(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`22 July 2010 (22.07.2010) (10) International Publication Number
`
`(43) International Publication Date
`
`WO 2010/083129 AZ
`
`
`G1)
`
`International Patent Classification:
`A61F 9/013 (2006.01)
`A61L 27/54 (2006.01)
`AGIF 2/14 (2006.01)
`A6IK 9/48 (2006.01)
`AGILE 27/52 (2006.01)
`
`2)
`
`International Application Number:
`PCT/US2010/020644
`
`(74)
`
`(22)
`
`International Filing Date:
`
`11 January 2010 (11.01.2010)
`
`(81)
`
`(25)
`
`(26)
`
`(30)
`
`(71)
`
`Filing Language:
`
`Publication Language:
`
`English
`
`English
`
`Priority Data:
`61/144,372
`
`13 January 2009 (13.01.2009)
`
`US
`
`Applicant (for all designated States except US): THE
`REGENTS OF THE UNIVERSITY OF CALIFOR-
`NIA [US/US]; 1111 Franklin Street, 12th Floor, Oakland,
`California 94607-5200 (US).
`
`fomia 94703 (US). WILDSOET,Christine F. [AU/US];
`2828 1/2 Cherry St., Berkeley, California 94705 (US).
`HEALY, Kevin, E.
`[US/US]; 3841 Moraga Avenue,
`Moraga, California 94556 (US).
`
`Agent: BORDEN,Paula A.; Bozicevic, Field & Francis
`LLP, 1900 University Avenue, Suite 200, East Palo Alto,
`California 94303 (US).
`
`Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU, ID,IL, IN, IS, JP, KE, KG, KM,KN,KP,
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
`MR, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI,
`NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(72)
`(75)
`
`Inventors; and
`James
`SU,
`only):
`(or US
`Inventors/Applicants
`[US/US]; 2132 Roosevelt Avenue, Apt. 5, Berkeley, Cali-
`
`(84)
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`
`(54) Title: IMPLANTABLE DELIVERY VEHICLE FOR OCULAR DELIVERY OF MUSCARINIC ANTAGONISTS
`
`[Continued on next page]
`
`nen SLT)
`1=--O--~ H-SIC)
`a8 H-A(T)
`one-DF== HACC)
`— + = ALT)
`ocrBrome ACHES
`
`O0B—_
`
`(57) Abstract: The present invention provides composi-
`tions and methods for treating ocular disorders such as
`myopia.
`
`
`
`
`
`RetinalThickness(mim)
`
`
`
`0.23
`
`* Ss
`
`5
`
`%
`
`Dy,
`
`a
`
`J
`i
`
`oo a
`
`~ ~ we a
`
`e ” ”
`
`_
`
`0.22
`
`0.24
`
`0.2
`
`0.19
`
`6
`
`5
`
`——
`40
`
`-
`45
`
`-
`
`20
`
`25
`
`Days
`
`FIG. 6
`
`
`
`
`
`WoO2010/083129A2THIMIMIMNIINANTIRINGANTINTTANAANA
`
`

`

`WO 2010/083129 A2 IfMMNN TINT TNT NEIMAN TAT IE ATA AA TAA
`
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, Published:
`TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
`—_without international search report and to be republished
`ES, FL, FR, GB, GR, HR, HU,IE, IS, IT, LT, LU, LV,
`upon receipt of that report (Rule 48.2(g))
`MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM,
`TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
`ML, MR, NE, SN, TD, TG).
`
`

`

`WO 2010/083129
`
`PCT/US2010/020644
`
`IMPLANTABLE DELIVERY VEHICLE FOR OCULAR DELIVERY OF MUSCARINIC ANTAGONISTS
`
`[0001]
`
`This application claims the benefit of U.S. Provisional Patent Application No.
`
`61/144,372, filed January 13, 2009, which application is incorporated herein by reference in its
`
`CROSS-REFERENCE
`
`entirety.
`
`STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH
`
`[0002]
`
`‘This invention was made with government support under Grant No. RO] EY12392
`
`awarded by the National Institutes of Health. The governmenthas certain rights in the
`
`invention.
`
`[0003]
`
`Degenerative myopia is a significant cause of world blindness and visual disability.
`
`BACKGROUND
`
`Degenerative myopia is a major cause of legal blindness in the United States. Overall,
`
`blindness most commonly occurs from myopic macular degeneration, retinal detachment,
`
`cataract and glaucoma, and of these, myopic macular degeneration is the most important.
`
`Degenerative myopia is thought to be due to decompensation of the nerve and supporting
`
`tissues of the part of the retina of the eye, the macular, which is used for fine vision. One cause
`
`of the damagc is the axial overgrowth of the cye during the regular growth phasc, followed by
`
`further increments of stretching during the adult years. By middle age, stressed eye tissues
`
`begin to show degeneration and failure of function; crucially, this includes the delicate nerves
`
`of the retina.
`
`[0004]
`
`Current treatments for high myopia progression include topical daily drops of
`
`muscarinic antagonists.
`
`Literature
`
`[0005]
`
`U.S. Patent Publication No. 2006/0188576; Su et al. (2009) Exp. Eye Res. 88:445.
`
`[0006]
`
`The present invention provides compositions and methods for treating ocular disorders
`
`SUMMARY OF THE INVENTION
`
`such as myopia.
`
`

`

`WO 2010/083129
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`PCT/US2010/020644
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`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0007]
`
`Figure 1 depicts an exemplary embodimentof delivery of a muscarinic antagonist in a
`
`biodegradable hydrogel matrix through the posterior sclera.
`
`[0008]
`
`Figure 2 depicts schematically the release of the muscarinic antagonist atropine at the
`
`sub-Tenon’s capsule.
`
`[0009]
`
`Figure 3 depicts anterior chamber depth over 21 days following implantation into the
`
`posterior sclera of atropine in a biodegradable hydrogel matrix.
`
`[0010]
`
`Figure 4 depicts lens thickness over 21 days following implantation into the posterior
`
`sclera of atropine in a biodegradable hydrogel matrix.
`
`[0011]
`
`Figure 5 depicts vitreous chamber depth over 21 days following implantation into the
`
`posterior sclera of atropine in a biodegradable hydrogel matrix.
`
`[0012]
`
`Figure 6 depicts retinal thickness over 21 days following implantation into the posterior
`
`sclera of atropine in a biodegradable hydrogel matrix.
`
`[0013]
`
`Figure 7 depicts choroidal thickness over 21 days following implantation into the
`
`posterior sclera of atropine in a biodegradable hydrogel matrix.
`
`[0014]
`
`Figure 8 depicts scleral thickness over 21 days following implantation into the posterior
`
`sclera of atropine in a biodegradable hydrogel matrix.
`
`[0015]
`
`Figure 9 depicts axial length over 21 days following implantation into the posterior
`
`sclera of atropine in a biodegradable hydrogel matrix.
`
`DEFINITIONS
`
`[0016]
`
`As used herein, the term "copolymer" describes a polymer which contains more than
`
`one type of subunit. The term encompasses polymer which include two, three, four, five, or six
`
`types of subunits.
`
`[0017]
`
`The terms "subject," “individual,” “host,” and "patient" are used interchangeably herein
`
`to a member or members of any mammalian or non-mammalian species. Subjects and patients
`
`thus include, without limitation, humans, non-humanprimates, canines, felines, ungulates(e.g.,
`
`equine, bovine, swine(e.g., pig)), avians, rodents (e.g., rats, mice), and other subjects. Non-
`
`human animal models, particularly mammals, e.g. a non-human primate, a murine (e.g., a
`
`mouse, a rat), lagomorpha, etc. may be used for experimental investigations.
`
`[0018]
`
`Treating" or "treatment" of a condition or disease includes: (1) preventing at least one
`
`symptom of the condition, i.e., causing a clinical symptom to not significantly develop in a
`
`mammal that may be exposed to or predisposed to the disease but does not yet experience or
`
`display symptomsofthe disease, (2) inhibiting the disease, i.e., arresting or reducing the
`
`2
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`

`

`WO 2010/083129
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`PCT/US2010/020644
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`development of the disease or its symptoms, or (3) relieving the disease, i.e., causing
`
`regression of the disease or its clinical symptoms.
`
`[0019]
`
`A "therapeutically effective amount" or "efficacious amount” means the amount of a
`
`compoundthat, when administered to a mammal or other subject for treating a disease, is
`
`sufficient, in combination with another agent, or alone in one or more doses, to effect such
`
`treatmentfor the disease. The "therapeutically effective amount" will vary depending on the
`
`compound, the disease and its severity and the age, weight, etc., of the subject to be treated.
`
`[0020]
`
`The term “unit dosage form,” as used herein, refers to physically discrete units suitable
`
`as unitary dosages for human and animal subjects, cach unit containing a predetermined
`
`quantity of compoundsof the present invention calculated in an amountsufficient to produce
`
`the desired effect in association with a pharmaceutically acceptable diluent, carrier or vehicle.
`
`The specifications for the unit dosage forms depend on the particular compound employed and
`
`the effect to be achieved, and the pharmacodynamics associated with each compoundin the
`
`host.
`
`[0021]
`
`The term “physiological conditions” is meant to encompass those conditions
`
`compatible with living cells, e.g., predominantly aqueous conditions of a temperature, pH,
`
`salinity, etc. that are compatible with living cells.
`
`wo
`
`[0022]
`
`A "pharmaceutically acceptable excipient,"
`
`"pharmaceutically acceptable diluent,"
`
`"pharmaceutically acceptable carrier,” and "pharmaceutically acceptable adjuvant" means an
`
`excipient, diluent, carricr, and adjuvantthat are uscful in preparing a pharmaccutical
`
`composition that are generally safe, non-toxic and neither biologically nor otherwise
`
`undesirable, and include an excipient, diluent, carrier, and adjuvant that are acceptable for
`
`veterinary use as well as human pharmaceutical use. "A pharmaceutically acceptable excipient,
`
`diluent, carrier and adjuvant"as used in the specification and claims includes one and more
`
`than one such excipient, diluent, carrier, and adjuvant.
`
`[0023]
`
`Before the present invention is further described,it is to be understood that this
`
`invention is not limited to particular embodiments described, as such may,of course, vary. It
`
`is also to be understoodthat the terminology used herein is for the purpose of describing
`
`particular embodiments only, and is not intended to be limiting, since the scope of the present
`
`invention will be limited only by the appended claims.
`
`[0024]
`
`Where a range of values is provided, it is understood that each intervening value, to the
`
`tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the
`
`upper and lowerlimit of that range and any otherstated or intervening value in that stated
`
`range, is encompassed within the invention. The upper and lowerlimits of these smaller
`
`3
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`

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`WO 2010/083129
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`PCT/US2010/020644
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`ranges may independently be included in the smaller ranges, and are also encompassed within
`
`the invention, subject to any specifically excludedlimit in the stated range. Where the stated
`
`range includes one or both of the limits, ranges excluding either or both of those included
`
`limits are also included in the invention.
`
`[0025]
`
`Unless defined otherwise, all technical and scientific terms used herein have the same
`
`meaning as commonly understood by oneof ordinary skill in the art to which this invention
`
`belongs. Although any methods and materials similar or equivalent to those described herein
`
`can also be used in the practice or testing of the present invention, the preferred methods and
`
`materials are now described. All publications mentioned herein are incorporated herein by
`
`reference to disclose and describe the methods and/or materials in connection with which the
`
`publicationsare cited.
`
`[0026]
`
`It must be noted that as used herein and in the appended claims, the singular forms“a,”
`
`“an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for
`
`example,reference to “‘a hydrogel”includes a plurality of such hydrogels and reference to “the
`
`muscarinic antagonist” includes reference to one or more muscarinic antagonists and
`
`equivalents thereof knownto those skilled in the art, and so forth. It is further noted that the
`
`claims may bedrafted to exclude any optional element. As such, this statement is intended to
`99 66
`
`serve as antecedent basis for use of such exclusive terminologyas “solely,”
`
`“only” and the like
`
`in connection with the recitation of claim elements, or use of a “negative” limitation.
`
`[0027]
`
`‘The publications discussed hercin are provided solely for their disclosure prior to the
`
`filing date of the present application. Nothing herein is to be construed as an admission that
`
`the present invention is not entitled to antedate such publication by virtue of prior invention.
`
`Further, the dates of publication provided may be different from the actual publication dates
`
`which may need to be independently confirmed.
`
`DETAILED DESCRIPTION
`
`[0028]
`
`The present disclosure provides compositions and methods for treating ocular disorders
`
`such as myopia. The present disclosure provides a biodegradable hydrogel comprising a
`
`muscarinic antagonist. The present disclosure provides methods of treating ocular disorders
`
`such as myopia, the method generally involving implanting into an individual in need thereof
`
`an effective amountof a subject biodegradable hydrogel, where the biodegradable hydrogelis
`
`implanted into or aroundthe eye.
`
`

`

`WO 2010/083129
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`PCT/US2010/020644
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`BIODEGRADABLE HYDROGELS
`
`[0029]
`
`The present disclosure provides a biodegradable hydrogel comprising a muscarinic
`
`antagonist. A subject muscarinic antagonist-biodegradable hydrogel composition includes a
`
`muscarinic antagonist distributed within a biodegradable hydrogel. The muscarinic antagonist
`
`is in some embodiments not covalently linked to the hydrogel. In other embodiments, the
`
`muscarinic antagonist is covalently linked to a moiety within the hydrogel.
`
`Muscarinic antagonists
`
`[0030]
`
`The present invention provides a biodegradable hydrogel comprising a muscarinic
`
`antagonist, and use of samefor treating an ocular disorder. Muscarinic antagonists suitable for
`
`use in a subject composition and/or in a subject method include, but are not limited to,
`
`atropine; scopolamine; a muscarinic antagonist as disclosed in WO 97/16187; a 3-dihydro-1-
`
`{1-[piperidin-4- yl] piperidin-4-yl}-2H-benzimidazol-2-one as described in U.S. Patent No.
`
`5,691,323; a 1, 3-dihydro-1-{4-amino-1-cyclohexyl}-2H- benzimidazol-2-one as described in
`
`U.S. Patent No. 5,691,323; a 1- [cycloalkylpiperidin-4-yl]-2IT benzimidazolone as described in
`
`U.S. Patent No. 5,718,912; a tricyclic compoundas described in U.S. Patent No. 5,461,052;
`
`pirenzepine (5,11-Dihydro-11-[4-methyl-1-piperaziny])acetyl]-6H-pyrido[2,3-b][1,4]benzo
`
`diazepin-6-one) or its dihydrochloride; telenzepine: 4,9-dihydro-3-methy]-4[(4-methyl-
`
`(1)piperazine)acetyl]1OH-thieno-[3,4 -b][1,5 ]-benzodiazepin-10-one, or its dihydrochloride; a
`
`1,3-dihydro-1-[1-(1 -heteroarylpiperidin-4-yl)piperidin-4-yl]-2H-benzimidazolone as described
`
`in U.S. Patent No. 5,756,508; a benzimidazolidin-2-one derivatives 1-substituted with a 4-
`
`piperidinyl moiety which in turn is 1-substituted, as described in WO 96/13262; a muscarinic
`
`Mzantagonist (e.g., imipramine, amitriptyline, nortriptyline, desipramine, 10-
`
`hydroxynortriptyline, and the like); himbacine ((3aR,4R,4aS,8aR,9aS)-4- { (E)-[(2R,6S)-1,6-
`
`dimethylpiperidin-2-yl]viny]} -3-methyldecahydronaphtho[2,3-c]furan-1(3A)-one) and
`
`himbacine analogs (see, e.g., WO 2005/118576; and WO 2006/076564); homatropine ((V,N-
`
`dimethy1-8-azoniabicyclo[3.2. 1]oct-3-yl) 2-hydroxy-2-phenyl-acetate bromide); tropicamide
`
`(N-ethyl-3-hydroxy-2-phenyl-N- (pyridin-4-ylmethyl) propanamide); oxyphenonium (2-(2-
`
`Cyclohexyl-2-hydroxy-2-phenylacetoxy)-N, N-diethyl-N-methylethanaminium); oxyphenonium
`
`bromide; dexetimide (3-(1-benzyl-4-piperidyl)-3-phenyl-piperidine-2,6-dione); benztropine
`
`((3-endo)-3-(diphenylmethoxy)-8-methyl-8-azabicyclo[3.2.1]octane); benztropine mesylate; 4-
`
`diphenyl-acetoxy-N-methyl-piperidine (4-DAMP); Hexahydro-sila-difenidol (HHSiD); 2-
`
`Methylimidazol-1-yl-substituted analogs of HHSiD; p-fluoro-HHSiD; AF-DX 116 ([11-([2-
`
`[(diethylamino)methyl1]-1-piperdinylJacetyl)-5, 11- dihydro-6H-pyrido[2,3-b][1,4]benzodiaze
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`

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`WO 2010/083129
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`PCT/US2010/020644
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`pine-6-one]); QNB (3-quinuclidinyl benzylate; 1-azabicyclo[2.2.2 Joct-3-yl
`
`hydroxy(diphenyl)acetate); and the like.
`
`[0031]
`
`Representative muscarinic antagonists include, but are not limited to, atropine, atropine
`
`sulfate, atropine oxide, methylatropine nitrate, homatropine hydrobromide, hyoscyamine (d,1)
`
`hydrobromide, scopolamine hydrobromide, ipratropium bromide, oxitropium bromide,
`
`tiotropium bromide, methantheline, propantheline bromide, anisotropine methyl bromide,
`
`clidinium bromide, copyrrolate (Robinul), isopropamide iodide, mepenzolate bromide,
`
`tridihexethy! chloride (Pathilone), hexocyclium methylsulfate, cyclopentolate hydrochloride,
`
`tropicamide, trihexyphenidyl hydrochloride, pirenzepine, telenzepine, AF-DX 116, and
`
`methoctramine.
`
`[0032]
`
`Combinations of two or more of the aforementioned muscarinic antagonist can be
`
`included in a biodegradable hydrogel matrix. For example, in some embodiments, a subject
`
`biodegradable hydrogel matrix comprises both atropine and scopolamine. As another example,
`
`in some embodiments, a subject biodegradable hydrogel matrix comprises both atropine and
`
`tropicamide. As another example, in some embodiments, a subject biodegradable hydrogel
`
`matrix comprises both atropine and pirenzapine. As another example, in some embodiments, a
`
`subject biodegradable hydrogel matrix comprises both pirenzapine andtropicamide.
`
`[0033]
`
`In some embodiments, a subject biodegradable hydrogel matrix comprises two
`
`muscarinic antagonists of different selectivities, e.g., two muscarinic antagonists selected from
`
`a nonsclective muscarinic antagonist, an M1 muscarinic antagonist, an M2 muscarinic
`
`antagonist, an M3 muscarinic antagonist, an M4 muscarinic antagonist, and an M5 muscarinic
`
`antagonist. For example, in some embodiments, a subject biodegradable hydrogel matrix
`
`comprises both a nonselective muscarinic antagonist and an M1 muscarinic antagonist. For
`
`example, in some embodiments, a subject biodegradable hydrogel matrix comprises both an
`
`M1 and an M2 muscarinic antagonist. As another example, in some embodiments, a subject
`
`biodegradable hydrogel matrix comprises both pirenzipine (M1) and QNB (M2). As another
`
`example, in some embodiments, a subject biodegradable hydrogel matrix comprises both
`
`atropine (nonselective) and 4-DAMP (M3, M4, MS). As another example, in some
`
`embodiments, a subject biodegradable hydrogel matrix comprises both HHSid (M3) and AP-
`
`DX 116 (M2).
`
`[0034]
`
`In some embodiments, a biodegradable hydrogel comprising a muscarinic antagonist
`
`(“a muscarinic antagonist-containing hydrogel’’) includes only one therapeutic agent, 1.e., a
`
`single muscarinic antagonist. In other embodiments, a muscarinic antagonist-containing
`
`hydrogel comprises two or more different muscarinic antagonists. In other embodiments, a
`
`6
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`

`

`WO 2010/083129
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`muscarinic antagonist-containing hydrogel comprises, in addition to a single muscarinic
`
`antagonist or two or more different muscarinic antagonists, one or more additional therapeutic
`
`agents (“active agents’’). A non-limiting example of a suitable additional therapeutic agentis 7-
`
`methylxanthine. Further non-limiting examples of suitable additional therapeutic agents
`
`include retinoic acid analogs.
`
`Biodegradable hydrogels
`
`[0035]
`
`The present disclosure provides a biodegradable hydrogel comprising a muscarinic
`
`antagonist. A suitable hydrogel is a polymer of two or more monomers, e.g., a homopolymeror
`
`a hetcropolymer comprising multiple monomers. Suitable hydrogel monomers include the
`
`following: lactic acid, glycolic acid, acrylic acid, 1-hydroxyethyl methacrylate GHEMA), ethyl
`
`methacrylate (EMA), propylene glycol methacrylate (PEMA), acrylamide (AAM), N-
`
`vinylpyrrolidone, methyl methacrylate (MMA), glycidyl methacrylate (GDMA), glycol
`
`methacrylate (GMA), ethylene glycol, fumaric acid, and the like. Commoncross linking agents
`
`include tetraethylene glycol dimethacrylate (TEGDMA)and N,N'-methylenebisacrylamide.
`
`The hydrogel can be homopolymeric, or can comprise co-polymers of two or moreof the
`
`aforementioned polymers.
`
`[0036]
`
`Exemplary hydrogels include, but are not limited to, a copolymerof poly(ethylene
`
`oxide) (PEO) and poly(propylene oxide) (PPO); Pluronic™ F-127 (a difunctional block
`
`copolymer of PEO and PPO of the nominal formula FOi90-PO¢6s-EOio0, where EO is ethylene
`
`oxide and PO is propylene oxide); poloxamer 407 (a tri-block copolymerconsisting of a
`
`central block of poly(propylene glycol) flanked by two hydrophilic blocks of poly(ethylene
`
`glycol)); a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) co-polymer with a
`
`nominal molecular weight of 12,500 Daltons and a PEO:PPOratio of 2:1); a poly(W-
`
`tsopropylacrylamide)-base hydrogel (a PNIPAAm-based hydrogel); a PNIPAAm-acrylic acid
`
`co-polymer (PNIPAAm-co-AAc); poly(2-hydroxyethyl methacrylate); poly(vinyl pyrrolidone);
`
`and the like.
`
`[0037]
`
`In some embodiments, the hydrogel is a temperature-sensitive hydrogel. In some
`
`embodiments, a temperature-sensitive hydrogel is a polyacrylic acid or derivative thereof,e.g.,
`
`poly (N-isopropylacrylamide) gel, and the increase in temperature causes the hydrogel to
`
`contract, thereby forcing the active agent out of the hydrogel. Alternatively, the temperature-
`
`sensitive hydrogel is an interpenetrating hydrogel network of poly(acrylamide) and
`
`poly(acrylic acid), and the increase in temperature causes the hydrogel to swell, thereby
`
`allowing the active agent to diffuse out of the gel. The temperature required for triggering
`
`

`

`WO 2010/083129
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`PCT/US2010/020644
`
`release of an active agent from the hydrogel is generally about normal body temperature,e.g.,
`
`about 37°C.
`
`[0038]
`
`As noted above, in some embodiments, the hydrogel comprises a muscarinic antagonist
`
`linked to one or more moieties in the hydrogel, or embedded in the hydrogel. In some
`
`embodiments, the muscarinic antagonist is a hydrophilic compound.
`
`[0039]
`
`The hydrogel can be modified with one or more proteolytically cleavable crosslinks.
`
`See, e.g., Kim and Healy (2003) Biomacromolecules 4:1214. One or more of the hydrogel
`
`polymers can be modified with a cell-binding moiety, e.g., a moiety that provides for binding
`
`to a cell-surface receptor. For example, a ccll-binding moicty can include an Arg-Gly-Asp
`
`(RGD) peptide.
`
`Nanoparticles or microparticles distributed within a hydrogel
`
`[0040]
`
`In some embodiments, a muscarinic antagonist is encapsulated within a nanoparticle or
`
`microparticle, and the muscarinic antagonist-containing nanoparticle or microparticle is
`
`distributed within a hydrogel. Thus, in some embodiments, a muscarinic antagonistis
`
`contained within a biodegradable microsphere, where a biodegradable microsphere comprises:
`
`a) a nanoparticle or a microparticle comprising one or more muscarinic antagonists; and b) a
`
`hydrogel matrix that forms an outer layer surrounding the nanoparticle or microparticle. The
`
`nanoparticle (or microparticle) can comprise an inner core comprising: 1) a hydrophobic
`
`polymer;i1) a hydrophilic polymer linked to the hydrophobic polymer, where the hydrophobic
`
`polymer and the hydrophilic polymers together form a nanoparticle or microparticle, where the
`
`hydrophobic polymer forms an inner layer of the nanoparticle or microparticle, and the
`
`hydrophilic polymer forms an outer layer of the nanoparticle or microparticle. In some
`
`embodiments, the microsphere further comprises one or more additional therapeutic agents
`
`(“active agents’’).
`
`[0041]
`
`A muscarinic antagonist can be present within the hydrophobic core of the nanoparticle
`
`or microparticle. In some embodiments, a muscarinic antagonist is present only within the
`
`hydrophobic core, e.g., within the space created by the hydrophobic polymer. In some
`
`embodiments, a muscarinic antagonist is present within the hydrophobic core, and the
`
`muscarinic antagonist not linked to any moiety of the nanoparticle or microparticle. In other
`
`embodiments, a muscarinic antagonist is present within the hydrophobic core, and the
`
`muscarinic antagonist is linked to one or more moieties present in the hydrophobic core, e.g.,
`
`the muscarinic antagonistis linked to a poly-L-lactide polymer. In other embodiments, the
`
`muscarinic antagonist is linked to the hydrophilic polymer, e.g., in some embodiments, the
`
`muscarinic antagonist is linked to a poly(ethylene glycol) (PEG)(e.g., the muscarinic
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`antagonist is linked to a reactive group present on derivatized PEG; e.g., the muscarinic
`
`antagonist is linked to an amine group present on derivatized PEG).
`
`[0042]
`
`In some embodiments, a muscarinic antagonist is present within the hydrophobic core;
`
`and a second active agent is linked to the hydrophilic polymer. For example, where a
`
`muscarinic antagonist is present within the hydrophobic core, and a second active agentis
`
`linked to the hydrophilic polymer, the second active agent is hydrophilic. In other
`
`embodiments, a second active agent is present within the hydrophobic core; and a muscarinic
`
`antagonist is linked to the hydrophilic polymer. or example, where a second active agentis
`
`present within the hydrophobic core, and a muscarinic antagonistis linked to the hydrophilic
`
`polymer, the muscarinic antagonist is hydrophilic.
`
`[0043]
`
`In some embodiments, a subject microsphere comprises a muscarinic antagonist and a
`
`second active agent, where the muscarinic antagonist is associated with or linked to the
`
`nanoparticle or microparticle (e.g., the muscarinic antagonist is present within the hydrophobic
`
`core, either free within the hydrophobic core, or linked to a hydrophobic polymer in the
`
`hydrophobic core, or is linked to a hydrophilic polymer in the nanoparticle or microparticle);
`
`and the second agentis linked to or associated with the hydrogel. In some of these
`
`embodiments, the muscarinic antagonist is hydrophobic and the second active agentis
`
`hydrophilic. Where a subject microsphere comprises a muscarinic antagonist and a second
`
`active agent, where the muscarinic antagonist is associated with or linked to the nanoparticle
`
`(or microparticle) and where the second active agent is associated with or linked to the
`
`hydrogel, a two-stage release profile is provided where the muscarinic antagonist is released
`
`from the hydrogel at a first rate and over a first time period, and the second active agentis
`
`released from the nanoparticle (or microparticle) at a second rate and over a second time
`
`period.
`
`Nanoparticle and microparticle polymers
`
`[0044]
`
`As noted above, in some embodiments, a subject biodegradable microsphere comprises:
`
`a) a nanoparticle or a microparticle comprising one or more muscarinic antagonists; and b) a
`
`hydrogel matrix that forms an outer layer surrounding the nanoparticle or microparticle. The
`
`nanoparticle or microparticle can have an average diameter of from about 1 nmto about 900
`
`um, e.g., the nanoparticle can have an average diameter of from about 1 nm to about 5 nm,
`
`from about 5 nm to about 25 nm, from about 25 nm to about 50 nm, from about 50 nm to about
`
`75 nm, from about 75 nm to about 100 nm, from about 100 nm to about 200 nm, from about
`
`200 nm to about 300 nm, from about 300 nm to about 400 nm, from about 400 nm to about 500
`
`nm, from about 500 nm to about 600 nm, from about 600 nm to about 700 nm, from about 700
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`nm to about 800 nm, from about 800 nm to about 900 nm, from about 900 nm to about 1 pum,
`
`from about 1 tmto about 10 tm, from about 10 tumto about 25 um, from about 25 jumto
`
`about 50 um, from about 50 um to about 75 um, from about 75 um to about 100 um, from
`
`about 100 um to about 200 um, from about 200 um to about 300 um, from about 300 pm to
`
`about 400 tum, from about 400 um to about 500 um, from about 500 um to about 600 um, from
`
`about 600 pm to about 700 um, from about 700 um to about 800 um, or from about 800 um to
`
`about 900 jum.
`
`[0045]
`
`The nanoparticle or microparticle comprises a hydrophobic polymer and a hydrophilic
`
`polymer. Suitable hydrophobic and hydrophilic polymers include biocompatible polymers
`
`comprising from about 50 to about 100,000 subunits, e.g., from about 50 subunits to about 100
`
`subunits, from about 100 subunits to about 500 subunits, from about 500 subunits to about
`
`1,000 subunits, from about 1,000 subunits to about 5,000 subunits, from about 5,000 subunits
`
`to about 10,000 subunits, from about 10,000 subunits to about 25,000 subunits, from about
`
`25,000 subunits to about 50,000 subunits, or from about 50,000 subunits to about 100,000
`
`subunits. In some embodiments, the linear polymer comprises more than 100,000 subunits.
`
`[0046]
`
`The subunits can all be identical, e.g., the polymer is a homopolymer.In other
`
`embodiments, more than one species of subunit is present, e.g., the polymer is a heteropolymer
`
`or co-polymer, In some embodiments, the polymeris a linear polymer. In other embodiments,
`
`the polymer may include one or more branches.
`
`[0047]
`
`Suitable polymers include natural polymers, semisynthctic polymers, and synthctic
`
`polymers. Suitable synthetic polymers include, but are not limited to, polymers or copolymers
`
`derived from polydioxane, polyphosphazene, polysulphoneresins, poly(acrylic acid),
`
`poly(acrylic acid) butyl ester, poly(ethylene glycol), poly(propylene), polyurethaneresins,
`
`poly(methacrylic acid), poly(methacrylic acid)-methyl ester, poly(methacrylic acid)-n butyl
`
`ester, poly(methacrylic acid)-t butyl ester, polytetrafluoroethylene, polyperfluoropropylene,
`
`poly N-vinyl carbazole, poly(methy] isopropenyl ketone), poly alphamethy] styrene,
`
`polyvinylacetate, poly(oxymethylene), poly(ethylene-co-viny] acetate), a polyurethane, a
`
`poly(vinyl alcohol), and polyethylene terephthalate; ethylene vinyl alcohol copolymer
`
`(commonly known by the generic name EVOHorbythe trade name EVAL);
`
`polybutylmethacrylate; poly(hydroxyvalerate); poly(L-lactic acid) or poly(L-lactide); poly(e-
`
`caprolactone); poly(actide-co-glycolide); poly(hydroxybutyrate); poly(hydroxybutyrate-co-
`
`valerate); polydioxanone; polyorthoester; polyanhydride; poly(glycolic acid) (PGA); poly(D,L-
`
`lactide) (PDLL); poly(L-Lactide)(PLL); copolymers of PGA, PDLA, and/or PLA;
`
`poly(glycolic acid-co-trimethylene carbonate); polyphosphoester; polyphosphoester urethane;
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`poly(amino acids); cyanoacrylates; poly(trimethylene carbonate); poly(iminocarbonate);
`
`copoly(ether-esters) (e.g., PEO/PLA); polyalkylene oxalates; polyphosphazenes;
`
`polyurethanes; silicones; polyesters; polyolefins; polyisobutylene and ethylene-alphaolefin
`
`copolymers; acrylic polymers and copolymers; vinyl halide polymers and copolymers, such as
`
`polyvinyl chloride; polyvinyl ethers, such as polyvinyl methyl] ether; polyvinylidene halides,
`
`such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile; polyvinyl
`
`ketones; polyvinyl aromatics, such as polystyrene; polyvinyl esters, such as polyvinyl acetate;
`
`copolymers of vinyl monomers with each other andolefins, such as ethylene-methy]
`
`methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins, and cthylene-vinyl
`
`acetate copolymers; polyamides, such as Nylon 66 and polycaprolactam; alkyd resins;
`
`polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxy resins; polyurethanes;
`
`rayon; rayon-triacetate; cellulose; cellulose acetate; cellulose butyrate; cellulose acetate
`
`butyrate; cellophane; cellulose nitrate; cellulose propionate; cellulose ethers; amorphous
`
`Teflon; and carboxymethy] cellulose.
`
`[0048]
`
`Suitable hydrophobic polymers include poly(L-lactide), poly(glycolide), poly(e-
`
`caprolactone), copolymers of lactide and/or glycolide or/and poly(e-caprolactone),
`
`hydrophobic peptides or a combination of hydrophobic peptides, polyurethanes. Any
`
`hydrophobic polymer that can form a micelle in water is suitable for use as a hydrophobic
`
`polymer. Suitable hydrophobic polymers include, e.g., poly(glycolide) or poly(glycolic acid);
`
`poly(c-caprolactonc); poly(D,L-lactide); poly (L-Lactidc); copolymers of these and other
`
`polyesters; polyamides; polyanhydrides; polyurethanes; poly(ortho esters);
`
`polyGminocarbonates). In some embodiments, the hydrophobic polymerof the nanoparticle (or
`
`microparticle) is poly-L-lactide.
`
`[0049]
`
`Suitable hydrophilic polymers include, but are not limited to, poly(ethylene glycol);
`
`poly(vinyl] alcohol); polyethers; polyGmethacrylic acid); poly(acrylic acid); polyIIEMA);
`
`hyaluronic acid; and hyaluronate.
`
`[0050]
`
`In some embodiments, the hydrophilic polymer of the nanoparticle or microparticle is a
`
`poly(ethylene glycol) polymer. Polyethylene glycol has the general formula R(O-CH2-CHz2),O-
`
`R, where R is hydrogen or a protective group such as an alkyl or an alkanol group, and where n
`
`is an integer from 1 to 1000.