Ocular inserts comprising a covalently linked steroid dimer

Abstract

The disclosure relates to compounds and compositions for sustained release of ocular therapeutics.

Claims

1. A method of treating a posterior ocular disorder or condition of an eye of a subject in need thereof, the method comprising intravitreally administering to the eye of the subject in need thereof an intravitreal implant comprising a steroidal compound represented by the structure: ##STR00038## the implant comprising the steroidal compound in an amount of at least 95% (w/w), thereby treating the posterior ocular disorder or condition of the eye of the subject in need thereof, the posterior ocular disorder or condition of the eye being macular edema or uveitis.

2. The method of claim 1, wherein the implant comprises the steroidal compound in an amount of at least 98% (w/w).

3. The method of claim 1, wherein the implant is a fiber, fiber mesh, woven fabric, non-woven fabric, pellet, cylinder, hollow tube, microparticle, nanoparticle, or shaped article.

4. The method of claim 3, wherein the implant is a cylinder.

5. The method of claim 1, wherein the implant releases the steroidal compound or dexamethasone in its free form in an amount sufficient to treat the posterior ocular disorder or condition of the eye of the subject in need thereof.

6. The method of claim 1, wherein the implant releases the steroidal compound or dexamethasone in its free form over a period of at least a day.

7. The method of claim 6, wherein the implant releases the steroidal compound or dexamethasone in its free form over a period of a least a month.

8. The method of claim 7, wherein the implant releases the steroidal compound or dexamethasone in its free form over a period of at least a year.

9. The method of claim 1, wherein the posterior ocular disorder or condition is macular edema.

10. The method of claim 9, wherein the macular edema is diabetic macular edema (DME).

11. The method of claim 9, wherein the macular edema is macular edema from a retinal disorder.

12. The method of claim 11, wherein the retinal disorder is a retinal vein occlusion (RVO).

13. The method of claim 12, wherein the retinal vein occlusion is a central RVO.

14. The method of claim 1, wherein the posterior ocular disorder or condition is uveitis.

15. The method of claim 1, wherein the eye of the subject is substantially free of infection.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1A to FIG. 1F are a series of images and a graph showing Compound 1 (Dexamethasone-Triethylene Glycol-Dexamethasone, Dex-TEG-Dex) formed into pellets in the glassy state and drug release through surface erosion from an intact pellet.

(2) FIG. 2A to FIG. 2G are a series of images showing Compound 1 (Dex-TEG-Dex) processed into different glassy state forms by multiple processing methods from the melt state.

(3) FIG. 3A to FIG. 3F are a series of images and graphs showing Compound 1 formed into heat extruded cylinders (FIGS. 3A-3D), purity of extrudate over time (FIG. 3E), and coating formed from Compound 1 (FIG. 3F).

(4) FIG. 4 is a graph showing cumulative drug release from a coating of Compound 1 (Dex-TEG-Dex) from titanium and poly(styrene-block-isobutylene-block-styrene) (SIBS) over time.

(5) FIG. 5 is a series of images showing surface erosion of an intravitreal implant of Compound 1 (Dex-TEG-Dex) over time.

(6) FIG. 6A to FIG. 6I are a series of images and graphs showing intravitreal implants of Compound 1 (Dex-TEG-Dex) formed into cylinders that inhibit inflammation in the eye.

(7) FIG. 7A to FIG. 7D are a series of images and graphs showing intravitreal implants of Compound 1 (Dex-TEG-Dex) and drug release over time.

(8) FIG. 8A to FIG. 8D are a series of images showing that intravitreal implants of Compound 1 (Dex-TEG-Dex) inhibit VEGF-induced retinal vascular leakage in the eye.

(9) FIG. 9A to FIG. 9E are a series of images and a graph showing Compound 2 (Hydrocortisone-Triethylene Glycol-Hydrocortisone, HC-TEG-HC) formed into heat-molded pellets, fibers, and extruded cylinders, as well as drug release over time.

(10) FIG. 10A to FIG. 10E are a series of images and a graph showing Compound 3 (Triamcinolone Acetonide-Triethylene Glycol-Triamcinolone Acetonide, TA-TEG-TA) formed into heat-molded pellets, fibers, and extruded cylinders, as well as drug release over time.

(11) FIG. 11A to FIG. 11C are an image and a graph showing Compound 4 (Dexamethasone-Triethylene Glycol-Hydrocortisone, Dex-TEG-HC) formed into heat-molded pellets and drug release over time.

(12) FIG. 12A to FIG. 12E are a series of images and a graph showing Compound 5 (Dexamethasone-Hexane-Dexamethasone, Dex-Hex-Dex) formed into heat-molded pellets, fibers, and extruded cylinders, as well as drug release over time.

(13) FIG. 13A to FIG. 13E are a series of images and a graph showing Compound 6 (Hydrocortisone-Succinate-Hydrocortisone, HC-SUCC-HC) formed into heat-molded pellets and fibers, as well as drug release over time.

(14) FIG. 14A to FIG. 14E are an image and a graph showing Compound 7 (Anecortave-Triethylene Glycol-Anecortave, Anec-TEG-Anec) formed into heat molded pellets and drug release over time.

(15) FIG. 15A to FIG. 15C are an image and a graph showing Compound 8 (Dexamethasone-Pentaethylene Glycol-Dexamethasone, Dex-EGS-Dex) formed into heat-molded pellets and drug release over time.

(16) FIG. 16A to FIG. 16E are a series of images and a graph showing Compound 9 (Fusidic Acid-Triethylene Glycol-Fusidic Acid (carbonate ester), FA-TEG-FA (CE)) formed into heat-molded pellets and fibers, as well as drug release over time.

(17) FIG. 17A to FIG. 17D are a series of images and a graph showing Compound 10 (Dexamethasone-Polyethylene Glycol (MW=200)-Dexamethasone, Dex-PEG200-Dex) formed into heat-molded pellets and extruded cylinders, as well as drug release over time.

(18) FIG. 18A and FIG. 18B are a series of images showing Compound 11 (Dexamethasone-Heptaethylene Glycol-Dexamethasone, Dex-EG7-Dex) formed into heat-molded pellets.

(19) FIG. 19A and FIG. 19B are a series of images showing Compound 12 (Dexamethasone-Nonaethylene Glycol-Dexamethasone, Dex-EG9-Dex) formed into heat-molded pellets.

(20) FIG. 20A and FIG. 20B are a series of images showing Compound 13 (Dexamethasone-Polyethylene Glycol (MW=300)-Dexamethasone, Dex-PEG300-Dex) formed into heat-molded pellets.

(21) FIG. 21A and FIG. 21B are a series of images showing Compound 14 (Cholesterol-Triethylene Glycol-Cholesterol, CHS-TEG-CHS) formed into heat-molded pellets.

(22) FIG. 22A and FIG. 22B are a series of images showing Compound 15 (Fusidic Acid-Triethylene Glycol-Fusidic Acid (ester), FA-TEG-FA (E)) formed into heat-molded pellets.

(23) FIG. 23A and FIG. 23B are a series of images showing Compound 16 (Ethinylestradiol-Triethylene Glycol-Ethinylestradiol, Ethin-TEG-Ethin) formed into heat-molded pellets.

(24) FIG. 24A and FIG. 24B are a series of an image and a graph showing a mixture of Compound 1 (Dex-TEG-Dex) and Compound 2 (HC-TEG-HC) formed into heat-molded pellets and drug release.

(25) FIG. 25A and FIG. 25B are a series of an image and a graph showing a mixture of Compound 1 (Dex-TEG-Dex) and Compound 3 (TA-TEG-TA) formed into heat-molded pellets and drug release.

(26) FIG. 26A and FIG. 26B are a series of an image and a graph showing a mixture of Compound 2 (HC-TEG-HC) and Compound 3 (TA-TEG-TA) formed into heat-molded pellets and drug release.

(27) FIG. 27A to FIG. 27C are a series of images showing Compound 17 (Prednisolone-Triethylene Glycol-Prednisolone, Pred-TEG-Pred) formed into heat-molded pellets and fibers.

DETAILED DESCRIPTION

(28) The release of drugs into the eye to treat ocular diseases has until recently been limited to eye drops and injections which lack sustained release profiles. This may be in part due to the unique anatomical and physiological features of the eye that can present challenges to drug delivery; ocular barriers include tear dilution, blood flow, lymphatic clearance and blood-ocular barriers that impede drug transport and lower the efficacy of many drugs [see e.g., Gower et al. Drug discovery in ophthalmology: past success, present challenges, and future opportunities, BMC Ophthalmology, 16:11, (Jan. 16, 2016).]. In particular, static barriers (different layers of cornea, sclera, and retina including blood aqueous and bloodretinal barriers), dynamic barriers (choroidal and conjunctival blood flow, lymphatic clearance, and tear dilution), and efflux pumps in conjunction pose a significant challenge for delivery of a drug alone or in a dosage form, especially to the back of the eye, e.g., the posterior segment [AAPS J. 2010 September; 12(3); 348-360].

(29) It is recognized in this disclosure that there is a need for drug delivery platforms that address one or more of these challenges and enable sustained release of ocular therapeutics.

(30) This disclosure features compositions and methods for the treatment of the eye and amelioration of ophthalmic diseases and conditions therewith. Also featured in this disclosure are treatments of the eye including a Schlemm's canal insert or a suprachoroidal insert. The treatment includes insertion of an article formed from therapeutic steroid prodrug dimers that are formed by conjugation of two steroids with a short chain linker. The prodrug dimers disclosed have properties that differ from that of the corresponding stand-alone drugs allowing them to be processed in various forms (e.g. fibers, cylinders, microparticles, etc.) in the glassy state and leading to sustained release of drug in the eye.

(31) This disclosure also features ocular inserts made of steroid drug dimers (e.g., anti-inflammatory steroid drug dimers or antibiotic steroid drug dimers). The ocular inserts can be in a form of fibers or cylinders, e.g., stents or tubes. The ocular inserts can provide a controlled rate of drug release over days, weeks, months, or even years. Alternatively, the ocular inserts can be in the form of cylinders or fibrous meshes (woven or non-woven) implanted intravitreally, subretinally, or suprachoroidally. The ocular insert of the disclosure can minimize inflammation associated with cataract or glaucoma surgery. Further, the Schlemm's canal and suprachoroidal inserts can provide a controlled rate of drug release over days, weeks, months, or even years. In particular embodiments, the Schlemm's canal inserts are inserted into the Schlemm's canal during cataract or glaucoma surgery to facilitate keeping the canal open, and functioning as a scaffold. In particular embodiments the article does not include non-therapeutic materials that could contribute to obstructing the passage of fluids. The Schlemm's canal insert of the disclosure can minimize inflammation of the canal and the surgical insertion point associated with cataract or glaucoma surgery. Alternatively, a suprachoroidal insert is used to reduce intraocular pressure.

(32) Drug Dimers

(33) The disclosure features articles formed from compounds of formula (A-I):
D1-L-D2  (A-I)

(34) or a pharmaceutically acceptable salt thereof, wherein each of D1 and D2 is, independently, a radical formed from a steroid; and L is a linker covalently linking D1 to D2. Each of D1 and D2 can be, independently, selected from a steroid (e.g., a glucocorticoid steroid, a corticosteroid, an IOP lowering steroid, or fusidic acid). L can be covalently linked to D1 and to D2 via one or more ester, carbonate, carbonate ester, or anhydride linkages. Ester, carbonate, carbonate ester, or anhydride linkages formed from a functional group on D1 and D2 can be selected from, e.g., hydroxyl or carboxy. For example, L can include the radical —C(O)—(R.sup.A)—C(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —O—(R.sup.A)—O—, where R.sup.A is a radical of a polyol and includes at least one free hydroxyl group or R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, —(CH.sub.2CH.sub.2O).sub.qCH.sub.2CH.sub.2—, —(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2CH.sub.2CH.sub.2—, or —(CH.sub.2CH(CH.sub.3)O).sub.sCH.sub.2CH(CH.sub.3)—, and q, r, and s are integers from 1 to 10 (e.g., 1 to 10, 1 to 5, or 5 to 10). The articles of the disclosure can be machined, molded, emulsion-processed, electrospun, electrosprayed, blow molded, dry spun, heat spun, melt spun, gel spun, or extruded to form a fiber, fiber mesh, woven fabric, non-woven fabric, pellet, cylinder, microparticle (e.g., a microbead), nanoparticle (e.g., a nanobead), tube, stent, or another shaped article sized and shaped for insertion adjacent to, or within, an eye.

(35) The compound can be further described by the formula (A-II):
D1-O-L-O-D2  (A-II),

(36) or a pharmaceutically acceptable salt thereof, wherein each of D1-0 and D2-O is, independently, a radical formed from a steroid (e.g., a glucocorticoid steroid, a corticosteroid, an IOP lowering steroid, or fusidic acid).

(37) In some embodiments, each of D1-0 and D2-O is, independently, described by any one of formulas (I-a) to (I-r):

(38) ##STR00007##

(39) where the bond between C.sub.1 and C.sub.2 is a single or a double bond; R.sub.1 represents H or a halogen atom; R.sub.5 represents H, C.sub.1-6 alkyl, or a halogen atom; R.sub.6 represents H or a halogen atom; R.sub.10 represents H, C.sub.1-6 alkyl, OH, or ═CH.sub.2; R.sub.11 represents H, OH, C.sub.1-6 alkyl, optionally substituted —C(O)C.sub.1-6 alkyl, —C(O)CH.sub.2OC(O)C.sub.1-6 alkyl, optionally substituted —OC(O)C.sub.1-6 alkyl, —OC(O)Ph, —OC(O)heterocyclyl, —CH.sub.2C(O)CH.sub.2OH, —C(O)C(O)OH, —C(O)C(O)OC.sub.1-6 alkyl, —C(O)SCH.sub.2F, or —OC(O)OC.sub.1-6 alkyl; or R.sub.10 and R.sub.11 taken together with carbons to which they are attached form an optionally substituted cyclic acetal or optionally substituted heterocyclyl; R.sub.12 represents H, OH, C.sub.1-6 alkyl, optionally substituted —C(O)C.sub.1-6 alkyl, —C(O)CH.sub.2OC(O)C.sub.1-6 alkyl, optionally substituted —OC(O)C.sub.1-6 alkyl, —OC(O)Ph, —OC(O)heterocyclyl, —CH.sub.2C(O)CH.sub.2OH, —C(O)C(O)OH, —C(O)C(O)OC.sub.1-6 alkyl, —C(O)SCH.sub.2F, or —OC(O)OC.sub.1-6 alkyl; or R.sub.10 and R.sub.12 taken together with carbons to which they are attached form an optionally substituted cyclic acetal or optionally substituted heterocyclyl; R.sub.15 represents H, OH, ═O, or a halogen atom; and R.sub.16 represents H or a halogen atom;

(40) ##STR00008##

(41) where the bond between C.sub.1 and C.sub.2 is a single or a double bond; R.sub.1 represents H or a halogen atom; R.sub.5 represents H, C.sub.1-6 alkyl, or a halogen atom; R.sub.6 represents H or a halogen atom; R.sub.10 represents H, C.sub.1-6 alkyl, OH, or ═CH.sub.2; R.sub.10b represents H, C.sub.1-6 alkyl, OH, ═CH.sub.2, or be absent; R.sub.12 represents H, OH, optionally substituted —C(O)C.sub.1-6 alkyl, —C(O)CH.sub.2OC(O)C.sub.1-6 alkyl, optionally substituted —OC(O)C.sub.1-6 alkyl, or —OC(O)Ph; or R.sub.10 and R.sub.11 taken together with carbons to which they are attached form an optionally substituted cyclic acetal or optionally substituted heterocyclyl; R.sub.15 represents H, OH, ═O, or a halogen atom; and R.sub.16 represents H or a halogen atom;

(42) ##STR00009##

(43) where the bond between C.sub.1 and C.sub.2 is a single or a double bond; R.sub.1 represents H or a halogen atom; R.sub.5 represents H, a halogen atom, or CH.sub.3; R.sub.6 represents H, a halogen atom; R.sub.10 represents H, OH, CH.sub.3, or ═CH.sub.2; R.sub.12 represents optionally substituted —C(O)C.sub.1-6 alkyl, —C(O)CH.sub.2OC(O)C.sub.1-6 alkyl, or —C(O)SCH.sub.2F; R.sub.15 represents OH or ═O; and R.sub.16 represents H or a halogen atom;

(44) ##STR00010##

(45) where the bond between C.sub.1 and C.sub.2 is a single or a double bond; R.sub.1 represents H or a halogen atom; R.sub.5 represents H, C.sub.1-6 alkyl, or a halogen atom; R.sub.6 represents H or a halogen atom; R.sub.10 represents H, C.sub.1-6 alkyl, OH, or ═CH.sub.2; R.sub.10b represents H, C.sub.1-6 alkyl, OH, or ═CH.sub.2, or is absent; R.sub.11 represents H, OH, C.sub.1-6 alkyl, optionally substituted —C(O)C.sub.1-6 alkyl, —C(O)CH.sub.2OC(O)C.sub.1-6 alkyl, optionally substituted —OC(O)C.sub.1-6 alkyl, —OC(O)Ph, —OC(O)heterocyclyl, —CH.sub.2C(O)CH.sub.2OH, —C(O)C(O)OH, —C(O)C(O)OC.sub.1-6 alkyl, —C(O)SCH.sub.2F, or —OC(O)OC.sub.1-6 alkyl; or R.sub.10 and R.sub.12 taken together with carbons to which they are attached form an optionally substituted cyclic acetal or optionally substituted heterocyclyl; R.sub.12 represents H, OH, C.sub.1-6 alkyl, optionally substituted —C(O)C.sub.1-6 alkyl, —C(O)CH.sub.2OC(O)C.sub.1-6 alkyl, optionally substituted —OC(O)C.sub.1-6 alkyl, —OC(O)Ph, —OC(O)heterocyclyl, —CH.sub.2C(O)CH.sub.2OH, —C(O)C(O)OH, —C(O)C(O)OC.sub.1-6 alkyl, —C(O)SCH.sub.2F, or —OC(O)OC.sub.1-6 alkyl; or R.sub.10 and R.sub.12 taken together with carbons to which they are attached form an optionally substituted cyclic acetal or optionally substituted heterocyclyl; and R.sub.16 represents H or a halogen atom;

(46) ##STR00011##

(47) where R.sub.5 represents H or a halogen atom; R.sub.15 represents a halogen atom or OH; and R.sub.16 represents H or a halogen atom;

(48) ##STR00012##

(49) where the bond between C.sub.1 and C.sub.2 is a double or a single bond; R.sub.16 represents H or a halogen atom; R.sub.5 represents H, CH.sub.3, or a halogen atom; R.sub.12 represents H or a halogen atom; R.sub.15 represents ═O or OH; R.sub.12 and R.sub.10 each, independently, represent —H, C.sub.1-10 alkyl, —OH, —O-acyl, or R.sub.12 and R.sub.10 combine to form a cyclic acetal of formula (XVIII-a) where:

(50) ##STR00013##

(51) e is an integer from 0 to 6; R.sub.20, R.sub.21, and R.sub.22 each, independently, represent H or C.sub.1-10 alkyl; and W.sub.1 represents H or CH.sub.3;

(52) ##STR00014##

(53) where the bond between C.sub.3 and R.sub.2 is a single or a double bond; R.sup.2 represents OH or ═O; R.sub.12 represents —C(═O)CH.sub.2OC(═O)CH.sub.3, —C(═O)CH.sub.2OH, or —C(═O)CH.sub.3; R.sub.15 represents H or OH.

(54) Drug dimers useful in the methods and compositions of the disclosure include homodimers (e.g., where D1 and D2 are the same) and heterodimers (e.g., where D1 and D2 differ). Glucocorticoids, anti-angiogenic steroids, intraocular pressure (TOP) lowering steroids, and corticosteroids that can be used in the methods and articles of the disclosure include, for example, medrysone, alclometasone, alclometasone dipropionate, amcinonide, beclometasone, beclomethasone dipropionate, betamethasone, betamethasone benzoate, betamethasone valerate, budesonide, ciclesonide, clobetasol, clobetasol butyrate, clobetasol propionate, clobetasone, clocortolone, loprednol, cortisol, cortisone, cortivazol, deflazacort, desonide, desoximetasone, desoxycortone, desoxymethasone, dexamethasone, diflorasone, diflorasone diacetate, diflucortolone, diflucortolone valerate, difluorocortolone, difluprednate, fluclorolone, fluclorolone acetonide, fludroxycortide, flumetasone, flumethasone, flumethasone pivalate, flunisolide, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin, fluocoritin butyl, fluocortolone, fluorocortisone, fluorometholone, fluperolone, fluprednidene, fluprednidene acetate, fluprednisolone, fluticasone, fluticasone propionate, formocortal, halcinonide, halometasone, hydrocortisone, hydrocortisone acetate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, loteprednol, meprednisone, 6a-methylprednisolone, methylprednisolone, methylprednisolone acetate, methylprednisolone aceponate, mometasone, mometasone furoate, mometasone furoate monohydrate, paramethasone, prednicarbate, prednisolone, prednisone, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, ulobetasol, anecortave acetate, anecortave, 11-epicortisol, 17α-hydroxyprogesterone, tetrahydrocortexolone, and tetrahydrocortisol.

(55) The disclosure features homodimers of the formula (A-I), or a pharmaceutically acceptable salt thereof, wherein D1 and D2 are radicals formed from the same steroid. L can be covalently linked to D1 and to D2 via one or more ester, carbonate, carbonate ester, or anhydride linkages. Ester, carbonate, carbonate ester, or anhydride linkages formed from a functional group on D1 and D2 can be selected from, e.g., hydroxyl or carboxy. For example, L can include the radical —C(O)—(R.sup.A)—C(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —O—(R.sup.A)—O—, where R.sup.A is a radical of a polyol and includes at least one free hydroxyl group or R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, —(CH.sub.2CH.sub.2O).sub.qCH.sub.2CH.sub.2—, —(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2CH.sub.2CH.sub.2—, or —(CH.sub.2CH(CH.sub.3)O).sub.sCH.sub.2CH(CH.sub.3)—, and q, r, and s are integers from 1 to 10 (e.g., 1 to 10, 1 to 5, or 5 to 10). The homodimer can be further described by one of formulas (II-a) to (II-r), below.

(56) In particular embodiments, the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (II):

(57) ##STR00015##

(58) wherein the bond between C.sub.1 and C.sub.2 is a single or a double bond; R.sub.1 represents H or a halogen atom; R.sub.5 represents H, C.sub.1-6 alkyl, or a halogen atom; R.sub.6 represents H or a halogen atom; R.sub.10 represents H, C.sub.1-6 alkyl, OH, or ═CH.sub.2; R.sub.11 represents H, OH, C.sub.1-6 alkyl, optionally substituted —C(O)C.sub.1-6 alkyl, —C(O)CH.sub.2OC(O)C.sub.1-6 alkyl, optionally substituted —OC(O)C.sub.1-6 alkyl, —OC(O)Ph, —OC(O)heterocyclyl, —CH.sub.2C(O)CH.sub.2OH, —C(O)C(O)OH, —C(O)C(O)OC.sub.1-6 alkyl, —C(O)SCH.sub.2F, or —OC(O)OC.sub.1-6 alkyl; or R.sub.10 and R.sub.11 taken together with carbons to which they are attached form an optionally substituted cyclic acetal or optionally substituted heterocyclyl; R.sub.12 represents H, OH, C.sub.1-6 alkyl, optionally substituted —C(O)C.sub.1-6 alkyl, —C(O)CH.sub.2OC(O)C.sub.1-6 alkyl, optionally substituted —OC(O)C.sub.1-6 alkyl, —OC(O)Ph, —OC(O)heterocyclyl, —CH.sub.2C(O)CH.sub.2OH, —C(O)C(O)OH, —C(O)C(O)OC.sub.1-6 alkyl, —C(O)SCH.sub.2F, or —OC(O)OC.sub.1-6 alkyl; or R.sub.10 and R.sub.12 taken together with carbons to which they are attached form an optionally substituted cyclic acetal or optionally substituted heterocyclyl; R.sub.15 represents H, OH, ═O, or a halogen atom; R.sub.16 represents H or a halogen atom; L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—; R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or O—(R.sup.A)—O is a radical of a polyol and includes at least one free hydroxyl group or O—(R.sup.A)—O is selected from: —O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O—, —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, or —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and n, m, and p are integers from 1 to 10. The drug dimer of formula (II-a) can be formed from a glucocorticoid steroid selected from the group consisting of medrysone, alclometasone, alclometasone dipropionate, amcinonide, beclometasone, beclomethasone dipropionate, betamethasone, betamethasone benzoate, betamethasone valerate, budesonide, ciclesonide, clobetasol, clobetasol butyrate, clobetasol propionate, clobetasone, clocortolone, cortisol, cortisone, deflazacort, desonide, desoximetasone, desoxycortone, desoxymethasone, dexamethasone, diflorasone, diflorasone diacetate, diflucortolone, diflucortolone valerate, difluorocortolone, difluprednate, fluclorolone, fluclorolone acetonide, fludroxycortide, flumetasone, flumethasone, flumethasone pivalate, flunisolide, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin, fluocoritin butyl, fluocortolone, fluorocortisone, fluorometholone, fluperolone, fluprednidene, fluprednidene acetate, fluprednisolone, fluticasone, fluticasone propionate, halcinonide, halometasone, hydrocortisone, hydrocortisone acetate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, loteprednol, meprednisone, 6a-methylprednisolone, methylprednisolone, methylprednisolone acetate, methylprednisolone aceponate, mometasone, mometasone furoate, mometasone furoate monohydrate, paramethasone, prednicarbate, prednisolone, prednisone, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, and ulobetasol.

(59) In some embodiments, the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (II-b):

(60) ##STR00016##

(61) wherein the bond between C.sub.1 and C.sub.2 is a single or a double bond; R.sub.1 represents H or a halogen atom; R.sub.5 represents H, C.sub.1-6 alkyl, or a halogen atom; R.sub.6 represents H or a halogen atom; R.sub.10 represents H, C.sub.1-6 alkyl, OH, or ═CH.sub.2; R.sub.10b represents H, C.sub.1-6 alkyl, OH, ═CH.sub.2, or be absent; R.sub.12 represents H, OH, optionally substituted —C(O)C.sub.1-6 alkyl, —C(O)CH.sub.2OC(O)C.sub.1-6alkyl, optionally substituted —OC(O)C.sub.1-6 alkyl, or —OC(O)Ph; or R.sub.10 and R.sub.11 taken together with carbons to which they are attached form an optionally substituted cyclic acetal or optionally substituted heterocyclyl; R.sub.15 represents H, OH, ═O, or a halogen atom; R.sub.16 represents H or a halogen atom; L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—; R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or O—(R.sup.A)—O is a radical of a polyol and includes at least one free hydroxyl group or O—(R.sup.A)—O is selected from: —O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O—, —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, or —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and n, m, and p are integers from 1 to 10. The drug dimer of formula (II-b) can be formed from a glucocorticoid steroid selected from the group consisting of alclometasone, beclometasone, betamethasone, betamethasone benzoate, betamethasone valerate, budesonide, cortisol, cortisone, desonide, desoximetasone, desoxycortone, desoxymethasone, dexamethasone, diflorasone, diflucortolone, difluorocortolone, fluclorolone, fluclorolone acetonide, fludroxycortide, flumetasone, flumethasone, flunisolide, flunisolide, fluocinolone, fluocinolone acetonide, fluocortolone, fluorocortisone, fluprednidene, fluprednisolone, halometasone, hydrocortisone, hydrocortisone butyrate, meprednisone, 6a-methylprednisolone, methylprednisolone, paramethasone, prednisolone, prednisone, prednylidene, triamcinolone, and triamcinolone acetonide.

(62) In particular embodiments, the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (II-c):

(63) ##STR00017##

(64) wherein L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—; R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or O—(R.sup.A)—O is a radical of a polyol and includes at least one free hydroxyl group or O—(R.sup.A)—O is selected from: —O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O—, —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, or —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and n, m, and p are integers from 1 to 10. The drug dimer of formula (II-c) can be formed from the glucocorticoid steroid fluclorolone acetonide.

(65) In some embodiments, the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (II-d):

(66) ##STR00018##

(67) wherein the bond between C.sub.1 and C.sub.2 is a single or a double bond; R.sub.1 represents H or a halogen atom; R.sub.5 represents H, a halogen atom, or CH.sub.3; R.sub.6 represents H, a halogen atom; R.sub.10 represents H, OH, CH.sub.3, or ═CH.sub.2; R.sub.12 represents optionally substituted —C(O)C.sub.1-6 alkyl, —C(O)CH.sub.2OC(O)C.sub.1-6 alkyl, or —C(O)SCH.sub.2F; R.sub.15 represents OH or ═O; R.sub.16 represents H or a halogen atom; L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—; R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or O—(R.sup.A)—O is a radical of a polyol and includes at least one free hydroxyl group or O—(R.sup.A)—O is selected from: —O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O—, —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, or —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and n, m, and p are integers from 1 to 10. The drug dimer of formula (II-d) can be formed from a glucocorticoid steroid selected from the group consisting of alclometasone, beclometasone, betamethasone, clobetasol, clobetasone, cortisol, cortisone, dexamethasone, diflorasone, fluclorolone, flumetasone, flumethasone, flumethasone pivalate, fluocinolone, fluorocortisone, fluorometholone, fluperolone, fluprednidene, fluprednidene acetate, fluprednisolone, fluticasone, halometasone, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, meprednisone, 6a-methylprednisolone, methylprednisolone, methylprednisolone acetate, mometasone, paramethasone, prednisolone, prednisone, prednylidene, tixocortol, triamcinolone, and ulobetasol.

(68) In particular embodiments, the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (II-e):

(69) ##STR00019##

(70) wherein L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—; R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or O—(R.sup.A)—O is a radical of a polyol and includes at least one free hydroxyl group or O—(R.sup.A)—O is selected from: —O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O—, —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, or —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and n, m, and p are integers from 1 to 10. The drug dimer of formula (II-e) can be formed from the glucocorticoid steroid cortivazol.

(71) In some embodiments, the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (II-f):

(72) ##STR00020##

(73) wherein the bond between C.sub.1 and C.sub.2 is a single or a double bond; R.sub.1 represents H or a halogen atom; R.sub.5 represents H, C.sub.1-6 alkyl, or a halogen atom; R.sub.6 represents H or a halogen atom; R.sub.10 represents H, C.sub.1-6 alkyl, OH, or ═CH.sub.2; R.sub.10b represents H, C.sub.1-6 alkyl, OH, or ═CH.sub.2, or is absent; R.sub.11 represents H, OH, C.sub.1-6 alkyl, optionally substituted —C(O)C.sub.1-6 alkyl, —C(O)CH.sub.2OC(O)C.sub.1-6 alkyl, optionally substituted —OC(O)C.sub.1-6 alkyl, —OC(O)Ph, —OC(O)heterocyclyl, —CH.sub.2C(O)CH.sub.2OH, —C(O)C(O)OH, —C(O)C(O)OC.sub.1-6 alkyl, —C(O)SCH.sub.2F, or —OC(O)OC.sub.1-6 alkyl; or R.sub.10 and R.sub.12 taken together with carbons to which they are attached form an optionally substituted cyclic acetal or optionally substituted heterocyclyl; R.sub.12 represents H, OH, C.sub.1-6 alkyl, optionally substituted —C(O)C.sub.1-6 alkyl, —C(O)CH.sub.2OC(O)C.sub.1-6 alkyl, optionally substituted —OC(O)C.sub.1-6 alkyl, —OC(O)Ph, —OC(O)heterocyclyl, —CH.sub.2C(O)CH.sub.2OH, —C(O)C(O)OH, —C(O)C(O)OC.sub.1-6 alkyl, —C(O)SCH.sub.2F, or —OC(O)OC.sub.1-6 alkyl; or R.sub.10 and R.sub.12 taken together with carbons to which they are attached form an optionally substituted cyclic acetal or optionally substituted heterocyclyl; R.sub.16 represents H or a halogen atom; L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—; R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or O—(R.sup.A)—O is a radical of a polyol and includes at least one free hydroxyl group or O—(R.sup.A)—O is selected from: —O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O, —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, or —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and n, m, and p are integers from 1 to 10. The drug dimer of formula (II-f) can be formed from a glucocorticoid steroid selected from the group consisting of medrysone, alclometasone, alclometasone dipropionate, amcinonide, beclometasone, beclomethasone dipropionate, betamethasone, betamethasone benzoate, betamethasone valerate, budesonide, ciclesonide, clobetasol, clobetasol butyrate, clobetasol propionate, clobetasone, clocortolone, cortisol, cortisone, cortivazol, deflazacort, desonide, desoximetasone, desoxymethasone, dexamethasone, diflorasone, diflorasone diacetate, diflucortolone, diflucortolone valerate, difluorocortolone, difluprednate, fludroxycortide, flumetasone, flumethasone, flumethasone pivalate, flunisolide, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin, fluocoritin butyl, fluocortolone, fluorocortisone, fluorometholone, fluperolone, fluprednidene, fluprednidene acetate, fluprednisolone, fluticasone, fluticasone propionate, formocortal, halcinonide, halometasone, hydrocortisone, hydrocortisone acetate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, loteprednol, meprednisone, 6a-methylprednisolone, methylprednisolone, methylprednisolone acetate, methylprednisolone aceponate, mometasone, mometasone furoate, mometasone furoate monohydrate, paramethasone, prednicarbate, prednisolone, prednisone, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, and ulobetasol.

(74) In particular embodiments, the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (II-g):

(75) ##STR00021##

(76) Wherein L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—; R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or O—(R.sup.A)—O is a radical of a polyol and includes at least one free hydroxyl group or O—(R.sup.A)—O is selected from: —O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O—, —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, or —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and n, m, and p are integers from 1 to 10. The drug dimer of formula (II-g) can be formed from the glucocorticoid steroid cortivazol.

(77) In some embodiments, the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (II-h):

(78) ##STR00022##

(79) wherein R.sub.5 represents H or a halogen atom; R.sub.15 represents a halogen atom or OH; R.sub.16 represents H or a halogen atom; L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—; R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or O—(R.sup.A)—O is a radical of a polyol and includes at least one free hydroxyl group or O—(R.sup.A)—O is selected from: —O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O—, —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, or —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and n, m, and p are integers from 1 to 10. The drug dimer of formula (II-h) can be formed from a glucocorticoid steroid selected from the group consisting of fluclorolone, fluocinolone, and triamcinolone.

(80) In particular embodiments, the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula

(81) ##STR00023##

(82) wherein L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—; R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or O—(R.sup.A)—O is a radical of a polyol and includes at least one free hydroxyl group or O—(R.sup.A)—O is selected from: —O(CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2O—, —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, or —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and n, m, and p are integers from 1 to 10. The drug dimer of formula can be formed from fluperolone.

(83) In some embodiments, the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (II-j):

(84) ##STR00024##

(85) wherein L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—; R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or O—(R.sup.A)—O is a radical of a polyol and includes at least one free hydroxyl group or O—(R.sup.A)—O is selected from: —O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O—, —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, or —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and n, m, and p are integers from 1 to 10. The drug dimer of formula (II j) can be formed from formocortal.

(86) In particular embodiments, the steroid is a corticosteroid and the drug dimer is further described by the formula (II-k):

(87) ##STR00025## wherein the bond between C.sub.1 and C.sub.2 is a double or a single bond; R.sub.16 represents H or a halogen atom; R.sub.5 represents H, CH.sub.3, or a halogen atom; R.sub.12 represents H or a halogen atom; R.sub.15 represents ═O or OH; R.sub.12 and R.sub.10 each, independently, represent —H, C.sub.1-10 alkyl, —OH, —O-acyl, or R.sub.12 and R.sub.10 combine to form a cyclic acetal of formula (II-ka) wherein:

(88) ##STR00026##

(89) e is an integer from 0 to 6; R.sub.20, R.sub.21, and R.sub.22 each, independently, represent H or C.sub.1-10 alkyl; W.sub.1 represents H or CH.sub.3; L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—; R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or O—(R.sup.A)—O is a radical of a polyol and includes at least one free hydroxyl group or O—(R.sup.A)—O is selected from: —O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O—, —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, or —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and n, m, and p are integers from 1 to 10. The drug dimer of formula (II-k) can be formed from a corticosteroid selected from the group consisting of alclometasone, beclomethasone, betamethasone, betamethasone valerate, budesonide, chloroprednisone, cloprednol, corticosterone, cortisone, desonide, desoximerasone, dexamethasone, diflorasone, diflucortolone, enoxolone, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocortolone, fluprednisolone, flurandrenolide, halometasone, hydrocortisone, hydrocortisone butyrate, meprednisone, methylprednicolone, paramethasone, prednisolone, prednisone, prednival, prednylidene, triamcinolone, and triamcinolone acetonide.

(90) In any of the above formulas (II-a)-(II-k), O—(R.sup.A)—O can be a radical of a polyol formed from a cyclitol, and sugar alcohol, or glycerin; or O—(R.sup.A)—O can be a radical formed from an alkane diol (e.g., a C.sub.1-10 alkane diol), diethylene glycol, triethylene glycol, tetraethylene glycol, or pentaethylene glycol.

(91) In particular embodiments, the steroid is an antibiotic steroid and the drug dimer is further described by the formula (II-m):

(92) ##STR00027##

(93) wherein L is —C(O)—(R.sup.A)—C(O)—, —(R.sup.A)—, or —C(O)—O—(R.sup.A)—O—C(O)— and R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms; or L is —O—(R.sup.A)—O— and R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or O—(R.sup.A)—O is a radical of a polyol and includes at least one free hydroxyl group or O—(R.sup.A)—O is selected from —O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O—, —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, and —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and n, m, and p are integers from 1 to 10. The drug dimer of formula (II-m) can be formed from fusidic acid.

(94) In particular embodiments, the steroid is an anti-angiogenic steroid or an intraocular pressure (TOP) lowering steroid, and the drug dimer is further described by the formula (II-n):

(95) ##STR00028##

(96) wherein R.sub.12 represents —C(═O)CH.sub.2OC(═O)CH.sub.3, —C(═O)CH.sub.2OH, or —C(═O)CH.sub.3; R.sub.15 represents H or OH; and L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—; R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or O—(R.sup.A)—O is a radical of a polyol and includes at least one free hydroxyl group or O—(R.sup.A)—O is selected from: —O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O—, —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, or —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and n, m, and p are integers from 1 to 10. The drug dimer of formula (II-n) can be formed from anecortave acetate, anecortave, 11-epicortisol, 17α-hydroxyprogesterone, tetrahydrocortexolone, or tetrahydrocortisol.

(97) In particular embodiments, the steroid is an anti-angiogenic steroid or an intraocular pressure (TOP) lowering steroid, and the drug dimer is further described by the formula (II-o):

(98) ##STR00029##

(99) wherein the bond between C.sub.3 and R.sub.2 is a single or a double bond; R.sub.2 represents OH or ═O; R.sub.12 represents —C(═O)CH.sub.2OC(═O)CH.sub.3, —C(═O)CH.sub.2OH, or —C(═O)CH.sub.3, R.sub.15 represents H or OH; and L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—; R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or O—(R.sup.A)—O is a radical of a polyol and includes at least one free hydroxyl group or O—(R.sup.A)—O is selected from: —O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O—, —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, or —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and n, m, and p are integers from 1 to 10. The drug dimer of formula (II-o) can be formed from anecortave acetate, anecortave, 11-epicortisol, 17α-hydroxyprogesterone, tetrahydrocortexolone, or tetrahydrocortisol.

(100) In particular embodiments, the steroid is an anti-angiogenic steroid or an intraocular pressure (TOP) lowering steroid, and the drug dimer is further described by the formula (II-p):

(101) ##STR00030##
wherein the bond between C.sub.3 and R.sub.2 is a single or a double bond; R.sub.2 represents OH or ═O; R.sub.15 represents H or OH; and L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—; R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or O—(R.sup.A)—O is a radical of a polyol and includes at least one free hydroxyl group or O—(R.sup.A)—O is selected from: —O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O—, —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, or —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and n, m, and p are integers from 1 to 10. The drug dimer of formula (II-p) can be formed from anecortave, 11-epicortisol, tetrahydrocortexolone, or tetrahydrocortisol.

(102) In particular embodiments, the steroid is an anti-angiogenic steroid or an intraocular pressure (TOP) lowering steroid, and the drug dimer is further described by the formula (II-r):

(103) ##STR00031##

(104) wherein the bond between C.sub.3 and R.sub.2 is a single or a double bond; R.sub.2 represents OH or ═O; and L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—; R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or O—(R.sup.A)—O is a radical of a polyol and includes at least one free hydroxyl group or O—(R.sup.A)—O is selected from: —O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O—, —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, or —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and n, m, and p are integers from 1 to 10. The drug dimer of formula (II-r) can be formed from 11-epicortisol or tetrahydrocortisol.

(105) Shaped Articles

(106) The pharmaceutical compositions of the disclosure can include an article in the form of fibers, fiber meshes, woven fabrics, non-woven fabrics, pellets, cylinders, microparticles (e.g., microbeads), nanoparticles (e.g., nanobeads), or other shaped articles, such as stents/tubes suitable for ophthalmology including contact lenses, sutures, microshunt devices, optical rings, punctal plugs, and ocular inserts. Additionally, the pharmaceutical compositions of the disclosure can include an article in the form of fibers, cylinders, or other shaped articles, such as stents/tubes sized for insertion into the Schlemm's canal of an eye. Alternatively, the pharmaceutical compositions of the disclosure can include an article in the form of pellets or cylinders sized for insertion into the suprachoroidal space of an eye. The articles can achieve desired drug loading and long term release profile relative to the corresponding stand-alone glucocorticoid or corticosteroid drug therapy. Alternatively, the articles of the disclosure may be injected intraocularly (e.g., for the treatment of inflammation occurring at the back of the eye).

(107) Processing Methods

(108) Articles of the disclosure can be formed using any number of the methods, for example, heat processing or solvent processing of the drug dimer of formula (I). Heat processing can include heat molding, injection molding, extrusion, 3D printing, melt electrospinning, fiber spinning, fiber extrusion, and/or blow molding. Solvent processing may include coating, micro printing, emulsion processing, dot printing, micropatterning, fiber spinning, solvent blow molding, electrospraying, and electrospinning.

(109) Electrospraying Method

(110) In some embodiments, the pharmaceutical compositions of the disclosure are dissolved in a solvent (e.g., acetone) at concentrations ranging from, e.g., 10-30% w/v, and are electrosprayed to form micro- and nanobeads. The solutions can be loaded into a syringe and can be injected at a particular rate, e.g., 0.5 mL/h, onto a stationary collection plate. Between the needle and collecting surface, a potential difference of, e.g., 18 kV, can be maintained. Exemplary concentration of 10% w/v is used to obtain nanoparticles. In other embodiments, a concentration of 30% w/v is used to obtain microbeads.

(111) Fiber Spinning Methods

(112) In some embodiments, the pharmaceutical compositions of the disclosure, e.g., fibers or fibrous meshes with aligned and unaligned morphologies are prepared by electrospinning. The pharmaceutical compositions of the disclosure are dissolved in a solvent (e.g., THF, or 1:1 ratio of DCM/THF). The solutions may be injected from a syringe at a particular rate, e.g., 0.5 mL/h, onto a cylindrical mandrel rotating at a particular rotational speed, e.g., 1150 rpm, to obtain aligned fibers, or onto a stationary collector surface to obtain unaligned fibers. A potential difference (e.g., 18 kV or 17 kV) can be maintained between the needle and collecting surface for aligned and random fibers.

(113) In other embodiments, fibers are prepared either from the melt at elevated temperatures, the glassy state intermediate, or from solution by dissolving the pharmaceutical compositions of the disclosure in a solvent (e.g., DCM, THF, or chloroform). As used herein, melt spinning describes heat processing from the melt state, heat spinning describes heat processing from the glassy state, and wet, dry, and gel spinning describe solution processing.

(114) The viscous melt, intermediate, or solution can be fed through a spinneret and fibers may be formed upon cooling (melt or heat spinning) or following solvent evaporation with warm air as the compound exits the spinneret (dry spinning). Wet spinning and gel spinning, performed according to methods known in the art, may also be used to produce the fibers of the disclosure. Heat spinning describes a process that is essentially the same as the melt spinning process, but performed with the glassy state intermediate and heated above the glass transition temperature (Tg) to get the viscous fluid to extrude/spin instead of the melt. Alternatively, tweezers may be dipped into melted material or concentrated solutions and retracted slowly in order to pull fibers. The rate of pulling and distance pulled may be varied to yield fibers and columnar structures of different thickness.

(115) Emulsion Method

(116) In some embodiments, microparticles or nanoparticles made from the pharmaceutical composition can be formed using an emulsion process. The pharmaceutical composition may be dissolved in an organic solvent (e.g., DCM, THF, etc.) and a surfactant (e.g., SDS, PVA, etc.) may be added to the solution/mixture at a low percentage (e.g., 1%). The resulting mixture may be stirred for the appropriate time at room temperature to form an emulsion. The emulsion may be subsequently added to Milli-Q water under stirring for an appropriate time (e.g., 1 h) to remove residual solvent. The resulting micro- or nanoparticles may be collected by centrifugation and dried to obtain the desired form.

(117) Extrusion Method

(118) In some embodiments, injectable cylinders made from the pharmaceutical composition may be formed by heat extrusion. The pharmaceutical composition may be loaded into a hot melt extruder, heated to a temperature above the melting point (for crystalline compositions) or glass transition temperature (for pre-melted or amorphous compositions), and extruded using a light compressive force to push the material through the nozzle and a light tensile force to pull the material out of the extruder. The extrudate may be cut to the desired length for appropriate drug dosing for the indication of interest.

(119) Bead Sizing and Milling

(120) In some embodiments, a milling process may be used to reduce the size of an article of the disclosure to form sized particles, e.g., beads, in the micrometer (microbeads) to nanometer size range (nanobeads). The milling process may be performed using a mill or other suitable apparatus. Dry and wet milling processes such as jet milling, cryo-milling, ball milling, media milling, sonication, and homogenization are known and can be used in methods described herein. Generally, in a wet milling process, a suspension of the material to be used as the core is agitated with or without excipients to reduce particle size. Dry milling is a process wherein the material to be used as the article core is mixed with milling media with or without excipients to reduce particle size. In a cyro-milling process, a suspension of the material to be used as the core is mixed with milling media with or without excipients under cooled temperatures. In some embodiments, subsequent heating of the milled microparticle above the Tg is needed to achieve a spherical shape, or particles with non-spherical shapes can be used as milled.

(121) Low Temperature Processing Using Intermediate Glassy State Articles

(122) In certain embodiments, the prodrug dimer has a limited window (e.g., short timeframe of seconds to minutes) of thermal stability, whereby the purity of the dimer is minimally affected at elevated temperatures. In some embodiments, it is beneficial to make an intermediate glassy state form (e.g., film, pellet, micro-particles, or other shaped article). This can be accomplished by heat or solvent processing to remove or reduce the crystallinity of the material to form a glassy state composition. The glassy state composition is subsequently heat processed at a lower temperature (e.g., processing just above the glass transition temperature (Tg), and below the melt temperature (Tm)). This can provide a longer timeframe for heat processing the glassy state material into the final shaped article, while reducing the impact of processing conditions on the purity of the prodrug dimer in the article. The process can include shaping the article by extrusion, or any other process described herein.

(123) Formulations

(124) The formulations of the disclosure provide optimal delivery of a drug as they release the drug from an article of the disclosure in a controlled manner, for example, by surface erosion. The surface erosion mechanism of drug release may allow the shaped article to maintain its physical form (shape), while gradually decreasing in size as the surface erodes (e.g., like a bar of soap), rather than bulk erosion that is characteristic of some polymer-based drug release vehicles (e.g., polylactic/glycolic acid). This can inhibit burst release and reduce the formation of inflammatory particulates (e.g., no crystalline particulates are formed when drug is released in the manner described herein). The drug can be controlled to be delivered over a desired period of time to a desired site of the eye. A slower and steadier rate of delivery (e.g., release of less than 10% of D1 or D2 (as a percentage of the total drug, D1 or D2, present in the fiber in prodrug form) at 37° C. in 100% bovine serum over 5 days) can in turn result in a reduction in the frequency with which the pharmaceutical composition must be administered to a subject, and improve the safety profile of the drug and improving patient compliance with dosing regimens. Drug release can also be tailored to avoid side effects of slower and longer release of the drug by engineering the article to provide steady release over a comparatively shorter period of time. Depending on the indication and the drug, the drug release can be tailored for dose and duration appropriate to the indication of interest.

(125) The rate of release of a drug can depend on many factors, for example, the drug composition of the drug dimer. Drug release rate from the drug dimer can be modulated by the cleavage of drug-linker bond through hydrolysis or enzymatic degradation. Therefore, the selection of linking moiety can affect drug release rate. Further, the drug release rate can be controlled by the selection of the functional group on the drug to conjugate through to the linker, for example, a primary vs. a secondary steroid hydroxyl group. The rate of release of a given drug from a drug dimer can also depend on the quantity of the loaded drug dimer as a percent of the final drug dimer formulation, e.g., by using an appropriate pharmaceutical excipient (e.g., bulking agent/excipient). Another factor that can affect the release rate of a drug from the article is size or surface area. In some embodiments, drug release is tailored based on the solubility of drug dimer (e.g., through selection of appropriate drug and/or linker) that will influence the rate of surface erosion (e.g., dissolution/degradation) from the article. In other embodiments, drug release is affected by changes in surface area of the formulation, e.g., by changing the diameter of the articles. By adjusting the vide supra factors, dissolution, degradation, diffusion, and controlled release may be varied over wide ranges. For example, release can be designed to be initiated over minutes to hours, and may extend over the course of days, weeks, months, or years.

(126) In some embodiments, the drug dimers of the disclosure are used as a drug delivery device (or, e.g., a drug depot) with a minimal need for additives. This can achieve a local, sustained release and a local biological effect, while minimizing a systemic response. In some embodiments, when present, the additives are in small amounts and do not affect the physical or bulk properties. In some embodiments, when present, the additives do not alter the drug release properties from the pharmaceutical composition but rather act to improve processing of the prodrug dimer into the shaped article. In some embodiments, the pharmaceutical compositions contain additives such as a plasticizer (e.g., to reduce thermal transition temperatures), an antioxidant (e.g., to increase stability during heat processing), a binder (e.g., to add flexibility to the fibers), a bulking agent (e.g., to reduce total drug content), a lubricant, dyes, or mixtures thereof. The additives may be present at 30% (w/w), e.g., 20% (w/w), 10% (w/w), 7% (w/w), 5% (w/w), 3% (w/w), 1% (w/w), 0.5% (w/w), or 0.1% (w/w). Examples of plasticizers are polyols, e.g., glycerol, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, propylene glycol, triacetin, sorbitol, mannitol, xylitol, fatty acids, monosaccharides (e.g., glucose, mannose, fructose, sucrose), ethanolamine, urea, triethanolamine, vegetable oils, lecithin, or waxes. Exemplary antioxidants are glutathione, ascorbic acid, cysteine, or tocopherol. The binders and bulking agents can be, e.g., polyvvinylpyrrolidone (PVP), starch paste, pregelatinized starch, hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC), or polyethylene glycol (PEG) 6000.

(127) Generally, it is desired that a formulation is sterile before or upon administration to a subject. A sterile formulation is essentially free of pathogenic microorganisms, such as bacteria, microbes, fungi, viruses, spores, yeasts, molds, and others generally associated with infections. In some embodiments, articles of the disclosure may be subject to an aseptic process and/or other sterilization process. An aseptic process typically involves sterilizing the components of a formulation, final formulation, and/or container closure of a drug product through a process such as heat, gamma irradiation, ethylene oxide, or filtration and then combining in a sterile environment. In some cases, an aseptic process is preferred. In other embodiments, terminal sterilization is preferred.

(128) Treatment

(129) In one embodiment, there is provided a method of treating a subject for an ocular disease or condition including administering to the subject a compound, article, or ocular insert described herein. Also provided is a method of treating a subject for an ocular disease or condition including inserting into the Schlemm's canal or suprachoroidal space in the eye of a subject a compound, article, or Schlemm's canal or suprachoroidal insert described herein. In one embodiment, the “subject” can be any animal, while in certain embodiments, the “subject” is a mammal and, in a preferred embodiment, a human.

(130) Diseases and conditions that can be treated using compounds, compositions and dosage forms as described herein include, but are not limited to, disorders of the eyelid, lacrimal system and orbit; inflammatory disorders of the conjunctiva; disorders of the sclera, iris and ciliary body; disorders of the lens; disorders of the choroid and retina, including disorders and conditions associated with chorioretinal inflammation or infection; disorders of the vitreous body and globe; disorders of the optic nerve and visual pathways; and disorders of the ocular muscles.

(131) An anterior ocular inflammatory disease or condition, or an infection, primarily affects or involves an anterior ocular region or site (i.e. front of the eye), such as a periocular muscle, an eye lid or an eye ball tissue or fluid which is located anterior to the posterior wall of the lens capsule or ciliary muscles. A posterior ocular disease or condition primarily affects or involves a posterior ocular region or site such as choroid or sclera (in a position posterior to a plane through the posterior wall of the lens capsule), vitreous, vitreous chamber, retina, optic nerve (i.e. the optic disc), and blood vessels and nerves which vascularize or innervate a posterior ocular region or site. As discussed in the Background, drug delivery to the posterior segment presents particular challenges and, in one embodiment, compounds, compositions and dosage forms as described herein may be used to treat a posterior ocular disease or condition by placement of an article of the disclosure adjacent to or within a structure of the eye.

(132) The articles of the disclosure may be used to treat, prevent, or manage inflammation or infection in the eye of a subject. For example, the ocular condition to be treated may be at the front of the eye. A front of the eye ocular condition includes a disease, ailment or condition, such as for example, post-surgical inflammation; uveitis; infections; aphakia; pseudophakia; astigmatism; blepharospasm; cataract; conjunctival diseases; conjunctivitis; corneal diseases; corneal ulcer; dry eye syndromes; eyelid diseases; lacrimal apparatus diseases; lacrimal duct obstruction; myopia; presbyopia; pupil disorders; corneal neovascularization; refractive disorders and strabismus. In some embodiments, articles of the disclosure may be used to treat, prevent, or manage an ocular condition at the back of the eye of a subject. A posterior ocular condition can include a disease, ailment, or condition, such as intraocular melanoma; acute macular neuroretinopathy; Behcet's disease; choroidal neovascularization; diabetic uveitis; histoplasmosis; infections, such as fungal or viral-caused infections; macular degeneration, such as acute macular degeneration, non-exudative age related macular degeneration and exudative age related macular degeneration; edema, such as macular edema (e.g., cystoid macular edema (CME), diabetic macular edema (DME), and macular edema from retinal vein occlusion); multifocal choroiditis; ocular trauma which affects a posterior ocular site or location; ocular tumors; retinal disorders, such as central retinal vein occlusion, diabetic retinopathy (including proliferative diabetic retinopathy), proliferative vitreoretinopathy (PVR), retinal arterial occlusive disease, retinal detachment, uveitic retinal disease; sympathetic opthalmia; Vogt Koyanagi-Harada (VKH) syndrome; uveal diffusion; a posterior ocular condition caused by or influenced by an ocular laser treatment; posterior ocular conditions caused by or influenced by a photodynamic therapy, photocoagulation, radiation retinopathy, epiretinal membrane disorders, branch retinal vein occlusion, anterior ischemic optic neuropathy, non-retinopathy diabetic retinal dysfunction, retinitis pigmentosa, retinoblastoma, and glaucoma. In some embodiments, the articles of the disclosure may be used to treat, prevent, or manage dry eye in a subject.

(133) In some embodiments, the articles of the disclosure may be used to treat, prevent, or manage inflammation in the eye of a subject (e.g., where the drug dimer is formed from one or more corticosteroids). Inflammation is associated with a variety of ocular disorders. Inflammation may also result from a number of ophthalmic surgical procedures, including cataract surgery and glaucoma surgery. In some embodiments, the pharmaceutical agent that is delivered into the eye by the articles of the disclosure and/or methods described herein may be a corticosteroid.

(134) In certain embodiments, the pharmaceutical agent includes one or more of hydrocortisone, cortisone, tixocortol, prednisolone, methylprednisolone, prednisone, triamcinolone acetonide, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone, halcinonide, betamethasone, dexamethasone, fluocortolone, hydrocortisone, aclometasone, prednicarbate, clobetasone, clobetasol, fluprednidene, glucocorticoid, mineralocorticoid, aldosterone, deoxycorticosterone, fludrocortisone, halobetasol, diflorasone, desoximetasone, fluticasone, flurandrenolide, alclometasone, diflucortolone, flunisolide, and beclomethasone. In some embodiments, the drug dimer of the disclosure are used as adjunctive therapy to reduce inflammation and fibrosis associated with devices (e.g., minimally invasive glaucoma surgery (MIGS) devices). In some embodiments, articles of the disclosure may be used to treat, prevent, or manage age-related macular degeneration (AMD) in a subject.

(135) In some embodiments, the articles of the disclosure may be used to treat, prevent, or manage infection in the eye of a subject (e.g., where the drug dimer is formed from an antibiotic steroid). In some embodiments, the pharmaceutical agent that is delivered into the eye by the articles of the disclosure and/or methods described herein may be fusidic acid.

(136) Ocular Inserts

(137) In some embodiments, the ocular inserts are shaped as fibers, rods, tubes, or stents. In some embodiments, the fibers have diameters in the range of 0.01-0.15 mm, e.g., 0.01-0.10 mm, 0.04-0.09 mm, 0.05-0.08 mm, or 0.05-0.15 mm. In some embodiments, the fibers have lengths sized for placement within the ocular space. In some embodiments, the ocular inserts are smaller than the canal diameter which ranges between 120 and 350 μm.

(138) The ocular inserts may have a blunt tip with a rounded shape. For example, the blunt tip may have a hemispherical shape.

(139) Some ocular inserts, such as tubes or stents, may include an inlet portion that is shaped and sized to extend through the trabecular meshwork of the eye. In some embodiments, the ocular insert is a hollow tube and can facilitate the flow of aqueous humor through its structure.

(140) Schlemm's Canal Inserts

(141) Schlemm's canal is located approximately in the apex of the angle of the junction of the cornea and the sclera and runs parallel to the margin of the cornea. The canal is lined with a single layer of vascular-derived endothelial cells and transports 2 to 3 μL per minute of aqueous humor from the anterior chamber to the venous plexus. The canal diameter ranges between 170 and 350 μm.

(142) Schlemm's canal inserts may be placed into Schlemm's canal of an eye to facilitate the flow of aqueous humor out of the anterior chamber of the eye by, e.g., supporting tissue in the trabecular meshwork and in Schlemm's canal. The flow facilitated by the presence of the Schlemm's canal insert may include axial flow along Schlemm's canal, flow into Schlemm's canal from the anterior chamber of the eye, and flow leaving Schlemm's canal via the outlets that communicate with the canal.

(143) After exiting Schlemm's canal via the outlets, aqueous humor enters the venous blood stream and is carried along with the venous blood leaving the eye. The pressure of the venous system tends to be around 5-10 mmHg above atmospheric pressure. Accordingly, the venous system provides a pressure backstop which assures that the pressure in the anterior chamber of the eye remains above atmospheric pressure.

(144) In some embodiments, the Schlemm's canal inserts act as reinforcing structures that hold the walls of Schlemm's canal in a patent state so that the walls of the canal provide a flow channel or fistula. The Schlemm's canal inserts may be sized and shaped to reinforce Schlemm's canal while occupying a relatively small portion of the total lateral cross sectional area of Schlemm's canal. In some embodiments, the Schlemm's canal insert provides minimal obstruction to aqueous humor flowing along the length of Schlemm's canal. Reinforcing Schlemm's canal with the Schlemm's canal insert of the disclosure may also encourage a safe healing response over time.

(145) Schlemm's canal inserts of the disclosure may be sized and shaped to facilitate the lateral flow of aqueous humor across and/or through the body of the Schlemm's canal insert. The lateral flow of aqueous humor may include the flow of aqueous humor through the trabecular mesh and into Schlemm's canal. The lateral flow of aqueous humor may also include the flow of aqueous humor through outlets that communicate with Schlemm's canal.

(146) In some patients, Schlemm's canal may have become compartmentalized. When this is the case, Schlemm's canal becomes a series of small compartments separated by discontinuities or partitions. In some embodiments, as the Schlemm's canal insert is advanced into Schlemm's canal, the distal tip of the Schlemm's canal insert penetrates the discontinuities/partitions. This penetrating action re-establishes fluid communication between adjacent compartments. The body of the Schlemm's canal insert facilitates flow across the partitions by remaining in Schlemm's canal after fluid communication has been re-established.

(147) In a diseased eye, Schlemm's canal and/or the upstream tissue can become closed in a way that the outflow of the aqueous humor is less than the inflow and thus the pressure inside the eye increases so that the optic nerve is correspondingly pinched. This visual disturbance, which is known as glaucoma, often leads to blindness of the affected eye or of both eyes. In some embodiments, the Schlemm's canal inserts are used in the treatment of glaucoma arising from local inflammation of the Schlemm's canal and/or the upstream tissue.

(148) The Schlemm's canal inserts can be shaped as fibers, rods, tubes, or stents and are capable of reducing local inflammation. In some embodiments, the fibers have diameters in the range of 0.01-0.15 mm, e.g., 0.01-0.10 mm, 0.04-0.09 mm, 0.05-0.08 mm, or 0.05-0.15 mm. In some embodiments, the fibers have lengths sized for placement within the Schlemm's canal. In other embodiments, the Schlemm's canal inserts are stiff and do not occupy the whole space of the Schlemm's canal. In some embodiments, the Schlemm's canal inserts are smaller than the canal diameter which ranges between 120 and 350 μm.

(149) The Schlemm's canal inserts may have a blunt tip with a rounded shape. For example, the blunt tip may have a hemispherical shape. The rounded shape of the blunt tip may increase the likelihood that the body of the Schlemm's canal implant will track Schlemm's canal as the Schlemm's canal insert is advanced into the canal during insertion of the article of the disclosure.

(150) Some Schlemm's canal inserts, such as tubes or stents, may include an inlet portion that is shaped and sized to extend through the trabecular meshwork of the eye. This inlet portion may provide a flow path between the anterior chamber and Schlemm's canal. In some embodiments, the Schlemm's canal insert is a hollow tube and can facilitate the flow of aqueous humor through its structure.

(151) Insertion of Schlemm's Canal Insert

(152) The Schlemm's canal insert can be introduced into the Schlemm's canal using a syringe or a surgical instrument specifically configured for the injection of the insert into the trabecular formations. This instrument may be a surgical probe that is introduced into Schlemm's canal during the procedure, and subsequently removed completely from the canal after the treatment. In some embodiments, the curved probe is connected to an injection introduced into Schlemm's canal.

(153) In some embodiments, the Schlemm's canal insert is placed into the Schlemm's canal using a Y-shaped tube that has a dual-bonded end and is small enough to fit inside Schlemm's canal. The procedure, similar to a nonpenetrating sclerostomy, begins with the creation of a deep scleral flap and the unroofing of a portion of Schlemm's canal. After Schlemm's canal is defined, the two legs of the tube are inserted in opposite directions down the canal, and the main stem is inserted through a small incision into the anterior chamber. In some embodiments, the Schlemm's canal insert is delivered to the canal and bypasses the juxtacanalicular portion of the trabecular meshwork.

(154) In some embodiments, the Schlemm's canal insert is a stent used in a bypass procedure that reestablishes normal outflow by stenting open the trabecular meshwork and Schlemm's canal. The stent may be inserted into Schlemm's canal internally through a clear corneal incision. This may allow aqueous to flow directly into the canal toward the episcleral drainage system, thus avoiding the trabecular meshwork.

(155) Suprachoroidal Inserts

(156) The suprachoroidal inserts can be introduced into the suprachoroidal space using a syringe or a surgical instrument specifically configured for the implantation of the insert to relieve intraocular pressure. The inserts of the disclosure can create a permanent conduit from the anterior chamber to the suprachoroidal space, draining the aqueous internally rather than accessing Schlemm's canal or the conventional aqueous outflow pathway. Implanted into the supraciliary space through a clear corneal incision, the insert may prevent the formation of a filtering bleb and spare the conjunctiva. The insert of the disclosure can be used for treatment of primary open-angle glaucoma. In an eye with glaucoma, the trabecular outflow pathway may be compromised. The insert of the disclosure can enhance fluid outflow from the anterior chamber of the eye.

(157) For example, the insert can be implanted in conjunction with phacoemulsification cataract surgery. The insert may be implanted through the phaco incision. Intracameral pupil-constricting and viscoelastic agents may be administered to aid in angle visualization and access. The insert can be placed onto a guide instrument that facilities the procedure. In some embodiments, the insert is introduced through paracentesis and guided to the implantation site across the anterior chamber using magnified visualization. The insert may be positioned toward the angle and introduced posterior to the scleral spur at the iris root. In some embodiments, the insert is introduced between ciliary body and the adjacent sclera, through which the insert is advanced. The insert may then be released from the guide instrument. The suprachoroidal insert can enhance the outflow through its structure into the superciliary or suprachoroidal space, and can also release an anti-inflammatory steroid, an antibiotic steroid, or an IOP lowering steroid.

(158) Intravitreal, Subretinal, or Suprachoroidal Injections

(159) Articles of the disclosure may be administered to the eye by intravitreal, subretinal, or suprachoroidal injection. For example, the article (e.g., a small cylinder sized for injection into the eye) can be placed directly into the space in the back of the eye, i.e., the vitreous cavity, which is filled with the vitreous humor gel. Intravitreal injections may be used to administer medications to treat a variety of conditions, including, without limitation, macular edema from retinal vein occlusion, diabetic macular edema, age-related macular degeneration (AMD), diabetic retinopathy, retinal vein occlusion, and uveitis. Alternatively, the articles can be implanted subretinally or suprachoroidally.

EXAMPLES

(160) The following examples, as set forth below, are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the methods and compounds claimed herein are performed, made, and evaluated, and are intended to be purely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their disclosure.

(161) Compounds 1-17 can be used in the methods, compositions, and articles of the disclosure.

(162) TABLE-US-00001 TABLE 1 Compounds of the disclosure Compound Dimer Abbreviation  1 Dexamethasone-Triethylene Glycol- Dex-TEG-Dex Dexamethasone  2 Hydrocortisone-Triethylene Glycol- HC-TEG-HC Hydrocortisone  3 Triamcinolone Acetonide-Triethylene TA-TEG-TA Glycol-Triamcinolone Acetonide  4 Dexamethasone-Triethylene Glycol- Dex-TEG-HC Hydrocortisone  5 Dexamethasone-Hexane- Dex-HEX-Dex Dexamethasone  6 Hydrocortisone-Succinate- HC-SUCC-HC Hydrocortisone  7 Anecortave-Triethylene Glycol- Anec-TEG-Anec Anecortave  8 Dexamethasone-Pentaethylene Dex-EG5-Dex Glycol-Dexamethasone  9 Fusidic Acid-Triethylene Glycol- FA-TEG-FA Fusidic Acid (carbonate ester) (CE) 10 Dexamethasone-Polyethylene Glycol Dex-PEG200-Dex (MW = 200)-Dexamethasone 11 Dexamethasone-Heptaethylene Dex-EG7-Dex Glycol-Dexamethasone 12 Dexamethasone-Nonaethylene Dex-EG9-Dex Glycol-Dexamethasone 13 Dexamethasone-Polyethylene Glycol Dex-PEG300-Dex (MW = 300)-Dexamethasone 14 Cholesterol-Triethylene Glycol- CHS-TEG-CHS Cholesterol 15 Fusidic Acid-Triethylene Glycol- FA-TEG-FA Fusidic Acid (ester) (E) 16 Ethinylestradiol-Triethylene Glycol- Ethin-TEG-Ethin Ethinylestradiol 17 Prednisolone-Triethylene Glycol- Pred-TEG-Pred Prednisolone

Example 1: Compound 1 (Dexamethasone-Triethylene Glycol-Dexamethasone) can be Synthesized, Processed into Pellets in the Glassy State by Heat Molding, and Release Drug Through Surface Erosion from an Intact Pellet

(163) Dexamethasone (1 mol equivalent) was suspended in dichloromethane on an ice bath and triethylamine (2 mol equivalent) and triethylene glycol bis(chloroformate) (0.6 mol equivalent) were added to the mixture. The ice bath was allowed to warm to room temperature and the reaction was stirred overnight. The solvent was removed and the solid residue was purified by column chromatography. Product was recrystallized twice from acetonitrile to give Compound 1 (FIG. 1A) as an off-white crystalline solid.

(164) Compound 1: HPLC (mobile phase: H.sub.2O/TFA and MeCN/TFA) 31.7 min; Elemental analysis: Anal. Calcd for C.sub.52H.sub.68F.sub.2O.sub.16: C, 63.27; H, 6.94; N, 0.00; Cl, 0.00 Found: C, 62.62; H, 6.84; N, <0.50; Cl<100 ppm. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ (ppm) 0.80 (d, J=7 Hz, 6H, 2×C16 α-CH.sub.3); 0.90 (s, 6H, 2×C18-CH.sub.3); 1.08 (m, 2H, 2×C16-H); 1.35 (m, 2H, 2×C14-H); 1.49 (s, 6H, 2×C19-CH.sub.3); 1.54 (q, J=13 Hz, 2H, 2×C13-H); 1.64 (q, J=11 Hz, 2H, 2×C15-CH.sub.2); 1.77 (m, 2H, 2×C15-CH.sub.2); 2.15 (m, 4H, 2×C6-CH.sub.2); 2.32 (m, 4H, 2×C7-CH.sub.2); 2.62 (m, 2H, 2×C12-CH.sub.2); 2.89 (m, 2H, 2×C12-CH.sub.2); 3.57 (s, 4H, 2×TEG OCH.sub.2); 3.65 (m, 4H, 2×TEG OCH.sub.2); 4.15 (m, 2H, 2×OCH); 4.22 (m, 4H, 2×TEG OCH.sub.2); 4.79 (d, 2H, AB, J=18.5 Hz, 2H, C21-CH.sub.2O—); 5.09 (d, 2H, AB, J=18.5 Hz, 2H, C21-CH.sub.2O—); 5.18 (s, 2H, C17-OH); 5.40 (d, 2H, J=4.5 Hz, C11-OH); 6.01 (d, 2H, J=1.9 Hz, 2×alkene C4-CH); 6.23 (dd, 2H, J=10.1 and 1.9 Hz, CH, 2×alkene C2-CH); 7.29 (d, 2H, C1-CH 2×alkene CH, 10.1 Hz, 2H). MS (ESI+) m/z: [M+H]+ Calcd for C.sub.52H.sub.69F.sub.2O.sub.16 987.46; Found 987.46.

(165) Compound 1 was formed into pellets in the glassy state by heat molding (FIG. 1B). Crystalline powder was melted at 185° C. and pellets were formed from 1 mm×1 mm cylindrical molds. The starting powder and heat-processed pellets were tested by differential scanning calorimetry (DSC; FIG. 1C) and powder x-ray diffraction (PXRD; FIG. 1D) to confirm heat-processing converted compound 1 from the crystalline state to the glassy state.

(166) Heat-molded pellets from Compound 1 (˜1 mm×1 mm) were placed in 20 mL glass vials and 2 mL of release buffer (either 100% phosphate buffered saline (PBS), 1% fetal bovine serum (FBS) in PBS, or 100% FBS) was added. Samples were incubated at 37° C. on a shaker rotating at 115 rpm. After 1 day, 3 days, 7 days, and subsequently in alternating 3 and 4 day intervals (i.e., 1, 3, 7, 10, 14 days etc.), release buffer was sampled directly (PBS) or syringe filtered, proteins were precipitated with acetonitrile, and drug release products were extracted. The samples were analyzed by high performance liquid chromatography (HPLC) to quantify drug products. Cumulative drug release was calculated and plotted as a percentage of the total drug in each pellet released over time (FIG. 1E). Representative images of the pellets confirm surface erosion over time in 100% FBS (FIG. 1F).

Example 2: Compound 1 (Dex-TEG-Dex) can be Processed into Different Forms in the Glassy State by Multiple Processing Methods from the Melt and Solution States

(167) Compound 1 was processed into different forms in the glassy state from the melt and solution states. Compound 1 was coated onto different surfaces from the solution state by dissolving in an organic solvent and applying on a surface using common coating techniques (e.g., dip-coating, spray coating, drop-coating, electrospraying, etc.). FIGS. 2A and 2B show Compound 1 coated on titanium and poly(styrene-block-isobutylene-block-styrene) (SIBS) surfaces, respectively, from acetone. Extruded cylinders were prepared by adding Compound 1 as a crystalline powder into a micro-extruder with different nozzles to form extruded material of different diameters. The micro-extruder was heated to 185° C. to melt the powder and form the extrudate. FIG. 2C shows an extruded cylinder with a 23 G diameter nozzle. Fibers of Compound 1 (FIG. 2D) were prepared by heat extrusion at 185° C. using a small diameter nozzle (e.g., 30-32 G) combined with a tensile force to pull the extrudate out of the nozzle. Fibers were also prepared by melting Compound 1 from a powder at 185° C. and pulling the melted material at different rates to yield fibers of different diameters. Compound 1 was processed into fibrous meshes by electrospinning from the solution state in tetrahydrofuran (FIG. 2E). Micro- and nano-particles were prepared by electrospraying (FIG. 2F) and emulsion (FIG. 2G) from the solution state. Different preparation conditions (solvents, concentrations, surfactants, surfactant concentrations, mixing conditions, etc.) resulted in different particle sizes and distributions.

Example 3: Processing Compound 1 (Dex-TEG-Dex) into an Intermediate Glassy State to Manufacture the Final Article

(168) Compound 1 (Dex-TEG-Dex) was formed into heat extruded cylinders directly from the crystalline powder by heating above the melting point (185° C.), as shown in FIGS. 3A and 3B, using the methods described above in Example 14. Compound 1 was also formed into heat extruded cylinders by forming an intermediate glassy state form from the melt followed by heat extrusion above the glass transition temperature (150° C.) as shown in FIGS. 3C and 3D. Purity of the extrudate over time is shown in FIG. 3E and demonstrates longer extrusion run times using the intermediate glassy state before Compound 1 drops in purity when compared to extrusion from the melt state.

(169) An intermediate glassy state was also formed from the solution state. Compound 1 was dissolved in acetone and was electrosprayed onto a polymer surface to form glassy state microparticles. The sprayed surface was heated to 150° C. to obtain a coating as shown in FIG. 3F.

Example 4: Drug Release from Compound 1 (Dex-TEG-Dex) Coated on Different Surfaces

(170) Compound 1 was coated onto titanium and SIBS as described in Example 3 above. Drug release from the coated material was carried out in PBS as described in Example 1 above. Cumulative drug release was calculated and plotted as a percentage of the total drug in each coated surface released over time (FIG. 4).

Example 5: Intravitreal Implants of Compound 1 (Dex-TEG-Dex) Undergo Surface Erosion in the Eye

(171) Compound 1 was formed into cylinders by heat molding as described in Example 1. The cylinders were injected intravitreally into rat eyes. Fundus microscopy was used to image the implants non-invasively over time to demonstrate surface erosion of the implant (FIG. 5).

Example 6: Intravitreal Implants of Compound 1 (Dex-TEG-Dex) Release Dexamethasone that Inhibits Endotoxin-Induced Inflammation in the Eye

(172) Compound 1 was formed into cylinders by heat molding (˜0.34 mm×0.8 mm; FIG. 6A) and heat extrusion from the intermediate glassy state (˜0.12 mm×1 mm; FIG. 6B) as described in Examples 1 and 3 above. The implants were loaded into 23 G and 30 G needles respectively and were sterilized by ethylene oxide (ETO) gas. An acute study evaluating only the 23 G heat molded implants was performed and a sub-chronic study evaluating both implants followed. The implants for each study were injected intravitreally into rat eyes and were imaged by fundus microscopy as seen in FIGS. 6C and 6D for the 23 G and 30 G implants, respectively. Inflammation in the eye was induced using an intravitreal injection of the endotoxin lipopolysaccharide (LPS) 1-day post-implantation for the acute study and 60 days post-implantation for the sub-chronic study. Both studies had a negative control arm with eyes receiving a sham 23 G injection and a positive control arm with eyes receiving a sham 23 G injection and dexamethasone eye drops. Optical coherence tomography (OCT) was used to image the eyes (FIG. 6E) and inflammation was assessed by quantifying the number of cells in the vitreous humour and the thickness of the retinal tissue measured from the OCT images. Vitreal cell count and retinal thickness data are shown in FIGS. 6F and 6G, respectively, for the acute study and in FIGS. 6H and 6I, respectively, for the sub-chronic study and demonstrate dexamethasone released from intravitreal implants of Compound 1 inhibit endotoxin-induced inflammation in the eye.

Example 7: Intravitreal Implants of Compound 1 (Dex-TEG-Dex) Release a Consistent Dose of Dexamethasone in the Eye

(173) Compound 1 was formed into cylinders by heat extrusion from the intermediate glassy state as described in Example 3. The cylinders were extruded with 23 G and 30 G nozzles. The cylinders were cut to length to form 30 G×1 mm cylinders, 30 G×6 mm cylinders, and 23 G×6 mm cylinders as shown in FIG. 7A. In vitro drug release in PBS was carried out as described in Example 1 with the dose and duration roughly following surface erosion theory as shown in FIGS. 7B and 7C. The cylinders were injected intravitreally into New Zealand white rabbits and dexamethasone was quantified in the vitreous humour at different time points. FIG. 7D plots the drug concentration over time for the different cylinders and shows a consistent dose of dexamethasone is released from the cylinders of Compound 1 in the eye.

Example 8: Intravitreal Implants of Compound 1 (Dex-TEG-Dex) Inhibit Vascular Endothelial Growth Factor (VEGF)-Induced Retinal Vascular Leakage in the Eye

(174) Compound 1 was formed into cylinders by heat extrusion from the intermediate glassy state as described in Example 3. The cylinders were extruded with 27 G and 30 G nozzles to get diameters ˜0.2 mm and ˜0.12 mm respectively. The cylinders were cut to different lengths, ETO gas sterilized, and injected intravitreally into the eyes of Dutch belted rabbits. VEGF was injected intravitreally at 1 week and 10 weeks post-implantation to induce retinal vascular leakage. Sham injection was used as a negative control. Intravitreal implants of Compound 1 provided sustained release of dexamethasone that inhibited VEGF-induced retinal vascular leakage as demonstrated by fundus microscopy (FIG. 8A) and fluorescein angiography (FIG. 8B) compared to negative control (FIGS. 8C and 8D).

Example 9: Intravitreal Implants of Compound 1 (Dex-TEG-Dex) are Used to Treat Inflammatory or Neovascularization Conditions or to Prevent or Reduce Inflammation in the Eye

(175) Cylinders of Compound 1 are formed using methods described above. The cylinders are injected into the vitreous humour and release dexamethasone to the surrounding tissues including tissues in the anterior eye, the posterior eye, and surrounding tissues. Dexamethasone released from the cylinder is released by surface erosion over the course of months to years. The intravitreal implants release drug that may be used in subjects with diabetic macular edema, macular edema from retinal vein occlusion, uveitis, cystoid macular edema, post-surgical inflammation (e.g. cataract or glaucoma surgery), age-related macular degeneration, and other ocular conditions.

Example 10: Compound 1 (Dex-TEG-Dex) as a Coating on Minimally Invasive Glaucoma Devices (MIGS)

(176) Coating of Compound 1 is applied onto a MIGS device as described in the methods above. The device is inserted into the eye of a subject to provide fluid flow and reduce intraocular pressure associated with glaucoma. The coating releases dexamethasone into the surrounding tissue to inhibit a tissue response to the device and reduce fibrosis. Drug is released from the device coating into the eye over months to years.

Example 11: Schlemm's Canal Fiber Implant of Compound 1 (Dex-TEG-Dex) are Used to Prevent or Reduce Post-Surgical Inflammation in the Eye

(177) A fiber or tube of Compound 1 is formed using the methods described above. The implant is inserted into the Schlemm's canal of a subject having received surgery and releases dexamethasone by surface erosion over weeks to months. The drug released helps to prevent or reduce inflammation associated with the surgical procedure.

Example 12: Intracameral Implants or Wafers of Compound 1 (Dex-TEG-Dex) are Used to Prevent Post-Surgical Inflammation in the Eye

(178) Fibers or cylinders are formed from Compound 1 according to the methods described above. The fibers are woven into a mesh and are placed into the eye of a subject having received surgery. Dexamethasone is released from the fiber mesh or cylinder by surface erosion at a steady rate over several months, e.g., three months. Inflammation in the eye is reduced as a result.

Example 13: Micro- or Nanoparticles of Compound 1 (Dex-TEG-Dex) in the Suprachoroidal Space Used to Treat Inflammatory or Neovascularization-Based Conditions or Prevent Inflammation in the Eye

(179) Micro- or nanoparticles of Compound 1 are formed using the methods described above. The particles are injected into the suprachoroidal space of a subject with an ocular condition associated with inflammation or neovascularization or as an adjunctive therapy to reduce inflammation associated with ocular surgery. Dexamethasone is released from the particles over months to years and reduces inflammation or neovascularization associated with the condition or surgery.

Example 14: Suprachoroidal Insert of Compound 1 (Dex-TEG-Dex) Reduces Intraocular Pressure

(180) A cylinder or tube of Compound 1 is formed using the methods described above. The implant is inserted into the eye of a subject with glaucoma to create a conduit from the anterior chamber into the suprachoroidal space. The conduit allows fluid to flow out of the eye to reduce intraocular pressure. The cylinder or tube undergoes surface erosion to release dexamethasone to modulate the tissue response to the implant and reduce inflammation associated with its placement. The conduit and drug release may last from months to years.

Example 15: Synthesis, Processing, and Drug Release from Heat-Molded Glassy State Pellets of Compounds 2-10 and 17

(181) Compounds 2-10 and 17 were synthesized using standard methods known in the art, similar to the synthesis of Compound 1 in Example 1 above. Details of synthesized Compounds 2 to 10 and 17 are shown in the tables below. Melting points (Tm) and glass transition temperatures (Tg) were determined to establish processing temperatures needed to heat-process the compounds into pellets, fibers, and cylinders for further testing.

(182) TABLE-US-00002 TABLE 2 Structures of Compounds 2-10 Compound Linking Tm & (Abbreviation) Steroid Linker Moiety Structure Tg (° C.)  2 Hydrocortisone Triethylene Carbonate FIG. 9A  127 & 113 (HC-TEG-HC) Glycol  3 Triamcinolone Triethylene Carbonate FIG. 10A 183 & 138 (TA-TEG-TA) Acetonide Glycol  4 Dexamethasone Triethylene Carbonate FIG. 11A 143 & 120 (Dex-TEG-HC) & Hydrocortisone Glycol  5 Dexamethasone Hexane Carbonate FIG. 12A 149 & 146 (Dex-HEX-Dex) Diol  6 Hydrocortisone Succinic Ester FIG. 13A 157 & 144 (HC-SUCC-HC) Acid  7 Anecortave Triethylene Carbonate FIG. 14A 102 & 100 (Anec-TEG-Anec) Glycol  8 Dexamethasone Pentaethylene Carbonate FIG. 15A n.d.* & 66 (Dex-EG5-Dex) Glycol  9 Fusidic Acid Triethylene Carbonate FIG. 16A 91 & 85 (FA-TEG-FA(CE)) Glycol Ester 10 Dexamethasone Polyethylene Carbonate FIG. 17A n.d.* & 96 (Dex-PEG200-Dex) Glycol (MW = 200) 17 Prednisolone Triethylene Carbonate FIG. 27A 128 & 112 (Pred-TEG-Pred) Glycol *n.d. = not determined

(183) Compounds 2-10 and 17 were processed into heat molded pellets (˜1 mm×1 mm), fibers from the melt state, and/or heat extruded cylinders from the melt or intermediate glassy state as described in Examples 1-3 above using the appropriate temperature for each compound (i.e. above the Tm or Tg as required). Drug release from the glassy state heat molded pellets was carried out in PBS and/or 100% FBS, as described in Example 1, for different time periods. Cumulative drug release plotted over time demonstrated drug release from different Compounds occurs mostly linearly at different rates from intact pellets in the timeframes tested, similar to Compound 1. Pellets of Compound 4, a heterodimer, released both dexamethasone and hydrocortisone. Figures corresponding to images of the pellets, fibers, and cylinders and drug release curves from pellets are shown in the table below.

(184) TABLE-US-00003 TABLE 3 Compounds processed in glassy state Processed Compounds in Glassy State Heat Molded Extruded Drug Compound Pellets Fibers Cylinders Release  2 FIG. 9B  FIG. 9C  FIG. 9D  FIG. 9E  (HC-TEG-HC)  3 FIG. 10B FIG. 10C FIG. 10D FIG. 10E (TA-TEG-TA)  4 FIG. 11B Not Tested Not Tested FIG. 11C (Dex-TEG-HC)  5 FIG. 12B FIG. 12C FIG. 12D FIG. 12E (Dex-Hex-Dex)  6 FIG. 13B FIG. 13C FIG. 13D FIG. 13E (HC-SUCC-HC)  7 FIG. 14B FIG. 14C FIG. 14D FIG. 14E (Anec-TEG-Anec)  8 FIG. 15B Not tested Not tested FIG. 15C (Dex-EG5-Dex)  9 FIG. 16B FIG. 16C FIG. 16D FIG. 16E (FA-TEG-FA(CE)) 10 FIG. 17B Not tested FIG. 17C FIG. 17D (Dex-PEG200-Dex) 17 FIG. 27B FIG. 27C Not tested Not tested (Pred-TEG-Pred)

Example 16: Synthesis and Processing of Compounds 11-16

(185) Compounds 11-16 were synthesized using standard methods known in the art, similar to the synthesis of Compound 1 in Example 1 above. Details of synthesized Compounds 11-16 are shown in the tables below. Melting points (Tm) and glass transition temperatures (Tg) were determined to establish processing temperatures needed to heat-process the compounds into pellets, fibers, and cylinders for further testing

(186) TABLE-US-00004 TABLE 4 Structures of Compounds 11-16 Compound Linking Tm & (Abbreviation) Steroid Linker Moiety Structure Tg (° C.) 11 Dexamethasone Heptaethylene Carbonate FIG. 18A 51 & 47 (Dex-EG7-Dex) Glycol 12 Dexamethasone Nonaethylene Carbonate FIG. 19A 41 & 37 (Dex-EG9-Dex) Glycol 13 Dexamethasone Polyethylene Carbonate FIG. 20A 77 & 75 (Dex-PEG300-Dex) Glycol (MW = 300) 14 Cholesterol Triethylene Carbonate FIG. 21A 99 & 22 (CHS-TEG-CHS) Glycol 15 Fusidic Acid Triethylene Ester FIG. 22A 87 & 84 (FA-TEG-FA(E)) Glycol 16 Ethinylestradiol Triethylene Carbonate FIG. 23A 61 & 53 (Ethin-TEG-Ethin) Glycol *n.d. = not determined

(187) TABLE-US-00005 TABLE 5 Heat-molded pellets formed from Compounds 11-16 Heat Molded Compound Pellets 11 FIG. 18B (Dex-EG7-Dex) 12 FIG. 19B (Dex-EG9-Dex) 13 FIG. 20B (Dex-PEG300-Dex) 14 FIG. 21B (CHS-TEG-CHS) 15 FIG. 22B (FA-TEG-FA(E)) 16 FIG. 23B (Ethin-TEG-Ethin)

Example 17: Intracameral Implants of Compound 7 (Anec-TEG-Anec) are Used to Lower Intraocular Pressure in the Eye

(188) Cylinders, pellets, or fibrous meshes of Compound 7 are formed using the methods described above. The implants are inserted intracamerally into subjects with glaucoma. The implants release anecortave through surface erosion over months to years and lower intraocular pressure in the eye.

Example 18: Suprachoroidal Inserts of Compound 7 (Anec-TEG-Anec) are Used to Lower Intraocular Pressure in the Eye

(189) A cylinder or tube of Compound 7 is formed using the methods described above. The implant is inserted into the eye of a subject with glaucoma to create a conduit from the anterior chamber into the suprachoroidal space. The cylinder or tube undergoes surface erosion to release anecortave. Both the conduit and released drug act to reduce intraocular pressure and may last from months to years.

Example 19: Intracameral Implants of Compound 9 (FA-TEG-FA (CE)) are Used to Prevent Post-Surgical Infection in the Eye

(190) Cylinders, pellets, or fibrous meshes of Compound 9 are formed using the methods described above. The implants are inserted intracamerally into subjects that are receiving an ocular surgical procedure. The implants release fusidic acid over days to weeks to a few months to prevent infection.

Example 20: Heat-Molded Pellets in the Glassy State can be Formed from Mixtures of Two Dimers and Drugs are Released from Both Compounds of the Intact Pellet

(191) Pellets in the glassy state were formed by heat molding a mixture of compounds as shown in the table below. The starting crystalline compounds were mixed together and were heat molded at a temperature above the higher melting point compound. Drug release from the pellets (˜1 mm×1 mm and 1 mg of total mixture) was carried out in PBS as described in Example 1. Cumulative drug release was calculated and plotted as a percentage of the total drug released over time. Linear drug release from intact pellets was observed for both compounds in the mixed pellets.

(192) TABLE-US-00006 TABLE 6 Heat-molded pellets formed from mixtures of two compounds and drug release Components Heat-Molded Mixture of Mixture Ratio Pellet Drug Release A Compound 1 1:1 FIG. 24A FIG. 24B (Dex-TEG-Dex) & w/w Compound 2 (HC-TEG-HC) B Compound 1 1:1 FIG. 25A FIG. 25B (Dex-TEG-Dex) & w/w Compound 3 (TA-TEG-TA) C Compound 2 1:1 FIG. 26A FIG. 26B (HC-TEG-HC) & w/w Compound 3 (TA-TEG-TA)

Example 21: Intracameral Implants of Compound 1 (Dex-TEG-Dex) and Compound 9 (FA-TEG-FA (CE)) are Used to Inhibit Post-Surgical Inflammation and Infection

(193) Cylinders, pellets, or fibrous meshes of Compound 1 and 9 are formed using the methods described above. The implants are inserted intracamerally into subjects that are receiving an ocular surgical procedure. The implants release dexamethasone and fusidic acid over days to weeks to a few months to reduce inflammation associated with the surgery and prevent infection.

Example 22: Delivery of Schlemm's Canal Insert into Schlemm's Canal

(194) The articles of the disclosure can be inserted into the Schlemm's canal in a surgical procedure that generally includes the steps of creating an incision in the ocular wall that provides access to the anterior chamber of the eye; advancing a cannula of the system through the incision, across a portion of the anterior chamber, to the trabecular meshwork, and piercing the trabecular meshwork; accessing Schlemm's canal with the cannula; and implanting the article (i.e., a Schlemm's canal insert) within the canal. The cannula typically includes a proximal end and a distal curved portion, the distal curved portion having a proximal end and a distal end and a radius of curvature defined between the ends; a body; a distal tip having a bevel, the bevel directly engaging the distal end of the curved portion of the cannula; and a lumen extending from the proximal end through the distal tip. A positioning element slidable within the cannula lumen may be employed during the step of implanting the Schlemm's canal insert within the canal. The Schlemm's canal insert may be implanted to reduce inflammation, reduce intraocular pressure, or to treat a medical condition such as glaucoma, pre-glaucoma, or ocular hypertension.

(195) The method for treating conditions of the eye may include advancing a conduit into Schlemm's canal, where the conduit has been loaded with the Schlemm's canal insert, and delivering the Schlemm's canal insert into Schlemm's canal at a size sufficient to disrupt the trabeculocanalicular tissues to reduce intraocular pressure.

(196) The method can be performed in conjunction with cataract surgery to insert the anti-inflammatory steroids for the purpose of reducing the risk of post-surgical complications.

(197) Some embodiments of the disclosure provided herein can be defined according to the following numbered items:

(198) 1. A method of treating an ocular condition in an eye of a subject in need thereof, said method comprising contacting the eye with an article formed from a compound of formula (A-I):
D1-L-D2  (A-I), or a pharmaceutically acceptable salt thereof, wherein each of D1 and D2 is, independently, a radical formed from a steroid selected from an antibiotic steroid, a glucocorticoid steroid, an anti-angiogenic steroid, an intraocular pressure (TOP) lowering steroid, and a corticosteroid; and L is a linker covalently linking D1 to D2.

(199) 2. The method of item 1, wherein L is covalently linked to D1 and to D2 via one or more ester, carbonate, carbonate ester, or anhydride linkages.

(200) 3. The method of item 2, wherein L is covalently linked to D1 and to D2 via one or more carbonate linkages.

(201) 4. The method of any one of items 1-3, wherein

(202) L comprises the radical —(C(O)—(R.sup.A)—C(O)— or —O—(R.sup.A)—O—;

(203) R.sup.A is a radical of a polyol and includes at least one free hydroxyl group or R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms,

(204) —(CH.sub.2CH.sub.2O).sub.qCH.sub.2CH.sub.2—, —(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2CH.sub.2CH.sub.2—, or —(CH.sub.2CH(CH.sub.3)O).sub.sCH.sub.2CH(CH.sub.3)—; and

(205) q, r, and s are integers from 1 to 10.

(206) 5. The method of any one of items 1-4, wherein D1 and D2 are formed from the same steroid and the compound is further described by one of formulas (II-a)-(II-r).

(207) 6. The method of any one of items 1-5, wherein D1 and D2 are formed from different steroids and each of D1 and D2 are, independently, further described by one of formulas (I-a)-(I-r).

(208) 7. The method of any one of items 1-6, wherein at least 70% (w/w) of the article is the compound of formula (A-I).

(209) 8. The method of item 7, wherein at least 90% (w/w) of the article is the compound of formula (A-I).

(210) 9. The method of any one of items 1-8, wherein the compound, D1, or D2 are released from the article through surface erosion.

(211) 10. The method of item 9, wherein the surface erosion releases less than 10% of D1 or D2, as a percentage of the total drug, D1 or D2, present in the article in prodrug form, at 37° C. in 100% bovine serum over 5 days; or the surface erosion releases less than 2% of D1 or D2, as a percentage of the total drug, D1 or D2, present in the article in prodrug form, at 37° C. in PBS over 5 days; or the surface erosion releases greater than 20% of D1 or D2, as a percentage of the total drug, D1 or D2, present in the article in prodrug form, at 37° C. in 100% bovine serum over not fewer than 6 days; or the surface erosion releases greater than 5.0% of D1 or D2, as a percentage of the total drug, D1 or D2, present in the article in prodrug form, at 37° C. in PBS over not fewer than 6 days; or D1 and/or D2 is released from the article at a rate such that t.sub.10 is greater than or equal to 1/10 of t.sub.50.

(212) 11. The method of any one of items 1-10, wherein the article further comprises from 0.1% to 10% (w/w) of one or more additives, wherein the one or more additives are selected from plasticizers, antioxidants, binders, lubricants, dyes, and mixtures thereof.

(213) 12. The method of any one of items 1-11, wherein the article is a fiber, fiber mesh, woven fabric, non-woven fabric, pellet, cylinder, microparticle, nanoparticle, or shaped article.

(214) 13. The method of any one of items 1-11, wherein the article is in the form of a punctal plug, a stent, or a tube.

(215) 14. The method of any one of items 1-11, wherein the article is a fiber, a cylinder, a stent, or a tube.

(216) 15. The method of any one of items 1-11, wherein the article is a cylinder and the method further comprises intravitreally, subretinally, or suprachoroidally injecting the article into the eye.

(217) 16. The method of any one of items 1-15, wherein the ocular condition is an inflammatory condition.

(218) 17. The method of item 16, wherein the inflammatory condition is macular edema from retinal vein occlusion, diabetic macular edema, uveitis, diabetic retinopathy, or age-related macular degeneration (AMD).

(219) 18. The method of item 16, wherein upon hydrolysis, D1 and D2 form a corticosteroid or a glucocorticoid steroid.

(220) 19. The method of item 18, wherein said compound is further described by the formula (III):

(221) ##STR00032##

(222) or a pharmaceutically acceptable salt thereof, wherein

(223) L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—; R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or O—(R.sup.A)—O is a radical of a polyol and includes at least one free hydroxyl group or O—(R.sup.A)—O is selected from: —O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O—, —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, or —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and n, m, and p are integers from 1 to 10.

(224) 20. The method of any one of items 1-15, wherein the ocular condition is a bacterial infection.

(225) 21. The method of any one of items 1-15, wherein the ocular condition is conjunctivitis, keratitis, trachoma, or endophthalmitis.

(226) 22. The method of item 20, wherein upon hydrolysis, D1 and D2 form fusidic acid.

(227) 23. The method of any one of items 1-15, wherein upon hydrolysis D1 and D2 form an anti-angiogenic steroid or an intraocular pressure (TOP) lowering steroid.

(228) 24. The method of item 23, wherein upon hydrolysis D1 and D2 form anecortave acetate, anecortave, 11-epicortisol, 17α-hydroxyprogesterone, tetrahydrocortexolone, or tetrahydrocortisol.

(229) 25. The method of item 23 or 24, wherein the compound of formula (A-I) is administered intravitreally to the eye of the subject.

(230) 26. The method of item 23 or 24, wherein the compound of formula (A-I) is administered to the suprachoroidal space of an eye of the subject.

(231) 27. The method of any one of items 23-26, wherein the subject has age related macular degeneration, and upon hydrolysis D1 and D2 form an anti-angiogenic steroid, a corticosteroid, or a glucocorticosteroid.

(232) 28. The method of any one of items 23-26, wherein the subject has glaucoma, and upon hydrolysis D1 and D2 form an intraocular pressure (TOP) lowering steroid.

(233) 29. The method of any one of items 1-28, wherein the article is formed by a process comprising the steps of:

(234) (a) heating the compound, or a pharmaceutically acceptable salt thereof, to form a melt; and

(235) (b) heat molding the melt to form the article.

(236) 30. The method of any one of items 1-28, wherein the article is formed by a process comprising the steps of:

(237) (a) heating the compound, or a pharmaceutically acceptable salt thereof, to form a melt; and

(238) (b) injection molding the melt to form the article.

(239) 31. The method of any one of items 1-28, wherein the article is formed by a process comprising the steps of:

(240) (a) heating the compound, or a pharmaceutically acceptable salt thereof, to form a melt; and

(241) (b) blow molding the melt to form the article.

(242) 32. The method of any one of items 1-28, wherein the article is formed by a process comprising the steps of:

(243) (a) dissolving the compound, or a pharmaceutically acceptable salt thereof, to form a solution; and

(244) (b) evaporating the solvent to form the article.

(245) 33. The method of any one of items 1-28, wherein the article is formed by a process comprising the steps of:

(246) (a) dissolving the compound, or a pharmaceutically acceptable salt thereof, to form a solution; and

(247) (b) electrospinning, dry spinning, wet spinning, gel spinning, or electrospraying the solution to form the article.

(248) 34. The method of any one of items 1-28, wherein the article is formed by a process comprising the steps of:

(249) (a) heating the compound, or a pharmaceutically acceptable salt thereof, to form a melt; and

(250) (b) electrospinning or electrospraying the melt to form the article.

(251) 35. The method of any one of items 1-28, wherein the article is formed by a process comprising the steps of:

(252) (a) heating the compound, or a pharmaceutically acceptable salt thereof, to form a melt;

(253) (b) extruding the melt to form the article.

(254) 36. A method of forming of any one of items 29-35, wherein the article is formed by a process comprising:

(255) (a) heating the compound, or a pharmaceutically acceptable salt thereof, to form a melt;

(256) (b) cooling the melt to form a glassy state composition; and

(257) (c) heating the glassy state composition to a temperature above the glass transition temperature of the glassy state composition and shaping the glassy state composition to form a shaped article.

(258) 37. A method of forming of any one of items 29-35, wherein the article is formed by a process comprising:

(259) (a) dissolving the compound, or a pharmaceutically acceptable salt thereof, in a solvent to form a solution;

(260) (b) evaporating the solvent to form a glassy state composition; and

(261) (c) heating the glassy state composition to a temperature above the glass transition temperature of the glassy state composition and shaping the glassy state composition to form a shaped article.

(262) 38. The method of item 36 or 37, wherein step (c) comprises extruding, molding, blow molding, heat spinning, electrospinning or electrospraying the glassy state composition to form the shaped article.

(263) 39. A method of forming of any one of items 29-35, wherein the article is formed by a process comprising:

(264) (a) dissolving the compound, or a pharmaceutically acceptable salt thereof, in a solvent to form a solution;

(265) (b) electrospraying or electrospinning the solution to form a glassy state composition; and

(266) (c) heating the glassy state composition to a temperature above the glass transition temperature of the glassy state composition and shaping the glassy state composition to form a coating.

(267) 40. The method of any one of items 1-39, wherein the article is free of controlled release excipient.

(268) 41. The method of any one of items 1-39, wherein the article is free of a crystallization inhibiting excipient.

(269) 42. The method of any one of items 1-39, wherein the article is free of a mechanical integrity enhancing excipient.

(270) 43. The method of any one of items 1-39, wherein the article is free of a binding excipient.

(271) 44. The method of any one of items 1-43, wherein the article optionally has a glassy state.

(272) 45. A compound of formula (II-n):

(273) ##STR00033##

(274) wherein

(275) R.sub.12 represents —C(═O)CH.sub.2OC(═O)CH.sub.3, —C(═O)CH.sub.2OH, or —C(═O)CH.sub.3;

(276) R.sub.15 represents H or OH;

(277) L is —C(O)O—(R.sup.A)—OC(O)— or —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—,

(278) R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or

(279) O—(R.sup.A)—O is a radical of a polyol and includes at least one free hydroxyl group or O—(R.sup.A)—O is selected from: —O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O—, —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, or —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and

(280) n, m, and p are integers from 1 to 10.

(281) 46. The compound of item 45, wherein the compound is formed from anecortave acetate, anecortave, 11-epicortisol, 17α-hydroxyprogesterone, tetrahydrocortexolone, or tetrahydrocortisol.

(282) 47. A compound of formula (II-o):

(283) ##STR00034##

(284) wherein

(285) the bond between C.sub.3 and R.sub.2 is a single or a double bond;

(286) R.sub.2 represents OH or ═O;

(287) R.sub.12 represents —C(═O)CH.sub.2OC(═O)CH.sub.3, —C(═O)CH.sub.2OH, or —C(═O)CH.sub.3;

(288) R.sub.15 represents H or OH;

(289) L is —C(O)O—(R.sup.A)—OC(O)— or —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—,

(290) R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or

(291) O—(R.sup.A)—O is a radical of a polyol and includes at least one free hydroxyl group or O—(R.sup.A)—O is selected from: —O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O—, —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, or —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and

(292) n, m, and p are integers from 1 to 10.

(293) 48. The compound of item 47, wherein the compound is formed from anecortave acetate, anecortave, 11-epicortisol, 17α-hydroxyprogesterone, tetrahydrocortexolone, or tetrahydrocortisol.

(294) 49. A compound of formula (II-p):

(295) ##STR00035##

(296) wherein

(297) the bond between C.sub.3 and R.sub.2 is a single or a double bond;

(298) R.sub.2 represents OH or ═O; R.sub.15 represents H or OH;

(299) L is —C(O)O—(R.sup.A)—OC(O)— or —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—;

(300) R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or

(301) O—(R.sup.A)—O is a radical of a polyol and includes at least one free hydroxyl group or O—(R.sup.A)—O is selected from: —O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O—, —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, or —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and

(302) n, m, and p are integers from 1 to 10.

(303) 50. The compound of item 49, wherein the compound is formed from anecortave, 11-epicortisol, tetrahydrocortexolone, or tetrahydrocortisol.

(304) 51. A compound of formula (II-r):

(305) ##STR00036##

(306) wherein

(307) the bond between C.sub.3 and R.sub.2 is a single or a double bond;

(308) R.sub.2 represents OH or ═O; and

(309) L is —C(O)O—(R.sup.A)—OC(O)— or —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—; and

(310) R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or

(311) O—(R.sup.A)—O is a radical of a polyol and includes at least one free hydroxyl group or O—(R.sup.A)—O is selected from: —O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O—, —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, or —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and

(312) n, m, and p are integers from 1 to 10.

(313) 52. The compound of item 50, wherein the compound is formed from 11-epicortisol or tetrahydrocortisol.

(314) 53. A method of treating an eye of a subject in need thereof, said method comprising:

(315) (i) providing an article formed from a compound of formula (A-I):
D1-L-D2

(316) or a pharmaceutically acceptable salt thereof, wherein each of D1 and D2 is, independently, a radical formed from a steroid selected from an antibiotic steroid, a glucocorticoid steroid, an TOP lowering steroid, and a corticosteroid; and L is a linker covalently linking D1 to D2, wherein the article is a fiber, a cylinder, a stent, or a tube; and

(317) (ii) inserting the article into a Schlemm's canal in the eye of the subject without blocking the fluid passage,

(318) wherein the article is free of controlled release polymer, free of a crystallization inhibiting excipient, free of a binding excipient, and/or free of a mechanical integrity enhancing excipient; or wherein the article optionally has a glassy state.

(319) 54. A method of reducing intraocular pressure in an eye of a subject in need thereof, said method comprising:

(320) (i) providing an article formed from a compound of formula (A-I):
D1-L-D2

(321) or a pharmaceutically acceptable salt thereof, wherein each of D1 and D2 is, independently, a radical formed from a steroid selected from an antibiotic steroid, a glucocorticoid steroid, an IOP lowering steroid, and a corticosteroid; and L is a linker covalently linking D1 to D2, wherein the article is sized to provide a fluid passageway between the suprachoroidal space and the anterior chamber thereby reducing intraocular pressure in the eye; and

(322) (ii) inserting the article into a suprachoroidal space of the eye, wherein the article is positioned to extend from the suprachoroidal space to the anterior chamber of the eye to provide the fluid passageway,

(323) wherein the article is free of controlled release polymer, free of a crystallization inhibiting excipient, free of a binding excipient, and/or free of a mechanical integrity enhancing excipient; or wherein the article optionally has a glassy state.

(324) 55. The method of item 53 or 54, wherein L is covalently linked to D1 and to D2 via one or more ester, carbonate, carbonate ester, or anhydride linkages.

(325) 56. The method of any one of items 53-55, wherein

(326) L comprises the radical —(C(O)—(R.sup.A)—C(O)— or —O—(R.sup.A)—O—;

(327) R.sup.A is a radical of a polyol and includes at least one free hydroxyl group or R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms,

(328) —(CH.sub.2CH.sub.2O).sub.qCH.sub.2CH.sub.2—, —(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2CH.sub.2CH.sub.2—, or —(CH.sub.2CH(CH.sub.3)O).sub.sCH.sub.2CH(CH.sub.3)—; and

(329) q, r, and s are integers from 1 to 10.

(330) 57. The method of any one of items 53-56, wherein D1 and D2 are formed from the same steroid and the compound is further described by one of formulas (II-a)-(II-m).

(331) 58. The method of any one of items 53-57, wherein D1 and D2 are formed from different steroids and each of D1 and D2 are, independently, further described by one of formulas (I-a)-(I-k).

(332) 59. The method of any one of items 53-58, wherein at least 70% (w/w) of the article is a compound of formula (A-I).

(333) 60. The method of item 59, wherein at least 90% (w/w) of the article is a compound of formula (A-I).

(334) 61. The method of any one of items 53-60, wherein the compound, D1, or D2 are released from the article through surface erosion.

(335) 62. The method of item 61, wherein the surface erosion releases less than 10% of D1 or D2, as a percentage of the total drug, D1 or D2, present in the article in prodrug form, at 37° C. in 100% bovine serum over 5 days; or the surface erosion releases less than 2% of D1 or D2, as a percentage of the total drug, D1 or D2, present in the article in prodrug form, at 37° C. in PBS over 5 days; or the surface erosion releases greater than 20% of D1 or D2, as a percentage of the total drug, D1 or D2, present in the article in prodrug form, at 37° C. in 100% bovine serum over not fewer than 6 days; or the surface erosion releases greater than 5.0% of D1 or D2, as a percentage of the total drug, D1 or D2, present in the article in prodrug form, at 37° C. in PBS over not fewer than 6 days; or D1 and/or D2 is released from the article at a rate such that t.sub.10 is greater than or equal to 1/10 of t.sub.50.

(336) 63. The method of any one of items 53-62, wherein the article further comprises from 0.1% to 10% (w/w) of one or more additives, wherein the one or more additives are selected from plasticizers, antioxidants, binders, lubricants, dyes, and mixtures thereof.

(337) 64. The method of any one of items 53-63, wherein the article is a fiber or cylinder.

(338) 65. The method of any one of items 53-63, wherein the article is in the form of a stent, or a tube.

(339) 66. The method of any one of items 53 or 55-65, wherein the article is positioned and sized to support the Schlemm's canal and keep the Schlemm's canal open.

(340) 67. The method of any one of items 53-66, wherein the ocular condition is an inflammatory condition.

(341) 68. The method of item 67, wherein the inflammatory condition is inflammation associated with cataract surgery.

(342) 69. The method of item 67, wherein the inflammatory condition is inflammation associated with glaucoma surgery.

(343) 70. The method of any one of items 67-69, wherein upon hydrolysis, D1 and D2 form a corticosteroid or a glucocorticoid steroid.

(344) 71. The method of item 70, wherein said compound is further described by the formula (III):

(345) ##STR00037##

(346) or a pharmaceutically acceptable salt thereof, wherein

(347) L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—; R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or O—(R.sup.A)—O is a radical of a polyol and includes at least one free hydroxyl group or O—(R.sup.A)—O is selected from: —O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O—, —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, or —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and n, m, and p are integers from 1 to 10.

(348) 72. The method of any one of items 53 or 55-66, wherein the ocular condition is a bacterial infection.

(349) 73. The method of any one of items 53 or 55-66, wherein the ocular condition is conjunctivitis, keratitis, trachoma, or endophthalmitis.

(350) 74. The method of item 73, wherein upon hydrolysis, D1 and D2 form fusidic acid.

(351) 75. The method of any one of items 53-74, wherein the article is formed by a process comprising the steps of:

(352) (a) heating the compound, or a pharmaceutically acceptable salt thereof, to form a melt; and

(353) (b) heat molding the melt to form the article.

(354) 76. The method of any one of items 53-74, wherein the article is formed by a process comprising the steps of:

(355) (a) heating the compound, or a pharmaceutically acceptable salt thereof, to form a melt; and

(356) (b) injection molding the melt to form the article.

(357) 77. The method of any one of items 53-74, wherein the article is formed by a process comprising the steps of:

(358) (a) heating the compound, or a pharmaceutically acceptable salt thereof, to form a melt; and

(359) (b) blow molding the melt to form the article.

(360) 78. The method of any one of items 53-74, wherein the article is formed by a process comprising the steps of:

(361) (a) dissolving the compound, or a pharmaceutically acceptable salt thereof, to form a solution; and

(362) (b) evaporating the solvent to form the article.

(363) 79. The method of any one of items 53-74, wherein the article is formed by a process comprising the steps of:

(364) (a) dissolving the compound, or a pharmaceutically acceptable salt thereof, to form a solution; and

(365) (b) electrospinning, dry spinning, wet spinning, gel spinning, or electrospraying the solution to form the article.

(366) 80. The method of any one of items 53-74, wherein the article is formed by a process comprising the steps of:

(367) (a) heating the compound, or a pharmaceutically acceptable salt thereof, to form a melt; and

(368) (b) electrospinning or electrospraying the melt to form the article.

(369) 81. The method of any one of items 53-74, wherein the article is formed by a process comprising the steps of:

(370) (a) heating the compound, or a pharmaceutically acceptable salt thereof, to form a melt;

(371) (b) extruding the melt to form the article.

(372) 82. A method of forming of any one of items 75-81, wherein the article is formed by a process comprising:

(373) (a) heating the compound, or a pharmaceutically acceptable salt thereof, to form a melt;

(374) (b) cooling the melt to form a glassy state composition; and

(375) (c) heating the glassy state composition to a temperature above the glass transition temperature of the glassy state composition and shaping the glassy state composition to form a shaped article.

(376) 83. A method of forming of any one of items 75-81, wherein the article is formed by a process comprising:

(377) (a) dissolving the compound, or a pharmaceutically acceptable salt thereof, in a solvent to form a solution;

(378) (b) evaporating the solvent to form a glassy state composition; and

(379) (c) heating the glassy state composition to a temperature above the glass transition temperature of the glassy state composition and shaping the glassy state composition to form a shaped article.

(380) 84. The method of item 82 or 83, wherein step (c) comprises molding, extruding, blow molding, heat spinning, electrospinning or electrospraying the glassy state composition to form the shaped article.

(381) 85. A method of forming of any one of items 75-81, wherein the article is formed by a process comprising:

(382) (a) dissolving the compound, or a pharmaceutically acceptable salt thereof, in a solvent to form a solution;

(383) (b) electrospraying or electrospinning the solution to form a glassy state composition; and

(384) (c) heating the glassy state composition to a temperature above the glass transition temperature of the glassy state composition and shaping the glassy state composition to form a coating.

(385) 86. The method of any one of items 53-85, wherein the article comprises less than 5% (w/w) of polymeric material of greater than 5 kDa.

(386) 87. The method of any one of items 53-85, wherein the article is free of controlled release polymer.

(387) 88. The method of any one of items 53-85, wherein the article is free of a crystallization inhibiting excipient

(388) 89. The method of any one of items 53-85, wherein the article is free of a mechanical integrity enhancing excipient.

(389) 90. The method of any one of items 53-85, wherein the article is free of a binding excipient.

(390) 91. The method of any one of items 53-74, wherein the article is a glassy state composition.

(391) 92. The method of any one of items 53-74, wherein drug release from the article exhibits a t.sub.10 that is equal to or greater than 1/10 of t.sub.50 when the drug release from the article is measured at 37° C. in phosphate buffered saline or in bovine serum.