SURFACE COATINGS AND IMPLANTABLE DEVICES COMPRISING DIMERIC STEROID PRODRUGS, AND USES THEREOF

Abstract

The disclosure features surface coatings formed from dimeric steroid prodrugs for the extended delivery of a drug from a surface, and for the treatment of a disease or condition. Also provided herein are drug depots formed from dimeric steroid prodrugs for the extended delivery of a drug for use in combination with implantable medical devices. Said dimeric steroid prodrugs are represented by the formula D1-L-D2, wherein D1 and D2 are independently a steroid radical and L is a linker covalently linking D1 to D2.

Claims

1. A system comprising an article body and a steroid material, the steroid material comprising a compound of formula (A-VIII):
D1-L-D2 (A-VIII) or a pharmaceutically acceptable salt thereof, wherein (i) each of D1 and D2 is, independently, a steroid radical; and L is a linker covalently linking D1 to D2, and (ii) the steroid material comprises the compound of formula (A-VIII) in an amount of at least 90% (w/w).

2. An article comprising an article body and a steroid material, the steroid material comprising a compound of formula (A-VIII):
D1-L-D2 (A-VIII) or a pharmaceutically acceptable salt thereof, wherein (i) each of D1 and D2 is, independently, a steroid radical; and L is a linker covalently linking D1 to D2, and (ii) the steroid material comprises the compound of formula (A-VIII) in an amount of at least 90% (w/w).

3. The system or article of either one of claims 1 or 2, wherein the steroid material is in the form of a second body, the second body being packaged with (e.g., as a kit) or affixed to the article body.

4. The system or article of claim 3, wherein the second body is affixed to the article body with an adhesive, a clamp, or a bolt.

5. The system or article of either one of claims 1 or 2, wherein the steroid material is in the form of a coating, the coating being on (e.g., at least partially covering) at least one surface of the article body.

6. The system or article of any one of the preceding claims, wherein the article body is an implant (e.g., sensor implant).

7. The system or article of any one of the preceding claims, wherein the steroid material (or second body or coating) is free of (e.g., comprises less than 5 wt. %, less than 2 wt. %, less than 1 wt. %) a controlled release excipient.

8. The system or article of any one of the preceding claims, wherein the steroid material provides release of free steroid therefrom without the need of a controlled release excipient.

9. The system or article of any one of the preceding claims, wherein the steroid material (or article body or coating) releases D1 and D2 at 37° C. in 100% bovine serum or at 37° C. in PBS at a rate such that t.sub.10 is greater than or equal to 1/10 of t.sub.50.

10. The system or article of any one of the preceding claims, wherein the steroid material (or article body or coating) comprises from 0.01 to 10% (w/w) of one or more plasticizing agents.

11. The system or article of any one of the preceding claims, wherein the steroid material is a surface coating or a co-implant (e.g., a drug depot co-implanted with the article body).

12. The system or article of claim 11, wherein the surface coating coats at most half (e.g., less than one-quarter, less than one-eighth, or less than one sixteenth) of the article body.

13. The system or article of claim 11, wherein the surface coating is a continuous layer on the article body (e.g., the surface coating does not contain cracks, fissures, gaps, or the like).

14. The system or article of claim 11, wherein the co-implant (e.g., the drug depot co-implanted with the article body) is selected from a pellet, a cylinder, a hollow tube, a microparticle, a nanoparticle, or a shaped article.

15. The system or article of claim 11, wherein the co-implant (e.g., the drug depot co-implanted with the article body) is separate from the article body (e.g., an implantable medical device).

16. The system or article of claim 11, wherein the co-implant (e.g., the drug depot co-implanted with the article body) is affixed (e.g., adhesively affixed, screwed, bolted, or the like) to the article body (e.g., an implantable medical device).

17. The system or article of any one of the preceding claims, wherein D1 and D2 are each anti-inflammatory steroids (e.g., dexamethasone), or pharmaceutically acceptable salts thereof, in their free form.

18. The system or article of any one of the preceding claims, wherein D1 and D2 are each intraocular pressure (IOP) lowering steroids (e.g., anecortave), or pharmaceutically acceptable salts thereof, in their free form.

19. A method of providing an implant into an individual, the method comprising (i) implanting an implant article into the individual at an implant location, and (ii) implanting a steroid material into the individual, the steroid material being implanted in proximity (e.g., within 20 mm, within 10 mm, within 5 mm, within 3 mm, or less) to the implant location, the steroid material being as described in an one of the preceding claims.

20. The method of claim 19, wherein the implant article and the steroid material are administered concurrently (e.g., wherein the steroid material is affixed to or coated on the implant article).

21. The method of claim 19, wherein the implant article and the steroid material are administered sequentially (e.g., the implant article or the steroid material implanted first, followed by implant of the other).

22. The method of any one of the preceding claims, wherein the steroid material remains implanted in the individual for at least 1 day, 1 week, 2 weeks, 1 month, or longer.

23. The method of any one of the preceding claims, wherein at least a portion of the steroid material is uptaken by the individual at a rate sufficient to produce a physiological effect (e.g., reduce inflammation (e.g., minimize an inflammatory response), reduce pressure (e.g., lower intraocular pressure (IOP)), or the like) in or around the implant location.

24. The method of any one of the preceding claims, wherein the rate at 37° C. in 100% bovine serum or at 37° C. in PBS is such that t.sub.10 is greater than or equal to 1/10 of t.sub.50.

25. The method of any one of the preceding claims, wherein inflammation in or around the implant location is reduced (e.g., by at least 10%, by at least 20%, by at least 30%, by at least 50%).

26. The method of any one of the preceding claims, wherein inflammation in or around the implant location is measured by fibrotic layer thickness (e.g., μm), collagen content (e.g., μM), hydroxyproline content (e.g., μM), inflammatory cell count (e.g. number of macrophages, foreign body giant cells, etc.), inflammatory cell type (e.g. myofibroblasts), inflammatory cytokines (e.g. IL-1β, TNF-α, etc.), or the like.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0152] FIG. 1 is the structure of a composition provided herein (e.g., Compound 1 (dexamethasone-triethylene glycol-dexamethasone, Dex-TEG-Dex)).

[0153] FIG. 2A-2C shows a series of substrates (SIBS, Titanium, and Dacron) uncoated, coated with a composition provided herein (e.g., compound 1), or coated with free dexamethasone.

[0154] FIG. 3 is a graph showing drug release from the coated surfaces shown in FIGS. 2B & 2C as well as a composition provided herein (e.g., compound 1) and dexamethasone coated onto a glass substrate.

[0155] FIG. 4 is a graph showing a composition provided herein (e.g., compound 1) coating retention on different substrates after drug release a buffered solution.

[0156] FIG. 5 is a graph showing loading of a composition provided herein (e.g., Compound 1) on substrates with surface areas of 1 cm.sup.2.

[0157] FIG. 6 is a graph showing loading of a composition provided herein (e.g., Compound 1) on substrates with surface areas of 3-6 mm.sup.2.

[0158] FIG. 7 is a graph showing loading of a composition provided herein (e.g., Compound 1) on substrates after dip coating.

[0159] FIG. 8 is a graph showing loading of a composition provided herein (e.g., Compound 1) on substrates after spray coating.

[0160] FIG. 9 is a graph showing the percent of a composition provided herein (e.g., Compound 1) spray coating retained following a 24-hour incubation in a buffered solution at 37° C.

[0161] FIG. 10A-10B shows a series of graphs showing purity and drug release from a composition provided herein (e.g., Compound 1) coated onto fibrous meshes pre- and post-sterilization.

[0162] FIG. 11 is an image of a composition provided herein (e.g., Compound 1) electrosprayed and annealed onto a polymeric surface.

[0163] FIG. 12A-12B shows a series of images of a composition provided herein (e.g., Compound 1) coated onto an angioplasty balloon and a cardiac stent.

[0164] FIG. 13A-13B shows the structure of a composition provided herein (e.g., Compound 2 (hydrocortisone-triethylene glycol-hydrocortisone; HC-TEG-HC)) and drug release from a coated surface of a substrate.

[0165] FIG. 14A-14B shows the structure of a composition provided herein (e.g., Compound 3 (triamcinolone acetonide-triethylene glycol-triamcinolone acetonide; TA-TEG-TA)) and drug release from a coated surface of a substrate.

[0166] FIG. 15A-B shows the structure of a composition provided herein (e.g., Compound 4 (dexamethasone-hexane-dexamethasone; Dex-HEX-Dex)) and drug release from a coated surface of a substrate.

[0167] FIG. 16A-B shows a side by side comparison of heat press and spray coating methods.

[0168] FIG. 17 shows heat press coatings at different surface areas and similar drug densities.

[0169] FIG. 18A-B shows the fibrotic response and drug release profiles between dexamethasone coated discs versus compositions provided herein (e.g., Compound 1 and Compound 4) coated discs. A reduced response correlates to sustained drug release.

[0170] FIG. 19A-19B injectable cylinders of an exemplary conjugated provided herein (e.g., Compound 1) and in vitro drug release from the injectable cylinders.

[0171] FIG. 20A-20B show fibrous meshes of compositions provided herein (e.g., Compound 1). FIG. 20C depicts the differential scanning calorimetry (DSC) analysis of compositions provided herein (e.g., Compound 1) as the starting powder and solvent-processed fibrous mesh. FIG. 20D depicts the power x-ray diffraction (PXRD) analysis of compositions provided herein (e.g., Compound 1) as the starting powder and solvent-processed fibrous mesh.

[0172] FIG. 21A-21C shows cylinders of compositions provided herein (e.g., Compound 1) and sutures injected adjacent to each other in the subcutaneous tissue of rats and a graph showing drug release from the cylinders.

DETAILED DESCRIPTION

[0173] While the clinical importance of sustained drug release delivery systems to maintain therapeutic concentration of drugs for extended periods of time (e.g., days to weeks, to months or even years) has been well acknowledged for decades, there has been a limited number of successfully commercialized products on the market to date. It is recognized herein that to develop sustained drug delivery systems, technical difficulties must be overcome, such as, for example, drug degradation during formulation process; lack of controlled release, including unwanted burst or incomplete release associated with diffusion or bulk erosion mechanisms of drug release; low encapsulation efficiency; and formulation complexity. Achieving long linear release profiles can be particularly difficult where the drug release system is entirely contained within a surface coating or drug depot.

[0174] Provided herein are surface coatings and drug depots formed from dimers that are processable as solids or liquids (e.g., from a melt or solution). In some embodiments, the solids or liquids are used to coat articles, such as medical devices. In some embodiments, most of the material in the surface coating is optionally in a glassy state. The surface coatings can provide a controlled rate of drug release over days, weeks, months, or years, due to interactions between the molecules that exist in a mostly amorphous state while holding the shaped form intact as the surface erodes. This disclosure also describes drug depots for use in combination with implantable medical devices. In some embodiments, the drug depots are formed from dimers. The drug depots can provide a controlled rate of drug release over days, weeks, months, or years, due to interactions between the molecules that exist in a mostly amorphous state while holding the shaped form intact as the surface erodes. In some embodiments, surface coatings and drug depots provided herein minimize inflammatory responses (e.g., because the drugs/prodrugs undergoing surface erosion from the article or drug depot can be released in the biological environment in a non-particulate (e.g., non-crystalline) form) In certain instances, coatings and drug depots formed from anti-inflammatory steroids have anti-inflammatory activity from the drugs being released from the prodrug shaped form.

[0175] In some embodiments, the surface coatings or drug depots provided herein are designed for the controlled and sustained release of a steroid drug from the prodrug dimer used to coat the article or in combination with an implantable medical device, respectively. The release rate from a surface coating or drug depot of the disclosure can be controlled through several engineerable design parameters, including: 1) selection of the steroid drug; 2) selection of the functional group of the drug for conjugation (e.g., if multiple exist); 3) selection of the linker; 4) selection of the linkage group (e.g., esters, carbonates, carbonate esters, or anhydrides); 5) selection of the surface area of the surface coatings or drug depots; and 6) selection of the drug loading in the surface coatings or drug depots (e.g., by adding traditional pharmaceutical excipients or mixing other steroid dimers as excipients when making the surface coatings or drug depots). Provided in certain instances herein is a coating and/or drug depot that comprises two or more radicals of a drug. Provided in certain instances herein is a coating and/or drug depot that comprises two or more steroid radicals (e.g., taken together with a linker to form a dimer provided herein). In some embodiments, the coating and/or drug depot comprising the two or more steroid radicals have a controlled release (e.g., as the free form of the two or more steroid radical) from the coating and/or drug depot. In some embodiments, the two or more steroid radicals come together to form a heterodimer (e.g., different steroid drugs on the two ends of a linker provided herein). In some embodiments, the two or more steroids come together to form a homodimer (e.g., the same steroid drugs on the two ends of a linker provided herein). In some embodiments, the coatings and/or drug depots comprise, steroid heterodimers, steroid homodimers, or a mixture thereof. Surface coatings or drug depots formed from the compounds provided herein can yield sustained and uniform release of the steroid compounds (e.g., without exhibiting any burst release (e.g., t.sub.10 can be equal to or greater than 1/10 of t.sub.50) and without reliance upon degradable matrices, which can cause undesirable local side effects (such as inflammation)). In some embodiments, the coatings and/or drug depots has a drug loading that is suitable for producing locally effective concentrations of a steroid drug for periods of days to weeks to months or even years.

[0176] Steroids can be used in combination with medical devices as combination products, or as adjunctive therapy, for a variety of medical fields including, for example, ophthalmology, oncology, laryngology, endocrinology and metabolic diseases, rheumatology, urology, neurology, cardiology, dental medicine, dermatology, otology, post-surgical medicine, orthopedics, pain management, and gynecology.

[0177] In certain embodiments, provided herein is a system comprising an article body and a steroid material. In some embodiments, the system is an article comprising an article body and a steroid material

[0178] Provided in some embodiments herein are surface coatings formed from compounds of formula (A-VIII) and articles or drug depots formed from compounds of formula (A-VIII):

D1-L-D2 (A-VIII)

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 an anabolic steroid, an androgenic steroid, a progestin steroid, an estrogen steroid, a cancer treatment steroid, an antibiotic steroid, a glucocorticoid steroid, a benign steroid, or a corticosteroid. In some embodiments, D1 and/or D2 are a mineralocorticoid 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 articles or implantable medical devices to which the surface coatings or drug depots, respectively, are applied can be any article and/or medical device, or surface thereof, described herein.

[0179] In some embodiments, the compound has the structure of formula (A-II):

D1-O-L-O-D2 (A-II),

or a pharmaceutically acceptable salt thereof, wherein each of D1-O and D2-O is, independently, a radical formed from a steroid.

[0180] In some embodiments, each of D1-O and D2-O is, independently, described by any one of formulas (I-a) to (I-zzz):

##STR00004##

where the bond between C.sub.1 and C.sub.2, C.sub.4 and C.sub.5, C.sub.5 and C.sub.6, C.sub.9 and C.sub.10, and C.sub.11 and C.sub.12 is a single or a double bond; R.sub.1 represents H, CH.sub.3, or HC(O); R.sub.2 represents ═O, OH, or H; or R.sub.1 and R.sub.2 taken together with carbons to which they are attached form an isoxazole; R.sub.3 represents H, a halogen atom, or OH; R.sub.6 represents H or CH.sub.3; R.sub.12 represents H, CH.sub.3, or CH.sub.3CH.sub.2; R.sub.13 represents CH.sub.3 or CH.sub.3CH.sub.2; R.sub.15 represents H or OH; R.sub.17 represents H or CH.sub.3; and R.sub.18 represents H or CH.sub.3;

##STR00005##

where the bond between C.sub.1 and C.sub.2, C.sub.4 and C.sub.5, C.sub.5 and C.sub.6, C.sub.9 and C.sub.10, and C.sub.11 and C.sub.12 is a single or a double bond; R.sub.1 represents H, CH.sub.3, or HC(O); R.sub.3 represents H, a halogen atom, or OH; R.sub.6 represents H or CH.sub.3; R.sub.12 represents H, CH.sub.3, or CH.sub.3CH.sub.2; R.sub.13 represents CH.sub.3 or CH.sub.3CH.sub.2; R.sub.15 represents H or OH; R.sub.17 represents H or CH.sub.3; and R.sub.18 represents H or CH.sub.3;

##STR00006##

where R.sub.12 represents H or CH.sub.3; and R.sub.17 represents H or CH.sub.3;

##STR00007##

where the bond between C.sub.1 and C.sub.2, C.sub.4 and C.sub.5, and C.sub.5 and C.sub.6 is a single or a double bond; C.sub.2 is O, C or CH.sub.2; R.sub.1 represents H, —CHOH, or is absent; R.sub.2 represents ═O or OH; or R.sub.1 and R.sub.2 taken together with carbons to which they are attached form a pyrazole; R.sub.3 represents H or OH; R.sub.12 represents H, CH.sub.3, optionally substituted alkynylene, C.sub.1-6alkoxy, or CH.sub.3CH.sub.2; R.sub.15 represents H or OH; R.sub.16 represents H or a halogen atom; R.sub.17 represents H or CH.sub.3; and R.sub.18 represents H or CH.sub.3;

##STR00008##

where the bond between C.sub.1 and C.sub.2, C.sub.4 and C.sub.5, and C.sub.5 and C.sub.6 is a single or a double bond; C.sub.2 is O, C or CH.sub.2; R.sub.1 represents H, —CHOH, or is absent; R.sub.3 represents H or OH; R.sub.11 represents H, OH, CH.sub.3, optionally substituted alkynylene, CH.sub.3CH.sub.2, ═O, —OC(O)CH.sub.2CH.sub.3, or is absent; R.sub.12 represents H, OH, CH.sub.3, optionally substituted alkynylene, CH.sub.3CH.sub.2, ═O, —OC(O)CH.sub.2CH.sub.3, or is absent; R.sub.15 represents H or OH; R.sub.16 represents H or a halogen atom; R.sub.17 represents H or CH.sub.3; and R.sub.18 represents H or CH.sub.3;

##STR00009##

where the bond between C.sub.1 and C.sub.10, C.sub.2 and C.sub.3, C.sub.3 and C.sub.4, C.sub.4 and C.sub.5, C.sub.5 and C.sub.6, C.sub.6 and C.sub.7, C.sub.8 and C.sub.10, C.sub.9 and C.sub.10, C.sub.11 and C.sub.12, C.sub.15 and C.sub.16 is a single or a double bond; R.sub.2 represents H, ═O, OH, —NOH, or C.sub.1-6alkoxy; R.sub.5 represents H, CH.sub.3, or a halogen atom; R.sub.6 represents H or CH.sub.3; or R.sub.5 and R.sub.6 taken together with carbons to which they are attached form a cyclopropane; R.sub.9 is H; R.sub.10 is H or ═CH.sub.2; or R.sub.9 and R.sub.10 taken together with carbons to which they are attached form a cyclopropane; R.sub.12 represents H, optionally substituted alkynylene, —CH.sub.2CH═CH.sub.2, CH.sub.3, —C(O)CH.sub.3, or —CH═CH.sub.2; R.sub.13 represents CH.sub.3 or CH.sub.2CH.sub.3; R.sub.15 represents H or ═CH.sub.2; and R.sub.17 represents H, CH.sub.3, or is absent;

##STR00010##

where the bond between C.sub.1 and C.sub.10, C.sub.2 and C.sub.3, C.sub.4 and C.sub.5, C.sub.6 and C.sub.7, C.sub.5 and C.sub.10, C.sub.9 and C.sub.10, C.sub.11 and C.sub.12, C.sub.15 and C.sub.16 is a single or a double bond; R.sub.5 represents H, CH.sub.3, or a halogen atom; R.sub.6 represents H or CH.sub.3; or R.sub.5 and R.sub.6 taken together with carbons to which they are attached form a cyclopropane; R.sub.9 is H; R.sub.10 is H or ═CH.sub.2; or R.sub.9 and R.sub.10 taken together with carbons to which they are attached form a cyclopropane; R.sup.11 represents H, OH, optionally substituted alkynylene, —C(O)CH.sub.3, —CH.sub.2CH═CH.sub.2, a halogen atom, —CH═CH.sub.2, —OC(O)CH.sub.3, CH.sub.3, —C(O)C(OH)CH.sub.3; R.sub.12 represents H, OH, optionally substituted alkynylene, —C(O)CH.sub.3, —CH.sub.2CH═CH.sub.2, a halogen atom, —CH═CH.sub.2, —OC(O)CH.sub.3, CH.sub.3, —C(O)C(OH)CH.sub.3; or R.sub.11 and R.sub.12 together with carbon to which they are attached form a lactone; R.sub.13 represents CH.sub.3 or CH.sub.2CH.sub.3; R.sub.15 represents H or ═CH.sub.2; and R.sub.17 represents H, CH.sub.3, or is absent;

##STR00011##

where the bond between C.sub.1 and C.sub.2, C.sub.1 and C.sub.10, C.sub.2 and C.sub.3, C.sub.3 and C.sub.4, C.sub.4 and C.sub.5, C.sub.6 and C.sub.7, C.sub.5 and C.sub.10, C.sub.7 and C.sub.8, and C.sub.8 and C.sub.9 is a single or a double bond; R.sub.2 represents OH, —OC(O)Ph, or C.sub.1-6alkoxy; R.sub.10 represents H or OH; R.sub.12 represents H, optionally substituted alkynylene; and R.sub.15 represents H or C.sub.1-6alkoxy;

##STR00012##

where the bond between C.sub.1 and C.sub.2, C.sub.1 and C.sub.10, C.sub.2 and C.sub.3, C.sub.3 and C.sub.4, C.sub.4 and C.sub.5, C.sub.6 and C.sub.7, C.sub.5 and C.sub.10, C.sub.7 and C.sub.8, and C.sub.8 and C.sub.9 is a single or a double bond; R.sub.10 represents H or OH; R.sub.11 represents H, OH, optionally substituted alkynylene, ═O, or is absent; R.sub.12 represents H, OH, optionally substituted alkynylene, ═O, or is absent; and R.sub.15 represents H or C.sub.1-6alkoxy;

##STR00013##

where R.sub.2 represents OH or C.sub.1-6alkoxy; and R.sub.10 represents H or CH.sub.3;

##STR00014##

where the bond between C.sub.1 and C.sub.2, C.sub.4 and C.sub.5, C.sub.5 and C.sub.6, C.sub.6 and C.sub.7, and C.sub.16 and C.sub.17 is a single or a double bond; C.sub.4 is NH, CH, or CH.sub.2; R.sub.1 represents H; R.sub.5 represents H or a halogen atom; R.sub.11 represents H, optionally substituted heteroaryl, —C(O)C.sub.1-6 alkyl, —C(O)OC.sub.1-6 alkyl, or —C(O)NHR, where R is optionally substituted alkyl or aryl; R.sub.12 represents H, optionally substituted heteroaryl, —C(O)C.sub.1-6 alkyl, —C(O)OC.sub.1-6 alkyl, or —C(O)NHR, where R is optionally substituted alkyl or aryl; and R.sub.18 represents H; or R.sub.1 and R.sub.18 taken together with carbons to which they are attached form a cyclopropane;

##STR00015##

where R.sub.12 is H or OH;

##STR00016##

where the bond between C.sub.4 and C.sub.5, and C.sub.5 and C.sub.6 is a single or a double bond; R.sub.5 represents H or C.sub.1-6 alkyl; R.sub.6 represents H or OH; R.sub.11 represents H, OH, —C(O)C.sub.1-6 alkyl, —C(O)CH.sub.2OH, or —CH(CH.sub.3)CH.sub.2CH.sub.2C(O)OH; and R.sub.12 represents H, OH, —C(O)C.sub.1-6 alkyl, —C(O)CH.sub.2OH, or —CH(CH.sub.3)CH.sub.2CH.sub.2C(O)OH;

##STR00017##

where R.sub.5 represents H or CH.sub.2CH.sub.3; and R.sub.14 represents H or OH;

##STR00018##

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.1-6alkyl, optionally substituted —OC(O)C.sub.1-6alkyl, —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;

##STR00019##

##STR00020##

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;

##STR00021##

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.1-6alkyl, OH, or ═CH.sub.2; R.sub.10b represents H, C.sub.1-6alkyl, 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.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.1-6alkyl, 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.1-6alkyl; 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;

##STR00022##

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;

##STR00023##

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:

##STR00024##

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;

##STR00025##

where 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;

##STR00026##

where the bond between C.sub.3 and R.sub.2, and C.sub.11 and R.sub.15 is a single or a double bond; R.sub.2 represents OH or ═O; R.sub.11 represents H, OH, —C(═O)CH.sub.2OH, or —C(═O)CH.sub.3; R.sub.12 represents H, OH, —C(═O)CH.sub.2OH, or —C(═O)CH.sub.3; R.sub.15 represents H, ═O, or OH;

##STR00027##

where the bond between C.sub.3 and R.sub.2, C.sub.7 and R.sub.6, and C.sub.12 and R.sub.14 is a single or a double bond; Rx represents OH, —NHCH.sub.2C(═O)OH, or —NHCH.sub.2CH.sub.2SO.sub.2OH; R.sub.2 represents OH or ═O; R.sub.5 represents H or OH; R.sub.6 represents H, ═O, or OH; R.sub.14 represents H, ═O, or OH;

##STR00028##

where the bond between C.sub.3 and R.sub.2, and C.sub.11 and R.sub.15 is a single or a double bond; R.sub.2 represents OH or ═O; R.sub.10 represents H or OH; R.sub.11 represents H, OH, —C(═O)CH.sub.2OH, —C(═O)OH, —C(═O)CH.sub.2OH, or —C(═O)CH.sub.3; R.sub.12 represents H, OH, —C(═O)CH.sub.2OH, —C(═O)OH, —C(═O)CH.sub.2OH, or —C(═O)CH.sub.3; R.sub.13 represents —CH.sub.2OH or —CH.sub.3; R.sub.15 represents H, OH, or ═O; R.sub.16 represents H or F;

##STR00029##

where Ry represents H or OH;

##STR00030##

where the bond between C.sub.3 and R.sub.2, and C.sub.11 and R.sub.15 is a single or a double bond; Rz represents H or —CH.sub.3; R.sub.1 represents H or —OCH.sub.2CH.sub.3; R.sub.2 represents OH or ═O; R.sub.12 represents —OH, —C(═O)CH.sub.3, —C(═O)CH.sub.2OH, or —CH(CH.sub.3)(CH.sub.2).sub.2CH(OH)CH(CH.sub.3).sub.2; R.sub.15 represents H, —N(CH.sub.3).sub.2, or ═O;

##STR00031##

where 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.11 represents H, —C(═O)CH.sub.3, —OC(═O)(CH.sub.2).sub.4CH.sub.3, or is absent; R.sub.12 represents H, —C(═O)CH.sub.3, —OC(═O)(CH.sub.2).sub.4CH.sub.3, or is absent; R.sub.17 represents CH.sub.3 or is absent;

##STR00032##

where the bond between C.sub.3 and R.sub.2, and C.sub.11 and R.sub.15 is a single or a double bond; Ry represents OH or ═O; R.sub.2 represents OH or ═O; R.sub.11 represents H, OH, —CH(OH)CH.sub.3, —C(═O)CH.sub.2OH, —C(═O)CH.sub.3, or —CH(OH)CH.sub.2OH; R.sub.12 represents H, OH, —CH(OH)CH.sub.3, —C(═O)CH.sub.2OH, —C(═O)CH.sub.3, or —CH(OH)CH.sub.2OH; R.sub.15 represents H, ═O, or OH;

##STR00033##

where the bond between C.sub.3 and R.sub.2, and C.sub.1 and R.sub.10 is a single or a double bond; R.sub.2 represents OH or ═O; R.sub.5 represents H, Cl, or —CH.sub.3; R.sub.10 represents H or ═CH.sub.2; R.sub.11 represents H, OH, —CH.sub.3, —C(═O)CH.sub.3, —C(═O)CH.sub.2OC(═O)CH.sub.3, or —OC(═O)CH.sub.3; R.sub.12 represents H, OH, —CH.sub.3, —C(═O)CH.sub.3, —C(═O)CH.sub.2OC(═O)CH.sub.3, or —OC(═O)CH.sub.3; R.sub.15 represents H or OH; R.sub.16 represents F or H; R.sub.17 represents H or —CH.sub.3; or

##STR00034##

wherein R.sub.1 is C(O)H or CH.sub.3; R.sub.2 represents H or F; R.sub.3 represents H or OH.

[0181] In certain embodiments, the compound has the structure of formula (A-VII):

D1-C(O)-L-C(O)-D2 (A-VII),

or a pharmaceutically acceptable salt thereof, wherein each of D1-C(O) and D2-C(O) is, independently, a radical formed from a steroid; L is —O—C(O)—O—(R.sup.A)—O—C(O)—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. Each of D1-C(O) and D2-C(O) can, independently, be formed, for example, from fusidic acid, cholic acid, chenodeoxycholic acid, ursodeoxycholic acid, or obeticholic acid. In the drug dimers of formula (A-VII), D1-C(O)— and D2-C(O)— can further be described, for example, by formulas (I-hh), (I-ii), (I-ttt), (I-uuu), and (I-vvv) below.

##STR00035##

where R.sub.5 represents H or C.sub.1-6alkyl, R.sub.14 represents H or OH;

##STR00036##

where the bond between C.sub.3 and R.sub.2, C.sub.7 and R.sub.6, and C.sub.12 and R.sub.14 is a single or a double bond; R.sub.2 represents OH or ═O; R.sub.5 represents H or OH; R.sub.6 represents H, ═O, or OH; R.sub.14 represents H, ═O, or OH;

##STR00037##

[0182] In some embodiments, drug dimers provided herein are homodimers and heterodimers. In some embodiments, the drug dimers comprise a steroid, including, for example, anabolic steroids, and androgenic steroids, progestin steroids, estrogen steroids, cancer treatment steroids, antibiotic steroids, glucocorticoid steroids, benign steroids, corticosteroids, anti-angiogenic steroids, intraocular pressure (IOP) lowering steroids, cholic acid-related bile acid steroids, steroid metabolites, cholesterol-derivatives, neurosteroids, pheromones, progestins, or other steroids. Examples of anabolic steroids include, but are not limited to, androisoxazole, androstenediol, bolandiol, bolasterone, clostebol, ethylestrenol, formyldienolone, 4-hydroxy-19-nortestosterone, methandriol, methenolone, methyltrienolone, nandrolone, norbolethone, oxymesterone, stenbolone, and trenbolone. Androgenic steroids are, for example, boldenone, fluoxymesterone, mestanolone, mesterolone, methandrostenolone, 17-methyltestosterone, 17-α-methyltestosterone 3-cyclopentyl enol ether, norethandrolone, normethandrone, oxandrolone, oxymesterone, oxymetholone, prasterone, stanlolone, stanozolol, testosterone, testosterone 17-chloral hemiacetal, testosterone proprionate, testosterone enanthate tiomesterone dehydroepiandrosterone (DHEA), androstenedione, androstenediol, androsterone, dihydrotestosterone (DHT), androstanolone, and derivatives thereof. Exemplary progestin steroids are norethisterone, norethisterone acetate, gestodene, levonorgestrel, allylestrenol, anagestone, desogestrel, dimethisterone, dydrogesterone, ethisterone, ethynodiol, ethynodiol diacetate, etonogestrel, gestodene, ethinylestradiol, haloprogesterone, 17-hydroxy-16-methylene-progesterone, 17 alpha-hydroxyprogesterone, lynestrenol, medroxyprogesterone, melengestrol, norethindrone, norethynodrel, norgesterone, gestonorone, norethisterone, norgestimate, norgestrel, levonorgestrel, norgestrienone, norvinisterone, pentagestrone, MENT (7-methyl-19-testosterone); norelgestromin, and trimigestone drospirenone, tibolone, megestrol, and derivatives thereof. Examples of estrogen steroid are estrogen, eguilenin, equilin, 17β-estradiol, estradiol benzoate, estriol, ethinyl estradiol, mestranol, moxestrol, mytatrienediol, quinestradiol, and quinestrol. Steroids used in cancer treatment are, for example, abiraterone, cyproterone acetate, dutasteride, enzalutamide, finasteride, and galeterone. Exemplary antibiotic steroid is fusidic acid. Glucocorticoids 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, 6α-methylprednisolone, methylprednisolone, methylprednisolone acetate, methylprednisolone aceponate, mometasone, mometasone furoate, mometasone furoate monohydrate, paramethasone, prednicarbate, prednisolone, prednisone, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, and ulobetasol. Exemplary benign steroids are cholesterol, 11-deoxycortisol, 11-deoxycorticosterone, pregnenolone, cholic acid, chenodeoxycholic acid, ursodeoxycholic acid, obeticholic acid, tetrahydrocortisone, tetrahydrodeoxycortisol, tetrahydrocorticosterone, 5α-dihydrocorticosterone, and 5α-dihydropregesterone. Exemplary anti-angiogenic steroids or intraocular pressure (IOP) lowering steroids are anecortave acetate, anecortave, 11-epicortisol, 17α-hydroxyprogesterone, tetrahydrocortexolone, and tetrahydrocortisol. Exemplary cholic acid-related bile acid steroids are deoxycholic acid, apocholic acid, dehydrocholic acid, glycochenodeoxycholic acid, glycocholic acid, glycodeoxycholic acid, hyodeoxycholic acid, lithocholic acid, α-muricholic acid, β-muricholic acid, γ-muricholic acid, ω-muricholic acid, taurochenodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, taurolithocholic acid, and tauroursodeoxycholic acid. Exemplary mineralocorticoid steroids are fludrocortisone and aldocortisone. Exemplary neurosteroids are alphaxalone, alphadolone, hydroxydione, minaxolone, tetrahydrodeoxycorticosterone, allopregnanolone, pregnanolone, ganoxolone, 3α-androstanediol, epipregnanolone, isopregnanolone, and 24(S)-hydroxycholesterol. Exemplary other steroids are flugestone, prebediolone, chlormadinone acetate, medrogestone, and segesterone acetate. Exemplary pheromones are androstadienol, androstadienone, androstenol, androstenone, estratetraenol, 5-dehydroprogesterone, 6-dehydro-retroprogesterone, allopregnanolone, and hydroxyprogesterone caproate. Exemplary steroid metabolites are tetrahydrotriamcinolone, cortienic acid, 11-dehydrocorticosterone, 11β-hydroxypregnenolone, ketoprogesterone, 17-hydroxypregnenolone, 17,21-dihydroxypregnenolone, 18-hydroxycorticosterone, deoxycortisone, 21-hydroxypregnenolone, and progesterone. Exemplary progestins are allopregnone-3α,20α-diol, allopregnone-3β,20β-diol, allopregnane-3β,21-diol-11,20-dione, allopregnane-3β,17α-diol-20-one, 3,20-allopregnanedione,3β,11β,17α,20β,21-pentol, allopregnane-3β,17α,20β,21-tetrol, allopregnane-3α,11β,17α,21-tetrol-20-one, allopregnane-3β,11β,17α,21-tetrol-20-one, allopregnane-3β,17α,20β-triol, allopregnane-3β,17α,21-triol-11,20-dione, allopregnane-3β,11β,21-triol-20-one, allopregnane-3β,17α,21-triol-20-one, allopregnane-3α-ol-20-one, allopregnane-3β-ol-20-one, pregnanediol, 3,20-pregnanedione, 4-pregnene-20,21-diol-3,11-dione, 4-pregnene-11β,17α,20β,21-tetrol-3-one, 4-pregnene-17α,20β,21-triol-3,11-dione, 4-pregnene-17α,20β,21-triol-3-one, and pregnenolone.

[0183] The drug dimers useful in making the articles or drug depots of the disclosure can have any of formulas (A-I)-(LXXVIII), described herein.

Steroid Homodimers

[0184] Provided in some embodiments herein are homodimers (e.g., drug depots or surface coatings formed from homodimers) of the formula (I):

D1-L-D2 (A-VIII)

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)-(LXXVIII), below.

[0185] In some embodiments, the steroid is an anabolic steroid and the drug dimer is further described by the formula (II):

##STR00038##

wherein the bond between C.sub.1 and C.sub.2, C.sub.4 and C.sub.5, C.sub.5 and C.sub.6, C.sub.9 and C.sub.10, and C.sub.11 and C.sub.12 is a single or a double bond; R.sub.1 represents H, CH.sub.3, or HC(O); R.sub.2 represents ═O, OH, or H; or R.sub.1 and R.sub.2 taken together with carbons to which they are attached form an isoxazole; R.sub.3 represents H, a halogen atom, or OH; R.sub.6 represents H or CH.sub.3; R.sub.12 represents H, CH.sub.3, or CH.sub.3CH.sub.2; R.sub.13 represents CH.sub.3 or CH.sub.3CH.sub.2; R.sub.15 represents H or OH; R.sub.17 represents H or CH.sub.3; R.sub.18 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (II) can be formed from an anabolic steroid selected from the group consisting of androisoxazole, androstenediol, bolandiol, bolasterone, clostebol, ethylestrenol, formyldienolone, 4-hydroxy-19-nortestosterone, methandriol, methenolone, methyltrienolone, nandrolone, norbolethone, oxymesterone, stenbolone, and trenbolone.

[0186] In certain embodiments, the steroid is an anabolic steroid and the drug dimer is further described by the formula (III):

##STR00039##

wherein the bond between C.sub.1 and C.sub.2, C.sub.4 and C.sub.5, C.sub.5 and C.sub.6, C.sub.9 and C.sub.10, and C.sub.11 and C.sub.12 is a single or a double bond; R.sub.1 represents H, CH.sub.3, or HC(O); R.sub.3 represents H, a halogen atom, or OH; R.sub.6 represents H or CH.sub.3; R.sub.12 represents H, CH.sub.3, or CH.sub.3CH.sub.2; R.sub.13 represents CH.sub.3 or CH.sub.3CH.sub.2; R.sub.15 represents H or OH; R.sub.17 represents H or CH.sub.3; R.sub.18 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (III) can be formed from an anabolic steroid selected from the group consisting of androstenediol, bolandiol, bolasterone, clostebol, formyldienolone, 4-hydroxy-19-nortestosterone, methandriol, methenolone, methyltrienolone, nandrolone, norbolethone, oxymesterone, stenbolone, and trenbolone.

[0187] In some embodiments, the steroid is an anabolic steroid and the drug dimer is further described by the formula (IV):

##STR00040##

wherein R.sub.12 represents H or CH.sub.3; R.sub.17 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (IV) can be formed from an anabolic steroid selected from 4-hydroxy-19-nortestosterone or oxymesterone.

[0188] In certain embodiments, the steroid is an androgenic steroid and the drug dimer is further described by the formula (V):

##STR00041##

wherein the bond between C.sub.1 and C.sub.2, C.sub.4 and C.sub.5, and C.sub.5 and C.sub.6 is a single or a double bond; C.sub.2 is O, C or CH.sub.2; R.sub.1 represents H, —CHOH, or is absent; R.sub.2 represents ═O or OH; or R.sub.1 and R.sub.2 taken together with carbons to which they are attached form a pyrazole; R.sub.3 represents H or OH; R.sub.12 represents H, CH.sub.3, optionally substituted alkynylene, C.sub.1-6alkoxy, or CH.sub.3CH.sub.2; R.sub.15 represents H or OH; R.sub.16 represents H or a halogen atom; R.sub.17 represents H or CH.sub.3; R.sub.18 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (V) can be formed from an androgenic steroid selected from the group consisting of boldenone, fluoxymesterone, mestanolone, mesterolone, methandrostenolone, 17-methyltestosterone, 17-α-methyltestosterone 3-cyclopentyl enol ether, norethandrolone, normethandrone, oxandrolone, oxymesterone, oxymetholone, prasterone, stanlolone, stanozolol, testosterone, testosterone enanthate tiomesterone dehydroepiandrosterone (DHEA), androstenedione, androstenediol, androsterone, and dihydrotestosterone (DHT).

[0189] In some embodiments, the steroid is an androgenic steroid and the drug dimer is further described by the formula (VI):

##STR00042##

wherein the bond between C.sub.1 and C.sub.2, C.sub.4 and C.sub.5, and C.sub.5 and C.sub.6 is a single or a double bond; C.sub.2 is O, C or CH.sub.2; R.sub.1 represents H, —CHOH, or is absent; R.sub.3 represents H or OH; R.sub.11 represents H, OH, CH.sub.3, optionally substituted alkynylene, CH.sub.3CH.sub.2, ═O, —OC(O)CH.sub.2CH.sub.3, or is absent; R.sub.12 represents H, OH, CH.sub.3, optionally substituted alkynylene, CH.sub.3CH.sub.2, ═O, —OC(O)CH.sub.2CH.sub.3, or is absent; R.sub.15 represents H or OH; R.sub.16 represents H or a halogen atom; R.sub.17 represents H or CH.sub.3; R.sub.18 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (VI) can be formed from an androgenic steroid selected from the group consisting of boldenone, fluoxymesterone, mestanolone, mesterolone, methandrostenolone, 17-methyltestosterone, norethandrolone, normethandrone, oxandrolone, oxymesterone, oxymetholone, prasterone, stanlolone, testosterone, testosterone proprionate, testosterone enanthate tiomesterone dehydroepiandrosterone (DHEA), androstenedione, androstenediol, androsterone, and dihydrotestosterone (DHT).

[0190] In certain embodiments, the steroid is an androgenic steroid and the drug dimer is further described by the formula (VII):

##STR00043##

wherein L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (VII) can be formed from the androgenic steroid fluoxymesterone.

[0191] In some embodiments, the steroid is an androgenic steroid and the drug dimer is further described by the formula (VIII):

##STR00044##

wherein L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (VIII) can be formed from the androgenic steroid oxymesterone.

[0192] In some embodiments, the steroid is an androgenic steroid and the drug dimer is further described by the formula (IX):

##STR00045##

wherein L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (IX) can be formed from the androgenic steroid oxymetholone.

[0193] In particular embodiments, the steroid is a progestin steroid and the drug dimer is further described by the formula (X):

##STR00046##

wherein the bond between C.sub.1 and C.sub.10, C.sub.2 and C.sub.3, C.sub.3 and C.sub.4, C.sub.4 and C.sub.5, C.sub.5 and C.sub.6, C.sub.6 and C.sub.7, C.sub.5 and C.sub.10, C.sub.9 and C.sub.10, C.sub.11 and C.sub.12, C.sub.15 and C.sub.16 is a single or a double bond; R.sub.2 represents H, ═O, OH, —NOH, or C.sub.1-6alkoxy; R.sub.5 represents H, CH.sub.3, or a halogen atom; R.sub.6 represents H or CH.sub.3; or R.sub.5 and R.sub.6 taken together with carbons to which they are attached form a cyclopropane; R.sub.9 is H; R.sub.10 is H or ═CH.sub.2; or R.sub.9 and R.sub.10 taken together with carbons to which they are attached form a cyclopropane; R.sub.12 represents H, optionally substituted alkynylene, —CH.sub.2CH═CH.sub.2, CH.sub.3, —C(O)CH.sub.3, or —CH═CH.sub.2; R.sub.13 represents CH.sub.3 or CH.sub.2CH.sub.3; R.sub.15 represents H or ═CH.sub.2; R.sub.17 represents H, CH.sub.3, or is absent; L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (X) can be formed from a progestin steroid selected from the group consisting of norethisterone, gestodene, levonorgestrel, allylestrenol, anagestone, desogestrel, dimethisterone, dydrogesterone, ethisterone, ethynodiol, etonogestrel, gestodene, ethinylestradiol, 17-hydroxy-16-methylene-progesterone, 17 alpha-hydroxyprogesterone, lynestrenol, medroxyprogesterone, melengestrol, norethindrone, norethynodrel, norgesterone, gestonorone, norethisterone, norgestrel, levonorgestrel, norgestrienone, pentagestrone, 7-methyl-19-testosterone (MENT), norelgestromin, tibolone, and megestrol.

[0194] In certain embodiments, the steroid is a progestin steroid and the drug dimer is further described by the formula (XI):

##STR00047##

wherein the bond between C.sub.1 and C.sub.10, C.sub.2 and C.sub.3, C.sub.4 and C.sub.5, C.sub.6 and C.sub.7, C.sub.5 and C.sub.10, C.sub.9 and C.sub.10, C.sub.11 and C.sub.12, C.sub.15 and C.sub.16 is a single or a double bond; R.sub.5 represents H, CH.sub.3, or a halogen atom; R.sub.6 represents H or CH.sub.3; or R.sub.5 and R.sub.6 taken together with carbons to which they are attached form a cyclopropane; R.sub.9 is H; R.sub.10 is H or ═CH.sub.2; or R.sub.9 and R.sub.10 taken together with carbons to which they are attached form a cyclopropane; R.sup.11 represents H, OH, optionally substituted alkynylene, —C(O)CH.sub.3, —CH.sub.2CH═CH.sub.2, a halogen atom, —CH═CH.sub.2, —OC(O)CH.sub.3, CH.sub.3, —C(O)C(OH)CH.sub.3; R.sub.12 represents H, OH, optionally substituted alkynylene, —C(O)CH.sub.3, —CH.sub.2CH═CH.sub.2, a halogen atom, —CH═CH.sub.2, —OC(O)CH.sub.3, CH.sub.3, —C(O)C(OH)CH.sub.3; or R.sub.11 and R.sub.12 together with carbon to which they are attached form a lactone; R.sub.13 represents CH.sub.3 or CH.sub.2CH.sub.3; R.sub.15 represents H or ═CH.sub.2; R.sub.17 represents H, CH.sub.3, or is absent; L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XI) can be formed from a progestin steroid selected from the group consisting of norethisterone, norethisterone acetate, gestodene, levonorgestrel, dimethisterone, dydrogesterone, ethisterone, ethynodiol, etonogestrel, gestodene, ethinylestradiol, haloprogesterone, 17-hydroxy-16-methylene-progesterone, 17 alpha-hydroxyprogesterone, medroxyprogesterone, melengestrol, norethindrone, norethynodrel, norgesterone, gestonorone, norethisterone, norgestimate, norgestrel, levonorgestrel, norgestrienone, 7-methyl-19-testosterone (MENT), norelgestromin, trimigestone, drospirenone, tibolone, and megestrol.

[0195] In some embodiments, the steroid is a progestin steroid and the drug dimer is further described by the formula (XII):

##STR00048##

Wherein L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XII) can be formed from the progestin steroid trimigestone.

[0196] In particular embodiments, the steroid is an estrogen steroid and the drug dimer is further described by the formula (XIII):

##STR00049##

wherein the bond between C.sub.1 and C.sub.2, C.sub.1 and C.sub.10, C.sub.2 and C.sub.3, C.sub.3 and C.sub.4, C.sub.4 and C.sub.5, C.sub.6 and C.sub.7, C.sub.5 and C.sub.10, C.sub.7 and C.sub.8, and C.sub.8 and C.sub.9 is a single or a double bond; R.sub.2 represents OH, —OC(O)Ph, or C.sub.1-6alkoxy; R.sub.10 represents H or OH; R.sub.12 represents H, optionally substituted alkynylene; R.sub.15 represents H or C.sub.1-6 alkoxy; L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XIII) can be formed from an estrogen steroid selected from the group consisting of estrogen, eguilenin, equilin, 17β-estradiol, estradiol benzoate, estriol, ethinyl estradiol, mestranol, moxestrol, mytatrienediol, quinestradiol, and quinestrol.

[0197] In some embodiments, the steroid is an estrogen steroid and the drug dimer is further described by the formula (XIV):

##STR00050##

wherein the bond between C.sub.1 and C.sub.2, C.sub.1 and C.sub.10, C.sub.2 and C.sub.3, C.sub.3 and C.sub.4, C.sub.4 and C.sub.5, C.sub.6 and C.sub.7, C.sub.5 and C.sub.10, C.sub.7 and C.sub.8, and C.sub.8 and C.sub.9 is a single or a double bond; R.sub.10 represents H or OH; R.sub.11 represents H, OH, optionally substituted alkynylene, ═O, or is absent; R.sub.12 represents H, OH, optionally substituted alkynylene, ═O, or is absent; R.sub.15 represents H or C.sub.1-6alkoxy; L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XIV) can be formed from an estrogen steroid selected from the group consisting of estrogen, eguilenin, equilin, 17β-estradiol, estriol, ethinyl estradiol, and moxestrol.

[0198] In some embodiments, the steroid is an estrogen steroid and the drug dimer is further described by the formula (XV):

##STR00051##

wherein R.sub.2 represents OH or C.sub.1-6 alkoxy; R.sub.10 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XV) can be formed from an estrogen steroid selected from the group consisting of estriol, mytatrienediol, and quinestradiol.

[0199] In particular embodiments, the steroid is a cancer treatment steroid and the drug dimer is further described by the formula (XVI):

##STR00052##

wherein the bond between C.sub.1 and C.sub.2, C.sub.4 and C.sub.5, C.sub.5 and C.sub.6, C.sub.6 and C.sub.7, and C.sub.16 and C.sub.17 is a single or a double bond; C.sub.4 is NH, CH, or CH.sub.2; R.sub.1 represents H; R.sub.5 represents H or a halogen atom; R.sub.11 represents H, optionally substituted heteroaryl, —C(O)C.sub.1-6 alkyl, —C(O)OC.sub.1-6 alkyl, or —C(O)NHR, wherein R is optionally substituted alkyl or aryl; R.sub.12 represents H, optionally substituted heteroaryl, —C(O)C.sub.1-6 alkyl, —C(O)OC.sub.1-6 alkyl, or —C(O)NHR, wherein R is optionally substituted alkyl or aryl; R.sub.18 represents H; or R.sub.1 and R.sub.18 taken together with carbons to which they are attached form a cyclopropane; L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XVI) can be formed from a cancer treatment steroid selected from the group consisting of abiraterone, cyproterone acetate, dutasteride, finasteride, and galeterone.

[0200] In some embodiments, the steroid is an antibiotic steroid and the drug dimer is further described by the formula (XVII):

##STR00053##

wherein L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XVII) can be formed from the steroid antibiotic fusidic acid.

[0201] In some embodiments, the steroid is an antibiotic steroid and the drug dimer is further described by the formula (XVIII):

##STR00054##

wherein L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XVIII) can be formed from the steroid antibiotic fusidic acid.

[0202] In some embodiments, the steroid is a benign steroid and the drug dimer is further described by the formula (XIX):

##STR00055##

wherein R.sub.12 is H or OH; L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XIX) can be formed from a benign steroid selected from 11-deoxycortisol and 11-deoxycorticosterone.

[0203] In some embodiments, the steroid is a benign steroid and the drug dimer is further described by the formula (XX):

##STR00056##

wherein the bond between C.sub.4 and C.sub.5, and C.sub.5 and C.sub.6 is a single or a double bond; R.sub.5 represents H or C.sub.1-6 alkyl; R.sub.6 represents H or OH; R.sub.11 represents H, OH, —C(O)C.sub.1-6 alkyl, —C(O)CH.sub.2OH, or —CH(CH.sub.3)CH.sub.2CH.sub.2C(O)OH; R.sub.12 represents H, OH, —C(O)C.sub.1-6 alkyl, —C(O)CH.sub.2OH, or —CH(CH.sub.3)CH.sub.2CH.sub.2C(O)OH; L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XX) can be formed from a benign steroid selected from the group consisting of cholesterol, 11-deoxycortisol, 11-deoxycorticosterone, pregnenolone, cholic acid, chenodeoxycholic acid, ursodeoxycholic acid, and obeticholic acid.

[0204] In some embodiments, the steroid is a benign steroid and the drug dimer is further described by the formula (XXI):

##STR00057##

wherein L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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.
The drug dimer of formula (XXI) can be formed from a benign steroid including 11-deoxycortisol.

[0205] In some embodiments, the steroid is a benign steroid and the drug dimer is further described by the formula (XXII):

##STR00058##

wherein R.sub.5 represents H or CH.sub.2CH.sub.3; R.sub.14 represents H or OH; L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XXII) can be formed from a benign steroid selected from the group consisting of cholic acid, chenodeoxycholic acid, ursodeoxycholic acid, and obeticholic acid.

[0206] In some embodiments, the steroid is a benign steroid and the drug dimer is further described by the formula (XXIII):

##STR00059##

wherein L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XXIII) can be formed from the benign steroid cholic acid.

[0207] In some embodiments, the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (XXIV):

##STR00060##

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.1-6alkyl; 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XXIV) 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.

[0208] In some embodiments, the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (XXV):

##STR00061##

[0209] In some embodiments, the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (XXVI):

##STR00062##

wherein L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XXVI) can be formed from the glucocorticoid steroid fluclorolone acetonide.

[0210] In some embodiments, the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (XXVII):

##STR00063##

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.1-6alkyl, 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XXVII) 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, 6α-methylprednisolone, methylprednisolone, methylprednisolone acetate, mometasone, paramethasone, prednisolone, prednisone, prednylidene, tixocortol, triamcinolone, and ulobetasol.

[0211] In certain embodiments, the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (XXVIII):

##STR00064##

wherein L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XXVIII) can be formed from the glucocorticoid steroid cortivazol.

[0212] In some embodiments, the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (XXIX):

##STR00065##

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.1-6alkyl, OH, or ═CH.sub.2; R.sub.10b represents H, C.sub.1-6alkyl, 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.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.1-6alkyl, 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.1-6alkyl; 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XXIX) 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.

[0213] In some embodiments, the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (XXX):

##STR00066##

Wherein L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XXX) can be formed from the glucocorticoid steroid cortivazol.

[0214] In some embodiments, the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (XXXI):

##STR00067##

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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XXXI) can be formed from a glucocorticoid steroid selected from the group consisting of fluclorolone, fluocinolone, and triamcinolone.

[0215] In some embodiments, the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (XXXII):

##STR00068##

[0216] In some embodiments, the steroid is a glucocorticoid steroid and the drug dimer is further described by the formula (XXXIII):

##STR00069##

[0217] In particular embodiments, the steroid is a corticosteroid and the drug dimer is further described by the formula (XXXIV):

##STR00070##

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 (XVIII-a) wherein:

##STR00071##

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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XXXIV) 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.

[0218] In any of the above formulas (II)-(XXXIV), 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.

[0219] In particular embodiments, the steroid is a corticosteroid and the drug dimer is further described by the formula (XXXV):

##STR00072##

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 (XXXV) can be formed from fusidic acid.

[0220] In some embodiments, the steroid is a corticosteroid and the drug dimer is further described by the formula (XXXVI):

##STR00073##

wherein R.sub.5 represents H or C.sub.1-6 alkyl; R.sub.14 represents H or OH; and 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 (XXXVI) can be formed from chenodeoxycholic acid, ursodeoxycholic acid, or obeticholic acid.

[0221] In some embodiments, the steroid is an anti-angiogenic steroid or an intraocular pressure (IOP) lowering steroid, and the drug dimer is further described by the formula (XXXVII):

##STR00074##

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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XXXVII) can be formed from anecortave acetate, anecortave, 11-epicortisol, 17α-hydroxyprogesterone, tetrahydrocortexolone, or tetrahydrocortisol.

[0222] In some embodiments, the steroid is an anti-angiogenic steroid or an intraocular pressure (IOP) lowering steroid, and the drug dimer is further described by the formula (XXXVIII):

##STR00075##

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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XXXVIII) can be formed from anecortave acetate, anecortave, 11-epicortisol, 17α-hydroxyprogesterone, tetrahydrocortexolone, or tetrahydrocortisol.

[0223] In some embodiments, the steroid is an anti-angiogenic steroid or an intraocular pressure (IOP) lowering steroid, and the drug dimer is further described by the formula (XXXIX):

##STR00076##

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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XXXIX) can be formed from anecortave, 11-epicortisol, tetrahydrocortexolone, or tetrahydrocortisol.

[0224] In some embodiments, the steroid is an anti-angiogenic steroid or an intraocular pressure (IOP) lowering steroid, and the drug dimer is further described by the formula (XL):

##STR00077##

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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XL) can be formed from 11-epicortisol or tetrahydrocortisol.

[0225] In some embodiments, the steroid is a benign steroid and the drug dimer is further described by the formula (XLI):

##STR00078##

wherein the bond between C.sub.11 and R.sub.15 is a single or a double bond; R.sub.11 represents H, OH, —C(═O)CH.sub.2OH, or —C(═O)CH.sub.3; R.sub.12 represents H, OH, —C(═O)CH.sub.2OH, or —C(═O)CH.sub.3; R.sub.15 represents H, ═O, 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XLI) can be formed from tetrahydrocortisone, tetrahydrodeoxycortisol, tetrahydrocorticosterone, 5α-dihydrocorticosterone, or 5α-dihydropregesterone.

[0226] In some embodiments, the steroid is a benign steroid and the drug dimer is further described by the formula (XLII):

##STR00079##

wherein the bond between C.sub.11 and R.sub.15 is a single or a double bond; R.sub.15 represents H 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XLII) can be formed from tetrahydrocortisone, or tetrahydrodeoxycortisol.

[0227] In some embodiments, the steroid is a benign steroid and the drug dimer is further described by the formula (XLIII):

##STR00080##

wherein the bond between C.sub.3 and R.sub.2, and C.sub.11 and R.sub.15 is a single or a double bond; R.sub.2 represents OH or ═O; R.sub.11 represents H, or OH; R.sub.15 represents H, ═O, 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XLIII) can be formed from tetrahydrocortisone, tetrahydrodeoxycortisol, tetrahydrocorticosterone, or 5α-dihydrocorticosterone.

[0228] In some embodiments, the steroid is a benign steroid and the drug dimer is further described by the formula (XLIV):

##STR00081##

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.11 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XLIV) can be formed from tetrahydrocortisone, tetrahydrocorticosterone, or 5α-dihydrocorticosterone.

[0229] In some embodiments, the steroid is a cholic acid-related bile acid steroid and the drug dimer is further described by the formula (XLV):

##STR00082##

wherein the bond between C.sub.7 and R.sub.6, and C.sub.12 and R.sub.14 is a single or a double bond; Rx represents OH, —NHCH.sub.2C(═O)OH, or —NHCH.sub.2CH.sub.2SO.sub.2OH; R.sub.2 represents OH or ═O; R.sub.5 represents H or OH; R.sub.6 represents H, ═O, or OH; R.sub.14 represents H, ═O, 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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 0-(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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XLV) can be formed from deoxycholic acid, apocholic acid, dehydrocholic acid, glycochenodeoxycholic acid, glycocholic acid, glycodeoxycholic acid, hyodeoxycholic acid, lithocholic acid, α-muricholic acid, β-muricholic acid, γ-muricholic acid, ω-muricholic acid, taurochenodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, taurolithocholic acid, or tauroursodeoxycholic acid.

[0230] In some embodiments, the steroid is a cholic acid-related bile acid steroid and the drug dimer is further described by the formula (XLVI):

##STR00083##

wherein the bond between C.sub.3 and R.sub.2, and C.sub.7 and R.sub.6 is a single or a double bond; Rx represents OH, —NHCH.sub.2C(═O)OH, or —NHCH.sub.2CH.sub.2SO.sub.2OH; R.sub.2 represents OH or ═O; R.sub.6 represents H, ═O, 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XLVI) can be formed from deoxycholic acid, apocholic acid, dehydrocholic acid, glycocholic acid, glycodeoxycholic acid, taurocholic acid, or taurodeoxycholic acid.

[0231] In some embodiments, the steroid is a cholic acid-related bile acid steroid and the drug dimer is further described by the formula (XLVII):

##STR00084##

wherein R.sub.6 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XLVII) can be formed from hyodeoxycholic acid, α-muricholic acid, 3-muricholic acid, γ-muricholic acid, or ω-muricholic acid.

[0232] In some embodiments, the steroid is a cholic acid-related bile acid steroid and the drug dimer is further described by the formula (XLVIII):

##STR00085##

wherein the bond between C.sub.3 and R.sub.2, and C.sub.12 and R.sub.14 is a single or a double bond; Rx represents OH, —NHCH.sub.2C(═O)OH, or —NHCH.sub.2CH.sub.2SO.sub.2OH; R.sub.2 represents OH or ═O; R.sub.5 represents H or OH; R.sub.14 represents H, ═O, 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (XLVIII) can be formed from dehydrocholic acid, glycochenodeoxycholic acid, glycocholic acid, α-muricholic acid, β-muricholic acid, γ-muricholic acid, ω-muricholic acid, taurochenodeoxycholic acid, taurocholic acid, or tauroursodeoxycholic acid.

[0233] In some embodiments, the steroid is a cholic acid-related bile acid steroid and the drug dimer is further described by the formula (XLIX):

##STR00086##

wherein the bond between C.sub.3 and R.sub.2, C.sub.7 and R.sub.6, and C.sub.12 and R.sub.14 is a single or a double bond; R.sub.2 represents OH or ═O; R.sub.5 represents H or OH; R.sub.6 represents H, ═O, or OH; R.sub.14 represents H, ═O, or OH; and L is —C(O)—(R.sup.A)—C(O)—, —(R.sup.A)—, or —C(O)—O—(R.sup.A)—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 (XLIX) can be formed from deoxycholic acid, apocholic acid, dehydrocholic acid, hyodeoxycholic acid, lithocholic acid, α-muricholic acid, β-muricholic acid, γ-muricholic acid, or ω-muricholic acid.

[0234] In some embodiments, the steroid is a cholic acid-related bile acid steroid and the drug dimer is further described by the formula (L):

##STR00087##

wherein R.sub.6 represents H or OH; R.sub.14 represents H or OH; and 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 0-(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 (L) can be formed from glycochenodeoxycholic acid, glycocholic acid, or glycodeoxycholic acid.

[0235] In some embodiments, the steroid is a steroid metabolite and the drug dimer is further described by the formula (LI):

##STR00088##

wherein the bond between C.sub.11 and R.sub.15 is a single or a double bond; R.sub.2 represents OH or ═O; R.sub.10 represents H or OH; R.sub.11 represents H, OH, —C(═O)CH.sub.2OH, —C(═O)OH, —C(═O)CH.sub.2OH, or —C(═O)CH.sub.3; R.sub.12 represents H, OH, —C(═O)CH.sub.2OH, —C(═O)OH, —C(═O)CH.sub.2OH, or —C(═O)CH.sub.3; R.sub.13 represents —CH.sub.2OH or —CH.sub.3; R.sub.15 represents H, OH, or ═O; R.sub.16 represents H or F; and L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (LI) can be formed from tetrahydrotriamcinolone, cortienic acid, 11-dehydrocorticosterone, 11β-hydroxypregnenolone, ketoprogesterone, 17-hydroxypregnenolone, 17,21-dihydroxypregnenolone, 18-hydroxycorticosterone, deoxycortisone, 21-hydroxypregnenolone, or progesterone.

[0236] In some embodiments, the steroid is a steroid metabolite and the drug dimer is further described by the formula (LII):

##STR00089##

wherein the bond between C.sub.3 and R.sub.2, and C.sub.11 and R.sub.15 is a single or a double bond; R.sub.2 represents OH or ═O; R.sub.10 represents H or OH; R.sub.12 represents —C(═O)CH.sub.2OH, —C(═O)OH, —C(═O)CH.sub.2OH, or —C(═O)CH.sub.3; R.sub.15 represents H, OH, or ═O; R.sub.16 represents H or F; and L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (LII) can be formed from tetrahydrotriamcinolone, cortienic acid, 17-hydroxypregnenolone, 17,21-dihydroxypregnenolone, or deoxycortisone.

[0237] In some embodiments, the steroid is a steroid metabolite and the drug dimer is further described by the formula (LIII):

##STR00090##

[0238] In some embodiments, the steroid is a steroid metabolite and the drug dimer is further described by the formula (LIV):

##STR00091##

wherein the bond between C.sub.3 and R.sub.2, and C.sub.11 and R.sub.15 is a single or a double bond; R.sub.2 represents OH or ═O; R.sub.10 represents H or OH; R.sub.11 represents H or OH; R.sub.13 represents H, —CH.sub.2OH, or —CH.sub.3; R.sub.15 represents H, OH, or ═O; R.sub.16 represents H or F; and L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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 0-(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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (LIV) can be formed from tetrahydrotriamcinolone, 11-dehydrocorticosterone, 17,21-dihydroxypregnenolone, 18-hydroxycorticosterone, or 21-hydroxypregnenolone.

[0239] In some embodiments, the steroid is a steroid metabolite and the drug dimer is further described by the formula (LV):

##STR00092##

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.10 represents H or OH; R.sub.11 represents H or OH; R.sub.12 represents —C(═O)CH.sub.2OH, —C(═O)OH, —C(═O)CH.sub.2OH, or —C(═O)CH.sub.3; R.sub.13 represents H, —CH.sub.2OH, or —CH.sub.3; R.sub.16 represents H or F; and L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (LV) can be formed from tetrahydrotriamcinolone, cortienic acid, 11-dehydrocorticosterone, 11β-hydroxypregnenolone, ketoprogesterone, 18-hydroxycorticosterone, or deoxycortisone.

[0240] In some embodiments, the steroid is a steroid metabolite and the drug dimer is further described by the formula (LVI):

##STR00093##

[0241] In some embodiments, the steroid is a steroid metabolite and the drug dimer is further described by the formula (LVII):

##STR00094##

[0242] In some embodiments, the steroid is a cholesterol-derivative and the drug dimer is further described by the formula (LVIII):

##STR00095##

wherein Ry 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (LVIII) can be formed from 22R-hydroxycholesterol or 20α-22R-dihydroxycholesterol.

[0243] In some embodiments, the steroid is a cholesterol-derivative and the drug dimer is further described by the formula (LIX):

##STR00096##

wherein Ry 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (LIX) can be formed from 22R-hydroxycholesterol or 20α-22R-dihydroxycholesterol.

[0244] In some embodiments, the steroid is a cholesterol-derivative and the drug dimer is further described by the formula (LX):

##STR00097##

wherein L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (LX) can be formed from 20α-22R-dihydroxycholesterol.

[0245] In some embodiments, the steroid is a neurosteroid and the drug dimer is further described by the formula (LXI):

##STR00098##

wherein the bond between C.sub.11 and R.sub.15 is a single or a double bond; Rz represents H or —CH.sub.3; R.sub.1 represents H or —OCH.sub.2CH.sub.3; R.sub.2 represents OH or ═O; R.sub.12 represents —OH, —C(═O)CH.sub.3, —C(═O)CH.sub.2OH, or —CH(CH.sub.3)(CH.sub.2).sub.2CH(OH)CH(CH.sub.3).sub.2; R.sub.15 represents H, —N(CH.sub.3).sub.2, 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (LXI) can be formed from alphaxalone, alphadolone, hydroxydione, minaxolone, tetrahydrodeoxycorticosterone, allopregnanolone, pregnanolone, ganoxolone, 3α-androstanediol, epipregnanolone, isopregnanolone, or 24(S)-hydroxycholesterol.

[0246] In some embodiments, the steroid is a neurosteroid and the drug dimer is further described by the formula (LXII):

##STR00099##

wherein R.sub.12 represents —C(═O)CH.sub.3, or —C(═O)CH.sub.2OH; and L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (LXII) can be formed from alphaxalone or alphadolone.

[0247] In some embodiments, the steroid is a neurosteroid and the drug dimer is further described by the formula (LXIII):

##STR00100##

wherein the bond between C.sub.3 and R.sub.2, and C.sub.11 and R.sub.15 is a single or a double bond; R.sub.2 represents OH or ═O; R.sub.15 represents H 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (LXIII) can be formed from alphadolone, hydroxydione, or tetrahydrodeoxycorticosterone.

[0248] In some embodiments, the steroid is a neurosteroid and the drug dimer is further described by the formula (LXIV):

##STR00101##

[0249] In some embodiments, the steroid is a neurosteroid and the drug dimer is further described by the formula (LXV):

##STR00102##

[0250] In some embodiments, the steroid is a pheromone and the drug dimer is further described by the formula (LXVI):

##STR00103##

wherein R.sub.2 represents OH or ═O; R.sub.11 represents H, —C(═O)CH.sub.3, —OC(═O)(CH.sub.2).sub.4CH.sub.3, or is absent; R.sub.12 represents H, —C(═O)CH.sub.3, —OC(═O)(CH.sub.2).sub.4CH.sub.3, or is absent; R.sub.17 represents CH.sub.3 or is absent; and L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (LXVI) can be formed from androstadienol, androstadienone, androstenol, androstenone, estratetraenol, 5-dehydroprogesterone, 6-dehydro-retroprogesterone, allopregnanolone, or hydroxyprogesterone caproate.

[0251] In some embodiments, the steroid is a progestin and the drug dimer is further described by the formula (LXVII):

##STR00104##

wherein the bond between C.sub.11 and R.sub.15 is a single or a double bond; R.sub.2 represents OH or ═O; R.sub.11 represents H, OH, —CH(OH)CH.sub.3, —C(═O)CH.sub.2OH, —C(═O)CH.sub.3, or —CH(OH)CH.sub.2OH; R.sub.12 represents H, OH, —CH(OH)CH.sub.3, —C(═O)CH.sub.2OH, —C(═O)CH.sub.3, or —CH(OH)CH.sub.2OH; R.sub.15 represents H, ═O, 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (LXVII) can be formed from allopregnone-3α,20α-diol, allopregnone-3β,20β-diol, allopregnane-3β,21-diol-11,20-dione, allopregnane-3β,17α-diol-20-one, 3,20-allopregnanedione, 3β,11β,17a, 203,21-pentol, allopregnane-3β,17α,20β,21-tetrol, allopregnane-3α,11β,17α,21-tetrol-20-one, allopregnane-3β,11β,17α,21-tetrol-20-one, allopregnane-3β,17α,20β-triol, allopregnane-3β,17α,21-triol-11,20-dione, allopregnane-3β,11β,21-triol-20-one, allopregnane-3β,17α,21-triol-20-one, allopregnane-3α-ol-20-one; allopregnane-3β-ol-20-one, pregnanediol, 3,20-pregnanedione, 4-pregnene-20,21-diol-3,11-dione, 4-pregnene-11β,17α,20β,21-tetrol-3-one, 4-pregnene-17α,20β,21-triol-3,11-dione, 4-pregnene-17α,20β,21-triol-3-one, or pregnenolone.

[0252] In some embodiments, the steroid is a progestin and the drug dimer is further described by the formula (LXVIII):

##STR00105##

wherein the bond between C.sub.3 and R.sub.2, and C.sub.11 and R.sub.15 is a single or a double bond; R.sub.2 represents OH or ═O; R.sub.12 represents H, OH, —CH(OH)CH.sub.3, —C(═O)CH.sub.2OH, —C(═O)CH.sub.3, or —CH(OH)CH.sub.2OH; R.sub.15 represents H, ═O, 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (LXVIII) can be formed from allopregnane-3β,17α-diol-20-one, 3,20-allopregnanedione,3β,11β,17α,20β,21-pentol, allopregnane-3β,17α,20β,21-tetrol, allopregnane-3α,11β,17α,21-tetrol-20-one, allopregnane-3β,11β,17α,21-tetrol-20-one, allopregnane-3β,17α,20β-triol, allopregnane-3β,17α,21-triol-11,20-dione, allopregnane-3β,17α,21-triol-20-one, 4-pregnene-11β,17α,20β,21-tetrol-3-one, 4-pregnene-17α,20β,21-triol-3,11-dione, or 4-pregnene-17α,20β,21-triol-3-one.

[0253] In some embodiments, the steroid is a progestin and the drug dimer is further described by the formula (LXIX):

##STR00106##

wherein R.sub.11 represents H, OH, —CH(OH)CH.sub.3, —C(═O)CH.sub.2OH, —C(═O)CH.sub.3, or —CH(OH)CH.sub.2OH; 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (LXIX) can be formed from allopregnone-3α,20α-diol, allopregnone-3β,20β-diol or allopregnane-3β,17α,20β-triol.

[0254] In some embodiments, the steroid is a progestin and the drug dimer is further described by the formula (LXX):

##STR00107##

wherein the bond between C.sub.3 and R.sub.2, and C.sub.11 and R.sub.15 is a single or a double bond; Ry represents OH or ═O; R.sub.2 represents OH or ═O; R.sub.11 represents H, OH, —CH(OH)CH.sub.3, —C(═O)CH.sub.2OH, —C(═O)CH.sub.3, or —CH(OH)CH.sub.2OH; R.sub.12 represents H, OH, —CH(OH)CH.sub.3, —C(═O)CH.sub.2OH, —C(═O)CH.sub.3, or —CH(OH)CH.sub.2OH; R.sub.15 represents H, ═O, 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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 0-(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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (LXX) can be formed from allopregnane-3β,21-diol-11,20-dione, 3,20-allopregnanedione,3β,11β,17α,20β,21-pentol, allopregnane-3β,17α,20β,21-tetrol, allopregnane-3α,11β,17α,21-tetrol-20-one, allopregnane-3β,11β,17α,21-tetrol-20-one, allopregnane-3β,17α,21-triol-11,20-dione, allopregnane-3β,11β,21-triol-20-one, allopregnane-3β,17α,21-triol-20-one, 4-pregnene-20,21-diol-3,11-dione, 4-pregnene-11β,17α,20β,21-tetrol-3-one, 4-pregnene-17α,20β,21-triol-3,11-dione, or 4-pregnene-17α,20β,21-triol-3-one.

[0255] In certain embodiments, the steroid is a progestin and the drug dimer is further described by the formula (LXXI):

##STR00108##

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.11 represents H, OH, —CH(OH)CH.sub.3, —C(═O)CH.sub.2OH, —C(═O)CH.sub.3, or —CH(OH)CH.sub.2OH; R.sub.12 represents H, OH, —CH(OH)CH.sub.3, —C(═O)CH.sub.2OH, —C(═O)CH.sub.3, or —CH(OH)CH.sub.2OH; and L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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 0-(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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (LXXI) can be formed from allopregnane-3β,21-diol-11,20-dione, 3,20-allopregnanedione,3β,11β,17α,20β,21-pentol, allopregnane-3α,11β,17α,21-tetrol-20-one, allopregnane-3β,11β,17α,21-tetrol-20-one, allopregnane-3β,17α,21-triol-11,20-dione, allopregnane-3β,11β,21-triol-20-one, 4-pregnene-20,21-diol-3,11-dione, 4-pregnene-11β,17α,20β,2 some particular embodiments, the steroid is a progestin and the drug dimer is further described by the formula (LXXII):

##STR00109##

wherein the bond between C.sub.3 and R.sub.2, and C.sub.11 and R.sub.15 is a single or a double bond; R.sub.2 represents OH or ═O; R.sub.11 represents H or OH; R.sub.15 represents H, ═O, 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (LXXII) can be formed from 3,20-allopregnanedione,3β,11β,17α,20β,21-pentol, allopregnane-3β,17α,20β,21-tetrol, 4-pregnene-20,21-diol-3,11-dione, 4-pregnene-11β,17α,20β,21-tetrol-3-one, 4-pregnene-17α,20β,21-triol-3,11-dione, or 4-pregnene-17α,20β,21-triol-3-one.

[0256] In some embodiments, the steroid is other steroid and the drug dimer is further described by the formula (LXXIII):

##STR00110##

wherein the bond between C.sub.16 and R.sub.10 is a single or a double bond; R.sub.2 represents OH or ═O; R.sub.5 represents H, Cl, or —CH.sub.3; R.sub.10 represents H or ═CH.sub.2; R.sub.11 represents H, OH, —CH.sub.3, —C(═O)CH.sub.3, —C(═O)CH.sub.2OC(═O)CH.sub.3, or —OC(═O)CH.sub.3; R.sub.12 represents H, OH, —CH.sub.3, —C(═O)CH.sub.3, —C(═O)CH.sub.2OC(═O)CH.sub.3, or —OC(═O)CH.sub.3; R.sub.15 represents H or OH; R.sub.16 represents F or H; R.sub.1 represents H or —CH.sub.3; and L is —C(O)O—(R.sup.A)—OC(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (LXXIII) can be formed from flugestone, prebediolone, chlormadinone acetate, medrogestone, or segesterone acetate.

[0257] In some embodiments, the steroid is other steroid and the drug dimer is further described by the formula (LXXIV):

##STR00111##

[0258] In some embodiments, the steroid is another steroid and the drug dimer is further described by the formula (LXXV):

##STR00112##

[0259] In some embodiments, the steroid is a mineralocorticoid steroid, and the drug dimer is further described by the formula (LXXVI):

##STR00113##

wherein R.sub.1 is C(O)H or CH.sub.3; R.sub.2 represents H or F; R.sub.3 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (LXXVI) can be formed from fludrocortisone or aldocortisone.

[0260] In some embodiments, the steroid is a mineralocorticoid steroid, and the drug dimer is further described by the formula (LXXVII):

##STR00114##

wherein R.sub.1 is C(O)H or CH.sub.3; R.sub.2 represents H or F; R.sub.3 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)—, or —C(O)—(R.sup.B)—C(O)O—(R.sup.A)—OC(O)—(R.sup.B)—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—; n, m, and p are integers from 1 to 10; and each R.sup.B is independently 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. The drug dimer of formula (LXXVII) can be formed from fludrocortisone or aldocortisone.

[0261] In some embodiments, the steroid is a mineralocorticoid steroid, and the drug dimer is further described by the formula (LXXVIII):

##STR00115##

Processing Methods

[0262] In some embodiments, articles or drug depots provided herein are formed using methods provided herein such as, for example, heat processing or solvent processing of the drug dimer of formula (I). Heat processing can include annealing after the surface coating is formed. Heat processing can also include heat molding, injection molding, extrusion, 3D printing, melt electrospinning, fiber spinning, fiber extrusion, blow molding, and/or annealing after the drug depot is formed. Solvent processing may include coating, micro printing, emulsion processing, dot printing, micropatterning, dip coating, spray coating, stamp coating, brush coating, drop and drag coating, electrospraying, and electrospinning to produce one or more layers at a surface. Solvent processing may also include electrospraying and electrospinning the drug depot onto one or more layers on the surface or around the medical device or a component of the medical device. Solvent-free coating methods may also be used including powder coating followed by annealing. Solvent-free methods may also be used including annealing a powder to form a drug depot of the invention. In some embodiments, a mold is used to produce a drug depot of the desired shape. For example, the compounds of the disclosure can be heat processed to form a melt, and poured into a mold to produce, upon cooling, a shaped drug depot.

[0263] In some embodiments, a portion or side of the article is masked to produce a single-sided or patterned coating (e.g., a checkerboard pattern, dot pattern, or striped pattern) on an article.

Electrospraying Method

[0264] In some embodiments, the compounds provided herein are dissolved in a solvent (e.g., acetone) at concentrations ranging from, e.g., 10-30% w/v, and are electrosprayed onto a surface to form surface coatings or drug depots of the invention. 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 concentrations of 10 to 30% w/v, depending upon the desired thickness of the drug depot or material being layered onto the surface.

Fiber Spinning Methods

[0265] In some embodiments, the drug depot of the disclosure is a fibrous pouch around the medical device or a component of the device or a fibrous wafer inserted adjacent to the medical device. The fibrous meshes can have aligned and unaligned morphologies and 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 the device or a component of the medical device rotating at a particular rotational speed, e.g., 1150 rpm, to obtain aligned fibers around the device or component, or 30 rpm, to obtain unaligned fibers around the device or component, or onto a stationary device or component to obtain unaligned fibers on only one side of the device or component. A potential difference (e.g., 18 kV or 17 kV) can be maintained between the needle and collecting surface for aligned and random fibers.

[0266] 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.

[0267] 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.

Extrusion Method

[0268] In some embodiments, cylinders made from the pharmaceutical composition may injected adjacent to a medical device upon implantation and/or at various time points after device implantation and 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.

[0269] The extrudate may be cut to the desired length for appropriate drug dosing for the indication of interest.

[0270] Low Temperature Processing Using Intermediate Glassy State Articles or Drug Depots

[0271] In certain embodiments, the 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 of the surface coating or drug depot. 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 surface coating or drug depot (e.g., annealing), while reducing the impact of processing conditions on the purity of the prodrug dimer in the article or drug depot.

[0272] Exemplary processing details are provided in the Examples.

Drug Delivery

[0273] In some embodiments, the compositions (e.g., pharmaceutical compositions), articles, and drug depots provided herein are tailored for optimal delivery of a drug (e.g., release the drug from an article or drug depot provided herein in a controlled manner, for example, by surface erosion). The surface erosion mechanism of drug release may allow the coating or drug depot 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 may inhibit burst release and reduce the formation of inflammatory particulates. The drug can be controlled to be delivered over a desired period of time. 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 surface coating or drug depot in prodrug form) at 37° C. in 100% bovine serum over 5 days) may in turn result in improved device function and longevity, a reduction in the frequency pharmaceuticals must be administered, and may reduce or avoid systemic side effects associated with use of the drug. Drug release can also be tailored to avoid side effects of slower and longer release of the drug by engineering the surface coating or drug depot to provide steady release over a comparatively shorter period of time. Depending on the indication, the medical device, and the drug, the drug release can be tailored for dose and duration appropriate to the indication of interest.

[0274] In some embodiments, the rate of release of a drug depends on the drug composition of the drug dimer. Drug release rate from the formed object of the drug dimer can be modulated by the cleavage of a drug-linker bond through hydrolysis or enzymatic degradation. In some embodiments, the linker can affect drug release rate. In some embodiments, the drug release rate is 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 may also depend on the quantity of the loaded drug dimer as a percent of the final drug dimer formulation, e.g., by using a pharmaceutical excipient (e.g., bulking agent/excipient) or a second steroid drug (e.g., active or benign) as a homodimer mixture, or within the same molecule as a heterodimer that acts as a bulking agent. 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 or drug depot. In other embodiments, drug release is affected by changes in the thickness and/or surface area of the formulation, e.g., by applying layers until the desired coating thickness is obtained, or by changing the size of the drug depot or the surface area to which the coating is applied. By adjusting the vide supra factors, dissolution, degradation, diffusion, and controlled release may be varied over wide ranges. For example, release may be designed to be initiated over minutes to hours, and may extend over the course of days, weeks, months, or years.

Uses and Pharmaceutical Compositions and Drug Depots

[0275] In some embodiments, the dimers provided herein are applied to an implantable drug delivery device (or, e.g., a drug depot) with minimal additives. This may 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 device coating or drug depot. 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, a radio-opaque agent, 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.

Sterilization of Formulations

[0276] Generally, it is desired that a medical device is sterile before or upon administration to a subject. In some embodiments, 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, medical devices containing the surface coatings or drug depots provided herein are subjected to an aseptic process and/or other sterilization process. In some embodiments, an aseptic process involves sterilizing the components of the device, the final device, and/or container closure of the combination 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.

Treatment Methods and Therapy with Drug Depots in Combination with Medical Devices

[0277] In certain instances, the surface coatings or drug depots provided herein are used in combination with an implantable medical device (e.g., employed in the fields of ophthalmology, oncology, laryngology, endocrinology and metabolic diseases, rheumatology, urology, neurology, cardiology, dental medicine, dermatology, otology, post-surgical medicine, orthopedics, pain management, and gynecology).

[0278] In some embodiments, a compound provided herein is selected for the desired property, such as, for example, corticosteroid dimers for use in treating inflammatory diseases or conditions or for reducing inflammation or foreign body response due to device itself or device implantation procedure; or the use of antibiotic steroid dimers for treating an infection or preventing device-related infections.

Surgical Procedures

[0279] In some embodiments, the surface coatings or drug depots provided herein are used in conjunction with a surgical procedure. For example, a device bearing a surface coating or drug depot provided herein can be implanted at a surgical site to reduce the risk of infection, inflammation, or to monitor a condition (such as when combined for use in an implantable sensor).

Articles and Implantable Medical Devices

[0280] Any article can be coated with the surface coatings of the invention. For example, articles suitable for contact with bodily fluids, such as medical can be coated using the compositions described herein. For example, the article can be blood dwelling medical device (e.g., a heart valve, vascular stent, endovascular coil, or catheter), urine dwelling medical device (e.g., a drainage catheter or ureteral stent), and/or subcutaneously dwelling medical device (e.g., an implantable sensor). The duration of contact may be short, for example, as with surgical instruments or long-term use articles such as implants.

[0281] Any implantable medical device can be used in combination with the surface coating or drug depots of the invention. For example, the implantable medical device can be blood dwelling medical device (e.g., a heart valve, vascular stent, endovascular coil, or catheter), urine dwelling medical device (e.g., a drainage catheter or ureteral stent), and/or subcutaneously dwelling medical device (e.g., an implantable sensor). The implantable medical devices include, without limitation, catheters, guide wires, vascular stents, probes, sensors, transdermal patches, vascular patches, orthopedics (e.g., screws and plates), hernia mesh, ophthalmological devices (i.e., punctal plug, contact lenses, minimally invasive glaucoma surgery (MIGS) devices, intraocular lens), vaginal slings, and tubing. For example, the article can be selected from dental devices, dental implants, drug delivery devices, grafts, stents, implantable cardioverter-defibrillators, heart valves, vena cava filters, endovascular coils, catheters, shunts, wound drains, drainage catheters, infusion ports, cochlear implants, endotracheal tubes, tracheostomy tubes, ventilator breathing tubes, implantable sensors, ophthalmic devices, orthopedic devices, periodontal implants, breast implants, penile implants, maxillofacial implants, cosmetic implants, valves, appliances, scaffolding, suturing material, needles, hernia repair meshes, tension-free vaginal tape and vaginal slings, prosthetic neurological devices, ear tubes, a wound dressing, a bandage, a gauze, a tape, a pad, a sponge, a contraceptive device, and feminine hygiene products.

[0282] In some embodiments, the implantable device is selected from dental devices, dental implants, drug delivery devices, grafts, stents, implantable cardioverter-defibrillators, heart valves, vena cava filters, endovascular coils, catheters, shunts, wound drains, drainage catheters, infusion ports, cochlear implants, endotracheal tubes, tracheostomy tubes, ventilator breathing tubes, implantable sensors, ophthalmic devices, orthopedic devices, periodontal implants, breast implants, penile implants, maxillofacial implants, cosmetic implants, valves, appliances, scaffolding, suturing material, needles, hernia repair meshes, tension-free vaginal tape and vaginal slings, prosthetic neurological devices, ear tubes, a wound dressing, a bandage, a gauze, a tape, a pad, a sponge, a contraceptive device, feminine hygiene products, prostheses, pacemakers, electrical leads, defibrillators, artificial hearts, ventricular assist devices, anatomical reconstruction prostheses, artificial heart valves, heart valve stents, pericardial patches, surgical patches, coronary stents, vascular grafts, vascular and structural stents, vascular or cardiovascular shunts, biological conduits, pledges, sutures, annuloplasty rings, stents, staples, valved grafts, dermal grafts for wound healing, orthopedic spinal implants, ophthalmic implants, intrauterine devices, maxial facial reconstruction plating, intraocular lenses, MIGS devices, clips, and sternal wires.

[0283] In some embodiments, surface coatings provided herein are used as a surface covering for an article (e.g., where the polymers or admixtures are of a type capable of being formed into 1) a self-supporting structural body, 2) a film; or 3) a fiber, preferably woven or knit). The composition may comprise a surface or in whole or in part of the article (e.g., a biomedical device or device of general biotechnological use). In some embodiments, applications include cardiac assist devices, tissue engineering polymeric scaffolds and related devices, cardiac replacement devices, cardiac septal patches, intra aortic balloons, percutaneous cardiac assist devices, extra-corporeal circuits, A-V fistual, dialysis components (tubing, filters, membranes, etc.), aphoresis units, membrane oxygenator, cardiac by-pass components (tubing, filters, etc.), pericardial sacs, contact lens, cochlear ear implants, sutures, sewing rings, cannulas, contraceptives, syringes, o-rings, bladders, penile implants, drug delivery systems, drainage tubes, pacemaker lead insulators, heart valves, blood bags, coatings for implantable wires, catheters, vascular stents, angioplasty balloons and devices, bandages, heart massage cups, tracheal tubes, mammary implant coatings, artificial ducts, craniofacial and maxillofacial reconstruction applications, ligaments, fallopian tubes.

[0284] In some embodiments, drug depots provided herein are retained by or affixed to the implantable medical device. For example, the drug depot can be glued to the surface of the implantable medical device or retained by a screw, washer, or bolt. In some embodiments, the implantable medical device includes a reservoir for holding a drug depot provided herein or can be held on its own (e.g. a fibrous pouch around the device or component). In another embodiment, the drug depot is implanted adjacent to (e.g., separately from) the implantable medical device (e.g., at the time of surgical implantation and/or subsequent to the implantation of the medical device).

[0285] The medical device can be an implanted device, percutaneous device, or cutaneous device. Implanted devices include articles that are fully implanted in a patient, e.g., are completely internal. Percutaneous devices include items that penetrate the skin, thereby extending from outside the body into the body. Cutaneous devices are used superficially. Implanted devices include, without limitation, prostheses such as pacemakers, electrical leads such as pacing leads, defibrillarors, artificial hearts, ventricular assist devices, anatomical reconstruction prostheses such as breast implants, artificial heart valves, heart valve stents, pericardial patches, surgical patches, coronary stents, vascular grafts, vascular and structural stents, vascular or cardiovascular shunts, biological conduits, pledges, sutures, annuloplasty rings, staples, valved grafts, dermal grafts for wound healing, orthopedic spinal implants, orthopedic pins, intrauterine devices, urinary stents, maxial facial reconstruction plating, dental implants, intraocular lenses, clips, sternal wires, bone, skin, ligaments, tendons, and combination thereof. Percutaneous devices include, without limitation, catheters or various types, cannulas, drainage tubes such as chest tubes, surgical instruments such as forceps, retractors, needles, and gloves, and catheter cuffs. Cutaneous devices include, without limitation, burn dressings, wound dressings and dental hardware, such as bridge supports and bracing components.

[0286] In some embodiments, an implantable medical device provided herein is generally structured from a base metallic, ceramic, or polymeric platform in a solid-state format. In some embodiment, the composition provided herein, either alone or as an admixture, controls the release of a therapeutic agent from the device for local drug delivery applications.

[0287] The following examples, as set forth below and as summarized in Table 3. 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 invention and are not intended to limit the scope of what the inventors regard as their invention.

EXAMPLES

[0288] The following examples are put forth to provide those of ordinary skill in the art with a description of how the compositions and methods described herein may be used, 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.

Example 1. Compound 1 (Dex-TEG-Dex) can be Synthesized, Coated onto Different Substrates, and Shows Sustained Release from the Coated Surfaces

[0289] 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 warmed 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 from acetonitrile twice to give Compound 1 (FIG. 1) as an off-white crystalline solid.

[0290] 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.

[0291] Different substrates including poly(styrene-block-isobutylene-block-styrene) (SIBS) films, titanium coupons, and fibrous Dacron (polyethylene terephthalate) meshes (FIG. 2A) were coated with compound 1 from acetone by drop coating (FIG. 2B) forming an amorphous (glassy) coating. Free dexamethasone was also drop coated onto the surface (FIG. 2C) and shows a crystalline coating morphology. The bottom of a glass vial was coated with compound 1 and dexamethasone from dichloromethane (DCM) using the drop coating method. Drug release from the coated surfaces in PBS at 37-C (FIG. 3) demonstrates a burst release for the crystalline dexamethasone coating and a slow, sustained drug release from the compound 1 coatings.

[0292] Compound 1 was drop coated with the same total amount of compound 1 from an organic solution (acetone) onto SIBS films, Dacron films, and fibrous Dacron meshes, and drug release was carried out in 100% FBS at 37 C. The coating was extracted from the substrates at different time points and was plotted as a percentage of coating retained over time (FIG. 4). The thin, high surface area coating on the fibrous Dacron mesh resulted in a quick release of coating from the surface. In contrast, the thicker, lower surface area coating on SIBS and Dacron films resulted in lower and longer sustained release from the surfaces.

Example 2. Drop Coating Compound 1 on a Substrate

[0293] Compound 1 was dissolved in acetone at various concentrations (10 to 100 mg/mL) and was drop coated onto substrate surfaces of different sizes at various volumes (0.2 to 5 μL). One to five coating layers were applied to the substrates and the coatings were dried at ambient conditions overnight. Coatings were extracted and total Compound 1 loaded onto the surfaces was determined by HPLC.

[0294] Drop coating led to predictable loading of Compound 1 on larger substrate surface areas (surface area of 1 cm.sup.2) (FIG. 5), but more variability was observed in the loading on smaller surface areas (surface area of 3-6 mm.sup.2) (FIG. 6). Coating solution on smaller substrates spread beyond the edge of the substrate and accounted for this observed variability. In cases where coating of only one side of the substrate is required, overflow of the coating beyond the edge of the substrate would be undesirable.

Example 3. Dip Coating of Compound 1 on a Substrate

[0295] Compound 1 was dissolved in acetone at various concentrations (1 to 25 mg/mL). Substrate materials (surface area of 6-12 mm.sup.2) were dipped in the coating solution once for 5 seconds and then allowed to dry overnight in ambient conditions. Drug loading was determined by extracting the coating and determining the concentration by HPLC analysis (FIG. 7). Dip coating led to comparatively low drug loading compared to drop coating in example 5. This method resulted in coating of both sides of the substrate, which may be preferred in some applications while being undesirable in other applications.

Example 4. Spray Coating of Compound 1 on a Substrate

[0296] Compound 1 was dissolved in acetone at various concentrations (20 to 200 mg/mL). The coating solution of Compound 1 was loaded into a spray coater and sprayed onto substrate materials (surface area of 3-6 mm.sup.2) located below the spray nozzle (10 cm distance). Multiple sprays were dispensed with a delay ranging from 2 seconds to 1 minute between sprays. Following spraying, the coated substrates were dried overnight in ambient conditions. Drug loading was determined by extracting the coating and determining the concentration by HPLC analysis. Spray coating led to predictable drug loadings, related to the concentration of the spray solution and the number of sprays (FIG. 8). High drug loading, up to 120 μg, with the potential for higher loading with increased concentrations and/or number of sprays. Spray coating led to coating of only one side of the substrate.

Example 5. Retention of Coating of Compound 1 During In Vitro Incubation

[0297] Substrates coated with Compound 1 by drop coating or spray coating were incubated in fetal bovine serum (FBS) to determine the amount of Compound 1 retained over time. Each coated substrate was placed in a glass vial containing 4 mL FBS and incubated at 37° C. on a rotating platform. After 1 to 4 days, the remaining coating was extracted and was determined by HPLC (FIG. 9). The amount of Compound 1 retained following 1-day incubation in FBS ranged from 15 to 100% of the initial amount loaded and roughly correlated with thickness (total loading) of the coating. Cracking of the thickest coating resulted in the lower retention than expected and may be improved by annealing.

Example 6. Ethylene Oxide (ETO) Gas Sterilization of Coatings of Compound 1

[0298] Compound 1 coated onto fibrous Dacron meshes were sterilized by ethylene oxide (ETO) gas at a temperature of 55° C. Pre- and post-ETO sterilized coated meshes were analyzed by HPLC to demonstrate no changes in coating (Compound 1) purity (FIG. 10A) and drug release (FIG. 10B) to demonstrate no changes in release properties due to the ETO sterilization process. Drug release was carried out in PBS at 37 C.

Example 7: Compound 1 (Dex-TEG-Dex) Electrosprayed and Annealed to Form the Final Coating

[0299] Compound 1 was dissolved in acetone and was electrosprayed onto a polymer surface to form an intermediate glassy state coating. The sprayed surface was heated to .sup.˜150° C. to anneal compound 1 and obtain the final coating as shown in FIG. 11

Example 8: Compound 1 (Dex-TEG-Dex) Coated onto an Angioplasty Balloon and Cardiac Stent

[0300] Compound 1 was dissolved in acetone and was drop coated onto an angioplasty balloon (FIG. 12A). Compound 1 was similarly spray coated onto a cardiac stent (FIG. 12B).

Example 9. Rat Study with Coatings of Compound 1

[0301] Coatings of Compound 1 in various dexamethasone amounts (1.4-23.3 μg) were spray coated onto substrates as described in Example 4 and sterilized by ETO gas. Coated substrates were injected into the dorsal subcutaneous space of male SD rats with starting weights of 100-124 g (Envigo, Frederick, Md. USA). Animals were euthanized at 0, 3, 7 and 14 days and the skin surrounding the injection sites dissected. Coating remaining at each time point was quantified by HPLC.

[0302] Skin bleaching was noted for the skin surrounding the highest coating amount (23.3 μg) in day 14 animals. These results suggested that dexamethasone released from Compound 1 coatings were biologically active at doses relevant for local drug delivery.

Example 10. Synthesis of Compound 2 (Hydrocortisone-Triethylene Glycol-Hydrocortisone), Coating onto Substrate Surface, and Drug Release from Coated Surface

[0303] Hydrocortisone (42.68 g, 118 mmol) (USP grade) was recrystallized from hot anhydrous ethanol to give highly pure form of starting drug (16.94 g, 40% recovery). Recrystallized hydrocortisone (5 g, 13.8 mmol, 1 equiv) was suspended in dichloromethane (300 mL) on an ice bath (.sup.˜0° C.) and triethylamine (3.86 mL, 2.80 g, 27.6 mmol, 2 equiv) and triethylene glycol bis(chloroformate) (1.70 mL, 2.28 g, 8.28 mmol, 0.6 equiv) were added to the mixture. The ice bath was allowed to warm to room temperature and the reaction was stirred overnight (.sup.˜18 h). The solvent was removed in vacuo and the solid residue purified by normal phase automated column chromatography (hexane-ethyl acetate gradient). The product containing fractions were combined, concentrated in vacuo and the solid was crystallized from ethanol twice. The final product was dried under high vacuum at 50° C. for 4 h to give Compound 2 (FIG. 13A) as an off-white crystalline solid (1.92 g, 30%).

[0304] Compound 2: HPLC (mobile phase: H.sub.2O/TFA and MeCN/TFA) 29.9 min; Elemental analysis: Anal. Calcd for C50H70O16: C, 64.78; H, 7.61; N, 0.00; Cl, 0.00 Found: C, 63.07; H, 7.71; N, <0.50; Cl <300 ppm. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ (ppm) 0.78 (s, 6H, 2×C19 α-CH.sub.3); 0.86 (dd, J=2.9 and 11.1 Hz, 2H, 2×C14-H), 0.99 (dd, J=4.0 and 13.7 Hz, 2H, 2×C8-H), 1.28 (t, J=6.0 Hz, 2H, 2×C7-CH); 1.36 (s, 6H, 2×C18-CH.sub.3); 1.45 (m, 2H, 2×C7-H′); 1.65 (m, 6H, 2×C15-H, 2×C1-CH); 1.78 (dt, J=4.2 and 13.4 Hz, 2H, 2×C1-CH′), 1.92 (m, 6H, 2×C16-CH.sub.2 and C6-CH.sub.2), 2.09 (m, 2H, C6-CH.sub.2′), 2.18 (m, 2H, 2×C9-CH.sub.2), 2.42 (m, 6H, 2×C2-CH.sub.2, 2×C9-CH); 3.56 (s, 4H, 2×TEG OCH.sub.2); 3.64 (m, 4H, 2×TEG OCH.sub.2); 4.22 (m, 4H, 2×TEG OCH.sub.2); 4.26 (m, 2H, 2×C11-OCH); 4.36 (d, J=4.0 Hz, OH); 4.76 (d, 2H, AB, J=17.7 Hz, 2H, C21-CH.sub.2O—); 5.11 (d, 2H, AB, J=17.7 Hz, 2H, C21-CH.sub.2O′—); 5.42 (s, 2H, C17-OH); 5.56 (m, 2H, 2×alkene C4-CH). MS (ESI+) m/z: [M+H]+ Calcd for C.sub.50H.sub.71O.sub.16 927.47; Found 927.47.

[0305] Compound 2 was dissolved in DCM and was drop coated onto the bottom of a glass vial and solvent was evaporated to form the surface coating. Drug release was carried out in PBS at 37 C with buffer changes and was monitored by HPLC. Cumulative drug release calculated from the total drug in the coating (FIG. 13B) and demonstrates consistent drug release from the coated surface over time.

Example 11. Synthesis of Compound 3 (Triamcinolone Acetonide-Triethylene Glycol-Triamcinolone Acetonide), Coating onto Substrate Surface, and Drug Release from Coated Surface

[0306] Triamcinolone acetonide (USP grade; 5 g, 11.5 mmol, 1 equiv) was suspended in dichloromethane (200 mL) on an ice bath (.sup.˜0° C.) and triethylamine (3.21 mL, 2.33 g, 23.0 mmol, 2 equiv) and triethylene glycol bis(chloroformate) (1.42 mL, 1.90 g, 6.90 mmol, 0.6 equiv) were added to the mixture. The ice bath was allowed to warm to room temperature and the reaction was stirred overnight (.sup.˜18 h). The solvent was removed in vacuo and the solid residue was purified by normal phase automated column chromatography (hexane-ethyl acetate gradient). The product containing fractions were combined, concentrated in vacuo and the solid was crystallized from acetonitrile twice. The final product was dried under high vacuum at 50° C. for 4 h to give Compound 3 (FIG. 14A) as an off-white crystalline solid (1.16 g, 19%).

[0307] Compound 3: HPLC (mobile phase: H.sub.2O/TFA and MeCN/TFA) 36.2 min; Elemental analysis: Anal. Calcd for C.sub.56H.sub.72F.sub.2O.sub.18: C, 62.79; H, 6.78; N, 0.00; Cl, 0.00 Found: C, 62.64; H, 6.77; N, <0.50; Cl <225 ppm. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ (ppm) 0.84 (s, 6H, 2×CH.sub.3); 1.14 (s, 6H, 2×CH.sub.3); 1.34 (s, 6H, 2×CH.sub.3), 1.36 (m, 2H, 2×CH); 1.48 (s, 6H, 2×CH.sub.3); 1.56 (m, 4H, 2×CH.sub.2); 1.69 (d, J=7.0 Hz, 2H, 2×CH); 1.82 (m, 2H, 2×CH); 1.93 (dt, 2H, J=6.6 and 12.3 Hz, 2×CH); 2.03 (dt, 2H, J=3.2 and 13.3 Hz, 2×CH); 2.33 (dd, 2H, J=3.5 and 13.4 Hz, 2×CH); 2.44 (m, 2H, 2×CH); 2.53 (m, 2H, 2×CH); 2.62 (dt, 2H, J=6.0 and 13.3 Hz, 2×CH); 3.57 (s, 4H, 2×TEG OCH.sub.2); 3.65 (m, 4H, 2×TEG OCH.sub.2); 4.20 (m, 2H, 2×OCH), 4.24 (m, 4H, 2×TEG OCH.sub.2); 4.75 (d, 2H, AB, J=18.0 Hz, 2H, C21-CH.sub.2O—); 4.87 (d, 2H, J=4.6 Hz, 2×C11-OCH), 5.18 (d, 2H, AB, J=18.0 Hz, 2H, C21-CH2O—); 5.48 (d, 2H, J=3.9 Hz, 2×C11-OH); 6.02 (m, 2H, 2×alkene C4-CH); 6.23 (dd, 2H, J=10.1 and 1.9 Hz, CH, 2×alkene .sub.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.56H.sub.73O.sub.18F.sub.2 1071.48; Found 1071.48.

[0308] Compound 3 was dissolved in DCM and was drop coated onto the bottom of a glass vial and solvent was evaporated to form the surface coating. Drug release was carried out in PBS at 37 C with buffer changes and was monitored by HPLC. Cumulative drug release calculated from the total drug in the coating (FIG. 14B) and demonstrates consistent drug release from the coated surface over time.

Example 12. Synthesis of Compound 4 (Dexamethasone-Hexane-Dexamethasone), Coating onto Substrate Surface, and Drug Release from Coated Surface

[0309] Dexamethasone (157 mg, 0.40 mmol, 1.0 equiv) was dissolved in THF (20 mL) under nitrogen and phosgene solution (2.86 mL of a 1.4 M solution in toluene, 4.0 mmol, 10 equiv) was added to the solution. The mixture was stirred at room temperature for 6 h. The excess phosgene and solvents were removed in vacuo and the solid residue was redissolved in DCM (20 mL). 1,6-hexanediol (24 mg, 0.20 mmol, 0.5 equiv) was added to the solution with pyridine (65 μL, 63 mg, 0.80 mmol, 2.0 equiv). The mixture was stirred overnight at room temperature (.sup.˜18 h). The mixture was concentrated onto reverse phase silica (1 g) and purified by automated reverse phase chromatography (acetonitrile-water). The product containing fractions were combined and concentrated in vacuo. The final product was dried under high vacuum at 50° C. for 4 h to give Compound 4 as an off-white glassy solid (38 mg, 20%).

[0310] Compound 4: HPLC (mobile phase: H.sub.2O/TFA and MeCN/TFA) 36.1 min; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ (ppm) 0.79 (d, J=7 Hz, 6H, 2×C16 α-CH.sub.3); 0.90 (s, 6H, Dex 2×C18-CH.sub.3); 1.08 (m, 2H, 2×C16-H); 1.37 (m, 6H, 2×CH.sub.2, 2×CH); 1.49 (s, 6H, C19-CH.sub.3); 1.63 (m, 8H, 4×CH.sub.2); 1.78 (m, 2H, C15-CH.sub.2); 2.15 (m, 4H, 2×CH.sub.2); 2.40 (m, 4H, 2×CH.sub.2); 2.62 (m, 2H, 2×CH); 2.88 (m, 2H, 2×C12-CH); 4.13 (m, 6H, 2×OCH.sub.2, 2×C11-OCH); 4.77 (d, 2H, AB, J=18.5 Hz, 2H, C21-CH.sub.2O—); 5.07 (d, 2H, AB, J=18.5 Hz, 2H, C21-CH.sub.2O—); 5.20 (s, 2H, C17-OH); 5.42 (s, 2H, C17-OH); 6.01 (d, 2H, J=1.9 Hz, alkene C4-CH); 6.22 (dd, 2H, J=10.1 and 1.9 Hz, CH, alkene C2-CH); 7.30 (d, 2H, C1-CH alkene CH, J=10.1 Hz, 2H). MS (ESI+) m/z: [M+H]+ Calcd for C.sub.52H.sub.69F.sub.2O.sub.14 955.47; Found 955.47.

[0311] Compound 4 was spray coated on substrates (surface area of 3-6 mm.sup.2) in a similar manner to compound 1 as shown in Example 4. Using 20 sprays of a 20 mg/mL coating solution, the loading of dexamethasone in the form of Compound 4 was 3.1±1.0 μg.

[0312] To study the drug release from coated surfaces, Compound 4 was drop coated on a substrate (surface area of 7 mm.sup.2) and solvent was evaporated to form the surface coating. Drug release was carried out in 100% FBS and agitation at 37 C with buffer changes and was monitored by HPLC. Cumulative drug release calculated from the total drug in the coating (FIG. 15B) and demonstrates consistent drug release from the coated surface over time.

Example 13. Heat Press Process for Coating a Substrate Surface and Drug Release from Coated Surface

[0313] A crystalline powder of compound 1 (Dex-TEG-DEX) was distributed evenly across the surface to be coated and a sheet of aluminum foil, or another material, was placed on top. The powder was pre-melted without additional pressure at 185° C. for 2 minutes. The dexamethasone sample was then compressed at 1500 PSI for 30 seconds.

[0314] Using this heat press process yielded a surface coating with a larger thickness and therefore a higher drug load (37.1±8.1 μg/mm.sup.2) in comparison to spray-coating and drying (7.8±1.2 μg/mm.sup.2) with less cracking and surface defects (FIG. 16A). Spray-coated surface coatings were produced as described in Example 4 using a 50 mg/mL solution and 80 sprays. The heat press method shows reduced cracking of the coating at 4 to 5× the thickness leading to higher defect-free drug loading. At similar drug densities, heat press and spray coating have similar drug release profiles.

[0315] Depending on Compound 1 mass, a wide range of drug loadings (4-37 ag/mm.sup.2) was achieved by applying temperatures from 150 C-180 C and pressures from 700-3000 PSI for 30 s-10 min. Temperatures and pressures were applied using a Carver laboratory press with metallic heated plates and the coating was deposited on polymer and metallic substrates.

[0316] Drug release profiles from Compound 1 surface coatings with similar drug densities (8.2-8.3 μg/mm.sup.2) formed from the heat press process and spray coating process were similar (FIG. 16B), confirming that drug release is a material property and not influenced by coating technique.

Example 14. Heat Press Process for Coating a Substrate Surface with Similar Drug Density at Different Surface Areas

[0317] A crystalline powder of Compound 1 was distributed evenly across a sheet of aluminum foil and pre-melted without applied pressure at 185° C. for 2 minutes to convert to an amorphous state. Pre-melted Compound 1 was ground manually using a mortar and pestle.

[0318] Polyester strips were used as a coating template and were placed at various distances apart (5 mm to 25 mm) on top of a substrate. Amorphous Compound 1 was distributed in small piles on the exposed substrate (between the polyester strips), covered with aluminum foil, and transferred to a Carver Laboratory press with heated metallic plates at a temperature of 180° C. A pressure of 1200 PSI was applied to the substrate for 1 minute to coat the exposed substrate. After initial coating, the substrate was removed from the heated press and allowed to cool gradually at ambient conditions. Once cooled, the aluminum foil was removed from the top and the coating was annealed at 180° C. for 20 seconds. Coatings looked uniform and free of defects (FIG. 17).

Example 15. Rat Study of Compound 1 Coated on Different Substrates

[0319] Compound 1 was dissolved in acetone and spray coated onto thin films of a polymeric substrate or drop coated onto discs of a different polymeric substrate. Both coatings were dried at ambient conditions over night and sterilized using Ethylene oxide (ETO) gas. Coated substrates were then implanted into the dorsal subcutaneous space in female Wistar rats with starting weights of 250-290 g. Animals were euthanized at the peak of inflammatory phase in days 3 and 7. The cells in the surrounding area of both substrates were assessed by morphometric image analysis on cross-section of excised substrates with associated tissue that were stained for CD68 (inflammatory cell marker), ASMA (fibroblast marker) and DAPI (nuclease marker). The number of recruited CD68 positive cells were reduced in response to both substrates coated with compound 1 compared to non-coated substrates. Thus, compound 1 suppresses inflammation in device related foreign body reaction and fibrosis in the rat subcutaneous model regardless of coating method or substrate.

Example 16. Rat Study with Coatings of Compound 1, Compound 4 and Dexamethasone to Investigate Suppression of Fibrosis

[0320] Compound 1 and Compound 4 were dissolved in acetone and drop coated onto polymeric discs (diameter: 3 mm, thickness: 2 mm). Discs were also drop coated using dexamethasone dissolved in acetone to obtain similar drug amounts as discs coated with compounds 1 and 4. The coatings were dried at ambient conditions over night and sterilized using Ethylene oxide (ETO) gas. Coated substrates were then implanted into the dorsal subcutaneous space in female Wistar rats with starting weights of 250-290 g. Animals were euthanized at day 7 (inflammatory phase) and day 21 (fibrotic phase) to assess the tissue response to coated versus non-coated implants. The thickness of the collagenous capsule wall surrounding the implant was quantified by morphometric image analysis on cross-section of excised capsules with associated tissue that were stained with Masson's Trichrome. The capsule wall diameter (fibrotic layer thickness) around non-coated implants increased by two folds from day 7 to day 21. The tissue surrounding the Dexamethasone coated implants did not show any difference to non-coated discs while Compounds 1 and 4 were statistically thinner at both time points. Thus, dexamethasone is not effective in suppressing device related fibrosis compared to Compounds 1 and 4 (FIG. 18A). This correlates well with in vitro drug release profiles demonstrating a burst release for dexamethasone and sustained release for Compounds 1 and 4 (FIG. 18B).

Example 19. Compound 1 (Dexamethasone-Triethylene Glycol-Dexamethasone; Dex-TEG-Dex) Extruded into Glassy State Injectable Cylinders or a Glassy State Cylindrical Drug Depot, and Release Drug Via Surface Erosion

[0321] Compound 1 was formed into cylinders by heat extrusion from the intermediate glassy state by pre-melting compound 1 prior to extrusion. The cylinders were extruded with 23G and 30G nozzles and cut to different lengths as shown in FIG. 19A. In vitro drug release was carried out in PBS at 37 C and drug release was quantified by HPLC. Cumulative drug release was plotted as a percentage of total drug in each cylinder as shown in FIG. 19B and drug release occurred via surface erosion. The cylinders can be used as a drug depot within a medical device or injected adjacent to the medical device to release dexamethasone.

Example 20. Compound 1 (Dex-TEG-Dex) can Formed into Fibrous Mesh Drug Depot in the Glassy State

[0322] Non-woven fibrous meshes with aligned (FIG. 20A) and unaligned (FIG. 20B) morphologies were prepared by electrospinning. Compound 1 was dissolved in tetrahydrofuran (THF) and was electrosprayed onto a cylindrical rotating mandrel to obtain aligned fibers or onto a stationary collector surface to obtain unaligned fibers. Compound 1 as the starting powder and solvent-processed fibrous mesh were tested by DSC (FIG. 20C) and PXRD (FIG. 20D) to confirm the meshes were in the glassy state. The fibrous meshes can be inserted as a wafer adjacent to a medical device or can be electrospun around the device or a device component forming a fibrous pouch that acts as a drug depot to release dexamethasone.

Example 21. Injectable Cylinders of Compound 1 (Dex-TEG-Dex) can be Injected Adjacent to a Medical Device Such as a Suture to Release an Anti-Inflammatory Corticosteroid

[0323] Cylinders of Compound 1 in various diameters (23G-32G) and 2 mm in length were processed as described in Example 1 and were loaded into needles with a piece of medical sutures as shown in FIG. 21A. The loaded needles were sterilized by ethylene oxide gas. The cylinders and sutures were injected into the dorsal subcutaneous space of male Sprague Dawley rats with starting weights of 100-124 g (Envigo, Frederick, Md. USA). Animals were euthanized at 7 and 28 days and the skin surrounding the injection sites were dissected. An image of a cylinder and suture in the subcutaneous tissue is shown in FIG. 21B. Pellet drug content at each time point was calculated from in-situ image analysis, confirmed by HPLC, and was plotted as cumulative drug release from the cylinders (FIG. 21C). The results show sustained dexamethasone release from injectable compound 1 cylinders in the subcutaneous tissue of rats.

SURFACE COATINGS AND IMPLANTABLE DEVICES COMPRISING DIMERIC STEROID PRODRUGS, AND USES THEREOF

Inventors

Cpc classification

Classification Explorer

A61N1/3968

HUMAN NECESSITIES

Classification Explorer

A61N1/0568

HUMAN NECESSITIES

Classification Explorer

A61L2300/222

HUMAN NECESSITIES

Classification Explorer

A61K47/55

HUMAN NECESSITIES

Classification Explorer

A61L2300/43

HUMAN NECESSITIES

Classification Explorer

A61K9/0024

HUMAN NECESSITIES

Classification Explorer

A61L2400/18

HUMAN NECESSITIES

Classification Explorer

A61N1/375

HUMAN NECESSITIES

Classification Explorer

A61N1/0575

HUMAN NECESSITIES

Classification Explorer

A61K47/554

HUMAN NECESSITIES

Classification Explorer

A61L27/28

HUMAN NECESSITIES

Classification Explorer

A61L31/16

HUMAN NECESSITIES

Classification Explorer

A61N1/0536

HUMAN NECESSITIES

Classification Explorer

A61L27/54

HUMAN NECESSITIES

International classification

Classification Explorer

A61L27/54

HUMAN NECESSITIES

Classification Explorer

A61L27/28

HUMAN NECESSITIES

Abstract

Claims

Description