Glass formulations and uses thereof
The disclosure features pharmaceutical compositions formed from prodrug dimers for the extended delivery of a drug and for the treatment of a disease or condition.
1. An article comprising a compound of formula (A-VIII):
D1-L-D2 (A-VIII)
or a pharmaceutically acceptable salt thereof, wherein
(i) each of D1 and D2 is, independently, a radical formed from a steroid; and L is a linker covalently linking D1 to D2,
(ii) at least 70% (w/w) of the article is the compound of formula (A-VIII),
(iii) the article is free of controlled release polymer and comprises the compound in amorphous form, and
(iv) the article is a fiber, pellet, cylinder, hollow tube, microparticle, or a nanoparticle.
2. The article of claim 1 , wherein the compound, D1, and/or D2 is released from the article through surface erosion.
3. The article of claim 1 , 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) heat molding, injection molding, the melt to form the article.
4. The article of claim 1 , wherein the article is formed by a process comprising the steps of: (a) dissolving the compound, or a pharmaceutically acceptable salt thereof, in a solvent to form a solution; and (b) evaporating the solvent to form the article.
5. The article of claim 4 , wherein step (b) comprises solvent casting to form a film or a fiber.
6. The article of claim 1 , wherein the article is formed by a process comprising the steps of: (a) dissolving the compound, or a pharmaceutically acceptable salt thereof, in a solvent to form a solution; and (b) electrospinning or electrospraying the solution to form the article.
7. The article of claim 1 , wherein the article is formed by a process comprising the steps of: (a) dissolving the compound, or a pharmaceutically acceptable salt thereof, in an organic solvent containing a surfactant to form an emulsion; and (b) removing organic solvent from the emulsion to form the in the shape of a nanoparticle or microparticle.
8. The article of claim 1 , wherein the article is formed by a process comprising the steps of: (a) heating the compound, or a pharmaceutically acceptable salt thereof, to form an intermediate glassy state material; and (b) heat extruding the intermediate glassy state material to form the article.
9. The article of claim 1 , wherein L has a molecular weight of from 80 to 800 Da.
10. The article of claim 1 , wherein L is covalently linked to D1 and to D2 via one or more ester, carbonate, carbonate ester, or anhydride linkages.
11. The article of claim 10 , wherein L is covalently linked to D1 and to D2 via one or more carbonate linkages.
12. The article of claim 1 , wherein
L comprises the radical —C(O)—(R A )—C(O)— or —O—(R A )—O—;
R A is a radical of a polyol and includes at least one free hydroxyl group or R A is selected from C 1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C 2-20 alkenylene, a linear or branched C 2-20 alkynylene, a C 5-10 arylene, a cyclic system of 3 to 10 atoms, —(CH 2 CH 2 O) q CH 2 CH 2 —, —(CH 2 CH 2 CH 2 CH 2 O) r CH 2 CH 2 CH 2 CH 2 —, or —(CH 2 CH(CH 3 )O) s CH 2 CH(CH 3 )—; and
q, r, and s are integers from 1 to 10.
13. The article of claim 1 , wherein each of D1 and D2 is selected from an anabolic steroid, an androgenic steroid, a progestin steroid, an estrogen steroid, a cancer treatment steroid, an antibiotic steroid, a glucocorticoid steroid, a benign steroid, an anti-angiogenic steroid, an intraocular pressure (IOP) lowering steroid, a cholic acid-related bile acid steroid, a cholesterol-derivative, other steroid, a pheromone, a steroid metabolite, a progestin, a neurosteroid, and a corticosteroid.
14. The article of claim 1 , wherein the compound is further described by one of formulas (II)-(LXXV).
15. The article of claim 1 , wherein D1 and D2 are formed from the same steroid.
16. The article of claim 1 , wherein D1 and D2 are formed from different steroids.
17. The article of claim 1 , wherein the article comprises a mixture of two or more compounds of formula (A-VIII).
18. The article of claim 1 , wherein at least 90% (w/w) of the article is the compound of formula (A-VIII).
19. The article of claim 1 , wherein at least 95% (w/w) of the article is the compound of formula (A-VIII).
20. The article of claim 1 , wherein the article further comprises from 0.1% to 10% (w/w) of one or more additives, wherein the one or more additives are selected from plasticizers, antioxidants, binders, lubricants, radio-opaque agents, and mixtures thereof.
21. The article of claim 1 , wherein the article has a glassy state.
22. The article of claim 1 , wherein each of D1 and D2 is released from the article at 37° C. in 100% bovine serum or at 37° C. in phosphate buffered saline (PBS) at a rate such that t 10 is greater than or equal to 1/10 of t 50 .
23. A method of treating an inflammatory disease or condition in a subject in need thereof, the method comprising administering to the subject an article in an amount sufficient to treat the inflammatory disease or disorder in the subject, wherein the article comprises a compound of formula (A-VIII):
D1-L-D2 (A-VIII)
or a pharmaceutically acceptable salt thereof, wherein
(i) each of D1 and D2 is, independently, a radical formed from a steroid; and L is a linker covalently linking D1 to D2,
(ii) at least 70% (w/w) of the article is the compound of formula (A-VIII),
(iii) the article is free of controlled release polymer, and comprises the compound in amorphous form.
24. The method of claim 23 , wherein the article is a fiber, pellet, cylinder, hollow tube, microparticle, or a nanoparticle.
25. The method of claim 23 , wherein the article is administered locally.
26. The method of claim 25 , wherein the article is administered intraocularly.
27. The method of claim 25 , wherein the article is administered into a joint space.
28. The method of claim 25 , wherein the inflammatory disease or condition is osteoarthritis.
29. A method of reducing inflammation at a location in a subject, the method comprising locally administering to the subject the article of claim 1 in an amount sufficient to reduce the inflammation in the subject at the location.