Glass preparation containing steroid dimer and use thereof

Abstract

Steroid dimer and the article formed by steroid dimer are disclosed.The steroid dimer is represented by D1-L-D2, wherein D1 and D2 are steroid moieties, and L is a covalent linker.The article comprising steroid dimer can be machined, molded, emulsion processed, electrospinning, electrospraying, blow molding, fiber spinning, wet spinning, dry spinning, melt spinning, heat spinning, gel spinning or extruded to form fiber, fiber web, woven fabric, nonwoven fabric, pellet, cylinder, microparticle, nanoparticle or formed article.The article is used as a drug delivery device (such as implant) for extending steroid delivery to a subject.

Description

[0001] Related applications

[0002] This is a Patent Cooperation Treaty application claiming the benefit of 35 U.S.C. §119 based on priority to U.S. Provisional Patent Application No. 62 / 625,460, filed on February 2, 2018, U.S. Provisional Patent Application No. 62 / 627,608, filed on February 7, 2018, and U.S. Provisional Patent Application No. 62 / 758,234, filed on November 9, 2018; each of which is incorporated herein by reference in its entirety. Background Art

[0003] Steroids are useful drugs in various fields of medicine such as ophthalmology, oncology, laryngology, endocrinology and metabolic diseases, rheumatology, urology, neurology, cardiology, dentistry, dermatology, otology, postoperative medicine, orthopedics, pain management, and gynecology. Summary of the Invention

[0004] The present disclosure features steroid dimers and articles formed from steroid dimers. The articles of the present disclosure can be machined, molded, emulsion processed, electrospun, electrosprayed, blown, fiber spun (e.g., wet spinning, dry spinning, melt spinning, thermal spinning, or gel spinning) or extruded to form fibers, fiber webs, woven fabrics, nonwoven fabrics, pellets, cylinders, microparticles (e.g., microbeads), nanoparticles (e.g., nanobeads), or any other type of shaped article from which the prodrug steroid dimer is released in a controlled manner.

[0005] In a first aspect, the present disclosure provides an article of manufacture comprising a compound of formula (A-VIII):

[0006] D1-L-D2 (A-VIII)

[0007] or a pharmaceutically acceptable salt thereof, wherein (i) D1 and D2 are each independently a group formed by a steroid; and L is a linker that covalently links D1 to D2, (ii) at least 90% (w / w) of the preparation is a compound of formula (A-VIII), (iii) the preparation does not contain a controlled release excipient, and (iv) D1 and D2 are in 100% bovine serum at 37° C. or in PBS at 37° C. such that t 10 Greater than or equal to t 50 The product is released from the preparation at a rate 1 / 10 of that of the product.

[0008] In another aspect, the disclosure features an article of manufacture comprising a compound of formula (A-VIII):

[0009] D1-L-D2 (A-VIII)

[0010] or a pharmaceutically acceptable salt thereof, wherein (i) D1 and D2 are each independently a group formed by a steroid; and L is a linker that covalently links D1 to D2, (ii) at least 90% (w / w) of the article is a compound of formula (A-VIII), (iii) the article is a fiber, a fiber web, a woven fabric, a non-woven fabric, a pellet, a cylinder, a hollow tube, a microparticle, a nanoparticle or a shaped article, and (iv) the article does not contain a controlled release excipient.

[0011] In some embodiments, the compound D1 or D2 is released from the article by surface erosion.

[0012] In another aspect, the disclosure features an article of manufacture formed from a compound of formula (A-VIII) or a pharmaceutically acceptable salt thereof:

[0013] D1-L-D2 (A-VIII)

[0014] wherein the article is formed by a process comprising the steps of: (a) heating the compound or a pharmaceutically acceptable salt thereof to form a melt; and (b) cooling the melt to form a composition, wherein D1 and D2 are each independently a group formed by a steroid; and L is a linker covalently linking D1 to D2. In certain embodiments, the article is free of controlled release excipients, free of crystallization-inhibiting excipients, free of mechanical integrity-enhancing excipients, and / or free of binding excipients; or the article optionally has a glassy state.

[0015] The disclosure further features an article of manufacture comprising a compound of formula (A-VIII):

[0016] D1-L-D2 (A-VIII)

[0017] or a pharmaceutically acceptable salt thereof, wherein the article is formed by a process comprising: (a) heating the compound or a pharmaceutically acceptable salt thereof to form a melt; and (b) injection molding the melt to form the article, wherein D1 and D2 are each independently a group formed from a steroid; and L is a linker covalently linking D1 to D2. In certain embodiments, the article is free of a controlled release excipient, free of a crystallization-inhibiting excipient, free of a mechanical integrity-enhancing excipient, and / or free of a binding excipient; or the article optionally has a glassy state.

[0018] The invention also features an article of manufacture comprising a compound of formula (A-VIII):

[0019] D1-L-D2 (A-VIII)

[0020] or a pharmaceutically acceptable salt thereof, wherein the article is formed by a process comprising: (a) heating the compound or a pharmaceutically acceptable salt thereof to form a melt; and (b) blow molding the melt to form the article, wherein D1 and D2 are each independently a group formed from a steroid; and L is a linker that covalently links D1 to D2. In certain embodiments, the article is free of a controlled release excipient, a crystallization-inhibiting excipient, a mechanical integrity-enhancing excipient, and / or a binding excipient; or the article optionally has a glassy state.

[0021] The present disclosure features an article of manufacture comprising a compound of formula (A-VIII):

[0022] D1-L-D2 (A-VIII)

[0023] or a pharmaceutically acceptable salt thereof, wherein the article is formed by a process comprising the following steps: (a) dissolving the compound or a pharmaceutically acceptable salt thereof to form a solution; and (b) evaporating the solvent to form the article (e.g., free-forming to form a film, forming a shaped article from a mold, or forming a fiber from a spinneret), wherein D1 and D2 are each independently a group formed from a steroid; and L is a linker that covalently links D1 to D2. In specific embodiments, step (b) comprises solvent casting to form a film or fiber. In specific embodiments, the article is free of controlled release excipients, free of crystallization-inhibiting excipients, free of mechanical integrity-enhancing excipients, and / or free of binding excipients; or the article optionally has a glassy state.

[0024] The present disclosure also features an article of manufacture comprising a compound of formula (A-VIII):

[0025] D1-L-D2 (A-VIII)

[0026] or a pharmaceutically acceptable salt thereof, wherein the article is formed by a process comprising the steps of: (a) dissolving the compound or a pharmaceutically acceptable salt thereof to form a solution; and (b) electrospinning or electrospraying the solution to form the article, wherein D1 and D2 are each independently a group formed by a steroid; and L is a linker that covalently links D1 to D2. In certain embodiments, the article is free of controlled release excipients, free of crystallization-inhibiting excipients, free of mechanical integrity-enhancing excipients, and / or free of binding excipients; or the article optionally has a glassy state.

[0027] The disclosure further features an article of manufacture comprising a compound of formula (A-VIII):

[0028] D1-L-D2 (A-VIII)

[0029] or a pharmaceutically acceptable salt thereof, wherein the article is formed by a process comprising: (a) heating the compound or a pharmaceutically acceptable salt thereof to form a melt; and (b) electrospinning or electrospraying the melt to form the article, wherein D1 and D2 are each independently a group formed from a steroid; and L is a linker covalently linking D1 to D2. In certain embodiments, the article is free of controlled release excipients, free of crystallization-inhibiting excipients, free of mechanical integrity-enhancing excipients, and / or free of binding excipients; or the article optionally has a glassy state.

[0030] The present disclosure features an article of manufacture comprising a compound of formula (A-VIII):

[0031] D1-L-D2 (A-VIII)

[0032] or a pharmaceutically acceptable salt thereof, wherein the article is formed by a process comprising the steps of: (a) heating the compound or a pharmaceutically acceptable salt thereof to form a melt; and (b) extruding the melt to form the article, wherein D1 and D2 are each independently a group formed by a steroid; and L is a linker that covalently links D1 to D2. In certain embodiments, the article is free of controlled release excipients, free of crystallization-inhibiting excipients, free of mechanical integrity-enhancing excipients, and / or free of binding excipients; or the article optionally has a glassy state.

[0033] In some embodiments of the articles of the present disclosure, the compound is processed (e.g., melt processed or solvent processed) as described herein to form a glassy solid. The glassy solid is then heated to above its glass transition temperature, Tg, and thermally processed (e.g., molded, blown, hot-spun, electrospun, electrosprayed, or extruded to form a shaped article (e.g., a fiber, a web, a woven fabric, a nonwoven fabric, a pellet, a cylinder, a microparticle (e.g., a microbead) or a nanoparticle (e.g., a nanobead) or another shaped article). In other embodiments, the microparticles are prepared by melting the compound to form glassy pellets or other shaped forms, crushing the glassy article into coarse or irregularly shaped particles, filtering the particles through a sieve, and heating the particles above Tg to round them into smoother spherical particles.

[0034] In an embodiment of any of the above articles, L has a molecular weight of 80 to 800 Da, e.g., 80 to 100 Da, 80 to 200 Da, 80 to 300 Da, 80 to 400 Da, 80 to 500 Da, 80 to 600 Da, or 80 to 700 Da. In another embodiment of any of the above articles, L is covalently linked to D1 and D2 via one or more ester, carbonic acid, carbonate, or anhydride bonds. In a specific embodiment, L is covalently linked to D1 and D2 via one or more carbonate bonds.

[0035] In certain embodiments of any of the above-described articles, L comprises a group -C(O)-(R A )-C(O)- or -O-(R A )-O-;R A C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, 3-10 atom ring system, -(CH2CH2O) q CH2CH2-、-(CH2CH2CH2CH2O) r CH2CH2CH2CH2-or-(CH2CH(CH3)O) s CH2CH(CH3)-; and q, r, and s are integers from 1 to 10 (e.g., 1 to 10, 1 to 5, or 5 to 10).

[0036] The disclosure features articles formed from the disclosed compounds.

[0037] In an embodiment of any of the above articles of manufacture, D1 and D2 are each anabolic steroids, androgenic steroids, progesterone steroids, estrogenic steroids, cancer treatment steroids, antibiotic steroids, glucocorticoid steroids, benign steroids, anti-angiogenic steroids, steroids that reduce intraocular pressure (IOP), bile acid-related bile acid steroids, cholesterol derivatives, other steroids, pheromones, steroid metabolites, progesterone, neurosteroids, and corticosteroids. In a specific embodiment of any of the above articles of manufacture, the compound is further described by one of Formulas (II)-(LXXV) as described herein. In another embodiment of any of the above articles of manufacture, D1 and D2 are each independently described by any of Formulas (Ia) to (I-vvv) as described herein.

[0038] In the preparations of the present disclosure, D1 and D2 may be formed from the same steroid, or D1 and D2 may be formed from different steroids.

[0039] In certain embodiments of any of the foregoing articles of manufacture, the article of manufacture comprises a mixture of two or more compounds of Formula (A-VIII).

[0040] In certain embodiments, at least 70% (w / w) of the preparation is a compound of Formula (A-VIII), e.g., at least 75% (w / w), at least 80% (w / w), at least 85% (w / w), at least 90% (w / w), at least 95% (w / w), or at least 99% (w / w).

[0041] In another embodiment of any of the above articles of manufacture, the compound is released from the article by surface erosion. In certain embodiments of any of the above articles of manufacture, surface erosion releases less than 20% (e.g., less than 18%, 15%, 12%, 10%, or 5%) of D1 or D2 (as a percentage of the total drug D1 or D2 present in the article as a prodrug) over 5, 6, 7, 8, 9, 10, or 12 days in 100% bovine serum at 37°C (e.g., less than 10% of D1 or D2 over 5 days in 100% bovine serum at 37°C). In other embodiments of any of the above articles of manufacture, the surface erodes to release less than 2.0% (e.g., less than 1.8%, 1.5%, 1.2%, 1.0%, or 0.5%) of D1 or D2 (as a percentage of the total drug D1 or D2 present in the article as a prodrug) over 5, 7, 10, or 14 days in PBS at 37°C (e.g., less than 2% of D1 or D2 over 5 days in PBS at 37°C). In still other embodiments of any of the above articles of manufacture, the surface erodes to release more than 20% (e.g., more than 22%, 24%, 26%, 28%, or 30%) of D1 or D2 (as a percentage of the total drug D1 or D2 present in the article as a prodrug) over no less than 6, 8, 10, or 12 days in 100% bovine serum at 37°C (e.g., more than 24% of D1 or D2 over 10 days in 100% bovine serum at 37°C). In other embodiments of any of the foregoing articles, the surface erodes to release more than 5.0% (e.g., more than 6.0%, 8.0%, 10%, 12%, or 15%) of D1 or D2 (as a percentage of the total drug D1 or D2 present in the article as a prodrug) over not less than 6, 8, 10, or 12 days in PBS at 37°C (e.g., more than 5% of D1 or D2 over 10 days in PBS at 37°C). The compound (D1 and / or D2) may be present in an amount such that t 10 Greater than or equal to t 50 It is released from the product at a rate of 1 / 10 of that of the

[0042] In yet another embodiment of any of the above articles, the article further comprises 0.1% to 10% (e.g., 0.1% to 5%, 0.1% to 2%, 0.5% to 2%, 1% to 10%) (w / w) of one or more additives, wherein the one or more additives are plasticizers (e.g., glycerol, triacetin, isopropyl alcohol, ethanol, or ethylene glycol), antioxidants (e.g., ascorbic acid, vitamin E, sodium metabisulfite, butylated hydroxytoluene, p-hydroxybenzyl alcohol, or butylated hydroxyanisole), binders (e.g., polyvinylpyrrolidone, carboxymethylcellulose, hydroxypropylcellulose, or hydroxypropylmethylcellulose), lubricants, radiopaque agents, and mixtures thereof.

[0043] In yet another embodiment of any of the above articles, the article is a fiber, a web, a woven fabric, a nonwoven fabric, a pellet, a cylinder, a microparticle (e.g., a microbead), a nanoparticle (e.g., a nanobead), or another shaped article. For example, the article is ground microbeads or nanobeads.

[0044] In other embodiments, the article is in the form of glassy fibers having an average diameter of about 0.01 to 1 mm, for example, 0.05 to 0.3 mm, 0.1 to 0.3 mm, 0.15 to 0.3 mm, 0.2 to 0.3 mm, 0.25 to 0.3 mm, 0.01 to 0.1 mm, 0.01 to 0.2 mm, 0.01 to 0.3 mm, 0.01 to 0.4 mm, 0.01 to 0.5 mm, 0.01 to 0.6 mm, 0.01 to 0.7 mm, 0.01 to 0.8 mm, or 0.01 to 0.9 mm. In some embodiments, the average length of the fibers can be in the range of about 20 mm to 20 meters, for example, 20 to 100 mm, 75 to 300 mm, 100 mm to 1 meter, 0.5 meter to 6 meters, or 1.0 meter to 20 meters.

[0045] In certain embodiments, the article is in the form of glassy pellets having an average diameter of about 0.2 to 5 mm, e.g., about 0.2 to 1 mm, about 0.2 to 2 mm, about 0.3 to 3 mm, about 1.5 to 5 mm, about 2 to 5 mm, about 2.5 to 5 mm, about 3 to 5 mm, about 3.5 to 5 mm, about 4 to 5 mm, or about 4.5 to 5 mm.

[0046] In some embodiments, the article is in the form of a glass cylinder having a length of about 0.5 to 20 mm, for example, about 0.5 to 1 mm, about 0.5 to 2 mm, about 0.5 to 4 mm, about 0.5 to 6 mm, about 0.5 to 8 mm, about 0.5 to 10 mm, about 0.5 to 12 mm, about 0.5 to 14 mm, about 0.5 to 16 mm, or about 0.5 to 18 mm. In some embodiments, the article is in the form of a glass cylinder having a diameter of about 0.1-1 mm, for example, about 0.1 to 0.2 mm, about 0.1 to 0.3 mm, about 0.1 to 0.4 mm, about 0.2 to 0.5 mm, about 0.1 to 0.6 mm, about 0.1 to 0.7 mm, about 0.1 to 0.8 mm, or about 0.1 to 0.9 mm. In some embodiments, the average diameter of the cylinder is in the range of about 0.01 to 1 mm, and the average length of the cylinder is about 0.1 to 4.0 mm. In some embodiments, the length of the cylinder is about 0.5 to 10 mm or about 1 to 10 mm.

[0047] In some embodiments, the article is mechanically stable. For example, the article is resistant to fracture due to deformation.

[0048] In other embodiments, the article is in the form of glassy microparticles, such as microbeads, having an average diameter of about 1 to 1000 μm, for example, about 10 to 1000 μm, about 100 to 1000 μm, about 200 to 1000 μm, about 500 to 1000 μm, about 700 to 1000 μm, or about 900 to 1000 μm.

[0049] In certain embodiments, the article is in the form of glassy nanoparticles, such as nanobeads, having an average diameter of about 0.01 to 1 μm, for example, about 0.05 to 1 μm, about 0.1 to 1 μm, about 0.2 to 1 μm, about 0.3 to 1 μm, about 0.4 to 1 μm, about 0.5 to 1 μm, about 0.6 to 1 μm, about 0.7 to 1 μm, about 0.8 to 1 μm, or about 0.9 to 1 μm.

[0050] The present disclosure features fibers formed from compounds of the present disclosure (e.g., compounds described by one of Formulas (II)-(LXXV) described herein, or steroid dimers wherein D1 and D2 are each independently described by any one of Formulas (Ia)-(I-ii) described herein). In certain embodiments, the fibers are free of release-controlling excipients, free of crystallization-inhibiting excipients, free of mechanical integrity-enhancing excipients, and / or free of binding excipients.

[0051] The present disclosure further features fibers formed from a compound of formula (A-VIII) or a pharmaceutically acceptable salt thereof:

[0052] D1-L-D2 (A-VIII)

[0053] The fiber is made by a process comprising the following steps: (a) dissolving the compound or a pharmaceutically acceptable salt thereof in a solvent to form a solution; and (b) electrospinning, dry spinning, wet spinning, or gel spinning the solution to form the fiber, wherein D1 and D2 are each independently a group formed by a steroid; and L is a linker that covalently links D1 to D2. In certain embodiments, the fiber is free of a controlled release excipient, a crystallization-inhibiting excipient, a mechanical integrity-enhancing excipient, and / or a binding excipient; or the fiber optionally has a glassy state.

[0054] The present disclosure further features fibers formed from a compound of formula (A-VIII) or a pharmaceutically acceptable salt thereof:

[0055] D1-L-D2 (A-VIII)

[0056] The fiber is made by a process comprising the steps of: (a) heating the compound or a pharmaceutically acceptable salt thereof to form a melt; and (b) extruding the melt to form the fiber (i.e., melt spinning), wherein D1 and D2 are each independently a group formed from a steroid; and L is a linker that covalently links D1 to D2. In certain embodiments, the fiber is free of a controlled release excipient, a crystallization-inhibiting excipient, a mechanical integrity-enhancing excipient, and / or a binding excipient; or the fiber optionally has a glassy state.

[0057] The present disclosure features fibers formed from compounds of formula (A-VIII) or pharmaceutically acceptable salts thereof:

[0058] D1-L-D2 (A-VIII)

[0059] The fiber is made by a process comprising the steps of: (a) heating the compound or a pharmaceutically acceptable salt thereof to form a melt; and (b) electrospinning the melt to form the fiber, wherein D1 and D2 are each independently a group formed from a steroid; and L is a linker covalently linking D1 to D2. In certain embodiments, the fiber is free of a controlled release excipient, a crystallization inhibiting excipient, a mechanical integrity enhancing excipient, and / or a binding excipient; or the fiber optionally has a glassy state.

[0060] In any embodiment of the above fibers, L has a molecular weight of 80 to 800 Da, e.g., 80 to 100 Da, 80 to 200 Da, 80 to 300 Da, 80 to 400 Da, 80 to 500 Da, 80 to 600 Da, or 80 to 700 Da. In another embodiment of any of the above fibers, L is covalently linked to D1 and D2 via one or more ester, carbonic acid, carbonate, or anhydride bonds. In a specific embodiment, L is covalently linked to D1 and D2 via one or more carbonate bonds.

[0061] In certain embodiments of any of the above fibers, L comprises the group -(C(O)-(R A )-C(O)- or -O-(R A )-O-;R A is a polyol radical and contains at least one free hydroxyl group, or R A C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, 3-10 atom ring system, -(CH2CH2O) q CH2CH2-、-(CH2CH2CH2CH2O) r CH2CH2CH2CH2-or-(CH2CH(CH3)O) s CH2CH(CH3)-; and q, r, and s are integers from 1 to 10 (e.g., 1 to 10, 1 to 5, or 5 to 10).

[0062] In any of the above fiber embodiments, D1 and D2 are each anabolic steroids, androgenic steroids, progesterone steroids, estrogenic steroids, cancer treatment steroids, antibiotic steroids, glucocorticoid steroids, mild steroids, anti-angiogenic steroids, steroids that reduce intraocular pressure (IOP), bile acid-related bile acid steroids, cholesterol derivatives, other steroids, pheromones, steroid metabolites, progesterone, neurosteroids, and corticosteroids. In specific embodiments of any of the above fibers, the compound is further described by one of Formulas (II)-(LXXV) described herein. In another embodiment of any of the above fibers, D1 and D2 are each independently described by any of Formulas (Ia) to (I-vvv) described herein.

[0063] In the fibers of the present disclosure, D1 and D2 may be formed from the same steroid, or D1 and D2 may be formed from different steroids.

[0064] In certain embodiments of any of the above fibers, the fibers comprise a mixture of two or more compounds of Formula (A-VIII).

[0065] In certain embodiments, at least 70% (w / w) of the fiber is a compound of formula (A-VIII), e.g., at least 75% (w / w), at least 80% (w / w), at least 85% (w / w), at least 90% (w / w), at least 95% (w / w), or at least 99% (w / w).

[0066] In another embodiment of any of the above fibers, the compound is released from the fiber by surface erosion. In certain embodiments of any of the above fibers, surface erosion releases less than 20% (e.g., less than 18%, 15%, 12%, 10%, or 5%) of D1 or D2 (as a percentage of the total drug D1 or D2 present in the fiber as a prodrug) over 5, 6, 7, 8, 9, 10, or 12 days in 100% bovine serum at 37°C (e.g., less than 10% of D1 or D2 over 5 days in 100% bovine serum at 37°C). In other embodiments of any of the above fibers, the surface erodes to release less than 2.0% (e.g., less than 1.8%, 1.5%, 1.2%, 1.0%, or 0.5%) of D1 or D2 (as a percentage of the total drug D1 or D2 present in the fiber as a prodrug) over 5, 7, 10, or 14 days in PBS at 37°C (e.g., less than 2% of D1 or D2 over 5 days in PBS at 37°C). In still other embodiments of any of the above fibers, the surface erodes to release more than 20% (e.g., more than 22%, 24%, 26%, 28%, or 30%) of D1 or D2 (as a percentage of the total drug D1 or D2 present in the fiber as a prodrug) over no less than 6, 8, 10, or 12 days in 100% bovine serum at 37°C (e.g., more than 24% of D1 or D2 over 10 days in 100% bovine serum at 37°C). In other embodiments of any of the above fibers, surface erosion releases more than 5.0% (e.g., more than 6.0%, 8.0%, 10%, 12%, or 15%) of D1 or D2 (as a percentage of the total drug D1 or D2 present in the fiber as a prodrug) over not less than 6, 8, 10, or 12 days in PBS at 37° C. (e.g., more than 5% of D1 or D2 over 10 days in PBS at 37° C.). In other embodiments, the compound (D1 and / or D2) is present in an amount such that t 10 Greater than or equal to t 50 It is released from the fiber at a rate of 1 / 10 of that of the original.

[0067] In yet another embodiment of any of the above fibers, the fibers further comprise 0.1% to 10% (e.g., 0.1% to 5%, 0.1% to 2%, 0.5% to 2%, 1% to 10%) (w / w) of one or more additives, wherein the one or more additives are plasticizers (e.g., glycerol, triacetin, isopropyl alcohol, ethanol, or ethylene glycol), antioxidants (e.g., ascorbic acid, vitamin E, sodium metabisulfite, butylated hydroxytoluene, parahydroxybenzyl alcohol, or butylated hydroxyanisole), binders (e.g., polyvinylpyrrolidone, carboxymethylcellulose, hydroxypropylcellulose, or hydroxypropylmethylcellulose), lubricants, radiopaque agents, and mixtures thereof.

[0068] The present disclosure features: (i) a fiber web formed from the fibers of the present disclosure; a woven fabric formed from the fibers of the present disclosure; and a nonwoven fabric formed from the fibers of the present disclosure. The fiber web, woven fabric, and nonwoven fabric can be formed from the fibers using methods known in the art. In certain embodiments, the fiber web is free of controlled release excipients, free of crystallization-inhibiting excipients, free of mechanical integrity-enhancing excipients, and / or free of binding excipients; or the fiber web optionally has a glassy state.

[0069] In another aspect, the disclosure features a glassy composition formed from a compound of the disclosure (e.g., a compound described by one of Formulas (II)-(LXXV) described herein, or a steroid dimer wherein D1 and D2 are each independently described by any one of Formulas (Ia)-(I-vvv) described herein). In particular embodiments, the glassy composition is free of release-controlling excipients, free of crystallization-inhibiting excipients, free of mechanical integrity-enhancing excipients, and / or free of binding excipients.

[0070] In another aspect, the disclosure further features a glassy composition formed from a compound of Formula (A-VIII) or a pharmaceutically acceptable salt thereof:

[0071] D1-L-D2 (A-VIII)

[0072] The glassy composition is prepared by a process comprising: (a) heating the compound or a pharmaceutically acceptable salt thereof to form a melt; and (b) cooling the melt to form the composition, wherein D1 and D2 are each independently a group formed from a steroid; and L is a linker covalently linking D1 to D2. In certain embodiments, the glassy composition is free of a controlled release excipient, a crystallization-inhibiting excipient, a mechanical integrity-enhancing excipient, and / or a binding excipient.

[0073] In any of the above embodiments of the glassy compositions, L has a molecular weight of 80 to 800 Da, e.g., 80 to 100 Da, 80 to 200 Da, 80 to 300 Da, 80 to 400 Da, 80 to 500 Da, 80 to 600 Da, or 80 to 700 Da. In another embodiment of any of the above glassy compositions, L is covalently linked to D1 and D2 via one or more ester, carbonic acid, carbonate, or anhydride bonds. In a specific embodiment, L is covalently linked to D1 and D2 via one or more carbonate bonds.

[0074] In certain embodiments of any of the above glassy compositions, L comprises a group -(C(O)-(R A )-C(O)- or -O-(R A )-O-;R A is a polyol radical and contains at least one free hydroxyl group, or R A C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, 3-10 atom ring system, -(CH2CH2O) q CH2CH2-、-(CH2CH2CH2CH2O) r CH2CH2CH2CH2-or-(CH2CH(CH3)O) s CH2CH(CH3)-; and q, r, and s are integers from 1 to 10 (e.g., 1 to 10, 1 to 5, or 5 to 10).

[0075] In any of the above embodiments of the glassy compositions, D1 and D2 are each anabolic steroids, androgenic steroids, progesterone steroids, estrogenic steroids, cancer therapeutic steroids, antibiotic steroids, glucocorticoid steroids, mild steroids, anti-angiogenic steroids, steroids that reduce intraocular pressure (IOP), bile acid-related bile acid steroids, cholesterol derivatives, other steroids, pheromones, steroid metabolites, progesterone, neurosteroids, and corticosteroids. In specific embodiments of any of the above glassy compositions, the compound is further described by one of Formulas (II)-(LXXV) as described herein. In another embodiment of any of the above glassy compositions, D1 and D2 are each independently described by any of Formulas (Ia) to (I-vvv) as described herein.

[0076] In the glassy compositions of the present disclosure, D1 and D2 may be formed from the same steroid, or D1 and D2 may be formed from different steroids.

[0077] In certain embodiments of any of the foregoing glassy compositions, the glassy composition comprises a mixture of two or more compounds of Formula (A-VIII).

[0078] In certain embodiments, at least 70% (w / w) of the glassy composition is a compound of Formula (A-VIII), e.g., at least 75% (w / w), at least 80% (w / w), at least 85% (w / w), at least 90% (w / w), at least 95% (w / w), or at least 99% (w / w).

[0079] In another embodiment of any of the above glassy compositions, the compound is released from the glassy composition by surface erosion. In certain embodiments of any of the above glassy compositions, surface erosion releases less than 20% (e.g., less than 18%, 15%, 12%, 10%, or 5%) of D1 or D2 (as a percentage of the total drug D1 or D2 present in the glassy composition as a prodrug) over 5, 6, 7, 8, 9, 10, or 12 days in 100% bovine serum at 37°C (e.g., less than 10% of D1 or D2 over 5 days in 100% bovine serum at 37°C). In other embodiments of any of the foregoing glassy compositions, surface erosion releases less than 2.0% (e.g., less than 1.8%, 1.5%, 1.2%, 1.0%, or 0.5%) of D1 or D2 (as a percentage of the total drug D1 or D2 present in the glassy composition as a prodrug) over 5, 7, 10, or 14 days in PBS at 37°C (e.g., less than 2% of D1 or D2 over 5 days in PBS at 37°C). In yet other embodiments of any of the foregoing glassy compositions, surface erosion releases greater than 20% (e.g., greater than 22%, 24%, 26%, 28%, or 30%) of D1 or D2 (as a percentage of the total drug D1 or D2 present in the glassy composition as a prodrug) in 100% bovine serum at 37°C for not less than 6, 8, 10, or 12 days (e.g., greater than 24% of D1 or D2 in 100% bovine serum at 37°C for 10 days). In other embodiments of any of the above glassy compositions, surface erosion releases more than 5.0% (e.g., more than 6.0%, 8.0%, 10%, 12%, or 15%) of D1 or D2 (as a percentage of the total drug D1 or D2 present in the glassy composition as a prodrug) over not less than 6, 8, 10, or 12 days in PBS at 37° C. (e.g., more than 5% of D1 or D2 over 10 days in PBS at 37° C.). In other embodiments, the compound (D1 and / or D2) is present in a manner such that t 10 Greater than or equal to t 50 The release rate is 1 / 10 of that from the glassy composition.

[0080] In yet another embodiment of any of the foregoing glassy compositions, the glassy composition further comprises 0.1% to 10% (e.g., 0.1% to 5%, 0.1% to 2%, 0.5% to 2%, 1% to 10%) (w / w) of one or more additives, wherein the one or more additives are plasticizers (e.g., glycerol, triacetin, isopropyl alcohol, ethanol, or ethylene glycol), antioxidants (e.g., ascorbic acid, vitamin E, sodium metabisulfite, butylated hydroxytoluene, p-hydroxybenzyl alcohol, or butylated hydroxyanisole), binders (e.g., polyvinylpyrrolidone, carboxymethylcellulose, hydroxypropylcellulose, or hydroxypropylmethylcellulose), lubricants, radiopaque agents, and mixtures thereof.

[0081] In certain embodiments of any of the foregoing glassy compositions, the glassy composition is machined, molded, emulsion processed, electrospun, electrosprayed, blown, or extruded.

[0082] In other embodiments of any of the above-described glassy compositions, the glassy composition is a fiber, a fiber web, a woven fabric, a nonwoven fabric, a pellet, a cylinder, a microparticle (e.g., a microbead), a nanoparticle (e.g., a nanobead), or another shaped article. For example, the glassy composition is a shaped article in the form of: (i) a fiber having an average diameter of about 0.01-1 mm; (ii) a pellet having an average diameter of about 0.2 to 5 mm; (iii) a cylinder having a length of about 0.5 to 20 mm and a diameter of about 0.01 to 1 mm; (iv) a microbead having an average diameter of about 1 to 1000 μm; or (v) a nanobead having an average diameter of about 0.01 to 1 μm. The glassy composition can be in the shape of a cylinder, a cube, a sheet, a star, a ring, a pyramid, a sphere, an irregular polygon, or a regular polygon.

[0083] In another aspect, the disclosure features a substrate comprising a coating formed from a compound of formula (A-VIII):

[0084] D1-L-D2 (A-VIII).

[0085] In certain embodiments, the coating is free of release-controlling excipients, free of crystallization-inhibiting excipients, free of mechanical integrity-enhancing excipients, and / or free of binding excipients; or the coating optionally has a glassy state.

[0086] In any of the above coating embodiments, L has a molecular weight of 80 to 800 Da.

[0087] In certain embodiments of any of the above coatings, L is covalently linked to D1 and D2 via one or more ester, carbonic acid, carbonate, or anhydride bonds. In certain embodiments, L is covalently linked to D1 and D2 via one or more carbonate bonds.

[0088] In certain embodiments, D1 and D2 are each anabolic steroids, androgenic steroids, progesterone steroids, estrogenic steroids, cancer therapeutic steroids, antibiotic steroids, glucocorticoid steroids, bland steroids, anti-angiogenic steroids, steroids that lower intraocular pressure (IOP), bile acid-related bile acid steroids, cholesterol derivatives, other steroids, pheromones, steroid metabolites, progesterone, neurosteroids, and corticosteroids.

[0089] In another embodiment of any of the above coatings, the compound is further described by one of Formulas (II)-(LXXV).

[0090] In yet another embodiment of any of the foregoing coatings, D1 and D2 are formed from the same steroid, or D1 and D2 are formed from different steroids.

[0091] In certain embodiments of any of the above coatings, the coating comprises a mixture of two or more compounds of Formula (A-VIII).

[0092] In other embodiments of any of the foregoing coatings, at least 70% (w / w) of the coating is a compound of Formula (A-VIII).

[0093] In other embodiments of any of the foregoing coatings, at least 90% (w / w) of the coating is the compound.

[0094] In any of the above coating embodiments, compound D1 or D2 is released from the coating by surface erosion.

[0095] In certain embodiments of any of the aforementioned coatings, the surface erodes to release less than 20% (e.g., less than 18%, 15%, 12%, 10%, or 5%) of D1 or D2 (as a percentage of the total drug D1 or D2 present in the coating as a prodrug) in 100% bovine serum at 37° C. for 5, 6, 7, 8, 9, 10, or 12 days (e.g., less than 10% of D1 or D2 in 100% bovine serum at 37° C. for 5 days). In other embodiments of any of the aforementioned coatings, the surface erodes to release less than 2.0% (e.g., less than 1.8%, 1.5%, 1.2%, 1.0%, or 0.5%) of D1 or D2 (as a percentage of the total drug D1 or D2 present in the coating as a prodrug) in PBS at 37° C. for 5, 7, 10, or 14 days (e.g., less than 2% of D1 or D2 in PBS at 37° C. for 5 days). In yet other embodiments of any of the foregoing coatings, surface erosion releases more than 20% (e.g., more than 22%, 24%, 26%, 28%, or 30%) of D1 or D2 (as a percentage of the total drug D1 or D2 present in the coating as a prodrug) in 100% bovine serum at 37°C for not less than 6 days, 8 days, 10 days, or 12 days (e.g., more than 24% of D1 or D2 after 10 days in 100% bovine serum at 37°C). In other embodiments of any of the above coatings, surface erosion releases more than 5.0% (e.g., more than 6.0%, 8.0%, 10%, 12%, or 15%) of D1 or D2 (as a percentage of the total drug D1 or D2 present in the coating as a prodrug) over not less than 6 days, 8 days, 10 days, or 12 days at 37° C. in PBS (e.g., more than 5% of D1 or D2 over 10 days at 37° C.). The compound (D1 and / or D2) may be present in an amount such that t 10 Greater than or equal to t 50 It is released from the coating at a rate of 1 / 10 of that of the original.

[0096] In certain embodiments, the article further comprises 0.1% to 10% (w / w) of one or more additives, wherein the one or more additives are plasticizers, antioxidants, binders, lubricants, radiopaque agents, and mixtures thereof.

[0097] In certain embodiments of any of the foregoing coatings, the substrate comprises a coating formed from a compound of the present disclosure.

[0098] In other embodiments of any of the foregoing coatings, at least 70% (w / w) of the coating is the compound.

[0099] In any of the foregoing coating embodiments, at least 90% (w / w) of the coating is the compound.

[0100] In any of the foregoing coating embodiments, the coating has a glassy state and is formed from a compound of the present disclosure.

[0101] The present disclosure further features coatings having a glassy state formed from the disclosed compounds.

[0102] The present disclosure features an implantable medical device that includes a coating of the present disclosure, wherein the coating is located on a surface of the implantable medical device.

[0103] In one aspect, the disclosure features compounds described by formula (AI):

[0104] D1-OLO-D2 (AI),

[0105] or a pharmaceutically acceptable salt thereof, wherein D1-O and D2-O are each independently a group formed by a steroid; L is -C(O)-OC(O)-(R B )-C(O)OC(O)-; and R B C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms, wherein the steroid is an anabolic steroid, an androgenic steroid, a progestin steroid, an estrogenic steroid, a cancer therapeutic steroid, an antibiotic steroid, a glucocorticoid steroid, a bland steroid, or a corticosteroid.

[0106] In a related aspect, the disclosure features compounds described by formula (A-II):

[0107] D1-OLO-D2 (A-II),

[0108] or a pharmaceutically acceptable salt thereof, wherein D1-O and D2-O are each independently a group formed by a steroid; L is -C(O)O-(R A )-OC(O)-; among which O-(R A )-O is a radical of a polyol and contains at least one free hydroxyl group, wherein the steroid is an anabolic steroid, an androgenic steroid, a progestin steroid, an estrogenic steroid, a cancer treatment steroid, an antibiotic steroid, a glucocorticoid steroid, a bland steroid, an anti-angiogenic steroid, a steroid that lowers intraocular pressure (IOP), a bile acid-related bile acid steroid, a cholesterol derivative, another steroid, a pheromone, a steroid metabolite, a progesterone, a neurosteroid, or a corticosteroid.

[0109] In another aspect, the disclosure features compounds described by formula (A-III):

[0110] D1-OLO-D2 (A-III),

[0111] or a pharmaceutically acceptable salt thereof, wherein D1-O and D2-O are each independently a group formed by a steroid; L is -C(O)O-(R A )-OC(O)-、-C(O)-(R B )-C(O)-or-C(O)-OC(O)-(R B )-C(O)OC(O)-;R A C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10, and each R B Independently C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms, wherein the steroid is an anabolic steroid, an androgenic steroid, a progestin steroid, an estrogenic steroid, a cancer treatment steroid, an antibiotic steroid, a glucocorticoid steroid, an antiangiogenic steroid, a steroid that lowers intraocular pressure (IOP), a bile acid-related bile acid steroid, a cholesterol derivative, another steroid, a pheromone, a steroid metabolite, a progesterone, a neurosteroid, or a bland steroid.

[0112] In a related aspect, the disclosure features compounds described by formula (A-IV):

[0113]

[0114] or a pharmaceutically acceptable salt thereof, wherein L is -C(O)O-(R A )-OC(O)-;R AIncluding C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10.

[0115] In embodiments of any of the above aspects, O-(R A )-O is a group of a polyol formed by a cyclic alcohol (e.g., bornesitol, boraxitol, inositol, ononitol, pinitol, pinpollitol, quebracho, quinic acid, shikimic acid, valienol or viscumitol), a sugar alcohol (e.g., sorbitol, mannitol, xylitol, maltitol, lactitol, erythritol, isomalt) or glycerol. In a specific embodiment, the linker L is formed by a polyol and contains 1, 2, 3 or 4 hydroxyl groups. In another embodiment, O-(R A )-O is a compound of an alkanediol (e.g., C 1-10 glycol), diethylene glycol, triethylene glycol, tetraethylene glycol or pentaethylene glycol.

[0116] In embodiments of the above aspects, D1-O and D2-O are each independently described by any one of formulas (Ia) to (I-sss) described herein. For example, at least one of D1-O and D2-O is formed from: (i) anabolic steroids including androstene, androstenediol, bolasterone, clostebol, ethynol, formosanol, 4-hydroxy-19-nortestosterone, methandrostenol, methenolol, methyltrienolone, nandrolone, norbolone, oxymethyltestosterone, stenbolone, and trenbolone; (ii) androgenic steroids including boldenone, fluoxymesterone, methenolol, Mesterolone, hydroxymetholone, 17-methyltestosterone, 17-alpha-methyltestosterone 3-cyclopentyl enol ether, norethandrolone, methylphenidate, oxandrolone, hydroxymethyltestosterone, oxymetholone, prasterone, stanlolone, stanozolol, testosterone, testosterone 17-chloral hemiacetal, testosterone propionate, testosterone enanthate, thiomethyltestosterone, dehydroepiandrosterone (DHEA), androstenedione, androstenediol, androstenone, dihydrotestosterone (DHT) and androstanolone; (ii) i) Progesterone steroids, including norethindrone, norethindrone acetate, gestodene, levonorgestrel, allylestradiol, anagestrel, desogestrel, demethinolone, dydrogesterone, ethinylestradiol, norethindrone, norethindrone diacetate, etonogestrel, gestodene, ethinylestradiol, halogenated progesterone, 17-hydroxy-16-methylene-progesterone, 17α-hydroxyprogesterone, linegestrel, medroxyprogesterone, melengestrol, norethindrone, norgestrel, norgestrel, norgestrel, norgestrel , norgestrel, levonorgestrel, norgestrel, norethenolone, pentagestrol, MENT (7-methyl-19-testosterone); norgestrelmin, and drospirenone, tibolone, and megestrol acetate; (iv) estrogenic steroids, including estrogens, eguilenin, equilinone, 17β-estradiol, estradiol benzoate, estriol, ethinyl estradiol, mestranol, moxestrol, dimethyl estriol, estriol cyclopentane, and ethinyl estradiol;(v) Glucocorticoids, including medrysone, alclomethasone, alclomethasone dipropionate, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone benzoate, betamethasone valerate, budesonide, ciclesonide, clobetasol, clobetasol butyrate, clobetasol propionate, clobetasone, clocortolone, loprednol, hydrocortisone, cortisone, cortivazole, deflazacort, desonide, desoximetasone, deoxycorticosterone, deoxymethasone, dexamethasone, diflorasone, diflorasone diacetate, diflucortolone, diflucortolone valerate, and diflucorticosterone , difluprednate, fluclosanide, fluclosonide, flurandrenolide, flumethasone, fludecathone, fludecathone pivalate, flunisolide, flunisolide, fluocinolone, fluocinolone acetonide, fluocinolone butyl, fluocortolone, fluocortolone, flumetholone, fluprednidone, fluprednidine, fluprednidine acetate, fluprednisolone, fluticasone, fluticasone propionate, formocortal, halcinonide, halometasone, hydrocortisone, hydrocortisone acetate, hydrocortisone acepro, hydrocortisone butyl, hydrocortisone butyrate, loteprednol, methylprednisone, 6a-methylprednisolone (vi) steroids including abiraterone, cyproterone acetate, dutasteride, enzalutamide, finasteride, galeterone, fusidic acid, cholesterol, 11-deoxycortisol, 11-deoxycorticosterone, pregnenolone, cholic acid, chenodeoxycholic acid, ursodeoxycholic acid, obeticholic acid, Tetrahydrocortisone, tetrahydrodeoxycortisol, tetrahydrocorticosterone, 5α-dihydrocortisol, and 5α-dihydroprogesterone; (vii) antiangiogenic steroids or steroids that lower intraocular pressure (IOP), including anecortave acetate, anecortave, 11-epicotinoids, 17α-hydroxyprogesterone, tetrahydrocorticosterone, and tetrahydrocortisol; (viii) bile acid steroids related to bile acids, including deoxycholic acid, orthocholic acid, dehydrocholic acid, glycochenodeoxycholic acid, glycocholic acid, glycodeoxycholic acid, hyodeoxycholic acid, lithocholic acid, and α-muricholic acid. (ix) neurosteroids, including alfaxalone, alfadolonone, hydroxypregnenone, minaxolone, tetrahydrodeoxycorticosterone, allopregnanolone, pregnanolone, ganoxolone, 3α-androstanediol, pregnanolone, allopregnanolone, and 24(S)-hydroxycholesterol; (x) other steroids, including flugestrel, prednisolone, chlormadinone acetate, medrogestone, and medroxyprogesterone acetate;(xi) pheromones, including androstenol, androstenone, androstenol, androstenone, estrenol, 5-dehydroprogesterone, 6-dehydro-progesterone, allopregnanolone, and hydroxyprogesterone caproate; (xii) steroid metabolites, including tetrahydrotriamcinolone, cortienic acid, or (xiii) progesterone, including allopregnanolone, 11-dehydrocorticosterone, 11β-hydroxypregnenolone, ketoprogesterone, 17-hydroxypregnenolone, 17,21-dihydroxypregnenolone, 18-hydroxycorticosterone, deoxycortisone, 21-hydroxypregnenolone, and progesterone; or (xiii) progesterone, including allopregnanolone, 11-dehydrocorticosterone, 11β-hydroxypregnenolone, ketoprogesterone, 17-hydroxypregnenolone, 17,21-dihydroxypregnenolone, 18-hydroxycorticosterone, deoxycortisone, 21-hydroxypregnenolone, and progesterone; or (xiii) progesterone, including allopregnanolone, 11-dehydrocorticosterone, 11β-hydroxypregnenolone, ketoprogesterone, 17-hydroxypregnenolone, 17,21-dihydroxypregnenolone, 18-hydroxycorticosterone, deoxycortisone, 21-hydroxypregnenolone, and progesterone; β,17α,21-tetraol-20-one, allopregnanol-3β,17α,20β-triol, allopregnanol-3β,17α,21-triol-11,20-dione, allopregnanol-3β,11β,21-triol-20-one, allopregnanol-3β,17α,21-triol-20-one, allopregnanol-3α-ol-20-one, allopregnanol-3β- Pregnane-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.

[0117] In a related aspect, the disclosure features compounds described by formula (A-VI):

[0118] D1-C(O)-LC(O)-D2(A-VI),

[0119] or a pharmaceutically acceptable salt thereof, wherein D1-C(O) and D2-C(O) are each independently a group formed by a steroid; L is -O-(R A )-O-or-OC(O)-O-(R A )-OC(O)O-;R A C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A)-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; and n, m and p are integers from 1 to 10.

[0120] In an embodiment of the compound of formula (A-VI), O-(R A )-O is a group of a polyol formed by a cyclic alcohol (e.g., bornesitol, boraxitol, inositol, ononitol, pinitol, pinpollitol, quebracho, quinic acid, shikimic acid, valienol or viscumitol), a sugar alcohol (e.g., sorbitol, mannitol, xylitol, maltitol, lactitol, erythritol, isomalt) or glycerol. In a specific embodiment, the linker L is formed by a polyol and contains 1, 2, 3 or 4 hydroxyl groups. In another embodiment, O-(R A )-O is a compound of an alkanediol (e.g., C 1-10 glycol), diethylene glycol, triethylene glycol, tetraethylene glycol or pentaethylene glycol.

[0121] The present disclosure further features compounds described by Formula (A-VII):

[0122] D1-C(O)-LC(O)-D2 (A-VII),

[0123] or a pharmaceutically acceptable salt thereof, wherein D1-C(O) and D2-C(O) are each independently a group formed by a steroid; L is -OC(O)-O-(R A )-OC(O)-O-; and R A C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, ring systems of 3 to 10 atoms.

[0124] In certain embodiments of the compounds of formula (A-VI) and (A-VII), at least one of D1-C(O) and D2-C(O) is formed from fusidic acid, cholic acid, chenodeoxycholic acid, ursodeoxycholic acid, or obeticholic acid.

[0125] In embodiments of any of the above compounds: (i) D1-O and D2-O are each formed from the same steroid, (ii) D1-C(O) and D2-C(O) are each formed from the same steroid, (iii) D1-O and D2-O are each formed from a different steroid, or (iv) D1-C(O) and D2-C(O) are each formed from a different steroid.

[0126] In certain embodiments of any of the above compounds, R A C 1-10 Alkylene.

[0127] In yet another embodiment of any of the above compounds, upon hydrolysis, D1 and D2 form corticosteroids including alclomethasone, beclomethasone, betamethasone, betamethasone valerate, budesonide, cloprednisone, clopredniol, corticosterone, cortisone, desonide, desoximerasone, dexamethasone, diflorasone, diflucortolone, glycyrrhetinic acid, fluclosonide, flumethasone, flunisolide, fluocinolone acetonide, flucortolone, fluprednisolone, flurandrenolide, halometasone, hydrocortisone, hydrocortisone butyrate, methylprednisone, methylprednisolone, paramethasone, prednisolone, prednisone, prednisolone valerate, prednididine, triamcinolone, and triamcinolone acetonide.

[0128] In another embodiment of any of the aforementioned compounds, the compound is further described by one of Formulas (II)-(LXXV) described herein.

[0129] In yet another embodiment of any of the above compounds, R A -(CH2CH2O) q CH2CH2-, q is an integer from 1 to 10, and upon hydrolysis, D1 and D2 each independently form dexamethasone, triamcinolone, betamethasone, prednisolone, prednisone, fluocinolone acetonide, fluocinolone acetonide, mometasone, mometasone furoate, anecoratve, hydrocortisone, triamcinolone acetonide, abiraterone, fusidic acid or cholesterol.

[0130] The articles of the present disclosure can be formed by the following steps: (a) heating a compound of Formula (A-VIII) to above its melting point (e.g., to 110-145° C., 130-185° C., 150-215° C., or 180-240° C., depending on the compound) to form a melt, and (b) cooling the melt to form the article. The article can be formed during step (a), before cooling, by pressing the melt into a mold, by extruding the melt from an orifice (e.g., to form a cylinder or another shape), or by forming droplets of the melt and cooling the droplets into glassy droplets. Fibers can be formed by spinning (e.g., melt spinning, heat spinning, or electrospinning) at different rates or pulling the melt (e.g., with tweezers) to produce glassy fibers of different diameters.

[0131] Alternatively, the articles of the present disclosure can be formed by the following steps: (a) dissolving the compound of formula (A-VIII) in a volatile organic solvent (e.g., acetone, methanol, dichloromethane, tetrahydrofuran, chloroform, or a mixture thereof) to form a solution, and (b) removing the organic solvent to form the article. The article can be formed by electrospraying, electrospinning, or fiber spinning the solution during step (b), before completely removing the organic solvent. For example, a 50:50 v / v mixture of dichloromethane / tetrahydrofuran of a 100% wt / v solution of the compound can be loaded at a rate of 0.5 mL / h and electrospun onto a cylindrical mandrel rotating at 1150 rpm to form aligned glassy fibers. Fibers can also be formed by wet spinning, dry spinning, or gel spinning to form glassy fibers of varying diameters. Microparticles can be prepared by electrospraying a solution containing the compound at a concentration of about 20% to 40% w / v or 25% to 50% w / v of the solution. Nanoparticles can be prepared by electrospraying a solution containing the compound at a concentration of about 3% to 15% w / v or 5% to 18% w / v of the solution. Alternatively, the shaped article can be formed by placing the solution in a mold and evaporating the volatile organic solvent to form the shaped article.

[0132] The present disclosure features a method of forming an article of manufacture comprising a compound of Formula (A-VIII) or a pharmaceutically acceptable salt thereof:

[0133] D1-L-D2 (A-VIII)

[0134] wherein D1 and D2 are each independently a group formed from a steroid; and L is a linker that covalently links D1 to D2, and wherein the article is formed by a process comprising the following steps: (a) heating the compound or a pharmaceutically acceptable salt thereof to form a melt; (b) cooling the melt to form a glassy composition; and (c) heating the glassy composition to a temperature above the glass transition temperature of the glassy composition and shaping the glassy composition to form a shaped article. Step (c) may comprise extruding, molding, blow molding, hot spinning, electrospinning, or electrospraying the glassy composition to form a shaped article. In particular embodiments, the method forms an article that is free of controlled release excipients, crystallization inhibiting excipients, mechanical integrity enhancing excipients, and / or binding excipients; or the method forms an article that optionally has a glassy state.

[0135] In a related aspect, the disclosure features a method of forming an article of manufacture comprising a compound of Formula (A-VIII) or a pharmaceutically acceptable salt thereof:

[0136] D1-L-D2 (A-VIII)

[0137] wherein D1 and D2 are each independently a group formed by a steroid; and L is a linker that covalently links D1 to D2, and wherein the article is formed by a process comprising the following steps: (a) dissolving the compound or a pharmaceutically acceptable salt thereof in a solvent to form a solution; (b) evaporating the solvent to form a glassy composition; and (c) heating the glassy composition to a temperature above the glass transition temperature of the glassy composition and shaping the glassy composition to form a shaped article. Step (c) may comprise extruding, molding, blow molding, hot spinning, electrospinning, or electrospraying the glassy composition to form a shaped article. In particular embodiments, the method forms an article that is free of controlled release excipients, free of crystallization-inhibiting excipients, free of mechanical integrity-enhancing excipients, and / or free of binding excipients; or the method forms an article that optionally has a glassy state.

[0138] In a further aspect, the disclosure features a method of forming an article of manufacture comprising a compound of Formula (A-VIII) or a pharmaceutically acceptable salt thereof:

[0139] D1-L-D2 (A-VIII)

[0140] wherein D1 and D2 are each independently a group formed from a steroid; and L is a linker that covalently links D1 to D2, and wherein the article is formed by a process comprising the following steps: (a) dissolving the compound or a pharmaceutically acceptable salt thereof in a solvent to form a solution; (b) electrospraying the solution to form a glassy composition; and (c) heating the glassy composition to a temperature above the glass transition temperature of the glassy composition and shaping the glassy composition to form a coating. In certain embodiments, the method forms an article that is free of a controlled release excipient, free of a crystallization-inhibiting excipient, free of a mechanical integrity-enhancing excipient, and / or free of a binding excipient; or the method forms an article that optionally has a glassy state.

[0141] In some embodiments of the articles of the present disclosure, the compound is processed (e.g., melt-processed or solvent-processed) as described herein to form a glassy solid. The glassy solid is then heated to above its glass transition temperature, Tg, and molded or extruded to form a shaped article (e.g., a fiber, a fiber web, a woven fabric, a nonwoven fabric, a pellet, a cylinder, a microparticle (e.g., a microbead), or a nanoparticle (e.g., a nanobead), or another shaped article. In other embodiments, the microparticles are prepared by melting the compound to form glassy pellets or other shaped forms, crushing the glassy article into coarse or irregularly shaped particles, filtering the particles through a sieve, and heating the particles above Tg to round them into smoother spherical particles.

[0142] In some embodiments of the methods and compositions of the present disclosure, the preparation is free of controlled-release excipients.

[0143] In certain embodiments of the methods and compositions of the present disclosure, the preparation is free of crystallization-inhibiting excipients.

[0144] In certain embodiments of the methods and compositions of the present disclosure, the article is free of mechanical integrity enhancing excipients.

[0145] In still further embodiments of the methods and compositions of the present disclosure, the preparation is free of binding excipients.

[0146] In another aspect, the disclosure features Compound 3. The disclosure further features a pharmaceutical composition comprising Compound 3 and a pharmaceutically acceptable excipient.

[0147] In another aspect, the disclosure features compound 17. The disclosure further features a pharmaceutical composition comprising compound 17 and a pharmaceutically acceptable excipient.

[0148] definition

[0149] As used herein, the term "free of a release-controlling polymer" means that an amount of polymeric material greater than 10 kDa is absent from the preparation of the present disclosure, the amount of polymeric material being sufficient to delay or slow the release of the steroid dimer from the preparation as compared to the release profile observed for an otherwise identical preparation lacking the polymeric material, wherein the release profile is measured in 100% fetal bovine serum (FBS) at 37°C.

[0150] As used herein, the term "free of a crystallization-inhibiting excipient" means that the preparation of the present disclosure is free of an excipient in an amount sufficient to reduce the amount of crystallized steroid dimer in the preparation compared to the amount of crystallized steroid dimer observed in an otherwise identical preparation that does not contain the excipient. The level of crystallinity can be measured using DSC or XRD. In certain embodiments, the preparation of the present disclosure is free of a crystallization-inhibiting excipient that is a polymeric material greater than 10 kDa.

[0151] As used herein, the term "free of mechanical integrity enhancing excipients" means that the article of the present disclosure is free of an amount of excipient sufficient to increase the mechanical integrity of the article compared to the mechanical integrity of an otherwise identical article without the excipient. For rod-shaped articles, the mechanical integrity of the article can be tested using a three-point or four-point mechanical bending test (ASTM C1684-18) for formulations containing or without excipients in the dry state (before drug release) or after 15-30% drug release. For articles having a rectangular shape, the mechanical integrity can be tested using a three-point mechanical bending test (ASTM D790-17) or a four-point mechanical bending test (ASTM D6272) for formulations containing or without excipients in the dry state (before drug release) or after 15-30% drug release. A decrease in mechanical integrity results in faster rupture of the article, thereby increasing the total surface area of ​​the article of that amount and resulting in a faster release profile, wherein the release profile is measured at 37°C in 100% FBS. In certain embodiments, the articles of the present disclosure are free of mechanical integrity enhancing excipients that are polymeric materials greater than 10 KDa.

[0152] As used herein, the term "free of bound excipients" means that the preparations of the present disclosure are free of an amount of excipient sufficient to delay or slow the release of the steroid dimer from the preparation as compared to the release profile observed for an otherwise identical preparation lacking the bound excipient, wherein the release profile is measured in 100% FBS at 37°C.

[0153] The term "antiangiogenic steroid" refers to a steroid that halts the process of developing new blood vessels (ie, angiogenesis). Examples of antiangiogenic steroids include anecortave acetate, anecortave, 11-epicocortisol, 17α-hydroxyprogesterone, tetrahydrocorticosterone, and tetrahydrocortisol.

[0154] As used herein, the term "mild steroid" refers to low glucocorticoid activity and low mineralocorticoid activity. Mild steroids include, but are not limited to, cholesterol, bile acids (such as cholic acid), and plant sterols (such as β-sitosterol). Exemplary mild steroids include cholesterol, 11-deoxycortisol, 11-deoxycorticosterone, pregnenolone, cholic acid, chenodeoxycholic acid, ursodeoxycholic acid, obeticholic acid, tetrahydrocortisone, tetrahydrodeoxycortisol, tetrahydrocorticosterone, 5α-dihydrocorticosterone, and 5α-dihydroprogesterone.

[0155] The term "cholesterol derivative" refers to a steroid derived from cholesterol. Examples of cholesterol derivatives are 22R-hydroxycholesterol and 20α-22R-dihydroxycholesterol.

[0156] The term "bile acid-related bile acid steroid" refers to a steroid derived from bile acid. Examples of bile acid-related bile acid steroids are deoxycholic acid, orthocholic 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.

[0157] As used herein, the term "cylinder" refers to the shape of the pharmaceutical composition of the present disclosure having parallel sides and a circular or elliptical cross-section, or a cross-section of a certain shape (e.g., a star-shaped cross-section). The average diameter of the cylinder can be in the range of about 0.01 to 1 mm in diameter, for example, about 0.01 to 0.2 mm, about 0.1 to 0.3 mm, about 0.1 to 0.4 mm, about 0.2 to 0.5 mm, about 0.1 to 0.6 mm, about 0.1 to 0.7 mm, about 0.1 to 0.8 mm, or about 0.1 to 0.9 mm. The average length of the cylinder can be in the range of about 0.05 to 20 mm, for example, about 0.05 to 1 mm, about 0.5 to 2 mm, about 0.5 to 4 mm, about 0.5 to 6 mm, about 0.5 to 8 mm, about 0.5 to 10 mm, about 0.5 to 12 mm, about 0.5 to 14 mm, about 0.5 to 16 mm, or about 0.5 to 18 mm. In some embodiments, the average diameter of the cylinder is in the range of about 0.01 to 1 mm, and the average length of the cylinder is about 0.1 mm to 4.0 mm. In some embodiments, the average length of the cylinder is about 0.5 to 10 mm or about 1 to 10 mm.

[0158] As used herein, the term "fiber" refers to the shape of the pharmaceutical composition of the present disclosure, which is elongated or linear. The average diameter of the fiber can be in the range of about 0.01 to 1 mm, for example, 0.05 to 0.3 mm, 0.1 to 0.3 mm, 0.15 to 0.3 mm, 0.2 to 0.3 mm, 0.25 to 0.3 mm, 0.01 to 0.1 mm, 0.01 to 0.2 mm, 0.01 to 0.3 mm, 0.01 to 0.4 mm, 0.01 to 0.5 mm, 0.01 to 0.6 mm, 0.01 to 0.7 mm, 0.01 to 0.8 mm, or 0.01 to 0.9 mm. The average length of the fibers can be in the range of about 20 to 20,000 mm, e.g., about 20 to 1000 mm, about 20 to 2,000 mm, about 100 to 2,000 mm, about 100 to 5,000 mm, about 1,000 to 8,000 mm, about 2,000 to 8,000 mm, about 2,000 to 10,000 mm, about 2,000 to 12,000 mm, about 2,000 to 15,000 mm, or about 5,000 to 18,000 mm.

[0159] As used herein, the term "fiber web" refers to a mesh or web having a plurality of attached or woven fibers. The fiber web can have aligned and non-aligned morphologies.

[0160] As used herein, the term "glassy state" refers to an amorphous solid comprising greater than 70%, 80%, 90%, 95%, 98%, or 99% (w / w) of one or more drug dimers of the present disclosure and exhibiting a glass transition temperature in the range of 38 to 150° C. In the glassy state, the level of crystallinity, as measured by DSC or XRD, is low, ranging from 0-15%, for example, 0-1%, 0-3%, 0-5%, 0-7%, 0-9%, 0-10%, or 0-13%. Thermal processing or solvent processing of one or more drug dimers can be used to form the glass formulations of the present disclosure.

[0161] The term "IOP-lowering steroid" refers to a steroid that lowers intraocular pressure. Examples of IOP-lowering steroids are anecortave acetate, anecortave, 11-epicocortisol, 17α-hydroxyprogesterone, tetrahydrocortisol and tetrahydrocortisol.

[0162] As used herein, the term "microparticles" refers to the shape of the pharmaceutical composition of the present disclosure, which can be regular or irregular in shape. The average diameter of the microparticles can be in the range of about 1 to 1000 μm, for example, about 10 to 1000 μm, about 100 to 1000 μm, about 200 to 1000 μm, about 500 to 1000 μm, about 700 to 1000 μm, or about 900 to 1000 μm. As used herein, "microbeads" refers to spherical microparticles.

[0163] As used herein, the term "nanoparticles" refers to the shape of pharmaceutical compositions of the present disclosure, which can be regular or irregular shapes. The average diameter of the nanoparticles can be in the range of about 0.01 to 1 μm, for example, about 0.05 to 1 μm, about 0.1 to 1 μm, about 0.2 to 1 μm, about 0.3 to 1 μm, about 0.4 to 1 μm, about 0.5 to 1 μm, about 0.6 to 1 μm, about 0.7 to 1 μm, about 0.8 to 1 μm or about 0.9 to 1 μm. As used herein, "nanobeads" refers to spherical nanoparticles.

[0164] The term "neurosteroid" refers to an endogenous or exogenous steroid that rapidly alters neuronal excitability by interacting with ligand-gated ion channels and other cell surface receptors. Exemplary neurosteroids are alfaxalone, alfadolonone, hydroxypregnenone, minaxolone, tetrahydrodeoxycorticosterone, allopregnanolone, pregnanolone, ganoxolone, 3α-androstanediol, pregnanolone, allopregnanolone, and 24(S)-hydroxycholesterol.

[0165] As used herein, the term "nonwoven fabric" refers to a web-like structure of fibers bonded together by entanglement.

[0166] The term "other steroids" refers to compounds having a steroid-based structure. Examples of such steroids are flugestrone, prednisolone, chlormadinone acetate, medrogestone, and medroxyprogesterone acetate.

[0167] As used herein, the term "pellet" refers to the shape of the pharmaceutical composition of the present disclosure, which is round, spherical, or cylindrical, or a combination thereof. The average diameter of the pellets can be in the range of about 0.2 to 5 mm, for example, about 0.2 to 1 mm, about 0.2 to 2 mm, about 0.3 to 3 mm, about 1.5 to 5 mm, about 2 to 5 mm, about 2.5 to 5 mm, about 3 to 5 mm, about 3.5 to 5 mm, about 4 to 5 mm, or about 4.5 to 5 mm.

[0168] As used herein, the term "pharmaceutically acceptable salt" means salts that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction, etc., within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharm. Sci. 66: 1-19, 1977. These salts can be prepared in situ during the final isolation and purification of the disclosed compounds, or separately by reacting the free base groups with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, carbonate, chloride, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, and the like. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

[0169] The term "pheromone" refers to a steroid hormone. Examples of pheromones are androstadienol, androstadienone, androstenol, androstenone, estrenol, 5-dehydroprogesterone, 6-dehydro-progesterone, allopregnanolone and hydroxyprogesterone caproate.

[0170] The term "steroid metabolite" refers to a metabolic product of a steroid. Examples of steroid metabolites are tetrahydrotriamcinolone, cortienic acid, 11-dehydrocorticosterone, 11β-hydroxypregnenolone, ketoprogesterone, 17-hydroxypregnenolone, 17,21-dihydroxypregnenolone, 18-hydroxycorticosterone, deoxycortisone, 21-hydroxypregnenolone, and progesterone.

[0171] The term "progesterone" refers to a natural or synthetic steroid hormone. Examples of progesterone are allopregnanol-3α,20α-diol, allopregnanol-3β,20β-diol, allopregnanol-3β,21-diol-11,20-dione, allopregnanol-3β,17α-diol-20-one, 3,20-allopregnanol-3β,11β,17α,20β,21-pentaol, allopregnanol-3β,17α,20β,21-tetrol, allopregnanol-3α,11β,17α,21-tetrol-20-one, allopregnanol-3β,11β,17α,21-tetrol-20-one, allopregnanol-3β,17α,20β-triol ... α,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.

[0172] As used herein, the term "surface erosion" refers to the process in which the pharmaceutical composition of the present invention gradually disintegrates and releases free drug from the drug dimer. Surface erosion can be customized to obtain the desired drug release rate. Surface erosion can depend on the drug composition of the drug dimer and can be regulated by cutting the drug-linker bond through hydrolysis and / or enzymatic degradation. The surface erosion and release rate of a given drug from the drug dimer can also depend on the amount of the loaded drug dimer (accounting for the percentage of the final drug dimer formulation), product size (e.g., size), the solubility of the drug dimer (e.g., by selecting suitable drug and / or linker) and / or the surface area of ​​the product. For example, the surface erosion mechanism of drug release allows the drug delivery product to be customized to have specific physical characteristics (size, diameter, surface area, total mass, etc.) to achieve the desired drug release rate, and drug release can be designed to start within a few minutes or hours, and can be continued for several days, weeks, months, or years.

[0173] As used herein, “t 50 " is the time at which 50% of the releasable drug is released from the article of the present disclosure. Time t 10 Correspondingly, it is the time when 10% of the releasable drug is released from the preparation of the present disclosure. When the release curve is completely linear, t 10 =t 50 When the drug is released in the initial burst, t 10 Much smaller than t 50In the compositions and methods of the present disclosure, t 10 Can be equal to or greater than t 50 Drug release from the preparations or compounds of the present disclosure can be measured as described in Example 1 in 100% bovine serum at 37°C or in PBS at 37°C.

[0174] As used herein, the term "woven fabric" refers to a pharmaceutical composition that resembles a material formed by weaving of fibers.

[0175] Chemical definition

[0176] "Acyl" refers to a chemical moiety having the formula -C(O)R', wherein R' is selected from C 1-10 Alkyl, C 2-20 Alkenyl, heteroalkyl, C 2-20 Alkynyl, C 5-10 Examples of acyl groups include, but are not limited to, acetyl, propionyl, butyryl, valeryl, and tetrahydrofuran-2-yl.

[0177] "Aliphatic" refers to the non-aromatic chemical portion of a hydrocarbon. Aliphatics can be cyclic, straight-chain, or branched, and can be saturated or unsaturated, and can have single, double, or triple bonds.

[0178] "Alkoxy" refers to a chemical substituent of the formula -OR, where R is an alkyl group. "Aryloxy" refers to a chemical substituent of the formula -OR, where R is a C 5-10 Aryl.

[0179] As used herein, the terms "alkylene," "alkenylene," "alkynylene," and the prefix "alkane" refer to divalent radicals of the specified size, typically C for saturated radicals (e.g., alkylene or alkane). 1-10 or C 1-20 , while for unsaturated groups (e.g., alkenylene or alkynylene) it is usually C 2-20 or C 2-20 . They include straight-chain, branched, and cyclic forms, as well as combinations of these, and when unsubstituted contain only C and H. Because they are divalent, they can link two parts of a molecule together. Examples are methylene, ethylene, propylene, cyclopropane-1,1-diyl, ethylidene, 2-butene-1,4-diyl, and the like. These groups may be substituted with groups generally suitable as substituents for the alkyl, alkenyl, and alkynyl groups described herein. Thus, C=O, for example, is a C1 alkylene substituted with =O.

[0180] "Alkylthio" refers to a chemical substituent of the formula -SR where R is an alkyl group.

[0181] "Arylthio" refers to a chemical substituent of the formula -SR, where R is C 5-10Aryl.

[0182] “C 1-20 "Alkyl" refers to a branched or unbranched saturated hydrocarbon group having from 1 to 20 carbon atoms, inclusive. The alkyl group may optionally include a monocyclic, bicyclic, or tricyclic ring, wherein each ring ideally has three to six members. The alkyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, mercapto, alkylthio, arylthio, halogen, hydroxy, fluoroalkyl, perfluoroalkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl.

[0183] “C 2-20 "Olefin" refers to a branched or unbranched hydrocarbon group containing one or more double bonds, ideally having 2 to 10 carbon atoms. 2-20 The olefin may optionally comprise a monocyclic, bicyclic or tricyclic ring, wherein each ring desirably has five or six members. 2-20 The alkenyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, thiol, alkylthio, arylthio, halogen, hydroxy, fluoroalkyl, perfluoroalkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl.

[0184] “C 2-20 "Alkyne" refers to a branched or unbranched hydrocarbon group containing one or more triple bonds, ideally having 2 to 10 carbon atoms. 2-20 The alkyne may optionally comprise a monocyclic, bicyclic, or tricyclic ring, wherein each ring desirably has five or six members. 2-20 Alkynyl groups may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, thiol, alkylthio, arylthio, halogen, hydroxy, fluoroalkyl, perfluoroalkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl.

[0185] "Carbonate" refers to a linking group having the formula -C(O)OC(O)-O-.

[0186] "Carboxyalkyl" refers to a chemical moiety of the formula -(R)-COOH, where R is an alkyl group.

[0187] "Cyclic acetal" refers to a ring structure comprising two oxygen atoms separated by a carbon atom, which is optionally substituted (e.g., 1,3-dioxolane). Exemplary substituents include, but are not limited to, alkyl, hydroxy, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, fluoroalkyl, carboxyl, carboxylalkyl, amino, aminoalkyl, monosubstituted amino, disubstituted amino, quaternary amino, phosphodiester, phosphoramidate, phosphate, phosphonic acid, phosphonate, sulfonate, sulfate, sulfhydryl, phenol, amidine, guanidine, and imidazole groups.

[0188] The term "ring system" refers to a compound comprising one or more covalently closed ring structures, wherein the atoms constituting the ring backbone are composed of any combination of the following atoms: carbon, oxygen, nitrogen, sulfur, and phosphorus. The ring system may be substituted or unsubstituted. Exemplary substituents include, but are not limited to, alkyl, hydroxy, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, fluoroalkyl, carboxyl, carboxyalkyl, amino, aminoalkyl, monosubstituted amino, disubstituted amino, and quaternary amino groups.

[0189] "Fluoroalkyl" refers to an alkyl group substituted with fluorine.

[0190] " assorted alkyl " refers to a side chain or unbranched alkyl radical wherein one or more methylene radicals (-CH2-) are substituted by nitrogen, oxygen, sulfur, carbonyl, thiocarbonyl, phosphoryl or sulfonyl moieties. Some examples include tertiary amine, ether, thioether, amide, thioamide, carbamate, thiocarbamate, phosphoramidate, sulfonamide and disulfide. Assorted alkyl can optionally include monocycle, dicycle or tricycle, wherein each ring ideally has three to six members. Assorted alkyl can be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoroalkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl and carboxyl.

[0191] "Hydroxyalkyl" refers to a chemical moiety of the formula -(R)-OH, where R is an alkyl group. BRIEF DESCRIPTION OF THE DRAWINGS

[0192] Figures 1A to 1F is a series of images and diagrams showing Compound 1 (dexamethasone-triethylene glycol-dexamethasone, Dex-TEG-Dex) forming glassy pellets and drug release from the intact pellets by surface erosion.

[0193] Figures 2A to 2E is a series of images showing Compound 1 (Dex-TEG-Dex) processed from the melt into different glassy forms by various processing methods.

[0194] Figures 3A to 3K is a series of images showing Compound 1 (Dex-TEG-Dex) processed from solution into different glassy forms by various processing methods.

[0195] Figure 4 is a graphical representation showing the cumulative drug release over time from Compound 1 (Dex-TEG-Dex) coatings of titanium and poly(styrene-block-isobutylene-block-styrene) (SIBS).

[0196] Figure 5is a graphical representation showing the drug release rate of Compound 1 (Dex-TEG-Dex) pellets.

[0197] Figure 6 are images and diagrams showing mechanical testing of extruded cylinders of Compound 1 (Dex-TEG-Dex) using a three-point bending test.

[0198] Figure 7A and Figure 7B is a series of graphs showing pellets before and after ETO sterilization analyzed by HPLC to determine changes in pellet purity, and drug release to determine changes in release properties due to the ETO sterilization process.

[0199] Figures 8A to 8F is a series of images and diagrams showing compound 1 formed into hot extruded cylinders ( Figures 8A-8D ), the purity of the extrudate changes with time ( Figure 8E ), and a coating formed from compound 1 ( Figure 8F ).

[0200] Figures 9A to 9E is a series of images and diagrams showing Compound 2 (hydrocortisone-triethylene glycol-hydrocortisone, HC-TEG-HC) formed into thermoformed pellets, fibers, and extruded cylinders and the drug release over time.

[0201] Figures 10A to 10E is a series of images and diagrams showing Compound 3 (triamcinolone acetonide-triethylene glycol-triamcinolone acetonide, TA-TEG-TA) formed into thermoformed pellets, fibers, and extruded cylinders and drug release over time.

[0202] Figures 11A to 11C are images and diagrams showing Compound 4 (dexamethasone-triethylene glycol-hydrocortisone, Dex-TEG-HC) formed into thermoformed pellets and drug release over time.

[0203] 12A to 12E is a series of images and diagrams showing Compound 5 (dexamethasone-hexane-dexamethasone, Dex-HEX-Dex) formed into thermoformed pellets, fibers, and extruded cylinders, and drug release over time.

[0204] 13A to 13E is a series of images and diagrams showing Compound 6 (hydrocortisone-succinate-hydrocortisone, HC-SUCC-HC) formed into thermoformed pellets and fibers, and drug release over time.

[0205] 14A to 14Eare images and diagrams showing Compound 7 (Aneccortave-triethylene glycol-Aneccortave, Anec-TEG-Anec) formed into thermoformed pellets and drug release over time.

[0206] Figures 15A to 15C are images and diagrams showing Compound 8 (dexamethasone-pentaethylene glycol-dexamethasone, Dex-EG5-Dex) formed into thermoformed pellets and drug release over time.

[0207] 16A to 16E is a series of images and diagrams showing compound 9 (fusidic acid-triethylene glycol-fusidic acid (carbonate), FA-TEG-FA(CE)) formed into thermoformed pellets and fibers, and drug release over time.

[0208] 17A to 17D is a series of images and diagrams showing Compound 10 (dexamethasone-polyethylene glycol (MW=200)-dexamethasone, Dex-PEG200-Dex) formed into thermoformed pellets and extruded cylinders, and drug release over time.

[0209] Figures 18A to 18G is a series of images and diagrams showing nanoparticle and microparticle formation of compounds 3 and 5, and cumulative drug release of compound 3 over time.

[0210] Figure 19A and Figure 19B is a series of images and diagrams showing a mixture of Compounds 1 and 2 formed into thermoformed pellets and drug release over time.

[0211] Figure 20A and Figure 20B are images and graphs showing a mixture of Compounds 1 and 3 formed into thermoformed pellets and drug release over time.

[0212] Figure 21A and Figure 21B are images and graphs showing a mixture of Compounds 2 and 3 formed into thermoformed pellets and drug release over time.

[0213] Figures 22A to 22C is a series of graphs showing the release of hydrocortisone over time from thermoformed pellets formed from compounds 2, 4, 6, or 1 and 2 ( Figure 22A ), release of dexamethasone from thermoformed pellets formed from compounds 1, 4, or 1 and 2 over time ( Figure 22B ), or the release of dexamethasone from thermoformed particles formed from compounds 1 and 5 over time ( Figure 22C ).

[0214] 23A to 23D is a series of images and diagrams showing Compound 11 (dexamethasone-heptaethylene glycol-dexamethasone, Dex-EG7-Dex) formed into thermoformed pellets and extruded cylinders, and the extruded cylinders after two weeks at 37°C in PBS.

[0215] 24A to 24D is a series of images and diagrams showing Compound 12 (dexamethasone-nonaethylene glycol-dexamethasone, Dex-EG9-Dex) formed into thermoformed pellets and extruded cylinders, and the extruded cylinders after two weeks at 37°C in PBS.

[0216] 25A to 25D is a series of images and diagrams showing compound 13 (dexamethasone-polyethylene glycol (MW=300)-dexamethasone, Dex-PEG300-Dex) formed into thermoformed pellets and extruded cylinders, and the extruded cylinders after two weeks at 37°C in PBS.

[0217] Figure 26A and Figure 26B is a series of images and diagrams showing the change in physical form (geometry) and drug release from thermoformed pellets of compounds 11 and 12 over time.

[0218] Figures 27A to 27C is a series of images showing compound 14 (cholesterol-triethylene glycol-cholesterol, CHS-TEG-CHS) formed into thermoformed pellets and fibers.

[0219] Figures 28A to 28C is a series of images showing compound 15 (fusidic acid-triethylene glycol-fusidic acid (ester), FA-TEG-FA(E)) formed into thermoformed pellets and fibers.

[0220] Figure 29A and Figure 29B is an image showing Compound 16 (ethinylestradiol-triethylene glycol-ethinylestradiol, Ethin-TEG-Ethin) formed into thermoformed pellets.

[0221] Figures 30A to 30C is a series of images showing Compound 17 (prednisolone-triethylene glycol-prednisolone, Pred-TEG-Pred) formed into thermoformed pellets and fibers. DETAILED DESCRIPTION

[0222] Although the clinical importance of sustained drug release delivery systems in maintaining therapeutic drug concentrations over extended periods of time (e.g., days to weeks, months, or even years) has been recognized for decades, the number of successfully commercialized products on the market to date is limited. It is recognized in the present disclosure that to develop a successful sustained drug delivery system, technical difficulties must be overcome, including drug degradation during formulation; lack of controlled release, including undesirable burst or incomplete release associated with diffusion or bulk erosion mechanisms of drug release; low encapsulation efficiency; and formulation complexity.

[0223] For topically administered sustained release delivery systems, the present disclosure recognizes that additional challenges may arise when the mass balance of the carrier or matrix of the drug hinders drug loading, or when the carrier and matrix produce undesirable effects (ie, such as local inflammation).

[0224] It is recognized in the present disclosure that there is an unmet need for a sustained-release drug system that is formulated to release a drug in a rate-controlled manner over an extended period of time (e.g., days to weeks, to months, or even years) via a surface erosion process in the absence or with minimal amounts of carriers and / or excipients, wherein the system primarily contains the drug and minimizes side effects associated with the use of a carrier or matrix.

[0225] The present disclosure describes prodrug dimers, which can be crystallizable forms and have unique properties so that they can be processed into viscous fluids from melts or solutions, thereby obtaining shaped articles in which most materials are in glassy states. The shaped articles can be kept together by secondary (e.g., non-crystalline) interactions and have the ability to release their prodrug / drug elements from these shaped forms when surface-mediated degradation / dissolution. Due to the unique interactions present in the molecules that are mainly amorphous, the shaped forms remain intact along with surface erosion, which can provide controlled drug release rate in a few days, weeks, months, or years. The present disclosure can change the demand for shape and form provided to the drug delivery reservoir or device by the carrier matrix, so the phase separation of the drug and the matrix and the incompatible problem of processing conditions between the formulation components can be alleviated. In addition, such materials can minimize inflammatory reactions, because the drug / prodrug experienced from the erosion of the shaped article surface can be released in a biological environment in the form of non-granular (e.g., non-crystalline), and when formed by anti-inflammatory steroids, there can be the inherent anti-inflammatory activity of the drug released from the prodrug shaped form.

[0226] The compounds of the present disclosure can be designed to control and sustain the release of steroid drugs from the prodrug dimers used to prepare shaped articles. The release rate of the articles of the present disclosure can be controlled by several transformable design parameters, including: 1) the selection of steroid drugs; 2) the selection of drug functional groups for conjugation (e.g., if there are multiple); 3) the selection of connectors; 4) the selection of linking groups (i.e., esters, carbonic acid, carbonates, or anhydrides); 5) the selection of the surface area of ​​shaped articles; and 6) the selection of drug loading in shaped articles (e.g., when preparing shaped articles, by adding traditional pharmaceutical excipients or mixing other steroid dimers as excipients). The present disclosure can also be applied to the controlled release of two or more steroid drugs by using heterodimers (i.e., different steroid drugs at the two ends of the connector), or by forming shaped articles with two or more steroid homodimers, mixtures of steroid heterodimers, or mixtures of steroid homodimers and steroid heterodimers. Articles formed from the compounds of the present disclosure can produce a sustained and uniform release of the steroid compound without exhibiting any burst release (e.g., 10 Can be equal to or greater than t 50 The high drug loading that can be present in the articles of manufacture of the present invention is suitable for producing locally effective concentrations of steroid drugs over a period of days to weeks to months or even years.

[0227] The present disclosure features compounds of formula (A-VIII) and articles formed from compounds of formula (A-VIII):

[0228] D1-L-D2 (A-VIII)

[0229] or a pharmaceutically acceptable salt thereof, wherein D1 and D2 are each independently a group formed by a steroid; and L is a linker that covalently links D1 to D2. Each of D1 and D2 can be independently selected from an anabolic steroid, an androgenic steroid, a progesterone steroid, an estrogenic steroid, a cancer therapy steroid, an antibiotic steroid, a glucocorticoid steroid, a mild steroid, or a corticosteroid. L can be covalently linked to D1 and D2 via one or more ester, carbonic acid, carbonate, or anhydride bonds. The ester, carbonic acid, carbonate, or anhydride bond formed by the functional groups on D1 and D2 can be selected from, for example, a hydroxyl group or a carboxyl group. For example, L can include the group -C(O)-(R A )-C(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-O-(R A )-O-, where R A is a polyol radical and contains at least one free hydroxyl group, or R ASelected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, 3-10 atom ring system, -(CH2CH2O) q CH2CH2-、-(CH2CH2CH2CH2O) r CH2CH2CH2CH2-or-(CH2CH(CH3)O) s CH2CH(CH3)-, and q, r, and s are integers from 1 to 10 (e.g., 1 to 10, 1 to 5, or 5 to 10). The articles of the present disclosure can be machined, molded, emulsion processed, electrospun, electrosprayed, blown, dry spun, hot spun, melt spun, gel spun, or extruded to form a fiber, a web, a woven fabric, a nonwoven fabric, a pellet, a cylinder, a microparticle (e.g., a microbead), a nanoparticle (e.g., a nanobead), or another shaped article.

[0230] The compound can be further described by formula (A-II):

[0231] D1-OLO-D2 (A-II),

[0232] or a pharmaceutically acceptable salt thereof, wherein D1-O and D2-O are each independently a group formed from a steroid.

[0233] In some embodiments, D1-O and D2-O are each independently described by any one of Formulas (Ia) to (I-sss):

[0234]

[0235] Among them, C1 and C2, C4 and C5, C5 and C6, C9 and C 10 and C 11 with C 12 The bond between them is a single bond or a double bond; R1 represents H, CH3 or HC(O); R2 represents =O, OH or H; or R1 and R2 together with the carbon to which they are attached form an isoxazole; R3 represents H, a halogen atom or OH; R6 represents H or CH3; R 12 Represents H, CH3 or CH3CH2; R 13 Represents CH3 or CH3CH2; R 15 Represents H or OH; R 17 represents H or CH3; and R 18 Indicates H or CH3;

[0236]

[0237] Among them, C1 and C2, C4 and C5, C5 and C6, C9 and C 10 and C 11 with C 12 The bond between them is a single bond or a double bond; R1 represents H, CH3 or HC(O); R3 represents H, a halogen atom or OH; R6 represents H or CH3; R 12 Represents H, CH3 or CH3CH2; R 13 Represents CH3 or CH3CH2; R 15 Represents H or OH; R 17 represents H or CH3; and R 18 Indicates H or CH3;

[0238]

[0239] where R 12 represents H or CH3; and R 17 Indicates H or CH3;

[0240]

[0241] wherein the bonds between C1 and C2, C4 and C5, and C5 and C6 are single or double bonds; C2 is O, C, or CH2; R1 represents H, -CHOH, or is absent; R2 represents =O or OH; or R1 and R2 together with the carbon to which they are attached form a pyrazole; R3 represents H or OH; R 12 represents H, CH3, optionally substituted alkynylene, C 1-6 Alkoxy or CH3CH2; R 15 Represents H or OH; R 16 Represents H or halogen atom; R 17 represents H or CH3; and R 18 Indicates H or CH3;

[0242]

[0243] wherein the bonds between C1 and C2, C4 and C5, and C5 and C6 are single bonds or double bonds; C2 is O, C, or CH2; R1 represents H, -CHOH, or is absent; R3 represents H or OH; R 11 represents H, OH, CH3, optionally substituted alkynylene, CH3CH2, =O, -OC(O)CH2CH3 or is absent; R 12 represents H, OH, CH3, optionally substituted alkynylene, CH3CH2, =O, -OC(O)CH2CH3 or is absent; R 15 Represents H or OH; R 16 Represents H or halogen atom; R 17 represents H or CH3; and R 18Indicates H or CH3;

[0244]

[0245]

[0246] Among them, C1 and C 10 , C2 and C3, C3 and C4, C4 and C5, C5 and C6, C6 and C7, C5 and C 10 , C9 and C 10 、C 11 with C 12 、C 15 with C 16 The bond between is a single bond or a double bond; R2 represents H, =O, OH, -NOH or C 1-6 Alkoxy; R5 represents H, CH3 or a halogen atom; R6 represents H or CH3; or R5 and R6 together with the carbon to which they are attached form a cyclopropane; R 12 represents H, optionally substituted alkynylene, -CH2CH=CH2, CH3, -C(O)CH3 or -CH=CH2; R 13 Represents CH3 or CH2CH3; R 15 represents H or =CH2; and R 17 Indicates H, CH3 or absence;

[0247]

[0248] Among them, C1 and C 10 , C2 and C3, C4 and C5, C6 and C7, C5 and C 10 , C9 and C 10 、C 11 with C 12 、C 15 with C 16 The bond between them is a single bond or a double bond; R5 represents H, CH3 or a halogen atom; R6 represents H or CH3; or R5 and R6 together with the carbon to which they are attached form a cyclopropane; R9 is H; R 10 is H or =CH2; or R9 and R 10 Together with the carbon to which they are attached, they form a cyclopropane; R 11 represents H, OH, an optionally substituted alkynylene group, -C(O)CH3, -CH2CH=CH2, a halogen atom, -CH=CH2, -OC(O)CH3, CH3, -C(O)C(OH)CH3; R 12 represents H, OH, an optionally substituted alkynylene group, -C(O)CH3, -CH2CH=CH2, a halogen atom, -CH=CH2, -OC(O)CH3, CH3, -C(O)C(OH)CH3; or R11 and R 12 Together with the carbon to which they are attached, they form a lactone; R 13 Represents CH3 or CH2CH3; R 15 represents H or =CH2; and R 17 Indicates H, CH3 or absence;

[0249]

[0250] Among them, C1 and C2, C1 and C 10 , C2 and C3, C3 and C4, C4 and C5, C6 and C7, C5 and C 10 , the bonds between C7 and C8 and between C8 and C9 are single bonds or double bonds; R2 represents OH, -OC(O)Ph or C 1-6 Alkoxy; R 10 Represents H or OH; R 12 represents H, optionally substituted alkynylene; and R 15 Indicates H or C 1-6 alkoxy;

[0251]

[0252] Among them, C1 and C2, C1 and C 10 , C2 and C3, C3 and C4, C4 and C5, C6 and C7, C5 and C 10 , the bonds between C7 and C8 and between C8 and C9 are single bonds or double bonds; R 10 Represents H or OH; R 11 represents H, OH, optionally substituted alkynylene, =O or absent; R 12 represents H, OH, optionally substituted alkynylene, =0 or is absent; and R 15 Indicates H or C 1-6 alkoxy;

[0253]

[0254] Where R2 represents OH or C 1-6 Alkoxy; and R 10 Indicates H or CH3;

[0255]

[0256] Among them, C1 and C2, C4 and C5, C5 and C6, C6 and C7 and C 16 with C 17 The bond between them is a single bond or a double bond; C4 is NH, CH or CH2; R1 represents H; R5 represents H or a halogen atom; R 11 represents H, optionally substituted heteroaryl, -C(O)C 1-6Alkyl, -C(O)OC 1-6 alkyl or -C(O)NHR, wherein R is an optionally substituted alkyl or aryl group; R 12 represents H, optionally substituted heteroaryl, -C(O)C 1-6 Alkyl, -C(O)OC 1-6 alkyl or -C(O)NHR, wherein R is optionally substituted alkyl or aryl; and R 18 Indicates H; or R1 and R 18 Together with the carbon to which they are attached, they form cyclopropane;

[0257]

[0258] where R 12 is H or OH;

[0259]

[0260] The bonds between C4 and C5 and between C5 and C6 are single bonds or double bonds; R5 represents H or C 1-6 Alkyl; R6 represents H or OH; R 11 Indicates H, OH, -C(O)C 1-6 alkyl, -C(O)CH2OH or -CH(CH3)CH2CH2C(O)OH; and R 12 Indicates H, OH, -C(O)C 1-6 Alkyl, -C(O)CH2OH or -CH(CH3)CH2CH2C(O)OH;

[0261]

[0262] wherein R5 represents H or CH2CH3; and R 14 Indicates H or OH;

[0263]

[0264] The bond between C1 and C2 is a single bond or a double bond; R1 represents H or a halogen atom; R5 represents H, C 1-6 Alkyl or halogen atom; R6 represents H or halogen atom; R 10 Indicates H, C 1-6 Alkyl, OH or =CH2; R 11 Indicates H, OH, C 1-6 Alkyl, optionally substituted -C(O)C 1-6 Alkyl, -C(O)CH2OC(O)C 1-6 Alkyl, optionally substituted -OC(O)C 1-6Alkyl, -OC(O)Ph, -OC(O)heterocyclyl, -CH2C(O)CH2OH, -C(O)C(O)OH, -C(O)C(O)OC 1-6 Alkyl, -C(O)SCH2F or -OC(O)OC 1-6 Alkyl; or R 10 and R 11 Together with the carbon atoms to which they are attached, they form an optionally substituted cyclic acetal or an optionally substituted heterocyclic group; R 12 Indicates H, OH, C 1-6 Alkyl, optionally substituted -C(O)C 1-6 Alkyl, -C(O)CH2OC(O)C 1-6 Alkyl, optionally substituted -OC(O)C 1-6 Alkyl, -OC(O)Ph, -OC(O)heterocyclyl, -CH2C(O)CH2OH, -C(O)C(O)OH, -C(O)C(O)OC 1-6 Alkyl, -C(O)SCH2F or -OC(O)OC 1-6 Alkyl; or R 10 and R 12 Together with the carbon atoms to which they are attached, they form an optionally substituted cyclic acetal or an optionally substituted heterocyclic group; R 15 represents H, OH, =O or a halogen atom; and R 16 represents H or halogen atom;

[0265]

[0266] The bond between C1 and C2 is a single bond or a double bond; R1 represents H or a halogen atom; R5 represents H, C 1-6 Alkyl or halogen atom; R6 represents H or halogen atom; R 10 Indicates H, C 1-6 Alkyl, OH or =CH2; R 10b Indicates H, C 1-6 Alkyl, OH, =CH2 or not present; R 12 represents H, OH, optionally substituted -C(O)C 1-6 Alkyl, -C(O)CH2OC(O)C 1-6 Alkyl, optionally substituted -OC(O)C 1-6 Alkyl or -OC(O)Ph; or R 10 and R 11 Together with the carbon atoms to which they are attached, they form an optionally substituted cyclic acetal or an optionally substituted heterocyclic group; R 15 represents H, OH, =O or a halogen atom; and R 16 represents H or halogen atom;

[0267]

[0268] wherein the bond between C1 and C2 is a single bond or a double bond; R1 represents H or a halogen atom; R5 represents H, a halogen atom or CH3; R6 represents H, a halogen atom; R 10 Represents H, OH, CH3 or =CH2; R 12 represents an optionally substituted -C(O)C 1-6 Alkyl, -C(O)CH2OC(O)C 1-6 Alkyl or -C(O)SCH2F; R 15 represents OH or =O; and R 16 represents H or halogen atom;

[0269]

[0270] The bond between C1 and C2 is a single bond or a double bond; R1 represents H or a halogen atom; R5 represents H, C 1-6 Alkyl or halogen atom; R6 represents H or halogen atom; R 10 Indicates H, C 1-6 Alkyl, OH or =CH2; R 10b Indicates H, C 1-6 Alkyl, OH or =CH2 or not present; R 11 Indicates H, OH, C 1-6 Alkyl, optionally substituted -C(O)C 1-6 Alkyl, -C(O)CH2OC(O)C 1-6 Alkyl, optionally substituted -OC(O)C 1-6 Alkyl, -OC(O)Ph, -OC(O)heterocyclyl, -CH2C(O)CH2OH, -C(O)C(O)OH, -C(O)C(O)OC 1-6 Alkyl, -C(O)SCH2F or -OC(O)OC 1-6 Alkyl; or R 10 and R 11 Together with the carbon atoms to which they are attached, they form an optionally substituted cyclic acetal or an optionally substituted heterocyclic group; R 12 Indicates H, OH, C 1-6 Alkyl, optionally substituted -C(O)C 1-6 Alkyl, -C(O)CH2OC(O)C 1-6 Alkyl, optionally substituted -OC(O)C 1-6 Alkyl, -OC(O)Ph, -OC(O)heterocyclyl, -CH2C(O)CH2OH, -C(O)C(O)OH, -C(O)C(O)OC 1-6 Alkyl, -C(O)SCH2F or -OC(O)OC 1-6 Alkyl; or R10 and R 12 Together with the carbon atoms to which they are attached, they form an optionally substituted cyclic acetal or an optionally substituted heterocyclic group; and R 16 represents H or halogen atom;

[0271]

[0272] Wherein R5 represents H or a halogen atom; R 15 represents a halogen atom or OH; and R 16 represents H or halogen atom;

[0273]

[0274]

[0275] The bond between C1 and C2 is a double bond or a single bond; R 16 represents H or a halogen atom; R5 represents H, CH3 or a halogen atom; R 12 Represents H or halogen atom; R 15 =O or OH; R 12 and R 10 Each independently represents -H, C 1-10 Alkyl, -OH, -O-acyl, or R 12 and R 10 Combined to form a cyclic acetal of formula (XVIII-a) wherein:

[0276]

[0277] e is an integer from 0 to 6; R 20 、R 21 and R 22 Each independently represents H or C 1-10 Alkyl; and W1 represents H or CH3;

[0278]

[0279]

[0280] The bond between C3 and R2 is a single bond or a double bond; R2 represents OH or =O; R 12 represents -C(=O)CH2OC(=O)CH3, -C(=O)CH2OH or -C(=O)CH3; R 15 Indicates H or OH;

[0281]

[0282] Where C3 and R2 and C 11 With R 15The bond between is a single bond or a double bond; R2 represents OH or =O; R 11 represents H, OH, -C(=O)CH2OH or -C(=O)CH3; R 12 represents H, OH, -C(=O)CH2OH or -C(=O)CH3; R 15 represents H, =O or OH;

[0283]

[0284] Among them, C3 and R2, C7 and R6 and C 12 With R 14 The bond between is a single bond or a double bond; Rx represents OH, -NHCH2C(=O)OH or -NHCH2CH2SO2OH; R2 represents OH or =O; R5 represents H or OH; R6 represents H, =O or OH; R 14 represents H, =O or OH;

[0285]

[0286]

[0287] Where C3 and R2 and C 11 With R 15 The bond between is a single bond or a double bond; R2 represents OH or =O; R 10 Represents H or OH; R 11 represents H, OH, -C(=O)CH2OH, -C(=O)OH, -C(=O)CH2OH or -C(=O)CH3; R 12 represents H, OH, -C(=O)CH2OH, -C(=O)OH, -C(=O)CH2OH or -C(=O)CH3; R 13 Represents -CH2OH or -CH3; R 15 Represents H, OH or =O; R 16 Indicates H or F;

[0288]

[0289]

[0290] Wherein Ry represents H or OH;

[0291]

[0292]

[0293] Where C3 and R2 and C 11 With R 15The bond between is a single bond or a double bond; Rz represents H or -CH3; R1 represents H or -OCH2CH3; R2 represents OH or =O; R 12 represents -OH, -C(=O)CH3, -C(=O)CH2OH or -CH(CH3)(CH2)2CH(OH)CH(CH3)2; R 15 represents H, -N(CH3)2 or =O;

[0294]

[0295] The bond between C3 and R2 is a single bond or a double bond; R2 represents OH or =O; R 11 Represents H, -C(=O)CH3, -OC(=O)(CH2)4CH3 or does not exist; R 12 Represents H, -C(=O)CH3, -OC(=O)(CH2)4CH3 or does not exist; R 17 Indicates CH3 or absence;

[0296]

[0297]

[0298] Where C3 and R2 and C 11 With R 15 The bond between is a single bond or a double bond; Ry represents OH or =O; R2 represents OH or =O; R 11 represents H, OH, -CH(OH)CH3, -C(=O)CH2OH, -C(=O)CH3 or -CH(OH)CH2OH; R 12 represents H, OH, -CH(OH)CH3, -C(=O)CH2OH, -C(=O)CH3 or -CH(OH)CH2OH; R 15 represents H, =O or OH;

[0299]

[0300] Where C3 and R2 and C 16 With R 10 The bond between is a single bond or a double bond; R2 represents OH or =O; R5 represents H, Cl or -CH3; R 10 Represents H or =CH2; R 11 represents H, OH, -CH3, -C(=O)CH3, -C(=O)CH2OC(=O)CH3 or -OC(=O)CH3; R 12 represents H, OH, -CH3, -C(=O)CH3, -C(=O)CH2OC(=O)CH3 or -OC(=O)CH3; R 15Represents H or OH; R 16 Indicates F or H; R 17 Represents H or -CH3.

[0301] In another embodiment, the compound is described by Formula (A-VII):

[0302] D1-C(O)-LC(O)-D2 (A-VII),

[0303] or a pharmaceutically acceptable salt thereof, wherein D1-C(O) and D2-C(O) are each independently a group formed by a steroid; L is -OC(O)-O-(R A )-OC(O)-O-; and R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. Each of D1-C(O) and D2-C(O) can be independently formed by, for example, fusidic acid, cholic acid, chenodeoxycholic acid, ursodeoxycholic acid, or obeticholic acid. In the drug dimer of formula (A-VII), D1-C(O)- and D2-C(O)- can be further described, for example, by the following formulas (I-hh), (I-ii), (I-ttt), (I-uuu), and (I-vvv).

[0304]

[0305] Where R5 represents H or C 1-6 Alkyl, R 14 Indicates H or OH;

[0306]

[0307]

[0308] Among them, C3 and R2, C7 and R6 and C 12 With R 14 The bond between is a single bond or a double bond; R2 represents OH or =O; R5 represents H or OH; R6 represents H, =O or OH; R 14 represents H, =O or OH;

[0309]

[0310] The drug dimer that can be used in the method and composition of the present invention includes homodimer and heterodimer.Steroid, including anabolic steroids, androgenic steroids, progesterone steroids, estrogen steroids, cancer treatment steroids, antibiotic steroids, glucocorticoid steroids, mild steroids, corticosteroids, anti-angiogenic steroids, steroids for reducing intraocular pressure (IOP), bile acid steroids related to bile acid, steroid metabolites, cholesterol derivatives, neurosteroids, pheromones, progesterone or other steroids, can be used in drug dimer.The example of anabolic steroid includes androstene diol, androstenediol, bolasterone, clostebol, ethynol, formylborone, 4-hydroxy-19-nortestosterone, methandrostenol, methinolone, methyltrienolone, nandrolone, norbolone, oxymethyltestosterone, stenbolone and trenbolone. Androgenic steroids are, for example, boldenone, fluoxymesterone, mesandrolone, mesterolone, hydroxymethyltestosterone, 17-methyltestosterone, 17-alpha-methyltestosterone 3-cyclopentyl enol ether, norethandrolone, mesandrolone, oxandrolone, hydroxymethyltestosterone, oxymetholone, prasterone, stanlolone, stanozolol, testosterone, testosterone 17-chloral hemiacetal, testosterone propionate, testosterone enanthate, thiomethyltestosterone, dehydroepiandrosterone (DHEA), androstenedione, androstenediol, androstenone, dihydrotestosterone (DHT), androstanolone and their derivatives. Exemplary progestin steroids are norethindrone, norethindrone acetate, gestodene, levonorgestrel, allylestradiol, anagestrel, desogestrel, demethinone, dydrogesterone, ethinylestradiol, norethindrone, norethindrone diacetate, etonogestrel, gestodene, ethinylestradiol, halogenated progesterone, 17-hydroxy-16-methylene-progesterone, 17α-hydroxyprogesterone, linegestrel, medroxyprogesterone, melengestrol, norethindrone, norgestrel, norgestrel, progesterone, norethindrone, norgestimate, norgestrel, levonorgestrel, norgestrel, norethenone, pentagestrol, MENT (7-methyl-19-testosterone); norgestromin, and drospirenone, tibolone, megestrol acetate, and derivatives thereof. Examples of estrogenic steroids are estrogens, eguilenin, equilin, 17β-estradiol, estradiol benzoate, estriol, ethinylestradiol, mestranol, moxestradiol, amitraz, estriol cyclopentane and ethinylestradiol. Steroids used in cancer treatment are, for example, abiraterone, cyproterone acetate, dutasteride, enzalutamide, finasteride and galeterone. An exemplary antibiotic steroid is fusidic acid.Glucocorticoids include, for example, medrysone, alclometasone, alclometasone dipropionate, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone benzoate, betamethasone valerate, budesonide, ciclesonide, clobetasol, clobetasol butyrate, clobetasol propionate, clobetasone, clocortolone, loprednol, hydrocortisone, cortisone, cortivazole, deflazacort, desonide, desoximetasone, deoxycorticosterone, deoxymethasone, dexamethasone, diflorasone, diflorasone diacetate, diflucortolone, diflucortolone valerate, diflucortolone, difluprednate, fluclosanone, fluclosanone acetonide, flurandrenolide, flumethasone, fludexamethasone, fludexamethasone pivalate, flunisolide , flunisolide, fluocinolone, fluocinolone acetonide, fluocinolone acetate, fluocinolone, fluocinolone butyl, fluocortolone, fluocortsone, fluorometholone, fluperone, fluprednidine, fluprednidine acetate, fluprednisolone, fluticasone, fluticasone propionate, formocortal, halcinonide, halometasone, hydrocortisone, hydrocortisone acetate, hydrocortisone acepro, hydrocortisone bupropionate, hydrocortisone butyrate, loteprednol, methylprednisone, 6a-methylprednisolone, methylprednisolone, methylprednisolone acetate, methylprednisolone acepro, mometasone, mometasone furoate, mometasone furoate monohydrate, paramethasone, prednicarbate, prednisolone, prednisone, prednidine, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, and ubetasol. Exemplary bland steroids are cholesterol, 11-deoxycortisol, 11-deoxycorticosterone, pregnenolone, cholic acid, chenodeoxycholic acid, ursodeoxycholic acid, obeticholic acid, tetrahydrocortisone, tetrahydrodeoxycortisol, tetrahydrocorticosterone, 5α-dihydrocorticosterone and 5α-dihydroprogesterone. Exemplary anti-angiogenic steroids or steroids that lower intraocular pressure (IOP) are anecortave acetate, anecortave, 11-epicotisol, 17α-hydroxyprogesterone, tetrahydrocorticosterone and tetrahydrocortisol. Exemplary bile acid-related bile acid steroids are deoxycholic acid, orthocholic 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 neurosteroids are alfaxalone, alfadolonone, hydroxypregnendione, minaxolone, tetrahydrodeoxycorticosterone, allopregnanolone, pregnanolone, ganoxolone, 3α-androstanediol, pregnanolone, allopregnanolone and 24 (S) -hydroxycholesterol. Exemplary other steroids are flugestrone, prednisolone, chlormadinone acetate, medrogestone and medroxyprogesterone acetate. Exemplary pheromones are androstadienol, androstadienone, androstenol, androstenone, estrenol, 5-dehydroprogesterone, 6-dehydro-progesterone, 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 allopregnanol-3α,20α-diol, allopregnanol-3β,20β-diol, allopregnanol-3β,21-diol-11,20-dione, allopregnanol-3β,17α-diol-20-one, 3,20-allopregnanol-3β,11β,17α,20β,21-pentaol, allopregnanol-3β,17α,20β,21-tetrol, allopregnanol-3α,11β,17α,21-tetrol-20-one, allopregnanol-3β,11β,17α,21-tetrol-20-one, allopregnanol-3β,17α,20β-triol, allopregnanol-3β,17α,20β-triol, and allopregnanol-3β,17α,20β-triol. 7α,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.

[0311] The drug dimers useful in preparing the articles of manufacture of the present disclosure can have any of Formulas (AI)-(LXXV) described herein.

[0312] Steroid homodimers

[0313] The present disclosure features homodimers of formula (I):

[0314] D1-L-D2 (A-VIII)

[0315] or a pharmaceutically acceptable salt thereof, wherein D1 and D2 are groups formed from the same steroid. L may be covalently linked to D1 and D2 via one or more ester, carbonic acid, carbonate or anhydride bonds. The ester, carbonic acid, carbonate or anhydride bonds formed by the functional groups on D1 and D2 may be selected from, for example, hydroxyl or carboxyl groups. For example, L may include the group -C(O)-(R A )-C(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-O-(R A )-O-, where R A is a polyol radical and contains at least one free hydroxyl group, or R ASelected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, 3-10 atom ring system, -(CH2CH2O) q CH2CH2-、-(CH2CH2CH2CH2O) r CH2CH2CH2CH2-or-(CH2CH(CH3)O) s CH2CH(CH3)-, and q, r, and s are integers from 1 to 10 (eg, 1 to 10, 1 to 5, or 5 to 10). The homodimer can be further described by one of the following formulae (II)-(LXXV).

[0316] In some embodiments, the steroid is an anabolic steroid, and the drug dimer is further described by formula (II):

[0317]

[0318] Among them, C1 and C2, C4 and C5, C5 and C6, C9 and C 10 and C 11 with C 12 The bond between them is a single bond or a double bond; R1 represents H, CH3 or HC(O); R2 represents =O, OH or H; or R1 and R2 together with the carbon to which they are attached form an isoxazole; R3 represents H, a halogen atom or OH; R6 represents H or CH3; R 12 Represents H, CH3 or CH3CH2; R 13 Represents CH3 or CH3CH2; R 15 Represents H or OH; R 17 Represents H or CH3; R 18 represents H or CH3; L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A)-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (II) can be formed by an anabolic steroid selected from androstene, androstenediol, bolasterone, clostebol, ethynol, formobolone, 4-hydroxy-19-nortestosterone, methanandrol, methenol, methyltrienolone, nandrolone, norbolone, oxymethyltestosterone, stenbolone and trenbolone.

[0319] In certain embodiments, the steroid is an anabolic steroid, and the drug dimer is further described by formula (III):

[0320]

[0321] Among them, C1 and C2, C4 and C5, C5 and C6, C9 and C 10 and C 11 with C 12 The bond between them is a single bond or a double bond; R1 represents H, CH3 or HC(O); R3 represents H, a halogen atom or OH; R6 represents H or CH3; R 12 Represents H, CH3 or CH3CH2; R 13 Represents CH3 or CH3CH2; R 15 Represents H or OH; R 17 Represents H or CH3; R 18 represents H or CH3; L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (III) can be formed by an anabolic steroid selected from androstene, androstenediol, bolasterone, clostebol, formylbolone, 4-hydroxy-19-nortestosterone, methanandrol, methenolone, methyltrienolone, nandrolone, norbolone, oxymethyltestosterone, stenbolone and trenbolone.

[0322] In certain embodiments, the steroid is an anabolic steroid and the drug dimer is further described by formula (IV):

[0323]

[0324] where R 12 Represents H or CH3; R 17 represents H or CH3; L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (IV) may be formed with an anabolic steroid selected from 4-hydroxy-19-nortestosterone or hydroxymethyltestosterone.

[0325] In certain embodiments, the steroid is an androgenic steroid, and the drug dimer is further described by Formula (V):

[0326]

[0327] wherein the bonds between C1 and C2, C4 and C5, and C5 and C6 are single or double bonds; C2 is O, C, or CH2; R1 represents H, -CHOH, or is absent; R2 represents =O or OH; or R1 and R2, together with the carbons to which they are attached, form a pyrazole; R3 represents H or OH; R 12 represents H, CH3, optionally substituted alkynylene, C 1-6 Alkoxy or CH3CH2; R 15 Represents H or OH; R 16 Represents H or halogen atom; R 17 Represents H or CH3; R 18 represents H or CH3; L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (V) can be formed by an androgenic steroid selected from the group consisting of boldenone, fluoxymesterone, mesandrolone, mesterolone, hydroxymethyltestosterone, 17-methyltestosterone, 17-α-methyltestosterone 3-cyclopentyl enol ether, norethandrolone, methylphenidate, oxandrolone, hydroxymethyltestosterone, oxymetholone, prasterone, stanlolone, stanozolol, testosterone, testosterone enanthate, thiomethyltestosterone, dehydroepiandrosterone (DHEA), androstenedione, androstenediol, androstenone and dihydrotestosterone (DHT).

[0328] In certain embodiments, the steroid is an androgenic steroid, and the drug dimer is further described by Formula (VI):

[0329]

[0330] wherein the bonds between C1 and C2, C4 and C5, and C5 and C6 are single bonds or double bonds; C2 is O, C, or CH2; R1 represents H, -CHOH, or is absent; R3 represents H or OH; R 11 represents H, OH, CH3, optionally substituted alkynylene, CH3CH2, =O, -OC(O)CH2CH3 or is absent; R 12 represents H, OH, CH3, optionally substituted alkynylene, CH3CH2, =O, -OC(O)CH2CH3 or is absent; R 15 Represents H or OH; R 16 Represents H or halogen atom; R 17 Represents H or CH3; R 18 represents H or CH3; L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(RA )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (VI) can be formed by an androgenic steroid selected from the group consisting of boldenone, fluoxymesterone, mesandrolone, mesterolone, hydroxymethyltestosterone, 17-methyltestosterone, norethandrolone, methylphenidate, oxandrolone, hydroxymethyltestosterone, oxymetholone, prasterone, stanlolone, testosterone, testosterone propionate, testosterone enanthate, thiomethyltestosterone, dehydroepiandrosterone (DHEA), androstenedione, androstenediol, androstenone and dihydrotestosterone (DHT).

[0331] In certain embodiments, the steroid is an androgenic steroid, and the drug dimer is further described by Formula (VII):

[0332]

[0333] Where L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;RA Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. Dimers of the drug of formula (VII) can be formed with the androgenic steroid fluoxymesterone.

[0334] In certain embodiments, the steroid is an androgenic steroid, and the drug dimer is further described by Formula (VIII):

[0335]

[0336] Where L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) nCH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, 3 to 10 atom ring system. Dimers of the drug of formula (VIII) can be formed with the androgenic steroid hydroxymethyltestosterone.

[0337] In some embodiments, the steroid is an androgenic steroid, and the drug dimer is further described by Formula (IX):

[0338]

[0339] Where L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10Arylene, ring system of 3 to 10 atoms. Dimers of the drug of formula (IX) can be formed with the androgenic steroid oxymetholone.

[0340] In certain embodiments, the steroid is a progesterone steroid, and the drug dimer is further described by formula (X):

[0341]

[0342] Among them, C1 and C 10 , C2 and C3, C3 and C4, C4 and C5, C5 and C6, C6 and C7, C5 and C 10 , C9 and C 10 、C 11 with C 12 、C 15 with C 16 The bond between is a single bond or a double bond; R2 represents H, =O, OH, -NOH or C 1-6 Alkoxy; R5 represents H, CH3 or a halogen atom; R6 represents H or CH3; or R5 and R6 together with the carbon to which they are attached form a cyclopropane; R9 is H; R 10 is H or =CH2; or R9 and R 10 Together with the carbon to which they are attached, they form a cyclopropane; R 12 represents H, optionally substituted alkynylene, -CH2CH=CH2, CH3, -C(O)CH3 or -CH=CH2; R 13 Represents CH3 or CH2CH3; R 15 Represents H or =CH2; R 17 Indicates H, CH3 or does not exist; L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) nCH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (X) can be formed by a progestogen steroid selected from the group consisting of norethindrone, norethindrone acetate, gestodene, levonorgestrel, allylestradiol, anagestrel, desogestrel, demethinone, dydrogesterone, ethinylestradiol, norethindrone, etonogestrel, gestodene, ethinylestradiol, 17-hydroxy-16-methylene-progesterone, 17α-hydroxyprogesterone, linegestrel, medroxyprogesterone, melengestrol, norethindrone, norethindrone, norgestrel, progesterone, norethindrone, norgestrel, levonorgestrel, norgestrel, pentagestrol, 7-methyl-19-testosterone (MENT), norelgestromin, tibolone and megestrol.

[0343] In certain embodiments, the steroid is a progesterone steroid, and the drug dimer is further described by Formula (XI):

[0344]

[0345] Among them, C1 and C 10 , C2 and C3, C4 and C5, C6 and C7, C5 and C 10 , C9 and C 10 、C 11 with C 12 、C 15 with C 16 The bond between them is a single bond or a double bond; R5 represents H, CH3 or a halogen atom; R6 represents H or CH3; or R5 and R6 together with the carbon to which they are attached form a cyclopropane; R9 is H; R 10 is H or =CH2; or R9 and R 10 Together with the carbon to which they are attached, they form a cyclopropane; R 11 represents H, OH, an optionally substituted alkynylene group, -C(O)CH3, -CH2CH=CH2, a halogen atom, -CH=CH2, -OC(O)CH3, CH3, -C(O)C(OH)CH3; R 12represents H, OH, an optionally substituted alkynylene group, -C(O)CH3, -CH2CH=CH2, a halogen atom, -CH=CH2, -OC(O)CH3, CH3, -C(O)C(OH)CH3; or R 11 and R 12 Together with the carbon to which they are attached, they form a lactone; R 13 Represents CH3 or CH2CH3; R 15 Represents H or =CH2; R 17 Indicates H, CH3 or does not exist; L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (XI) can be formed by a progestogen steroid selected from the group consisting of norethindrone, norethindrone acetate, gestodene, levonorgestrel, demethinone, dydrogesterone, ethinylestradiol, etonogestrel, gestodene, ethinylestradiol, halogenated progesterone, 17-hydroxy-16-methylene-progesterone, 17α-hydroxyprogesterone, medroxyprogesterone, melengestrol, norethindrone, norethindrone, norgestrel, progesterone, norethindrone, norgestrel, norgestrel, levonorgestrel, norgestrel, 7-methyl-19-testosterone (MENT), norgestromin, trometholone, drospirenone, tibolone and megestrol.

[0346] In some embodiments, the steroid is a progesterone steroid, and the drug dimer is further described by formula (XII):

[0347]

[0348] Where L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, ring system of 3 to 10 atoms. Dimers of the drug of formula (XII) can be formed with the progesterone steroid trimethoate.

[0349] In certain embodiments, the steroid is an estrogenic steroid, and the drug dimer is further described by formula (XIII):

[0350]

[0351] Among them, C1 and C2, C1 and C 10 , C2 and C3, C3 and C4, C4 and C5, C6 and C7, C5 and C 10 , the bonds between C7 and C8 and between C8 and C9 are single bonds or double bonds; R2 represents OH, -OC(O)Ph or C 1-6 Alkoxy; R 10 Represents H or OH; R 12 represents H, optionally substituted alkynylene; R 15 Indicates H or C 1-6 Alkoxy; L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (XIII) can be formed by an estrogen steroid selected from estrogen, eguilenin, equilin, 17β-estradiol, estradiol benzoate, estriol, ethinylestradiol, mestranol, moxestradiol, dimethyl estriol, estriol cyclopentane and ethinylestradiol.

[0352] In some embodiments, the steroid is an estrogenic steroid, and the drug dimer is further described by Formula (XIV):

[0353]

[0354] Among them, C1 and C2, C1 and C 10 , C2 and C3, C3 and C4, C4 and C5, C6 and C7, C5 and C 10 , the bonds between C7 and C8 and between C8 and C9 are single bonds or double bonds; R 10 Represents H or OH; R 11 represents H, OH, optionally substituted alkynylene, =O or absent; R 12 represents H, OH, optionally substituted alkynylene, =O or absent; R 15 Indicates H or C 1-6 Alkoxy; L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (XIV) may be formed with an estrogen steroid selected from the group consisting of estrogen, eguilenin, equilin, 17β-estradiol, estriol, ethinylestradiol, and moxestradiol.

[0355] In some embodiments, the steroid is an estrogenic steroid, and the drug dimer is further described by Formula (XV):

[0356]

[0357] Where R2 represents OH or C 1-6 Alkoxy; R 10 represents H or CH3; L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (XV) can be formed with an estrogenic steroid selected from estriol, dimethyl estriol and estriol cyclopentyl ether.

[0358] In certain embodiments, the steroid is a cancer treatment steroid, and the drug dimer is further described by Formula (XVI):

[0359]

[0360] Among them, C1 and C2, C4 and C5, C5 and C6, C6 and C7 and C 16 with C 17 The bond between them is a single bond or a double bond; C4 is NH, CH or CH2; R1 represents H; R5 represents H or a halogen atom; R 11 represents H, optionally substituted heteroaryl, -C(O)C 1-6 Alkyl, -C(O)OC 1-6 alkyl or -C(O)NHR, wherein R is an optionally substituted alkyl or aryl group; R 12 represents H, optionally substituted heteroaryl, -C(O)C 1-6 Alkyl, -C(O)OC 1-6 alkyl or -C(O)NHR, wherein R is an optionally substituted alkyl or aryl group; R 18 Indicates H; or R1 and R 18 Together with the carbon to which they are attached, they form a cyclopropane; L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) pCH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (XVI) can be formed with a cancer treatment steroid selected from abiraterone, cyproterone acetate, dutasteride, finasteride and galeterone.

[0361] In some embodiments, the steroid is an antibiotic steroid, and the drug dimer is further described by Formula (XVII):

[0362]

[0363] Where L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. Drug dimers of formula (XVII) can be formed with the steroid antibiotic fusidic acid.

[0364] In certain embodiments, the steroid is an antibiotic steroid, and the drug dimer is further described by formula (XVIII):

[0365]

[0366] Where L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. Drug dimers of formula (XVIII) can be formed with the steroid antibiotic fusidic acid.

[0367] In some embodiments, the steroid is a bland steroid, and the drug dimer is further described by Formula (XIX):

[0368]

[0369] where R 12 is H or OH; L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A)-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (XIX) may be formed with a bland steroid selected from 11-deoxycortisol and 11-deoxycorticosterone.

[0370] In certain embodiments, the steroid is a bland steroid, and the drug dimer is further described by formula (XX):

[0371]

[0372] The bonds between C4 and C5 and between C5 and C6 are single bonds or double bonds; R5 represents H or C 1-6 Alkyl; R6 represents H or OH; R 11 Indicates H, OH, -C(O)C 1-6 Alkyl, -C(O)CH2OH or -CH(CH3)CH2CH2C(O)OH; R 12 Indicates H, OH, -C(O)C 1-6 Alkyl, -C(O)CH2OH or -CH(CH3)CH2CH2C(O)OH; L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A)-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (XX) can be formed with a bland steroid selected from cholesterol, 11-deoxycortisol, 11-deoxycorticosterone, pregnenolone, cholic acid, chenodeoxycholic acid, ursodeoxycholic acid and obeticholic acid.

[0373] In some embodiments, the steroid is a bland steroid, and the drug dimer is further described by formula (XXI):

[0374]

[0375] Where L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, 3 to 10 atom ring system. Drug dimers of formula (XXI) can be formed with bland steroids including 11-deoxycortisol.

[0376] In certain embodiments, the steroid is a bland steroid and the drug dimer is further described by formula (XXII):

[0377]

[0378] Wherein R5 represents H or CH2CH3; R 14 represents H or OH; L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) mCH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (XXII) can be formed with a bland steroid selected from cholic acid, chenodeoxycholic acid, ursodeoxycholic acid and obeticholic acid.

[0379] In some embodiments, the steroid is a bland steroid, and the drug dimer is further described by formula (XXIII):

[0380]

[0381] Where L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10Arylene, 3 to 10 atom ring system. Drug dimers of formula (XXIII) can be formed with mild steroid bile acids.

[0382] In certain embodiments, the steroid is a glucocorticoid steroid, and the drug dimer is further described by formula (XXIV):

[0383]

[0384] The bond between C1 and C2 is a single bond or a double bond; R1 represents H or a halogen atom; R5 represents H, C 1-6 Alkyl or halogen atom; R6 represents H or halogen atom; R 10 Indicates H, C 1-6 Alkyl, OH or =CH2; R 11 Indicates H, OH, C 1-6 Alkyl, optionally substituted -C(O)C 1-6 Alkyl, -C(O)CH2OC(O)C 1-6 Alkyl, optionally substituted -OC(O)C 1-6 Alkyl, -OC(O)Ph, -OC(O)heterocyclyl, -CH2C(O)CH2OH, -C(O)C(O)OH, -C(O)C(O)OC 1-6 Alkyl, -C(O)SCH2F or -OC(O)OC 1-6 Alkyl; or R 10 and R 11 Together with the carbon atoms to which they are attached, they form an optionally substituted cyclic acetal or an optionally substituted heterocyclic group; R 12 Indicates H, OH, C 1-6 Alkyl, optionally substituted -C(O)C 1-6 Alkyl, -C(O)CH2OC(O)C 1-6 Alkyl, optionally substituted -OC(O)C 1-6 Alkyl, -OC(O)Ph, -OC(O)heterocyclyl, -CH2C(O)CH2OH, -C(O)C(O)OH, -C(O)C(O)OC 1-6 Alkyl, -C(O)SCH2F or -OC(O)OC 1-6 Alkyl; or R 10 and R 12 Together with the carbon atoms to which they are attached, they form an optionally substituted cyclic acetal or an optionally substituted heterocyclic group; R 15 represents H, OH, =O or a halogen atom; R 16 represents H or a halogen atom; L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A)-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (XXIV) can be selected from medrysone, alclomethasone, alclomethasone dipropionate, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone benzoate, betamethasone valerate, budesonide, ciclesonide, clobetasol, clobetasol butyrate, clobetasol propionate, clobetasone, clocortolone, hydrocortisone, cortisone, deflazacort, desonide, desoximetasone, deoxycorticosterone, deoxymethasone, dexamethasone, diflorasone, diflorasone diacetate, diflucortolone, diflucortolone valerate, diflucortolone, difluprednate, fluclosanone, fluclosanone acetonide, flurandrenolide, flumethasone, fludexamethasone, fludexamethasone pivalate, flunisolide, flunisolide, flu Fluocinolone, fluocinolone acetate, fluocinolone, fluocinolone butyl, fluocortolone, fluocortsone, fluorometholone, fluperone, fluprednidine, fluprednidine acetate, fluprednisolone, fluticasone, fluticasone propionate, halcinonide, halometasone, hydrocortisone, hydrocortisone acetate, hydrocortisone acepro, hydrocortisone bupropionate, hydrocortisone butyrate, loteprednol, methylprednisone, 6a-methylprednisolone, methylprednisolone, methylprednisolone acetate, methylprednisolone acepro, mometasone, mometasone furoate, mometasone furoate monohydrate, paramethasone, prednicarbate, prednisolone, prednisone, prednidine, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, and ubetasol form a glucocorticoid steroid.

[0385] In some embodiments, the steroid is a glucocorticoid steroid, and the drug dimer is further described by Formula (XXV):

[0386]

[0387] The bond between C1 and C2 is a single bond or a double bond; R1 represents H or a halogen atom; R5 represents H, C 1-6 Alkyl or halogen atom; R6 represents H or halogen atom; R 10 Indicates H, C 1-6 Alkyl, OH or =CH2; R 10b Indicates H, C 1-6 Alkyl, OH, =CH2 or not present; R 12 represents H, OH, optionally substituted -C(O)C 1-6 Alkyl, -C(O)CH2OC(O)C 1-6 Alkyl, optionally substituted -OC(O)C 1-6 Alkyl or -OC(O)Ph; or R 10 and R 11 Together with the carbon atoms to which they are attached, they form an optionally substituted cyclic acetal or an optionally substituted heterocyclic group; R 15 represents H, OH, =O or a halogen atom; R 16represents H or a halogen atom; L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, ring systems of 3 to 10 atoms. The drug dimer of formula (XXV) can be formed by a glucocorticoid steroid selected from alclomethasone, beclomethasone, betamethasone, betamethasone benzoate, betamethasone valerate, budesonide, hydrocortisone, cortisone, desonide, desoximetasone, deoxycorticosterone, deoxymethasone, dexamethasone, diflorasone, diflucortolone, diflucorticosterone, fluclosanolide, fluclosanide, flurandrenolide, flumethasone, fludexamethasone, flunisolide, flunisolide, fluocinolone, fluocinolone, fluocinolone, fluocinolone, fluocinolone, fluocinolone, fluocinolone, fluocinolone, fluocinolone, fluocinolone, fluocinolone, fluocinolone, fluocinolone, fluocinolone, fluocinolone, fluocinolone, fluocinolone, fluocinolone, fluprednidone, fluprednisolone, halometasone, hydrocortisone, hydrocortisone butyrate, methylprednisone, 6a-methylprednisolone, methylprednisolone, paramethasone, prednisolone, prednisone, prednidine, triamcinolone and triamcinolone acetonide.

[0388] In certain embodiments, the steroid is a glucocorticoid steroid, and the drug dimer is further described by Formula (XXVI):

[0389]

[0390] Where L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, 3 to 10 atom ring system. Dimers of the drug of formula (XXVI) can be formed with the glucocorticoid steroid fluclosanone.

[0391] In some embodiments, the steroid is a glucocorticoid steroid, and the drug dimer is further described by Formula (XXVII):

[0392]

[0393] wherein the bond between C1 and C2 is a single bond or a double bond; R1 represents H or a halogen atom; R5 represents H, a halogen atom or CH3; R6 represents H, a halogen atom; R 10 Represents H, OH, CH3 or =CH2; R 12 represents an optionally substituted -C(O)C 1-6 Alkyl, -C(O)CH2OC(O)C 1-6 Alkyl or -C(O)SCH2F; R 15 Indicates OH or =O; R 16represents H or a halogen atom; L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (XXVII) can be formed by a glucocorticoid steroid selected from the group consisting of alclomethasone, beclomethasone, betamethasone, clobetasol, clobetasone, hydrocortisone, cortisone, dexamethasone, diflorasone, fluclosanol, flumethasone, fludexamethasone, fludexamethasone pivalate, fluocinolone, fluocortolone, fluorometholone, fluperone, fluprednidene, fluprednidene acetate, fluprednisolone, fluticasone, halometasone, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, methylprednisone, 6a-methylprednisolone, methylprednisolone, methylprednisolone acetate, mometasone, paramethasone, prednisolone, prednisone, prednidine, tixocortolone, triamcinolone and ubetasol.

[0394] In certain embodiments, the steroid is a glucocorticoid steroid, and the drug dimer is further described by formula (XXVIII):

[0395]

[0396] Where L is -C(O)O-(RA )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, 3 to 10 atom ring system. Drug dimers of formula (XXVIII) can be formed with the glucocorticoid steroid cortivazole.

[0397] In some embodiments, the steroid is a glucocorticoid steroid, and the drug dimer is further described by formula (XXIX):

[0398]

[0399] The bond between C1 and C2 is a single bond or a double bond; R1 represents H or a halogen atom; R5 represents H, C 1-6 Alkyl or halogen atom; R6 represents H or halogen atom; R 10 Indicates H, C 1-6 Alkyl, OH or =CH2; R 10b Indicates H, C 1-6 Alkyl, OH or =CH2 or not present; R 11 Indicates H, OH, C 1-6 Alkyl, optionally substituted -C(O)C 1-6Alkyl, -C(O)CH2OC(O)C 1-6 Alkyl, optionally substituted -OC(O)C 1-6 Alkyl, -OC(O)Ph, -OC(O)heterocyclyl, -CH2C(O)CH2OH, -C(O)C(O)OH, -C(O)C(O)OC 1-6 Alkyl, -C(O)SCH2F or -OC(O)OC 1-6 Alkyl; or R 10 and R 11 Together with the carbon atoms to which they are attached, they form an optionally substituted cyclic acetal or an optionally substituted heterocyclic group; R 12 Indicates H, OH, C 1-6 Alkyl, optionally substituted -C(O)C 1-6 Alkyl, -C(O)CH2OC(O)C 1-6 Alkyl, optionally substituted -OC(O)C 1-6 Alkyl, -OC(O)Ph, -OC(O)heterocyclyl, -CH2C(O)CH2OH, -C(O)C(O)OH, -C(O)C(O)OC 1-6 Alkyl, -C(O)SCH2F or -OC(O)OC 1-6 Alkyl; or R 10 and R 12 Together with the carbon atoms to which they are attached, they form an optionally substituted cyclic acetal or an optionally substituted heterocyclic group; R 16 represents H or a halogen atom; L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O, -O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) pCH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (XXIX) can be selected from medrysone, alclomethasone, alclomethasone dipropionate, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone benzoate, betamethasone valerate, budesonide, ciclesonide, clobetasol, clobetasol butyrate, clobetasol propionate, clobetasone, clocortolone, hydrocortisone, cortisone, cortivazole, deflazacort, desonide, desoximetasone, desoximetasone, dexamethasone, diflorasone, diflorasone diacetate, diflucortolone, diflucortolone valerate, diflucortolone, difluprednate, flurandrenolide, flumethasone, fludexamethasone, fludexamethasone pivalate, flunisolide, flunisolide, fluocinolone, fluocinolone acetonide, Fluocinolone acetonide, fluocortidine, fluocortidine butyl, fluocortolone, fluocortsone, fluorometholone, fluperone, fluprednidine, fluprednidine acetate, fluprednisolone, fluticasone, fluticasone propionate, formocorttal, halcinonide, halometasone, hydrocortisone, hydrocortisone acetate, hydrocortisone acepro, hydrocortisone bupropionate, hydrocortisone butyrate, loteprednol, methylprednisone, 6a-methylprednisolone, methylprednisolone, methylprednisolone acetate, methylprednisolone acepro, mometasone, mometasone furoate, mometasone furoate monohydrate, paramethasone, prednicarbate, prednisolone, prednisone, prednidine, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, and ubetasol form the glucocorticoid steroid.

[0400] In certain embodiments, the steroid is a glucocorticoid steroid, and the drug dimer is further described by formula (XXX):

[0401]

[0402] Where L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O)nCH2CH2O-, -O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, 3 to 10 atom ring system. Drug dimers of formula (XXX) can be formed with the glucocorticoid steroid cortivazole.

[0403] In some embodiments, the steroid is a glucocorticoid steroid, and the drug dimer is further described by Formula (XXXI):

[0404]

[0405] Wherein R5 represents H or a halogen atom; R 15 Represents a halogen atom or OH; R 16 represents H or a halogen atom; L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) mCH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (XXXI) may be formed with a glucocorticoid steroid selected from fluclosanone, fluocinolone acetonide and triamcinolone.

[0406] In certain embodiments, the steroid is a glucocorticoid, and the drug dimer is further described by formula (XXXII):

[0407]

[0408] Where L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10Arylene, a ring system of 3 to 10 atoms. Dimers of the drug of formula (XXXII) can be formed with fluperone.

[0409] In some embodiments, the steroid is a glucocorticoid steroid, and the drug dimer is further described by formula (XXXIII):

[0410]

[0411] Where L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. Dimers of the drug of formula (XXXIII) can be formed with formocort.

[0412] In certain embodiments, the steroid is a corticosteroid, and the drug dimer is further described by Formula (XXXIV):

[0413]

[0414] The bond between C1 and C2 is a double bond or a single bond; R 16represents H or a halogen atom; R5 represents H, CH3 or a halogen atom; R 12 Represents H or halogen atom; R 15 =O or OH; R 12 and R 10 Each independently represents -H, C 1-10 Alkyl, -OH, -O-acyl, or R 12 and R 10 Combined to form a cyclic acetal of formula (XVIII-a) wherein:

[0415]

[0416] e is an integer from 0 to 6; R 20 、R 21 and R 22 Each independently represents H or C 1-10 Alkyl; W1 represents H or CH3; L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (XXXIV) can be formed by a corticosteroid selected from the group consisting of alclomethasone, beclomethasone, betamethasone, betamethasone valerate, budesonide, cloprednisone, cloprednol, corticosterone, cortisone, desonide, desoximerasone, dexamethasone, diflorasone, diflucortolone, glycyrrhetinic acid, fluclosonide, flumethasone, flunisolide, fluocinolone acetonide, flucortolone, fluprednisolone, flurandrenolide, halometasone, hydrocortisone, hydrocortisone butyrate, methylprednisone, methylprednisolone, paramethasone, prednisolone, prednisone, prednisolone valerate, prednididine, triamcinolone and triamcinolone acetonide.

[0417] In any of the above formulae (II)-(XXXIV), O-(R A )-O may be a group of a polyol formed from a cyclic alcohol, a sugar alcohol or glycerol; or O-(R A )-O can be an alkanediol (e.g., C 1-10 The group formed by alkanediol), diethylene glycol, triethylene glycol, tetraethylene glycol or pentaethylene glycol.

[0418] In certain embodiments, the steroid is a corticosteroid, and the drug dimer is further described by Formula (XXXV):

[0419]

[0420] Where L is -C(O)-(R A )-C(O)-、-(R A )-or-C(O)-O-(R A )-OC(O)-andR A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms; or L is -O-(R A )-O- and R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from -O(CH2CH2O) nCH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O and -O(CH2CH(CH3)O) p CH2CH(CH3)O-; and n, m and p are integers from 1 to 10. The drug dimer of formula (XXXV) can be formed from fusidic acid.

[0421] In certain embodiments, the steroid is a corticosteroid, and the drug dimer is further described by Formula (XXXVI):

[0422]

[0423] Where R5 represents H or C 1-6 Alkyl; R 14 represents H or OH; and L is -C(O)-(R A )-C(O)-、-(R A )-or-C(O)-O-(R A )-OC(O)-andR A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms; or L is -O-(R A )-O- and R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-and-O(CH2CH(CH3)O) p CH2CH(CH3)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.

[0424] In certain embodiments, the steroid is an anti-angiogenic steroid or an intraocular pressure (IOP) lowering steroid, and the drug dimer is further described by formula (XXXVII):

[0425]

[0426] where R 12 represents -C(=O)CH2OC(=O)CH3, -C(=O)CH2OH or -C(=O)CH3; R 15 represents H or OH; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. Drug dimers of formula (XXXVII) can be formed from anecortave acetate, anecortave, 11-epicocortisol, 17α-hydroxyprogesterone, tetrahydrocortisol, and tetrahydrocortisol.

[0427] In certain embodiments, the steroid is an anti-angiogenic steroid or an intraocular pressure (IOP) lowering steroid, and the drug dimer is further described by formula (XXXVIII):

[0428]

[0429] The bond between C3 and R2 is a single bond or a double bond; R2 represents OH or =O; R 12 represents -C(=O)CH2OC(=O)CH3, -C(=O)CH2OH or -C(=O)CH3, R 15 represents H or OH; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. Drug dimers of formula (XXXVIII) can be formed from anecortave acetate, anecortave, 11-epicocortisol, 17α-hydroxyprogesterone, tetrahydrocortisol, and tetrahydrocortisol.

[0430] In certain embodiments, the steroid is an anti-angiogenic steroid or an intraocular pressure (IOP) lowering steroid, and the drug dimer is further described by formula (XXXIX):

[0431]

[0432] The bond between C3 and R2 is a single bond or a double bond; R2 represents OH or =O; R15 represents H or OH; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, 3 to 10 atom ring system. Drug dimers of formula (XXXIX) can be formed from anecortave, 11-epicocortisol, tetrahydrocortisol, and tetrahydrocortisol.

[0433] In certain embodiments, the steroid is an anti-angiogenic steroid or an intraocular pressure (IOP) lowering steroid, and the drug dimer is further described by formula (XL):

[0434]

[0435] wherein the bond between C3 and R2 is a single bond or a double bond; R2 represents OH or =O; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B)-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, 3 to 10 atom ring system. Dimers of the drug of formula (XL) can be formed with 11-epicocortisol or tetrahydrocortisol.

[0436] In certain embodiments, the steroid is a bland steroid, and the drug dimer is further described by Formula (XLI):

[0437]

[0438] Among them C 11 With R 15 The bond between is a single bond or a double bond; R 11 represents H, OH, -C(=O)CH2OH or -C(=O)CH3; R 12 represents H, OH, -C(=O)CH2OH or -C(=O)CH3; R 15 represents H, =O or OH; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, 3 to 10 atom ring system. Dimers of the drug of formula (XLI) can be formed from tetrahydrocortisone, tetrahydrodeoxycortisol, tetrahydrocorticosterone, 5α-dihydrocorticosterone and 5α-dihydroprogesterone.

[0439] In certain embodiments, the steroid is a bland steroid and the drug dimer is further described by Formula (XLII):

[0440]

[0441] Among them C 11 With R 15 The bond between is a single bond or a double bond; R 15 represents H or =O; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A)-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. Drug dimers of formula (XLII) can be formed from tetrahydrocortisone or tetrahydrodeoxycortisol.

[0442] In certain embodiments, the steroid is a bland steroid and the drug dimer is further described by Formula (XLIII):

[0443]

[0444] Where C3 and R2 and C 11 With R 15 The bond between is a single bond or a double bond; R2 represents OH or =O; R 11 Represents H or OH; R 15 represents H, =O or OH; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) pCH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, 3 to 10 atom ring system. The drug dimer of formula (XLIII) can be formed from tetrahydrocortisone, tetrahydrodeoxycortisol, tetrahydrocorticosterone or 5α-dihydrocorticosterone.

[0445] In certain embodiments, the steroid is a bland steroid and the drug dimer is further described by Formula (XLIV):

[0446]

[0447] The bond between C3 and R2 is a single bond or a double bond; R2 represents OH or =O; R 11 represents H or OH; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10Arylene, 3 to 10 atom ring system. Drug dimers of formula (XLIV) can be formed from tetrahydrocortisone, tetrahydrocorticosterone, or 5α-dihydrocorticosterone.

[0448] In certain embodiments, the steroid is a bile acid-related bile acid steroid, and the drug dimer is further described by Formula (XLV):

[0449]

[0450] Among them, C7, R6 and C 12 With R 14 The bond between is a single bond or a double bond; Rx represents OH, -NHCH2C(=O)OH or -NHCH2CH2SO2OH; R2 represents OH or =O; R5 represents H or OH; R6 represents H, =O or OH; R 14 represents H, =O or OH; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-, -O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (XLV) can be formed with deoxycholic acid, orthocholic 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.

[0451] In certain embodiments, the steroid is a bile acid-related bile acid steroid, and the drug dimer is further described by Formula (XLVI):

[0452]

[0453] wherein the bonds between C3 and R2 and between C7 and R6 are single bonds or double bonds; Rx represents OH, -NHCH2C(=O)OH or -NHCH2CH2SO2OH; R2 represents OH or =O; R6 represents H, =O or OH; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10Arylene, a ring system of 3 to 10 atoms. Dimers of the drug of formula (XLVI) can be formed from deoxycholic acid, orthocholic acid, dehydrocholic acid, glycocholic acid, glycodeoxycholic acid, taurocholic acid, or taurodeoxycholic acid.

[0454] In certain embodiments, the steroid is a bile acid-related bile acid steroid, and the drug dimer is further described by Formula (XLVII):

[0455]

[0456] wherein R6 represents H or OH; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-, -O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (XLVII) can be formed from hyodeoxycholic acid, α-muricholic acid, β-muricholic acid, γ-muricholic acid, or ω-muricholic acid.

[0457] In certain embodiments, the steroid is a bile acid-related bile acid steroid, and the drug dimer is further described by Formula (XLVIII):

[0458]

[0459] Where C3 and R2 and C 12 With R 14 The bond between is a single bond or a double bond; Rx represents OH, -NHCH2C(=O)OH or -NHCH2CH2SO2OH; R2 represents OH or =O; R5 represents H or OH; R 14 represents H, =O or OH; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (XLVIII) can be formed with 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.

[0460] In certain embodiments, the steroid is a bile acid-related bile acid steroid, and the drug dimer is further described by Formula (XLIX):

[0461]

[0462] Among them, C3 and R2, C7 and R6 and C 12 With R 14 The bond between is a single bond or a double bond; R2 represents OH or =O; R5 represents H or OH; R6 represents H, =O or OH; R 14 represents H, =O or OH; and L is -C(O)-(R A )-C(O)-、-(R A )-or-C(O)-O-(R A )-OC(O)-andR A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms; or L is -O-(R A )-O- and R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-and-O(CH2CH(CH3)O) p CH2CH(CH3)O-; and n, m, and p are integers from 1 to 10. The drug dimer of formula (XLIX) can be formed from deoxycholic acid, orthocholic acid, dehydrocholic acid, hyodeoxycholic acid, lithocholic acid, α-muricholic acid, β-muricholic acid, γ-muricholic acid, or ω-muricholic acid.

[0463] In certain embodiments, the steroid is a bile acid-related bile acid steroid, and the drug dimer is further described by formula (L):

[0464]

[0465] Wherein R6 represents H or OH; R 14 represents H or OH; and L is -C(O)-(R A)-C(O)-、-(R A )-or-C(O)-O-(R A )-OC(O)-andR A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms; or L is -O-(R A )-O- and R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-and-O(CH2CH(CH3)O) p CH2CH(CH3)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.

[0466] In certain embodiments, the steroid is a steroid metabolite, and the drug dimer is further described by Formula (LI):

[0467]

[0468] Among them C 11 With R 15 The bond between is a single bond or a double bond; R2 represents OH or =O; R 10 Represents H or OH; R 11 represents H, OH, -C(=O)CH2OH, -C(=O)OH, -C(=O)CH2OH or -C(=O)CH3; R 12 represents H, OH, -C(=O)CH2OH, -C(=O)OH, -C(=O)CH2OH or -C(=O)CH3; R 13 Represents -CH2OH or -CH3; R 15 Represents H, OH or =O; R 16 represents H or F; and L is -C(O)O-(RA )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. Drug dimers of formula (LI) can be formed with tetrahydrotriamcinolone, cortienic acid, 11-dehydrocorticosterone, 11β-hydroxypregnenolone, ketone progesterone, 17-hydroxypregnenolone, 17,21-dihydroxypregnenolone, 18-hydroxycorticosterone, deoxycortisone, 21-hydroxypregnenolone or progesterone.

[0469] In certain embodiments, the steroid is a steroid metabolite, and the drug dimer is further described by Formula (LII):

[0470]

[0471] Where C3 and R2 and C 11 With R 15 The bond between is a single bond or a double bond; R2 represents OH or =O; R 10 Represents H or OH; R 12 represents -C(=O)CH2OH, -C(=O)OH, -C(=O)CH2OH or -C(=O)CH3; R 15Represents H, OH or =O; R 16 represents H or F; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. Dimers of the drug of formula (LII) can be formed from tetrahydrotriamcinolone, cortienic acid, 17-hydroxypregnenolone, 17,21-dihydroxypregnenolone, or deoxycortisone.

[0472] In certain embodiments, the steroid is a steroid metabolite, and the drug dimer is further described by formula (LIII):

[0473]

[0474] Where L is -C(O)-(R A )-C(O)-、-(R A )-or-C(O)-O-(R A )-OC(O)-andR A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms; or L is -O-(R A )-O- and R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-and-O(CH2CH(CH3)O) p CH2CH(CH3)O-; and n, m and p are integers from 1 to 10. The drug dimer of formula (LIII) can be formed from cortienic acid.

[0475] In certain embodiments, the steroid is a steroid metabolite, and the drug dimer is further described by Formula (LIV):

[0476]

[0477] Where C3 and R2 and C 11 With R 15 The bond between is a single bond or a double bond; R2 represents OH or =O; R 10 Represents H or OH; R 11 Represents H or OH; R 13 Represents H, -CH2OH or -CH3; R 15 Represents H, OH or =O; R 16 represents H or F; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, 3 to 10 atom ring system. Drug dimers of formula (LIV) can be formed from tetrahydrotriamcinolone, 11-dehydrocorticosterone, 17,21-dihydroxypregnenolone, 18-hydroxycorticosterone, or 21-hydroxypregnenolone.

[0478] In certain embodiments, the steroid is a steroid metabolite, and the drug dimer is further described by Formula (LV):

[0479]

[0480] The bond between C3 and R2 is a single bond or a double bond; R2 represents OH or =O; R 10 Represents H or OH; R 11 Represents H or OH; R 12 represents -C(=O)CH2OH, -C(=O)OH, -C(=O)CH2OH or -C(=O)CH3; R 13 Represents H, -CH2OH or -CH3; R 16 represents H or F; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, 3 to 10 atom ring system. Drug dimers of formula (LV) can be formed with tetrahydrotriamcinolone, cortienic acid, 11-dehydrocorticosterone, 11β-hydroxypregnenolone, ketone progesterone, 18-hydroxycorticosterone or deoxycortisone.

[0481] In certain embodiments, the steroid is a steroid metabolite, and the drug dimer is further described by Formula (LVI):

[0482]

[0483] Where L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) mCH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. Dimers of the drug of formula (LVI) can be formed with tetrahydrotriamcinolone.

[0484] In certain embodiments, the steroid is a steroid metabolite, and the drug dimer is further described by Formula (LVII):

[0485]

[0486] Where L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10Arylene, 3 to 10 atom ring system. Drug dimers of formula (LVII) can be formed with 18-hydroxycorticosterone.

[0487] In certain embodiments, the steroid is a cholesterol derivative, and the drug dimer is further described by formula (LVIII):

[0488]

[0489] wherein Ry represents H or OH; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. Drug dimers of formula (LVIII) can be formed from 22R-hydroxycholesterol or 20α-22R-dihydroxycholesterol.

[0490] In certain embodiments, the steroid is a cholesterol derivative, and the drug dimer is further described by Formula (LIX):

[0491]

[0492] wherein Ry represents H or OH; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, 3 to 10 atom ring system. Drug dimers of formula (LIX) can be formed from 22R-hydroxycholesterol or 20α-22R-dihydroxycholesterol.

[0493] In certain embodiments, the steroid is a cholesterol derivative, and the drug dimer is further described by formula (LX):

[0494]

[0495] Where L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, 3 to 10 atom ring system. Drug dimers of formula (LX) can be formed from 20α-22R-dihydroxycholesterol.

[0496] In certain embodiments, the steroid is a neurosteroid and the drug dimer is further described by formula (LXI):

[0497]

[0498] Among them C 11 With R 15 The bond between is a single bond or a double bond; Rz represents H or -CH3; R1 represents H or -OCH2CH3; R2 represents OH or =O; R 12 represents -OH, -C(=O)CH3, -C(=O)CH2OH or -CH(CH3)(CH2)2CH(OH)CH(CH3)2; R 15 represents H, -N(CH3)2 or =O; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. Dimers of the drug of formula (LXI) can be formed by alfaxalone, alfadolonone, hydroxypregnenone, minaxolone, tetrahydrodeoxycorticosterone, allopregnanolone, pregnanolone, ganoxolone, 3α-androstanediol, pregnanolone, allopregnanolone or 24(S)-hydroxycholesterol.

[0499] In certain embodiments, the steroid is a neurosteroid and the drug dimer is further described by formula (LXII):

[0500]

[0501] where R 12 represents -C(=O)CH3 or -C(=O)CH2OH; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(RA )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. Dimers of the drug of formula (LXII) can be formed with alfaxalone or alfadolonone.

[0502] In certain embodiments, the steroid is a neurosteroid and the drug dimer is further described by formula (LXIII):

[0503]

[0504] Where C3 and R2 and C 11 With R 15 The bond between is a single bond or a double bond; R2 represents OH or =O; R 15 represents H or =O; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) pCH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. Dimers of the drug of formula (LXIII) can be formed with alfadolone, hydroxyprogesterone, or tetrahydrodeoxycorticosterone.

[0505] In certain embodiments, the steroid is a neurosteroid and the drug dimer is further described by Formula (LXIV):

[0506]

[0507] Where L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, 3 to 10 atom ring system. Dimers of the drug of formula (LXIV) can be formed from 3α-androstanediol.

[0508] In certain embodiments, the steroid is a neurosteroid and the drug dimer is further described by Formula (LXV):

[0509]

[0510] Where L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, 3 to 10 atom ring system. Drug dimers of formula (LXV) can be formed from 24(S)-hydroxycholesterol.

[0511] In certain embodiments, the steroid is a pheromone and the drug dimer is further described by Formula (LXVI):

[0512]

[0513] Wherein R2 represents OH or =O; R 11 Represents H, -C(=O)CH3, -OC(=O)(CH2)4CH3 or does not exist; R 12 Represents H, -C(=O)CH3, -OC(=O)(CH2)4CH3 or does not exist; R17 represents CH3 or does not exist; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (LXVI) can be formed by androstadienol, androstadienone, androstenol, androstenone, estrenol, 5-dehydroprogesterone, 6-dehydro-progesterone, allopregnanolone or hydroxyprogesterone caproate.

[0514] In certain embodiments, the steroid is progesterone, and the drug dimer is further described by Formula (LXVII):

[0515]

[0516] Among them C 11 With R 15 The bond between is a single bond or a double bond; R2 represents OH or =O; R 11 represents H, OH, -CH(OH)CH3, -C(=O)CH2OH, -C(=O)CH3 or -CH(OH)CH2OH; R 12represents H, OH, -CH(OH)CH3, -C(=O)CH2OH, -C(=O)CH3 or -CH(OH)CH2OH; R 15 represents H, =O or OH; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (LXVII) can be composed of allopregnanol-3α,20α-diol, allopregnanol-3β,20β-diol, allopregnanol-3β,21-diol-11,20-dione, allopregnanol-3β,17α-diol-20-one, 3,20-allopregnanol-3β,11β,17α,20β,21-pentaol, allopregnanol-3β,17α,20β,21-tetraol, allopregnanol-3α,11β,17α,21-tetraol-20-one, allopregnanol-3β,11β,17α,21-tetraol-20-one, allopregnanol-3β,17α,20β-triol, allopregnanol-3 β,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.

[0517] In certain embodiments, the steroid is progesterone, and the drug dimer is further described by Formula (LXVIII):

[0518]

[0519] Where C3 and R2 and C 11 With R 15 The bond between is a single bond or a double bond; R2 represents OH or =O; R 12 represents H, OH, -CH(OH)CH3, -C(=O)CH2OH, -C(=O)CH3 or -CH(OH)CH2OH; R 15 represents H, =O or OH; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (LXVIII) can be composed of allopregnanol-3β,17α-diol-20-one, 3,20-allopregnanol-20-one, 3β,11β,17α,20β,21-pentaol, allopregnanol-3β,17α,20β,21-tetraol, allopregnanol-3α,11β,17α,21-tetraol-20-one, allopregnanol-3β,11β,17α,21-tetraol-20-one, Pregnane-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 is formed.

[0520] In certain embodiments, the steroid is progesterone, and the drug dimer is further described by formula (LXIX):

[0521]

[0522] where R 11 represents H, OH, -CH(OH)CH3, -C(=O)CH2OH, -C(=O)CH3 or -CH(OH)CH2OH; R 15 represents H or OH; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B)-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (LXIX) can be formed from allopregnane-3α,20α-diol, allopregnane-3β,20β-diol or allopregnane-3β,17α,20β-triol.

[0523] In certain embodiments, the steroid is progesterone, and the drug dimer is further described by formula (LXX):

[0524]

[0525] Where C3 and R2 and C 11 With R 15 The bond between is a single bond or a double bond; Ry represents OH or =O; R2 represents OH or =O; R 11 represents H, OH, -CH(OH)CH3, -C(=O)CH2OH, -C(=O)CH3 or -CH(OH)CH2OH; R 12 represents H, OH, -CH(OH)CH3, -C(=O)CH2OH, -C(=O)CH3 or -CH(OH)CH2OH; R 15 represents H, =O or OH; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(RA )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (LXX) can be composed of allopregnanol-3β,21-diol-11,20-dione, 3,20-allopregnanol-11,20-dione, 3β,11β,17α,20β,21-pentaol, allopregnanol-3β,17α,20β,21-tetraol, allopregnanol-3α,11β,17α,21-tetraol-20-one, allopregnanol-3β,11β,17α,21-tetraol-20-one, allopregnanol-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 are formed.

[0526] In certain embodiments, the steroid is progesterone, and the drug dimer is further described by formula (LXXI):

[0527]

[0528] The bond between C3 and R2 is a single bond or a double bond; R2 represents OH or =O; R 11represents H, OH, -CH(OH)CH3, -C(=O)CH2OH, -C(=O)CH3 or -CH(OH)CH2OH; R 12 represents H, OH, -CH(OH)CH3, -C(=O)CH2OH, -C(=O)CH3 or -CH(OH)CH2OH; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, ring systems of 3 to 10 atoms. The drug dimer of formula (LXXI) can be formed by allopregnanol-3β,21-diol-11,20-dione, 3,20-allopregnanol-11,20-dione, 3β,11β,17α,20β,21-pentaol, allopregnanol-3α,11β,17α,21-tetraol-20-one, allopregnanol-3β,11β,17α,21-tetraol-20-one, allopregnanol-3β,17α,21-triol-11,20-dione, allopregnanol-3β,11β,21-triol-20-one, 4-pregnene-20,21-diol-3,11-dione, 4-pregnene-11β,17α,20β,21-tetraol-3-one or 4-pregnene-17α,20β,21-triol-3,11-dione.

[0529] In certain embodiments, the steroid is progesterone, and the drug dimer is further described by formula (LXXII):

[0530]

[0531] Where C3 and R2 and C 11 With R 15 The bond between is a single bond or a double bond; R2 represents OH or =O; R 11 Represents H or OH; R 15 represents H, =O or OH; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10Arylene, a ring system of 3 to 10 atoms. The drug dimer of formula (LXXII) can be formed by 3,20-allopregnanedione, 3β,11β,17α,20β,21-pentaol, allopregnanedione-3β,17α,20β,21-tetraol, 4-pregnene-20,21-diol-3,11-dione, 4-pregnene-11β,17α,20β,21-tetraol-3-one, 4-pregnene-17α,20β,21-triol-3,11-dione or 4-pregnene-17α,20β,21-triol-3-one.

[0532] In certain embodiments, the steroid is another steroid, and the drug dimer is further described by formula (LXXIII):

[0533]

[0534] Among them C 16 With R 10 The bond between is a single bond or a double bond; R2 represents OH or =O; R5 represents H, Cl or -CH3; R 10 Represents H or =CH2; R 11 represents H, OH, -CH3, -C(=O)CH3, -C(=O)CH2OC(=O)CH3 or -OC(=O)CH3; R 12 represents H, OH, -CH3, -C(=O)CH3, -C(=O)CH2OC(=O)CH3 or -OC(=O)CH3; R 15 Represents H or OH; R 16 Indicates F or H; R 17 represents H or -CH3; and L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) nCH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. Drug dimers of formula (LXXIII) can be formed from flugestone, prednisolone, chlormadinone acetate, medrogestone, and medroxyprogesterone acetate.

[0535] In certain embodiments, the steroid is another steroid, and the drug dimer is further described by formula (LXXIV):

[0536]

[0537] Where L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. Dimers of the drug of formula (LXXIV) can be formed with fluprogesterone.

[0538] In certain embodiments, the steroid is another steroid, and the drug dimer is further described by formula (LXXV):

[0539]

[0540] Where L is -C(O)O-(R A )-OC(O)-、-C(O)-OC(O)-(R A )-C(O)OC(O)-or-C(O)-(R B )-C(O)O-(R A )-OC(O)-(R B )-C(O)-;R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or O-(R A )-O is selected from: -O(CH2CH2O) n CH2CH2O-、-O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-or-O(CH2CH(CH3)O) p CH2CH(CH3)O-; n, m and p are integers from 1 to 10; and each R B Independently selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, a ring system of 3 to 10 atoms. Dimers of the drug of formula (LXXV) can be formed with fluprogesterone.

[0541] preparation

[0542] Pharmaceutical composition of the present disclosure can include the product of fiber, fiber web, woven fabric, nonwoven fabric, pill, cylinder, hollow tube, particulate (for example, microbead), nanoparticle (for example, nanobead) form, or other finished product.In some embodiments, pharmaceutical composition of the present disclosure has the non-circular shape (for example, by star-shaped die or adopt or do not adopt other any form of forming process of die) that affects (for example, increase) surface area.Suitable pharmaceutical composition for the present disclosure can be the small particles of regular or irregular shape, which can be solid, porous or hollow.

[0543] Different forms of the pharmaceutical compositions of the present disclosure (e.g., fibers, fiber meshes, woven fabrics, nonwoven fabrics, pellets, cylinders, hollow tubes, microparticles (e.g., microbeads), nanoparticles (e.g., nanobeads), or other shaped articles) can have the advantages of providing a controllable surface area, ease of injection, no need for removal after drug release is complete, and allow for adjustment of the drug release rate required for a given indication. When used as an injectable drug delivery device, the drug release rate and interaction with cells are strongly dependent on the size distribution of the pharmaceutical composition form.

[0544] Processing methods

[0545] The articles of the present disclosure can be formed using a variety of methods, for example, thermal processing or solvent processing of the drug dimer of formula (I). Thermal processing can include thermoforming, injection molding, extrusion, 3D printing, melt electrospinning, fiber spinning, fiber extrusion and / or blow molding. Solvent processing can include coating, microprinting, emulsion processing, dot printing, micropatterning, fiber spinning, solvent blowing, electrospraying and electrospinning.

[0546] Electrospray method

[0547] In some embodiments, the pharmaceutical composition of the present disclosure is dissolved in a solvent (e.g., acetone) at a concentration of, for example, 10-30% w / v, and electrosprayed to form microbeads and nanobeads. The solution can be loaded into a syringe and can be injected onto a stationary collection plate at a specific rate, for example, 0.5 mL / h. Between the needle and the collection surface, a potential difference of, for example, 18 kV can be maintained. Nanoparticles are obtained using an exemplary concentration of 10% w / v. In other embodiments, microbeads are obtained using a concentration of 30% w / v.

[0548] Fiber spinning

[0549] In some embodiments, pharmaceutical composition of the present disclosure is prepared by electrospinning, for example, with a fiber mesh of aligned and misaligned morphology. Pharmaceutical composition of the present disclosure is dissolved in a solvent (for example, THF or the DCM / THF of a 1:1 ratio). The solution can be injected from a syringe at a specific rate, for example 0.5 mL / h, into a cylindrical mandrel rotated at a specific rotational speed, for example 1150 rpm, to obtain aligned fiber, or injected onto a stationary collector surface to obtain misaligned fiber. For aligned and random optical fibers, a potential difference (for example, 18 kV or 17 kV) can be maintained between a needle and the collecting surface.

[0550] In other embodiments, fibers are prepared from a melt at elevated temperature, a glassy intermediate, or a solution formed by dissolving a pharmaceutical composition of the present disclosure in a solvent (e.g., DCM, THF, or chloroform). As used herein, melt spinning describes thermal processing from a molten state, hot spinning describes thermal processing from a glassy state, and wet spinning, dry spinning, and gel spinning describe solution processing.

[0551] Viscous melt, intermediate or solution can be sent into spinneret, and can form fiber when cooling (melt spinning or hot spinning) or after evaporating solvent with hot air when compound leaves spinneret (dry spinning).Wet spinning and gel spinning carried out according to methods known in the art can also be used to produce fiber of the present disclosure.Hot spinning describes the process substantially the same as melt spinning process, but is carried out with glassy intermediate, and is heated to more than glass transition temperature (Tg) so that viscous fluid replaces melt extrusion / spinning.Or, tweezers can be immersed in molten material or concentrated solution, then slowly retracted to pull out fiber.Pulling rate and pulling distance can be changed, to produce fiber and columnar structure with different thicknesses.

[0552] Emulsion method

[0553] In some embodiments, an emulsion method can be used to form microparticles or nanoparticles made from a pharmaceutical composition. The pharmaceutical composition can be dissolved in an organic solvent (e.g., DCM, THF, etc.), and a low percentage (e.g., 1%) of a surfactant (e.g., SDS, PVA, etc.) can be added to the solution / mixture. The resulting mixture can be stirred at room temperature for an appropriate time to form an emulsion. Subsequently, the emulsion can be added to Milli-Q water under stirring and kept for an appropriate time (e.g., 1 hour) to remove residual solvent. The resulting microparticles or nanoparticles can be collected by centrifugation and dried to obtain the desired form.

[0554] Extrusion

[0555] In some embodiments, the injectable cylinder made of pharmaceutical composition can be formed by heat extrusion.Pharmaceutical composition can be loaded into hot melt extruder, be heated to the temperature (for crystalline composition) or glass transition temperature (for pre-melted or amorphous composition) higher than melting point, and use light compression force to extrude to push material through nozzle, and use light pulling force that material is pulled out from extruder.Extrudate can be cut into required length for carrying out suitable administration for purpose indication.

[0556] Bead sizing and grinding

[0557] In some embodiments, the size of the articles of the present invention can be reduced using a grinding process to form particles, such as beads, of a size in the micrometer (micron beads) to nanometer size range (nano beads). The grinding process can be carried out using a grinder or other suitable equipment. Dry and wet grinding processes such as jet grinding, cryogenic grinding, ball milling, media grinding, ultrasonic treatment, and homogenization are known and can be used in the methods described herein. Typically, in a wet grinding process, a suspension of the material to be used as the core is stirred with or without an excipient to reduce particle size. Dry grinding is a process in which the material to be used as the core of the article is mixed with a grinding medium with or without an excipient to reduce particle size. In a cryogenic grinding process, a suspension of the material to be used as the core is mixed with a grinding medium with or without an excipient at a cooling temperature. In some embodiments, the ground microparticles need to be subsequently heated to above the Tg to obtain a spherical shape, or particles with a non-spherical shape can be used for grinding.

[0558] Low temperature processing using intermediate glassy products

[0559] In certain embodiments, the prodrug dimer has a limited thermal stability window (e.g., a short time range of a few seconds to a few minutes), thereby minimizing the effect on the purity of the dimer at elevated temperatures. In some embodiments, it is beneficial to prepare an intermediate glassy form (e.g., a film, pellet, microparticle, or other shaped article). This can be achieved by thermal processing or solvent processing to remove or reduce the crystallinity of the material to form a glassy composition. The glassy composition is then thermally processed at a lower temperature (e.g., just above the glass transition temperature (Tg) and processed below the melting temperature (Tm)). This can provide a longer time frame for thermally processing the glassy material into the final shaped article while reducing the effect of processing conditions on the purity of the prodrug dimer in the article.

[0560] Exemplary processing details are provided in the Examples.

[0561] Drug delivery

[0562] When pharmaceutical composition of the present disclosure releases medicine from goods of the present disclosure in a controlled manner, for example, by surface erosion, pharmaceutical composition of the present disclosure provides optimal drug delivery. The surface erosion mechanism of drug release can make shaped articles maintain its physical form (shape), while gradually reducing size (for example, like a soap bar) as surface erosion occurs, rather than the overall erosion that is unique to some polymer-based drug release media (for example, polylactic acid / glycolic acid). This can suppress sudden release and reduce the formation of inflammatory particles (for example, when releasing medicine in a manner described herein, crystalline particles are not formed). Medicine can be controlled to be delivered within the desired time period. A slow and steady delivery rate (e.g., less than 10% of D1 or D2 is released (as a percentage of the total drug D1 or D2 present in the fiber as a prodrug) over 5 days at 37°C in 100% bovine serum) can, in turn, result in a reduction in the frequency with which the drug composition must be administered to a subject and an improvement in the safety profile of the drug. Drug release can also be tailored by engineering the article to provide a steady release over a relatively short period of time to avoid the side effects of slow and prolonged drug release. Depending on the indication and drug, drug release can be tailored to a dose and duration appropriate for the indication of interest.

[0563] The release rate of the drug can depend on many factors, for example, the drug composition of the drug dimer. The rate of drug release from the object formed by the drug dimer can be adjusted by cutting the drug-linker bond through hydrolysis or enzymatic degradation. Therefore, the choice of the connecting part can affect the drug release rate. In addition, the drug release rate can be controlled by selecting the functional group to be conjugated to the linker on the drug, such as the first and second steroid hydroxyl groups. The rate at which a given drug is released from the drug dimer may also depend on the percentage of the amount of the loaded drug dimer in the final drug dimer formulation, for example, by using a drug excipient (for example, filler / excipient) or a second steroid drug (for example, active or mild) as a homodimer mixture, or in the same molecule with a heterodimer acting as a filler. Another factor that can affect the rate of drug release from, for example, microbeads is the size of the microbeads. In some embodiments, drug release is customized based on the solubility of the drug dimer (for example, by selecting a suitable drug and / or linker), which will affect the surface erosion rate (for example, dissolution / degradation) of the product. In other embodiments, drug release is affected by changes in the surface area of ​​the formulation, for example, by varying the diameter of the microbeads. By adjusting the above factors, dissolution, degradation, diffusion, and controlled release can be varied over a wide range. For example, release can be designed to begin within minutes to hours and to continue over the course of days, weeks, months, or years.

[0564] Uses and pharmaceutical compositions

[0565] In some embodiments, the drug dimer of the present disclosure is used as a drug delivery device (or, for example, a drug depot) with minimal demand for additives. This can achieve local, sustained release and local biological effects while minimizing systemic reactions. In some embodiments, when present, the additive is a small amount and does not affect physical or bulk properties. In some embodiments, when present, the additive does not change the release properties of the drug from the pharmaceutical composition, but serves to improve the processing of the prodrug dimer into a shaped article. In some embodiments, the pharmaceutical composition includes additives, such as plasticizers (for example, to reduce thermal transition temperature), antioxidants (for example, to improve stability during thermal processing), adhesives (for example, to increase flexibility of the fiber), fillers (for example, to reduce total drug content), lubricants, radiopaque agents or mixtures thereof. The additive can be present in an amount of 30% (w / w), for example 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, for example glycerol, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, propylene glycol, triacetin, sorbitol, mannitol, xylitol, fatty acids, monosaccharides (for example glucose, mannose, fructose, sucrose), ethanolamine, urea, triethanolamine, vegetable oils, lecithin or waxes. Exemplary antioxidants are glutathione, ascorbic acid, cysteine ​​or tocopherol. Binders and fillers may be, for example, polyvinylpyrrolidone (PVP), starch paste, pregelatinized starch, hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), or polyethylene glycol (PEG) 6000.

[0566] Methods involving treating a subject may include preventing the disease, disorder, or condition in a subject who may be susceptible to, but has not yet been diagnosed as having, the disease, disorder, or condition; inhibiting the disease, disorder, or condition, e.g., arresting its progression; and alleviating the disease, disorder, or condition, e.g., causing regression of the disease, disorder, and / or condition. Treating a disease or condition includes ameliorating at least one symptom of a particular disease or condition, even if the underlying pathophysiology is not affected (e.g., treating pain in a subject by administering an agent, even if such agent does not treat the cause of the pain).

[0567] The pharmaceutical compositions comprising the drug dimers described herein can be administered to a subject by any route known in the art. These routes include, but are not limited to, oral, sublingual, nasal, intradermal, subcutaneous, intramuscular, rectal, vaginal, intravenous, intraarterial, intracisternal, intraperitoneal, intravitreal, periocular, topical (such as powder, cream, ointment or drops), buccal and inhalation administration. Ideally, the products of the present disclosure are administered parenterally (intravenously, intramuscularly or subcutaneously) as an injection, or topically (intraocularly or intra-articularly) as an injection. The preparation is mixed under aseptic conditions with a pharmaceutically acceptable carrier or suspending agent or resuspending agent (e.g., for microparticles and nanoparticles) and any desired preservative or buffer that may be needed.

[0568] The disclosed products comprising drug dimers as described herein can be applied to the subject to be delivered in an amount sufficient to deliver a therapeutically effective amount of an incorporated medicament as a part of a preventive or therapeutic treatment or a part of an adjuvant therapy to the subject to avoid the side effects of another drug or therapy. Typically, the effective amount of a medicament or component refers to the amount necessary to cause the desired biological response. The desired concentration of the medicament in the disclosed products will depend on many factors, including but not limited to the absorption, inactivation and excretion rate of the drug, and the delivery rate of the compound from the subject composition, the desired biological endpoint, the drug to be delivered, the target tissue, etc. It should be noted that the dosage value can also vary with the severity of the condition to be alleviated. It should also be understood that for any specific subject, the specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the composition. Typically, administration will be determined using techniques known to those skilled in the art.

[0569] One of ordinary skill in the art can readily determine the concentration and / or amount of any pharmaceutical agent to be administered to a subject. Known methods can also be used to determine local tissue concentrations, diffusion rates from drug dimers, and local blood flow before and after administration of the therapeutic formulation.

[0570] Sterilization of preparations

[0571] Generally, it is desirable that the preparation be sterile before or when being applied to a subject. Sterile preparations are substantially free of pathogenic microorganisms, such as bacteria, microorganisms, fungi, viruses, spores, yeasts, molds and other microorganisms generally relevant to infection. In some embodiments, the products of the present disclosure can undergo aseptic processing and / or other sterilization processes. Aseptic processing generally includes sterilizing the preparation, final formulation and / or container closure of the pharmaceutical product by processes such as heat, gamma radiation, ethylene oxide or filtration, and then merging in a sterile environment. In some cases, aseptic processing is preferred. In other embodiments, terminal sterilization is preferred.

[0572] Treatment

[0573] The formulations of the present disclosure may be used in the fields of ophthalmology, oncology, laryngology, endocrinology and metabolic diseases, rheumatology, urology, neurology, cardiology, dentistry, dermatology, otology, post-operative medicine, orthopedics, pain management, and gynecology.

[0574] The compounds of the present disclosure can be selected based on the desired properties, for example, using a corticosteroid dimer to treat an inflammatory disease or condition; using an antibiotic steroid dimer to treat an infection; or using an anticancer steroid dimer to treat a proliferative disorder.

[0575] Ophthalmic applications

[0576] In certain embodiments, the articles of manufacture of the present disclosure may be used to prevent, treat, or manage diseases or conditions of the back of the eye, such as the retina, macula, choroid, sclera, and / or uvea.

[0577] In some embodiments, the articles of manufacture of the present disclosure are used as injectable drug delivery devices for ophthalmology (e.g., intravitreal injection, coating on a minimally invasive glaucoma surgery (MIGS) device, or implanted blebs). During intravitreal injection, the drug is placed directly into the space behind the eye called the vitreous cavity, which is filled with a jelly-like fluid called the vitreous humor. Intravitreal injection can be used to treat retinal diseases such as diabetic retinopathy, macular degeneration, macular edema, uveitis, and retinal vein occlusion.

[0578] In certain embodiments, the articles of manufacture of the present disclosure may be used to treat, prevent, or manage ocular conditions, i.e., diseases, discomforts, or conditions that affect or involve the eye or one or more parts or regions of the eye. In some embodiments, the articles of manufacture of the present disclosure may be used to treat, prevent, or manage ocular conditions in the front of the eye of a subject. Ocular conditions in the front of the eye include diseases, discomforts, or conditions such as post-operative inflammation; uveitis; infection; aphakia; pseudophakia; astigmatism; blepharospasm; cataracts; conjunctival diseases; conjunctivitis; corneal diseases; corneal ulcers; dry eye syndrome; eyelid diseases; lacrimal apparatus diseases; tear duct obstruction; myopia; presbyopia; pupil disorders; corneal neovascularization; refractive errors, and strabismus. In some embodiments, the articles of manufacture of the present disclosure may be used to treat, prevent, or manage ocular conditions in the back of the eye of a subject. Ocular conditions at the back of the eye may include diseases, disorders, or conditions such as intraocular melanoma; acute macular neuroretinopathy; Behcet's disease; choroidal neovascularization; uveitis; diabetic uveitis; histoplasmosis; infections, such as those caused by fungi or viruses; macular degeneration, such as acute macular degeneration, non-exudative age-related macular degeneration, and exudative age-related macular degeneration; edema, such as macular edema (e.g., cystoid macular edema (CME) and diabetic macular edema (DME)); multifocal choroiditis; ocular trauma affecting the area or location at the back of the eye; ocular tumors; retinal disorders, such as central retinal vein occlusion, diabetic retinopathy (including proliferative diabetic retinopathy), proliferative vitreoretinopathy (PVR), retinal artery occlusive disease, retinal detachment, uveitic retinal disease; sympathetic ophthalmia; Vogt's disease; Koyanagi-Harada (VKH) syndrome; uveitis spreading; posterior eye conditions caused or affected by ocular laser treatment; posterior eye conditions caused or affected by photodynamic therapy, photocoagulation, radiation retinopathy, epiretinal membrane disorders, branch retinal vein occlusion, anterior ischemic optic neuropathy, non-retinopathy, diabetic retinal dysfunction, retinitis pigmentosa, retinoblastoma and glaucoma. In some embodiments, the preparations of the present disclosure can be used to treat, prevent or control dry eye in a subject. In some embodiments, the preparations of the present disclosure can be used to treat, prevent or control inflammation in the eyes of a subject (e.g., where the drug dimer is formed by one or more corticosteroids). Inflammation is associated with a variety of eye conditions. Various ophthalmic surgical procedures (including cataract surgery) can also lead to inflammation. In some embodiments, the agent delivered to the eye by the preparations and / or methods of the present disclosure described herein can be a corticosteroid.In certain embodiments, the pharmaceutical agent comprises hydrocortisone, cortisone, tixocortol, prednisolone, methylprednisolone, prednisone, triamcinolone acetonide, mometasone, amcinonide, budesonide, desonide, fluocinolone acetonide, fluocinolone acetonide, halcinonide, betamethasone, dexamethasone, fluocortolone, hydrocortisone, aclometasone, prednicarbate, clobetasone, clobetasol, fluprednidine, glucocorticoids, mineralocorticoids, aldosterone, deoxycorticosterone, fludrocortisone, ulbetasol, diflorasone, desoximetasone, fluticasone, flurandrenolide, alclometasone, diflucortolone, flunisolide and beclomethasone. In some embodiments, the drug dimers of the present disclosure are used as adjunctive therapy to reduce inflammation and fibrosis associated with devices (e.g., minimally invasive glaucoma surgery (MIGS) devices). In some embodiments, the articles of manufacture of the present disclosure may be used to treat, prevent, or manage age-related macular degeneration (AMD) in a subject.

[0579] Treatment of osteoarthritis

[0580] In some embodiments, the products of the present disclosure are used to treat osteoarthritis (OA). For OA of the knee, if other conservative treatments are ineffective, intra-articular (IA) injections (e.g., steroids) are preferred as a last non-surgical option. Steroids can be used to reduce inflammation of the tendons and ligaments of osteoarthritic joints. IA steroid injections result in short-term relief of OA pain and can be considered an adjunct to core treatment for alleviating moderate to severe pain in OA patients. Exemplary steroids used in the treatment of OA are betamethasone, methylprednisolone, dexamethasone, and triamcinolone acetonide. In some embodiments, microspheres of the present disclosure composed of drug dimers are injected into the knee joint to treat OA.

[0581] surgical procedures

[0582] In some embodiments, the articles of manufacture of the present disclosure are used in conjunction with surgical procedures. For example, the articles of manufacture of the present disclosure can be implanted at a surgical site to reduce the risk of recurrence of infection, inflammation, or a disease (such as cancer) being treated by surgery.

[0583] Example

[0584] The following examples are presented to provide one of ordinary skill in the art with instructions for using, preparing, and evaluating the compositions and methods described herein and are purely exemplary of the present disclosure and are not intended to limit the scope of what the inventors regard as their disclosure. Compounds 1-17 can be used in the methods, compositions, and articles of manufacture of the present disclosure.

[0585] Table 1. Compounds of the present disclosure

[0586]

[0587]

[0588] Example 1. Compound 1 (Dex-TEG-Dex) can be synthesized, processed into glassy pellets by thermoforming, and the drug released from the intact pellets by surface erosion.

[0589] Dexamethasone (1 mol equivalent) was suspended in dichloromethane on an ice bath, and triethylamine (2 mol equivalent) and triethylene glycol bis(chloroformate) (0.6 mol equivalent) were added to the mixture. The ice bath was allowed to warm to room temperature, and the reaction was stirred overnight. The solvent was removed, and the solid residue was purified by column chromatography. The product was recrystallized twice from acetonitrile to give compound 1 ( Figure 1A ).

[0590] Compound 1: HPLC (mobile phase: H2O / TFA and MeCN / TFA) 31.7 min; elemental analysis: for C 52 H 68 F2O 16 Analysis calculated: 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. 1H NMR (400MHz, DMSO-d6) δ (ppm) 0.80 (d, J = 7Hz, 6H, 2×C16α-CH3); 0.90 (s, 6H, 2×C18-CH3); 1. 08(m,2H,2×C16-H);1.35(m,2H,2×C14-H);1.49(s,6H,2×C19-CH3);1.54(q,J=13Hz,2H,2× C13-H); 1.64 (q, J=11Hz, 2H, 2×C15-CH2); 1.77 (m, 2H, 2×C15-CH2); 2.15 (m, 4H, 2×C6-CH2); 2.32(m,4H,2×C7-CH2); 2.62(m,2H,2×C12-CH2); 2.89(m,2H,2×C12-CH2); 3.57(s,4H,2×TEG OCH2); 3.65(m,4H,2×TEG OCH2); 4.15(m,2H,2×OCH); 4.22(m,4H,2×TEG OCH2); 4.79 (d, 2H, AB, J = 18.5 Hz, 2H, C21-CH2O-); 5.09 (d, 2H, AB, J = 18.5 Hz, 2H, C21-CH2O-); 5.18 (s, 2H, C17-OH); 5.40 (d, 2H, J = 4.5 Hz, C11-OH); 6.01 (d, 2H, J = 1.9 Hz, 2x olefin C4-CH); 6.23 (dd, 2H, J = 10.1 and 1.9 Hz, CH, 2x olefin C2-CH); 7.29 (d, 2H, C1-CH2x olefin CH, 10.1 Hz, 2H). MS (ESI+) m / z: [M+H]+, for C 52 H 69 F2O 16 The calculated value is 987.46; the measured value is 987.46.

[0591] Compound 1 was formed into glassy pellets by thermoforming ( Figure 1B The crystalline powder was melted at 185°C and formed into pellets using a 1 mm x 1 mm cylindrical die. The starting powder and the heat-treated pellets were characterized by differential scanning calorimetry (DSC); Figure 1C ) and powder X-ray diffraction (PXRD; Figure 1D ) were tested to confirm the thermal processing transformation of compound 1 from a crystalline state to a glassy state.

[0592] Thermoformed pellets (approximately 1 mm x 1 mm) from Compound 1 were then placed in 20 mL glass vials and 2 mL of release buffer (100% phosphate buffered saline (PBS), 1% fetal bovine serum (FBS) in PBS, or 100% FBS) was added. The samples were incubated at 37°C on a shaker rotating at 115 rpm. After 1 day, 3 days, 7 days, and then at alternating intervals of 3 and 4 days (i.e., 1, 3, 7, 10, 14 days, etc.), the release buffer was sampled directly (PBS) or syringe filtered, the protein was precipitated with acetonitrile, and the drug release product was extracted. The samples were analyzed by high performance liquid chromatography (HPLC) to quantify the drug product. The cumulative drug release was calculated and plotted as the percentage of total drug in each pellet released over time ( Figure 1E Representative images of pellets demonstrating surface erosion over time in 100% FBS ( Figure 1F ).

[0593] Example 2. Compound 1 (Dex-TEG-Dex) can be processed from the molten state into different glassy forms by various processing methods.

[0594] Compound 1 was processed from the molten state into different forms of glass. Thermoformed pellets ( Figure 2A ) were prepared as described in Example 1 using a cylindrical die (approximately 0.35 mm diameter and 0.8 mm length). Extruded cylinders ( Figure 2B ) was prepared by adding Compound 1 as a crystalline powder into a micro-extruder with different nozzles to form extrudates of different diameters. The micro-extruder was heated to 185° C. to melt the powder and form extrudates. Figure 2C An extruded cylinder with a 23G diameter nozzle is shown, cut and fitted into a 23G needle. Figure 2D ) is formed by dispersing Compound 1 in powder form on a PTFE sheet and heating it to 185°C. Fibers of Compound 1 are made by hot extrusion at 185°C using a small diameter nozzle (e.g., 30-32G) and pulling the extrudate out of the nozzle with a pulling force. Fibers can also be made by melting Compound 1 from a powder at 185°C and pulling the molten material at different rates to produce fibers of different diameters ( Figure 2E ).

[0595] Example 3. Compound 1 (Dex-TEG-Dex) can be processed from solution to different glassy forms by various processing methods.

[0596] Compound 1 was processed from solution into various glassy forms using organic solvents, including coatings, nonwoven webs, fibers, and microparticles and nanoparticles. Compound 1 was drop-coated from acetone onto titanium ( Figure 3A) and poly(styrene-block-isobutylene-block-styrene) (SIBS) surfaces ( Figure 3B ), and can be coated using other common techniques (e.g., dipping, spraying, electrospraying, etc.).

[0597] With aligned ( Figure 3C ) and misaligned ( Figure 3D ) morphology of nonwoven fiber webs were prepared by electrospinning. Compound 1 was dissolved in tetrahydrofuran (THF) and electrosprayed onto a cylindrical rotating mandrel to obtain aligned fibers, or onto a fixed collector surface to obtain non-aligned fibers. The DSC ( Figure 3E ) and PXRD( Figure 3F ) Compound 1 was tested as a starting powder and as a solvent processed fiber web to confirm that the web was in the glassy state.

[0598] Fibers were prepared by dissolving compound 1 in dichloromethane (DCM), THF, or chloroform and pulling compound 1 from the solution ( Figure 3G ). The pulling rate and pulling distance were varied to produce fibers and columnar structures of varying thicknesses.

[0599] Electrosprayed microparticles and nanoparticles were prepared as follows: Compound 1 was dissolved in acetone. Compound 1 was electrosprayed into the nanoparticles using a concentration of 10% w / v ( Figure 3H ), while compound 1 was electrosprayed into the microparticles using a concentration of 30% w / v ( Figure 3A ).

[0600] Microparticles of compound 1 were prepared by emulsification from DCM using sodium dodecyl sulfate ( Figure 3J ). Microparticles were analyzed by DSC ( Figure 3K ) to confirm that they are in the glassy state. Different preparation conditions (solvents, concentrations, surfactants, surfactant concentrations, mixing conditions, etc.) lead to different particle sizes and distributions.

[0601] Example 4: Drug Release from Compound 1 (Dex-TEG-Dex) Coated on Different Surfaces

[0602] Compound 1 was coated on titanium and SIBS as described in Example 3 above. Drug release from the coating materials was performed in PBS as described in Example 1 above. Cumulative drug release was calculated and plotted as the percentage of total drug released per coated surface over time ( Figure 4 ).

[0603] Example 5: Due to the surface erosion mechanism of drug release, the drug release properties from thermoformed pellets of Compound 1 (Dex-TEG-Dex) can be modulated by changing the physical properties of the pellets.

[0604] Compound 1 was thermoformed into pellets having diameters of about 1 mm and about 0.35 mm using the conditions described in Examples 1 and 2 above to obtain pellets having different masses of Compound 1 and different surface areas. The detailed information of the samples is summarized in the table below. Drug release from the different samples was performed in 100% FBS over a period of 7 days as described in Example 1. Due to the surface erosion mechanism of drug release, the expected variation in drug release from different surface areas is Figure 5 Illustrated in FIG is a plot of surface area versus average drug released per day obtained from a linear release profile.

[0605] Table 2. Thermoformed pellets formed from Compound 1. Different masses and surface areas were obtained by varying the number of pellets of a given size.

[0606]

[0607] Example 6: Mechanical testing of extruded cylinders of Compound 1 (Dex-TEG-Dex) using the three-point bending test (ASTM C1684-18)

[0608] The mechanical properties of extruded cylinders of Compound 1 were quantified by three-point bending tests using ASTM C1684-18 (Standard Test Method for Flexural Strength and Ambient Temperature of Advanced Ceramics—Strength of Cylindrical Rods). ASTM C1684-18 was followed as closely as possible, but modifications were necessary due to the small size of the extruded cylinders. Representative fracture force data from three-point bending tests of Compound 1 cylinders (approximately 0.25 mm x 6 mm) are given in Figure 6 Shown in.

[0609] Example 7: Ethylene oxide gas sterilization of thermoformed pellets of Compound 1 (Dex-TEG-Dex)

[0610] Thermoformed pellets of Compound 1 (approximately 1 mm in diameter) were sterilized at 55°C using ethylene oxide (ETO) gas. The pellets were analyzed by HPLC before and after ETO sterilization to confirm that the purity of the pellets (Compound 1) remained unchanged ( Figure 7A ) and the drug release was analyzed ( Figure 7B ) to demonstrate that the ETO sterilization process did not cause changes in release properties. As described in Example 1, drug release was performed in PBS containing 1% FBS or 100% FBS.

[0611] Example 8: Processing Compound 1 (Dex-TEG-Dex) into an intermediate glassy state to produce a final product

[0612] Using the method described in Example 2 above, Figure 8A and 8BAs shown, compound 1 (Dex-TEG-Dex) was directly formed into hot extruded cylinders from crystalline powder by heating above the melting point (185°C). Figure 8C and 8D As shown, compound 1 was also formed into hot extruded cylinders by forming an intermediate glassy form from the melt and subsequently hot extruding above the glass transition temperature (150°C). The purity of the extrudate over time was Figure 8E , and using an intermediate glassy state shows longer extrusion run times before the purity of Compound 1 decreases compared to extrusion from the molten state.

[0613] The intermediate glassy state is also formed from the solution state. Compound 1 is dissolved in acetone and electrosprayed onto the polymer surface to form glassy particles. The sprayed surface is heated to about 150°C to obtain Figure 8F Coating shown.

[0614] Example 9: Synthesis of compounds

[0615] Similar to the synthesis of compound 1 in Example 1 above, the compounds in Table 3 below were synthesized using standard methods known in the art. The table below also shows the detailed information of the synthesized compounds. All compounds were synthesized to HPLC purity ≥ 98% and were obtained by 1 The structure was confirmed by H NMR and ESI MS. The melting point (Tm) and glass transition temperature (Tg) were determined to determine the processing temperature required for thermal processing of the compound into pellets, fibers, and cylinders for further testing.

[0616] Table 3. Structures of compounds

[0617]

[0618]

[0619] *nd = Not Determined

[0620] Example 10: Formation of Glassy Pellets, Fibers and / or Cylinders from Compounds 2-10 and 17, and Drug Release from Intact Glassy Pellets

[0621] Compounds 2-10 and 17 were processed into thermoformed pellets (about 1 mm x about 1 mm), fibers from the molten state, and / or hot extruded cylinders from the molten state or intermediate glassy state, as described in Examples 1, 2, and 7 above, using a temperature appropriate for each compound (i.e., above Tm or Tg as needed). Compounds 2-10 and 17 were processed into articles to convert the crystalline compounds into a glassy state and confirmed by DSC for use in thermoformed pellets. Drug release from thermoformed pellets was performed in PBS and / or 100% FBS for different time periods, as described in Example 1. Cumulative drug release plotted over time showed that drug release from the different compounds occurred primarily linearly at a rate different from that of the intact pellets over the time range tested, similar to drug release from compound 1. Pellets of heterodimer compound 4 released dexamethasone and hydrocortisone. The following table shows the accompanying figures corresponding to the images of the pellets, fibers, and cylinders, as well as the drug release profiles of the pellets.

[0622] Table 4. Compounds and drug release in glassy state

[0623]

[0624] Example 11. Glassy Nanoparticles and Microparticles Formed from Compounds 3 (TA-TEG-TA) and 5 (Dex-HEX-Dex) Provide Sustained Drug Release

[0625] Using conditions similar to those described for compound 1 in Example 3 above, electrospray and emulsification were used to extract compound 3 ( Figure 18A and 18B ) and 5( Figure 18C and 18D ) Nanoparticles and microparticles were prepared using a 2-hydroxy-2-pyrrolidone (2-pyrrolidone) ionomer ... Figure 18E An example DSC chromatogram is shown, Figure 18F The particle size distribution of microparticles prepared from an emulsion of compound 3 in DCM using SDS as a surfactant is shown. Drug release from the microparticles of compound 3 was performed in PBS solution containing 50% FBS, similar to that described in Example 1. Cumulative drug release was calculated and plotted as a percentage of total drug released over time ( Figure 18G ).

[0626] Example 12: Glassy thermoformed pellets can be formed from a mixture of two dimers and release drug from both compounds in the intact pellets

[0627] As shown in the table below, glassy pellets were formed by thermoforming a mixture of compounds. The starting crystalline compounds were mixed together and thermoformed at a temperature higher than that of the higher melting point compound. Drug release from the pellets (approximately 1 mm x 1 mm and approximately 1 mg of total mixture) was performed in PBS as described in Example 1. Cumulative drug release was calculated and plotted as a percentage of total drug released over time. Linear drug release from the intact pellets was observed for both compounds in the mixed pellets.

[0628] Table 4. Thermoformed pellets formed from a mixture of two compounds and drug release

[0629]

[0630]

[0631] Example 13: Method for Modulating Drug Release from Glassy Articles

[0632] Drug release from glassy articles can be controlled in a variety of ways, such as by changing the environment in which the article is placed or by adjusting the article's physical properties to exploit surface erosion mechanisms of drug release. While the environment and physical properties of the article are fixed, other properties, such as processing conditions, formulation, and / or compound structure via linker modifications, can be adjusted to tailor the article to achieve the desired drug release profile for the intended application. To illustrate this point, Figure 22A The release of hydrocortisone from thermoformed pellets (approximately 1 mm x 1 mm) of Compound 2 (HC-TEG-HC), Compound 4 (Dex-TEG-HC), and Compound 6 (HC-SUCC-HC) described in Example 9 above, and Mixture A (Compounds 1 and 2 (1:1 w / w)) described in Example 10 above, at 37°C in PBS is plotted. Similarly, Figure 22B Plotted is the release of dexamethasone from thermoformed pellets (approximately 1 mm x 1 mm) of Compound 1 (Dex-TEG-Dex) and Compound 4 (Dex-TEG-HC) described above in Examples 1 and 9, and Mixture A (Compounds 1 and 2 (1:1 w / w)) described above in Example 10 at 37° C. in PBS. Linear drug release from the intact pellet was observed for all pellets, but differences in drug release rates varied depending on the use of different linkers, the use of a second steroid dimer as an excipient, or the use of a second steroid in heterodimeric form. Figure 22C The release of dexamethasone from thermoformed pellets (approximately 1 mm x 1 mm) of Compound 1 (Dex-TEG-Dex) and Compound 5 (Dex-Hex-Dex) in 100% FBS shown in further exemplifies how the linker can affect drug release rate.

[0633] Example 14: Compounds 11 (Dex-EG7-Dex), 12 (Dex-EG9-Dex), and 13 (Dex-PEG300-Dex) can be formed into glassy thermoformed pellets and extruded cylinders, but undergo changes in physical form (shape) and drug release over time in release medium at 37°C

[0634] Compounds 11, 12, and 13 were processed into thermoformed pellets (about 1 mm x about 1 mm) and hot extruded cylinders as described in Examples 1, 2, and 7 above using temperatures appropriate for the compound and are shown in the table below. The hot-processed articles made from compounds 11, 12, and 13 were glassy as confirmed by DSC. For compounds 11 and 12, drug release from the thermoformed pellets was performed in PBS and 100% FBS as described in Example 1. Both compounds underwent changes in physical form (shape) and drug release in PBS and 100% FBS, and Figure 26A and 26B The pellets of compounds 11 and 12 in PBS at 37°C are exemplified in FIG. The changes in drug release correspond to changes in the physical form (geometry) of the pellets. As shown in the table below, similar changes in physical form (shape) were observed for extruded cylinders of compounds 11, 12, and 13, which formed as small drops at the bottom of the vial in PBS at 37°C in less than 2 weeks.

[0635] Table 5. Compounds 11, 12, and 13 processed in the glassy state

[0636]

[0637] Example 15: Compound 14 (CHS-TEG-CHS) can form pellets and fibers, but has residual crystallinity, and the pellets cannot release drug in the release medium at 37°C

[0638] Compound 14 was processed into thermoformed pellets (approximately 1 mm x approximately 1 mm) and fibers as described in Examples 1 and 2 above and are shown in the table below. The thermoformed pellets exhibited residual crystallinity as confirmed by DSC. Drug release from the thermoformed pellets was performed in PBS and 100% FBS as described in Example 1, but no drug was released from the pellets in either release medium.

[0639] Table 6. Compound 7 processed in glassy state

[0640]

[0641] Example 16: Compounds 15 (FA-TEG-FA(E)) and 16 (Ethin-TEG-Ethin) can form glassy pellets and fibers but cannot release drugs in the release medium at 37°C

[0642] Compounds 15 and 16 were processed into thermoformed pellets (approximately 1 mm x approximately 1 mm) and fibers as described in Examples 1 and 2 above and are shown in the table below. The thermoformed articles were glassy as confirmed by DSC. Drug release from the thermoformed pellets was performed in PBS and 100% FBS as described in Example 1, but no drug was released from the pellets in either release medium.

[0643] Table 7. Compounds 15 and 16 processed in the glassy state

[0644]

[0645] Example 17. Microparticles and Nanoparticles for Treating Local Inflammation

[0646] According to the above method, microparticles and nanoparticles are formed from compound 1. The microparticles and nanoparticles are then injected into the joints of subjects suffering from inflammation, such as arthritis, and dexamethasone is released into the subjects at a steady rate over three months. The local inflammation of the subject's joints is alleviated. Similarly, other compounds of the present disclosure can also be used to form microparticles and nanoparticles and injected into the subject's joints for the treatment of, for example, inflammation, and the drug is released at a steady rate over several months (e.g., three months).

[0647] Example 18. Drug Dimer

[0648] Compounds 18-20 described below can be prepared using methods similar to those described herein. These compounds can be processed as described herein to produce products that produce an extended release profile after implantation in a subject and can be used in the methods, compositions, and products of the present disclosure.

[0649] Compound dimer abbreviation 18 Dexamethasone-glycerol-dexamethasone Dex-Gly-Dex 19 Hydrocortisone-hexane-hydrocortisone HC-Hex-HC 20 Prednisolone-TEG-Abiraterone Pred-TEG-Abir

[0650] Example 19. Effect of Compounds on Product Stability and Drug Release Profile

[0651] Each of compounds 1, 4, 5, 8, and 10-13 had moderate variation in the linker that covalently tethered the two dexamethasone groups to the dimer. All compounds were observed to be capable of being processed into articles (e.g., glassy amorphous solids). However, articles formed from different compounds were observed to exhibit significantly different stabilities (under physiologically relevant conditions) and significantly different dexamethasone release profiles.

[0652] Preparations formed from compounds 11, 12, and 13 with dexamethasone and a longer PEG linker appeared to undergo a change in physical form (shape), whereas preparations formed from compounds 1 and 8 with dexamethasone and a shorter PEG linker did not undergo such a change. Figure 23D 、 24D As shown in 25D and 25D, compounds 11, 12 and 13 formed spherical droplets after two weeks in PBS. Figure 1F It was shown that the pellets formed from Compound 1 maintained their shape as they gradually became smaller due to surface erosion.

[0653] It was also observed that the preparations formed from the different compounds exhibited significantly different dexamethasone release profiles. Due to these changes in physical form (shape) of the preparations of compounds 11, 12, and 13, the drug release mechanism was not by surface erosion and was therefore not linear or predictable (see Figure 26A and 26B ). The changes in physical form (shape) observed for the product correspond to changes in release rate. In addition, if Figure 26B As shown, drug release eventually ceased completely. Unexpectedly, the longer length PEG linker resulted in a preparation that failed to exhibit the beneficial properties of the shorter length compounds. On the other hand, the release profiles of dexamethasone from preparations formed from compounds 1, 5, 8, and 10 were observed to be generally linear over a period of 12 weeks or longer (see, e.g., Figure 1E 、 12E , 15C and 17D). In contrast, the release curves of dexamethasone from preparations formed from compounds 11 and 12 were observed to be non-linear (see Figure 26A and 26B ). Surprisingly, in preparations formed from compound 12, dexamethasone release ceased at only about 3% of the cumulative release after only 2 weeks in PBS.

[0654] like Figure 22C The release curves of dexamethasone from thermoformed pellets (approximately 1 mm x 1 mm) of Compound 1 (Dex-TEG-Dex) and Compound 5 (Dex-Hex-Dex) in 100% FBS illustrate how the linker affects the drug release rate. The differences in these release profiles suggest that preparations formed from Compound 1 may be preferred for applications where dexamethasone release is desired for only 1 or 2 months (e.g., for pellets of approximately 1 mm x 1 mm in 100% FBS), whereas preparations formed from Compound 5 may be preferred for applications where dexamethasone release is desired for 6 months or longer.

[0655] In addition, the drug itself (i.e., D1 and / or D2) can affect the release rate of the compound. For example, compared to other drug dimers that similarly contain triethylene glycol linkers such as compounds 1, 3, and 7 (respectively Figure 1E 、 10E Compared with 14E), compounds 9 (FA-TEG-FA(CE)) and 2 were released very quickly in 100% FBS, but in a controlled manner, as shown in Table 2. Figure 16E and 9E As shown. It was also observed that compounds 14-16 showed no release after several weeks at 37°C in 100% FBS, each of which also had a triethylene glycol linker but was formed from a different drug or contained a different linking moiety (i.e., compounds 9 and 15). These differences in release profiles suggest that even if drug dimers share the same linker, the drug itself can affect the release profile.

[0656] Although all compounds can be processed into different preparations in the glassy / amorphous state, the differences between them become apparent once these compounds are placed in aqueous or biological environments.

[0657] Some embodiments of the disclosure provided herein can be defined according to the following numbered items:

[0658] 1. A product comprising a compound of formula (A-VIII):

[0659] D1-L-D2 (A-VIII)

[0660] or a pharmaceutically acceptable salt thereof,

[0661] in

[0662] (i) D1 and D2 are each independently a group formed from a steroid; and L is a linker that covalently links D1 to D2,

[0663] (ii) at least 90% (w / w) of the preparation is a compound of formula (A-VIII),

[0664] (iii) the product does not contain a controlled release excipient, and

[0665] (iv) D1 and D2 were in 100% bovine serum at 37°C or in PBS at 37°C so that t 10 Greater than or equal to t 50 The product is released from the preparation at a rate 1 / 10 of that of the product.

[0666] 2. A product comprising a compound of formula (A-VIII):

[0667] D1-L-D2 (A-VIII)

[0668] or a pharmaceutically acceptable salt thereof,

[0669] in

[0670] (i) D1 and D2 are each independently a group formed from a steroid; and L is a linker that covalently links D1 to D2,

[0671] (ii) at least 90% (w / w) of the preparation is a compound of formula (A-VIII),

[0672] (iii) the article is a fiber, a web, a woven fabric, a nonwoven fabric, a pellet, a cylinder, a hollow tube, a microparticle, a nanoparticle, or a shaped article, and

[0673] (iv) The preparation does not contain a release-controlling excipient.

[0674] 3. The article of claim 1 or 2, wherein the compound D1 or D2 is released from the article by surface erosion.

[0675] 4. A product comprising a compound of formula (A-VIII):

[0676] D1-L-D2 (A-VIII)

[0677] or a pharmaceutically acceptable salt thereof, wherein the preparation is formed by a process comprising the steps of:

[0678] (a) heating the compound or a pharmaceutically acceptable salt thereof to form a melt; and

[0679] (b) heating and shaping the melt to form the article,

[0680] wherein D1 and D2 are each independently a group formed from a steroid; and L is a linker that covalently links D1 to D2.

[0681] 5. A product comprising a compound of formula (A-VIII):

[0682] D1-L-D2 (A-VIII)

[0683] or a pharmaceutically acceptable salt thereof, wherein the preparation is formed by a process comprising the steps of:

[0684] (a) heating the compound or a pharmaceutically acceptable salt thereof to form a melt; and

[0685] (b) injection molding the melt to form the article,

[0686] wherein D1 and D2 are each independently a group formed from a steroid; and L is a linker that covalently links D1 to D2.

[0687] 6. A product comprising a compound of formula (A-VIII):

[0688] D1-L-D2 (A-VIII)

[0689] or a pharmaceutically acceptable salt thereof, wherein the preparation is formed by a process comprising the steps of:

[0690] (a) heating the compound or a pharmaceutically acceptable salt thereof to form a melt; and

[0691] (b) blow molding the melt to form the article,

[0692] wherein D1 and D2 are each independently a group formed from a steroid; and L is a linker that covalently links D1 to D2.

[0693] 7. A product comprising a compound of formula (A-VIII):

[0694] D1-L-D2 (A-VIII)

[0695] or a pharmaceutically acceptable salt thereof, wherein the preparation is formed by a process comprising the steps of:

[0696] (a) dissolving the compound or a pharmaceutically acceptable salt thereof to form a solution; and

[0697] (b) evaporating the solvent to form the article,

[0698] wherein D1 and D2 are each independently a group formed from a steroid; and L is a linker that covalently links D1 to D2.

[0699] 8. The article of claim 7, wherein step (b) comprises solvent casting to form a film or fiber.

[0700] 9. A product comprising a compound of formula (A-VIII):

[0701] D1-L-D2 (A-VIII)

[0702] or a pharmaceutically acceptable salt thereof, wherein the preparation is formed by a process comprising the steps of:

[0703] (a) dissolving the compound or a pharmaceutically acceptable salt thereof to form a solution; and

[0704] (b) electrospinning or electrospraying the solution to form the article,

[0705] wherein D1 and D2 are each independently a group formed from a steroid; and L is a linker that covalently links D1 to D2.

[0706] 10. A product comprising a compound of formula (A-VIII):

[0707] D1-L-D2 (A-VIII)

[0708] or a pharmaceutically acceptable salt thereof, wherein the preparation is formed by a process comprising the steps of:

[0709] (a) heating the compound or a pharmaceutically acceptable salt thereof to form a melt; and

[0710] (b) electrospinning or electrospraying the melt to form the article,

[0711] wherein D1 and D2 are each independently a group formed from a steroid; and L is a linker that covalently links D1 to D2.

[0712] 11. A product comprising a compound of formula (A-VIII):

[0713] D1-L-D2 (A-VIII)

[0714] or a pharmaceutically acceptable salt thereof, wherein the preparation is formed by a process comprising the steps of:

[0715] (a) heating the compound or a pharmaceutically acceptable salt thereof to form a melt; and

[0716] (b) extruding said melt to form said article,

[0717] wherein D1 and D2 are each independently a group formed from a steroid; and L is a linker that covalently links D1 to D2.

[0718] 12. The preparation of any one of items 1-11, wherein the molecular weight of L is 80 to 800 Da.

[0719] 13. The article of any one of items 1 to 12, wherein L is covalently linked to D1 and D2 via one or more ester, carbonic acid, carbonate, or anhydride bonds.

[0720] 14. The article of claim 13, wherein L is covalently linked to D1 and D2 via one or more carbonate bonds.

[0721] 15. The product of any one of items 1 to 14, wherein

[0722] L includes the group -(C(O)-(R A )-C(O)- or -O-(R A )-O-;

[0723] R A is a polyol radical and contains at least one free hydroxyl group, or R A Selected from C 1-20Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, 3-10 atom ring system, -(CH2CH2O) q CH2CH2-、-(CH2CH2CH2CH2O) r CH2CH2CH2CH2-or-(CH2CH(CH3)O) s CH2CH(CH3)-; and

[0724] q, r, and s are integers from 1 to 10.

[0725] 16. An article formed from the compound of any one of items 84-102, 108 and 110.

[0726] 17. The product of any one of items 1 to 16, wherein D1 and D2 are each selected from anabolic steroids, androgenic steroids, progesterone steroids, estrogenic steroids, cancer treatment steroids, antibiotic steroids, glucocorticoid steroids, mild steroids, anti-angiogenic steroids, steroids that lower intraocular pressure (IOP), bile acid-related bile acid steroids, cholesterol derivatives, other steroids, pheromones, steroid metabolites, progesterone, neurosteroids and corticosteroids.

[0727] 18. The article of any one of items 1-17, wherein the compound is further described by one of formulas (II)-(LXXV).

[0728] 19. The preparation of any one of items 1 to 18, wherein D1 and D2 are formed from the same steroid, or wherein D1 and D2 are formed from different steroids.

[0729] 20. The article of claim 19, wherein the article comprises a mixture of two or more compounds of formula (A-VIII).

[0730] 21. The preparation of any one of items 1 to 20, wherein at least 70% (w / w) of the preparation is a compound of formula (A-VIII).

[0731] 22. The preparation of any one of items 1 to 21, wherein at least 90% (w / w) of the preparation is a compound of formula (A-VIII).

[0732] 23. The article of any one of items 1 to 22, wherein the compound D1 or D2 is released from the article by surface erosion.

[0733] 24. The preparation of claim 23, wherein after 5 days at 37°C in 100% bovine serum, the surface erodes to release less than 10% of D1 or D2 (as a percentage of the total drug D1 or D2 present in the preparation as a prodrug); or after 5 days at 37°C in PBS, the surface erodes to release less than 2% of D1 or D2 (as a percentage of the total drug D1 or D2 present in the preparation as a prodrug); or after not less than 6 days at 37°C in 100% bovine serum, the surface erodes to release more than 20% of D1 or D2 (as a percentage of the total drug D1 or D2 present in the preparation as a prodrug); or after not less than 6 days at 37°C in PBS, the surface erodes to release more than 5.0% of D1 or D2 (as a percentage of the total drug D1 or D2 present in the preparation as a prodrug); or D1 and / or D2 are such that t 10 Greater than or equal to t 50 It is released from the product at a rate of 1 / 10 of that of the

[0734] 25. The article of any one of items 1-24, wherein the article further comprises 0.1% to 10% (w / w) of one or more additives, wherein the one or more additives are selected from plasticizers, antioxidants, binders, lubricants, radiopaque agents, and mixtures thereof.

[0735] 26. The article of any one of items 1 to 25, wherein the article is a fiber, a web, a woven fabric, a nonwoven fabric, a pellet, a cylinder, a hollow tube, a microparticle, a nanoparticle, or a shaped article.

[0736] 27. The article of any one of items 1-26, wherein the article is free of release-controlling excipients, free of crystallization-inhibiting excipients, free of mechanical integrity-enhancing excipients, and / or free of binding excipients; or the article optionally has a glassy state.

[0737] 28. Fiber formed from the compound of any one of items 84-102, 108, and 110.

[0738] 29. Fibers formed from a compound of formula (A-VIII) or a pharmaceutically acceptable salt thereof:

[0739] D1-L-D2(A-VIII)

[0740] wherein the fibers are produced by a process comprising the following steps:

[0741] (a) dissolving the compound or a pharmaceutically acceptable salt thereof in a solvent to form a solution; and

[0742] (b) electrospinning, dry spinning, wet spinning or gel spinning the solution to form the fiber,

[0743] wherein D1 and D2 are each independently a group formed from a steroid; and L is a linker that covalently links D1 to D2.

[0744] 30. Fibers formed from a compound of formula (A-VIII) or a pharmaceutically acceptable salt thereof:

[0745] D1-L-D2 (A-VIII)

[0746] wherein the fibers are produced by a process comprising the following steps:

[0747] (a) heating the compound or a pharmaceutically acceptable salt thereof to form a melt; and

[0748] (b) extruding said melt to form said fibers,

[0749] wherein D1 and D2 are each independently a group formed from a steroid; and L is a linker that covalently links D1 to D2.

[0750] 31. Fibers formed from a compound of formula (A-VIII) or a pharmaceutically acceptable salt thereof:

[0751] D1-L-D2 (A-VIII)

[0752] wherein the fibers are produced by a process comprising the following steps:

[0753] (a) heating the compound or a pharmaceutically acceptable salt thereof to form a melt; and

[0754] (b) electrospinning the melt to form the fibers,

[0755] wherein D1 and D2 are each independently a group formed from a steroid; and L is a linker that covalently links D1 to D2.

[0756] 32. The fiber of any one of items 29-31, wherein the molecular weight of L is 80 to 800 Da.

[0757] 33. The fiber of any one of items 29-32, wherein L is covalently linked to D1 and D2 via one or more ester, carbonic acid, carbonate, or anhydride bonds.

[0758] 34. The fiber of any one of items 29 to 33, wherein

[0759] L includes the group -(C(O)-(R A )-C(O)- or -O-(R A )-O-;

[0760] R Ais a polyol radical and contains at least one free hydroxyl group, or R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, 3-10 atom ring system, -(CH2CH2O) q CH2CH2-、-(CH2CH2CH2CH2O) r CH2CH2CH2CH2-or-(CH2CH(CH3)O) s CH2CH(CH3)-; and

[0761] q, r, and s are integers from 1 to 10.

[0762] 35. The fiber of any one of items 29-34, wherein D1 and D2 are each selected from anabolic steroids, androgenic steroids, progesterone steroids, estrogenic steroids, cancer treatment steroids, antibiotic steroids, glucocorticoid steroids, mild steroids, anti-angiogenic steroids, steroids that lower intraocular pressure (IOP), bile acid-related bile acid steroids, cholesterol derivatives, other steroids, pheromones, steroid metabolites, progesterone, neurosteroids and corticosteroids.

[0763] 36. The fiber of any one of items 29-34, wherein the compound is further described by one of formulas (II)-(LXXV).

[0764] 37. The fiber of any one of items 28-36, wherein D1 and D2 are formed from the same steroid, or wherein D1 and D2 are formed from different steroids.

[0765] 38. The fiber of item 37, wherein the fiber comprises a mixture of two or more compounds of formula (A-VIII).

[0766] 39. The fiber of any one of items 28 to 38, wherein at least 70% (w / w) of the fiber is a compound of formula (A-VIII).

[0767] 40. The fiber of any one of items 28 to 38, wherein at least 90% (w / w) of the fiber is a compound of formula (A-VIII).

[0768] 41. The fiber of any one of items 28 to 40, wherein the compound D1 or D2 is released from the fiber by surface erosion.

[0769] 42. The fiber of claim 41 , wherein after 5 days at 37° C. in 100% bovine serum, the surface erodes to release less than 10% of D1 or D2 (as a percentage of the total drug D1 or D2 present in the fiber as a prodrug); or after 5 days at 37° C. in PBS, the surface erodes to release less than 2% of D1 or D2 (as a percentage of the total drug D1 or D2 present in the fiber as a prodrug); or after not less than 6 days at 37° C. in 100% bovine serum, the surface erodes to release more than 20% of D1 or D2 (as a percentage of the total drug D1 or D2 present in the fiber as a prodrug); or after not less than 6 days at 37° C. in PBS, the surface erodes to release more than 5.0% of D1 or D2 (as a percentage of the total drug D1 or D2 present in the fiber as a prodrug); or D1 and / or D2 are such that t 10 Greater than or equal to t 50 It is released from the fiber at a rate of 1 / 10 of that of the original.

[0770] 43. The fiber of any one of items 28-42, wherein the fiber further comprises 0.1% to 10% (w / w) of one or more additives, wherein the one or more additives are selected from plasticizers, antioxidants, adhesives, lubricants, radiopaque agents, and mixtures thereof.

[0771] 44. The fiber of any one of items 28-43, wherein the fiber is free of a release-controlling excipient, free of a crystallization-inhibiting excipient, free of a mechanical integrity-enhancing excipient, and / or free of a binding excipient; or the fiber optionally has a glassy state.

[0772] 45. A web or woven fabric formed from the fibers of any one of items 28 to 44.

[0773] 46. ​​A nonwoven fabric formed from the fibers of any one of items 28 to 44.

[0774] 47. A glassy composition formed from the compound of any one of items 84-102, 108 and 110.

[0775] 48. A glassy composition formed from a compound of formula (A-VIII) or a pharmaceutically acceptable salt thereof:

[0776] D1-L-D2 (A-VIII)

[0777] The composition is prepared by a process comprising the following steps:

[0778] (a) heating the compound or a pharmaceutically acceptable salt thereof to form a melt; and

[0779] (b) cooling the melt to form the composition,

[0780] wherein D1 and D2 are each independently a group formed from a steroid; and L is a linker that covalently links D1 to D2.

[0781] 49. The glassy composition of item 47 or 48, wherein the molecular weight of L is 80 to 800 Da.

[0782] 50. The glassy composition of any one of items 47-49, wherein L is covalently linked to D1 and D2 via one or more ester, carbonic acid, carbonate, or anhydride bonds.

[0783] 51. The glassy composition of any one of items 47 to 50, wherein

[0784] L includes the group -(C(O)-(R A )-C(O)- or -O-(R A )-O-;

[0785] R A is a polyol radical and contains at least one free hydroxyl group, or R A Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 Arylene, 3-10 atom ring system, -(CH2CH2O) q CH2CH2-、-(CH2CH2CH2CH2O) r CH2CH2CH2CH2-or-(CH2CH(CH3)O) s CH2CH(CH3)-; and

[0786] q, r, and s are integers from 1 to 10.

[0787] 52. The glassy composition of any one of items 47-51, wherein D1 and D2 are each selected from anabolic steroids, androgenic steroids, progesterone steroids, estrogenic steroids, cancer therapeutic steroids, antibiotic steroids, glucocorticoid steroids, mild steroids, anti-angiogenic steroids, steroids that lower intraocular pressure (IOP), bile acid-related bile acid steroids, cholesterol derivatives, other steroids, pheromones, steroid metabolites, progesterone, neurosteroids and corticosteroids.

[0788] 53. The glassy composition of any one of items 47-52, wherein the compound is further described by one of formulas (II)-(LXXV).

[0789] 54. The glassy composition of any one of items 47-53, wherein D1 and D2 are formed from the same steroid, or wherein D1 and D2 are formed from different steroids.

[0790] 55. The glassy composition of claim 54, wherein the glassy composition comprises a mixture of two or more compounds of formula (A-VIII).

[0791] 56. The glassy composition of any one of items 47 to 55, wherein at least 70% (w / w) of the glassy composition is a compound of formula (A-VIII).

[0792] 57. The glassy composition of any one of items 47 to 56, wherein at least 90% (w / w) of the glassy composition is a compound of formula (A-VIII).

[0793] 58. The glassy composition of any one of items 47 to 57, wherein the compound D1 or D2 is released from the glassy composition by surface erosion.

[0794] 59. The glassy composition of claim 58, wherein after 5 days at 37°C in 100% bovine serum, surface erosion releases less than 10% of D1 or D2 (as a percentage of the total drug D1 or D2 present in the glassy composition as a prodrug); or after 5 days at 37°C in PBS, surface erosion releases less than 2% of D1 or D2 (as a percentage of the total drug D1 or D2 present in the glassy composition as a prodrug); or after 6 days at 37°C in 100% bovine serum, surface erosion releases more than 20% of D1 or D2 (as a percentage of the total drug D1 or D2 present in the glassy composition as a prodrug); or after 6 days at 37°C in PBS, surface erosion releases more than 5.0% of D1 or D2 (as a percentage of the total drug D1 or D2 present in the glassy composition as a prodrug); or D1 and / or D2 are such that t 10 Greater than or equal to t 50 The release rate is 1 / 10 of that from the glassy composition.

[0795] 60. The glassy composition of any one of items 47-59, wherein the glassy composition further comprises 0.1% to 10% (w / w) of one or more additives, wherein the one or more additives are selected from plasticizers, antioxidants, binders, lubricants, radiopaque agents, and mixtures thereof.

[0796] 61. The glassy composition of any one of items 47-60, wherein the glassy composition is formed by machining, molding, fiber spinning, electrospinning, electrospraying, blow molding, or extrusion.

[0797] 62. The glassy composition of any one of items 47-61, wherein the glassy composition is a fiber, a fiber web, a woven fabric, a nonwoven fabric, a pellet, a cylinder, a hollow tube, a microparticle, a nanoparticle, or a shaped article in the shape of a cylinder, a cube, a sheet, a star, a ring, a pyramid, a sphere, an irregular polygon, or a regular polygon.

[0798] 63. The glassy composition of claim 62, wherein the glassy composition is a shaped article in the form of:

[0799] (i) fibers having an average diameter of about 0.01 to 1 mm;

[0800] (ii) pellets having an average diameter of about 0.2 to 5 mm;

[0801] (iii) a cylinder with a diameter of about 0.01 to 1 mm and a length of 0.5 to 20 mm;

[0802] (iv) microparticles having an average diameter of about 1 to 1000 μm; or

[0803] (v) Nanoparticles with an average diameter of about 0.01 to 1 μm.

[0804] 64. The glassy composition of any one of items 47-63, wherein the glassy composition is free of release-controlling excipients, free of crystallization-inhibiting excipients, free of mechanical integrity-enhancing excipients, and / or free of binding excipients.

[0805] 65. A substrate comprising a coating formed from a compound of formula (A-VIII):

[0806] D1-L-D2 (A-VIII)

[0807] in

[0808] (i) D1 and D2 are each independently a group formed from a steroid; and L is a linker that covalently links D1 to D2 via one or more carbonic acid or carbonate bonds,

[0809] (ii) at least 90% (w / w) of the preparation is a compound of formula (A-VIII), and

[0810] (iii) The preparation does not contain a release-controlling excipient.

[0811] 66. The substrate of item 65, wherein the molecular weight of L is 80 to 800 Da.

[0812] 67. The substrate of item 65 or 66, wherein L is covalently linked to D1 and D2 via one or more carbonate bonds.

[0813] 68. The substrate of any one of items 65-67, wherein D1 and D2 are each selected from anabolic steroids, androgenic steroids, progesterone steroids, estrogenic steroids, cancer treatment steroids, antibiotic steroids, glucocorticoid steroids, mild steroids, anti-angiogenic steroids, steroids that lower intraocular pressure (IOP), bile acid-related bile acid steroids, cholesterol derivatives, other steroids, pheromones, steroid metabolites, progesterone, neurosteroids and corticosteroids.

[0814] 69. The substrate of any one of items 65-68, wherein the compound is further described by one of formulas (II)-(LXXV).

[0815] 70. The substrate of any one of items 65-69, wherein D1 and D2 are formed from the same steroid, or wherein D1 and D2 are formed from different steroids.

[0816] 71. The substrate of item 70, wherein the coating comprises a mixture of two or more compounds of formula (A-VIII).

[0817] 72. The substrate of any one of items 65-71, wherein at least 70% (w / w) of the coating is a compound of formula (A-VIII).

[0818] 73. The substrate of any one of items 65-72, wherein at least 90% (w / w) of the coating is a compound of formula (A-VIII).

[0819] 74. The substrate of any one of items 65 to 73, wherein the compound D1 or D2 is released from the coating by surface erosion.

[0820] 75. The substrate of claim 74, wherein the surface erodes to release less than 10% of D1 or D2 (as a percentage of the total drug D1 or D2 present in the coating as a prodrug) after 5 days in 100% bovine serum at 37°C; or the surface erodes to release less than 2% of D1 or D2 (as a percentage of the total drug D1 or D2 present in the coating as a prodrug) after 5 days in PBS at 37°C; or the surface erodes to release more than 20% of D1 or D2 (as a percentage of the total drug D1 or D2 present in the coating as a prodrug) after not less than 6 days in 100% bovine serum at 37°C; or the surface erodes to release more than 5.0% of D1 or D2 (as a percentage of the total drug D1 or D2 present in the coating as a prodrug) after not less than 6 days in PBS at 37°C; or D1 and / or D2 are such that t 10 Greater than or equal to t 50 It is released from the coating at a rate of 1 / 10 of that of the original.

[0821] 76. The substrate of any one of items 65-75, wherein the article further comprises 0.1% to 10% (w / w) of one or more additives, wherein the one or more additives are selected from plasticizers, antioxidants, adhesives, lubricants, radiopaque agents, and mixtures thereof.

[0822] 77. The substrate of any one of items 65-76, wherein the coating is free of release-controlling excipients, free of crystallization-inhibiting excipients, and free of mechanical integrity-enhancing excipients; or the coating optionally has a glassy state.

[0823] 78. A substrate comprising a coating formed from the compound of any one of items 84-102, 108 and 110.

[0824] 79. The substrate of item 78, wherein at least 70% (w / w) of the coating is the compound.

[0825] 80. The substrate of item 78, wherein at least 90% (w / w) of the coating is the compound.

[0826] 81. The substrate of any one of items 78 to 80, wherein the coating has a glassy state and is formed from the compound of any one of items 84 to 102, 108 and 110.

[0827] 82. A coating having a glassy state formed from the compound of any one of items 84 to 102, 108 and 110.

[0828] 83. An implantable medical device comprising the substrate of any one of items 65-82, wherein the coating is located on a surface of the implantable medical device.

[0829] 84. Compounds described by formula (AI):

[0830] D1-OLO-D2 (AI),

[0831] or a pharmaceutically acceptable salt thereof, wherein

[0832] D1-O and D2-O are each independently a group formed from a steroid;

[0833] L is -C(O)-OC(O)-(R B )-C(O)OC(O)-; and

[0834] R B Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10arylene, a ring system of 3 to 10 atoms,

[0835] wherein the steroid is an anabolic steroid, an androgenic steroid, a progestin steroid, an estrogenic steroid, a cancer therapy steroid, an antibiotic steroid, a glucocorticoid steroid, a mild steroid, an anti-angiogenic steroid, a steroid that lowers intraocular pressure (IOP), a bile acid-related bile acid steroid, a cholesterol derivative, another steroid, a pheromone, a steroid metabolite, a progesterone, a neurosteroid, or a corticosteroid.

[0836] 85. The compound described by formula (A-II):

[0837] D1-OLO-D2 (A-II),

[0838] or a pharmaceutically acceptable salt thereof, wherein

[0839] D1-O and D2-O are each independently a group formed from a steroid;

[0840] L is -C(O)O-(R A )-OC(O)-;

[0841] Among them O-(R A )-O is a radical of a polyol and contains at least one free hydroxyl group,

[0842] wherein the steroid is an anabolic steroid, an androgenic steroid, a progestin steroid, an estrogenic steroid, a cancer therapy steroid, an antibiotic steroid, a glucocorticoid steroid, a mild steroid, an anti-angiogenic steroid, a steroid that lowers intraocular pressure (IOP), a bile acid-related bile acid steroid, a cholesterol derivative, another steroid, a pheromone, a steroid metabolite, a progesterone, a neurosteroid, or a corticosteroid.

[0843] 86. Compounds described by formula (A-III):

[0844] D1-OLO-D2 (A-III),

[0845] or a pharmaceutically acceptable salt thereof, wherein

[0846] D1-O and D2-O are each independently a group formed from a steroid;

[0847] L is -C(O)O-(R A )-OC(O)-、-C(O)-(R B )-C(O)-or-C(O)-OC(O)-(R B )-C(O)OC(O)-;

[0848] RA Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms, or O-(R A )-O is a polyol radical and contains at least one free hydroxyl group, or is selected from:

[0849] -O(CH2CH2O) n CH2CH2O-,

[0850] -O(CH2CH2CH2CH2O) m CH2CH2CH2CH2O-, or

[0851] -O(CH2CH(CH3)O) p CH2CH(CH3)O-;

[0852] n, m, and p are integers from 1 to 10; and

[0853] R B Selected from C 1-20 Alkylene, straight chain or branched heteroalkylene of 1 to 20 atoms, straight chain or branched C 2-20 Alkenylene, straight chain or branched C 2-20 Alkynylidene, C 5-10 arylene, a ring system of 3 to 10 atoms,

[0854] wherein the steroid is an anabolic steroid, an androgenic steroid, a progestin steroid, an estrogenic steroid, a cancer therapy steroid, an antibiotic steroid, an antiangiogenic steroid, a steroid that lowers intraocular pressure (IOP), a bile acid-related bile acid steroid, a cholesterol derivative, another steroi...

Claims

1. A compound having the following structure:

2. A compound having the following structure:

Images