (Fluka® ) in 999.5 ml of mil ⁇ Q ultrapure water. 0.5 ml of Tween 20TM surfactant was added to the solution. Solutions having between 20 and 50 percent by volume of Imeron300® contrast agent in the isotonic buffered 5 saline solution were then prepared for evaluation. [00128] The contrast agent solutions which were prepared were then placed in 4 ml vials in aliquots of 2 mi each. To the vials, 50-80 mg of the hydrated hydrogel Samples A-C were added.
  • Each Sample was first hydrated by adding to 100 mg of dry hydrogel microparticles either 900 mg of isotonic phosphate buffered saline solution or D 2 O to obtain 1 ml swollen hydrogel. Buoyancy properties were measured immediately and every 10 minutes thereafter until buoyancy equilibrium was achieved and/or surpassed.
  • FIG. 8 An automated syringe plunger 2 having a motor 4 for providing a variable feed rate of 0 to 250 mm/h and a gear box 6 was further equipped with a Lorenz pressure transducer 8 capable of measuring forces in the 0 to 500 N range.
  • the syringe plunger 2 was in communication with a syringe body 10 as shown.
  • the digital output of the transducer was recorded using a personal computer.
  • the syringe body 10 was filled with 5 ml of a solution of contrast agent in isotonic phosphate buffer/surfactant (TweenTM 20) solution in a concentration of about 30-32 volume percent contrast agent. Microparticles were provided to the syringe as well in an amount of 56 mg dry mass. The syringe contents were then injected through the microcatheter 12 which was attached to the distal end 14 of the syringe. The microcatheter had a lumen diameter of 533 ⁇ m. The force needed to push the microparticles through the catheter into the Petri dish 16 (shown for receiving microparticle solution) was measured and recorded as pressure.
  • TweenTM 20 isotonic phosphate buffer/surfactant
  • microspheres for embolization typically have a water content of about 90% such that a vial for embolization would therefore contain 0.2 mg of embolization particles in 9.8 ml of injection liquid (2 mi of hydrated microparticles in 8 ml supernatant liquid).
  • the solution is typically drawn up in 1 ml syringes for final delivery.
  • the injection density thus equals:
  • the Sample C spheres demonstrated approximately the same equilibrium water content as typical embolization spheres. To achieve the same injection density desired for typical surgical procedures, 56 mg of Sample C microspheres were added to 5 mi of a 31 volume percent contrast agent solution in isotonic phosphate buffer and surfactant as noted above.
  • Sample B and C microspheres were evaluated in different microcatheters of equal lumen diameter at a pH of 7.4. Injections in both the horizontal and vertical direction were made under different buoyancy levels and using different swelling levels (based on pH of
  • the results of the various catheter simulation tests shows that the invention can be used to form injectible microparticles having a density which substantially matches the density of the injection medium for embolization use.
  • the particles' compressibility can further be such that it can be injected without forces over more than about 5 kg on the syringe plunger.
  • the pH of the injection medium can be taken down to about 6 or injections can be done horizontally to increase the ease of passage of Sample B and C microparticles through the catheter. Once within the blood stream, the particles can expand to their original size in the pH 7.4 environment.
  • the syringe pressure test stand of Fig. 8 was used, however, an optical microscope was used to evaluate the microparticles as they passed through a progressively narrowed pipette which was attached to polyethylene tubing connected to the syringe containing a phosphate buffer solution suspension of microparticles of Sample C.
  • the pipette narrowed to an inner diameter of 490 ⁇ m and the pipette was mounted to a Petri dish such that the narrowest part was submerged in phosphate buffer solution to avoid optical distortion and to collect the liquid ejected from the pipette during measurement.
  • Sample C microparticles were further subjected to mechanical and thermal stress stability testing. Microparticles, after passing through a Terumo Progreat Tracker catheter were washed with deionized water to remove residual buffer solution along with contrast agent. They were dehydrated for 12 h at 60° C and then transferred to an SEM for surface analysis. They were compared with particles from the original batch of microparticles which had undergone the same hydration/dehy drat ion cycle in milliQ ultrapure water, but which had not been passed through the catheter. Figs 9A and 9B show the surface of the Sample C microparticles just after the hydration/dehydration cycle and the film thickness of an exemplary Sample C microparticle, respectively.
  • a sterilizer was filled with 2 1 of deionized water and 10 vials each having 56 mg of Sample C microparticles in 3.3g of solution of isotonic phosphate buffer/surfactant (TweenTM
  • Microparticles were formed in accordance with a preferred embodiment herein.
  • a deionized water solution of polyvinyl alcohol (PVA) was prepared using about 23g of PVA of weight average molecular weight of about 85,000-124,000, which PVA was about 87-89% hydrolyzed and 1000 g water.
  • a phosphate buffer solution was prepared using 900 g deionized water, 4.53 g disodium hydrogen phosphate, 0.26 g sodium dihydrogen phosphate and 0.056 g ethylenediamine tetraacetic acid (EDTA).
  • EDTA ethylenediamine tetraacetic acid
  • Methyl methacrylate (MMA) monomer was vacuum distilled prior to use.
  • Polymerization was carried out in a three-necked, round-bottomed, 2000-ml flask with a KPG mechanical stirring apparatus attached. The flask was also equipped with a thermometer, reflux condenser and a pressure release valve with a nitrogen inlet. The polymerization process further utilized 100 ml of the PVA solution prepared above, 900 ml of the phosphate buffer solution, 0.65 g of dilauroyl peroxide, 200.2 g methacrylic acid methyl ester and 2.86 g triethylene glycol dimethacrylate.
  • the PVA and buffer solutions were provided to the reactor flask.
  • the distilled MMA and triethylene glycol dimethacrylate were introduced, dilauroyl peroxide then added to the same flask and the components were agitated to ensure dissolved solids.
  • the reaction flask was flushed with argon and the stirrer speed set to at 150 rpm to produce particle sizes of a majority in the range of 300-355 ⁇ m. Stirring continued for approximate 5 minutes.
  • the stirrer was then set to 100 rpm and argon flushing was discontinued.
  • the reaction flask was then subjected to a water bath which was heated to 70° C and held at approximately that temperature for about 2 hours.
  • the temperature of the bath was then increased to 73° C and held for an hour, then the water bath temperature was raised again to 85° C and held for another hour.
  • the stirring and heat were discontinued.
  • the solution was filtered and the resulting polymethylacrylate microparticles were dried in an oven at 70° C for about 12 hours.
  • the microparticies were subjected to sieving and collected in size fractions of from 100-150; 150-200; 200-250; 250-300; 300-355; 355-400; and 400-450 ⁇ m with a maximum yield at 300-355 ⁇ m.
  • the PMMA microparticles thus formed were then hydrolyzed. A portion of 100 g 250-300 ⁇ m sized microparticles, 150 g potassium hydroxide and 1400 g of ethylene glycol were added to a 2000 ml flask, reflux condenser with drying tube connected, and the mixture was heated at 165° C for 8 hours for full hydrolysis. The mixture was allowed to cool to room temperature, solution decanted and the microparticles were washed with deionized water. The procedure was repeated for other calibrated sizes of microparticles (the following reaction times applied: 300-355 micron particles: 10 hours; 355-400 micron particles: 12 hours and 400-455 micron particles: 14 hours).
  • microparticles were finally acidified with hydrochloric acid to a pH of 7.4, and dried in an oven at approximately 70° C.
  • Microparticles formed in accordance with Example 15 were then esterified in this Example.
  • 800 g of dried microparticles from Example 15 were weighed in a 2L reaction vessel with a reflux condenser.
  • 250 g thionyl chloride in 1.5 L diethyl ether were added under stirring. Stirring was continued at room temperature for 20 hours. The solvent and volatile reactants were removed by filtration and subsequent vacuum drying. Then 500 g trifiuoroethanol in 1.5 L ether were introduced and the suspension stirred for another 20 hours at room temperature. The particles were finally dried under vacuum.
  • Example 16 In an alternative surface treatment to Example 16, 800 g dried microparticles from Example 15 were reacted with 1140 g trifiuoroethanol and 44 g sulfuric acid added as a catalyst. The mixture was stirred for 20 hours at room temperature, filtered and dried under vacuum. EXAMPLE 18
  • the solution composition was 0.835 g poly[bis(trifluoroethoxy) phosphazene, 550 g ethyl acetate and 450 g isopentyl acetate. It was fed through the nozzle's 1.3 mm wide inner bore at a rate of 10-30 g/min, At the nozzle head, it was atomized with pressurized air (2.5 bar). The total amount of spray solution (3kg) was calculated to coat the particle with a 150 nm thick poly[bis(trifluoroethoxy) phosphazene film.
  • Microparticles were formed in accordance with the procedure of Example 15 with the exception that an exterior barium sulfate coating was prepared on the microparticles after neutralization of the particles and the microparticles were not dried after neutralization prior to the barium sulfate coating step.
  • an exterior barium sulfate coating was prepared on the microparticles after neutralization of the particles and the microparticles were not dried after neutralization prior to the barium sulfate coating step.
  • 2500 ml hydrated particles were subjected to 2000 ml of 0.5 M sodium sulfate (Na 2 SO 4 ) solution and saturated for 4-12 hours.
  • To the particle suspension was then slowly added 1950 ml of 0.5 M barium chloride (BaC ⁇ ) solution under stirring at room temperature.
  • the resulting particles in a swollen state included a barium sulfate powder coated surface.
  • the particles were then dried and esterified in the manner noted above in Example 16.
  • the particles were then coated using the fluidized bed process of Example 21 below.
  • the resulting microparticles were externally coated with a non-adhesive barium sulfate powder.
  • Barium sulfate coatings prepared in accordance with this invention and procedure are capable of preventing particle agglomeration during drying and also increase density.
  • the concentration and ratios of barium sulfate may be varied to provide different results and a use of an excess of sodium sulfate can minimize residual barium chloride.
  • the particles formed in accordance with this example were effectively washed with hot water to minimize excess barium sulfate powder that may contaminate vials, etc.
  • the barium sulfate works effectively to prevent adhesion of particles prior to drying to assist in fluidization of the hydrated microparticles.
  • Fluidized bed coating of barium sulfate powdered beads was performed using polymethacrylate beads with a surface layer of barium sulfate formed in accordance with Example 20 but an excess of barium chloride was used such that barium ions diffused inside the core and formed a precipitate inside the hydrogel core.
  • the particles were washed three times with 2 L of deionized water each. This procedure precipitated barium sulfate inside the particles. [00156] The resulting precipitate was precipitated within the pores of the hydrogel core and could not be removed by multiple washings with water. The particles thus formed were found to have a permanent increased density in contrast to unmodified particles. The density increase was controllable by the molar amount of barium chloride used. Amounts ranging from 0-15 mol % of barium chloride were used reproducibly with this procedure.
  • Both Examples 20 and 21 provided particles having anti-adhesive properties that tend not to agglomerate during drying processes; therefore avoiding surface damage. Generally, such an advantage helps minimize the amount of particles needed for a fluidized bed procedure as the particles can be fluidized without being completely dried.
  • the residual water content may be increased up to 1 : 1 based on dry weight without agglomeration.
  • the Examples also produce particles with increased density properties wherein the density change appears to be permanent.
  • barium sulfate may be introduced in accordance with the invention in a range of from 0 to about 100 mo!%, and preferably 0 to about 15 mo!% to provide particles that have preferred elasticity, density and mechanical stability properties.
  • the particles (now 600 g) with 50 weight percent (wt%) water inside were spray coated with APTMS/ poly[bis(trifluoroethoxy) phosphazene in an MP-I Precision CoaterTM fluidized bed coating apparatus according to Example 18 with the exception that an additional am ⁇ nosilane adhesion promoter was used.
  • the process equipment used was the same as that of Example 18, but the coating provided included three different layers.
  • a bottom coating of 3- aminopropyltrimethoxysilane (APTMS) adhesion promoter was provided upon which was a second coating layer of a mixture of APTMS and poly[bis(trifluoroethoxy) phosphazene and a third, top coating layer of po!y[bis(trifluoroethoxy) phosphazene.
  • All three spray solutions were prepared by dissolving the coating materia! in isopentyl acetate and ethyl acetate in a 1: 1 weight percentage ratio mixture.
  • the first solution included 35 ⁇ l APTMS dissolved in 200 g acetate mixture.
  • the second solution included 25 ⁇ l APTMS and 125 mg poly [bis (trifluoroethoxy) phosphazene in 150 mg of the acetate mixture and the third included 50 mg poly [bis (trifluoroethoxy) phosphazene in 60 g of the acetate mixture.
  • the spray solution quantities and concentrations refer to the coating of a 300 g batch with 350 ⁇ m particles.
  • the absorbed water evaporated at a rate of 5 - 10 g/min. The process was stopped after 30 min when the coating thickness reached 100 nm and the residual water content was 18.4 wt%.
  • the samples were incubated for 30-60 minutes at room temperature under gentle shaking of the vial. Supernatant liquid was discarded and particles were washed three times with 2 ml of deionized water, saline or PBS buffer solution prior to visualization with optical and fluorescence microscopy.
  • the dyes tested included triphenylmethane derived dyes such as
  • Fluoescein diacetate and Rhodamin 6G which were evaluated along with carbocyanine based dyes such as DiI.
  • carbocyanine based dyes such as DiI.
  • the triphenylmethane based Fluorecein and Rhoamine dyes exhibited a specific affinity for the hydrophilic PMMA hydrogel core through ionic interactions. They were able to easily withstand the rigorous conditions of repeated washing and steam sterilization without substantial leaching.
  • Use of these and other dyes may be used to visually identify selected microspheres, which may be provided and dyed for identification to indicate certain sizes of microspheres for use in selected clinical or diagnostic applications. Color-coding may also be used to identify selected microspheres on the basis of other properties, such as content of certain therapeutic or diagnostic agents. Applications according to the present invention may also improve the imaging visualization by enhancing the particles' buoyancy behavior.
  • microspheres may be produced in calibrated sizes ranging from about 1 to about 10,000 nanometers in diameter.
  • microspheres of the present invention may be provided in sizes of about 40, about 100, about 250, about 400, about 500, about 700, and about 900 nanometers in diameter, with a visually distinctive color imparted to each size of microsphere.
  • Other sizes, size ranges, and calibrated sized microspheres lacking color dye are also included in the present invention.
  • microspheres or particles may be provided in different size ranges, but their elasticity may be controlled according to the present invention to specifically provide for proximal or distal embolization behavior, due to potentially differing ranges of compressibility which may alter the traveling distance of the particles or microspheres upon their release within a selected blood vessel.
  • Microspheres of the present invention may also be provided in customized sizes and/or with customized colors as specified by a user for specific clinical diagnostic or therapeutic applications,
  • different-sized microspheres of the present invention may further be provided with color-coding to allow user identification and visual confirmation of the sized microspheres in use at any given stage of the clinical procedure.
  • microspheres of different sizes or other inherent qualities may further be facilitated by the use of transport packaging and/or delivery devices which are color- coded to allow user identification and visual confirmation of the sized microspheres in use at any given stage of the clinical procedure in exemplary applications according to the present invention.
  • color coding may aid the clinician in accurate patient dosing.
  • such color-coded devices may be used in combination with color-coding of the microspheres themselves, with corresponding microsphere and packaging/delivery device color-coding.
  • FIGs. 12A-12G show yet another exemplary restorative application of the present invention used for erectile dysfunction.
  • Fig. 12A shows a sagittal view of a human penis.
  • Fig. 12B shows an axial view of the penis at the level A-A' indicated on Fig. 12A.
  • Fig. 12B the relative positions of the cavernous artery 320, the corpora cavernosa 310, and the urethra 305 are shown
  • Figs. 12C and 12D are detailed views arising from Fig 12B, showing the penis at non-erect and erect stages, respectively.
  • Fig. 12A shows a sagittal view of a human penis.
  • Fig. 12B shows an axial view of the penis at the level A-A' indicated on Fig. 12A.
  • Fig. 12B the relative positions of the cavernous artery 320, the corpora cavernosa 310, and the urethra
  • FIG. 12C 5 it is noted that, at a non-erect stage, the subtunical veins 325 are open, the sinusoidal spaces 330 are relatively small, and the trabecular smooth muscles 340 are contracted. Also noted on Fig. 12C is the arterial vascular supply to the sinusoidal spaces 330, consisting of the helicine arteries 335 arising from the cavernous arteries 320. Upon erection, as shown in Fig. 12D, there is engorgement of the sinusoidal spaces 330, compressing the subtunical veins 325, and relaxation of the trabecular smooth muscle 340.
  • Fig. 12E shows the axial view of Fig. 12B, with an injection needle 130 extending into the corpora cavernosa 330 for the purpose of injecting microspheres containing one or more active agents therein. 330.
  • microspheres containing one or more active agents 140 may be injected into the corpora cavernosa 330 after placement of a needle 130 attached to an injection syringe (not shown in Fig. 12E) and application of negative pressure to ascertain that the needle 130 is not placed within a vascular space.
  • microspheres 140 of the present invention are injected within the interstitial spaces of the corpora cavernosa 330, as shown in Figs. 12F and 12G, which also detail the penis at non-erect and erect stages, respectively.
  • therapeutic release of active agent may be accomplished as a reaction to naturally-occurring or artificially induced or enhanced releasing stimuli as disclosed herein.
  • naturally-occurring stimuli may be related to sexual stimulation.
  • Artificially induced or enhanced releasing stimuli may result from the controlled delivery of therapeutic molecules or protein in a pulsatile or triggered fashion.

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Abstract

L'invention porte sur des particules pour une utilisation dans des opérations de rétablissement pour traiter un dysfonctionnement érectile. Les particules comprennent du poly[bis(trifluoroéthoxy)phosphazène] et/ou des dérivés de celui-ci qui peuvent être présents dans la totalité des particules ou à l'intérieur d'un enrobage externe des particules. Les particules peuvent également comprendre un noyau ayant un hydrogel formé à partir d'un polymère à base acrylique. De telles particules peuvent être chargées pour fournir un traitement localisé par un agent actif ayant pour but de rétablir un fonctionnement érectile normal du pénis et de traiter un dysfonctionnement érectile. De plus, de telles particules peuvent être fournies à un utilisateur avec une coloration personnalisée ou dans diverses couleurs codées pour indiquer différentes doses d'agent actif contenu dans celles-ci.
PCT/US2007/083216 2007-10-31 2007-10-31 Particules polymères chargeables pour une utilisation thérapeutique dans un dysfonctionnement érectile WO2009058147A1 (fr)

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CN110742872A (zh) * 2018-08-22 2020-02-04 深圳善康医疗健康产业有限公司 一种纳曲酮植入剂的制备方法
WO2020080806A1 (fr) * 2018-10-15 2020-04-23 Chong Kun Dang Pharmaceutical Corp. Compositions injectables de microparticules de naltrexone à action prolongée
CN113122045A (zh) * 2021-04-16 2021-07-16 安徽中铁工程材料科技有限公司 一种聚合物胶乳界面稳定剂、乳化沥青防水涂料及其制备方法
WO2021237322A1 (fr) * 2020-05-29 2021-12-02 Luiz Peracchi Edson Implant sous-cutané réabsorbable de longue durée à libération prolongée de substance pharmacologiquement active pré-concentrée en polymère pour le traitement de la dysfonction érectile et de l'hyperplasie bénigne de la prostate
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10253166B2 (en) 2017-09-07 2019-04-09 International Business Machines Corporation Flame-retardant microcapsule containing cyclic phosphazene
CN110742871A (zh) * 2018-08-22 2020-02-04 深圳善康医疗健康产业有限公司 一种纳曲酮植入剂微球压片工艺
CN110742872A (zh) * 2018-08-22 2020-02-04 深圳善康医疗健康产业有限公司 一种纳曲酮植入剂的制备方法
CN110742871B (zh) * 2018-08-22 2021-02-23 深圳善康医疗健康产业有限公司 一种纳曲酮植入剂微球压片工艺
CN110742872B (zh) * 2018-08-22 2021-02-23 深圳善康医疗健康产业有限公司 一种纳曲酮植入剂的制备方法
WO2020080806A1 (fr) * 2018-10-15 2020-04-23 Chong Kun Dang Pharmaceutical Corp. Compositions injectables de microparticules de naltrexone à action prolongée
US11000479B2 (en) 2018-10-15 2021-05-11 Chong Kun Dang Pharmaceutical Corp. Injectable long-acting naltrexone microparticle compositions
WO2021237322A1 (fr) * 2020-05-29 2021-12-02 Luiz Peracchi Edson Implant sous-cutané réabsorbable de longue durée à libération prolongée de substance pharmacologiquement active pré-concentrée en polymère pour le traitement de la dysfonction érectile et de l'hyperplasie bénigne de la prostate
EP4159206A4 (fr) * 2020-05-29 2024-04-24 Luiz Peracchi, Edson Implant sous-cutané réabsorbable de longue durée à libération ?prolongée de substance pharmacologiquement active pré-concentrée en polymère pour le traitement de la dysfonction érectile et de l'hyperplasie bénigne de la prostate
RU2822514C1 (ru) * 2020-05-29 2024-07-08 ПЕРАККИ Эдсон ЛУИЗ Подкожный полимерный имплантат длительного действия с контролируемым высвобождением фармакологического преконцентрированного вещества для лечения эректильной дисфункции и доброкачественной гиперплазии предстательной железы
CN113122045A (zh) * 2021-04-16 2021-07-16 安徽中铁工程材料科技有限公司 一种聚合物胶乳界面稳定剂、乳化沥青防水涂料及其制备方法

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