(12) United States Patent (10) Patent No.: US 8,883,214 B2 Wildsoet Et Al

USOO8883214B2

(12) United States Patent (10) Patent No.: US 8,883,214 B2 Wildsoet et al. (45) Date of Patent: Nov. 11, 2014

(54) IMPLANTABLE DELIVERY VEHICLE FOR (2013.01); A61L 2430/16 (2013.01); A61 K OCULAR DELIVERY OF MUSCARINC 47/32 (2013.01); A61 L 2300/622 (2013.01); ANTAGONSTS A61L 27/52 (2013.01); A61L 27/54 (2013.01); A61 K9/06 (2013.01); A61 L 2300/624 (75) Inventors: Christine F. Wildsoet, Berkeley, CA (2013.01) (US); James Su, Berkeley, CA (US); USPC ...... 424/489: 514/220; 514/291 Kevin E. Healy, Moraga, CA (US) (58) Field of Classification Search (73) Assignee: The Regents of the University of CPC ...... A61 K9/0051; A61 K9/06; A61K 47/32 California, Oakland, CA (US) USPC ...... 424/489: 514/220, 291, 30, 322 See application file for complete search history. (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 (56) References Cited U.S.C. 154(b) by 82 days. U.S. PATENT DOCUMENTS

(21) Appl. No.: 13/144,065 2005, 0169882 A1* 8, 2005 Lowe et al...... 424/78.27 2005/0271590 A1* 12/2005 Schwartz et al...... 424.95 (22) PCT Filed: Jan. 11, 2010 2006,0188576 A1 8, 2006 Takruri et al. 2008/0241222 A1* 10/2008 Whitcup et al...... 424/428 (86). PCT No.: 2009/0104.243 A1* 4/2009 Utkhede et al...... 424/423 S371 (c)(1), OTHER PUBLICATIONS (2), (4) Date: Sep. 29, 2011 Chou et al., Title: The effectiveness of 0.5% atropine in controlling (87) PCT Pub. No.: WO2010/083129 high myopia in children; J. Ocul Pharmacol Ther. 13(1), pp. 61-67; published Feb. 1997, by PubMed.* PCT Pub. Date: Jul. 22, 2010 Product information of Pluronic F-127, published Jan. 9, 2008 by Invitrogen, Ltd.* (65) Prior Publication Data Su, et al. “Effects of poly(2-hydroeyethyl methacrylate) and poly US 2012/OO15035A1 Jan. 19, 2012 (vinyl-pyrrollidone) hydrogel implants on myopic and normal chick sckera’, Exp Eye Res. (2009), 88(3):445-457. Related U.S. Application Data * cited by examiner (60) Provisional application No. 61/144,372, filed on Jan. 13, 2009. Primary Examiner — Johann R Richter (51) Int. Cl. Assistant Examiner — Yanzhi Zhang A 6LX 9/50 (2006.01) (74) Attorney, Agent, or Firm — Paula A. Borden; A6 IK 47/32 (2006.01) Bozicevic, Field & Francis LLP. A6L 27/52 (2006.01) A6IL 27/54 (2006.01) (57) ABSTRACT A6 IK9/00 (2006.01) The present invention provides compositions and methods for A6 IK9/06 (2006.01) treating ocular disorders such as myopia. (52) U.S. Cl. CPC ...... A61K 9/0051 (2013.01); A61 L 2300/432 20 Claims, 9 Drawing Sheets U.S. Patent Nov. 11, 2014 Sheet 1 of 9 US 8,883,214 B2

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O 5 O 25 says FG. 9 US 8,883,214 B2 1. 2 IMPLANTABLE DELIVERY VEHICLE FOR FIG. 7 depicts choroidal thickness over 21 days following OCULAR DELVERY OF MUSCARNC implantation into the posterior Sclera of atropine in a biode ANTAGONSTS gradable hydrogel matrix. FIG. 8 depicts scleral thickness over 21 days following CROSS-REFERENCE implantation into the posterior Sclera of atropine in a biode gradable hydrogel matrix. This application claims the benefit of U.S. Provisional FIG.9 depicts axial length over 21 days following implan Patent Application No. 61/144,372, filed Jan. 13, 2009, which tation into the posterior Sclera of atropine in a biodegradable application is incorporated herein by reference in its entirety. hydrogel matrix. 10 STATEMENT REGARDING FEDERALLY DEFINITIONS SPONSORED RESEARCH As used herein, the term “copolymer describes a polymer This invention was made with government Support under which contains more than one type of subunit. The term Grant No. R01EY 12392 awarded by the National Institutes of 15 encompasses polymer which include two, three, four, five, or Health. The government has certain rights in the invention. six types of Subunits. The terms “subject,” “individual.” “host, and “patient” are BACKGROUND used interchangeably herein to a member or members of any mammalian or non-mammalian species. Subjects and Degenerative myopia is a significant cause of world blind patients thus include, without limitation, humans, non-human ness and visual disability. Degenerative myopia is a major primates, canines, felines, ungulates (e.g., equine, bovine, cause of legal blindness in the United States. Overall, blind Swine (e.g., pig)), avians, rodents (e.g., rats, mice), and other ness most commonly occurs from myopic macular degenera Subjects. Non-human animal models, particularly mammals, tion, retinal detachment, cataract and glaucoma, and of these, 25 e.g. a non-human primate, a murine (e.g., a mouse, a rat). myopic macular degeneration is the most important. Degen lagomorpha, etc. may be used for experimental investiga erative myopia is thought to be due to decompensation of the tions. nerve and Supporting tissues of the part of the retina of the “Treating or “treatment of a condition or disease eye, the macular, which is used for fine vision. One cause of includes: (1) preventing at least one symptom of the condi the damage is the axial overgrowth of the eye during the 30 tion, i.e., causing a clinical symptom to not significantly regular growth phase, followed by further increments of develop in a mammal that may be exposed to or predisposed stretching during the adult years. By middle age, stressed eye to the disease but does not yet experience or display symp tissues begin to show degeneration and failure of function; toms of the disease, (2) inhibiting the disease, i.e., arresting or crucially, this includes the delicate nerves of the retina. reducing the development of the disease or its symptoms, or Current treatments for high myopia progression include 35 (3) relieving the disease, i.e., causing regression of the disease topical daily drops of muscarinic antagonists. or its clinical symptoms. A “therapeutically effective amount’ or “efficacious LITERATURE amount’ means the amount of a compound that, when admin istered to a mammal or other Subject for treating a disease, is 40 Sufficient, in combination with another agent, or alone in one U.S. Patent Publication No. 2006/0188576; Suet al. (2009) or more doses, to effect such treatment for the disease. The Exp. Eye Res. 88:445. “therapeutically effective amount will vary depending on the compound, the disease and its severity and the age, SUMMARY OF THE INVENTION weight, etc., of the subject to be treated. 45 The term “unit dosage form,” as used herein, refers to The present invention provides compositions and methods physically discrete units Suitable as unitary dosages for for treating ocular disorders such as myopia. human and animal Subjects, each unit containing a predeter mined quantity of compounds of the present invention calcu BRIEF DESCRIPTION OF THE DRAWINGS lated in an amount sufficient to produce the desired effect in 50 association with a pharmaceutically acceptable diluent, car FIG. 1 depicts an exemplary embodiment of delivery of a rier or vehicle. The specifications for the unit dosage forms muscarinic antagonist in a biodegradable hydrogel matrix depend on the particular compound employed and the effect through the posterior Sclera. to be achieved, and the pharmacodynamics associated with FIG. 2 depicts schematically the release of the muscarinic each compound in the host. antagonist atropine at the Sub-Tenon's capsule. 55 The term "physiological conditions' is meant to encom FIG.3 depicts anterior chamber depth over 21 days follow pass those conditions compatible with living cells, e.g., pre ing implantation into the posterior Sclera of atropine in a dominantly aqueous conditions of a temperature, pH, salinity, biodegradable hydrogel matrix. etc. that are compatible with living cells. FIG. 4 depicts lens thickness over 21 days following A "pharmaceutically acceptable excipient,” “pharmaceuti implantation into the posterior Sclera of atropine in a biode 60 cally acceptable diluent.” “pharmaceutically acceptable car gradable hydrogel matrix. rier, and pharmaceutically acceptable adjuvant’ means an FIG. 5 depicts vitreous chamber depth over 21 days fol excipient, diluent, carrier, and adjuvant that are useful in lowing implantation into the posterior Sclera of atropine in a preparing a pharmaceutical composition that are generally biodegradable hydrogel matrix. safe, non-toxic and neither biologically nor otherwise unde FIG. 6 depicts retinal thickness over 21 days following 65 sirable, and include an excipient, diluent, carrier, and adju implantation into the posterior Sclera of atropine in a biode vant that are acceptable for veterinary use as well as human gradable hydrogel matrix. pharmaceutical use. A pharmaceutically acceptable excipi US 8,883,214 B2 3 4 ent, diluent, carrier and adjuvant” as used in the specification antagonist-biodegradable hydrogel composition includes a and claims includes one and more than one such excipient, muscarinic antagonist distributed within a biodegradable diluent, carrier, and adjuvant. hydrogel. The muscarinic antagonist is in some embodiments Before the present invention is further described, it is to be not covalently linked to the hydrogel. In other embodiments, understood that this invention is not limited to particular 5 the muscarinic antagonist is covalently linked to a moiety embodiments described, as Such may, of course, vary. It is within the hydrogel. also to be understood that the terminology used herein is for Muscarinic Antagonists the purpose of describing particular embodiments only, and is The present invention provides a biodegradable hydrogel not intended to be limiting, since the scope of the present comprising a muscarinic antagonist, and use of same for invention will be limited only by the appended claims. 10 treating an ocular disorder. Muscarinic antagonists Suitable Where a range of values is provided, it is understood that for use in a Subject composition and/or in a Subject method each intervening value, to the tenth of the unit of the lower include, but are not limited to, atropine; Scopolamine; a mus limit unless the context clearly dictates otherwise, between carinic antagonist as disclosed in WO97/16187; a 3-dihydro the upper and lower limit of that range and any other stated or 1-1-piperidin-4-yl)piperidin-4-yl-2H-benzimidazol-2- intervening value in that stated range, is encompassed within 15 one as described in U.S. Pat. No. 5,691.323; a 1,3-dihydro the invention. The upper and lower limits of these smaller 1-4-amino-1-cyclohexyl-2H-benzimidazol-2-one aS ranges may independently be included in the Smaller ranges, described in U.S. Pat. No. 5,691.323; a 1-cycloalkylpiperi and are also encompassed within the invention, Subject to any din-4-yl-2H benzimidazolone as described in U.S. Pat. No. specifically excluded limit in the stated range. Where the 5,718.912; a tricyclic compound as described in U.S. Pat. No. stated range includes one or both of the limits, ranges exclud 5,461,052: pirenzepine (5.11-Dihydro-11-4-methyl-1-pip ing either or both of those included limits are also included in erazinyl)acetyl-6H-pyrido 2,3-b1,4)benzo diazepin-6- the invention. one) or its dihydrochloride; telenzepine: 4,9-dihydro-3-me Unless defined otherwise, all technical and scientific terms thyl-4-(4-methyl-(1)piperazine)acetyl1OH-thieno-3,4-b used herein have the same meaning as commonly understood 1.5-benzodiazepin-10-one, or its dihydrochloride; a 1,3- by one of ordinary skill in the art to which this invention 25 dihydro-1-1-(1-heteroarylpiperidin-4-yl)piperidin-4-yl)- belongs. Although any methods and materials similar or 2H-benzimidazolone as described in U.S. Pat. No. 5,756,508; equivalent to those described herein can also be used in the a benzimidazolidin-2-one derivatives 1-substituted with a practice or testing of the present invention, the preferred 4-piperidinyl moiety which in turn is 1-substituted, as methods and materials are now described. All publications described in WO96/13262: a muscarinic Mantagonist (e.g., mentioned herein are incorporated herein by reference to 30 imipramine, amitriptyline, nortriptyline, desipramine, 10-hy disclose and describe the methods and/or materials in con droxynortriptyline, and the like); himbacine ((3aR.4R,4aS, nection with which the publications are cited. 8aR.9aS)-4-(E)-(2R,6S)-1,6-dimethylpiperidin-2-ylvii It must be noted that as used herein and in the appended nyl-3-methyldecahydronaphtho2.3-clfuran-1 (3H)-one) claims, the singular forms “a,” “an,” and “the include plural and himbacine analogs (see, e.g., WO 2005/118576; and WO referents unless the context clearly dictates otherwise. Thus, 35 2006/076564); homatropine ((N,N-dimethyl-8-azoniabicy for example, reference to “a hydrogel includes a plurality of clo3.2.1]oct-3-yl)2-hydroxy-2-phenyl-acetate bromide); Such hydrogels and reference to “the muscarinic antagonist' tropicamide (N-ethyl-3-hydroxy-2-phenyl-N-(pyridin-4-yl includes reference to one or more muscarinic antagonists and methyl)propanamide); oxyphenonium (2-(2-Cyclohexyl-2- equivalents thereof known to those skilled in the art, and so hydroxy-2-phenylacetoxy)-N,N-diethyl-N-methyletha forth. It is further noted that the claims may be drafted to 40 naminium); oxyphenonium bromide; dexetimide(3-(1- exclude any optional element. As such, this statement is benzyl-4-piperidyl)-3-phenyl-piperidine-2,6-dione); intended to serve as antecedent basis for use of such exclusive benztropine ((3-endo)-3-(diphenylmethoxy)-8-methyl-8- terminology as “solely.” “only' and the like in connection aZabicyclo3.2.1]octane); benztropine mesylate: 4-diphenyl with the recitation of claim elements, or use of a “negative' acetoxy-N-methyl-piperidine (4-DAMP); Hexahydro-sila limitation. 45 difenidol (HHSiD); 2-Methylimidazol-1-yl-substituted The publications discussed herein are provided solely for analogs of HHSiD; p-fluoro-HHSiD, AF-DX 116 (11-(2- their disclosure prior to the filing date of the present applica (diethylamino)methyl-1-piperidinyl)acetyl)-5,11-dihydro tion. Nothing herein is to be construed as an admission that 6H-pyrido 2,3-b1,4)benzodiazepine-6-one); QNB (3-qui the present invention is not entitled to antedate Such publica nuclidinyl benzylate: 1-azabicyclo[2.2.2]oct-3-yl hydroxy tion by virtue of prior invention. Further, the dates of publi 50 (diphenyl)acetate); and the like. cation provided may be different from the actual publication Representative muscarinic antagonists include, but are not dates which may need to be independently confirmed. limited to, atropine, atropine Sulfate, atropine oxide, methy latropine nitrate, homatropine hydrobromide, hyoscyamine DETAILED DESCRIPTION (d. 1) hydrobromide, Scopolamine hydrobromide, ipratro 55 pium bromide, oxitropium bromide, tiotropium bromide, The present disclosure provides compositions and methods methantheline, propantheline bromide, anisotropine methyl for treating ocular disorders such as myopia. The present bromide, clidinium bromide, copyrrolate (Robinul), isopro disclosure provides a biodegradable hydrogel comprising a pamide iodide, mepenzolate bromide, tridihexethyl chloride muscarinic antagonist. The present disclosure provides meth (Pathilone), hexocyclium methylsulfate, cyclopentolate ods of treating ocular disorders such as myopia, the method 60 hydrochloride, tropicamide, trihexyphenidyl hydrochloride, generally involving implanting into an individual in need pirenzepine, telenzepine, AF-DX 116, and methoctramine. thereofan effective amount of a subject biodegradable hydro Combinations of two or more of the aforementioned mus gel, where the biodegradable hydrogel is implanted into or carinic antagonist can be included in a biodegradable hydro around the eye. gel matrix. For example, in Some embodiments, a subject Biodegradable Hydrogels 65 biodegradable hydrogel matrix comprises both atropine and The present disclosure provides a biodegradable hydrogel Scopolamine. As another example, in Some embodiments, a comprising a muscarinic antagonist. A subject muscarinic Subject biodegradable hydrogel matrix comprises both atro US 8,883,214 B2 5 6 pine and tropicamide. As another example, in Some embodi acrylic acid co-polymer (PNIPA Am-co-AAc); poly(2-hy ments, a subject biodegradable hydrogel matrix comprises droxyethyl methacrylate); poly(vinyl pyrrolidone); and the both atropine and pirenzapine. As another example, in some like. embodiments, a subject biodegradable hydrogel matrix com In some embodiments, the hydrogel is a temperature-sen prises both pirenzapine and tropicamide. sitive hydrogel. In some embodiments, a temperature-sensi In some embodiments, a Subject biodegradable hydrogel tive hydrogel is a polyacrylic acid or derivative thereof, e.g., matrix comprises two muscarinic antagonists of different poly(N-isopropylacrylamide) gel, and the increase in tem selectivities, e.g., two muscarinic antagonists selected from a perature causes the hydrogel to contract, thereby forcing the nonselective muscarinic antagonist, an M1 muscarinic active agent out of the hydrogel. Alternatively, the tempera 10 ture-sensitive hydrogel is an interpenetrating hydrogel net antagonist, an M2 muscarinic antagonist, an M3 muscarinic work of poly(acrylamide) and poly(acrylic acid), and the antagonist, an M4 muscarinic antagonist, and an M5 musca increase in temperature causes the hydrogel to Swell, thereby rinic antagonist. For example, in Some embodiments, a Sub allowing the active agent to diffuse out of the gel. The tem ject biodegradable hydrogel matrix comprises both a nonse perature required for triggering release of an active agent lective muscarinic antagonist and an M1 muscarinic 15 from the hydrogel is generally about normal body tempera antagonist. For example, in some embodiments, a subject ture, e.g., about 37° C. biodegradable hydrogel matrix comprises both an M1 and an As noted above, in Some embodiments, the hydrogel com M2 muscarinic antagonist. As another example, in some prises a muscarinic antagonist linked to one or more moieties embodiments, a subject biodegradable hydrogel matrix com in the hydrogel, or embedded in the hydrogel. In some prises both pirenzipine (M1) and QNB (M2). As another embodiments, the muscarinic antagonist is a hydrophilic example, in some embodiments, a Subject biodegradable compound. hydrogel matrix comprises both atropine (nonselective) and The hydrogel can be modified with one or more proteolyti 4-DAMP (M3, M4, M5). As another example, in some cally cleavable crosslinks See, e.g., Kim and Healy (2003) embodiments, a subject biodegradable hydrogel matrix com Biomacromolecules 4:1214. One or more of the hydrogel prises both HHSid (M3) and AF-DX 116 (M2). 25 polymers can be modified with a cell-binding moiety, e.g., a In some embodiments, a biodegradable hydrogel compris moiety that provides for binding to a cell-surface receptor. For ing a muscarinic antagonist ("a muscarinic antagonist-con example, a cell-binding moiety can include an Arg-Gly-Asp taining hydrogel’) includes only one therapeutic agent, i.e., a (RGD) peptide. single muscarinic antagonist. In other embodiments, a mus Nanoparticles or Microparticles Distributed within a Hydro carinic antagonist-containing hydrogel comprises two or 30 gel In some embodiments, a muscarinic antagonist is encap more different muscarinic antagonists. In other embodi sulated within a nanoparticle or microparticle, and the mus ments, a muscarinic antagonist-containing hydrogel com carinicantagonist-containing nanoparticle or microparticle is prises, in addition to a single muscarinic antagonist or two or distributed within a hydrogel. Thus, in some embodiments, a more different muscarinicantagonists, one or more additional 35 muscarinic antagonist is contained within a biodegradable therapeutic agents (“active agents'). A non-limiting example microsphere, where a biodegradable microsphere comprises: of a Suitable additional therapeutic agent is 7-methylxan a) a nanoparticle or a microparticle comprising one or more thine. Further non-limiting examples of suitable additional muscarinic antagonists; and b) a hydrogel matrix that forms therapeutic agents include retinoic acid analogs. an outer layer Surrounding the nanoparticle or microparticle. Biodegradable Hydrogels 40 The nanoparticle (or microparticle) can comprise an inner The present disclosure provides a biodegradable hydrogel core comprising: i) a hydrophobic polymer; ii) a hydrophilic comprising a muscarinic antagonist. A suitable hydrogel is a polymer linked to the hydrophobic polymer, where the hydro polymer of two or more monomers, e.g., a homopolymer or a phobic polymer and the hydrophilic polymers together form heteropolymer comprising multiple monomers. Suitable a nanoparticle or microparticle, where the hydrophobic poly hydrogel monomers include the following: lactic acid, gly 45 merforms an inner layer of the nanoparticle or microparticle, colic acid, acrylic acid, 1-hydroxyethyl methacrylate and the hydrophilic polymer forms an outer layer of the (HEMA), ethyl methacrylate (EMA), propylene glycol meth nanoparticle or microparticle. In some embodiments, the acrylate (PEMA), acrylamide (AAM), N-vinylpyrrolidone, microsphere further comprises one or more additional thera methyl methacrylate (MMA), glycidyl methacrylate peutic agents (“active agents'). (GDMA), glycol methacrylate (GMA), ethylene glycol, 50 A muscarinic antagonist can be present within the hydro fumaric acid, and the like. Common cross linking agents phobic core of the nanoparticle or microparticle. In some include tetraethylene glycol dimethacrylate (TEGDMA) and embodiments, a muscarinic antagonist is present only within N,N'-methylenebisacrylamide. The hydrogel can be the hydrophobic core, e.g., within the space created by the homopolymeric, or can comprise co-polymers of two or more hydrophobic polymer. In some embodiments, a muscarinic of the aforementioned polymers. 55 antagonist is present within the hydrophobic core, and the Exemplary hydrogels include, but are not limited to, a muscarinic antagonist not linked to any moiety of the nano copolymer of poly(ethylene oxide) (PEO) and poly(propy particle or microparticle. In other embodiments, a muscarinic lene oxide) (PPO); PluronicTMF-127 (a difunctional block antagonist is present within the hydrophobic core, and the copolymer of PEO and PPO of the nominal formula EOoo muscarinic antagonist is linked to one or more moieties POs-EO, where EO is ethylene oxide and PO is propylene 60 present in the hydrophobic core, e.g., the muscarinic antago oxide); poloxamer 407 (a tri-block copolymer consisting of a nist is linked to a poly-L-lactide polymer. In other embodi central block of poly(propylene glycol) flanked by two hydro ments, the muscarinic antagonist is linked to the hydrophilic philic blocks of poly(ethylene glycol)); a poly(ethylene polymer, e.g., in some embodiments, the muscarinic antago oxide)-poly(propylene oxide)-poly(ethylene oxide) co-poly nist is linked to a poly(ethylene glycol) (PEG) (e.g., the mus mer with a nominal molecular weight of 12,500 Daltons and 65 carinic antagonist is linked to a reactive group present on a PEO:PPO ratio of 2:1); a poly(N-isopropylacrylamide)- derivatized PEG, e.g., the muscarinic antagonist is linked to base hydrogel (a PNIPA Am-based hydrogel); a PNIPA Am an amine group present on derivatized PEG). US 8,883,214 B2 7 8 In some embodiments, a muscarinic antagonist is present from about 50,000 subunits to about 100,000 subunits. In within the hydrophobic core; and a second active agent is Some embodiments, the linear polymer comprises more than linked to the hydrophilic polymer. For example, where a 100,000 subunits. muscarinicantagonist is present within the hydrophobic core, The Subunits can all be identical, e.g., the polymer is a and a second active agent is linked to the hydrophilic polymer, homopolymer. In other embodiments, more than one species the second active agent is hydrophilic. In other embodiments, of subunit is present, e.g., the polymer is a heteropolymer or a second active agent is present within the hydrophobic core; co-polymer. In some embodiments, the polymer is a linear and a muscarinic antagonist is linked to the hydrophilic poly polymer. In other embodiments, the polymer may include one mer. For example, where a second active agent is present or more branches. within the hydrophobic core, and a muscarinic antagonist is 10 linked to the hydrophilic polymer, the muscarinic antagonist Suitable polymers include natural polymers, semisynthetic is hydrophilic. polymers, and synthetic polymers. Suitable synthetic poly In some embodiments, a Subject microsphere comprises a mers include, but are not limited to, polymers or copolymers muscarinic antagonist and a second active agent, where the derived from polydioxane, polyphosphaZene, polysulphone muscarinicantagonist is associated with or linked to the nano 15 resins, poly(acrylic acid), poly(acrylic acid) butyl ester, poly particle or microparticle (e.g., the muscarinic antagonist is (ethylene glycol), poly(propylene), polyurethane resins, poly present within the hydrophobic core, either free within the (methacrylic acid), poly(methacrylic acid)-methyl ester, poly hydrophobic core, or linked to a hydrophobic polymer in the (methacrylic acid)-n butyl ester, poly(methacrylic acid)-t hydrophobic core, or is linked to a hydrophilic polymer in the butyl ester, polytetrafluoroethylene, polyperfluoropropylene, nanoparticle or microparticle); and the second agent is linked poly N-vinyl carbazole, poly(methyl isopropenyl ketone), to or associated with the hydrogel. In some of these embodi poly alphamethyl styrene, polyvinylacetate, poly(oxymeth ments, the muscarinic antagonist is hydrophobic and the sec ylene), poly(ethylene-co-vinyl acetate), a polyurethane, a ond active agent is hydrophilic. Where a subject microsphere poly(vinyl alcohol), and polyethylene terephthalate; ethylene comprises a muscarinic antagonist and a second active agent, vinyl alcohol copolymer (commonly known by the generic where the muscarinic antagonist is associated with or linked 25 name EVOH or by the trade name EVAL); polybutyl to the nanoparticle (or microparticle) and where the second methacrylate; poly(hydroxyvalerate); poly(L-lactic acid) or active agent is associated with or linked to the hydrogel, a poly(L-lactide); poly(e-caprolactone); poly(lactide-co-gly two-stage release profile is provided where the muscarinic collide); poly(hydroxybutyrate); poly(hydroxybutyrate-co antagonist is released from the hydrogel at a first rate and over Valerate); polydioxanone; polyorthoester, polyanhydride; a first time period, and the second active agent is released 30 poly(glycolic acid) (PGA); poly(D.L-lactide) (PDLL); poly from the nanoparticle (or microparticle) at a second rate and (L-Lactide)(PLL); copolymers of PGA, PDLA, and/or PLA; over a second time period. poly(glycolic acid-co-trimethylene carbonate); polyphos Nanoparticle and Microparticle Polymers phoester, polyphosphoester urethane; poly(amino acids); As noted above, in some embodiments, a subject biode cyanoacrylates; poly(trimethylene carbonate); poly(imi gradable microsphere comprises: a) a nanoparticle or a 35 nocarbonate); copoly(ether-esters) (e.g., PEO/PLA); poly microparticle comprising one or more muscarinic antago alkylene oxalates; polyphosphaZenes; polyurethanes; sili nists; and b) a hydrogel matrix that forms an outer layer cones; polyesters; polyolefins; polyisobutylene and ethylene Surrounding the nanoparticle or microparticle. The nanopar alphaolefin copolymers; acrylic polymers and copolymers; ticle or microparticle can have an average diameter of from vinyl halide polymers and copolymers, such as polyvinyl about 1 nm to about 900 um, e.g., the nanoparticle can have an 40 chloride; polyvinyl ethers, such as polyvinyl methyl ether; average diameter of from about 1 nm to about 5 nm, from polyvinylidene halides, such as polyvinylidene fluoride and about 5 nm to about 25 nm, from about 25 nm to about 50 nm, polyvinylidene chloride; polyacrylonitrile; polyvinyl from about 50 nm to about 75 nm, from about 75 nm to about ketones; polyvinyl aromatics, such as polystyrene; polyvinyl 100 nm, from about 100 nm to about 200 nm, from about 200 esters, such as polyvinyl acetate; copolymers of vinyl mono nm to about 300 nm, from about 300 nm to about 400 nm, 45 mers with each other and olefins, such as ethylene-methyl from about 400 nm to about 500 nm, from about 500 nm to methacrylate copolymers, acrylonitrile-styrene copolymers, about 600 nm, from about 600 nm to about 700 nm, from ABS resins, and ethylene-vinyl acetate copolymers; polya about 700 nm to about 800 nm, from about 800 nm to about mides, such as Nylon 66 and polycaprolactam, alkyd resins; 900 nm, from about 900 nm to about 1 lum, from about 1 um polycarbonates; polyoxymethylenes; polyimides; poly to about 10um, from about 10um to about 25um, from about 50 ethers; epoxy resins; polyurethanes; rayon; rayon-triacetate; 25um to about 50 um, from about 50 um to about 75um, from cellulose; cellulose acetate; cellulose butyrate; cellulose about 75um to about 100 um, from about 100 um to about 200 acetate butyrate; cellophane; cellulose nitrate; cellulose pro um, from about 200 um to about 300 um, from about 300 um pionate; cellulose ethers; amorphous Teflon; and carboxym to about 400 um, from about 400 um to about 500 um, from ethyl cellulose. about 500 um to about 600 um, from about 600 um to about 55 Suitable hydrophobic polymers include poly(L-lactide), 700 um, from about 700 um to about 800 um, or from about poly(glycolide), poly(e-caprolactone), copolymers of lactide 800 um to about 900 um. and/or glycolide or/and poly(e-caprolactone), hydrophobic The nanoparticle or microparticle comprises a hydropho peptides or a combination of hydrophobic peptides, polyure bic polymer and a hydrophilic polymer. Suitable hydrophobic thanes. Any hydrophobic polymer that can form a micelle in and hydrophilic polymers include biocompatible polymers 60 water is suitable for use as a hydrophobic polymer. Suitable comprising from about 50 to about 100,000 subunits, e.g., hydrophobic polymers include, e.g., poly(glycolide) or poly from about 50 subunits to about 100 subunits, from about 100 (glycolic acid); poly(e-caprolactone); poly(D.L-lactide); subunits to about 500 subunits, from about 500 subunits to poly(L-Lactide); copolymers of these and other polyesters; about 1,000 subunits, from about 1,000 subunits to about polyamides; polyanhydrides; polyurethanes; poly(ortho 5,000 subunits, from about 5,000 subunits to about 10,000 65 esters); poly(iminocarbonates). In some embodiments, the subunits, from about 10,000 subunits to about 25,000 sub hydrophobic polymer of the nanoparticle (or microparticle) is units, from about 25,000 subunits to about 50,000 subunits, or poly-L-lactide. US 8,883,214 B2 9 10 Suitable hydrophilic polymers include, but are not limited An active agent (e.g., a muscarinic antagonist) can be to, poly(ethylene glycol); poly(Vinyl alcohol); polyethers; attached to the PEG via a linking group. The linking group is poly(methacrylic acid); poly(acrylic acid); poly(HEMA): any biocompatible linking group, where “biocompatible' hyaluronic acid; and hyaluronate. indicates that the compound or group is non-toxic and may be In some embodiments, the hydrophilic polymer of the utilized in vitro or in vivo without causing injury, sickness, nanoparticle or microparticle is a poly(ethylene glycol) poly disease, or death. PEG can be bonded to the linking group, for mer. Polyethylene glycol has the general formula R(O— example, via an ether bond, an ester bond, a thiol bond or an CH-CH)O—R, where R is hydrogen or a protective amide bond. Suitable biocompatible linking groups include, group Such as an alkyl or an alkanol group, and where n is an but are not limited to, an ester group, an amide group, an integer from 1 to 1000. 10 PEG having a molecular weight in a range of from about 2 imide group, a carbamate group, a carboxyl group, a hydroxyl kDa to about 100 kDa, can be used, where the term “about.” group, a carbohydrate, a Succinimide group (including, for in the context of PEG, indicates that in preparations of poly example, Succinimidyl Succinate (SS). Succinimidyl propi ethylene glycol, some molecules will weigh more, Some less, onate (SPA), succinimidyl butanoate (SBA), succinimidyl than the stated molecular weight. For example, PEG suitable 15 carboxymethylate (SCM), succinimidyl succinamide (SSA) for conjugation to IFN-C has a molecular weight of from or N-hydroxy Succinimide (NHS)), an epoxide group, an about 2 kDa to about 5 kDa, from about 5 kDa to about 10 oxycarbonylimidazole group (including, for example, carbo kDa, from about 10 kDa to about 15 kDa, from about 15 kDa nyldimidazole (CDI)), a nitro phenyl group (including, for to about 20 kDa, from about 20 kDa to about 25 kDa, from example, nitrophenyl carbonate (NPC) or trichlorophenyl about 25kDa to about 30 kDa, from about 30 kDa to about 40 carbonate (TPC)), a trysylate group, an aldehyde group, an kDa, from about 40 kDa to about 50 kDa, from about 50 kDa isocyanate group, a vinylsulfone group, a tyrosine group, a to about 60 kDa, from about 60 kDa to about 70 kDa, from cysteine group, a histidine group or a primary amine. about 70 kDa to about 80 kDa, from about 80 kDa to about 90 A non-limiting example of a Suitable co-polymer forming kDa, or from about 90 kDa to about 100 kDa. a nanoparticle or microparticle is a poly(lysine-g(lactide-b- In some embodiments, the PEG is linear. In other embodi 25 ethylene glycol) terpolymer. Park and Healy (2003) Biocon ments, the PEG is branched. Branched PEG derivatives such jugate Chem 14: 31119. One or more of the hydrogel poly as those described in U.S. Pat. No. 5,643,575, “star-PEG's mers can be modified with a cell-binding moiety, e.g., a and multi-armed PEG's such as those described in Shearwa moiety that provides for binding to a cell-surface receptor. For ter Polymers, Inc. catalog “Polyethylene Glycol Derivatives example, a cell-binding moiety can include an Arg-Gly-Asp 1997-1998.” Star PEGs are described in the art including, 30 (RGD) peptide. e.g., in U.S. Pat. No. 6,046,305. Hydrogels PEG has at least one hydroxyl group, e.g., a terminal hydroxyl group, which hydroxyl group can be modified to As noted above, in some embodiments, a Subject biode generate a functional group that is reactive with an amino gradable microsphere comprises: a) a nanoparticle or a group, e.g., an epsilon amino group of a lysine residue, a free 35 microparticle comprising one or more muscarinic antago amino group at the N-terminus of a polypeptide, or any other nists; and b) a hydrogel matrix that forms an outer layer amino group Such as an amino group of asparagine, Surrounding the nanoparticle or microparticle. A hydrogel is glutamine, arginine, or histidine. a polymer comprising monomeric units. Suitable hydrogel The PEG can be derivatized so that an active agent (e.g., a monomers include the following: lactic acid, glycolic acid, muscarinic antagonist) can be linked to the PEG polymer. 40 acrylic acid, 1-hydroxyethyl methacrylate (HEMA), ethyl Suitable derivatives of PEG that are reactive with the free methacrylate (EMA), propylene glycol methacrylate carboxyl group at the carboxyl-terminus of a peptide include, (PEMA), acrylamide (AAM), N-vinylpyrrolidone, methyl but are not limited to PEG-amine, and hydrazine derivatives methacrylate (MMA), glycidyl methacrylate (GDMA), gly of PEG (e.g., PEG-NH NH). col methacrylate (GMA), ethylene glycol, fumaric acid, and A PEG polymer can be derivatized such that it comprises a 45 the like. Common cross linking agents include tetraethylene terminal thiocarboxylic acid group, —COSH, which selec glycol dimethacrylate (TEGDMA) and N,N'-methylenebi tively reacts with amino groups to generate amide derivatives. sacrylamide. The hydrogel can be homopolymeric, or can Because of the reactive nature of the thio acid, selectivity of comprise co-polymers of two or more of the aforementioned certain amino groups over others is achieved. For example, polymers. —SH exhibits sufficient leaving group ability in reaction with 50 The hydrogel that Surrounds the nanoparticle or micropar N-terminal amino group at appropriate pH conditions such ticle is generally hydrophilic. Suitable polymers for inclusion that the S-amino groups in lysine residues are protonated and in the hydrogel include, but are not limited to, poly(N-isopro remain non-nucleophilic. On the other hand, reactions under pylacrylamide); poly(N-isopropylacrylamide-co-acrylic Suitable pH conditions may make Some of the accessible acid); hyaluronic acid or hyaluronate; crosslinked hyaluronic lysine residues to react with selectivity. 55 acid or hyaluronate; PHEMA; or copolymers p(NIPA Am)- PEG can comprise a reactive ester such as an N-hydroxy based sIPNs and other hydrogel sIPNs (semi-interpenetrating succinimidate at the end of the PEG chain. Such an N-hy networks). droxysuccinimidate-containing PEG molecule reacts with In some embodiments, the hydrogel is a temperature-sen select amino groups at particular pH conditions such as neu sitive hydrogel. In some embodiments, a temperature-sensi tral 6.5-7.5. For example, the N-terminal amino groups may 60 tive hydrogel is a polyacrylic acid or derivative thereof, e.g., be selectively modified under neutral pH conditions. How poly(N-isopropylacrylamide) gel, and the increase in tem ever, if the reactivity of the reagent were extreme, accessible perature causes the hydrogel to contract, thereby forcing the NH groups of lysine may also react. active agent out of the hydrogel. Alternatively, the tempera An active agent (e.g., a muscarinic antagonist) can be ture-sensitive hydrogel is an interpenetrating hydrogel net coupled directly to PEG (i.e., without a linking group) 65 work of poly(acrylamide) and poly(acrylic acid), and the through an amino group, a Sulfhydryl group, a hydroxyl increase in temperature causes the hydrogel to Swell, thereby group, or a carboxyl group. allowing the active agent to diffuse out of the gel. The tem US 8,883,214 B2 11 12 perature required for triggering release of an active agent detail herein. Pharmaceutically acceptable excipients have from the hydrogel is generally about normal body tempera been amply described in a variety of publications, including, ture, e.g., about 37° C. for example, A. Gennaro (2000) “Remington: The Science As noted above, in Some embodiments, the hydrogel com and Practice of Pharmacy.” 20th edition, Lippincott, Will prises a muscarinic antagonist linked to one or more moieties 5 iams, & Wilkins: Pharmaceutical Dosage Forms and Drug in the hydrogel, or embedded in the hydrogel. In some Delivery Systems (1999) H. C. Ansel et al., eds., 7" ed., embodiments, the muscarinic antagonist is a hydrophilic Lippincott, Williams, & Wilkins; and Handbook of Pharma compound. ceutical Excipients (2000) A. H. Kibbe et al., eds., 3" ed. The hydrogel can be modified with one or more proteolyti Amer. Pharmaceutical Assoc. cally cleavable crosslinks See, e.g., Kim and Healy (2003) 10 The pharmaceutically acceptable excipients, such as Biomacromolecules 4:1214. vehicles, adjuvants, carriers or diluents, are readily available Treatment Methods to the public. Moreover, pharmaceutically acceptable auxil The present disclosure provides a method of treating an iary Substances, such as pH adjusting and buffering agents, ocular disorder in an individual in need thereof, the method tonicity adjusting agents, stabilizers, wetting agents and the generally involving intraocular or peri-ocular implantation of 15 like, are readily available to the public. an effective amount of a hydrogel comprising a muscarinic Unit dosage forms of a muscarinic antagonist-containing antagonist. hydrogel for injection can comprise a hydrogel as described As a non-limiting example, muscarinic antagonist-con above, where the hydrogel comprises a muscarinic antago taining hydrogel is injected, e.g., at the posterior pole of the nist, a composition as a solution insterile water, normal saline eye. As a non-limiting example, a muscarinic antagonist or another pharmaceutically acceptable carrier. A biocompat containing hydrogel is injected into the Sub-Tenon's capsule. ible hydrogel that comprises a muscarinic antagonist, as As a non-limiting example, a muscarinic antagonist-contain described above, is also referred to herein as “a muscarinic ing hydrogel is delivered via intra-orbital injection. antagonist-containing hydrogel. A muscarinic antagonist In some embodiments, an effective amount of a muscarinic containing hydrogel will in Some embodiments further com antagonist-containing hydrogel is an amount that provides for 25 prise one or more additional therapeutic agents (“active at least a slowing of high myopia progression, e.g., such that agents'). the rate of progression is slowed by at least about 10%, at least The term “unit dosage form,” as used herein, refers to about 15%, at least about 20%, at least about 25%, at least physically discrete units Suitable as unitary dosages for about 30%, at least about 40%, at least about 50%, or more human and animal Subjects, each unit containing a predeter than 50%. 30 mined quantity of a Subject microsphere comprising an active In some embodiments, an effective amount of a muscarinic agent calculated in an amount Sufficient to produce the antagonist-containing hydrogel is an amount that is effective desired effect in association with a pharmaceutically accept to improve corrected visual acuity by at least about 10%, at able diluent, carrier or vehicle. The specifications for a sub least about 15%, at least about 20%, at least about 25%, at ject microsphere depend on the particular active agent con least about 30%, at least about 40%, at least about 50%, or 35 tained within the microsphere and the effect to be achieved, more than 50%. and the pharmacodynamics associated with each compound In some embodiments, an effective amount of a muscarinic in the host. antagonist-containing hydrogel is an amount that is effective The total Volume of a muscarinic antagonist-containing to improve low contrast visual acuity by at least about 10%, at hydrogel (e.g., a unit dosage form) that can be administered to least about 15%, at least about 20%, at least about 25%, at 40 the eye ranges from about 1 Jul to about 1 ml, e.g., from about least about 30%, at least about 40%, at least about 50%, or 1 ul to about 5ul, from about 5ul to about 10 ul, from about more than 50%. 10 ul to about 15 ul, from about 15 ul to about 25 ul, from In some embodiments, an effective amount of a muscarinic about 25 ul to about 50 ul, from about 50 ul to about 75 ul, antagonist-containing hydrogel is an amount that is effective from about 75ul to about 100 ul, from about 100 ul to about to maintain or increase retinal thickness over time. Retinal 45 200 ul, from about 200 ul to about 300 ul, from about 300 ul thickness can be determined by, e.g., optical coherence to about 500 ul, from about 500 ul to about 750 ul, or from tomography (OCT). about 750 ul to about 1 ml. In some embodiments, an effective amount of a muscarinic A unit dosage form of a muscarinic antagonist-containing antagonist-containing hydrogel is an amount that is effective hydrogel can include from about 1 ng to about 10 mg of an to improve retinal function by at least about 10%, at least 50 active agent, e.g., a muscarinicantagonist (and optionally one about 15%, at least about 20%, at least about 25%, at least or more additional active agents). about 30%, at least about 40%, at least about 50%, or more Where a muscarinic antagonist-containing hydrogel com than 50%. Retinal function can be assessed by multifocal prises a microsphere (e.g., a nanoparticle or a microparticle electroretinogram. contained within a hydrogel), a unit dosage form of a musca Whether a particular muscarinic antagonist, or an amount 55 rinic antagonist-containing hydrogel can include from about of a muscarinic antagonist, is effective to achieve a clinical 10 to about 10 microspheres, where a unit dosage form of a benefit in treating myopia (e.g., high myopia), can be deter Subject microsphere comprises from about 1 ng to about 10 mined using an animal myopia model. For a chick model of mg of an active agent, e.g., a muscarinic antagonist (and myopia, see, e.g., Lawrence and AZar (2002)Ophthalmol. optionally one or more additional active agents). Clin. North Am. 14:127; and Schmid and Wildsoet (1997) 60 In some embodiments, multiple doses of a muscarinic Ophthalmol. Physiol. Opt. 17:61. For a guinea pig model of antagonist-containing hydrogel are administered. The fre myopia, see, e.g., McFadden et al. (2004) Vision Res. 44.643. quency of administration of a muscarinic antagonist-contain Pharmaceutical Formulations ing hydrogel can vary depending on any of a variety of fac A muscarinic antagonist-containing hydrogel can be for tors, e.g., severity of the symptoms, etc. For example, in some mulated with one or more pharmaceutically acceptable 65 embodiments, a muscarinic antagonist-containing hydrogel excipients. A wide variety of pharmaceutically acceptable is administered once a year, once every six months, once excipients are known in the art and need not be discussed in every three months, once every two months, once per month, US 8,883,214 B2 13 14 twice per month, three times per month, every other week at the posterior pole of the eye; Group 2) PNIPAAm-co-AAC (qow), once per week (qw), or twice per week (biw). hydrogel/saline (no atropine) treatment by injection of the A muscarinic antagonist-containing hydrogel composition PNIPA Am-co-AAC hydrogel/saline into the posterior pole of is administered to an individual typically using a localized the eye; and Group 3) daily atropine eye drops (directly onto route of administration (e.g., intra-ocular administration or 5 the lens). There were six animals in each group. As a control, peri-ocular administration, etc., via injection). Administra the fellow eye of the treated was left untreated in each animal. tion can be acute (e.g., of short duration, e.g., a single admin Ocular dimensions data of treated and untreated (control) istration, administration for one day to one week), or chronic eyes were obtained over 21 days following treatment. The (e.g., of long duration, e.g., administration for longer than one data are depicted in FIGS. 3-9. week, e.g., administration over a period of time of from about 10 H-S(T): hydrogel with saline (treated eye): H-S(C): 2 weeks to about one month, from about one month to about untreated fellow eye; 3 months, from about 3 months to about 6 months, from about H-A(T): hydrogel with atropine (treated eye); H-A(C): 6 months to about 1 year, or longer than one year). untreated fellow eye; Subjects Suitable for Treatment AO(T): atropine eye drop daily (treated eye); AO(C): Individuals in need of treatment with a subject method 15 untreated fellow eye. include individuals with myopia; individuals who have been While the present invention has been described with refer treated for myopia; and individuals who have never been ence to the specific embodiments thereof, it should be under treated for myopia. “Myopia' includes simple myopia; stood by those skilled in the art that various changes may be degenerative myopia (e.g., malignant, pathological, or pro made and equivalents may be substituted without departing gressive myopia); and induced or acquired myopia. Myopia from the true spirit and scope of the invention. In addition, includes, low myopia (myopia of between Zero and -3.00 many modifications may be made to adapt a particular situa diopters); medium myopia (myopia myopia of between -3.00 tion, material, composition of matter, process, process step or and -6.00 diopters); and high myopia (myopia of -6.00 diopt steps, to the objective, spirit and scope of the present inven ers or less, e.g., s-6.00 diopters, e.g., from -6.00 diopters to tion. All such modifications are intended to be within the -7.00 diopters, from -7.00 diopters to -8.00 diopters, from 25 Scope of the claims appended hereto. -8.00 diopters to -10.00 diopters, or less than -10.00 diopt ers). In some embodiments, the individual has degenerative What is claimed is: myopia. In some embodiments, the individual has high myo 1. A method of treating high myopia in an individual hav pia. In some embodiments, a Subject method is suitable for ing high myopia, the method comprising administering to the treating high myopia progression. In some embodiments, the 30 individual an effective amount of a muscarinic antagonist individual has, in addition to myopia, glaucoma. In some containing biodegradable hydrogel, wherein the hydrogel is embodiments, the individual has, in addition to myopia, cata selected from the groups consisting of a bifunctional block racts. In some embodiments, the individual has, in addition to copolymer of poly(ethylene oxide) (PEO) and poly(propy myopia, retinal detachment. In some embodiments, the indi lene oxide) (PPO), a poly(N-isopropylacrylamide)-based vidual has, in addition to myopia, macular degeneration. 35 hydrogel, or a poly(N-isopropylacrylamide)-acrylic acid copolymer, and poly(2-hydroxyethylene methacrylate), EXAMPLES wherein the muscarinic antagonist-containing hydrogel is administered by intraorbital injection. The following examples are put forth so as to provide those 2. The method of claim 1, wherein the hydrogel is a bifunc of ordinary skill in the art with a complete disclosure and 40 tional block copolymer of PEO and PPO. description of how to make and use the present invention, and 3. The method of claim 1, wherein the hydrogel is a poly are not intended to limit the scope of what the inventors regard (N-isopropylacrylamide)-based hydrogel. as their invention nor are they intended to represent that the 4. The method of claim 3, wherein the hydrogel is a poly experiments below are all or the only experiments performed. (N-isopropylacrylamide)-acrylic acid copolymer. Efforts have been made to ensure accuracy with respect to 45 5. The method of claim 1, wherein the hydrogel is com numbers used (e.g. amounts, temperature, etc.) but some prises poly(2-hydroxyethylene methacrylate). experimental errors and deviations should be accounted for. 6. The method of claim 1, wherein the hydrogel comprises Unless indicated otherwise, parts are parts by weight, poly(vinyl pyrrolidone). molecular weight is weight average molecular weight, tem 7. The method of claim 1, wherein the muscarinic antago perature is in degrees Celsius, and pressure is at or near 50 nist is encapsulated in a nanoparticle or a microparticle. atmospheric. Standard abbreviations may be used, e.g., bp. 8. The method of claim 7, wherein the nanoparticle com base pair(s): kb, kilobase(s); pl. picoliter(s); S or sec, second prises a hydrophobic polymer and a hydrophilic polymer, (s); min, minute(s); h or hr, hour(s); aa, amino acid(s): kb, wherein the hydrophobic polymer forms a hydrophobic core. kilobase(s); bp, base pair(s); nt, nucleotide(s); i.m., intramus 9. The method of claim8, wherein the hydrophilic polymer cular(ly); i.p., intraperitoneal(ly); s.c., Subcutaneous(ly); and 55 is a poly(ethylene glycol) polymer. the like. 10. The method of claim 8, wherein the hydrophobic poly mer is poly(L-lactide). Example 1 11. The method of claim 7, wherein the muscarinic antago nist is not linked to a nanoparticle polymer. Implantation of a Biodegradable Hydrogel Matrix 60 12. The method of claim 1, wherein the hydrogel comprises for Ocular Delivery of Atropine poly(N-isopropylacrylamide-co-acrylic acid). 13. The method of claim 1, wherein the muscarinic antago Atropine was included in a poly(N-isopropylacrylamide)/ nist is atropine. acrylic acid co-polymer (PNIPA Am-co-AAC) hydrogel. A 14. The method of claim 1, wherein the muscarinic antago chick model was used to compare: Group 1) PNIPA Am-co 65 nist is pirenzepine. AAC hydrogel/atropine treatment by injection of the 15. The method of claim 1, wherein the muscarinic antago PNIPA Am-co-AAC hydrogel/atropine adjacent to the sclera nist is a combination of atropine and Scopolamine. US 8,883,214 B2 15 16 16. The method of claim 1, wherein the muscarinic antago nist is a 1-cycloalkylpiperidin-4-yl-2H benzimidazolone. 17. The method of claim 1, wherein the muscarinic antago nist is telenzepine. 18. The method of claim 1, wherein the muscarinic antago nist-containing hydrogel is administered via intraorbital injection at the posterior pole. 19. The method of claim 1, wherein the muscarinic antago nist-containing hydrogel is administered via Sub-Tenon's injection at the posterior pole. 10 20. The method of claim 1, wherein the individual is a human.