US 2016O235674A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0235674 A1 McDonnell et al. (43) Pub. Date: Aug. 18, 2016

(54) SUSTAINED DELIVERY OF THERAPEUTIC filed on Feb. 25, 2010, provisional application No. AGENTS TO AN EYE COMPARTMENT 61/308,035, filed on Feb. 25, 2010. (71) Applicant: The Johns Hopkins University, Publication Classification Baltimore, MD (US) (51) Int. Cl. (72) Inventors: Peter J. McDonnell, Baltimore, MD A619/16 (2006.01) (US); Yasin A. Khan, Baltimore, MD A619/00 (2006.01) (US); Samuel K. Lai, Carrboro, NC (52) U.S. Cl. (US); Renata T. Kashiwabuchi, CPC ...... A61K 9/1676 (2013.01); A61 K9/0048 Baltimore, MD (US); Ashley Behrens, (2013.01); A61 K9/1647 (2013.01); A61 K Baltimore, MD (US); Justin S. Hanes, 9/1641 (2013.01) Baltimore, MD (US) (57) ABSTRACT (21) Appl. No.: 15/138,132 Compositions and methods for treating eye disorders by (22) Filed: Apr. 25, 2016 administering a drug delivery system into an eye compart ment of the patient, wherein the drug delivery system contains Related U.S. Application Data a particle containing a core; a coating associated with the (63) Continuation of application No. 14/521,904, filed on particl C, wherein the coating is covalently or non-covalently Oct. 23, 2014, which is a continuation of application associated with the particle and presents a hydrophilic region No. 13 /58 4 s 4, filed on Aug. 27, 2012, now Pat. No to the environment around the particle; and a therapeutic 028,880,193 63 21 on Feb.fied" 25, 2011 lition NPOTUS oil, reducedagent redisclosed. orThey IOP after compartment administration can of theexhibit drug • 1-a-s delivery systems to a patient than if a drug delivery system (60) Provisional application No. 61/308,053, filed on Feb. including an uncoated particle were administered to the 25, 2010, provisional application No. 61/308,042, patient. Patent Application Publication Aug. 18, 2016 US 2016/0235674 A1

S8, s gi: S Sii; US 2016/0235674 A1 Aug. 18, 2016

SUSTAINED DELIVERY OF THERAPEUTC ever, are readily eliminated during aqueous humor clearance. AGENTS TO AN EYE COMPARTMENT As a result, the retention of medications injected into the AC is short and their bioavailability fails to meet clinical guide TECHNICAL FIELD lines. 0006. The delivery of medications to the posterior seg 0001. The compositions and methods disclosed herein can ment of the eye has also been a challenge for ophthalmolo be used for treating eye disorders, for example by adminis gists. Currently, the Successful management of many retinal tering a drug delivery system into an eye compartment of a diseases often requires multiple intravitreal injections of patient. medication per year. Retinal diseases, such as diabetic retin opathy and age-related , among others, BACKGROUND continue to represent major causes of irreversible vision loss 0002 Treatment of eye disorders can pose significant in the United States. The treatment of these conditions is problems. For example, the management of many corneal complicated by the difficulty of delivering medications to the diseases requires that therapeutic agents, such as drugs or . The direct delivery of drugs to the vitreous chamber other medications, remain at therapeutic levels in the corneal has become an important tool in the arsenal of retinal disease tissue for extended periods of time. Topical drops remain the management. most common route of drug administration to the eye, espe 0007 Unfortunately, the chronic and progressive nature of cially the . Certain patients, however, including those many retinal diseases necessitates repeated injections to pro patients having fungal and/or amoebic infections of the cor vide continued treatment. The current regimens, which vary nea, as well as corneal transplant recipients, require therapeu based on the disease, its stage, and the medications used, can tic doses of medications to be continuously maintained in the include up to six intraocular injections per year. Each intrav corneal tissues. To achieve Such therapeutic doses of a par itreal injection, however, is associated with the risk of devel ticular medication in corneal tissues. Such patients are oping serious and vision-threatening infections and even trau required to endure lengthy and arduous dosing regimens that matic retinal injury. often involve topically instilling medications hourly. 0003. The efficacy of topical dosing can be diminished by SUMMARY poor patient compliance. The repeated administration of one 0008. In one aspect, the invention provides methods for or more medications can also lead to toxicity, which can be treating eye disorders in a patient in need thereof. The meth related to excess dosing of the medications and/or their pre ods can include, for example, administering a drug delivery servative agents. Injections of free-standing medications into system into an eye compartment of the patient, the drug the corneal stroma also have been employed in certain situa delivery system having (i) a particle including a core; (ii) a tions. This approach, however, fails to result in Sustained coating associated with the particle, wherein the coating is presence of medications within the therapeutic window due to covalently or non-covalently associated with the particle and rapid diffusion of the medication out of the cornea. The com presents a hydrophilic region to the environment around the bination of poor compliance and poor penetration of topi particle; and (iii) atherapeutically effective amount ofathera cally-administered medications into the corneal stroma can peutic agent, thereby treating the eye disorder. In some result in treatment failure, even when the pathogenic organ embodiments, the eye compartment exhibits reduced inflam ism or other cause of disease is known to be “sensitive' to the mation or IOP than if a drug delivery system using an therapy or should otherwise respond to the medication being uncoated particle were administered to the patient. The applied to the eye. inflammation or IOP can be reduced by, for example, at least 0004 Such treatment difficulties are not only observed about 10%, or at least about 30%, or at least about 50%. In with corneal diseases. Disorders common to the anterior Some embodiments, the core includes a biocompatible poly chamber (AC) can also pose problems. For example, C. extraction is one of the most commonly performed Surgical 0009. In some embodiments, the coating includes one or procedures in the United States. Both the incidence of cata more molecules having hydrophilic regions and hydrophobic racts and the frequency of their extraction Surgeries continue regions. For example, at least about 50% of the hydrophobic to rise. Anti-inflammatory agents and antimicrobials both are regions in the coating molecules have a molecular mass of required during the post-operative period and typically must least about 2 kDa, or at least about 3 kDa. The hydrophobic be administered for many weeks. Unfortunately, the poor regions can include, for example, PPO. The hydrophilic ocular bioavailability of these drugs often necessitates com regions can include, for example, PEG. The particles can have plicated and arduous dosing regimens that can lead to poor a diameter of for example, less than about 100,000 nm, or patient compliance, which, in turn, ultimately contributes to less than about 50,000 nm, or less than about 10,000 nm, or poor Surgical outcomes and other complications. Current less than about 5,000 nm, or less than about 1,000 nm. In state-of-the art treatment involves Sustained delivery systems some embodiments, the particle has a diameter of about 200 that are injected into the Subconjunctival space at the end of . Surgery. However, Such Sustained release drug systems afford 0010. The particle can include, for example, a biodegrad limited intraocular bioavailability of delivered medications able polymer Such as poly(lactic-co-glycolic acid). The coat due to barriers to drug penetration. Further, medications ing can be, for example, bound covalently to the particle, or it delivered to an extraocular site, even in a Sustained manner, can be non-covalently associated with the particle. In some will have lower intraocular bioavailability due to barriers that embodiments, the coating includes one or more of Pluronic prevent penetration. P103, Pluronic P105, and poloxamer 407. 0005. Injecting medications directly into the AC of the eye 0011. In some embodiments, administering the drug at the end of Surgery has been an alternative to topical treat delivery system involves injecting the drug delivery system ment. Free-standing medications injected into the AC, how into an eye compartment, such as the vitreous chamber, the US 2016/0235674 A1 Aug. 18, 2016

, the stroma or the anterior chamber. The drug delivery DETAILED DESCRIPTION system can include atherapeutic agent such as one or more of an anti-inflammatory drug, an antimicrobial agent, an anti 0015 The presently disclosed subject matter may be angiogenesis agent, an immunosuppressant, an antibody, an embodied in many different forms and should not be con strued as limited to the embodiments set forth herein. Indeed, antibody fragment, a steroid, a chemotherapeutic agent, an many modifications and other embodiments of the presently ocular anti-hypertensive drug and combinations thereof. In disclosed subject matter will come to mind for one skilled in Some embodiments, the drug delivery system provides sus the art to which the presently disclosed subject matter per tained release of the therapeutic agent over a period of time, tains having the benefit of the teachings presented in the for example at least about 1 day, or at least about 1 week, or at descriptions included herein. Therefore, it is to be understood least about 4 weeks. that the presently disclosed subject matter is not to be limited 0012. In another aspect, the invention provides drug deliv to the specific embodiments disclosed and that modifications ery systems. The drug delivery system can include: (i) a and other embodiments are intended to be included within the particle including a core; (ii) a coating associated with the Scope of the disclosed Subject matter. particle, wherein the coating is covalently or non-covalently 0016. Although specific terms are employed herein, they associated with the particle and presents a hydrophilic region are used in a generic and descriptive sense only and not for to the environment around the particle; and (iii) a therapeuti purposes of limitation. Unless otherwise defined, all technical cally effective amount of a therapeutic agent. The drug deliv and scientific terms used herein have the same meaning as ery system can be suitable for administration into an eye commonly understood by one of ordinary skill in the art to compartment, such as the vitreous chamber, the Sclera, the which this presently described subject matter belongs. corneal Stroma and the anterior chamber. The core can 0017 Following long-standing patent law convention, the include, for example, a biocompatible polymer. In some terms “a” “an and “the refer to “one or more' when used in embodiments, the drug delivery system brings about reduced this application, including the claims. Thus, for example, inflammation or IOP when administered to the patient than if reference to “a subject' includes one or a plurality of subjects, a drug delivery system using an uncoated particle were unless the context clearly is to the contrary (e.g., a plurality of administered to the patient, for example by at least about Subjects), and so forth. 10%, or at least about 30%, or at least about 50%. In some 0018. Throughout the specification and claim(s), the terms embodiments, the coating includes one or more molecules “comprising.” “having.” “including.” or “containing” and any having hydrophilic regions and hydrophobic regions. For grammatical derivations thereof, are intended to be non-lim example, at least about 50% of the hydrophobic regions in the iting, i.e., they are inclusive or open-ended, such that recita coating molecules have a molecular mass of least about 2 tion of particular elements in a list does not exclude other like, kDa, or at least about 3 kDa. In some embodiments, the but unrecited, elements that can be substituted or added to the hydrophobic regions comprise PPO. In some embodiments, recited elements. the hydrophilic regions comprise PEG. The particle can 0019 For the purposes of this specification and appended include, for example, a biodegradable polymer Such as poly claims, unless otherwise indicated, all numbers expressing (lactic-co-glycolic acid). The coating can include, for amounts, sizes, dimensions, proportions, shapes, formula example, one or more of Pluronic P103, Pluronic P105 and tions, parameters, percentages, parameters, quantities, char poloxamer 407. The particles can have a diameter of for acteristics, and other numerical values used in the specifica example, less than about 100,000 nm, or less than about tion and claims, are to be understood as being modified in all 50,000 nm, or less than about 10,000 nm, or less than about instances by the term “about even though the term “about 5,000 nm, or less than about 1,000 nm. In some embodiments, may not expressly appear with the value, amount or range. the particle has a diameter of about 200 nm. In some embodi Accordingly, unless indicated to the contrary, the numerical ments, the therapeutic agent is one or more of an anti-inflam parameters set forth in the following specification and matory drug, an antimicrobial agent, an anti-angiogenesis attached claims are not and need not be exact, but may be agent, an immunosuppressant, an antibody, an antibody frag approximate and/or larger or Smaller as desired, reflecting ment, a steroid, a chemotherapeutic agent, an ocular anti tolerances, conversion factors, rounding off, measurement hypertensive drug and combinations thereof. The drug deliv error and the like, and other factors known to those of skill in ery system can be suitable for administration into the eye the art depending on the desired properties sought to be compartment by injection. obtained by the presently disclosed subject matter. For 0013 The drug delivery system can also include, for example, the term “about when referring to a value can be example, (i) a Substrate; (ii) a coating associated with the meant to encompass variations of, in Some embodiments, Substrate, wherein the coating presents a hydrophilic region +100%; in some embodiments, t50%; in some embodiments, to the environment around the Substrate; and (iii) a therapeu +20%; in some embodiments, it 10%; in some embodiments, tically effective amount of a therapeutic agent. The drug +5%: in some embodiments, it 1%; in some embodiments, delivery system can, for example, bring about reduced +0.5%; and in some embodiments, +0.1% from the specified inflammation when administered to the patient than if a drug amount, as such variations are appropriate to perform the delivery system comprising an uncoated Substrate were disclosed methods or employ the disclosed compositions. administered to the patient. 0020. Further, the term “about when used in connection with one or more numbers or numerical ranges, should be BRIEF DESCRIPTION OF THE DRAWINGS understood to refer to all Such numbers, including all numbers in a range and modifies that range by extending the bound 0014 FIG. 1 is a graph depicting the inflammation profile aries above and below the numerical values set forth. The in female New Zealand white rabbits after intracameral injec recitation of numerical ranges by endpoints includes all num tion of several particle-coating combinations according to the bers, e.g., whole integers, including fractions thereof. Sub compositions and methods disclosed herein. sumed within that range (for example, the recitation of 1 to 5 US 2016/0235674 A1 Aug. 18, 2016

includes 1, 2, 3, 4, and 5, as well as fractions thereof, e.g., 1.5. a metal, a metal oxide (e.g., silica), a quantum dot, a thera 2.25, 3.75, 4.1, and the like) and any range within that range. peutic agent in pure or substantially pure form (e.g., in crystal 0021. In one aspect, methods for treating one or more eye form), and the like, as well as any combination of any of the disorders are disclosed. The methods can involve, for foregoing. The particle can include, without limitation, one or example, administering a drug delivery system into an eye more lipid-based drug carriers. compartment of a patient. In some embodiments, the drug 0024. The particles of the drug delivery system can delivery system can include: i) a particle containing a core; ii) include a biocompatible polymer. As used herein, the term a coating disposed on the Surface of the particle, wherein the “biocompatible polymer encompasses any polymer that can coating molecules have hydrophilic regions; and iii) a thera be administered to a patient without adverse effects to the peutic agent, for example a therapeutically effective amount patient, or for which any adverse effects are deemed by a ofatherapeutic agent. The coating molecules can include, for person having ordinary skill in the art to be outweighed by the example, hydrophobic regions. In some embodiments, at benefits brought about by the drug delivery system in light of least about 50% of the hydrophobic regions in the coating the mode of administration, the therapeutic agent employed, molecules have a molecular mass of least about 2 kDa. In and/or the eye disorder to be treated, and also when consid Some embodiments, the drug delivery system can include a ered in light of the availability of alternative therapeutic regi particle and a coating; and in some embodiments, a particle, men and their characteristics. coating and therapeutic agent. The drug delivery system can 0025. Examples of biocompatible polymers include but contain, for example, a pharmaceutically acceptable carrier. are not limited to polystyrenes; poly(hydroxy acid); poly The drug delivery system can be suitable for administration (lactic acid); poly(glycolic acid); poly(lactic acid-co-glycolic into an eye compartment of a patient, for example by injection acid); poly(lactic-co-glycolic acid); poly(lactide); poly(gly into the eye compartment. In some embodiments, the core collide); poly(lactide-co-glycolide); polyanhydrides; poly includes a biocompatible polymer. As used herein, unless the orthoesters; polyamides; polycarbonates; polyalkylenes; context indicates otherwise, “drug delivery system” and “par polyethylenes; polypropylene; polyalkylene glycols; poly ticle composition' can be used interchangeably. (ethylene glycol); polyalkylene oxides; poly(ethylene 0022. The particle in the drug delivery system can be of oxides); polyalkylene terephthalates; poly(ethylene tereph various sizes. The appropriate particle size can vary based on thalate); polyvinyl alcohols; polyvinyl ethers; polyvinyl the method of administration, the eye compartment to which esters; polyvinyl halides; poly(vinyl chloride); polyvinylpyr the drug delivery system is administered, the therapeutic rolidone; polysiloxanes; poly(vinyl alcohols); poly(vinyl agent employed and the eye disorder to be treated, as will be acetate); polyurethanes; co-polymers of polyurethanes; appreciated by a person of skill in the art in light of the derivativized celluloses; alkyl cellulose; hydroxyalkyl cellu teachings disclosed herein. For example, in Some embodi loses; cellulose ethers; cellulose esters; nitro celluloses; ments the particle has a diameter of at least about 1 nm, or methyl cellulose; ethyl cellulose; hydroxypropyl cellulose; from about 1 nm to about 50 microns. The particle can also hydroxy-propyl methyl cellulose; hydroxybutyl methyl cel have a diameter of, for example, from about 1 nm to about 30 lulose; cellulose acetate; cellulose propionate; cellulose microns; or from about 1 nm to about 10 microns; or from acetate butyrate; cellulose acetate phthalate; carboxylethyl about 1 nm to about 6 microns; from about 1 nm to about 5 cellulose; cellulose triacetate; cellulose sulfate sodium salt; microns; or from about 1 nm to about 3 microns; or from polymers of acrylic acid; methacrylic acid; copolymers of about 1 nm to about 1000 nmi; or from about 25 nm to about methacrylic acid; derivatives of methacrylic acid; poly(m- 750 nmi; or from about 50 nm to about 500 nmi; or from about ethyl methacrylate); poly(ethyl methacrylate); poly(butyl 100 nm to about 300 nm. In some embodiments, the average methacrylate); poly(isobutyl methacrylate); poly(hexyl particle size can be about 1 nm, about 10 nm, about 50 nm, methacrylate); poly(isodecyl methacrylate); poly(lauryl about 100 nm, about 150 nm, about 200 nm, about 250 nm, methacrylate); poly(phenyl methacrylate); poly(methyl acry about 300 nm, about 350 nm, about 400 nm, about 450 nm, late); poly(isopropyl acrylate); poly(isobutyl acrylate); poly about 500 nm, about 550 nm, about 600 nm, about 650 nm, (octadecyl acrylate); poly(butyric acid); poly(Valeric acid); about 700 nm, about 750 nm, about 800 nm, about 850 nm, poly(lactide-co-caprolactone); copolymers of poly(lactide about 900 nm, about 950 nm, or about 1000 nm, or about co-caprolactone); blends of poly(lactide-co-caprolactone); 2,000 nm, or about 5,000 nm, or about 6,000 nm, or about hydroxyethyl methacrylate (HEMA); copolymers of HEMA 10,000 nm, or about 20,000 nm, or about 50,000 nm, or about with acrylate; copolymers of HEMA with polymethyl 100,000 nm. In some embodiments, the particle size can be methacrylate (PMMA); polyvinylpyrrolidone/vinyl acetate about 100 microns or less, about 50 microns or less, about 30 copolymer (PVP/VA); acrylate polymers/copolymers; acry microns or less, about 10 microns or less, about 6 microns or late/carboxyl polymers; acrylate hydroxyl and/or carboxyl less, about 5 microns or less, about 3 microns or less, about copolymers; polycarbonate-urethane polymers; silicone-ure 1000 nm or less, about 800 nm or less, about 600 nm or less, thane polymers; epoxy polymers; cellulose nitrates; polytet about 500 nm or less, about 400 nm or less, about 300 nm or ramethylene ether glycol urethane; polymethylmethacrylate less, about 200 nm or less, or about 100 nm or less. In some 2-hydroxyethylmethacrylate copolymer; embodiments, the particle can be a nanoparticle or a micro polyethylmethacrylate-2-hydroxyethylmethacrylate copoly particle, as these terms are defined herein. In some embodi mer, polypropylmethacrylate-2-hydroxyethylmethacrylate ments, the drug delivery system can contain a plurality of copolymer; polybutylmethacrylate-2-hydroxyethyl particles. The particles can be all nanoparticles, all micropar methacrylate copolymer, polymethylacrylate-2-hydroxyeth ticles, or a combination of nanoparticles and microparticles. ylmethacrylate copolymer, polyethylacrylate-2-hydroxyeth 0023. In some embodiments, the drug delivery system ylmethacrylate copolymer; polypropylacrylate-2- includes a particle comprising a core. The core can be, for hydroxymethacrylate copolymer, polybutylacrylate-2- example, a small molecule, a polymer, a lipid, a protein, a hydroxyethylmethacrylate copolymer; carbohydrate, a viral carrier, a viroSome, a sterol, a liposome, copolymermethylvinylether maleicanhydride copolymer; US 2016/0235674 A1 Aug. 18, 2016 poly (2-hydroxyethyl methacrylate) acrylate polymer/co polymers having Substitutions, additions of chemical groups polymer; acrylate carboxyl and/or hydroxyl copolymer, ole and other modifications routinely made by those skilled in the fin acrylic acid copolymer, ethylene acrylic acid copolymer; art polyamide polymers/copolymers; polyimide polymers/co 0027. In some embodiments, the drug delivery systems polymers; ethylene vinylacetate copolymer, polycarbonate contain a particle with a coating on the Surface, wherein the urethane; silicone urethane; polyvinylpyridine copolymers; coating molecules have hydrophilic regions and, optionally, polyether Sulfones; polygalactin, poly-(isobutyl cyanoacry hydrophobic regions, wherein the coated particle causes less late), and poly(2-hydroxyethyl-L-glutamine); polydimethyl inflammation than a similar, but uncoated particle, as mea siloxane; poly(caprolactones); poly(ortho esters); Sured by standard protocols, for example upon injection into polyamines; polyethers; polyesters; polycarbamates; poly the anterior chamber of a New Zealand white rabbit or a ureas; polyimides; polysulfones; polyacetylenes; polyethy human. eneimines; polyisocyanates; polyacrylates; polymethacry 0028. The drug delivery system can also include a coating. The coating can be disposed on the Surface of the particle, for lates; polyacrylonitriles; polyarylates; and combinations, example by bonding, adsorption or by complexation. The copolymers and/or mixtures of two or more of any of the coating can also be intermingled or dispersed within the par foregoing. In some cases, the particle includes a hydrophobic ticle as well as disposed on the surface of the particle. material and at least one bioactive agent. In certain embodi 0029. The coating can be, for example, polyethylene gly ments, the hydrophobic material is used instead of a polymer. col, polyvinyl alcohol (PVA), or similar substances. The coat In other embodiments, the hydrophobic material is used in ing can be, for example, vitamin E-PEG 1 k or vitamin E-PEG addition to a polymer. 5 k or the like. Vitamin E-PEG 5k can help present a dense 0026. In some embodiments, the presently disclosed par coating of PEG on the Surface of a particle. The coating can ticles contain a biodegradable polymer. The biodegradable also include nonionic Surfactants such as those composed of polymer can contain a synthetic polymer, although natural polyaklyene oxides, e.g., polyoxyethylene (PEO), also polymers also can be used. The polymer can be, for example, referred to herein as polyethylene glycol, or polyoxypropy poly(lactic-co-glycolic acid) (PLGA), polystyrene or combi lene (PPO), also referred to herein as polypropylene glycol (PPG), and can include co-polymers of more than one alky nations thereof. The polystyrene can, for example, be modi lene oxide. The copolymers can be, for example, random fied with carboxyl groups. Other examples of biodegradable copolymers, block copolymers or graft copolymers. In some polymers include poly(hydroxy acid); poly(lactic acid); poly embodiments, the coating includes a polyoxyethylene-poly (glycolic acid); poly(lactic acid-co-glycolic acid); poly(lac oxypropylene copolymer, e.g., block copolymers of ethylene tide); poly(glycolide); poly(lactide-co-glycolide); polyanhy oxide and propylene oxide. (i.e., poloxamers). Examples of drides; polyorthoesters; polyamides; polycarbonates; poloxamers suitable for use in the coatings include, for polyalkylenes; polyethylene; polypropylene; polyalkylene example, poloxamers 188, 237, 338 and 407. These polox glycols; poly(ethylene glycol); polyalkylene oxides; poly amers are available under the trade name Pluronic R. (avail (ethylene oxides); polyalkylene terephthalates; poly(ethyl able from BASF, Mount Olive, N.J.) and correspond to Plu ene terephthalate); polyvinyl alcohols; polyvinyl ethers: ronic(R)-68, F-87, F-108 and F-127, respectively. Poloxamer polyvinyl esters; polyvinyl halides; poly(vinyl chloride); 188 (corresponding to Pluronic RF-68) is a block copolymer polyvinylpyrrolidone; polysiloxanes; poly(vinyl alcohols); with an average molecular mass of about 7,000 to about poly(vinyl acetate); polyurethanes; co-polymers of polyure 10,000 Da, or about 8,000 to about 9,000 Da, or about 8,400 thanes; derivativized celluloses; alkyl cellulose; hydroxy Da. Poloxamer 237 (corresponding to Pluronic R) F-87) is a alkyl celluloses; cellulose ethers; cellulose esters; nitro cel block copolymer with an average molecular mass of about luloses; methyl cellulose; ethyl cellulose; hydroxypropyl 6,000 to about 9,000 Da, or about 6,500 to about 8,000 Da, or cellulose; hydroxy-propyl methyl cellulose; hydroxybutyl about 7,700 Da. Poloxamer 338 (corresponding to Pluronic R. methyl cellulose; cellulose acetate; cellulose propionate; cel F-108) is a block copolymer with an average molecular mass lulose acetate butyrate; cellulose acetate phthalate; carboxy of about 12,000 to about 18,000 Da, or about 13,000 to about lethyl cellulose; cellulose triacetate; cellulose sulfate sodium 15,000 Da, or about 14,600 Da. Poloxamer 407 (correspond salt; polymers of acrylic acid; methacrylic acid; copolymers ing to Pluronic RF-127) is a polyoxyethylene-polyoxypropy of methacrylic acid; derivatives of methacrylic acid; poly lene triblock copolymer in a ratio of between about EPs (methyl methacrylate); poly(ethyl methacrylate); poly(butyl Eloi to about Eos Pro Eos, or about Eos Pss Eloi, or about methacrylate); poly(isobutyl methacrylate); poly(hexyl Eos Pro Eos, with an average molecular mass of about methacrylate); poly(isodecyl methacrylate); poly(lauryl 10,000 to about 15,000 Da, or about 12,000 to about 14,000 methacrylate); poly(phenyl methacrylate); poly(methyl acry Da, or about 12,000 to about 13,000 Da, or about 12,600 Da. late); poly(isopropyl acrylate); poly(isobutyl acrylate); poly For example, the NF forms of poloxamers or Pluronic R poly (octadecyl acrylate); poly(butyric acid); poly(Valeric acid); mers can be used. poly(lactide-co-caprolactone); copolymers of poly(lactide 0030. In some embodiments, the coating can be, for co-caprolactone); blends of poly(lactide-co-caprolactone); example Pluronic R. P103 or Pluronic(R) P105. Pluronic(R) polygalactin; poly-(isobutyl cyanoacrylate); poly(2-hy P103 is a block copolymer with an average molecular mass of droxyethyl-L-glutam-nine); and combinations, copolymers about 3,000 Dato about 6,000 Da, or about 4,000 Dato about and/or mixtures of one or more of any of the foregoing. 6,000 Da, or about 4,950 Da. Pluronic.R. P105 is a block Furthermore, as a person of ordinary skill in the art would copolymer with an average molecular mass of about 5,000 Da appreciate, Some of the polymers listed above as “biocompat to about 8,000 Da, or about 6,000 Da to about 7,000 Da, or ible' can also be considered biodegradable, whether or not about 6,500 Da. they are included in the above listing of representative biode 0031. In some embodiments, the coating can have an aver gradable polymers. As used herein, "derivatives” include age molecular weight of about 9,000 Da or greater, about US 2016/0235674 A1 Aug. 18, 2016

10,000 Da or greater, about 11,000 Da or greater or about about 2.5 kDa to about 4.5 kDa, or from about 2.5 kDa to 12,000 Da or greater. In exemplary embodiments, the coating about 3.5 kDa. In some embodiments, at least about 10%, or can have an average molecular weight of from about 10,000 at least about 25%, or at least about 50%, or at least about to about 15,000 Da, or about 12,000 to about 14,000 Da, or 75%, or at least about 90%, or at least about 95%, or at least about 12,000 to about 13,000 Da, or about 12,600 Da. In some about 99% or more of the hydrophobic regions in these coat embodiments, the coating can be selected from Pluronic R. ings have molecular weights within these ranges. In some P103, P105, F-68, F-87, F-108 and F-127, from PluronicOR) embodiments, the coatings are biologically inert. Com P103, P105, F-87, F-108 and F-127, or from Pluronic RP103, pounds that generate both a hydrophilic Surface and an P105, F-108 and F-127, or from Pluronic(R) P103, P105 and uncharged or Substantially neutrally-charged Surface can be F-127. In some embodiments, the coating can be Pluronic R. biologically inert. F-127. In representative embodiments, the coating is associ 0035. In some embodiments, the coating can include, for ated with the particles. For example, the coating can be example, one or more of the following: anionic proteins (e.g., covalently attached to the particles. In representative embodi bovine serum albumin), Surfactants (e.g., cationic Surfactants ments, the coating is polyethylene glycol, which is covalently Such as for example dimethyldioctadecyl-ammonium bro attached to the particle, yielding what is commonly referred mide), Sugars or Sugar derivatives (e.g., cyclodextrin), nucleic to as a PEGylated particle. acids, polymers (e.g., heparin), mucolytic agents, N-acetyl 0032. In some embodiments, the coating is non-covalently cysteine, mugwort, bromelain, papain, clerodendrum, acetyl associated with the particle. This association can be held cysteine, bromhexine, carbocisteine, eprazinone, mesna, together by any force or mechanism of molecular interaction ambroXol, Sobrerol, domiodol, letosteine, Stepronin, tiopro that permits two Substances to remain in Substantially the nin, gelsolin, thymosin B4, dornase alfa, neltenexine, same positions relative to each other, including intermolecu erdosteine, various DNases including rhDNase, agar, agar lar forces, dipole-dipole interactions, van der Waals forces, ose, alginic acid, amylopectin, amylose, beta-glucan, callose, hydrophobic interactions, electrostatic interactions and the carrageenan, cellodextrins, cellulin, cellulose, chitin, chito like. In some embodiments, the coating is adsorbed onto the san, chrysolaminarin, curdlan, cyclodextrin, dextrin, ficoll, particle. According to representative embodiments, a non fructan, fucoidan, galactomannan, gellan gum, glucan, glu covalently bound coating can be comprised of portions or comannan, glycocalyx, glycogen, hemicellulose, hydroxy segments that promote association with the particle, for ethyl starch, kefiran, laminarin, mucilage, glycosaminogly example by electrostatic or van der Waals forces. In some can, natural gum, paramylon, pectin, polysaccharide peptide, embodiments, the interaction is between a hydrophobic por schizophyllan, sialyl lewis X, starch, starch gelatinization, tion of the coating and the particle. Embodiments include Sugammadex, Xanthan gum, Xyloglucan, L-phosphatidylcho particle coating combinations which, however attached to the line (PC), 1,2-dipalmitoylphosphatidycholine (DPPC), oleic particle, present a hydrophilic region, e.g. a PEG rich region, acid, Sorbitan triolcate, Sorbitan monooleate, Sorbitan mono to the environment around the particle coating combination. laurate, polyoxyethylene (20) Sorbitan monolaurate, poly The particle coating combination can provide both a hydro oxyethylene (20) sorbitan monooleate, natural lecithin, oleyl philic Surface and an uncharged or Substantially neutrally polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, charged surface, which can be biologically inert. polyoxyethylene (4) lauryl other, block copolymers of oxy 0033 Suitable coatings for use according to the composi ethylene and oxypropylene, synthetic lecithin, diethylene tions and methods disclosed herein can be made up of mol glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, iso ecules having hydrophobic regions as well as hydrophilic propyl myristate, glyceryl monooleate, glyceryl monostear regions. Without wishing to be bound by any particular ate, glyceryl monoricinoleate, cetyl alcohol, Stearyl alcohol, theory, it is believed that the hydrophobic regions of the polyethylene glycol 400, cetyl pyridinium chloride, benza coating molecules are able to form adsorptive interactions Ikonium chloride, olive oil, glyceryl monolaurate, corn oil, with the Surface of the particle, and thus maintain a non cotton seed oil, Sunflower seed oil, lecithin, oleic acid, sorbi covalent association with it, while the hydrophilic regions tan trioleate, and combinations of two or more of any of the orient toward the Surrounding, frequently aqueous, environ foregoing. ment. In some embodiments the hydrophilic regions are char 0036. The particle-coating combinations can be made up acterized in that they avoid or minimize adhesive interactions of any combination of particle and coating Substances dis with Substances in the Surrounding environment. Suitable closed or suggested herein. Examples of Such combinations hydrophobic regions in the coatings can include, for example, include, for example, polystyrene-PEG, or PLGA-Pluronic R. PPO, vitamin E and the like, either alone or in combination F-127. with each other or with other substances. Suitable hydrophilic 0037. In some embodiments, the coating is associated regions in the coatings can include, for example, PEG, hep with the particle, either through covalent or non-covalent arin, polymers that form hydrogels and the like, alone or in interactions with the particle. Coatings that can be covalently combination with each other or with other substances. bound to the particle include, for example, PEG. PEG can be 0034 Representative coatings according to the composi covalently bound to any suitable polymer that can be included tions and methods disclosed herein can include molecules in the particle. An example of a polymer that can be coated having, for example, hydrophobic segments such as PPO with PEG is polystyrene. Other particles that can be PEGy segments with molecular weights of at least about 1.8 kDa, or lated are known in the art. at least about 2 kDa, or at least about 2.5 kDa, or at least about 0038. The drug delivery system can include one or more 3 kDa, or at least about 3.5 kDa, or at least about 4.0 kDa, or therapeutic agents. Any therapeutic agent can be used which at least about 4.5 kDa, or at least about 5.0 kDa or more. In is Suitable to administration in the drug delivery system dis Some embodiments, the coatings can have PPO segments closed herein, as would be appreciated by a person of ordi with molecular weights of from about from about 1.8 kDa to nary skill. Examples of types of Such therapeutic agents about 10 kDa, or from about 2 kDa to about 5 kDa, or from include anti-inflammatory drugs, antimicrobial agents, anti US 2016/0235674 A1 Aug. 18, 2016 angiogenesis agents, immunosuppressants, antibodies, Ste 0041. The drug delivery system can be administered via roids, chemotherapeutic agents, ocular anti-hypertensive any route which is effective to deliver an effective amount of drugs and combinations thereof. Examples of therapeutic the therapeutic agent to the eye compartment to be treated. agents that can be used the drug delivery system disclosed For example, the drug delivery system can be injected into the herein include acyclovir, amikacin, anecortane acetate, eye compartment to be treated, such as, for example, the anthracenedione, anthracycline, an azole, amphotericin B, vitreous chamber, Subretinal space, Subchoroidal space, the bevacizumab, camptothecin, cefuroxime, chloramphenicol, episclera, the , the Sclera or the anterior chamber, chlorhexidine, chlorhexidine digluconate, clortrimazole, a and the cornea and compartments therein (e.g., Subepithelial, clotrimazole cephalosporin, corticosteroids, dexamethasone, intrastromal, endothelial). desamethaZone, econazole, eftazidime, epipodophyllotoxin, 0042. The drug delivery systems disclosed herein provide fluconazole, flucytosine, fluoropyrimidines, fluoroquino Sustained release of a therapeutic agent over a period of time. lines, gatifloxacin, glycopeptides, imidazoles, itraconazole, For example, after administration of the drug delivery system, ivermectin, ketoconazole, levofloxacin, macrollides, micona the therapeutic agent can be released for at least about 6 hours, Zole, miconazole nitrate, moxifloxacin, natamycin, neomy at least about 12 hours, at least about 1 day, at least about 2 cin, nystatin, ofloxacin, polyhexamethylene biguanide, pred days, at least about 3 days, at least about one week, at least nisolone, prednisolone acetate, pegaptainib, platinum about 2 weeks, at least about 3 weeks, at least about 4 weeks, analogues, polymicin B, propamidineisethionate, pyrimidine at least about 5 weeks, at least about 6 weeks, at least about 7 nucleoside, ranibizumab, squalamine lactate, Sulfonamides, weeks, at least about 2 months, at least about 3 months, at triamcinolone, triamcinolone acetonide, triazoles, Vancomy least about 6 months, at least about 9 months, at least about 1 cin, anti-vascular endothelial growth factor (VEOF) agents, year or more. Furthermore, according to the compositions VEGF antibodies, VEGF antibody fragments, Vinca alkaloid, and methods disclosed herein, administration of the drug timolol, betaxolol, travoprost, latanoprost, bimatoprost, bri delivery systems to the patient causes less inflammation or monidine, dorzolamide, acetazolamide, pilocarpine, ciprof IOP over time than if other drug delivery systems are admin loxacin, azithromycin, gentamycin, tobramycin, cefazolin, istered. Notwithstanding the foregoing, there may be some Voriconazole, gancyclovir, cidofovir, foScarnet, diclofenac, initial inflammation shortly after administration, even with nepafenac, ketorolac, ibuprofen, indomethacin, fluorometha the drug delivery system disclosed herein. However, a reduc lone, rimexolone, anecortave, cyclosporine, methotrexate, tion of inflammation or IOP can be observed after about 2 tacrolimus and combinations thereof. days post-administration, or after about 5 days post-admin istration. Inflammation or IOP is reduced overtime, even with 0039. The drug delivery systems disclosed herein, which administration of conventional or previously available drug can include one or more therapeutic agents, can be used to delivery systems. However, the reduction or avoidance of treat eye disorders according to the methods disclosed herein. inflammation or IOP when using methods and compositions The drug delivery system can be used to treat any eye disorder disclosed herein is persistent and can continue to be observed that, in the judgment of a person of ordinary skill in the art, for up to 30 days, up to 20 days, up to 15 days, or up to 10 days would be effectively treated with any of the drug delivery post-administration. The reduction or avoidance of inflam systems disclosed herein. Examples of eye disorders that may mation or IOP can continue for at least about 10 days, at least be treated according to the compositions and methods dis about 15 days, at least about 20 days, or at least about 30 days closed herein include amoebic , , bac post-administration. terial keratitis, viral keratitis, onchorcercalkeratitis, bacterial 0043. In some embodiments, the drug delivery systems , viral keratoconjunctivitis, corneal dys disclosed herein when administered to the vitreous chamber, trophic diseases, Fuchs' endothelial dystrophy, Sjogren's the sclera, the anterior chamber or other eye compartment of syndrome, Stevens-Johnson syndrome, autoimmune dry eye a patient, achieve reduced or decreased inflammation, and diseases, environmental dry eye diseases, corneal neovascu thus, for example, reduced intraocular pressure (IOP) over larization diseases, post-corneal transplant rejection prophy that which would be brought about if, for example, an laxis and treatment, autoimmune , infectious uveitis, uncoated polymer particle, for example a particle otherwise anterior uveitis, posterior uveitis (including toxoplasmosis), similar to the coated particle, were administered to same eye pan-uveitis, an inflammatory disease of the vitreous or retina, compartment in the patient. Furthermore, drug delivery sys prophylaxis and treatment, macular , tems including particles and coatings according to the com macular degeneration, age related macular degeneration, pro positions and methods disclosed herein can reduce or avoid liferative and non-proliferative diabetic , hyper an increase in IOP over that which would be observed if tensive retinopathy, an autoimmune disease of the retina, uncoated particles of similar size were administered. Accord primary and metastatic intraocular melanoma, other intraocu ingly, the particle size threshold for inducing or increasing lar metastatic tumors, open angle , closed angle IOP can be higher for coated particles than it would be for glaucoma, pigmentary glaucoma and combinations thereof. uncoated particles. As a result, it may be possible to use larger 0040. According to the methods disclosed herein, the drug particles for administration into an eye compartment, for delivery system can be administered into an eye compartment example into the AC, if such particles are coated according to ofapatient with an eye disorder. The drug delivery system can the compositions and methods disclosed herein. In some be administered to any eye compartment that is susceptible to embodiments, the drug delivery systems disclosed herein an eye disorder treatable with the compositions and methods provide the advantage of avoiding or reducing aggregation of disclosed herein. Examples of Such eye compartments particles after administration. include the vitreous chamber, subretinal space, subchoroidal 0044) Inflammation and LOP can be measured after space, the episclera, the conjunctiva, the Sclera, the anterior administration of the compositions disclosed herein by meth chamber, and the cornea and compartments therein (e.g., ods known in the art. For example, a Reichert Tono-Pen subepithelial, intrastromal, endothelial). contact tonometer can be used to assess the IOP, and changes US 2016/0235674 A1 Aug. 18, 2016

in IOP, in any eye compartment disclosed herein, for example made with PLGA particles as well as those made with poly the AC. The Subjects, for example animals, can be evaluated styrene particles. Furthermore, the increased retention is on several post-injection days, for example at 1, 7, 14 and 30 observed with polystyrene particles covalently coated with days post-injection using the same evaluation procedure on PEG coating as well as in PLGA particles with non-co each day. One or more measurements, for example about five, valently associated Pluronic RPF-127 coating. Accordingly, can be obtained for each subject at each time point. When where increased retention is demonstrated for one type of measuring IOP according to methods known in the art, for particle composition, for example, covalently-PEGylated example the method described above, IOP is shown to be polystyrene particles—one of ordinary skill in the art may reduced by, for example, at least about 10%, or at least about expect that similar results would be obtained for other types 30%, or at least about 50% over what is observed when a drug of particle compositions, e.g., PLGA particles non-covalently delivery system using an uncoated particle, for example a coated with a poloxamer. For instance, as shown in the particle that is otherwise similar to the coated particle, is examples, PEGylated polystyrene particles behave similarly administered to the patient. To measure inflammation, Slit to and can serve as a model for PLGA particles with non lamp biomicroscopy can be performed to examine any eye covalently associated coatings such as Pluronic R. PF-127 compartment disclosed herein, for example, the AC, for signs coating. These findings are consistent with the art usage of of inflammation. The examination can involve observation of polystyrene particles as models for other biocompatible par criteria such as the presence of cells, flare and . The ticles and polymers. Subjects can be evaluated on several post-injection days, for 0047 Topically-administered medications to the eye often example at 1, 7, 14 and 30 days post-injection using the same exhibit a poor ability to penetrate the corneal stroma. Further, evaluation procedure on each day. After general and/or local free-standing drugs, when injected into the corneal stroma, anesthesia is achieved, each Subject can be examined for are cleared rapidly by diffusion, thereby limiting the amount gross abnormalities. The exams can be performed by the same of time the medication remains at therapeutic concentrations trained ophthalmologist, and the ophthalmologist can be at the site of the injection. In some embodiments, the pres blinded to the assignment of the treatment and control sub ently disclosed subject matter demonstrates, for example, that jects. Quantification of inflammation of an eye compartment intrastromally injected particle compositions can be retained Such as the AC can be performed using a modified version of with the corneal stroma for periods of time greater than free the Standard Uveitis Nomenclature clinical grading scheme, standing drugs. For example, 200-nm and 1-um latex par as detailed more fully in the examples. When measuring ticles injected intrastromally into living rabbits exhibited inflammation according to methods known in the art, for approximately 20% retention after two weeks. Uncoated 200 example the method described above, inflammation is shown nm latex particles, however, caused Substantial fibrin aggre to be reduced by, for example, at least about 10%, or at least gation Suggestive of inflammation after intraocular injection about 30%, or at least about 50% over what is observed when in living rabbits. By varying size and Surface chemistry in a drug delivery system using an uncoated particle, for accordance with the principles set forth herein, particles can example a particle that is otherwise similar to the coated be engineered to reduce or avoid corneal inflammation and particle, is administered to the patient. When comparing an edema. IOP or inflammation measurement obtained after administra 0048. In some embodiments, the presently disclosed sub tion of a coated particle versus an IOP or inflammation mea ject matter includes delivery systems for intrastromal injec Surement obtained for an uncoated particle, the measure tion of medications that are combined with the particles dis ments compared can, and frequently should be taken at closed herein. Medications can include, but are not limited to, similar time points post injection. For example, an IOP mea anti-inflammatory agents, antimicrobial agents, anti-angio Surement for a coated particle taken 7 days post-injection is genesis agents, immunosuppressants, and/or combinations generally compared with an IOP measurement for an thereof. Such combinations of medications can allow for the uncoated particle taken 7 days post-injection. treatment of conditions that require more than one medica 0045. A further advantage of certain embodiments of the tion. More particularly, in some embodiments, the presently drug delivery systems disclosed herein is that they can be disclosed subject matter includes particle compositions con composed of generally recognized as safe (GRAS) materials, taining anti-inflammatory agents for treating and/or prevent without the formation of new chemical entities (NCEs). ing inflammatory processes of the cornea. Some embodi Avoidance of NCE formation can be an advantage because ments of the presently disclosed subject matter include NCES can be subject to a lengthy and expensive regulatory particle compositions containing immunosuppressant agents review process before they are permitted to be marketed. for preventing graft rejection after corneal transplantation. 0046. As described in detail in the Examples, the particle 0049. In some embodiments, the presently disclosed sub compositions can be retained within an eye compartment, ject matter includes particles coated with and/or otherwise including for example the Stroma, the anterior chamber or the carrying antibodies, wherein the antibodies serve as a thera vitreous chamber for periods of time greater than those peutic agent and can be released over time. In some embodi observed with free-standing drugs. Furthermore, coated par ments, the presently disclosed subject matter includes par ticle compositions can exhibit increased retention over ticles combining a therapeutic antibody coating with other uncoated particle compositions. This effect is seen in par therapeutic agents, e.g., one or more medications. ticles with covalently-attached coatings, for example PEG 0050. Further, the presently disclosed subject matter coated particles, as well as in particles with non-covalently includes pharmaceutical formulations including Solutions of associated coatings, of which Pluronic RPF-127-coated par the presently disclosed particle compositions, wherein the ticles are representative, and indeed the extent of the effect particles are combined with antibacterial agents, antifungal can be very similar for covalently-attached and non-co agents, anti-amoebic agents, antiviral agents, and combina valently associated coatings (see FIG. 1). FIG. 1 also demon tions thereof for treating and/or preventing infectious pro strates that this effect is also seen in particle compositions cesses of the cornea. The presently disclosed subject matter US 2016/0235674 A1 Aug. 18, 2016 also includes pharmaceutical formulations including Solu presently disclosed particle compositions containing one or tions of the presently disclosed particle compositions con more anti-viral agents. Any anti-viral agent known in the art taining and/or coated with anti-angiogenesis agents (such as, can be combined with the presently disclosed particle com for example, antibodies) for use in chronic inflammatory positions. A representative anti-viral agent includes, but is not diseases of the cornea and/or other diseases that can lead to limited to, acyclovir. corneal neovascularization. Combinations of the above-men 0057. Onchoceral keratitis, also referred to as “River tioned pharmaceutical formulations also are contemplated by Blindness is caused by the nematode Onchocerca volvulus the presently disclosed subject matter. and can be treated by administering to the corneal stroma of a 0051. In a representative embodiment, the presently dis subject in need of treatment thereof the presently disclosed closed subject matter provides methods for treating keratitis, particle compositions containing one or more anti-parasitic i.e., of the cornea, by injecting the presently agents. Any anti-parasitic agent known in the art can be com disclosed particle compositions containing one or more thera bined with the presently disclosed particle compositions. A peutic agents into the corneal Stroma. Conditions treated by representative anti-parasitic agent includes, but is not limited the presently disclosed methods include, but are not limited to, ivermectin. to, amoebic keratitis, fungal keratitis, bacterial keratitis, viral 0058. Further, representative embodiments of the pres keratitis, and onchorcercal keratitis. ently disclosed methods include a method for reversing or 0052 Amoebic keratitis can be caused by acanthamoeba preventing graft rejection following corneal transplantation, and can be treated by administering to the corneal stroma of a the method involving administering to the corneal Stroma of a subject in need of treatment thereof the presently disclosed subject in need of treatment thereof the presently disclosed particle compositions containing one or more anti-amoebic particle compositions containing one or more immunosup agents. Any anti-amoebic agent known in the art can be com pressive agents. Any immunosuppressive agent known in the bined with the presently disclosed particle compositions. art can be combined with the presently disclosed particle Representative, anti-amoebic agents include, but are not lim compositions. Representative immunosuppressive agents ited to, polyhexamethylene biguanide (PHMB), propamidine include, but are not limited to, corticosteroids, such as dex isethionate, miconazole nitrate, neomycin, chlorhexidine amethasone and prednisolone acetate. digluconate, polymicin B, clortrimazole, and combinations 0059. In some embodiments, the presently disclosed sub thereof. ject matter demonstrates that, rather than injecting free-stand 0053 Fungal keratitis can be caused by, for example, ing drugs into the anterior chamber (AC) of an eye, particles aspergillus finigates, fitsarium, and/or yeasts, such as Can injected into the AC can be retained for at least several weeks. dida, and can be treated by administering to the corneal The time period spans the entire duration of typical post stroma of a subject in need of treatment thereof the presently operative treatment. By delivering medications combined disclosed particle compositions containing one or more anti with the presently disclosed particle compositions, the limi fungal agents. Any anti-fungal agent known in the art can be tations of topical and intracameral free drug injection can be combined with the presently disclosed particle compositions. eliminated. This approach was limited in the past by particle Representative, anti-fungal agents include, but are not limited mediated increase in intraocular pressure (IOP) and inflam to, natamycin, nystatin, amphotericin B, chlorhexidine, flu mation responses. The presently disclosed subject matter orinated pyrimidines, such as flucytosine, azoles, such as overcomes these limitations by Suitably modifying particle imidazoles and triazoles, including, but not limited to, keto size and/or surface chemistry. conazole, miconazole, itraconazole, fluconazole, econazole, 0060 For example, the presently disclosed subject matter and clotrimazole, and combinations thereof. demonstrates that particles injected directly into the AC of an 0054 Bacterial keratitis can be caused, for example, by eye can be retained for long periods of time, thereby provid Streptococcus, Pseudomonas, Enterobacteriaceae (including ing an effective vehicle for sustained ocular drug delivery. For Klebsiella, Enterobacter, Serratia, and Proteus), and Staphy example, the presently disclosed subject matter demonstrates lococcus species. Such infections can be treated by adminis that 200-nm latex particles, covalently coated with a repre tering to the corneal stroma of a subject in need of treatment sentative coating Such as, for example, poly(ethylene glycol), thereofthe presently disclosed particle compositions contain can be retained in the eyes of living rabbits for at least four ing one or more anti-bacterial agents. Any anti-bacterial agent weeks with greater than 30% retention. Based on experiments known in the art can be combined with the presently disclosed disclosed herein, other coated particles described herein, for particle compositions. Representative, anti-bacterial agents example PLGA non-covalently coated with poloxamer, can include, but are not limited to, cephalosporins, macrollides, bring about similar outcomes. In contrast, free drugs injected glycopeptides, Sulfonamides, chloramphenicol, fluoroquino into the AC are cleared rapidly, for example, at the same rate lines, including, but not limited to, levofloxacin, gatifloxacin, as the aqueous humor turnover. moxifloxacin, and ofloxacin, and combinations thereof. 0061 Further, uncoated 200-nm latex particles caused 0055. Further, up to 20% of cases of fungal keratitis (par substantial fibrin aggregation in the AC of living rabbits. The ticularly candidiasis) can be complicated by bacterial co presently disclosed subject matter demonstrates that by Suit infection. Thus, in Some embodiments, the presently dis ably modifying size and/or Surface chemistry, particles can be closed methods include combination therapies involving engineered to avoid causing an increase in IOP and inflam administering to the corneal Stroma of a subject in need of mation in the AC. For example, the presently disclosed sub treatment thereof the presently disclosed particle composi ject matter demonstrates that 200-nm latex particles, tions containing one or more anti-fungal agents and one or covalently coated with PEG, did not induce an increase in IOP more anti-bacterial agents. after injection into the AC of a living rabbit. Based on experi 0056 Viral keratitis can, for example, be caused by a ments disclosed herein, other coated particles described herpes simplex virus and can be treated by administering to herein, for example PLGA non-covalently coated with polox the corneal stroma of a subject in need of treatment thereofthe amer, can bring about similar outcomes. US 2016/0235674 A1 Aug. 18, 2016

0062. In some embodiments, the presently disclosed sub of delivered medications due to barriers to drug penetration. ject matter includes medications for intracameral injection Further, free drugs, when injected into the vitreous require combined within particles including, but not limited to, anti multiple injections per year due to drug metabolism and clear inflammatory drugs, antimicrobials, anti-angiogenesis ance. In contrast, the presently disclosed particle composi agents, immunosuppressants, and/or combinations thereof. tions, when injected into the vitreous, can be retained for long Such combinations of medications can allow for the treatment periods of time. of conditions that require more than one medication. For 0068. In some embodiments, the presently disclosed sub example, the presently disclosed subject matter includes par ject matter includes medications combined with particles, ticle compositions containing anti-inflammatory agents alone wherein the medications include, but are not limited to, anti or included with anti-angiogenesis agents for treating chronic inflammatory drugs, antimicrobials, anti-angiogenesis corneal and/or anterior chamber inflammatory processes. In agents, immunosuppressants, anti-neoplastic agents and/or Some embodiments, the presently disclosed Subject matter combinations thereof. Such combinations allow for the treat provides particle compositions containing immunosuppres ment of conditions that require more than one medication. sant agents either alone or in combination with anti-inflam 0069. More particularly, the presently disclosed subject matory agents and/or antimicrobial agents for use in post matter includes particle compositions containing anti-inflam corneal transplant cases. matory agents for the treatment and/or prevention of macular 0063. Further, the presently disclosed subject matter edema and/or other inflammatory diseases of the retina. In includes pharmaceutical formulations containing solutions of Some embodiments, the presently disclosed subject matter the presently disclosed particle compositions, wherein the includes particle compositions containing anti-neoplastic particle compositions contain anti-inflammatory and/or anti agents for treatment of intraocular cancers. In yet other microbial agents for injection after cataract extraction or embodiments, the presently disclosed subject matter includes other ophthalmic Surgeries. The presently disclosed subject particle compositions containing immunosuppressant agents matter also includes pharmaceutical formulations of Solu for the treatment of autoimmune and/or inflammatory dis tions of the presently disclosed particle compositions, eases of the retina. wherein the particle compositions contain antibacterial, anti 0070. In other embodiments, the presently disclosed sub fungal, amoebicidal, antiviral agents, or combinations ject matter includes particles coated with and/or otherwise thereof, for treating chronic infectious processes of the cornea carrying antibodies, wherein the antibodies are a therapeutic and/or the anterior chamber. Combinations of the above agent and can be released over time. In yet other embodi mentioned pharmaceutical formulations also are contem ments, the presently disclosed subject matter includes par plated by the presently disclosed subject matter. ticles combining a therapeutic antibody coating with other 0064. For example, the presently disclosed subject matter therapeutic agents, e.g., one or more medications. provides a method for intracameral administration of the 0071. The presently disclosed subject matter also includes presently disclosed particle compositions containing one or pharmaceutical formulations for intravitreal injection con more therapeutic agents to an anterior chamber of an eye of a taining Solutions of the presently disclosed particle composi Subject in need of treatment thereof. Depending on the con tions containing and/or coated with anti-angiogenesis agents dition of the Subject, the therapeutic agent can be selected (antibodies) for use in degenerative diseases of the retina from the group consisting of an , e.g., Vancomycin, and/or proliferative retinopathy and/or other vascular dis amikacin, eftazidime, cefuroxime, moxifloxacin, or a steroid, eases of the retina. Some representative embodiments include e.g., triamcinolone, dexamethasone, and prednisolone. The pharmaceutical formulations containing Solutions of particle presently disclosed particle compositions can be adminis compositions containing anti-inflammatory and/or antimi tered prophylactically to prevent or reduce the occurrence of crobial agents for the prevention and/or treatment of post a post-operative infection of the anterior chamber or can be Surgical complications and/or infections after vitreoretinal administered therapeutically to treat an infection of the ante operations. Further, pharmaceutical formulations containing rior chamber, e.g., endophthalmitis. Solutions containing antibacterial and/or antifungal and/or 0065. In some embodiments, the presently disclosed par anti-amoebic and/or antiviral agents for treatment of infec ticle compositions can provide an effective vehicle for Sus tious processes of the vitreous and/or retina, including, but tained drug delivery directly to the retina. For example, the not limited to, endophthalmitis also are disclosed. Combina presently disclosed subject matter demonstrates that 200-nm tions of the above-mentioned pharmaceutical formulations latex particles, coated with a representative coating such as, also are contemplated by the presently disclosed Subject mat for example poly(ethylene glycol) covalently bound to the ter. particles, can be retained in the eyes of living rabbits for more 0072 For example, the presently disclosed subject matter than one month with no significant clearance and for over two provides a method for treating age-related macular degenera months with only minimal clearance. tion in a subject in need of treatment thereof, the method 0066 Further, the presently disclosed subject matter involving administering via intravitreal injection to a vitreous shows that uncoated 200-nm latex particles caused Substan chamber and/or retina of an eye of the subject the presently tial fibrin aggregation Suggestive of inflammation after disclosed particle compositions containing one or more thera intraocular injection in living rabbits. Also, uncoated 200-nm peutic agents selected from the group consisting of anti latex particles were found to cause visible vitreous opacities vascular endothelial growth factor (VEGF) agents, including, after intravitreal injection in living rabbits. By suitably modi but not limited to pegaptainib, bevacizumab, anecortane fying size and/or Surface chemistry, the presently disclosed acetate, squalamine lactate, ranibizumab, or corticosteroids, particle compositions can be engineered to avoid visual including, but not limited to, triamcinolone acetonide. obstruction and inflammation in the vitreous chamber. 0073. In other embodiments, the presently disclosed sub 0067. Other sustained release drug systems, when injected ject matter provides a method for treating proliferative dia subconjunctivally, afford limited intraocular bioavailability betic retinopathy in a subject in need of treatment thereof, the US 2016/0235674 A1 Aug. 18, 2016

method involving administering via intravitreal injection to a 1 mm, or from about 1 nm to about 100 microns, or from about vitreous chamber and/or retina of an eye of the subject the 1 nm to about 10 microns, or from about 1 nm to about 1 presently disclosed particle compositions containing one or micron. A Substrate can be, for example, Suitable for admin more therapeutic agents selected from the group consisting of istration to a patient by any means known in the art, for steroids, such as triamcinolone acetonide, Ovine hyalu example by injection or other form of systemic administra ronidase. VEGF antibodies, such as bevacizumab, or VEGF tion, whether rectally, transmucosally, transnasally, intesti antibody fragments, such as ranibizumab, and combinations nally, parenterally, intramuscularly, Subcutaneously, thereof. intramedullarily, intrathecally, intraventricularly, intrave 0074. In yet other embodiments, the presently disclosed nously, intraperitoneally, iniranasally, intraocularly, or tran Subject matter provides a method for treating ocular cancer in Surethrally; or topically; or via implantation into any region of a subject in need of treatment thereof, the method involving the body of a patient. In some embodiments, the coating administering via intravitreal injection to a vitreous chamber presents a hydrophilic region to the environment around the and/or retina of an eye of a subject the presently disclosed Substrate. The drug delivery system can include, for example, particle compositions containing one or more anti-neoplastic atherapeutically effective amount of a therapeutic agent. The agents. Representative anti-neoplastic agent include, but are drug delivery system can, for example, bring about reduced not limited to, fluoropyrimidine, pyrimidine nucleoside, inflammation when administered to the patient than if a drug platinum analogue, anthracycline, anthracenedione, epipodo delivery system comprising an uncoated particle were admin phyllotoxin, camptothecin, Vinca alkaloid, and combinations istered to the patient. As would be appreciated by a person of thereof. ordinary skill, the compositions and methods disclosed 0075. The particles according to the compositions and herein can be applied to drug delivery systems of any size methods disclosed herein can be of any size that is consistent range, up to and including of a size Suitable for implants, with effective treatment of the eye disorders disclosed herein, in the judgment of a person of ordinary skill in the art. For including for example, intraocular implants, or the like. example, particles of any size can be used provided they do 0077. The drug delivery system can also include, for not obstruct the flow of intraocular fluids into and/or out of the example, (i) a Substrate; (ii) a coating associated with the eye compartment into which the particle composition is Substrate, wherein the coating presents a hydrophilic region administered, which could increase inflammation or IOP. Par to the environment around the Substrate; and (iii) a therapeu ticles having a diameter of for example, from about 1 nm to tically effective amount of a therapeutic agent. In some about 100,000 nm, or from about 1 nm to about 50,000 nm, or embodiments, the drug delivery system is Suitable for admin from about 50 nm to about 50,000 nm, or from about 1 nm to istration to a patient. The drug delivery system can, for about 30,000 nm, or from about 1 nm to about 10,000 nm, or example, bring about reduced inflammation when adminis from about 1 nm to about 1,000 nm, can be used according to tered to the patient than if a drug delivery system comprising the compositions and methods disclosed herein. Particles an uncoated Substrate were administered to the patient. having a diameter of for example, at least about 1 nm, at least about 10 nm, at least about 50 nm, at least about 100 nm, at 0078. In some embodiments the particles of the composi least about 300 nm, at least about 500 nm or more can be used. tions and methods disclosed herein are nanoparticles. As used Particles having a diameter of less than about 100,000 nm, or herein, the term “nanoparticle' refers to a particle having at less than about 50,000 nm, or less than about 25,000 nm, or least one dimension in the range of about 1 nm to about 1000 less thanabout 10,000 nm, or less than about 6,000 nm, or less nm, including any integer value between 1 nm and 1000 nm than about 5,000 nm, or less than about 2,000 nm, or less than (including about 1, 2, 5, 10, 20, 50, 60, 70, 80,90, 100, 150, about 1,000 nm, or less than about 800 nm, or less than about 200, 250, 300,400, 500, 600, 700, 800, 900 and 1000 nm and 600 nm, or less than about 500 nm, or less than about 200 nm. all integers and fractional integers in between). In some can be used. Particles of different diameters may be appro embodiments, the nanoparticle has at least one dimension, priate for administration to different eye compartments. For e.g., a diameter, of about 100 nm. In some embodiments, the example, particles for intravitreal administration can have a nanoparticle has a diameter of about 200 nm. In other diameter of at least about 1 nm, or from about 1 nm to about embodiments, the nanoparticle has a diameter of about 500 50,000 nm, or any other diameter range disclosed herein. nm. In yet other embodiments, the nanoparticle has a diam Particles for administration into the anterior chamber can eter of about 1000 nm (1 lum). In such embodiments, the have a diameter of, for example, from about 1 nm to about particle also can be referred to as a “microparticle.” As used 7,000 nm, or from about 10 nm to about 6,000 nm, or from herein, “microparticle' refers to a particle having at least one about 100 nm to about 2,000 nm, or from about 600 to about dimension in the range of about 1 um to about 100 um, 1000 nm, or less than about 6,000 nm, or less thanabout 2,000 including any integer value between 1 Lum and 100 Lum (in nm, or less than about 1,000 nm, or less than about 800 nm. cluding about 1, 2, 5, 10, 20,3040, 50, 60, 70,80,90 and 100 0076. In some embodiments, the drug delivery system can umandall integers and fractional integers in between). Exem include, for example, (i) a Substrate; and (ii) a coating asso plary microparticles have a diameter of less than about 100 ciated with the substrate. As used herein, a “substrate' is any microns, less than about 50 microns, less than about 10 Substance, device or apparatus that can be coated according to microns, less than about 5 microns, or less than about 3 the compositions and methods disclosed herein and thereafter microns, or less than about 2 microns. The term “particle' as administered to a patient. A substrate can be, for example, a used herein is meant to include nanoparticles and micropar medical device or an implant, or a particle as described ticles. herein. The substrate can be of any size that is consistent with (0079. It will be appreciated by one of ordinary skill in the effective delivery of a therapeutic agent to a patient, in the art that particles suitable for use with the presently disclosed judgment of a person of ordinary skill in light of the compo methods can exist in a variety of shapes, including, but not sitions and methods disclosed herein. A substrate can have a limited to, spheroids, rods, disks, pyramids, cubes, cylinders, diameter of for example, at least about 1 nm, or at least about nanohelixes, nanosprings, nanorings, rod-shaped particles, 1 micron, or at least about 1 mm, or at least about 10 mm; or arrow-shaped particles, teardrop-shaped particles, tetrapod from about 1 nm to about 10 mm, or from about 1 nm to about shaped particles, prism-shaped particles, and a plurality of US 2016/0235674 A1 Aug. 18, 2016

other geometric and non-geometric shapes. In some embodi TABLE 1-continued ments, the presently disclosed particles have a spherical shape. Representative Characteristics of COOH- and 0080. In some embodiments, the presently disclosed par PEG-Modified PS Particles ticles include polystyrene particles. For example, the pres Nominal ently disclosed particles include carboxyl-modified polysty Size (nm) Surface Chemistry Diameter (nm) 3-potential (mV) rene particles. The presently disclosed particles in some SOO COOH 515.07.2 -61.O.O.S embodiments can be tagged, e.g., with a fluorescent mol 500 PEG 529.1 - 8.1 -5.6+ 0.4 ecule, to enable them to be detected or monitored when administered to a Subject. For example, in some embodi ments, the particles include yellow-green fluorescent car I0085. In certain embodiments, the particles can be com boxyl-modified polystyrene particles (Molecular Probes, bined with an active ingredient, e.g., a drug, medication, or Eugene, Oreg.). therapeutic agent. Active ingredients include, but are not lim 0081 Further, in some embodiments, the presently dis ited to, any component, compound, or Small molecule that closed particles can be surface modified, e.g., by covalently can be used to bring about a desired effect, e.g., a therapeutic attaching PEG, often referred to as being PEGylated. Such effect. For example, a desired effect can include the diagno particles can be prepared as disclosed in Lai et al., “Rapid sis, cure, mitigation, treatment, or prevention of a disease or transport of large polymeric nanoparticles in fresh undiluted condition. human mucus. Proc. Natl. Acad. Sci. U.S.A., 104(5):1482 I0086. The active ingredient can be adsorbed, encapsu 1.487 (2007) and Suh et al., “PEGylation of nanoparticles lated, entangled, embedded, incorporated, bound to the Sur improves their cytoplasmic transport.” Int. J Nanomed., 204), face, or otherwise associated with the particle. As used herein, 735-741 (2007). “combined encompasses adsorbed, encapsulated, associ 0082 For example, one 100- to 500-nm yellow-green ated, entangled, embedded, incorporated, bound to the Sur fluorescent, carboxyl-modified polystyrene (PS) particles face, or any other means for holding two Substances or items (Molecular Probes, Eugene, Oreg.) can be dialyzed exten together. As provided hereinabove, in Some embodiments the sively against PBS (300 kDa, Spectrum Lab, Rancho presently disclosed particles can include a functional group, Dominguez, Calif.). Polyethylene glycol can be covalently e.g., a carboxyl group. Other functional groups include, but attached to the particles via carboxyl-amine reaction. Briefly, are not limited to, a Sulhydryl, hydroxyl, and/or amino group. diamine PEG (molecular mass >2,000 Da, e.g., 3,400 Da; The functional groups can be available, for example, for drug Nektar Therapeutics, San Carlos, Calif.) can be dissolved in binding (covalent or electrostatic) or for other desired pur 50 mM 2-(N-morpholino)ethanesulfonic acid (MES) buffer poses within the scope of the presently disclosed subject (Sigma, St. Louis, Mo.) at pH 6. PEG can be added to differ ent sized nondialyzed particles to yield final concentrations of matter. 3:1 PEG:COOH and 1% solids/mL. After 15 minutes, I0087. The subject treated by the presently disclosed meth 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (Sigma, ods in their many embodiments is desirably a human Subject, St Louis, Mo.) can be added to a final concentration of 4 although it is to be understood that the methods described mg/mL, pH adjusted to 6.5, and incubated on an orbital herein are effective with respect to all vertebrate species, shaker for 2 hours at room temperature. To quench the reac which are intended to be included in the term “subject.” tion, glycine (J. T. Baker, Phillipsburg, N.J.) can be added to Accordingly, a “subject' can include a human Subject for a final concentration of 100 mM. The solution can be incu medical purposes, such as for the treatment of an existing bated for 30 minutes at room temperature and subsequently condition or disease or the prophylactic treatment for prevent dialyzed extensively against PBS in a 300,000 kDa MWCO ing the onset of a condition or disease, oran animal Subject for Float-a-lyzer (Spectrum Laboratories, Rancho Dominguez, medical, Veterinary purposes, or developmental purposes. Calif.). Unmodified particles were dialyzed similarly to Suitable animal Subjects include mammals including, but not remove all traces of sodium azide originally added by the limited to, primates, e.g., humans, monkeys, apes, and the manufacturer. like; bovines, e.g., cattle, oxen, and the like; Ovines, e.g., 0083. Size and S-potential can be determined by dynamic sheep and the like; caprines, e.g., goats and the like; porcines, light scattering and laser Doppler anemometry, respectively, e.g., pigs, hogs, and the like; equines, e.g., horses, donkeys, using, for example, a Zetasizer 3000 (Malvern Instruments, Zebras, and the like; felines, including wild and domestic cats; Southborough, Mass.). Size measurements can be performed, canines, including dogs; lagomorphs, including rabbits, for example, at 25°C. at a scattering angle of 90°. Samples hares, and the like; and rodents, including mice, rats, and the can be further diluted in double-distilled water. like. In some embodiments, the Subject is a human including, 0084 Representative characteristics of particles prepared but not limited to, fetal, neonatal, infant, juvenile, and adult by the method of Lai et al. are summarized in Table 1. subjects. Further, a “subject' can include a patient afflicted with or suspected of being afflicted with a condition or dis TABLE 1. ease. Thus, the terms “subject' and “patient” are used inter Representative Characteristics of COOH- and changeably herein. PEG-Modified PS Particles I0088. The terms “treat' or “treating, and grammatical Nominal derivatives thereof, as used herein refer to any type of treat Size (nm) Surface Chemistry Diameter (nm) 3-potential (mV) ment that imparts a benefit to a subject afflicted with a disease or illness, including any measurable improvement in the con 1OO COOH 109.23.1 -41.0 + 1.9 1OO PEG 122:45.2 -4.4 + 1.1 dition of the Subject, reducing a symptom of the condition, 2OO COOH 216.6 4.5 -588; 4.2 inhibiting an underlying cause or mechanism related to the 2OO PEG 2323 - 6.8 -2.1 + 0.3 condition, delaying the progression of the condition, prevent ing or delaying the onset of the disease or illness, e.g., pro US 2016/0235674 A1 Aug. 18, 2016 phylactic treatment, enhancing normal physiological func The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. tionality, and the like. Thus, treating does nor require a cure. 1-46, latest edition, Pagamonon Press, and the references cited therein. 0089. The term “effective, as that term is used in the 0094. Initial dosages also can be estimated from in vivo specification and/or claims, means adequate to accomplish a data, Such as animal models. Animal models useful for testing desired, expected, or intended result. More particularly, a the efficacy of therapeutic agents to treat or prevent the vari “therapeutically effective amount’ as provided herein refers ous diseases described above are well-known in the art. Dos to an amount of the presently disclosed particle compositions age amounts will depend on, among other factors, the activity necessary to provide the desired therapeutic effect, e.g., an of the therapeutic agent, its bioavailability, the mode of amount that is effective to prevent, alleviate, ameliorate or administration and various factors discussed above. Dosage otherwise treat symptoms of disease or prolong the Survival amount and interval can be adjusted individually to provide of the subject being treated. As would be appreciated by one levels of the therapeutic agents(s) sufficient to maintain a of ordinary skill in the art upon review of the present disclo therapeutic or prophylactic effect. Skilled artisans will be sure and as provided in more detail herein below, the exact able to optimize effective local dosages without undue amount required will vary from Subject to Subject, depending experimentation. on age, general condition of the Subject, the severity of the condition being treated, the particular compound and/or com 0.095 The presently disclosed particle compositions can position administered, and the like. An appropriate “thera be administered once per day, a few or several times per day, peutically effective amount” in any individual case can be or even multiple times per day, depending upon, among other determined by one of ordinary skill in the art by reference to things, the indication being treated and the judgment of the the pertinent texts and literature and/or by using routine prescribing physician. experimentation. 0096 Preferably, the presently disclosed particle compo sitions will provide therapeutic or prophylactic benefit with 0090 The presently disclosed particle compositions can out causing Substantial toxicity. Toxicity of the particle com be administered therapeutically to achieve a therapeutic ben positions can be determined using standard pharmaceutical efit or prophylactically to achieve a prophylactic benefit. By procedures. The dose ratio between toxic and therapeutic (or therapeutic benefit is meant treating the underlying disorder prophylactic) effect is the therapeutic index. Compositions including eradication or amelioration of one or more of the that exhibit high therapeutic indices are preferred. symptoms associated with the underlying disorder Such that 0097. As provided hereinabove, the presently disclosed the patient reports an improvement in feeling or condition, particles, in particular embodiments, will contain one or more notwithstanding that the patient can still be afflicted with the “active compounds' or “therapeutic agents.” Pharmaceutical underlying disorder. For example, administration of a particle compositions containing the presently disclosed particle composition to a patient Suffering from a condition provides compositions also are provided herein. therapeutic benefit not only when the underlying condition is 0098. These pharmaceutical compositions include the eradicated or ameliorated, but also when the patient reports a presently disclosed active compounds in a pharmaceutically decrease in the severity or duration of the symptoms associ acceptable carrier. The term “pharmaceutically acceptable' ated with the condition. Therapeutic benefit also includes with respect to a component, such as a salt, carrier, excipient halting or slowing the progression of the disease, regardless or diluent of a composition according to the presently dis of whether improvement is realized by the patient. closed Subject matter refers to a component that is compatible 0091 For prophylactic administration, the presently dis with the other ingredients of the composition in that it can be closed particle compositions can be administered to a subject combined with the presently disclosed particle compositions at risk of developing a particular ocular condition or disorder. without eliminating the therapeutic efficacy of the active Alternatively, prophylactic administration can be applied to compounds or therapeutic agents and is suitable for use with avoid the onset of symptoms in a patient diagnosed with the subjects as provided herein without undue adverse side underlying condition or disorder. effects (including, but not limited to, toxicity, irritation, and allergic response) to the Subject to which the particular par 0092. The amount of the presently disclosed particle com ticle composition is administered. Examples of pharmaceu positions administered to a Subject will depend upon a variety tically acceptable components include, without limitation, of factors, including, for example, the particular indication any of the standard pharmaceutical carriers, such as phos being treated, the mode of administration, whether the phate buffered saline solutions, water, emulsions such as oil/ desired benefit is prophylactic or therapeutic, the severity of water emulsion, microemulsions, and various types of wet the indication being treated and the age and weight of the ting agents. patient, the bioavailability of the particular active compound, 0099. When used to treat or prevent conditions and dis and the like. Determination of an effective dosage is well eases as described herein, the presently disclosed active com within the capabilities of those skilled in the art. pounds can be administered singly, as mixtures of one or 0093. Effective dosages can be estimated initially from in more active compounds or in mixture or combination with vitro assays. For example, an initial dosage for use in animals other agents useful for treating Such diseases and/or the can be formulated to achieve a circulating blood or serum symptoms associated with Such diseases. concentration of active compound that is at or above an IC50 0100 Further, in representative embodiments, certain of the particular therapeutic agent as measured in an in vitro active compounds and/or therapeutic agents disclosed herein assay known in the art. Calculating dosages to achieve Such are prodrugs. The term “prodrug” refers to atherapeutic agent circulating blood or serum concentrations taking into account that has been chemically derivatized such that, upon admin the bioavailability of the particular compound is well within istration to a subject, the derivative is metabolized to yield the the capabilities of skilled artisans. For guidance, see Fingl & biologically-active therapeutic agent. Accordingly, upon Woodbury, “General Principles. In: Goodman and Oilman's administration to a recipient, a prodrug is capable of provid US 2016/0235674 A1 Aug. 18, 2016 ing (directly or indirectly) a compound of the presently dis Example 1 closed subject matter or an inhibitorily active metabolite or residue thereof. Prodrugs can increase the bioavailability of Preparation and Characterization of PEG-Coated the presently disclosed compounds when Such compounds Particles are administered to a Subject (e.g., by allowing an orally 0105. Fluorescent, carboxyl-modified polystyrene par administered compound to be more readily absorbed into the ticles (Molecular Probes, Eugene, Oreg.) were covalently blood) or can enhance delivery of the parent compound to a modified with 2-3.4 kDa amine-modified PEG (Nektar biological compartment (e.g., the brain or lymphatic system) Therapeutics, San Carlos, Calif.) via a carboxyl-amine reac relative to a metabolite species. tion, as previously published. Unconjugated PEG was removed by three rounds of washing and centrifugation. The 0101 Pharmaceutical compositions containing the pres PEG-coated particles were stored at 4°C. until use. A near ently disclosed particle compositions, including active com neutral 4-potential measured by Doppler anemometry was pounds (or prodrugs thereof), can be manufactured by means used to confirm PEG conjugation. These particles are also of conventional mixing, dissolving, granulating, dragee-mak referred to herein as coated latex particles. ing levigating, emulsifying, encapsulating, entrapping and/or lyophilization processes. The presently disclosed pharma Example 2 ceutical compositions can be formulated in conventional manner using one or more physiologically acceptable carri Particle Administration to the Corneal Stroma ers, diluents, excipients or auxiliaries that facilitate process ing of the active compounds into preparations that can be used 0106 Particles according to Example 1 were administered pharmaceutically. to the corneal stroma in one of two ways depending on the most appropriate dose for a clinical situation. Direct intras 0102 Useful injectable compositions containing the pres tromal injections were used to provide Smaller Volumes of ently disclosed particle compositions include sterile Suspen particle solution to the cornea. Such injections involved inser sions, solutions or emulsions of the active compound(s) in tion of a small gauge needle into the stromal layer of the aqueous or oily vehicles. The compositions also can contain cornea. These injection sites are most often self sealing. They formulating agents, such as Suspending, stabilizing and/or can, however, be closed with the aid of corneal glue and/or dispersing agents. The compositions Suitable for injection can contact placement if leakage occurs. be presented in unit dosage form, e.g., in ampules or in mul 0107 Larger doses of particles were administered by first tidose containers, and can contain added preservatives. Alter creating a pocket in the corneal stroma. The pocket was natively, an injectable composition can be provided in powder created outside the visual axis and the size was determined form for reconstitution with a suitable vehicle, including, but based on the required dose. The particles were then adminis not limited to, sterile water, buffer, dextrose solution, and the tered directly into the pocket, which was then closed with like, before use. To this end, the presently disclose particles corneal glue and placement of a contact lens for the first can be dried by any art-known technique, such as lyophiliza post-operative day. tion, and reconstituted prior to use. Example 3 0103) In addition to the presently disclosed particle com positions, the pharmaceutical formulations can contain other Particle Administration to the Anterior Chamber additives, such as pH-adjusting additives. In particular, useful pH-adjusting agents include acids, such as hydrochloric acid, Intraoperative Injection bases or buffers, such as sodium lactate, sodium acetate, Sodium phosphate, sodium citrate, sodium borate, or sodium 0.108 Small incisions are created in the cornea during gluconate. Further, the formulations can contain anti-micro cataract extraction Surgery. These incisions, which are used bial preservatives. Useful anti-microbial preservatives for removing the cataractous lens and implanting the artificial include methylparaben, propylparaben, and benzyl alcohol. lens, are closed by a process of hydroSealing at the end of The anti-microbial preservative is typically employed when Surgery. The particles are injected into the AC through the the formulation is placed in a vial designed for multidose use. Surgical incision and sealed in the chamber once the wound is closed. EXAMPLES Non-Operative Administration 0104. The presently disclosed subject matter now will be 0109. A small gauge needle was inserted through the described more fully hereinafter with reference to the accom peripheral cornea and used to inject the Solution of particles panying Examples, in which some, but not all embodiments according to Example 1 into the AC. These injection sites are of the inventions are shown. The following Examples have most commonly self-sealing, however, corneal glue and/or been included to provide guidance to one of ordinary skill in contact lens placement were used for the first 24 hours to the art for practicing representative embodiments of the pres prevent leakage. ently disclosed subject matter. In light of the present disclo sure and the general level of skill in the art, those of skill can Example 4 appreciate that the following Examples are intended to be exemplary only and that numerous changes, modifications, Particle Administration into the Vitreous Chamber and alterations can be employed without departing from the 0110. Injections of particle solutions into the vitreous scope of the presently disclosed subject matter. The following chamber were performed through the pars plana, an anatomic Examples are offered by way of illustration and not by way of location that is devoid of vasculature and retinal tissue, lim limitation. iting the risk of bleeding and retinal and/or lens injury. A US 2016/0235674 A1 Aug. 18, 2016

Small gauge needle was used to inject particles according to been proposed to decrease the need for post-operative topical Example 1. Injection sites of this size are self sealing, elimi drop. Free drugs, however, are cleared with the aqueous nating the need for closure. Injections were performed after humor (AH). The presently disclosed subject matter demon first disinfecting and topically anesthetizing the site. strates the use of particles for longer-term delivery of medi cations to the anterior chamber (AC), by evaluating the clear Example 5 ance rates and complications associated with the Sustained and Targeted Drug Delivery with administration of IC particles. Intrasomal Microparticles and Nanoparticles for Treating Chronic Keratitis and Corneal Graft Methods Rejection 0117 Nine rabbit eyes were examined in this embodi Purpose ment. Baseline fluorescence and intraocular pressures (IOP) were assessed. Groups included: (a) control—100 uL of IC 0111. Many cases of amoebic and fungal keratitis, as well saline; (b) uncoated—100 uL of IC 200-nm uncoated latex as corneal graft rejection, remain refractory to topical therapy. particles; and (c) coated—100LL of IC 200-nm latex particle, Intrastromal (IS) injection of medications has been intro which were coated with PEG. The particles were linked to duced as an alternative to topical administration, but IS injec fluorescence tags, which allowed detection by in vivo fluo tion remains limited due to drug loss by diffusion and clear rescence. Fluorescence images and IOP measurements were ance. The presently disclosed subject matter demonstrates obtained at Zero (0) minutes; one hour; six hours; daily for one that IS administration of micro- and nanoparticles such as week; and every two days for one month. Relative particle latex particles can be used for sustained delivery of antimi retention was evaluated by comparing fluorescence images to crobials or immunosuppressant agents to the cornea. those obtained at=0. Methods 0112 This embodiment included studying three groups, Results each with three rabbits. The three groups included: (a) a 0118 No fluorescence was detected in the control group. control group receiving 10 uL of saline into an intrastromal Particle loss was observed immediately after injection in both pocket; (b) a microparticle group receiving 10 uL of 1-um experimental groups: Significant percentages of both the particles covalently coated with PEG in the pocket; and (c) a coated and uncoated particles remained after one day and 15 nanoparticle group receiving 10 uL of 200-nm particles days. After 30 days, 33% and 18% of the total particles were covalently coated with PEG into the pocket. retained in the coated and uncoated groups, respectively. A 0113. The retention of the particles was assessed by in significantly greater clearance of uncoated particles (P<0.05) vivo fluorescence. The images were obtained at Zero (0) min was observed. Only one animal, from the uncoated group, utes; one hour, six hours; daily for one week; and every other developed elevated IOP after the injection, which resolved day for fourteen days. The initial fluorescence value for each progressively within 16 days. eye was used to determine the relative clearance of particles from the corneal stroma. Conclusion Results 0119 The presently disclosed subject matter demon 0114 Micro- and nanoparticles were cleared from the strates that intraoperative IC injection of particles of nano stroma at similar rates (P<0.05). At one hour, a clearance of size or larger can be a useful tool for providing Sustained 21% of the 1-um particles and 23% of the 200-nm particles delivery of post-operative medications to the AC for as longas was observed. At 24 hours, a loss of 52% and 41% of the total one month. injection 1-um particles and 200-nm particles, respectively, was observed. The rate of clearance became more gradual Example 7 with time: at 14 days, 79% and 73% of the original dose of the 1-um particles and 200-nm particles were lost, respectively. Intravitreal Particles for the Sustained Treatment of The control group had no detectable fluorescence at any time Degenerative and Proliferative Diseases of the point. Retina Conclusion Purpose 0115 The observation that more than 20% of the presently I0120 Intravitreal injection of angiogenesis inhibitors has disclosed particles are still present in the corneal stroma after become commonplace in the treatment of retinal diseases, 14 days indicates that IS micro- and nanoparticles provide a Such as age-related macular degeneration and proliferative method for long-term delivery of medications to the cornea . Unfortunately, this route of delivery and could be useful in the management and treatment of requires repeated injections, increasing the risk of infection chronic keratitis and graft rejection. and retinal injury. The presently disclosed Subject matter Example 6 determines the length of time particles can be retained in the vitreous chamber after pars plana injection and demonstrates Intracameral Injection of Particles for Sustained the use of the presently disclosed drug carriers for the long Delivery of Post-Operative Medications to the term treatment of diseases of a retina. Anterior Chamber Purpose Methods 0116 Intracameral (IC) administration of antimicrobial I0121 The study was conducted on nine rabbit eyes and and anti-inflammatory agents during intraocular Surgery has included three groups: (a) a control group received a 100-uI. US 2016/0235674 A1 Aug. 18, 2016

intravitreal injection of saline; (b) an uncoated group received tions of biodegradable poly(lactic-co-glycolic acid, PLGA); 100 uL of intravitreal 200-nm uncoated latex particle solu one group had no pluronics coating (PLGA-PVA), another tion; and (c) a coated group received 100 uL of intravitreal with moderate pluronics coating (PLGA-F68) and another 200-nm latex particles coated with PEG. The baseline fluo with dense pluronics coating (PLGA-F127). The control rescence and intraocular pressure (IOP) were assessed prior group received a sham IC injection with phosphate buttered to injection through the pars plana. The particles were fluo saline (PBS). rescence tagged and assessment of retention was made by analysis of in vivo fluorescence imaging. Images and IOP Pre-Injection Assessment measurements were obtained at Zero (0) minutes, one hour, I0128. The intraocular pressure (IOP) and anterior cham daily for one week, and every five days for one month. The ber (AC) inflammation were evaluated in all animals to estab fluorescence images from each time point were compared to lish baseline levels before particle Suspension injection. Ani those obtained immediately after the intravitreal injection to mals with elevated IOP or any signs of inflammation were determine the relative retention rates for each eye. excluded from the study. The animals were anesthetized with an intramuscular injection (IM) of ketamine/xylazine solu Results tion. Once general anesthesia was achieved a drop of 0.5% 0122 No significant differences between the clearance proparacaine topical anesthetic Solution was instilled onto the profiles of the coated and uncoated particles were observed. surface of the right eye of the animal and a wire No significant decline in the particles retained in the vitreous speculum was placed to keep the lid open. chambers was observed over 30 days (P<0.05). No detectable 0129. A Reichert Tono-Pen contact tonometer was used to fluorescence signal was observed in the control group. No assess the IOP, five measurements were obtained for each changes in IOP were observed in any group. animal at each time point. A slit-lamp biomicroscope exam was then performed to examine the AC for signs of inflam Conclusion mation; criteria included presence of cells, flare and fibrin. 0123. The presently disclosed particles provide sustained Injection Preparation and predictable release of medications and can be an effective system for long-term intravitreal drug delivery and the treat 0.130 Injections were performed immediately after the ment of various retinal diseases. particles were synthesized. The Suspension was homogenized using a table-top lab Vortex and doses of 120 uL were mea Example 8 sured and pipetted into individual microcentrifuge tubes. The particle Suspensions were Vortexed again immediately prior Inflammation Profile Following Intracameral to drawing them into the administration syringes. In order to Injection of Particles ensure that none of the particle Suspension was lost in the deadspace of the Syringefneedle during injection, an air cush Materials and Methods ion was created between the plunger and the particle Suspen sion by first drawing air into the Syringe prior to the Suspen Particle Synthesis S1O. 0.124. Fluorescent carboxyl-modified polystyrene par ticles 100-1000 nm in size (Molecular Probes, Eugene, Oreg.) Particle Injection were covalently conjugated with 2 kDa diamine PEG, accord 0131 The animals were anesthetized as outlined above. ing to methods known in the art. Once general anesthesia was achieved, a drop of 0.5% pro 0125 PLGA (15 kDa) was fluorescently labeled with paracaine was instilled onto the right eye of the animal prior Alexa Fluor 647 cadaverine (AF647: Invitrogen Corporation, to placement of a wire eyelid speculum. A 30 gauge needle Carlsbad, Calif.) using a modified method, as previously attached to an empty 1 cc Luer-lock syringe was inserted into described. Fluorescently labeled nanoparticles were formed the AC through the peripheral cornea using a narrow angle of by emulsion method. To form the emulsion, 100 mg of approach, and 120 L of aqueous humor (AH) was extracted. PLGA-AF647 dissolved in one ml of dichloromethane While holding the needle in the place in the AC, the extraction (DCM) was homogenized at 10k rpm for 2 min in 15 ml of Syringe was detached and the Syringe containing the particle aqueous phase (2% PVA, 10% F127, or 10% F68), then added suspension (or control PBS) was attached to the needle and to 100 ml aqueous phase (0.1% PVA, 1% F127, or 1% F68) the contents were injected into the AC. The needle and and stirred for 2 h to remove solvent. Particles were collected, Syringe were quickly withdrawn and a drop of cyanoacrylate washed twice, and resuspended. corneal glue was immediately placed on the injection site. 0126 Size and Zeta-potential were determined by The animals were monitored until anesthesia reversal, at dynamic light scattering and laser Doppler anemometry, which time they were returned to their cages. respectively, using a Zetasizer Nano ZS90 (Malvern Instru ments). Post-injection Assessment 0.132. The animals were evaluated on post-injection days Groups and Numbers 1, 7, 14 and 30 and the same evaluation procedure was per 0127. This study included 30 eyes from 30 New Zealand formed on each day. After general and local anesthesia were white rabbits. There were 5 experimental groups and one achieved, each animal was examined for gross abnormalities. control group, each with n=5 animals. Two experimental IOP was measured as indicated above. Slit-lamp biomicros groups received intracameral (IC) injections of polystyrene copy was performed to evaluate and quantify AC inflamma (PS) particles; uncoated (PS-COOH) and coated with poly tion. The exams were performed by the same trained ophthal (ethylene) glycol (PS-PEG). Three groups received IC injec mologist who was blinded to the assignment of the treatment US 2016/0235674 A1 Aug. 18, 2016

and control animals. The AC inflammation was quantified TABLE 1 using a modified version of the Standard Uveitis Nomencla The mean AC inflammation scores from among the animals (n = 5) ture clinical grading scheme, as detailed below. in each group for each time point evaluated in this study. Modified Standardization of Uveitis Nomenclature (SUN) Post Injection Day Scheme Particle Day 0 Day 1 Day 7 Day 14 Day 30 PS-COOH O 6.8 4.2 3.8 3.2 0133) PS-PEG O 5.4 2.8 1.8 1.2 PLGA-PVA O 8.6 5 4.2 3.6 PLGA-F68 O 7.8 4.4 3.8 3.4 PLGA-F127 O S.6 2.8 2 1.4 Part 1. Grading Scheme for Anterior Chamber Cells Control O 5.2 2.2 1.8 1.1

Grade Cells in Field 0.136 Although the foregoing subject matter has been O <1 described in some detail by way of illustration and example O.S 1-5 for purposes of clarity of understanding, it will be understood 1 6-15 by those skilled in the art that certain changes and modifica 2 16-2S tions can be made without departing from the spirit and scope 3 26-SO of the invention. 4 >50 0.137 All publications, patent applications, patents, and other references are herein incorporated by reference to the same extent as if each publication, patent application, patent, and other reference was specifically and individually indi cated to be incorporated by reference. It will be understood Part 2. Grading Scheme for Anterior Chamber Flare that, although a number of patent applications, patents, and other references are referred to herein, such reference does Grade Description not constitute an admission that any of these documents forms O None part of the common general knowledge in the art. 1 Faint 2 Moderate ( and lens details clear) REFERENCES 3 Marked (iris and lens details hazy) 4 Intense (fibrin or plastic aqueous) 0.138 Bourges et al., “Ocular drug delivery targeting the retina and retinal pigment epithelium using polylactide nanoparticles. Investigative Ophthalmology & Visual Sci ence (VIOS), 44(8):3562-3569 (2003); Part 3. Grading Scheme for Anterior Chamber Fibrin Reaction 0.139. De Kozak et al., “Intraocular injection of tamoxifen Grade Fibrin Morphology loaded nanoparticles: a new treatment of experimental autoimmune uveoretinitis, Eur: J. Immunol., 34:3702 O None 3712 (2004); 1 Spots, non-continuous Lines or semi-transparent 0140 Lai et al., “Rapid transport of large polymeric nano membranes particles in fresh undiluted human mucus. Proc. Natl. 3 Flat opaque patches Acad Sci. USA., 104(5):1482-1487 (2007). 4 Isometric masses 0.141. Sub et al., “PEGylation of nanoparticles improves their cytoplasmic transport.” Int. J. Nanomed., 204):735 741 (2007); 0.142 Yang et al., “Biodegradable nanoparticles com Results posed entirely of safe materials that rapidly penetrate 0134. The mean inflammation scores for each group are human mucus. Agnew. Chem. Int. Ed, 50: 1-5 (2011): presented below in Table 1 as well as in FIG.1. At day 1 there 0.143 U.S. Pat. No. 7,550,154 B2 to Saltzman et al. for was clinically visible AC inflammation in all animals in all “Methods of Treatment With Drug Loaded Polymeric groups, including the control group. The inflammation trend Materials issued Jun. 23, 2009: was similar for all groups: a rapid rise from the time of 0144 U.S. Pat. No. 7,638,137 B2 to Chauhan et al. for injection with a peak score at Day 1, followed by a progres “Ophthalmic Drug Delivery System, issued Dec. 29, sive decline until the end of the study (Day 30). 2009. (0145 U.S. Pat. No. 7,645,736 B2 to Bender et al. for 0135 The inflammation was significantly higher in the “Integrin inhibitors for the Treatment of Eye Diseases.” PS-COOH, PLGA-PVA, and PLGA-F68 groups compared to issued Jan. 12, 2010; the PS-PEG, PLGA-F127 and Saline groups at all time 0146 U.S. Pat. No. 7,648,959 B132 to Bender et al. for points. There was no significant difference among the scores “Methods and Compositions for the Treatment of Diseases of PS-COOH, PLGA-PVA and PLGA-F68 groups (at any of the Eye, issued Jan. 19, 2010; time point), and likewise there was no significant difference 0147 U.S. Patent Application Publication No. US2007/ among the scores of the PS-PEG, PLGA-F127 and Saline 0087989 A1 to Huang et al. for “Methods of Treating (Control) groups at any time point (P<0.05). Ocular Conditions.” published Apr. 19, 2007: US 2016/0235674 A1 Aug. 18, 2016

0148 U.S. Patent Application Publication No. US2007/ 75. The method of claim 66, wherein the anti-angiogenic 0238654 A1 to Deschatelets et al. for “Compstatin and agent is released from the drug delivery system into the Vit Analogs thereof for Eye Disorders.” published Oct. 11, reous chamber of the patient’s eye over a period of time of at 2007; least six months. 0149 U.S. Patent Application Publication No. US2008/ 76. The method of claim 66, wherein the anti-angiogenic 0287341 A1 to Chen for “Treatment of Vascular Abnor agent is an anti-VEGF agent. malities using Nanoparticles, published Nov. 20, 2008; 77. The method of claim 66, wherein the patient is a human. 0150 U.S. Patent Application Publication No. US2009/ 78. The method of claim 66, wherein the drug delivery 001 1040A1 to Naash et al. for “Use of Compacted Nucleic system is lyophilized and then reconstituted prior to admin Acid Nanoparticles in Non-Viral Treatments of Ocular istration by intravitreal injection. Diseases.” published Jan. 8, 2009: 79. The method of claim 66, wherein the drug delivery 0151 U.S. Patent Application Publication No. US2009/ system is provided in a sterile Suspension. 0220572A1 to Deschatelets et al. for “Injectable Combi 80. The method of claim 79, wherein the sterile suspension nation Therapy for Eye Disorders.” Sep. 3, 2009: includes a Suspending agent. 0152 U.S. Patent Application Publication No. US2009/ 81. An injectable composition for administration to the 0226531A1 to Lyons et al. for “Methods and Composition vitreous chamber of the eye of a patient, comprising a drug for Intraocular Delivery of Therapeutic SiRNA,” Sep. 10, delivery system that comprises: 2009; (i) microparticles having a diameter of 30 Lum or less 0153 U.S. Patent Application Publication No, US2009/ including a core which includes the biodegradable poly 0291919A1 to Kaushaletal. for “Compositions and Meth mer polylactide-co-glycolide; ods for Treating or Preventing Ophthalmic Light Toxicity.” (ii) a coating non-covalently associated with the micropar published Nov. 26, 2009; and ticles, wherein the coating is formed of a molecule that 0154 U.S. Patent Application Publication No. US2010/ has a polyethylene glycol hydrophilic region and a 0034749A1 to Schulze etal, for “Use of Cationic Colloidal hydrophobic region; Preparation for the Diagnosis and Treatment of Ocular (iii) a therapeutically effective amount of an anti-angio Diseases,” published Feb. 11, 2010. genic agent; (iv) in a sterile suspension suitable for intravitreal delivery: 1.-65. (canceled) wherein the drug delivery system provides Sustained 66. A method for treating an eye disorder in a patient in release of the anti-angiogenic agent into the vitreous need thereof, comprising administering by intravitreal injec chamber of the eye of the patient over a period of time of tion into the vitreous chamber of the eye an effective amount at least three months and of a drug delivery system which comprises: wherein the vitreous chamber of the eye exhibits at least (i) microparticles including a core which includes the bio 10% less inflammation or intraocular pressure than if the degradable polymer polylactide-co-glycolide; particles were uncoated, for at least about 30 days post (ii) a coating non-covalently associated with the micropar administration. ticles, wherein the coating is a molecule that has a hydro 82. The injectable composition of claim 81, wherein the philic region and a hydrophobic region, and wherein the composition includes a Suspending agent. hydrophilic region is polyethylene glycol; and 83. The injectable composition of claim 81, wherein the (iii) a therapeutically effective amount of an anti-angio anti-angiogenic agent is an anti-VEGF agent. genic agent, 84. The injectable composition of claim 81, wherein the wherein the drug delivery system provides Sustained drug delivery system provides Sustained release of the anti release of the anti-angiogenic agent into the vitreous angiogenic agent into the vitreous chamber of the eye over a chamber over a period of time of at least three months; period of time of at least six months. and 85. The injectable system of claim 81, wherein the drug wherein the vitreous chamber of the eye exhibits at least delivery system provides Sustained release of the anti-angio 10% less inflammation or intraocular pressure than if the genic agent into the vitreous chamber of the eye over a period particles were uncoated, for at least about 30 days post of time of at least six months. administration. 86. The injectable system of claim 81, wherein the patient 67. The method of claim 66, wherein the diameter of the is a human. microparticles is about 50 microns or less. 87. A drug delivery system for intravitreal injection into the 68. The method of claim 66, wherein the diameter of the vitreous chamber of the eye of a patient, comprising: microparticles is about 30 microns or less. (i) microparticles having a diameter of 30 Lum or less 69. The method of claim 66, wherein the coating molecule including a core which includes the biodegradable poly is a block-copolymer. mer polylactide-co-glycolide; 70. The method of claim 66, wherein the microparticles (ii) a coating non-covalently associated with the micropar consist essentially of polylactide-co-glycolide. ticles, wherein the coating is a molecule that has a hydro 71. The method of claim 66, wherein the disorder is macu philic region and a hydrophobic region, and wherein the lar degeneration. hydrophilic region is polyethylene glycol; 72. The method of claim 66, wherein the disorder is age (iii) a therapeutically effective amount of a anti-angiogenic related macular degeneration. agent, 73. The method of claim 66, wherein the disorder is dia (iv) in a sterile Suspension; and betic retinopathy. (v) a means for intravitreal injection; 74. The method of claim 66, wherein the disorder is corneal wherein the drug delivery system provides Sustained neovascularization. release of the anti-angiogenic agent into the vitreous US 2016/0235674 A1 Aug. 18, 2016

chamber of the eye patient’s over a period of time of at wherein the vitreous chamber of the eye exhibits at least least three months and wherein the vitreous chamber of 10% less inflammation or intraocular pressure than if the the eye exhibits at least 10% less inflammation or particles were uncoated for at least about 30 days post intraocular pressure than if the particles were uncoated administration. for at least about 30 days post-administration. 96. The injectable composition of claim 95, wherein the 88. The drug delivery system of claim 87, wherein the drug delivery system provides Sustained release of the anti composition includes a Suspending agent. VEGF agent into the vitreous chamber of the eye over a 89. The drug delivery system of claim 87, wherein the period of time of at least six months. anti-angiogenic agent is an anti-VEGF agent. 97. The injectable composition of claim 95, wherein the 90. The drug delivery system of claim 87, wherein the drug microparticles consist essentially of polylactide-co-gly delivery system provides Sustained release of the anti-angio collide. genic agent into the vitreous chamber of the eye over a period 98. The injectable composition of claim 95, wherein the of time of at least six months. patient is a human. 99. An injectable system for intravitreal injection into the 91. The drug delivery system of claim 87, wherein the vitreous chamber of the eye of a patient, comprising a drug patient is a human. delivery system that comprises: 92. A method for treating macular degeneration in a human (i) microparticles having a diameter of 30 Lum or less in need thereof, comprising administering by intravitreal including a core which includes the biodegradable poly injection into the vitreous chamber of the eye of a patient an mer polylactide-co-glycolide; effective amount of a drug delivery system which comprises: (ii) a coating non-covalently associated with the micropar (i) microparticles having a diameter of 30 um or less ticles; wherein the coating is a molecule that has a poly including a core which consists essentially of the biode ethylene glycol hydrophilic region and a hydrophobic gradable polymer polylactide-co-glycolide; region; (ii) a coating non-covalently associated with the micropar (iii) a therapeutically effective amount of an anti-VEGF ticles, wherein the coating is a molecule that has a poly agent, ethylene glycol hydrophilic region and a hydrophobic (iv) in a sterile Suspension, wherein the sterile Suspension region, includes a Suspending agent; and (iii) a therapeutically effective amount of an anti-VEGF (v) a means for intravitreal injection. agent, 100. The injectable system of claim 99, wherein the micro wherein the drug delivery system provides Sustained particles consist essentially of polylactide-co-glycolide. release of the anti-VEGF agent into the vitreous cham 101. The injectable system of claim 99, wherein the patient ber over a period of time of at least three months; is a human. wherein the vitreous chamber of the eye exhibits at least 102. A method for treating an eye disorder in a patient in 10% less inflammation or intraocular pressure than if the need thereof, comprising administering by intravitreal injec particles were uncoated for at least about 30 days post tion into the vitreous chamber of the eye an effective amount administration; and of a drug delivery system which comprises: wherein the drug delivery system is lyophilized and then (i) microparticles including a core which includes the bio reconstituted prior to administration by intravitreal degradable polymer polylactide-co-glycolide; injection in a sterile Suspension that includes a Suspend (ii) a coating non-covalently associated with the micropar ing agent. ticles; wherein the coating is a molecule that has a hydro philic region and a hydrophobic region, and wherein the 93. The method of claim 92, wherein the anti-angiogenic hydrophilic region is polyethylene glycol; agent is released from the drug delivery system into the Vit (iii) a therapeutically effective amount of an anti-angio reous chamber over a period of time of at least six months. genic agent, 94. The method of claim 92, wherein the patient is a human. wherein the drug delivery system provides Sustained 95. An injectable composition for administration to the release of the anti-angiogenic agent into the vitreous vitreous chamber of the eye of a patient, comprising a drug chamber over a period of time of at least three months; delivery system that comprises: and (i) microparticles having a diameter of 30 um or less wherein the vitreous chamber of the eye exhibits at least including a core which includes the biodegradable poly 10% less inflammation or intraocular pressure than if the mer polylactide-co-glycolide; particles were uncoated. (ii) a coating non-covalently associated with the micropar 103. The method of claim 102, wherein the microparticles ticle; wherein the coating is a molecule that has a poly have a diameter of about 50 microns or less. ethylene glycol hydrophilic region and a hydrophobic 104. The method of claim 102, wherein the microparticles region; have a diameter of about 30 microns or less. (iii) a therapeutically effective amount of an anti-VEGF 105. The method of claim 102, wherein the coating mol agent, ecule is a block-copolymer. (iii) in a sterile suspension suitable for intravitreal delivery 106. The method of claim 102, wherein the microparticle that includes a suspending agent; consists essentially of polylactide-co-glycolide. wherein the drug delivery system provides Sustained 107. The method of claim 102, wherein the disorder is release of the anti-VEGF agent into the vitreous cham macular degeneration. ber of the eye over a period of time of at least three 108. The method of claim 102, wherein the disorder is months, and age-related macular degeneration. US 2016/0235674 A1 Aug. 18, 2016

109. The method of claim 102, wherein the disorder is wherein the system provides sustained release of the anti diabetic retinopathy. angiogenic agent into the vitreous chamber of the eye 110. The method of claim 102, wherein the disorder is patient’s over a period of time of at least three months corneal neovascularization. and 111. The method of claim 102, wherein the anti-angiogenic wherein the vitreous chamber of the eye exhibits at least agent is released from the drug delivery system into the vit 10% less inflammation or intraocular pressure than if the reous chamber of the patient’s eye over a period of time of at particles were uncoated. least six months. 124. The injectable system of claim 123, wherein the 112. The method of claim 102, wherein the anti-angiogenic microparticles consist essentially of polylactide-co-gly agent is an anti-VEGF agent. collide. 113. The method of claim 102, wherein the patient is a 125. The injectable system of claim 123, wherein the human. patient is a human. 114. The method of claim 102, wherein the drug delivery 126. The injectable system of claim 123, wherein the com system is lyophilized and then reconstituted prior to admin position includes a suspending agent. istration by intravitreal injection. 127. The injectable system of claim 123, wherein the anti 115. The method of claim 102, wherein the drug delivery angiogenic agent is an anti-VEGF agent. system is provided in a sterile suspension. 128. A method for treating macular degeneration in a 116. The method of claim 115, wherein the sterile suspen human in need thereof, comprising administering by intrav Sion includes a suspending agent. itreal injection into the vitreous chamber of the eye of a 117. An injectable composition for administration to the patient an effective amount of a drug delivery system which Vitreous chamber of the eye of a patient, comprising a drug comprises: delivery system that comprises: (i) microparticles having a diameter of 30 um or less (i) microparticles having a diameter of 30 um or less including a core which consists essentially of the biode including a core which includes the biodegradable poly gradable polymer polylactide-co-glycolide; mer polylactide-co-glycolide; (ii) a coating non-covalently associated with the micropar (ii) a coating non-covalently associated with the micropar ticles; wherein the coating is a molecule that has a poly ticles; wherein the coating is a molecule that has a poly ethylene glycol hydrophilic region and a hydrophobic ethylene glycol hydrophilic region and a hydrophobic region; region; (iii) a therapeutically effective amount of an anti-VEGF (iii) a therapeutically effective amount of an anti-angio agent, genic agent; wherein the drug delivery system provides sustained (iv) in a sterile suspension suitable for intravitreal delivery: release of the anti-VEGF agent into the vitreous cham wherein the drug delivery system provides sustained release ber over a period of time of at least three months; of the anti-angiogenic agent into the vitreous chamber of the wherein the vitreous chamber of the eye exhibits at least eye of the patient over a period of time of at least three 10% less inflammation or intraocular pressure than if the months. particles were uncoated; and 118. The injectable composition of claim 117, wherein the wherein the drug delivery system is lyophilized and then composition includes a suspending agent. reconstituted prior to administration by intravitreal 119. The injectable composition of claim 117, wherein the injection in a sterile suspension that includes a suspend anti-angiogenic agent is an anti-VEGF agent. ing agent. 120. The injectable composition of claim 117, wherein the 129. The method of claim 128, wherein the anti-VEGF drug delivery system provides sustained release of the anti agent is released from the drug delivery system into the vit angiogenic agent into the vitreous chamber of the eye over a reous chamber over a period of time of at least six months. period of time of at least six months. 130. The method of claim 128, wherein the patient is a 121. The injectable composition of claim 117, wherein the human. microparticles consist essentially of polylactide-co-gly 131. An injectable composition for administration to the collide. Vitreous chamber of the eye of a patient, comprising a drug 122. The injectable composition of claim 117, wherein the delivery system that comprises: patient is a human. (i) microparticles having a diameter of 30 Lim or less 123. An injectable system for intravitreal injection into the including a core which includes the biodegradable poly Vitreous chamber of the eye of a patient, comprising a drug mer polylactide-co-glycolide; delivery system that comprises: (ii) a coating non-covalently associated with the micropar (i) microparticles having a diameter of 30 um or less ticles; wherein the coating is a molecule that has a poly including a core which includes the biodegradable poly ethylene glycol hydrophilic region and a hydrophobic mer polylactide-co-glycolide; region; (ii) a coating non-covalently associated with the micropar (iii) a therapeutically effective amount of an anti-VEGF ticles; wherein the coating is a molecule that has a poly agent; ethylene glycol hydrophilic region and a hydrophobic (iv) in a sterile suspension suitable for intravitreal delivery region; that includes a suspending agent; (iii) a therapeutically effective amount of an anti-angio wherein the drug delivery system provides sustained genic agent; release of the anti-VEGF agent into the vitreous cham (iv) in a sterile suspension; and ber of the eye over a period of time of at least three (v) a means for intravitreal injection, months and US 2016/0235674 A1 Aug. 18, 2016 20

wherein the vitreous chamber of the eye exhibits at least 10% less inflammation or intraocular pressure than if the particles were uncoated. 132. The injectable composition of claim 131, wherein the drug delivery system provides Sustained release of the anti angiogenic agent into the vitreous chamber of the eye over a period of time of at least six months. 133. The injectable composition of claim 131, wherein the patient is a human. 134. An injectable system for intravitreal injection into the vitreous chamber of the eye of a patient, comprising a drug delivery system that comprises: (i) microparticles having a diameter of 30 um or less including a core which includes the biodegradable poly mer polylactide-co-glycolide; (ii) a coating non-covalently associated with the micropar ticles; wherein the coating is a molecule that has a poly ethylene glycol hydrophilic region and a hydrophobic region; (iii) a therapeutically effective amount of an anti-VEGF agent, (iv) in a sterile Suspension, wherein the sterile Suspension includes a suspending agent; and (X) a means for intravitreal injection. 135. The injectable system of claim 134, wherein the patient is a human.