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
  • A61K9/0048—Eye, e.g. artificial tears
  • A61K9/0051—Ocular inserts, ocular implants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
  • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1682—Processes
  • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

• This invention is in the field of pharmaceutical compositions comprising biodegradable microparticles encapsulating high weight percent drug and providing sustained release over a prolonged period of time of drug levels bioequivalent to direct administration of drug.
• Polymeric microparticles have been used for drug delivery for decades. Numerous methods to increase the amount of drag which can be delivered, and to manipulate rate of release, and release profile, have been described. Methods have included altering microparticle size, shape, polymer composition, inclusion of additives such as surfactants and pore forming agents, and inclusion of ligands and bioadhesive agents.
• Glaucoma is an ophthalmic disease characterized by the gradual degeneration of retinal ganglion cells (RGCs). RGCs synapse with bipolar cells and transmit visual inputs to the brain along the optic nerve. Degeneration of these cells leads to gradual vision loss and ultimately blindness if untreated. Glaucoma is the second leading cause of blindness (Biomdahl et al, Acta. Opth. Scan., 75, 310-319 (1997)). Glaucoma will affect approximately 60.5 million people in 2010, increasing to 796 million people in 2020 (Quigley et al, Brit, J. Opth, 90, 262-267 (2006)). This includes peoples suffering from both open angle (OAG) and angle closure glaucoma (ACG).
• OAG open angle
• ACG angle closure glaucoma
• IOP intraocular pressure
• eye drop typically deliver very small amounts of drug, requiring large numbers of doses per day for IOP management. Compliance with this treatment regime is poor with more than half of patients unable to maintain consistently lowered IOP through drops (Rotchford and Murphy, Brit. J Opthmal,, 12, 234-236 (1998)).
• U.S. Patent No. 6,726,918 to Wong describes methods for treating inflammation-mediated conditions of the eye, the methods including implanting into the vitreous of the eye a bioerodible implant containing a steroidal anti-inflammatory and a bioerodible polymer, wherein the implant delivers an agent to the vitreous in amount sufficient to reach a concentration equivalent to at least about 0.65 ⁇ g/ml dexamethasone within about 48 hours and maintains a concentration equivalent to at least about 0 .03 ⁇ g/ml dexamethasone for at least about three weeks. Wong does not disclose administering the implants by subconjunctive injection.
• Chang describes biocompatible microparticles containing an alpa-2-adrenergic receptor agonist and a biodegradable polymer.
• the microparticles can allegedly be used to treat glaucoma.
• Chang alleges that the microparticles release the active agent for a period of time of at least about one week, such as between two and six months. Chang discloses that the microaprticles can be administered subconjunctivally.
• U.S. Patent Application Publication No. 2004/0234611 to Ahlheim et al. describes an ophthalmic depot formulation containing an active agent embedded in a pharmacologically acceptable biocompatible polymer or a lipid encapsulating agent for periocular or subconjunctival administration.
• the formulation can be in the form of microparticles or nanoparticles.
• Ahlheim discloses that the depot formulations are adapted to release all or substantially all of the active material over an extended period of time (e.g., several weeks up to 6 months).
• Suitable active agents are listed in paragraphs 0033 to 0051 ; however, the preferred active agent is a stauiosporine, a phthalazine, or a pharmaceutically salt thereof.
• Suitable polymers are listed in paragraphs 0014 to 0026. Ahlheim contains no examples showing in vitro or in vivo release of any active agents.
• sustained release polymeric microparticulate compositions which have been optimized to maximize drug loading and release an effective amount of a drag (or drugs) for a desired period of time. It is a further object of the present invention to provide such formulations useful for reducing intraocular pressure (IOP) which provide sustained release of an amount of drug comparable to that administered topically for more than 14 days in vivo, and methods of making and using thereof.
• IOP intraocular pressure
• compositions of one or more active agents useful for reducing intraocular pressure (IOP) which provide sustained release for more than 14 days in vivo, and methods using thereof, wherein the compositions exhibit minimal adverse side effects and is well tolerated by patients.
• IOP intraocular pressure
• Biodegradable polymeric microparticle compositions containing one or more poorly water soluble active agents, especially those useful for treating or preventing one or more diseases or disorders of the eye, and methods of making and using thereof, are described.
• the microparticles are optimized for the drug to be delivered, so that the hydrophobicity or hydrophilicity of the polymer and charge of the polymer maximizes loading of the drug, and the selection and molecular weight of the polymers maximize release of an effective amount of the drug for the desired period of time.
• the microparticle compositions contain one or more water insoluble active agents useful for managing elevated intraocular pressure (IOP) in the eye.
• the microparticle compositions contain one or more water insoluble active agents that promote regeneration of the optic nerve.
• the microparticle compositions contain one or more water insoluble active agents useful for treating one or more anti-inflammatory diseases, such as uveitus.
• the microsphere compositions release an effective amount of the one or more active agents for a period greater than 14 days in vivo, preferably greater than 30 days, preferably greater than 60 days in vivo, more preferably up to 73 days in vivo, more preferably greater than 90 days in vivo, even more preferably over 100 days in vivo, and most preferably greater than 120 days in vivo.
• the desired amount and duration of release is dependent upon several factors including the disease or disorder to be treated, the one or more active agents to be delivered, and the frequency of administration.
• the drug is released over a shorter period of time, for example, 14-21 days for steroids such as prednisolone.
• the formulations preferably release drug over longer time periods, such as those listed above.
• the microspheres are formed from polylactide- co-glycolide ("PLGA”); in another embodiment, the microspheres are formed from a blend of PLGA and polylactic acid (“PLA”).
• PLGA polylactide- co-glycolide
• PLA polylactic acid
• LA polylactide- co-glycolide
• PLA polylactic acid
• the microsphere compositions release a water insoluble drag for at least 35 days, preferably for at least 50 days, more preferably for at least 75 days, most preferably for at least 100 days.
• the sustained release of drug, in combination with the ability to administer the drag in a minimally invasive manner, should increase patient compliance.
• the percent loading of the drug in the microspheres is from about 1% to about 25% by weight, preferably from about 1% to about 20% by weight, more preferably from about 1% to about 10% by weight.
• the percent loading is dependent on the drug to be encapsulated, the polymer or polymers used to form the microparticles, and/or the procedure used to prepare the microparticles.
• microsphere compositions can be administered to the eye using a variety of techniques in the art.
• the compositions are administered to the eye by injection.
• the microsphere composition is administered subconjunctival ⁇ . Subconjunctival administration is minimally invasive, and minimizes systemic absorption of the active agents.
• Figure 1 is a graph showing the cumulative prednisolone acetate release ( ⁇ g/mg of polymer) in vitro as a function of time (days) for microparticles prepared from PLGA 502H ( ⁇ ), PLGA 503 H (x), and a blend of PLGA 502H and PLA (T).
• Figure 2 is a graph showing the cumulative prednisolone acetate release ( ⁇ g/mg of polymer) in vitro as a function of time (days) for microparticles prepared from PLGA 502H ( ⁇ ), PLGA 502H with PEG-1500 (JL), PLGA 502H with sonication (15% amp) (T), PLGA 502H with sonication (30% amp) ( ⁇ ), PLGA 502H with sonication (38% amp) (•), and PLGA 502H with homogenizer (o).
• Figure 3 is a graph showing the in vitro cumulative methotrexate release ( ⁇ g/mg) as a function of time (days) from microspheres prepared from PLGA 503H.
• Figure 4 are graphs showing the in vitro and in vivo cumulative methotrexate release ( ⁇ g/mg) as a function of time (days) from microspheres prepared from PLGA 502H.
• Figure 5 is a graph showing the release of triamcinolone ( ⁇ g/mg) in vivo and in vivo as a function of time (days) from PLGA 502H microparticles.
• Figure 6 is a graph showing the in vitro release profile of travoprost
• Figure 7 is a graph showing the in vitro release of AG 1478 ( ⁇ g drug/mg polymer) as a function of time (days) from PLGA 503 H microparticles.
• Figure 8 is a graph showing the cumulative release of AGl 478 ( ⁇ g/mg polymer) in vitro from microspheres prepared from PLGA 503H via an oil-in-water emulsion technique, wherein percent drug loading is 2.5% (D) and 5.0% (A).
• Figure 9 is a graph showing the in vitro release profile of AG 1478 ( ⁇ g drug/mg polymer) as a function of time (days) for AG 1478 -loaded PLGA 503H microparticles prepared using a S/O/W emulsion process (x), a O/W emulsion process (D), and a O/W co-solvent emulsion process (•).
• Figure 10 is a graph showing the cumulative release of AG 1478 ( ⁇ g/mg polymer) in vitro as a function of time (days) from microspheres prepared from PLGA 503H (•), PLGA 504 (0), and PLGA 504H (D) using an oil-in-water emulsion cosolvent technique.
• Figure 1 1 is a graph showing the cumulative release of AG 1478 ( ⁇ g/mg polymer) in vitro as a function of time (days) from microspheres prepared from PLGA 504 (0) and PLGA 504H ( ⁇ ) prepared using an oil-in- water cosolvent technique.
• Nanoparticle refers to particle or a structure in the nanometer (ran) range, typically from about 1 nm to about 1000 ran in diameter, which is encapsulated within the polymer.
• Microparticles specifically refers to particles having a diameter from about 5 to about 25 microns, preferably from about 10 to about 25 microns, more preferably from about 10 to about 20 microns.
• microparticle encompasses microspheres, microcapsules and microparticles, unless specified otherwise.
• the relative sizes of microparticles and nanoparticles in the context of the present invention are such that the latter can be incorporated into the former.
• a micro- or nanoparticle may be of composite construction and is not necessarily a pure substance; it may be spherical or any other shape.
• Formulations can be prepared using a pharmaceutically acceptable "carrier” composed of materials that are considered safe and effective and may be administered to an individual without causing undesirable biological side effects or unwanted interactions.
• the "carrier” is all components present in the pharmaceutical formulation other than the active ingredient or ingredients.
• carrier includes, but is not limited to, solvents, suspending agents, dispersants, buffers, pH modifying agents, isotonicity modifying agents, preservatives, antimicrobial agents, and combinations thereof.
• “Poorly water soluble drug”, as used herein, refers to a drug having a solubility of less than 10 mg/ml at 25 0 C, preferably less than 5 mg/ml at 25°C, more preferably less than 1 mg/ml at 25 0 C, most preferably less than 0.5 mg/ml at 25 0 C.
• Water-soluble drug refers to a drug having a solubility of greater than 10 mg/ml at 25 0 C, preferably greater than 25 mg/ml at 25 0 C, more preferably greater than 50 mg/ml at 25 0 C, most preferably greater than 100 mg/ml at 25 0 C.
• Hydrophilic polymer refers to polymers that have an affinity for water, though are not water soluble.
• Hydrophilic polymer refers to polymers that tend to repel water.
• microparticle compositions described herein contain one or more poorly water soluble active agents.
• the one or more active agents are useful for treating diseases or disorders of the eye.
• Suitable classes of active agents include, but are not limited to, active agents that lower intraocular pressure, antibiotics, anti-inflammatory agents, chemotherapeutic agents, and steroids.
• the active agents described above can be administered alone or in combination to treat diseases or disorders of the eyes.
• the poorly water soluble drug can be co-administered with a water-soluble drug, either in the same microspheres or in different microspheres or microparticles.
• the water-soluble drugs can be formulated in polymeric microparticles in which the hydrophilicity, molecular weight, and/or monomer composition has been optimized to maximize loading of the drug in the microparticles and to provide sustained release for a period greater than 14 days in vivo, preferably greater than 30 days, preferably greater than 60 days in vivo, more preferably up to 73 days in vivo, more preferably greater than 90 days in vivo, even more preferably over 100 days in vivo, and most preferably greater than 120 days in vivo, most preferably at least 175 days in vivo, Microparticles containing water-soluble active agents, and methods of making and using thereof, are described in WO 2008/157614.
• the microparticles contain one or more active agents that manage (e.g., reduce) elevated IOP in the eye.
• active agents include, but are not limited to, prostaglandins analogs, such as travoprost, bimatoprost, latanoprost, unoprostine, and combinations thereof; and carbonic anhydrase inhibitors (CAI), such as methazolamide, and 5- acylimino- and related imino-substituted analogs of methazolamide; and combinations thereof.
• the microparticles can be administered alone or in combination with microparticles containing a second drug that lowers IOP.
• the second drug can be poorly water soluble or water-soluble and can be formulated in the same microparticles or different raicroparticles as described above.
• the microparticles compositions can contain one or more poorly water soluble antibiotics.
• antibiotics include, but are not limited to, cephaloridine, cefamandole, cefamandole nafate, cefazolin, cefoxitin, cephacetrile sodium, cephalexin, cephaloglycin, cephalosporin C, cephalothin, cafcillin, cephamycins, cephapirin sodium, cephradine, penicillin BT, penicillin N, penicillin O, phenethicillin potassium, pivampic ulin, amoxicillin, ampicillin, cefatoxin, cefotaxime, moxalactam, cefoperazone, cefsulodin, ceflizoxime, ceforanide, cefiaxone, ceftazidime thienamyc ⁇ n, N-formimidoyl thienamycin, clavulanic acid, penemcarboxyl ⁇ c acid, piperacillin
• the poorly water soluble active agent is an inhibitor of a growth factor receptor.
• Suitable inhibitors include, but are not limited to, inhibitors of Epidermal Growth Factor Receptor (EGFR), such as AGl 478, and EGFR kinase inhibitors, such as BIBW 2992, erlotinib, gefitinib, lapatinib, and vandetanib.
• AG 1478 is a potent inhibitor of the epidermal growth factor receptor (EGFR). It was developed initially as a small-molecule tyrosine kinase antagonist to treat tumors, such as breast and ovarian, that have large excesses of EGFR on their surfaces. EGFR is present in many cell types in the body and is responsible for mediating basic cell behaviors such as proliferation and fate choice of cells, thus making systemic knockdown of EGFR problematic.
• EGFR epidermal growth factor receptor
• the microparticle compositions can contain one or more poorly water soluble chemotherapeutic agents and/or steroids.
• the poorly water soluble chemotherapeutic agent is methotrexate.
• Methotrexate is an antimetabolite which has been used to treat autoimmune disorders as well as certain types of cancers. In the eye, methotrexate is used to treat a number of inflammatory diseases, such as uveitis. Methotrexate is known to cause adverse side effects when administered system ⁇ cally. Sustained, local delivery has the potential to reduce the amount of methotrexate in serum or eliminate it completely and thus mitigate adverse side effects.
• the drug is a poorly water soluble steroid, such as prednisolone acetate, triamcinolone, prednisolone, hydrocortisone, hydrocortisone acetate, hydrocortisone valerate, vidarabine, fluorometholone, fluocinolone acetonide, triamcinolone acetonide, dexamethasone, dexamethasone acetate, and combinations thereof.
• a poorly water soluble steroid such as prednisolone acetate, triamcinolone, prednisolone, hydrocortisone, hydrocortisone acetate, hydrocortisone valerate, vidarabine, fluorometholone, fluocinolone acetonide, triamcinolone acetonide, dexamethasone, dexamethasone acetate, and combinations thereof.
• the side effects most associate with ophthalmic surgery are postoperative ocular inflammation and/or infection.
• Topical administration of eye drops containing a steroid and an antibiotic has typically been used for controlling inflammation and preventing infection.
• poor patient compliance and/or the risk of re-opening the stitched wound due to continuous touching of the wound when applying the drops are limitations of such formulations. Therefore, it is preferable to use sustained release formulations that release the steroid and/or antibiotic over extended periods of time (e.g., 2-3 weeks) to minimize dosing frequency, improve compliance, reduce side effects, and keep the stitched wound intact.
• Triamcinolone is a steroid used to treat macular odeama, a complication of diabetes and retinal vein occlusion.
• the one or more active agents can be administered as the free acid or base or as a pharmaceutically acceptable acid addition or base addition salt.
• Examples of pharmaceutically acceptable salts include but are not limited to mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids.
• the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
• Such conventional nontoxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, tolunesulfonic, naphthalenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic salts.
• inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids
• organic acids such as acetic, propionic, succinic, glycolic, ste
• the pharmaceutically acceptable salts of the compounds can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, p. 704; and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use," P. Heinrich Stahl and Camille G. Wermuth, Eds., Wiley- VCH, Weinheim, 2002.
• pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.
• pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.
• the microparticles described here can be formed from natural and/or synthetic polymeric materials.
• Polymer or “polymeric”, as used herein, refers to oligomers, adducts, homopolymers, random copolymers, pseudo- copolymers, statistical copolymers, alternating copolymers, periodic copolymer, bipolymers, terpolymers, quaterpolymers, other forms of copolymers, substituted derivatives thereof, and combinations of two or more thereof (i.e., polymer blends).
• the polymers can be linear, branched, block, graft, monodisperse, poly disperse, regular, irregular, tactic, isotactic, syndiotactic, stereoregular, atactic, stereoblock, single-strand, double-strand, star, comb, dendritic, and/or ionomeric.
• Bioerodible polymers may be used, so long as they are biocompatible.
• Preferred bio-erodible polymers are polyhydroxyacids such as poly lactic acid and copolymers thereof. These are approved for implantation into humans.
• Another class of approved biodegradable polymers are the polyhydroxyalkanoates.
• polyamides polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes and copolymers thereof, alkyl cellulose, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, polymers of acrylic and methacrylic esters, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxy-propyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxylethyl cellulose, cellulose
• the bioerodable polymers may be used to provide delayed or extended release of nanoparticles comprising a diagnostic, therapeutic, or prophylactic agent.
• the percent loading is increased by "matching" the hydrophilicity or hydrophobicity of the polymer to the agent to be encapsulated.
• this can be achieved by selecting the monomer ratios so that the copolymer is more hydrophilic for hydrophilic drugs or less hydrophilic for hydrophobic drugs.
• the polymer can be made more hydrophilic, for example, by introducing carboxyl groups onto the polymer.
• a combination of a hydrophilic drug and a hydrophobic drug can be encapsulated in microparticles prepared from a blend of a more hydrophilic PLGA and a hydrophobic polymer, such as PLA.
• the percent loading of the one or more active agents in the microparticles is from about 1 to 50 weight percent, most preferably 5 to 30 weight percent, more preferably 10 to 20 weight percent.
• the preferred polymer is a PLGA copolymer or a blend of PLGA and PLA.
• the molecular weight of PLGA is from about 10 kD to about 80 kD, more preferably from about 10 kD to about 35 kD.
• the molecular weight range of PLA is from about 20 to about 30 kDa.
• the ratio of lactide to glycolide is from about 75:25 to about 50:50. In one embodiment, the ratio is 50:50.
• microsphere compositions described herein can release an effective amount of one or more active agents suitable for managing elevated IOP, for a period greater than 14 days in vivo, preferably greater than 60 days in vivo, more preferably up to 73 days in vivo, more preferably greater than 90 days in vivo, even more preferably over 100 days in vivo, and most preferably greater than 107 days in vivo. Release for a period of 90 days or greater corresponds to the typical time period between ophthalmologist visits for patients suffering from glaucoma.
• the sustained release of drug, in combination with the ability to administer the drug in a minimally invasive manner, should increase patient compliance.
• the drug is released over a period of greater than 150 days, more preferably over 200 days, more preferably over 250 days.
• release is influenced by a variety of factors, including molecular weight of the polymer, hydrophilicity or hydrophobicity of the polymer, percent loading of the drag, and/or methods of manufacturing the microspheres.
• release of prednisolone acetate was less at a given time period for microspheres prepared from PLGA 502H compared to microspheres prepared from PLGA 503 H and a blend of PLGA 502H and PLA.
• Release of prednisolone acetate is also influenced by the method in which the microspheres are prepared.
• PLGA 502H microspheres prepared using sonication or homogenization exhibited greater release than PLGA 502H microspheres prepared without sonication or homogenization or prepared with PEG 1500.
• release was greater for PLGA 503 H microspheres prepared using an oil-in- water emulsion technique having a drug loading of 5.0% compared to a loading of 2.5%.
• the microspheres exhibited a more rapid release of drag over the first 50 days, followed by a more linear release over the next 125 days.
• Hydrophilicity of the polymer influences the release profile of AG 1478.
• release of AG 1478 was greater from microspheres prepared from PLGA having carboxylic end groups, such as PLGA 503 H and 504H, compared to the non-carboxylated polymer, PLGA 504, using the oil-in- water cosolvent technique. This is likely due to the fact that AG 1478 interacts more strongly with the less hydrophilic polymer PLGA 504, thus slowing the rate of release.
• Typical solvents are organic solvents such as methylene chloride, which leave low levels of residue that are generally accepted as safe.
• Suitable water-insoluble solvents include methylene chloride, chloroform, carbon tetrachloride, dicholorethane, ethyl acetate and cyclohexane.
• Additional solvents include, but are not limited to, alcohols such as methanol (methyl alcohol), ethanol, (ethyl alcohol), 1-propanol (n-propyl alcohol), 2-propanol (isopropyl alcohol), 1-butanol (n-butyl alcohol), 2-butanol (sec-butyl alcohol), 2-methyl- 1-propanol (isobutyl alcohol), 2-methyl-2-propanol (t- butyl alcohol), 1-pentanol (n-pentyl alcohol), 3 -methyl- 1-butanol (isopentyl alcohol), 2,2-dimethyl- 1-propanol (neopentyl alcohol), cyclopentanol (cyclopentyl alcohol), 1-hexanol (n-hexanol), cyclohexanol (cyclohexyl alcohol), 1-heptanol (n-heptyl alcohol), 1-octanol (n-octyl alcohol), 1- nonanol (
• microsphere compositions include, but are not limited to, sterility, preservation, isotonicity, and buffering.
• ophthalmic solutions and suspensions are described in Ansel et ah, Pharmaceutical Dosage Forms and Drug Delivery Systems 6 th Ed,, pp. 396-408, Williams and Wilkins (1995).
• Suspensions are often more advantageous than solution as they typically have increased corneal contact time and thus can provide higher efficacy.
• Ophthalmic suspensions must contain particles of appropriate chemical characteristics and size to be non-irritating to the eyes. The suspension must also not agglomerate upon administration. Excipients, such as dispersants, can be included to prevent aggregation of the particles.
• microspheres are typically suspended in sterile saline, phosphate buffered saline, or other pharmaceutically acceptable carriers for admini stration to the eye .
• Materials that may be used to formulate or prepare the microparticles include anionic, cationic, amphoteric, and non-ionic surfactants.
• Anionic surfactants include di-(2 ethylhexyl) sodium sulfosuccinate; non-ionic surfactants include the fatty acids and the esters thereof; surfactants in the amphoteric group include (1) substances classified as simple, conjugated and derived proteins such as the albumins, gelatins, and glycoproteins, and (2) substances contained within the phospholipid classification, for example, lecithin.
• the amine salts and the quaternary ammonium salts within the cationic group also comprise useful surfactants.
• surfactant compounds useful to form coacervates include polysaccharides and their derivatives, the mucopolysaccharides and the polysorbates and their derivatives.
• Synthetic polymers that may be used as surfactants include compositions such as polyethylene glycol and polypropylene glycol.
• suitable compounds that may be utilized to prepare coacervate systems include glycoproteins, glycolipids, galactose, gelatins, modified fluid gelatins and galacturonic acid.
• Hydrophobic surfactants such as fatty acids and cholesterol are added during processes to improve the resulting distribution of hydrophobic drugs in hydrophobic polymeric microparticles.
• fatty acids include butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, caprylic acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, heptadecylic acid, stearic acid, nonadecanoic acid, arachic acid, isocrotonic acid, undecylenic acid, oleic acid, elaidic acid, sorbic acid, linoleic acid, linolenic acid and arachidonic acid.
• the surfactant polyvinyl alcohol is used to prepare the microparticles.
• percent loading is dependent on the nature of surfactant used in the double emulsion methods described above. For example, using the PLGA/PLA blend and 20% timolol maleate by weight, a loading of 18.76 ⁇ g of timolol/mg of spheres was obtained when a 5% PVA solution was used. In contrast, the load of timolol was 2.3 ⁇ g per mg of spheres when the spheres were prepared using a 5% poly(ethylene ⁇ alt-maleic anhydride) (PEMA) solution.
• PEMA poly(ethylene ⁇ alt-maleic anhydride)
• microparticles can be made, including, but not limited to, spray drying, interfacial polymerization, hot melt encapsulation, phase separation encapsulation, spontaneous emulsion, solvent evaporation microencapsulation, solvent removal microencapsulation, coacervation, low temperature microsphere formation, and phase inversion nanoencapsulation ("PtM").
• spray drying interfacial polymerization
• hot melt encapsulation phase separation encapsulation
• spontaneous emulsion spontaneous emulsion
• solvent evaporation microencapsulation solvent removal microencapsulation
• coacervation low temperature microsphere formation
• PtM phase inversion nanoencapsulation
• the dispersion of the one or more active agents within the polymer matrix can be enhanced by varying: (1) the solvent used to solvate the polymer; (2) the ratio of the polymer to the solvent; (3) the particle size of the material to be encapsulated; (4) the percentage of the active agent(s) relative to the polymer (e.g., drug loading); and/or the polymer concentration.
• the core material to be encapsulated is dispersed or dissolved in a solution.
• the solution is aqueous and preferably the solution includes a polymer.
• the solution or dispersion is pumped through a micronizing nozzle driven by a flow of compressed gas, and the resulting aerosol is suspended in a heated cyclone of air, allowing the solvent to evaporate from the microdroplets.
• the solidified microparticles pass into a second chamber and are trapped in a collection flask.
• Interfacial polycondensation is used to microencapsulate a core material in the following manner.
• One monomer and the core material are dissolved in a solvent.
• a second monomer is dissolved in a second solvent (typically aqueous) which is immiscible with the first.
• An emulsion is formed by suspending the first solution through stirring in the second solution. Once the emulsion is stabilized, an initiator is added to the aqueous phase causing interfacial polymerization at the interface of each droplet of emulsion.
• Hot Melt Encapsulation In hot melt microencapsulation, the core material (to be encapsulated) is added to molten polymer. This mixture is suspended as molten droplets in a nonsolvent for the polymer (often oil-based) which has been heated to approximately 10 0 C above the melting point of the polymer. The emulsion is maintained through vigorous stirring while the nonsolvent bath is quickly cooled below the glass transition of the polymer, causing the molten droplets to solidify and entrap the core material.
• a nonsolvent for the polymer often oil-based
• Solvent Evaporation Microencapsulation In solvent evaporation microencapsulation, the polymer is typically dissolved in a water immiscible organic solvent and the material to be encapsulated is added to the polymer solution as a suspension or solution in an organic solvent. An emulsion is formed by adding this suspension or solution to a beaker of vigorously stirring water (often containing a surface active agent, for example, polyethylene glycol or polyvinyl alcohol, to stabilize the emulsion). The organic solvent is evaporated while continuing to stir. Evaporation results in precipitation of the polymer, forming solid microcapsules containing core material.
• a surface active agent for example, polyethylene glycol or polyvinyl alcohol
• the solvent evaporation process can be used to entrap a liquid core material in a polymer such as PLA, PL A/PGA copolymer, or PLA/PCL copolymer microcapsules.
• the polymer or copolymer is dissolved in a miscible mixture of solvent and nonsolvent, at a nonsolvent concentration which is immediately below the concentration which would produce phase separation (i.e., cloud point).
• the liquid core material is added to the solution while agitating to form an emulsion and disperse the material as droplets. Solvent and nonsolvent are vaporized, with the solvent being vaporized at a faster rate, causing the polymer or copolymer to phase separate and migrate towards the surface of the core material droplets.
• phase-separated solution is then transferred into an agitated volume of nonsolvent, causing any remaining dissolved polymer or copolymer to precipitate and extracting any residual solvent from the formed membrane.
• the result is a microcapsule composed of polymer or copolymer shell with a core of liquid material.
• Solvent evaporation microencapsulation can result in the stabilization of insoluble or poorly soluble drug particles in a polymeric solution for a period of time ranging from 0.5 hours to several months. .
• insoluble or poorly soluble drug particles within the polymeric solution could be critical during scale-up.
• said particles can remain homogeneously dispersed throughout the polymeric solution as well as the resulting polymer matrix that forms during the process of microencapsulation.
• the homogeneous distribution of drug particles can be achieved in any kind of device, including microparticles, nanoparticles, rods, films, and other device.
• Solvent evaporation microencapsulation (SEM) has several advantages. SEM allows for the determination of the best polymer-solvent- insoluble particle mixture that will aid in the formation of a homogeneous suspension that can be used to encapsulate the particles.
• SEM stabilizes the insoluble particles or within the polymeric solution, which will help during scale-up because one will be able to let suspensions of insoluble particles sit for long periods of time, making the process less time-dependent and less labor intensive.
• SEM allows for the encapsulated particles to remain suspended within a polymeric solution for up to 30 days, which may increase the amount of insoluble material entrapped within the polymeric matrix, potentially improving the physical properties of the drug delivery vehicle.
• SEM allows for the creation of m ⁇ croparticles or nanoparticles that have a more optimized release of the encapsulated material. For example, if the insoluble particle is localized to the surface of the microparticle or nanoparticle, the system will have a large 'burst' effect.
• creating a homogeneous dispersion of the insoluble particle within the polymeric matrix will help to create a system with release kinetics that begin to approach the classical 'zero-ordered' release kinetics that are often perceived as being ideal in the field of drug delivery).
• the microspheres are prepared using an oil-in- water emulsion cosolvent technique, in which an organic cosolvent, such as DMSO 5 is used to prepare the microspheres.
• Solvent Removal Microencapsulation the polymer is typically dissolved in an oil miscible organic solvent and the material to be encapsulated is added to the polymer solution as a suspension or solution in organic solvent. Surface active agents can be added to improve the dispersion of the material to be encapsulated. An emulsion is formed by adding this suspension or solution to vigorously stirring oil, in which the oil is a nonsolvent for the polymer and the polymer/solvent solution is immiscible in the oil. The organic solvent is removed by diffusion into the oil phase while continuing to stir. Solvent removal results in precipitation of the polymer, forming solid microcapsules containing core material. Phase Separation Microencapsulation
• phase separation microencapsulation the material to be encapsulated is dispersed in a polymer solution with stirring. While continually stirring to uniformly suspend the material, a nonsolvent for the polymer is slowly added to the solution to decrease the polymer's solubility. Depending on the solubility of the polymer in the solvent and nonsolvent, the polymer either precipitates or phase separates into a polymer rich and a polymer poor phase. Under proper conditions, the polymer in the polymer rich phase will migrate to the interface with the continuous phase, encapsulating the core material in a droplet with an outer polymer shell.
• Spontaneous emulsification involves solidifying emulsified liquid polymer droplets by changing temperature, evaporating solvent, or adding chemical cross-linking agents.
• the physical and chemical properties of the encapsulant, and the material to be encapsulated dictates the suitable methods of encapsulation. Factors such as hydrophobicity, molecular weight, chemical stability, and thermal stability affect encapsulation. Coacervation
• Coacervation is a process involving separation of colloidal solutions into two or more immiscible liquid layers (Ref. Dowben, R. General Physiology, Harper & Row, New York, 1969, pp. 142-143.). Through the process of coacervation compositions comprised of two or more phases and known as coacervates may be produced.
• Phase Inversion Nanoencapsulation A preferred process is PIN.
• a polymer is dissolved in an effective amount of a solvent.
• the agent to be encapsulated is also dissolved or dispersed in the effective amount of the solvent.
• the polymer, the agent and the solvent together form a mixture having a continuous phase, wherein the solvent is the continuous phase.
• the mixture is introduced into an effective amount of a nonsolvent to cause the spontaneous formation of the microencapsulated product, wherein the solvent and the nonsolvent are miscible.
• a hydrophobic agent is dissolved in an effective amount of a first solvent that is free of polymer.
• the hydrophobic agent and the solvent form a mixture having a continuous phase.
• a second solvent and then an aqueous solution are introduced into the mixture.
• the introduction of the aqueous solution causes precipitation of the hydrophobic agent and produces a composition of micronized hydrophobic agent having an average particle size of 1 micron or less.
• the process uses a mixed solvent including at least one water-insoluble solvent and water that contains a surfactant, such as PVA.
• the drug is either dissolved or dispersed together with a substance that has a high molecular weight (such as a polymer) into an organic solvent composition, optionally containing non- ionic surfactants of various hydrophilic-lipopliilic ratios.
• the composition is then introduced into an aqueous solution that contains a surfactant like PVA.
• the water-insoluble solvent forms an oil phase (inner phase) and is stirred into the aqueous solution as a water phase (outer phase).
• the O/ W emulsion is combined with fresh water that contains surfactant such as PVA and is stirred to help aid the solvent evaporation.
• the aqueous solution contains an activator such as polyvinyl alcohol, whereby the oil phase is enclosed as small droplets within the aqueous solution as shells.
• the proportion of the water-miscible solvent in the oil phase is from 5% to 95%.
• the polymer is heated to a point of sufficient fluidity to allow ease of manipulation (for example, stirring with a spatula).
• the temperature required to do this is dependent on the intrinsic properties of the polymer. For example, for crystalline polymers, the temperature will be above the melting point of the polymer.
• the agent is added to the molten polymer and physically mixed while maintaining the temperature. The molten polymer and agent are mixed until the mixture reaches the maximum level of homogeneity for that particular system. The mixture is allowed to cool to room temperature and harden. This may result in melting of the agent in the polymer and/or dispersion of the agent in the polymer.
• This method increases microparticle loading as well as uniformity of the resulting microparticles and of the agent within the microparticles.
• an agent is formed into microspheres by double-emulsion solvent evaporation, transfer of the agent from the inner phase to the outer water phase can be prevented. This makes it possible to increase the percentage of agent entrapped within the microspheres, resulting in an increased amount of the drug in the microspheres.
• the distribution of the agent in particles can also be made more uniform. This can improve the release kinetics of the agent.
• the agent is dissolved or dispersed together with a substance that has a high molecular weight in an organic solvent composition; with or without non- ionic surfactants of various hydrophilic-lipophilic ratios.
• the composition is introduced into an aqueous solution that contains a surfactant like PVA.
• the water-insoluble solvent forms an oil phase (inner phase) and is stirred into the aqueous solution as a water phase (outer phase).
• the O/W emulsion is combined with fresh water that contains PVA and is stirred to help aid the solvent evaporation.
• the aqueous solution contains an activator such as polyvinyl alcohol, whereby the oil phase is enclosed as small droplets within the aqueous solution as shells.
• the microparticles are formed using a water-in- oil double emulsion (w/o/w) solvent evaporation technique.
• the one or more active agents are dissolved in deionized water.
• the polymer is dissolved in an organic solvent or cosolvent.
• the aqueous and organic phases are emulsified via vortexing to obtain the desired active agent to polymer ratio (e.g., 10%, 20%, or greater).
• the emulsion is then added dropwise to an aqueous solution of a surfactant (such as polyvinyl alcohol) and allowed to stir/harden for 3 hours.
• a surfactant such as polyvinyl alcohol
• the resulting microparticles are collected, such as by centrifugation, washed with deionlzed water, and dried (e.g., freeze drying).
• the percent loading is increased by "matching" the hydrophilicity or hydrophobicity of the polymer to the agent to be encapsulated.
• this can be achieved by selecting the monomer ratios so that the copolymer is more hydrophilic.
• the polymer can be made more hydrophilic, for example, by treating the polymer with a carboxyl solution.
• the percent loading of the one or more active agents in the microparticles is from about 1 to about 50 wt%, preferably from about 1 to about 20 wt%, more preferably from about 10 to about 20 wt%. In one embodiment, the percent loading of the drug is 10 wt% or 20 wt%. As demonstrated by the examples, the percent loading is increased by "matching" the hydrophilicity or hydrophobicity of the polymer to the poorly water soluble agent to be encapsulated. Alternatively, the polymer can be made more hydrophilic, for example, by introducing carboxyl groups on to the polymer.
• a combination of a hydrophilic drug and a hydrophobic drug can be encapsulated in microparticles prepared from a blend of a more hydrophilic PLGA and a hydrophobic polymer, such as PLA.
• IV. Methods of Use A. Disorders to be Treated
• microsphere compositions described herein can be administered to treat or prevent diseases or disorders, most preferably of the eye.
• dosage of the drug which is released at the site of administration should be bioequivalent as defined by the Food and Drug Administration for the drug when administered in solution, suspension or enterally, in the absence of the microparticles.
• the microsphere compositions can be administered to manage (e.g., reduce) IOP in patients needing such treatment, for example, patients suffering from glaucoma.
• Glaucoma is an ophthalmic disease characterized by the gradual degeneration of retinal ganglion cells (RGCs). RGCs synapse with bipolar cells and transmit visual inputs to the brain along the optic nerve. Degeneration of these cells leads to gradual vision loss and ultimately blindness if untreated.
• microspheres described herein can also be used to deliver one or more active agents that promote neural regeneration, for example, in patients suffering from glaucoma.
• AGl 478 has been shown to promote neural regeneration.
• AG 1478 is an inhibitor of EGFR.
• the neural degeneration in glaucoma is accompanied by extensive remodeling of the extracellular matrix (ECM) including the production of chondroitin sulfate proteoglycans (CSPGs) which inhibit regeneration.
• ECM extracellular matrix
• CSPGs chondroitin sulfate proteoglycans
• Administration of an EGFR inhibitor, such as AG 1478 has been shown to lead to a reduction in activated astrocytes, a reduction in the production of CSPGs, and regeneration in the optic nerve.
• AG 1478 can be co-administered with neural progenitor cells to replace lost retinal ganglion cells (RGCs) along with sustained delivery of AGl 478 to promote regeneration.
• RRCs retinal ganglion cells
• the optic nerve crush model is an excellent first model for studying methods to promote regeneration in glaucoma as well as in the CNS more broadly.
• EGFR also known as human EGF receptor (HER) and ErbBl
• HER human EGF receptor
• ErbBl ErbBl
• EGFR has seven different but structurally similar ligands, including EGF 5 transforming growth factor- ⁇ l (TGF-Pl), and transforming growth factor- ⁇ (TGF- ⁇ ).
• TGF-Pl EGF 5 transforming growth factor- ⁇ l
• TGF- ⁇ TGF- ⁇
• Ligands of EGFR stimulate astrocyte proliferation and differentiation, induce morphological changes and process formation, and enhance their mobility in vitro .
• EGFR activation is increased in astrocytes and their activation in the cribriform plates to the damaged optic nerve bundles creates compression, backward bowing, and disorganization of the optic nerve head- characteristic features of glaucomatous eyes with high or normal intraocular pressure.
• the EGFR ligands EGF and TGF- ⁇ l greatly increase CSPG production after injury, including neurocan and phosphacan, while upregulation of CSPGs by astrocytes is mediated specifically by the EGFR receptor.
• EGFR optic nerve astrocytes and brain astrocytes to form cribriform structures with cavernous spaces, similar to the structures that reactive astrocytes form in the glial scar.
• EGFR also plays a role in astrocyte phenotype. In normal tissue astrocytes are quiescent, producing only a moderate amount of CSPGs and retaining a stellate morphology. After injury, these quiescent astrocytes are activated and become reactive, with elongated processes and increased motility.
• Astrocytes upregulate and activate EGFR in three different optic nerve injury models: transient eye ischemia, chronic glaucoma, and optic nerve transection.
• EGFR tyrosine kinase inhibitor AG1478-a potent, reversible antagonist of EGFR-in a rodent model of glaucomatous optic neuropathy and an optic nerve crush model, reverses this upregulation and activation of astrocytes and increases the survival of RGCs.
• EGFR activation mediates inhibition of axon regeneration in retinal explants by production of CSPGs and myelin.
• Uveitis specifically refers to inflammation of the middle layer of the eye, termed the "uvea” but in common usage may refer to any inflammatory process involving the interior of the eye. Uveitis is estimated to be responsible for approximately 10% of the blindness in the United States. Uveitis requires an urgent referral and thorough examination by an ophthalmologist, along with urgent treatment to control the inflammation. Uveitis is usually categorized anatomically into anterior, intermediate, posterior and panuveitic forms. Anywhere from two-thirds to 90% of uveitis cases are anterior in location (anterior uveitis), frequently termed limbal - or inflammation of the iris and anterior chamber.
• Symptoms include red eye, injected conjunctiva, pain and decreased vision. Signs include dilated ciliary vessels, presence of cells and flare in the anterior chamber, and keratic precipitates ("KP") on the posterior surface of the cornea.
• Intermediate uveitis consists of vitritis - inflammatory cells in the vitreous cavity, sometimes with snowbanking, or deposition of inflammatory material on the pars plana. Posterior uveitis is the inflammation of the retina and choroid. Pan-uveitis is the inflammation of all the layers of the uvea.
• uveitis myriad conditions can lead to the development of uveitis, including systemic diseases as well as syndromes confined to the eye. In anterior uveitis, no specific diagnosis is made in approximately one-half of cases. However, anterior uveitis is often one of the syndromes associated with HLA-B27.
• the prognosis is generally good for those who receive prompt diagnosis and treatment, but serious complication (including cataracts, glaucoma, band keratopathy, retinal edema and permanent vision loss) may result if left untreated.
• Uveitis can be treated using steroids, such as prednisolone, and chemotherapeutic agents, such as methotrexate.
• the microspheres are loaded with ofloxacin, prednisolone, or a combination thereof.
• the microspheres preferably provide release of the one or more active agents for a period of between 14 and 21 days.
• the microspheres provide sustained release of the one or more active agents over a period greater than three weeks, preferably over a period of greater than 49 days, more preferably over a period of two months, most preferably over a period of three months.
• microspheres loaded with an antibiotic, a steroid, or combinations thereof are administered to a patient post eye surgery.
• the microspheres are loaded with ofloxacin, prednisolone, or a combination thereof.
• the microspheres preferably provide release of the one or more active agents for a period of between 14 and 21 days.
• the microspheres provide sustained release of the one or more active agents over a period greater than three weeks, preferably over a period of greater than 49 days, more preferably over a period of two months, most preferably over a period of three months .
• Dry eye syndrome (Keratoconjunctivitis sicca (KCS)) is one of the most common problems treated by eye physicians. Over ten million Americans suffer from dry eyes. It is usually caused by a problem with the quality of the tear film that lubricates the eyes.
• Dry eye syndrome has many causes.
• One of the most common reasons for dryness is simply the normal aging process. As we grow older, bodies produce less oil - 60% less at age 65 then at age 18. This is more pronounced in women, who tend to have drier skin then men. The oil deficiency also affects the tear film. Without as much oil to seal the watery layer, the tear film evaporates much faster, leaving dry areas on the cornea.
• Macular degeneration is a medical condition predominantly found in elderly adults in which the center of the inner lining of the eye, known as the macula area of the retina, suffers thinning, atrophy, and in some cases, bleeding. This can result in loss of central vision, which entails inability to see fine details, to read, or to recognize faces. According to the American Academy of Ophthalmology, it is the leading cause of central vision loss (blindness) in the United States today for those over the age of fifty years. Although some macular dystrophies that affect younger individuals are sometimes referred to as macular degeneration, the term generally refers to age-related macular degeneration (AMD or ARMD). Macular degeneration can be treated using anti-angio genesis inhibitors.
• AMD age-related macular degeneration
• the microspheres are loaded with a poorly water soluble anti-angiogenesis inhibitor or growth factor for the treatment of macular degeneration.
• the composition can be administered using a variety of techniques well known in the art including, but not limited to, topically and by injection. Suitable dosage forms include but are not limited to, ointments and solutions and suspensions, such as eye drops.
• the compositions are administered to the eye by injection.
• the microsphere composition is administered subconjunctivally.
• Subconjunctival refers to administration under the conjunctiva of the eye.
• the conjunctiva is the clear membrane that coats the inner aspect of the eyelids and the outer surface of the eye.
• the microsphere compositions are generally administered as suspensions in a pharmaceutically acceptable carrier, such as phosphate buffered saline (PBS).
• PBS phosphate buffered saline
• Subconjunctival administration of drugs typically by injection, has shown minimal concentration of drug in the plasma and notable concentrations in the eye, including the aqueous humor.
• kits contain the microsphere compositions and optionally one or more pharmaceutically acceptable excipients or carriers.
• the kit can contain the microspheres in dry powder form in one container, such as a vial, jar, or ampule, and the pharmaceutically acceptable carrier in another container, such as a vial, jar, or ampule.
• the kit typically contains instructions for resuspending the microparticles in the carrier and for administering the composition. If excipients are present, they can be in one or both containers.
• the kit can contain the microparticles resuspended in the carrier and optionally one or more pharmaceutically excipients. The kit would typically contain instructions for administering the composition.
• the kit can also contain one or more apparatus for preparing and/or administering the compositions, such as a needle and syringe.
• the container(s) containing the microspheres and the carrier can be packaged using techniques well known in the art. Suitable package materials include, but are not limited to, boxes
• H means the polymer is terminated with a carboxyHc acid group.
• Poly(D,L-lactic acid) (PLA, M n - ⁇ 20-30 kDa) and polyvinyl alcohol) (PVA, 88mol% hydrolyzed) were purchased from Polyscienes (Warrington, PA, USA).
• Methotrexate and Prednisolone acetate were purchased from Sigma (St. Louis, MO, USA).
• microspheres were prepared by phase separation using a single emulsion solvent evaporation method. Two hundred milligrams of the specific polymer was dissolved in 1 niL of dichloromethane (DCM) and 4 mL of trifluoroethanol (TFE). 40 mg of prednisolone acetate or 20 mg of methotrexate was added to the polymer solution and vortexed to obtain the desired drug to polymer ratio: 20% (40 mg drug/200 mg polymer) for prednisolone acetate and 10% (20 mg drug/200 mg polymer) for methotrexate. The organic phase was added dropwise to 200 mL of 5% (w/v) PVA aqueous solution.
• DCM dichloromethane
• TFE trifluoroethanol
• aqueous and organic phases were emulsified via stirring/hardening for three hours.
• Microspheres were collected by centrifugation, washed three times with deionized water, and freeze dried for three days. Blank microspheres were made at the same time under identical conditions except no drug was added.
• the volume-weighted mean diameter of the microparticles from each batch can be determined using a Beckman Coulter Multsizer 3 (Fullerton, CA, USA) with a 100 ⁇ m diameter aperture based on a sample size of at least 80,000 microspheres. Scanning electron microscopy (SEM) analysis can be used to examine the morphology of the spheres. Microspheres can be sputter coated with gold for 30 seconds at 25 mA and SEM micrographs can be taken on a FEI XL-30 environmental SEM operating at 4 kV. Example 2. In vitro Release Studies of Prednisolone acetate-Loaded Microspheres Microspheres
• phosphate buffered saline PBS
• Samples were prepared in triplicate. The mixtures were incubated at 37°C on a labquake rotating shaker. At specific time points, 1, 3, 5, and 8 hours and 1, 3, and 7 days, and once every 7 days thereafter until no pellets were present, the mixture was centrifuged and the supernatant and the supernatant was collected. One milliliter of phosphate buffered saline was then added to replace the withdrawn supernatant and the microspheres were resuspended and returned to the shaker.
• PBS phosphate buffered saline
• Figure 1 shows the in vitro release profile for 20% prednisolone acetate-loaded microspheres. Prednisolone acetate was released less rapidly from PLGA 502H microspheres than from microspheres prepared from PLGA 503H or a blend of PLGA 502H and PLA.
• Figure 2 shows the in vitro release profiles from the microparticles made using the modified procedures describes in methodologies (a)-(c) above. As is shown in the graph, the modified procedures had little effect on the duration of release of prednisolone acetate.
• Figure 4 shows the in vivo release profile of methotrexate from PLGA 502H microspheres. The graph shows that an effective amount of methotrexate was released in vivo over at least 35 days.
• Triamcinolone microspheres were prepared using a water-in-oil-in- water (w/o/w) double emulsion solvent evaporation technique.
• Figure 5 shows the in vitro release profile for triamcinolone-loaded microspheres. The microspheres provide a burst release over the first one to two days followed by linear release of an effective amount of triamcinolone over a period of about 60 days.
• Travosprost is a liquid at room temperature. 1 mg of Travoprost was mixed with 50 ⁇ l of ethanol. The travoprost solution was added dropwise to the polymer solution and vortexed. The resulting solution was added dropwise to 100 ml of a 5% PVA solution while stirring. The solution was stirred for 3 hours to harden the microspheres, and the microspheres were collected, washed, and lyophilized.
• Example 6 The in vitro release profile was measured using the procedure in Example 2. The results are shown in Figure 6.
• the PLGA 503H-loaded microspheres release drug over a period of at least 7 days in a linear manner. At day 7, approximately 22% of the drug had been released.
• Example 6 Preparation and In Vitro Release Studies of AG1478- Loaded Microspheres
• the in vitro release profile for microspheres prepared using the single emulsion technique is shown in Figure 7.
• the microspheres released an effective amount of AG1478 in a linear manner for at least 126 days.
• FIG. 8 shows the release profile from microspheres prepared from PLGA 503H using via oil-in-water emulsion containing 2.5% and 5% AGl 478.
• the microspheres loaded with 5% AG1478 released a greater amount of drug at a given time point than microspheres loaded with 2.5% AG1478.
• Figure 10 shows the release profile of AG 1478 from microspheres prepared from PLGA 503H, PLGA 504, and PLGA 504H.
• the microspheres exhibit similar release profiles over the first 20 days. However, over the next 60 days, release of AG1478 was greater from the microspheres prepared from PLGA 503H and PLGA 504H. This likely due to the fact that the poorly water soluble AG 1478 associates more strongly with the less hydrophilic PLGA 504 than with the more hydrophilic PLGA 503H and 504H.
• Figure 11 shows the release profile of AG 1478 from microspheres prepared from PLGA 504 and PLGA 504 H. The microspheres exhibited similar release profiles over the first 20 days.

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