CONTROLLED RELEASE DRUG DIMERS

Abstract

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.

Claims

1. An article comprising a compound having a structure of Formula (II-A):
D1-L-D2 (II-A) wherein: D1 is a first radical; D2 is a second radical; L is a (e.g., hydrolyzable) linker covalently linking D1 to D2, or a pharmaceutically salt or solvate thereof, wherein the first and second radicals are non-steroidal.

2. The compound of any one of the preceding claims, wherein D1 and/or D2 are attached to the linker through a hydroxyl radical, an amine radical, an amide radial, a carboxylate radical, or a thiol radical.

3. The compound of any one of the preceding claims, wherein D1 and/or D2 are attached to the linker through a hydroxyl radical, an amine radical, or a carboxylate radical.

4. The compound of claim 3, wherein the first radical and the second radical are each independently selected from a nonsteroidal anti-inflammatory drug (NSAID) (e.g., pranoprofen, bromfenac, and indoprofen), a CNS agent (e.g., an analgesic agent, an anti-psychotic agent (e.g., haloperidol), an anti-depressive agent, an anti-histamine, an anti-convulsant (e.g., L-DOPA)), a rho kinase (ROCK) inhibitor (e.g., ripasudil and fasudil), an anthraquinone (e.g., diacerein), an anti-cancer agent (e.g., podophyllotoxin, SN-38, and melphalan), an anti-viral agent (e.g., trifluridine and podophyllotoxin), an anti-oxidant (e.g., ferulic acid and kaempferol), a muscarinic antagonist, an anti-microbial agent (e.g., cefazolin and tedizolid), or an anti-coagulant (e.g., warfarin) in their free form.

5. The compound of any one of the preceding claims, wherein at least one of the first radical or the second radical is a solid (e.g., at a temperature of less than or equal to 30° C.) in their free form.

6. The compound of any one of the preceding claims, wherein the first radical and the second radical are each a solid (e.g., at a temperature of less than or equal to 30° C.) in their free form.

7. The compound of any one of the preceding claims, having the structure of Formula (II-B): ##STR00087## wherein: L is a linker, or a pharmaceutically acceptable salt thereof.

8. The compound of any one of the preceding claims, having the structure of Formula (II-C): ##STR00088## wherein: L is a linker, or a pharmaceutically acceptable salt thereof.

9. The compound of any one of the preceding claims, having the structure of Formula (II-D): ##STR00089## wherein: R.sup.m and R.sup.m′ are each independently H or optionally substituted alkyl; R.sup.n and R.sup.n′ are each independently H or optionally substituted alkyl; and L is a linker, or a pharmaceutically acceptable salt thereof.

10. The compound of any one of the preceding claims, having the structure of Formula (II-E): ##STR00090## wherein: R.sup.m and R.sup.m′ are each independently H or optionally substituted alkyl; R.sup.n and R.sup.n′ are each independently H or optionally substituted alkyl; R.sup.o and R.sup.o′ are each independently H or optionally substituted alkyl; and L is a linker, or a pharmaceutically acceptable salt thereof.

11. The compound of any one of the preceding claims, having the structure of Formula (II-F): ##STR00091## wherein: L is a linker, or a pharmaceutically acceptable salt thereof.

12. The compound of any one of claims 7-10, wherein any one of R.sup.m, R.sup.n, or R.sup.o is adjoined to any one of R.sup.m′, R.sup.n′, or R.sup.o′ by the linker.

13. The compound of any one of claims 7-11, wherein R.sup.m is adjoined to R.sup.m′ by the linker.

14. The compound of any one of claims 7-11, wherein R.sup.n is adjoined to R.sup.n′ by the linker.

15. The compound of any one of claims 10-11, wherein R.sup.o is adjoined to R.sup.o′ by the linker.

16. The compound of any one of the preceding claims, wherein the linker is a hydrolyzable linker.

17. The compound of any one of the preceding claims, wherein the hydrolyzable linker comprises one or more hydrolyzable group.

18. The compound of any one of the preceding claims, wherein the linker is alkyl (e.g., saturated alkyl or unsaturated alkyl), heteroalkyl, or alkoxy, wherein the alkyl, heteroalkyl, or alkoxy is optionally substituted.

19. The compound of any one of the preceding claims, wherein the alkyl, heteroalkyl, or alkoxy are each independently substituted with one or more groups, each group being independently selected from oxo, —O—, —S—, silicone, amino, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted.

20. The compound of any one of the preceding claims, wherein the linker comprises one or more linker groups, each linker group being independently selected from oxo, —O—, —S—, optionally substituted alkylene (e.g., alkenyl, alkynyl, branched (e.g., polypropylene), haloalkyl), optionally substituted heteroalkylene (e.g, polyTHF), and optionally substituted cycloalkylene.

21. The compound of any one of the preceding claims, wherein the linker comprises one or more linker groups, each linker group being independently selected from alkyl, alkoxy, and cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl are optionally substituted.

22. The compound of any one of the preceding claims, wherein the linker comprises one or more linker groups selected from oxo, —O—, —S—, unsubstituted alkylene, (CH.sub.2CH.sub.2).sub.n, (CHCH).sub.n, O(CH.sub.2CH.sub.2O).sub.n, (CH.sub.2CH.sub.2O).sub.n, and (CH(CH.sub.3)C(═O)O).sub.n, wherein n is 1-20.

23. The compound of any one of any one of the preceding claims, wherein the linker comprises one or more linker group selected from oxo, unsubstituted alkylene, (CH.sub.2CH.sub.2).sub.n, (CHCH).sub.n, O(CH.sub.2CH.sub.2O).sub.n, (CH.sub.2CH.sub.2O).sub.n, (CH(CH.sub.3)C(═O)O).sub.n, or (CH.sub.2CH.sub.2).sub.nC═O(CH(CH.sub.3)C(═O)O).sub.n, wherein n is 1-20.

24. The compound of any one of claims 1-21, wherein the linker is alkyl (alkylene) substituted with one or more groups selected from —OH, halo, oxo, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl.

25. The compound of any one of claims 1-21, wherein the linker is unsubstituted alkyl (alkylene).

26. The compound of any one of claims 1-21, wherein the linker is heteroalkyl (heteroalkylene) substituted with one or more groups selected from halo or alkyl.

27. The compound of any one of claims 1-21, wherein the linker is unsubstituted heteroalkyl (heteroalkylene).

28. The compound of any one of the preceding claims, wherein the linker is selected from the group consisting of: —(CR.sub.2).sub.y—, —(C═O)(CR.sub.2).sub.y(C═O)—, —O(CR.sub.2).sub.yO—, —(C═O)O(CR.sub.2).sub.yO(C═O)—, —O(CR.sub.2).sub.y—, —(CR.sub.2).sub.yO—, and —O(CH.sub.2CH.sub.2O).sub.y—, wherein y is 1-10 and each R is independently selected from the group consisting of H, halogen, alkyl, or is taken together with another R to form an optionally substituted cycloalkyl.

29. The compound of any one of the preceding claims, wherein the linker is hydrolyzed in a buffered solution.

30. The compound of any one of the preceding claims, wherein the linker is hydrolyzed by an enzyme.

31. The compound of claim 29, wherein the enzyme is a hydrolase (e.g., a protease or an esterase).

32. A compound selected from the group consisting of: ##STR00092## ##STR00093## or any pharmaceutically acceptable salt thereof.

33. The compound of any one of the preceding claims, wherein the compound is processable (e.g., into an article or the amorphous state).

34. The compound of any one of the preceding claims, wherein the compound is a solid (e.g., has a melting point (e.g., T.sub.m or T.sub.g) of at least 37° C.).

35. The compound of any one of the preceding claims, wherein the compound is a crystalline solid, a film, a glass, or an amorphous solid (e.g., at a temperature of at least 37° C.).

36. The compound of any one of the preceding claims, wherein the compound has crystallinity of at most 15% (e.g., determined by PXRD, DSC, or polarized light microscopy).

37. The compound of any one of the preceding claims, wherein the compound is substantially not crystalline (e.g., determined by PXRD, DSC, or polarized light microscopy).

38. The compound of any one of the preceding claims, wherein the compound is amorphous (e.g., determined by PXRD, DSC, or polarized light microscopy).

39. The compound of any one of the preceding claims, wherein the thermal melting point (T.sub.m) is greater than or equal to the glass transition temperature (T.sub.g).

40. The compound of any one of the preceding claims, wherein the compound has a melting point of at least 37° C.

41. The compound of anyone of the preceding claims, wherein the compound has a melting point of at least 100° C.

42. The compound of any one of the preceding claims, wherein either one or both of the first and/or second radicals are released (e.g., in their free form), the release being sustained release and/or extended release.

43. The compound of any one of the preceding claims, wherein either one or both of the first and/or second radicals being released (e.g., in their free form) for at least 14 days (e.g., in solution, buffer solution, serum, biological environment, in vivo, or the like).

44. A pharmaceutical implant or coating comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

45. The pharmaceutical implant or coating of claim 43, wherein the implant or coating comprises at least 50 wt. % (at least 60 wt. %, at least 70 wt. %, at least 80 wt. %, at least 90 wt. %, at least 95 wt. %, at least 98 wt. %, or the like) of the compound and/or pharmaceutically acceptable salt thereof.

46. The pharmaceutical implant or coating according to claim 43 or 44, wherein the implant or coating undergoes surface erosion to release the compound, the first radical, and/or the second radical.

47. The pharmaceutical implant or coating any one of claims 43-45, wherein the first radical and the second radical are released from the pharmaceutical implant or coating at near zero-order in a buffered solution or in vivo.

48. The pharmaceutical implant or coating of any one of claims 43-46, wherein the first radical and the second radical are released from the pharmaceutical implant or coating at 37° C. in 100% bovine serum or at 37° C. in phosphate buffered saline (PBS) at a rate such that t.sub.10 is greater than or equal to 1/10 of t.sub.50.

49. A pharmaceutical composition comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

50. The implant, article, or composition of any one of the preceding claims, wherein the pharmaceutical composition is suitable for administration to an individual in need thereof.

51. A method for treating a disease or disorder (e.g., or the symptoms thereof) in an individual in need thereof, the method comprising implanting the article, implant, or composition of any one of the preceding claims into the individual.

52. The method of claim 50, wherein the disease or disorder is an acute or a chronic disease or disorder.

53. The method of any one of claim 50 or 51, wherein the disease or disorder is selected from a neurodegenerative disease or disorder (e.g., Parkinson's Disease), pain, an ocular disease or disorder (e.g., glaucoma), asthma, constipation, anxiety, inflammation, psychosis, convulsion, epilepsy, infection (e.g., microbial, bacterial, viral, fungal), cancer, diabetes, osteoporosis, arthritis, and depression.

54. The method of any one of claims 50-52, wherein removal of the article or implant from the individual administered the article or implant is not required (e.g., because the implant is completely or almost completely (e.g., bio- or physiologically) degraded or degradable (e.g., at least 80 wt. %, at least 85 wt. %, at least 90 wt. %, at least 95 wt. %, at least 98 wt. %, at least 99 wt. %, or the like)).

55. The method of any one of claims 50-52, wherein the article or implant is not removed (e.g., because the implant is completely or almost completely (e.g., bio- or physiologically) degraded or degradable (e.g., at least 80 wt. %, at least 85 wt. %, at least 90 wt. %, at least 95 wt. %, at least 98 wt. %, at least 99 wt. %, or the like)) from an individual administered the article or implant.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0143] FIGS. 1A-1F show Compound 1 (dexamethasone-triethylene glycol-dexamethasone, Dex-TEG-Dex) (FIG. 1A) formed into pellets (FIG. 1B) in the glassy state. Results of testing by differential scanning calorimetry (DSC) (FIG. 1C) and X-ray powder diffraction (XRPD) (FIG. 1D) are shown, and drug release overtime was determined (FIG. 1E). FIG. 1F shows representative images of the pellets incubated in drug release medium over time.

[0144] FIG. 2 shows a chemical structure (Indoprofen-TEG-Indoprofen, FIG. 2A) and article (FIG. 2B) exemplified herein. FIG. 2C shows a surface coated with the composition and the release from the coating (FIG. 2D).

[0145] FIG. 3 shows a chemical structure (Fasudil-Hep-Fasudil, FIG. 3A) and article (FIG. 3B) exemplified herein.

[0146] FIG. 4 shows a chemical structure (Bromfenac-TEG-Bromfenac, FIG. 4A) as well as a surface coated with a composition (FIG. 4B) and the release of the composition (FIG. 4C).

[0147] FIG. 5 shows a chemical structure (Fasudil-Seb-Fasudil, FIG. 5A) and article (FIG. 5B) exemplified herein.

[0148] FIG. 6 shows a compound provided herein (L-Dopa-CDM-L-Dopa).

[0149] FIG. 7 shows a compound provided herein (Bromfenac-TEG-Bromfenac—formaldehyde bridge).

[0150] FIG. 8 shows a compound provided herein (Indomethacin-TEG-Indomethacin, FIG. 8A) as well as an article formed from the compound (FIG. 8B).

[0151] FIG. 9 shows a chemical structure (FIG. 9A) and article (FIG. 9B) exemplified herein (naloxone-adipate-naloxone). FIG. 9C shows the drug release profile for the composition (pellet) in phosphate-buffered saline (PBS) over 20 days. FIG. 9D represents the 20-day progression of the surface erosion drug release profile for the composition in PBS.

[0152] FIG. 10 shows 7-day progression of the surface erosion drug release profile for a surface coated with a composition (naloxone-adipate-naloxone) provided herein in fetal bovine serum (FBS) (FIG. 10A and FIG. 10B).

[0153] FIG. 11 shows the chemical structure of a composition (naltrexone-adipate-naltrexone) provided herein.

[0154] FIG. 12 shows a chemical structure (FIG. 12A) and article (FIG. 12B) exemplified herein (Nalmefene-Adip-Nalmefene). FIG. 12C shows the drug release profile for the composition (pellet) in phosphate-buffered saline (PBS) over 14 days. FIG. 12D represents the 14-day progression of the surface erosion drug release profile for the composition in PBS.

[0155] FIG. 13 shows a chemical structure (FIG. 13A) and article (FIG. 13B) exemplified herein (Naloxone-Seb-Naloxone). FIG. 13C shows the drug release profile for the composition (pellet) in phosphate-buffered saline (PBS) over 14 days. FIG. 13D represents the 14-day progression of the surface erosion drug release profile for the composition in PBS.

[0156] FIG. 14 shows a chemical structure (FIG. 14A) and article (FIG. 14B) exemplified herein (Naloxone-CDM-Naloxone). FIG. 14C shows the drug release profile for the composition (pellet) in phosphate-buffered saline (PBS) over 14 days. FIG. 14D represents the 14-day progression of the surface erosion drug release profile for the composition in PBS.

[0157] FIG. 15 shows a chemical structure (FIG. 15A) and article (FIG. 15B) exemplified herein (Naltrexone-Seb-Naltrexone). FIG. 15C shows the drug release profile for the composition (pellet) in phosphate-buffered saline (PBS) over 14 days. FIG. 15D represents the 14-day progression of the surface erosion drug release profile for the composition in PBS.

[0158] FIG. 16 shows a chemical structure (FIG. 16A) and article (FIG. 16B) exemplified herein (Naltrexone-1,4-cyclohexyl-Naltrexone). FIG. 16C shows the drug release profile for the composition (pellet) in phosphate-buffered saline (PBS) over 14 days. FIG. 16D represents the 14-day progression of the surface erosion drug release profile for the composition in PBS.

[0159] FIG. 17 shows the chemical structure of a composition (Naltrexone-1,4-terephthalate-Naltrexone) that did not form a heat processed pellet exemplified herein.

[0160] FIG. 18 shows a chemical structure (FIG. 18A) and article (FIG. 18B) exemplified herein (Naltrexone-dodecane-Naltrexone). FIG. 18C shows the drug release profile for the composition (pellet) in phosphate-buffered saline (PBS) over 14 days. FIG. 18D represents the 14-day progression of the surface erosion drug release profile for the composition in PBS.

[0161] FIG. 19 shows a chemical structure (FIG. 19A) and article (FIG. 19B) exemplified herein (Naltrexone-3-ethyl-3-methylglutaric acid-Naltrexone). FIG. 19C shows the drug release profile for the composition (pellet) in phosphate-buffered saline (PBS) over 14 days. FIG. 19D represents the 14-day progression of the surface erosion drug release profile for the composition in PBS.

[0162] FIG. 20 shows a chemical structure (FIG. 20A) and article (FIG. 20B) exemplified herein (Naltrexone-Hex-Naltrexone). FIG. 20C shows the drug release profile for the composition (pellet) in phosphate-buffered saline (PBS) over 14 days. FIG. 20D represents the 14-day progression of the surface erosion drug release profile for the composition in PBS.

[0163] FIG. 21 shows a chemical structure (FIG. 21A) and article (FIG. 21B) exemplified herein (Naltrexone-CDM-Naltrexone). FIG. 21C shows the drug release profile for the composition (pellet) in phosphate-buffered saline (PBS) over 14 days. FIG. 21D represents the 14-day progression of the surface erosion drug release profile for the composition in PBS.

[0164] FIG. 22 shows the chemical structure of a composition (Hydromorphone-Adip-Hydromorphone) exemplified herein.

[0165] FIG. 23 shows the chemical structure of a composition (Codeine-Adip-Codeine) exemplified herein.

DETAILED DESCRIPTION

[0166] Provided herein are prodrug dimers that can be in a crystallizable form and have unique properties that allow them to be processed as viscous fluids from a melt or solution (e.g., in order to yield shaped articles where most of the material is in a glassy state). The shaped articles may be held together by secondary (e.g., non-crystalline) interactions and have the ability to release their prodrug/drug elements from these shaped forms upon surface mediated degradation/dissolution. This may provide a controlled rate of drug release over days, weeks, months, or years due to unique interactions between the molecules that exist in a mostly amorphous state while holding the shaped form intact as the surface erodes. This disclosure may alter the need for a carrier matrix to provide shape and form to a drug delivery depot or device, and, therefore, may mitigate the issues of phase separation of drug from the matrix, and incompatible processing conditions between the formulations' components.

[0167] The compounds and articles provided herein can be designed for the controlled and sustained release of a drug from the prodrug dimer used to make the shaped article. The release rate from an article provided can be controlled through several engineerable design parameters, including, for example, but not limited to: 1) selection of the drug; 2) selection of the functional group of the drug for conjugation (e.g., if multiple exist); 3) selection of the linker; 4) selection of the linkage group (i.e., esters, carbonates, carbonate esters, or anhydrides); 5) selection of the surface area of the shaped article; and 6) selection of the drug loading in the shaped article (e.g., by adding traditional pharmaceutical excipients or mixing other drug dimers as excipients when making the shaped article). In some embodiments, the controlled release of two or more drugs through the use of heterodimers (i.e., different drugs on the two ends of the linkers). Articles formed from the compounds provided herein can yield sustained and uniform release of the drug compounds, without exhibiting any burst release (e.g., t.sub.10 can be equal to or greater than 1/10 of t.sub.50) and without reliance upon degradable matrices, which can cause undesirable local side effects (such as inflammation). The high drug loading that can be present in the articles of the disclosure are suitable for producing locally effective concentrations of a drug for periods of days to weeks to months or even years.

Definitions

[0168] The term “annealing,” as used herein, generally refers to the process of heating an article formed from the compound of formula (A-I) above its glass transition temperature, Tg, (e.g., depending upon the compound, heating to 110-145° C., 130-185° C., 150-215° C., or 180-240° C.) for a period sufficient to reduce residual stress in the article (e.g., from 1 second to 48 hours) followed by cooling.

[0169] The term “free of controlled release polymer,” as used herein, generally refers to the absence of an amount of a polymeric material of greater than 10 KDa in the articles provided herein that is sufficient to delay or slow the release of the drug dimer from the article in comparison to the release profile observed for an otherwise identical article containing none of the polymeric material, where the release profile is measured at 37° C. in 100% fetal bovine serum (FBS).

[0170] The term “free of a crystallization inhibiting excipient,” as used herein, generally refers to the absence of an amount of an excipient in the articles of the disclosure that is sufficient to reduce the amount of crystalline drug dimer in the article in comparison to the amount of crystalline drug dimer observed in an otherwise identical article containing none of the excipient. The level of crystallinity can be measured using DSC or XRD. In particular embodiments, the articles provided herein are free of a crystallization inhibiting excipient that is a polymeric material of greater than 10 KDa.

[0171] The term “free of a mechanical integrity enhancing excipient,” as used herein, generally refers to the absence of an amount of an excipient in the articles, in some embodiments herein, that is sufficient to increase the mechanical integrity of the article in comparison to the mechanical integrity of an otherwise identical article containing none of the excipient. In some embodiments, the mechanical integrity of an article can be tested using a 3- or 4-point mechanical bend test (ASTM C1684-18) on the formulation with or without the excipient with the article in the shape of a rod either in the dry state (prior to drug release), hydrated state (after immersion in release medium), or after 15-30% drug release in hydrated state. In some embodiments, (e.g., for articles with a rectangular shape) the mechanical integrity can be tested using a 3-point mechanical bend test (ASTM D790-17) or 4-point mechanical bend test (ASTM D6272) on the formulation with or without excipient either in the dry state (prior to drug release), hydrated state (after immersion in release medium) or after 15-30% drug release in hydrated state. In some embodiments, a reduction in mechanical integrity causes the articles to break apart sooner (e.g., increasing the total surface area of the quantity of articles, and resulting in a more rapid release profile, where the release profile is measured at 37° C. in 100% FBS). In particular embodiments, the articles of the disclosure are free of a mechanical integrity enhancing excipient that is a polymeric material of greater than 10 KDa.

[0172] The term “free of a binding excipient,” as used herein, generally refers to the absence of an amount of an excipient in the articles of the disclosure that is sufficient to delay or slow the release of the drug dimer from the article in comparison to the release profile observed for an otherwise identical article containing none of the binding excipient, where the release profile is measured at 37° C. in 100% FBS.

[0173] The term “anti-cancer agent,” as used herein, generally refers to a drug that is used in the treatment of cancer. Examples of anti-cancer agents include SN-38, melphalan, and podophyllotoxin.

[0174] The term “SN-38,” as used herein, generally refers to a drug having the following structure:

##STR00010##

[0175] The term “anthraquinone,” as used herein, generally refers to a drug that belongs to the class of anthraquinone compounds. An example of an anthraquinone is diacerein.

[0176] The term “anticoagulant,” as used herein, generally refers to a drug that prevents or reduces coagulation of blood, prolonging clotting time. An exemplary anticoagulant is warfarin.

[0177] The term “antimicrobial agent,” as used herein, generally refers to a drug that kills microorganisms or inhibits their growth. Examples of antimicrobial agents include, e.g., cefazolin and tedizolid.

[0178] The term “antioxidant,” as used herein, generally refers to a compound or drug that can inhibit oxidation. Exemplary antioxidants include, without limitation, ferulic acid and kaempferol.

[0179] The term “antiviral agent,” as used herein, generally refers to a drug for the treatment of infections caused by viruses. Exemplary antiviral agents include, without limitation, trifluridine and podophyllotoxin.

[0180] The term “central nervous system agent” or “CNS agent,” as used herein, generally refers to a drug that affects the central nervous system. An example of a CNS agent includes L-DOPA.

[0181] The term “cylinder,” as used herein, generally refers to the shape of the pharmaceutical compositions of the disclosure that has parallel sides and a circular or oval cross section, or a shaped cross section (e.g., a star shaped cross section). A mean diameter of the cylinder can range from about 0.01 to 1 mm diameter, e.g., 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. A mean length of the cylinder can range from about 0.05 to 20 mm, e.g., 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 mean diameter of the cylinder is in the range of about 0.01 to 1 mm and the mean length of the cylinder is about 0.1 mm to 4.0 mm. In some embodiments, the mean length of the cylinder is about 0.5 to 10 mm, or about 1 to 10 mm.

[0182] The term “fiber,” as used herein, generally refers to the shape of the pharmaceutical compositions of the disclosure that is elongated or threadlike. A mean diameter of the fiber can range from about 0.01 to 1 mm, e.g., 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. A mean length of the fiber can range from 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.

[0183] The term “fiber mesh,” as used herein, generally refers to a web or a net in having many attached or woven fibers. The fiber mesh can have aligned and unaligned morphologies.

[0184] The term “glassy state,” as used herein, generally refers to an amorphous solid including greater than 70%, 80%, 90%, 95%, 98%, or 99% (w/w) of one or more drug dimers of the invention and exhibiting a glass transition temperature above 38° C. In the glassy state, as measured by DSC or XRD, the level of crystallinity is low, ranging from 0-15%, e.g., 0-1%, 0-3%, 0-5%, 0-7%, 0-9%, 0-10%, or 0-13%. Glass formulations of the invention can be formed using heat processing or solvent processing one or more drug dimers.

[0185] The term “microparticle,” as used herein, generally refers to the shape of the pharmaceutical compositions of the disclosure, which can be regularly or irregularly shaped. A mean diameter of the microparticle can range from about 1 to 1000 μm, e.g., 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, a “microbead” refers to a microparticle that is spherical.

[0186] The term “nanoparticle,” as used herein, generally refers to the shape of the pharmaceutical compositions of the disclosure, which can be regularly or irregularly shaped. A mean diameter of the nanoparticle can range from about 0.01 to 1 μm, e.g., 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, a “nanobead” refers to a nanoparticle that is spherical.

[0187] The term “nonsteroidal anti-inflammatory drug” or “NSAID,” as used herein, generally refers to a drug that reduces pain, decreases fever, prevents blood clots and, in higher doses, decreases inflammation. Exemplary nonsteroidal anti-inflammatory drugs include, without limitation, pranoprofen, bromfenac, and indoprofen.

[0188] The term “non-woven fabric,” as used herein, generally refers to a web structure bonded together by entangling fibers.

[0189] The term “analgesic,” as used herein, generally refers to a powerful pain-reducing medication. Exemplary analgesics are oxycodone and morphine.

[0190] The term “pellet,” as used herein, generally refers to the shape of the pharmaceutical compositions of the disclosure that is rounded, spherical, or cylindrical, or a combination thereof. A mean diameter of the pellet can range from about 0.2 to 5 mm, e.g., from about 0.2 to 1 mm, from about 0.2 to 2 mm, from about 0.3 to 3 mm, from about 1.5 to 5 mm, from about 2 to 5 mm, from about 2.5 to 5 mm, from about 3 to 5 mm, from about 3.5 to 5 mm, from about 4 to 5 mm, or from about 4.5 to 5 mm.

[0191] The term “pharmaceutically acceptable salt” as used herein, generally represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharm. Sci. 66:1-19, 1977. The salts can be prepared in situ during the final isolation and purification of the compounds of the disclosure or separately by reacting the free base group with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, carbonate, chloride, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, 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 salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

[0192] The term “rho kinase inhibitor” or “ROCK inhibitor” generally refers to a drug that targets rho kinase. Exemplary ROCK inhibitors include, without limitation, ripasudil and fasudil.

[0193] The term “surface erosion,” as used herein, generally refers to a process of a gradual disintegration of the pharmaceutical compositions of the disclosure and release of a free drug from the drug dimer. Surface erosion can be tailored to achieve desired drug release rates. Surface erosion can depend on the drug composition of the drug dimer, and can be modulated by the cleavage of drug-linker bond through hydrolysis and/or enzymatic degradation. The rate of surface erosion and release of a given drug from a drug dimer may also depend on the quantity of the loaded drug dimer as a percent of the final drug dimer formulation, article size (e.g. dimensions), solubility of drug dimer (e.g., through selection of appropriate drug and/or linker), and/or surface area of the article. For example, surface erosion mechanism of drug release allows drug delivery articles to be tailored with specific physical features (dimensions, diameters, surface areas, total mass, etc.) to achieve desired drug release rates, and drug release may be designed to be initiated within minutes or hours, and may continue to occur over days, weeks, months, or years.

[0194] As used herein, “t.sub.50” generally refers to the time at which 50% of the releasable drug has been released from an article of the invention. Time t.sub.10 is, correspondingly, the time at which 10% of the releasable drug has been released from an article of the invention. When the release curve is perfectly linear, t.sub.10=⅕ of t.sub.50. When there is an initial burst of released drug, t.sub.10 is much less than ⅕ of t.sub.50. In the compositions and methods of the disclosure, t.sub.10 can be equal to or greater than 1/10 of t.sub.50. Drug release from an article or compound of the disclosure can be measured at 37° C. in 100% bovine serum, or at 37° C. in phosphate buffered saline (PBS), as described in Example 1.

[0195] The term “woven fabric,” as used herein, generally refers to pharmaceutical compositions that resemble materials that are formed by weaving of fibers.

Chemical Definitions

[0196] By “acyl” is meant a chemical moiety with the formula —C(O)R′, where R′ is selected from the group consisting of C.sub.1-10 alkyl, C.sub.2-20 alkene, heteroalkyl, C.sub.2-20 alkyne, C.sub.5-10 aryl, and cyclic system. Examples of acyl groups include, without limitation, acetyl, propanoyl, butanoyl, pentanoyl, and tetrahydrofuran-2-oyl.

[0197] By “aliphatic” is meant a non-aromatic chemical moiety of hydrocarbons. Aliphatics may be cyclic, straight, or branched chains, and may be saturated or unsaturated, and may have single, double, or triple bonds.

[0198] By “alkoxy” is meant a chemical substituent of the formula —OR, wherein R is an alkyl group. By “aryloxy” is meant a chemical substituent of the formula —OR, wherein R is a C.sub.5-10 aryl group.

[0199] As used herein, the terms “alkylene,” “alkenylene,” “alkynylene,” and the prefix “alk” refer to divalent groups having a specified size, typically C.sub.1-10 or C.sub.1-20 for the saturated groups (e.g., alkylene or alk) and C.sub.2-20 or C.sub.2-20 for the unsaturated groups (e.g., alkenylene or alkynylene). They include straight-chain, branched-chain, and cyclic forms as well as combinations of these, containing only C and H when unsubstituted. Because they are divalent, they can link together two parts of a molecule. Examples are methylene, ethylene, propylene, cyclopropan-1,1-diyl, ethylidene, 2-butene-1,4-diyl, and the like. These groups can be substituted by the groups typically suitable as substituents for alkyl, alkenyl and alkynyl groups as set forth herein. Thus C═O is a C1 alkylene that is substituted by ═O, for example.

[0200] By “alkylthio” is meant a chemical substituent of the formula —SR, wherein R is an alkyl group.

[0201] By “arylthio” is meant a chemical substituent of the formula —SR, wherein R is a C.sub.5-10 aryl group.

[0202] By “C.sub.1-20 alkyl” is meant a branched or unbranched saturated hydrocarbon group, having 1 to 20 carbon atoms, inclusive. An alkyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has three to six members. The alkyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.

[0203] By “C.sub.2-20 alkene” is meant a branched or unbranched hydrocarbon group containing one or more double bonds, desirably having from 2 to 10 carbon atoms. A C.sub.2-20 alkene may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members. The C.sub.2-20 alkene group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.

[0204] By “C.sub.2-20 alkyne” is meant a branched or unbranched hydrocarbon group containing one or more triple bonds, desirably having from 2 to 10 carbon atoms. A C.sub.2-20 alkyne may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members. The C.sub.2-20 alkyne group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.

[0205] By “carbonate ester” is meant a linkage group having the formula —C(O)O—C(O)—O—.

[0206] By “carboxyalkyl” is meant a chemical moiety with the formula —(R)—COOH, wherein R is an alkyl group.

[0207] By “cyclic acetal” is meant a ring structure including two oxygen atoms separated by a carbon atom which is optionally substituted (e.g., 1,3-dioxolane). Exemplary substituents include, without limitation, alkyl, hydroxyl, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, fluoroalkyl, carboxyl, carboxyalkyl, amino, aminoalkyl, monosubstituted amino, disubstituted amino, quaternary amino, phosphodiester, phosphoramidate, phosphate, phosphonate, phosphonate ester, sulfonate, sulfate, sulfhydryl, phenol, amidine, guanidine, and imidazole groups.

[0208] The term “cyclic system” refers to a compound that contains one or more covalently closed ring structures, in which the atoms forming the backbone of the ring are composed of any combination of the following: carbon, oxygen, nitrogen, sulfur, and phosphorous. The cyclic system may be substituted or unsubstituted. Exemplary substituents include, without limitation, alkyl, hydroxyl, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, fluoroalkyl, carboxyl, carboxyalkyl, amino, aminoalkyl, monosubstituted amino, disubstituted amino, and quaternary amino groups.

[0209] By “fluoroalkyl” is meant an alkyl group that is substituted with a fluorine.

[0210] By “heteroalkyl” is meant a branched or unbranched alkyl group in which one or more methylenes (—CH.sub.2—) are replaced by nitrogen, oxygen, sulfur, carbonyl, thiocarbonyl, phosphoryl, or sulfonyl moieties. Some examples include tertiary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, phosphoramidates, sulfonamides, and disulfides. A heteroalkyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has three to six members. The heteroalkyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.

[0211] By “hydroxyalkyl” is meant a chemical moiety with the formula —(R)—OH, wherein R is an alkyl group.

[0212] In general, alkyl groups are each independently substituted or unsubstituted. Each recitation of “alkyl” provided herein, unless otherwise stated, includes a specific and explicit recitation of an unsaturated “alkyl” group. Similarly, unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR.sup.a, —SR.sup.a, —OC(O)—R.sup.a, —N(R.sup.a).sub.2, —C(O)R.sup.a, —C(O)OR.sup.a, —C(O)N(R.sup.a).sub.2, —N(R.sup.a)C(O)OR.sup.a, —OC(O)—N(R.sup.a).sub.2, —N(R.sup.a)C(O)R.sup.a, —N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2), —S(O).sub.tOR.sup.a (where t is 1 or 2), —S(O).sub.tR.sup.a (where t is 1 or 2) and —S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2) where each R.sup.a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0213] “Carbocyclyl” or “cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl or cycloalkyl is saturated (i.e., containing single C—C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds). Examples of saturated cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as “cycloalkenyl.” Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term “carbocyclyl” is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —R.sup.b—OR.sup.a, —R.sup.b—OC(O)—R.sup.a, —R.sup.b—OC(O)—OR.sup.a, —R.sup.b—OC(O)—N(R.sup.a).sub.2, —R.sup.b—N(R.sup.a).sub.2, —R.sup.b—C(O)R.sup.a, —R.sup.b—C(O)OR.sup.a, —R.sup.b—C(O)N(R.sup.a).sub.2, —R.sup.b—O—R.sup.c—C(O)N(R.sup.a).sub.2, —R.sup.b—N(R.sup.a)C(O)OR.sup.a, —R.sup.b—N(R.sup.a)C(O)R.sup.a, —R.sup.b—N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2), —R.sup.b—S(O).sub.tR.sup.a (where t is 1 or 2), —R.sup.b—S(O).sub.tOR.sup.a (where t is 1 or 2) and —R.sup.b—S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), where each R.sup.a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R.sup.b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R.sup.c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0214] In general, optionally substituted groups are each independently substituted or unsubstituted. Each recitation of an optionally substituted group provided herein, unless otherwise stated, includes an independent and explicit recitation of both an unsubstituted group and a substituted group (e.g., substituted in certain embodiments, and unsubstituted in certain other embodiments). Unless otherwise stated, substituted groups may be substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR.sup.a, —SR.sup.a, —OC(O)—R.sup.a, —N(R.sup.a).sub.2, —C(O)R.sup.a, —C(O)OR.sup.a, —C(O)N(R.sup.a).sub.2, —N(R.sup.a)C(O)OR.sup.a, —OC(O)—N(R.sup.a).sub.2, —N(R.sup.a)C(O)R.sup.a, —N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2), —S(O).sub.tOR.sup.a (where t is 1 or 2), —S(O).sub.tR.sup.a (where t is 1 or 2) and —S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2) where each R.sup.a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0215] Provided is a compound of formula (A-I) and articles formed from a compound of formula (A-I):

D1-L-D2 (A-I),

or a pharmaceutically acceptable salt thereof, wherein each of D1 and D2 is, independently, a radical formed from a drug; and L is a linker covalently linking D1 to D2. Each of D1 and D2 can be, independently, selected from a nonsteroidal anti-inflammatory drug (NSAID), an (e.g., opioid) analgesic, a CNS agent, a ROCK inhibitor, an anthraquinone, an anti-cancer agent, an antiviral agent, an antioxidant, a muscarinic antagonist, an antimicrobial agent, or an anticoagulant. In some embodiments, the article or compound provided herein does not comprise an opioid radical. In some embodiments, the article or compound provided herein does not release an opioid conjugate or an opioid radical in its free form. L can be covalently linked to D1 and to D2 via one or more ester, carbonate, carbonate ester, anhydride, amide, or carbamate linkages. Ester, carbonate, carbonate ester, or anhydride linkages formed from a functional group on D1 and D2 can be selected from, e.g., hydroxyl or carboxyl. For example, L can include the radical —C(O)—(R.sup.A)—C(O)—, —C(O)—OC(O)—(R.sup.A)—C(O)O—C(O)—, or —O—(R.sup.A)—O—, where R.sup.A is a radical of a polyol and includes at least one free hydroxyl group or R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, —(CH.sub.2CH.sub.2O).sub.qCH.sub.2CH.sub.2—, —(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.rCH.sub.2CH.sub.2CH.sub.2CH.sub.2—, or —(CH.sub.2CH(CH.sub.3)O).sub.sCH.sub.2CH(CH.sub.3)—, and q, r, and s are integers from 1 to 10 (e.g., 1 to 10, 1 to 5, or 5 to 10). The articles of the disclosure can be machined, molded, emulsion-processed, electrospun, electrosprayed, blow molded, or extruded to form a fiber, fiber mesh, woven fabric, non-woven fabric, film, surface coating, pellet, cylinder, microparticle, nanoparticle, or another shaped article.

Drugs Dimerized Via a Hydroxy Moiety

[0216] In some embodiments, the compound has a structure of formula (A-II):

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

or a pharmaceutically acceptable salt thereof, wherein each of D1-O and D2-O is, independently, a radical formed from a drug bearing a hydroxyl group; L is —C(O)—(R.sup.A)—C(O)— or —C(O)—O—(R.sup.A)—O—C(O)—; R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or O—(R.sup.A)—O is a radical of a polyol and includes at least one free hydroxyl group or is selected from: [0217] —O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O—, [0218] —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, or [0219] —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and
n, m, and p are integers from 1 to 10. Each of D1-O and D2-O can, independently, be formed, for example, from podophyllotoxin, SN-38, trifluridine, kaempferol, tedizolid, warfarin, resveratrol, epinephrine, forskolin, doxorubicin, erythromycin, etoposide, sirolimus, phenytoin, DL-atenolol, thalidomide, acetazolamide, chloroxine, stavudine, sulfacetamide, meloxicam, salbutamol, haloperidol, zileuton, piroxicam, primidone, (−)-chloramphenicol, cladribine, chlortalidone, losartan, L-methyldopa, mitoxantrone, carbidopa, dicoumarol, pindolol, (E)-entacapone, hydroxyzine, propranolol, amoxicillin, cefdinir, labetalol, pemetrexed, digoxin, abacavir, metirosine, cefradine, nelarabine, lorazepam, isoprenaline, oxazepam, daunorubicin, fenamisal, misoprostol, (−)-S-timolol, miglustat, tetracycline, (+)-tramadol, digitoxin, spectinomycin, masoprocol, levobunolol, chlortetracycline, novobiocin, ergotamine, rifaximin, methysergide, cefmenoxime, cefaloglycin, or nitroxoline, or described by any one of formulas (I-e)-(I-v), and (I-y)-(I-ax):

##STR00011## ##STR00012## ##STR00013##

Drugs Dimerized Via a Carboxy Moiety

[0220] In some embodiments, the compound has a structure of formula (A-III):

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

or a pharmaceutically acceptable salt thereof, wherein each of D1-C(O) and D2-C(O) is, independently, a radical formed from a drug bearing a carboxyl group; L is —O—(R.sup.A)—O—, —O—C(O)—O—(R.sup.A)—O—C(O)—O—, or —NH—(R.sup.A)—NH—; R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or O—(R.sup.A)—O is a radical of a polyol and includes at least one free hydroxyl group or O—(R.sup.A)—O is selected from: [0221] —O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O—, [0222] —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, or [0223] —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and
n, m, and p are integers from 1 to 10. Each of D1-C(O) and D2-C(O) can, independently, be formed, for example, from pranoprofen, bromfenac, indoprofen, L-DOPA, diacerein, melphalan, ferulic acid, cefazolin, flutathione, methotrexate, indomethacin, furosemide, naproxen, nalidixic acid, baclofen, bumetanide, amlexanox, L-methyldopa, lisinopril, carbidopa, D-(−)-ampicillin, cefalotin, cetirizine, amoxicillin, cefdinir, metirosine, nedocromil, cefixime, piperacillin, ceforanide, cefuroxime, gabapentin, benazeprilat, or ketorolac. In the drug dimers of formula (A-III), D1-C(O)— and D2-C(O)— can further be described, for example, by formulas (I-y) to (I-af) below.

##STR00014## ##STR00015##

Drugs Dimerized Via an Amino Moiety

[0224] In some embodiments the compound has a structure of formula (A-IV):

D1-NH—C(O)-L-C(O)—NH-D2 (A-IV),

or a pharmaceutically acceptable salt thereof, wherein each of D1-NH and D2-NH is, independently, a radical formed from a drug bearing a primary amino functional group; L is —O—(R.sup.A)—O— or —(R.sup.A)—; R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or O—(R.sup.A)—O is a radical of a polyol and includes at least one free hydroxyl group or O—(R.sup.A)—O is selected from: [0225] —O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O—, [0226] —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, or [0227] —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and
n, m, and p are integers from 1 to 10.

[0228] In some embodiments, the compound has a structure of formula (A-V):

##STR00016##

or a pharmaceutically acceptable salt thereof, wherein each of

##STR00017##

is, independently, a radical formed from a drug bearing a secondary amino functional group; L is —O—(R.sup.A)—O— or —(R.sup.A)—; R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or O—(R.sup.A)—O is a radical of a polyol and includes at least one free hydroxyl group or O—(R.sup.A)—O is selected from: [0229] —O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O—, [0230] —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, or [0231] —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and
n, m, and p are integers from 1 to 10. In these embodiments, the moiety O—(R.sup.A)—O can be a radical of a polyol formed from a cyclitol, a sugar alcohol, a linear or cyclic alkane diol, or glycerin. In particular embodiments, O—(R.sup.A)—O is a radical formed from an alkane diol, diethylene glycol, triethylene glycol, tetraethylene glycol, or pentaethylene glycol.

[0232] In some embodiments, the compound has a structure of formula (A-VI):

D1-N═C(R.sup.1)-L-C(R.sup.1)═NH-D2 (A-VI),

or a pharmaceutically acceptable salt thereof, wherein each of D1-N and D2-N is, independently, a radical formed from a drug bearing a primary amino functional group; R.sup.1 is a H or C.sub.1-4 alkyl; L is —(R.sup.A)—; and R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms.

[0233] In some embodiments, the compound has a structure of formula (A-VII):

D1-NH-L-NH-D2 (A-VII),

or a pharmaceutically acceptable salt thereof, wherein each of D1-N and D2-N is, independently, a radical formed from a drug bearing a primary amino functional group; and L is —CH.sub.2—O—C(O)—O—(R.sup.A)—O—C(O)—O—CH.sub.2—, —CH(CH.sub.3)—O—C(O)—O—(R.sup.A)—O—C(O)—O—CH(CH.sub.3)—; and R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or O—(R.sup.A)—O is a radical of a polyol and includes at least one free hydroxyl group or O—(R.sup.A)—O is selected from: [0234] —O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O—, [0235] —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, or [0236] —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and
n, m, and p are integers from 1 to 10.

[0237] Each of the drugs bearing a primary or secondary amino functional group can, independently, be formed, for example, from epinephrine, trifluridine, mitomycin C, fluorouracil, glutathione, doxorubicin, methotrexate, nifedipine, prazosin, bromidinidine, trimethoprim, theophylline, carbamazepine, sulfamethoxazole, omeprazole, furosemide, tiabendazole, hydrochlorothiazide, DL-atenolol, dapsone, pyrimethamine, albendazole, sulfadiazine, acetazolamide, lamotrigine, sulfapyridine, lansoprazole, zonisamide, azathioprine, valdecoxib, imiquimod, baclofen, sulfacetamide, bumetanide, salbutamol, oxcarbazepine, torasemide, sulfafurazole, zileuton, tadalafil, topamax, mafenide, famotidine, indapamide, cladribine, chlortalidone, adefovir dipivoxil, amlexanox, felbamate, isradipine, amoxapine, clozapine, brimonidine, sulfamethoxydiazine, metolazone, (E)-nitrofurazone, ILosartan, L-methyldopa, lisinopril, hydroflumethiazide, dofetilide, minoxidil, nepafenac, mitoxantrone, carbidopa, sulfamethizole, pindolol, primaquine, D-(−)-ampicillin, diclofenamide, melphalan, sulfaphenazole, bupropion, (E)-nizatidine, propranolol, sumatriptan, amoxicillin, cefdinir, labetalol, valaciclovir, pemetrexed, abacavir, metirosine, amiloride, cefradine, nelarabine, (E)-dacarbazine, bendroflumethiazide, methyclothiazide, isoprenaline, ethoxzolamide, daunorubicin, fenamisal, cefixime, benzthiazide, dorzolamide, (−)-S-timolol, tocainide, neptazane, tetracycline, guanfacine, trimetrexate, spectinomycin, methylphenidate, levobunolol, guanethidine, cyclothiazide, guanabenz, chlortetracycline, novobiocin, polythiazide, ergotamine, acetylsulfafurazole, ceforanide, quinethazone, sulfacytine, cefmenoxime, cefaloglycin, cefuroxime, gabapentin, benazeprilat, tamsulosin, ripasudil, or fasudil. In the drug dimers of formulas (A-IV)-(A-VII), the drug radical can further be described, for example, by formula (I-ag) to (I-ax) below.

##STR00018## ##STR00019## ##STR00020##

Drugs Dimerized Via an Enolizable Ketone Moiety

[0238] In some embodiments, the compound has a structure of formula (A-VIII):

D1-E-L-E-D2 (A-VIII),

or a pharmaceutically acceptable salt thereof, wherein each of D1-E and D2-E is, independently, a radical formed from a drug bearing an enolizable ketone functional group (i.e., a ketone adjacent a C—H group that together permit an enol tautomerization); L is —C(O)—(R.sup.A)—C(O)— or —C(O)—O—(R.sup.A)—O—C(O)—; R.sup.A is selected from C.sub.1-20 alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linear or branched C.sub.2-20 alkenylene, a linear or branched C.sub.2-20 alkynylene, a C.sub.5-10 arylene, a cyclic system of 3 to 10 atoms, or O—(R.sup.A)—O is a radical of a polyol and comprises at least one free hydroxyl group or is selected from: [0239] —O(CH.sub.2CH.sub.2O).sub.nCH.sub.2CH.sub.2O—, [0240] —O(CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.mCH.sub.2CH.sub.2CH.sub.2CH.sub.2O—, or [0241] —O(CH.sub.2CH(CH.sub.3)O).sub.pCH.sub.2CH(CH.sub.3)O—; and
n, m, and p are integers from 1 to 10.

[0242] Drug dimers useful in the methods and compositions of the disclosure include homodimers and heterodimers. Drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs), CNS agents, ROCK inhibitors, anthraquinones, anti-cancer agents, antiviral agents, antioxidants, muscarinic antagonists, antimicrobial agents, and anticoagulants, can be used in drug dimers. Examples of NSAIDs include pranoprofen, bromfenac, and indoprofen. An exemplary CNS agent is L-DOPA. Exemplary ROCK inhibitors include ripasudil and fasudil. An exemplary anthraquinone is diacerein. Exemplary anti-cancer agents are podophyllotoxin, SN-38, and melphalan. Exemplary antioxidants are ferulic acid and kaempferol. Exemplary antimicrobial agents include cefazolin and tedizolid. Exemplary antiviral agents include trifluridine and podophyllotoxin. An exemplary anticoagulant is warfarin.

[0243] The drug dimers useful in making the articles of the disclosure can have any of formulas (II)-(IV), (IX)-(XXXIV), and (XLII)-(XLIV), described herein.

Drug Homodimers

[0244] The disclosure features homodimers of the formula (A-I):

D1-L-D2 (A-I)

or a pharmaceutically acceptable salt thereof, wherein D1, D2, and L are as described above. The homodimer can be further described by one of formulas (II)-(IV), (IX)-(XXXIV), and (XLII)-(XLIV), below.

[0245] In some embodiments, the drug is a nonsteroidal anti-inflammatory drug (NSAID) and the drug dimer is further described by the formula (II):

##STR00021##

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

[0246] In some embodiments, the drug is an NSAID and the drug dimer is further described by the formula (III):

##STR00022##

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

[0247] In some embodiments, the drug is an NSAID and the drug dimer is further described by the formula (IV):

##STR00023##

[0248] In some embodiments, the drug is a CNS agent and the drug dimer is further described by the formula (IX):

##STR00024##

[0249] In some embodiments, the drug is a CNS agent and the drug dimer is further described by the formula (X):

##STR00025##

[0250] In some embodiments, the drug is a CNS agent and the drug dimer is further described by the formula (XI):

##STR00026##

[0251] In some embodiments, the drug is a ROCK inhibitor and the drug dimer is further described by formula (XII):

##STR00027##

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

[0252] In some embodiments, the drug is a ROCK inhibitor and the drug dimer is further described by the formula (XIII):

##STR00028##

[0253] In some embodiments, the drug is an anthraquinone and the drug dimer is further described by the formula (XIV):

##STR00029##

[0254] In some embodiments, the drug is an anti-cancer or antiviral agent and the drug dimer is further described by the formula (XV):

##STR00030##

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

[0255] In some embodiments, the drug is an anti-cancer agent and the drug dimer is further described by the formula (XVI):

##STR00031##

[0256] In some embodiments, the drug is an anti-cancer agent and the drug dimer is further described by the formula (XVII):

##STR00032##

[0257] In some embodiments, the drug is an anti-cancer agent and the drug dimer is further described by the formula (XVIII):

##STR00033##

[0258] In some embodiments, the drug is an antioxidant and the drug dimer is further described by the formula (XIX):

##STR00034##

[0259] In some embodiments, the drug is an antioxidant and the drug dimer is further described by the formula (XX):

##STR00035##

[0260] In some embodiments, the drug is an antioxidant and the drug dimer is further described by the formula (XXI):

##STR00036##

[0261] In some embodiments, the drug is an antioxidant and the drug dimer is further described by the formula (XXII):

##STR00037##

[0262] In some embodiments, the drug is an antioxidant and the drug dimer is further described by the formula (XXIII):

##STR00038##

[0263] In some embodiments, the drug is an antioxidant and the drug dimer is further described by the formula (XXIV):

##STR00039##

[0264] In some embodiments, the drug is an antimicrobial agent and the drug dimer is further described by the formula (XXVI):

##STR00040##

[0265] In some embodiments, the drug is an antimicrobial agent and the drug dimer is further described by the formula (XXVII):

##STR00041##

[0266] In some embodiments, the drug is an antiviral agent and the drug dimer is further described by the formula (XXVIII):

##STR00042##

[0267] In some embodiments, the drug is an antiviral agent and the drug dimer is further described by the formula (XXIX):

##STR00043##

[0268] In some embodiments, the drug is an anticoagulant and the drug dimer is further described by the formula (XXX):

##STR00044##

[0269] In some embodiments, the drug is an NSAID and the drug dimer is further described by the formula (XXXI):

##STR00045##

[0270] In some embodiments, the drug is a CNS agent and the drug dimer is further described by the formula (XXXII):

##STR00046##

[0271] In some embodiments, the drug is an anti-cancer agent and the drug dimer is further described by the formula (XXXIII):

##STR00047##

[0272] In some embodiments, the drug is a neural-protective and anti-oxidant and the drug dimer is further described by the formula (XXXIV):

##STR00048##

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

[0273] In some embodiments, the drug is a neural-protective and anti-oxidant and the drug dimer is further described by the formula (XXXV):

##STR00049##

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

[0274] In some embodiments, the drug is an antineoplastic and the drug dimer is further described by the formula (XXXVI):

##STR00050##

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

[0275] In some embodiments, the drug is an antineoplastic and the drug dimer is further described by the formula (XXXVII):

##STR00051##

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

[0276] In some embodiments, the drug is an alpha-adrenergic agonist, antiglaucoma drug, bronchodilator, or mydriatic and the drug dimer is further described by the formula (XXXVIII):

##STR00052##

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

[0277] In some embodiments, the drug is an alpha-adrenergic agonist, antiglaucoma drug, bronchodilator, or mydriatic and the drug dimer is further described by the formula (XXXIX):

##STR00053##

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

[0278] In some embodiments, the drug is an antibiotic or antineoplastic and the drug dimer is further described by the formula (XLII):

##STR00054##

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

[0279] In some embodiments, the drug is an antibiotic or antineoplastic and the drug dimer is further described by the formula (XLIII):

##STR00055##

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

[0280] In some embodiments, the drug is an antibiotic or antineoplastic and the drug dimer is further described by the formula (XLIV):

##STR00056##

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

[0281] In some embodiments, the compound, or pharmaceutically acceptable salt thereof, provided in Table 1 comprises both a first radical and a second radical, which when combined in a dimer are processable (e.g., wherein the radicals may or may not be processable themselves, when in their free form) (e.g., FIG. 2-FIG. 8). In some embodiments, the compound, or pharmaceutically acceptable salt thereof, provided in Table 1 comprises a first radical and a second radical that are the same. In some embodiments, both the first radical and the second radical of the conjugate, or pharmaceutically acceptable salt thereof, provided in Table 1 is attached to the linker at a hydroxyl, a carboxylate, or an amine of each the first radical and the second radical.

TABLE-US-00001 TABLE 1 Example Structure Name 1 [00057] embedded image (ethane-1,2- diylbis(oxy))bis(ethane- 2,1-diyl) bis(2-(4-(1- oxoisoindolin-2- yl)phenyl)propanoate) 2 [00058] 1,10-bis(4-(isoquinolin- 5-ylsulfonyl)-1,4- diazepan-1-yl)decane- 1,10-dione 3 [00059] (ethane-1,2- diylbis(oxy))bis(ethane- 2,1-diyl) bis(2-(2-amino- 3-(4- bromobenzoyl)phenyl) acetate) 4 [00060] embedded image heptane-1,7-diylbis(4- (isoquinolin-5- ylsulfonyl)-1,4- diazepane-1- carboxylate) 5 [00061] cyclohexane-1,4- diylbis(methylene) (2S,2′S)-bis(2-amino-3- (3,4- dihydroxyphenyl) propanoate) 6 [00062] 2,2′-(((3,14-dioxo- 2,4,7,10,13,15- hexaoxahexadecane- 1,16- diyl)bis(azanediyl))bis(3- (4-bromobenzoyl)-2,1- phenylene))diacetic acid 7 [00063] embedded image (ethane-1,2- diylbis(oxy))bis(ethane- 2,1-diyl) bis(2-(1-(4- chlorobenzoyl)-5- methoxy-2-methyl-1H- indol-3-yl)acetate)

Formulations

[0282] The pharmaceutical compositions of the disclosure can include an article in the form of fibers, fiber meshes, woven fabrics, non-woven fabrics, pellets, cylinders, hollow tubes, microparticles, nanoparticles, or other shaped articles. In some embodiments, the pharmaceutical composition of the disclosure has a non-circular shape that affects, e.g., increases, the surface area (e.g., extruded through star-shaped dye or any other form shaping process with or without a dye mold). Suitable pharmaceutical compositions for use with this disclosure can be small regularly or irregularly shaped particles, which can be solid, porous, or hollow.

[0283] Different forms of pharmaceutical compositions of the present disclosure (e.g., fibers, fiber meshes, woven fabrics, non-woven 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, being easily injected, not requiring removal after completion of drug release, and allow for tailoring drug release rates required for a given indication. When used as an injectable drug delivery device, drug release rate and interaction with cells are strongly dependent on the size distribution of the pharmaceutical composition form.

Processing Methods

[0284] Articles of the disclosure can be formed using any number of the methods, for example, heat processing or solvent processing of the drug dimer of formula (A-I). Heat processing can include heat molding, injection molding, extrusion, 3D printing, melt electrospinning, fiber spinning, fiber extrusion, and/or blow molding. Solvent processing may include coating, micro printing, dot printing, micropatterning, fiber spinning, solvent blow molding, electrospraying, and electrospinning. Processing methods to form an intermediate glassy state may be any of the above heat and solvent based methods as well as heat and solvent based methods that lead to glassy state material with no defined shape (e.g. spray drying, lyophilization, powder melting, etc.).

Electrospraying

[0285] In some embodiments, the pharmaceutical compositions of the disclosure are dissolved in a solvent (e.g., acetone) at concentrations ranging from, e.g., 10-30% w/v, and are electrosprayed to form micro- and nanobeads. The solutions can be loaded into a syringe and can be injected at a particular rate, e.g., 0.5 mL/h, onto a stationary collection plate. Between the needle and collecting surface, a potential difference of, e.g., 18 kV, can be maintained. Exemplary concentration of 10% w/v is used to obtain nanoparticles. In other embodiments, a concentration of 30% w/v is used to obtain microbeads.

Fiber Spinning

[0286] In some embodiments, the pharmaceutical compositions of the disclosure, e.g., fibrous meshes with aligned and unaligned morphologies are prepared by electrospinning. The pharmaceutical compositions of the disclosure are dissolved in a solvent (e.g., THF, or 1:1 ratio of DCM/THF). The solutions may be injected from a syringe at a particular rate, e.g., 0.5 mL/h, onto a cylindrical mandrel rotating at a particular rotational speed, e.g., 1150 rpm, to obtain aligned fibers, or onto a stationary collector surface to obtain unaligned fibers. A potential difference (e.g., 18 kV or 17 kV) can be maintained between the needle and collecting surface for aligned and random fibers.

[0287] In other embodiments, fibers are prepared either from the melt at elevated temperatures, the glassy state intermediate, or from solution by dissolving the pharmaceutical compositions of the disclosure in a solvent (e.g., DCM, THF, or chloroform). As used herein, melt spinning describes heat processing from the melt state, heat spinning describes heat processing from the glassy state, and wet, dry, and gel spinning describe solution processing.

[0288] The viscous melt, intermediate, or solution can be fed through a spinneret and fibers may be formed upon cooling (melt or heat spinning) or following solvent evaporation with warm air as the compound exits the spinneret (dry spinning). Wet spinning and gel spinning, performed according to methods known in the art, may also be used to produce the fibers of the disclosure. Heat spinning describes a process that is essentially the same as the melt spinning process, but performed with the glassy state intermediate and heated above the glass transition temperature (Tg) to get the viscous fluid to extrude/spin instead of the melt. Alternatively, tweezers may be dipped into melted material or concentrated solutions and retracted slowly in order to pull fibers. The rate of pulling and distance pulled may be varied to yield fibers and columnar structures of different thickness.

Emulsion

[0289] In some embodiments, micro-particles or nano-particles made from the pharmaceutical composition can be formed using an emulsion process. The pharmaceutical composition may be dissolved in an organic solvent (e.g. DCM, THF, etc.) and a surfactant (e.g. SDS, PVA, etc.) may be added to the solution/mixture at a low percentage (e.g. 1%). The resulting mixture may be stirred for the appropriate time at room temperature to form an emulsion. The emulsion may be subsequently added to Milli-Q water under stirring for an appropriate time (e.g. 1 h) to remove residual solvent. The resulting micro- or nano-particles may be collected by centrifugation and dried to obtain the desired form.

Extrusion

[0290] In some embodiments, injectable cylinders made from the pharmaceutical composition may be formed by heat extrusion. The pharmaceutical composition may be loaded into a hot melt extruder, heated to a temperature above the melting point (for crystalline compositions) or glass transition temperature (for pre-melted or amorphous compositions), and extruded using a light compressive force to push the material through the nozzle and a light tensile force to pull the material out of the extruder. The extrudate may be cut to the desired length for appropriate drug dosing for the indication of interest.

Bead Sizing and Milling

[0291] In some embodiments, a milling process may be used to reduce the size of an article of the disclosure to form sized particles, e.g., beads, in the micrometer (microbeads) to nanometer size range (nanobeads). The milling process may be performed using a mill or other suitable apparatus. Dry and wet milling processes such as jet milling, cryo-milling, ball milling, media milling, sonication, and homogenization are known and can be used in methods described herein. Generally, in a wet milling process, a suspension of the material to be used as the core is agitated with or without excipients to reduce particle size. Dry milling is a process wherein the material to be used as the article core is mixed with milling media with or without excipients to reduce particle size. In a cyro-milling process, a suspension of the material to be used as the core is mixed with milling media with or without excipients under cooled temperatures. In some embodiments, subsequent heating of the milled microparticle above the Tg is needed to achieve a spherical shape, or particles with non-spherical shapes can be used as milled.

Low Temperature Processing Using Intermediate Glassy State Articles

[0292] In certain embodiments, the prodrug dimer has a limited window (e.g., short timeframe of seconds to minutes) of thermal stability, whereby the purity of the dimer is minimally affected at elevated temperatures. In some embodiments, it is beneficial to make an intermediate glassy state form (e.g., film, surface coating, pellet, micro-particles, or other shaped article). This can be accomplished by heat or solvent processing to remove or reduce the crystallinity of the material to form a glassy state composition. The glassy state composition is subsequently heat processed at a lower temperature (e.g., processing just above the glass transition temperature (Tg), and below the melt temperature (Tm)). This can provide a longer timeframe for heat processing the glassy state material into the final shaped article, while reducing the impact of processing conditions on the purity of the prodrug dimer in the article.

[0293] Exemplary processing details are provided in the Examples.

Drug Delivery

[0294] The pharmaceutical compositions of the disclosure provide optimal delivery of a drug as they release the drug from an article of the disclosure in a controlled manner, for example, by surface erosion. The surface erosion mechanism of drug release may allow the shaped article to maintain its physical form, while gradually decreasing in size as the surface erodes (e.g., like a bar of soap), rather than bulk erosion that is characteristic of some polymer-based drug release vehicles (e.g., polylactic/glycolic acid). This may inhibit burst release and reduce the formation of inflammatory particulates (e.g., no or minimal crystalline particulates are formed or released from the articles when drug is released in the manner described herein). The drug can be controlled to be delivered over a desired period of time. A slower and steadier rate of delivery (e.g., release of less than 10% of D1 or D2 (as a percentage of the total drug, D1 or D2, present in the fiber in prodrug form) at 37° C. in 100% bovine serum over 5 days) may in turn result in a reduction in the frequency with which the pharmaceutical composition must be administered to a subject, and improve the safety profile of the drug. Drug release can also be tailored to avoid side effects of slower and longer release of the drug by engineering the article to provide steady release over a comparatively shorter period of time. Depending on the indication and the drug, the drug release can be tailored for dose and duration appropriate to the indication of interest.

[0295] The rate of release of a drug can depend on many factors, for example, the drug composition of the drug dimer. Drug release rate from the formed object of the drug dimer can be modulated by the cleavage of drug-linker bond through hydrolysis or enzymatic degradation. Therefore, the selection of linking moiety can affect drug release rate. Further, the drug release rate can be controlled by the selection of the functional group on the drug to conjugate through to the linker, for example, a primary vs. a secondary hydroxyl group. The rate of release of a given drug from a drug dimer may also depend on the quantity of the loaded drug dimer as a percent of the final drug dimer formulation, e.g., by using a pharmaceutical excipient (e.g., bulking agent/excipient). Another factor that can affect the release rate of a drug from, for example a microbead, is the microbead size. In some embodiments, drug release is tailored based on the solubility of drug dimer (e.g., through selection of appropriate drug and/or linker) that will influence the rate of surface erosion (e.g., dissolution/degradation) from the article. In other embodiments, drug release is affected by changes in surface area of the formulation, e.g., by changing the diameter of the microbeads. By adjusting the vide supra factors, dissolution, degradation, diffusion, and controlled release may be varied over wide ranges. For example, release may be designed to be initiated over minutes to hours, and may extend over the course of days, weeks, months, or years.

Uses and Pharmaceutical Compositions

[0296] In some embodiments, the drug dimers of the disclosure are used as a drug delivery device (or, e.g., a drug depot) with a minimal need for additives. This may achieve a local, sustained release and a local biological effect, while minimizing a systemic response. In some embodiments, when present, the additives are in small amounts and do not affect the physical or bulk properties. In some embodiments, when present, the additives do not alter the drug release properties from the pharmaceutical composition but rather act to improve processing of the prodrug dimer into the shaped article. In some embodiments, the pharmaceutical compositions contain additives such as a plasticizer (e.g., to reduce thermal transition temperatures), an antioxidant (e.g., to increase stability during heat processing), a binder (e.g., to add flexibility to the fibers), a bulking agent (e.g., to reduce total drug content), a lubricant, a radio-opaque agent, or mixtures thereof. The additives may be present at 30% (w/w), e.g., 20% (w/w), 10% (w/w), 7% (w/w), 5% (w/w), 3% (w/w), 1% (w/w), 0.5% (w/w), or 0.1% (w/w). Examples of plasticizers are polyols, e.g., glycerol, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, propylene glycol, triacetin, sorbitol, mannitol, xylitol, fatty acids, monosaccharides (e.g., glucose, mannose, fructose, sucrose), ethanolamine, urea, triethanolamine, vegetable oils, lecithin, or waxes. Exemplary antioxidants are glutathione, ascorbic acid, cysteine, or tocopherol. The binders and bulking agents can be, e.g., polyvvinylpyrrolidone (PVP), starch paste, pregelatinized starch, hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC), or polyethylene glycol (PEG) 6000.

[0297] Methods involving treating a subject may include preventing a disease, disorder or condition from occurring in the subject which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition. Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected (e.g., such treating the pain of a subject by administration of an agent even though such agent does not treat the cause of the pain).

[0298] Pharmaceutical compositions containing the drug dimers described herein may be administered to a subject via any route known in the art. These include, but are not limited to, oral, sublingual, nasal, intradermal, subcutaneous, intramuscular, rectal, vaginal, intravenous, intraarterial, intracisternally, intraperitoneal, intravitreal, periocular, topical (as by powders, creams, ointments, or drops), buccal and inhalational administration. Desirably, the articles of the disclosure are administered parenterally as injections (intravenous, intramuscular, or subcutaneous), or locally as injections (intraocularly or into a joint space). The formulations are admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.

[0299] The articles provided herein may be administered to a subject to be delivered in an amount sufficient to deliver to a subject a therapeutically effective amount of an incorporated pharmaceutical agent as part of prophylactic or therapeutic treatment, or as a part of adjunctive therapy to avoid side-effects of another drug or therapy. In general, an effective amount of a pharmaceutical agent or component refers to the amount necessary to elicit the desired biological response. The desired concentration of pharmaceutical agent in the article of the disclosure will depend on numerous factors, including, but not limited to, absorption, inactivation, and excretion rates of the drug as well as the delivery rate of the compound from the subject compositions, the desired biological endpoint, the agent to be delivered, the target tissue, etc. It is to be noted that dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. Typically, dosing will be determined using techniques known to one skilled in the art.

[0300] The concentration and/or amount of any pharmaceutical agent to be administered to a subject may be readily determined by one of ordinary skill in the art. Known methods are also available to assay local tissue concentrations, diffusion rates from drug dimers and local blood flow before and after administration of the therapeutic formulation.

Sterilization of Formulations

[0301] Generally, it is desired that a formulation is sterile before or upon administration to a subject. A sterile formulation is essentially free of pathogenic microorganisms, such as bacteria, microbes, fungi, viruses, spores, yeasts, molds, and others generally associated with infections. In some embodiments, articles of the disclosure may be subject to an aseptic process and/or other sterilization process. An aseptic process typically involves sterilizing the components of a formulation, final formulation, and/or container closure of a drug product through a process such as heat, gamma irradiation, ethylene oxide, or filtration and then combining in a sterile environment. In some cases, an aseptic process is preferred. In other embodiments, terminal sterilization is preferred.

Treatment Methods

[0302] The formulations of the disclosure may be used in the fields of ophthalmology, oncology, laryngology, endocrinology and metabolic diseases, rheumatology, urology, neurology, cardiology, dental medicine, dermatology, otology, post-surgical medicine, orthopedics, pain management, and gynecology. In some embodiments, a formulation provided herein may be used to treat a CNS disease or disorder.

[0303] The compound of the disclosure can be selected for the desired property, such as a nonsteroidal anti-inflammatory drug (NSAID) dimers for the use in treating inflammation, pain management, knee osteoarthritis, postoperative pain; (e.g., opioid) analgesic dimers for the use of chronic pain treatment; CNS agent dimers for the use of treating Parkinson's Disease or in ophthalmology; ROCK inhibitor dimers for the use of treating glaucoma, asthma, cancer, insulin resistance, or osteoporosis; anthraquinone dimers for the use of treating osteoarthritis; anti-cancer agent dimers for the use of chemotherapy and treating cancer; antiviral agent dimers for treating or preventing viral infections; and antioxidant dimers for the use of treating inflammation, cancer, as a neural protective agent, and as an antiatherogenic agent

EXAMPLES

[0304] The following examples are put forth to provide those of ordinary skill in the art with a description of how the compositions and methods described herein may be used, made, and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention.

1. Analytical Methods

Analytical Example 1: High Performance Liquid Chromatography (HPLC)

[0305] Samples (20.0 mg) were dissolved in acetonitrile (10.0 mL) to make 2 mg/mL solutions. The samples were loaded onto an Agilent 1260 Series HPLC with a Phenomenex Gemini-NX C18 Column (5 μm; 110 Å; 250×4.6 mm; 00G-4454-E0) equipped with a Phenomenex SecurityGuard Analytical Guard Pre-Column (KJO-4282) containing Gemini C18 4×3.0 mm Guard Cartridge (AJO-7597). For the system: solvent A was Water+0.05% trifluoroacetic acid (TFA); solvent B was Acetonitrile+0.05% TFA; the flow rate was 1.0 mL/min and the injection volume was 5 μL. Solvent gradient profiles were designated as either Method 1 or Method 2, with the details shown in Tables 2 and 3 respectively. Detection method was UV @242 nm (Low Polarity) or UV @296 nm (Timolol), with UV Spectra from 190 to 400 nm collected in both cases.

TABLE-US-00002 TABLE 2 Method 1 Time % A % B (min) Solvent Solvent 0 80 20 40 16 84 42 0 100 50 0 100

TABLE-US-00003 TABLE 3 Method 2 Time % A % B (min) Solvent Solvent 0 98 2 30 68 32 35 0 100 45 0 100

[0306] Method 3: Samples (20.0 mg) were dissolved in methanol (10.0 mL) to make 2 mg/mL solutions. For the system: solvent A was 90% 10 mM potassium phosphate buffer (pH 6.6)+10% methanol (v/v); solvent B was 90% methanol+10% 10 mM potassium phosphate buffer (pH 6.6) (v/v); the flow rate was 1.0 mL/min and injection volume was 5 μL; detection method was UV @220 nm and UV Spectra from 190 to 400 nm. The samples were loaded onto an Agilent 1200 series HPLC with a Phenomenex Gemini-NX C18 Column (5 μm; 110 Å; 250×4.6 mm; OOG-4454-E0) equipped with a Phenomenex SecurityGuard Analytical Guard Pre-Column (KJO-4282) containing Gemini C18 4×3.0 mm Guard Cartridge (AJO-7597). The solvent gradient profile is shown in Table 4:

TABLE-US-00004 TABLE 4 Time % A % B (min) Solvent Solvent 0.0 50 50 3.5 15 85 9.5 0 100 26.5 0 100 32.5 50 50 40.0 50 50

Analytical Example 2: Nuclear Magnetic Resonance (NMR)

[0307] Compounds (10 mg) were dissolved in 666 μL of either CDCl.sub.3 or DMSO-d6 and loaded in an 8-inch length, 5 mm diameter NMR tube. The instrument was a Varian Mercury 400 NMR spectrometer. Proton NMR spectra were obtained with 16 scans using the default method. FIDs were processed with MestRe-C software.

Analytical Example 3: Mass Spectrometry (MS)

[0308] Compounds were dissolved in acetonitrile at 1 mg/ml and used directly for analysis on an Agilent 6538 QTOF, using ESI MS+ as ion source.

Analytical Example 4: Melting Point

[0309] Compound powder was prepared neat in a glass capillary tube, and melting temperature was measured manually with standard glass capillary tube melting point apparatus.

Analytical Example 5: Differential Scanning Calorimetry

[0310] 5-10 mg of compounds were weighed in an aluminum pan. Using a Hitachi Differential Scanning Calorimeter DSC7020, samples were heated from room temperature to 110-280° C. at 10° C./min, cooled to −30° C. at 10° C./min, and heated again to 110-280° C. at 10° C./min.

Analytical Example 6: Light Microscopy

[0311] Heat molded pellets were imaged using a Leica DMV6 light microscope equipped with Leica application suite X software.

II. Chemical Synthesis

[0312] Solvents, reagents and starting materials were purchased from commercial vendors and used as received unless otherwise described. All reactions were performed at room temperature unless otherwise stated. Starting materials were purchased from commercial sources or synthesized according to the methods described herein or using literature procedures.

Chemical Synthesis Example 1

[0313] Compound 1 (Dexamethasone-Triethylene Glycol-Dexamethasone) can be Synthesized, Processed into Pellets in the Glassy State by Heat Molding, and Release Drug Through Surface Erosion from an Intact Pellet

[0314] Dexamethasone (1 mol equivalent) was suspended in dichloromethane on an ice bath and triethylamine (2 mol equivalent) and triethylene glycol bis(chloroformate) (0.6 mol equivalent) were added to the mixture. The ice bath was allowed to warm to room temperature and the reaction was stirred overnight. The solvent was removed and the solid residue was purified by column chromatography. Product was recrystallized twice from acetonitrile to give Compound 1 (FIG. 1A) as an off-white crystalline solid.

[0315] Compound 1: HPLC (Method 1) 31.7 min; Elemental analysis: Anal. Calcd for C.sub.52H.sub.68F.sub.2O.sub.16: C, 63.27; H, 6.94; N, 0.00; Cl, 0.00 Found: C, 62.62; H, 6.84; N, <0.50; Cl<100 ppm. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ (ppm) 0.80 (d, J=7 Hz, 6H, 2×C16 α-CH.sub.3); 0.90 (s, 6H, 2×C18-CH.sub.3); 1.08 (m, 2H, 2×C16-H); 1.35 (m, 2H, 2×C14-H); 1.49 (s, 6H, 2×C19-CH.sub.3); 1.54 (q, J=13 Hz, 2H, 2×C13-H); 1.64 (q, J=11 Hz, 2H, 2×C15-CH.sub.2); 1.77 (m, 2H, 2×C15-CH.sub.2); 2.15 (m, 4H, 2×C6-CH.sub.2); 2.32 (m, 4H, 2×C7-CH.sub.2); 2.62 (m, 2H, 2×C12-CH.sub.2); 2.89 (m, 2H, 2×C12-CH.sub.2); 3.57 (s, 4H, 2×TEG OCH.sub.2); 3.65 (m, 4H, 2×TEG OCH.sub.2); 4.15 (m, 2H, 2×OCH); 4.22 (m, 4H, 2×TEG OCH.sub.2); 4.79 (d, 2H, AB, J=18.5 Hz, 2H, C21-CH.sub.2O—); 5.09 (d, 2H, AB, J=18.5 Hz, 2H, C21-CH.sub.2O—); 5.18 (s, 2H, C17-OH); 5.40 (d, 2H, J=4.5 Hz, C11-OH); 6.01 (d, 2H, J=1.9 Hz, 2×alkene C4-CH); 6.23 (dd, 2H, J=10.1 and 1.9 Hz, CH, 2×alkene C2-CH); 7.29 (d, 2H, C1-CH 2×alkene CH, 10.1 Hz, 2H). MS (ESI+) m/z: [M+H]+ Calcd for C.sub.52H.sub.69F.sub.2O.sub.16 987.46; Found 987.46.

[0316] Compound 1 was formed into pellets in the glassy state by heat molding (FIG. 1B). Crystalline powder was melted at 185° C. and pellets were formed from 1 mm×1 mm cylindrical molds. The starting powder and heat-processed pellets were tested by differential scanning calorimetry (DSC; FIG. 1C) and X-ray powder diffraction (XRPD; FIG. 1D) to confirm heat-processing converted Compound 1 from the crystalline state to the glassy state.

[0317] Heat-molded pellets from Compound 1 (˜1 mm×1 mm) were then placed in 20 mL glass vials and 2 mL of release buffer (either 100% phosphate buffered saline (PBS), 1% fetal bovine serum (FBS) in PBS, or 100% FBS) was added. Samples were incubated at 37° C. on a shaker rotating at 115 rpm. After 1 day, 3 days, 7 days, and subsequently in alternating 3 and 4 day intervals (i.e., 1, 3, 7, 10, 14 days etc.), release buffer was sampled directly (PBS) or syringe filtered, proteins were precipitated with acetonitrile, and drug release products were extracted. The samples were analyzed by high performance liquid chromatography (HPLC) to quantify drug products. Cumulative drug release was calculated and plotted as a percentage of the total drug in each pellet released over time (FIG. 1E). Representative images of the pellets confirm surface erosion over time in 100% FBS (FIG. 1F)

Chemical Synthesis Example 2

(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl)bis(2-(4-(1-oxoisoindolin-2-yl)phenyl)propanoate) (Indoprofen-TEG-Indoprofen, Compound 2)

[0318] ##STR00064##

[0319] To a solution of indoprofen (883 mg, 3.14 mmol, 2.00 eq) in DMF (20 mL) was added K.sub.2CO.sub.3 (434 mg, 3.14 mmol, 2.00 eq) and triethylene glycol di(p-toluenesulfonate) (0.72 g, 1.57 mmol, 1.00 eq). The mixture was stirred at 80° C. for 3 h, after which the mixture was poured into water (150 mL) and extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with water (3×50 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the crude product. This was purified by reversed-phase HPLC to provide the product (460 mg, 43%) as an off-white solid. Melting point: 104° C. HPLC (Method 2) 33.4 min; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 7.92 (d, J=7.60 Hz, 2H), 7.81 (d, J=8.40 Hz, 4H), 7.56-7.64 (m, 2H), 7.47-7.55 (m, 4H), 7.36 (d, J=8.40 Hz, 4H), 4.83 (s, 4H), 4.14-4.33 (m, 4H), 3.76 (q, J=7.20 Hz, 2H), 3.64 (t, J=4.40 Hz, 4H), 3.54 (s, 4H), 1.52 (s, 3H), 1.50 (s, 3H). LCMS m/z: [M+H]+ Calcd for C.sub.40H.sub.41N.sub.2O.sub.8 677.29; Found 677.2.

Chemical Synthesis Example 3

heptane-1,7-diyl bis(4-(isoquinolin-5-ylsulfonyl)-1,4-diazepane-1-carboxylate) (Fasudil-Hep-Fasudil, Compound 3)

[0320] ##STR00065##

[0321] A solution of 1,7-heptanediol bis(chloroformate) (501 mg, 1.95 mmol, 1.00 eq), fasudil hydrochloride (1.28 g, 3.89 mmol) and TEA (985 mg, 9.73 mmol, 1.35 mL, 5.00 eq) in DMF (2 mL) was stirred at 25° C. for 2 h. The reaction mixture was poured into H2O (200 mL) and extracted with ethyl acetate (3×60 mL). The combined organic phase was washed with brine (3×100 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product which was purified by reversed-phase HPLC to give compound 3 as a white gum (586 mg, 39%). HPLC retention time (Method 2): 34.6 min; 1H NMR (400 MHz, CDCl3) δ (ppm) 9.36 (s, 2H), 8.70 (d, J=6.40 Hz, 2H), 8.40 (d, J=6.40 Hz, 2H) 8.30-8.36 (m, 2H), 8.21 (d, J=8.00 Hz, 2H), 7.70 (t, J=7.76 Hz, 2H) 4.02 (t, J=6.80 Hz, 4H), 3.52-3.63 (m, 8H), 3.38-3.47 (m, 8H), 1.92-2.00 (m, 4H), 1.59 (br s, 4H), 1.32 (br s, 6H). LCMS m/z: [M+H]+ Calcd for C37H47N6O8S2 767.29; Found 767.1.

Chemical Synthesis Example 4

(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl) bis(2-(2-amino-3-(4-bromobenzoyl)phenyl)acetate) (Bromfenac-TEG-Bromfenac, Compound 4)

[0322] ##STR00066##

[0323] To a solution of triethylene glycol di(p-toluenesulfonate) (700 mg, 1.53 mmol, 1.00 eq) in DMF (20 mL) was added bromfenac sodium (1.02 g, 3.05 mmol, 2.0 eq). The mixture was stirred at 50° C. for 10 h. The reaction mixture was poured into water (150 mL) and extracted with ethyl acetate (3×60 mL). The combined organic phase was washed with water (3×100 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the crude product which was purified by reversed-phase HPLC to give Compound 4 as a yellow gum (572 mg, 47%). HPLC (Method 2) 38.9 min; .sup.1H NMR (400 MHz, DMSO-d6); δ (ppm) 7.71 (br d, J=8.40 Hz, 4H), 7.49 (br d, J=8.40 Hz, 4H), 7.24 (br dd, J=19.20, 7.53 Hz, 4H), 6.98 (br s, 4H), 6.47-6.60 (m, 2H), 4.12-4.21 (m, 4H), 3.70 (s, 4H), 3.60-3.65 (m, 4H), 3.51 (s, 4H). LCMS m/z: [M+H]+ Calcd for C36H35Br2N2O8 781.08; Found 782.9.

Chemical Synthesis Example 5

1,10-bis(4-(isoquinolin-5-ylsulfonyl)-1,4-diazepan-1-yl)decane-1,10-dione (Fasudil-Seb-Fasudil, Compound 5)

[0324] ##STR00067##

[0325] To a solution of fasudil hydrochloride (1.51 g, 4.60 mmol, 2.0 eq.) and TEA (582 mg, 5.75 mmol, 800 uL, 2.5 eq) in THF (30 mL) was added sebacoyl chloride (0.55 g, 2.30 mmol, 1.0 eq) and DMAP (56.2 mg, 460 umol, 0.2 eq) at 0° C. The mixture was stirred at 20° C. for 2 h after which the mixture was filtered and the filtrate was concentrated in vacuo to give the crude product. This was purified by reversed-phase HPLC to give compound 5 as a light yellow gum (520 mg, 30%). HPLC retention time (Method 2): 33.9 min; .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 9.27-9.41 (m, 2H), 8.64-8.75 (m, 2H), 8.40 (d, J=6.00 Hz, 2H), 8.30-8.36 (m, 2H), 8.16-8.25 (m, 2H), 7.64-7.77 (m, 2H), 3.54-3.78 (m, 9H), 3.32-3.53 (m, 9H), 2.24 (br t, J=7.20 Hz, 4H), 1.95-2.02 (m, 4H), 1.23-1.33 (m, 10H). LCMS m/z: [M+H]+ Calcd for C.sub.38H.sub.49N.sub.6O.sub.6S.sub.2 749.32; Found 749.3.

Chemical Synthesis Example 6

cyclohexane-1,4-diylbis(methylene) (2S,2′S)-bis(2-amino-3-(3,4-dihydroxyphenyl)propanoate) (L-Dopa-CDM-L-Dopa, Compound 6)

[0326] ##STR00068##

[0327] A solution of dibenzyl-Boc-L-DOPA (8.74 g, 18.3 mmol, 2.40 eq), 1,4-Cyclohexanedimethanol (1.10 g, 7.63 mmol, 1.00 eq.) and DPTS (449 mg, 1.53 mmol, 0.20 eq) in DCM (100 mL) was stirred at 0° C. After all the solids were dissolved DIC (27.0 g, 214 mmol, 33.1 mL, 28.0 eq) was added in one portion and the mixture was stirred at 25° C. for 6 h under N.sub.2. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the crude product which was purified by column chromatography (SiO.sub.2, Petroleum ether: Ethyl acetate=5:1 to 0:1, TLC, Petroleum ether: Ethyl acetate=3:1, the product R.sub.f=0.5) to give the product (10.0 g, crude) as a white solid. .sup.1H NMR: (400 MHz, CDCl.sub.3) δ (ppm) 7.40-7.49 (m, 8H), 7.27-7.40 (m, 12H), 6.86 (d, J=8.40 Hz, 2H), 6.75 (d, J=1.60 Hz, 2H), 6.64 (dd, J=8.40, 1.63 Hz, 2H), 5.11 (s, 8H), 4.94 (br d, J=7.20 Hz, 2H), 4.52 (br d, J=7.20 Hz, 2H), 4.05-4.18 (m, 6H), 2.98 (br s, 4H), 1.71 (s, 6H), 1.38-1.47 (m, 18H).

[0328] A mixture of 1,4-cyclohexanedimethanol bis(dibenzyl-Boc-L-DOPA) ester (10.0 g, 9.40 mmol, 1.00 eq) and Pd/C (2.00 g, 9.40 mmol, 1.0 eq) in THF (100 mL) was degassed and purged with H.sub.2 3 times, the mixture was stirred at 20° C. for 6 h under H.sub.2 atmosphere (50 psi). The reaction mixture was filtered and concentrated in vacuo to give the intermediate 1,4-cyclohexanedimethanol bis(Boc-L-DOPA) ester (10.0 g, crude) as a yellow oil without further purification which was used in the next step.

[0329] A solution of 1,4-cyclohexanedimethanol bis(Boc-L-DOPA) ester (10.0 g, 14.2 mmol, 1.00 eq) and HCl/dioxane (4 M, 150 mL, 42.2 eq) in dioxane (20 mL) was stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo and the pH was adjusted to pH 8 with sat.NaHCO.sub.3. The mixture was extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with brine (2×100 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the crude product which was purified by reversed phase prep-HPLC to give the product soln which was adjusted to pH 8 with sat.NaHCO.sub.3. The mixture was extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with brine (2×100 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give compound 6 as a light yellow solid (449 mg, 893 umol, 6.3%). HPLC (Method 2) 18.8 min; Melting point: 161-166° C.; .sup.1H NMR (400 MHz, MeOD) δ (ppm) 6.68 (d, J=8.00 Hz, 2H), 6.60 (d, J=2.00 Hz, 2H), 6.49 (dd, J=8.00, 2.02 Hz, 2H), 3.79-3.94 (m, 4H), 3.63 (t, J=6.40 Hz, 2H), 2.81 (dd, J=6.40, 3.55 Hz, 4H), 1.64 (br t, J=7.60 Hz, 4H), 1.37-1.53 (m, 2H), 0.82-0.97 (m, 4H). LCMS m/z: [M+H]+ Calcd for C.sub.26H.sub.35N.sub.2O.sub.8 503.2; Found 503.2.

Chemical Synthesis Example 7

2,2′-(((3,14-dioxo-2,4,7,10,13,15-hexaoxahexadecane-1,16-diyl)bis(azanediyl))bis(3-(4-bromobenzoyl)-2,1-phenylene))diacetic acid (Bromfenac-TEG-Bromfenac—formaldehyde Bridge, Compound 7)

[0330] ##STR00069##

[0331] Chloromethyl chloroformate (2.94 ml, 33.1 mmol) is added to an ice-cold solution of triethyleneglycol (2.22 ml, 16.5 mmol) in dichloromethane (30 ml) followed by pyridine (5.33 ml, 66.2 mmol) at such a rate that the temperature is kept below 10° C. After stirring overnight at room temperature the reaction mixture is washed twice with 0.5 M HCl followed by water and aqueous sodium bicarbonate. The organic layer is dried (MgSO4) and concentrated in vacuo to give triethyleneglycol bis(chloromethyl carbonate) (11.1 g, 33.1 mmol) as a colorless oil.

[0332] To a solution of bromfenac (2.12 g, 6.62 mmol) in DMF (20 mL) is added potassium carbonate (0.91 g, 6.62 mmol) and triethyleneglycol bis(chloromethyl carbonate) (1.11 g, 3.31 mmol). The mixture is heated to 100° C. for 2 h. The reaction mixture is diluted with water (200 mL) and extracted with DCM (2×200 mL). The DCM layers are combined and washed with water (5×400 mL), dried (MgSO.sub.4) and concentrated in vacuo to give the crude product (Compound 7).

Chemical Synthesis Example 8

(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl) bis(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate) (Indomethacin-TEG-Indomethacin, Compound 8)

[0333] ##STR00070##

[0334] To a stirred solution of (1.073 g, 3.0 mmol) in dry DCM (100 mL) under nitrogen was added 4-(dimethylamino)pyridine (732 mg, 6.0 mmol), triethyleneglycol (225 mg, 1.5 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.15 g, 6.0 mmol) and the mixture was stirred overnight. The mixture was concentrated onto 5 g normal phase silica. Purification was performed by normal phase automated chromatography (ethyl acetate-hexane). Product containing fractions were combined and concentrated to give compound 8 as an off-white solid (759 mg, 61%). Melting point: 102° C. HPLC retention time (Method 1): 44.1 min, ESI MS+ Found, C.sub.44H.sub.42Cl.sub.2N.sub.2NaO.sub.10.sup.+ Mass: 851.21 .sup.1H NMR (400 MHz, DMSO-d6) δ (ppm); 7.82 (m, 8H), 7.01 (s, 2H), 6.92 (d, J=8.0 Hz, 2H), 6.65 (d, J=8.0 Hz, 2H), 4.12 (m, 4H), 3.65 (m, 10H), 3.54 (m, 4H), 3.41 (s, 4H), 2.19 (s, 6H).

Chemical Synthesis Example 9

Procedure for Preparation of Drug Dimer Form Enolizable Ketone Functional Group

[0335] Compounds bearing an enolizable ketone can be prepared by reaction with lithium diisopropylamide in tetrahydrofuran to drive the enol tautomer to the formation of the lithium enolate, followed by reaction with an appropriate linking moiety to form the drug dimer. An exemplary reaction scheme (Scheme 1) is shown below where the compound is formed from hydromorphone and the linkage group is a carbonate.

##STR00071##

Chemical Synthesis Example 10

bis((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl) adipate. Compound A)

[0336] ##STR00072##

[0337] Dimeric compositions bearing an enolizable ketone (e.g., oxycodone) are prepared by reaction with lithium diisopropylamide (LDA, 2 equiv.) in tetrahydrofuran at −78° C. for 5 min to 1 hr, driving the enol tautomer to the formation of the lithium enolate. The appropriate linker precursor (e.g., adipoyl chloride, 0.5 eq.) is added and the reaction is stirred for 1 hr to 16 hrs at room temperature to form the drug dimer (e.g., oxycodone-adip-oxycodone).

Chemical Synthesis Example 11

bis((4R,4aS,7aR,12bS)-3-allyl-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl) adipate (naloxone-adipate-naloxone ester, Compound 9)

[0338] ##STR00073##

[0339] To a stirred suspension of naloxone hydrochloride (250 mg, 0.687 mmol) in dry DCM (50 mL) under nitrogen was added 4-(dimethylamino)pyridine (168 mg, 1.374 mmol), adipic acid (50 mg, 0.343 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (263 mg, 1.374 mmol) and the mixture was stirred overnight. The mixture was concentrated onto 2 g reverse phase silica. Purification was performed by reverse phase chromatography (aqueous-MeCN gradient). Product containing fractions were combined, extracted with DCM, dried (MgSO.sub.4) and concentrated to give Compound 9 as an off-white solid (100 mg, 38%). Melting point: 120° C.; HPLC (Method 1) retention time: 6.75 min; ESI MS+ Found, C.sub.44H.sub.48N.sub.2NaO.sub.10.sup.+, Mass: 787.32 g/mol; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 6.82 (2H, d, J=8.0 Hz); 6.74 (2H, d, J=8.0 Hz); 5.82 (2H, m, (3-CH allyl); 5.21 (2H, d, J=16.8 Hz, γ-CH-allyl, trans); 5.12 (2H, d, J=10.0 Hz, γ-CH-allyl, cis); 5.04 (2H, s); 4.85 (2H, s); 3.10 (6H, m); 2.85 (6H, m); 2.54 (6H, m); 2.32 (2H, m); 2.03 (2H, m); 1.95 (2H, m); 1.74 (6H, m); 1.43 (2H, m); 1.22 (2H, m).

Chemical Synthesis Example 12

bis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl) adipate (naltrexone-adipate-naltrexone, Compound 10)

[0340] ##STR00074##

[0341] To a solution of naltrexone hydrochloride (1.63 g, 4.31 mmol) in DCM (120 mL) under nitrogen was added 4-(dimethylamino)pyridine (1.00 g, 8.21 mmol), adipic acid (300 mg, 2.05 mmol) and dimethylaminopropyl-N′-ethylcarbodiimide hydrochloride (1.57 g, 8.21 mmol, 4.00 eq) at 0° C. The mixture was stirred at 25° C. for 8 h. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Agela DuraShell C18 250*50 mm*10 um; mobile phase: [water (0.05% NH.sub.3H.sub.2O+10 mM NH.sub.4HCO.sub.3)-ACN]; B %: 55%-85%, 20 min) to give the product as an off-white solid (658 mg, 60%). Melting point: 187° C. HPLC (Method 3) retention time: 7.0 min, ESI MS+ Found, C.sub.46H.sub.53N.sub.2O.sub.10.sup.+ Mass: 793.37 1H NMR (400 MHz, DMSO) δ 6.84 (d, J=8.2 Hz, 2H), 6.72 (d, J=8.3 Hz, 2H), 5.15 (s, 1H), 4.92 (s, 2H), 3.17 (d, J=5.6 Hz, 2H), 3.09 (s, 1H), 3.05 (s, 1H), 2.91 (td, J=14.3, 5.0 Hz, 2H), 2.70-2.52 (m, 8H), 2.38 (tt, J=11.2, 6.3 Hz, 6H), 2.11 (dt, J=12.6, 2.4 Hz, 2H), 1.95 (td, J=12.1, 3.8 Hz, 2H), 1.84-1.74 (m, 3H), 1.73 (d, J=3.3 Hz, 2H), 1.45 (td, J=14.0, 3.4 Hz, 2H), 1.33-1.21 (m, 2H), 0.95-0.81 (m, 2H), 0.55-0.42 (m, 4H), 0.20-0.07 (m, 4H).

Chemical Synthesis Example 13

bis((4R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl) adipate, Nalmefene-Adip-Nalmefene, Compound 11)

[0342] ##STR00075##

[0343] To a solution of nalmefene (2.44 g, 7.18 mmol) in DCM (100 mL) was added 4-(dimethylamino)pyridine (1.25 g, 10.26 mmol), adipic acid (0.500 g, 3.42 mmol) and dimethylaminopropyl-N′-ethylcarbodiimide hydrochloride (2.62 g, 13.69 mmol) at 0° C. under N.sub.2 atmosphere. The mixture was stirred at 20° C. for 10 h. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Welch Xtimate C18 250*70 mm #10 um; mobile phase: [water (0.04% NH.sub.3H.sub.2O+10 mM NH4HCO3)-ACN]; B %: 80%-100%, 300 min) to give the product (1.30 g, 48% yield) as a light yellow solid. Melting point: 87° C. HPLC (Method 3) retention time: 9.0 min, ESI MS+ Found, C.sub.48H.sub.57N.sub.2O.sub.8.sup.+ Mass: 789.41 .sup.1H NMR (400 MHz, DMSO) δ 6.75 (d, J=8.11 Hz, 2H) 6.63 (d, J=8.11 Hz, 2H) 5.03 (d, J=1.10 Hz, 2H) 4.94 (s, 2H) 4.87 (s, 2H) 4.76 (d, J=1.75 Hz, 2H) 3.00 (br dd, J=11.95, 6.69 Hz, 4H) 2.48-2.71 (m, 8H) 2.15-2.46 (m, 8H) 1.87-2.07 (m, 4H) 1.64-1.78 (m, 4H) 1.43-1.55 (m, 2H) 1.10-1.28 (m, 4H) 0.74-0.89 (m, 2H) 0.36-0.54 (m, 4H) 0.00-0.16 (m, 4H)

Chemical Synthesis Example 14

bis((4R,4aS,7aR,12bS)-3-allyl-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl) decanedioate (Naloxone-Seb-Naloxone, Compound 12)

[0344] ##STR00076##

[0345] To a solution of naloxone hydrochloride dihydrate (1.04 g, 2.60 mmol) in DCM (100 mL) under nitrogen was added 4-(dimethylamino)pyridine (604 mg, 4.94 mmol), sebacic acid (250 mg, 1.24 mmol) and dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (948 mg, 4.94 mmol) at 0° C. The mixture was stirred at 25° C. for 8 h. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Agela DuraShell C18 250*80 mm*10 um; mobile phase: [water (10 mM NH.sub.4HCO.sub.3)-ACN]; B %: 55%-85%, 20 min) to give the product (855 mg, 84% yield) as a white solid. Melting point: 86° C. HPLC (Method 3) retention time: 8.8 min, ESI MS+ Found, C.sub.48H.sub.57N.sub.2O.sub.10.sup.+ Mass: 821.40 .sup.1H NMR (400 MHz, DMSO) δ ppm 6.83 (d, J=8.16 Hz, 2H) 6.73 (d, J=8.16 Hz, 2H) 5.86 (ddt, J=16.97, 10.38, 6.27, 6.27 Hz, 2H) 5.25 (br d, J=17.19 Hz, 2H) 5.15 (br d, J=10.42 Hz, 2H) 5.07 (s, 2H) 4.90 (s, 2H) 3.07-3.20 (m, 6H) 2.84-3.00 (m, 4H) 2.52-2.62 (m, 6H) 2.37 (td, J=12.49, 5.02 Hz, 2H) 2.09-2.13 (m, 2H) 2.07 (s, 2H) 1.95 (td, J=12.02, 3.45 Hz, 2H) 1.72-1.80 (m, 2H) 1.63 (quin, J=7.18 Hz, 4H) 1.25-1.48 (m, 12H)

Chemical Synthesis Example 15

bis((4R,4aS,7aR,12bS)-3-allyl-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl) (cyclohexane-1,4-diylbis(methylene)) bis(carbonate) (Naloxone-CDM-Naloxone, Compound 13)

[0346] ##STR00077##

[0347] To a solution of cyclohexanedimethanol bis(4-nitrophenyl carbonate) (1.00 g, 2.11 mmol, 1.00 eq) and naloxone hydrochloride dihydrate (1.81 g, 4.53 mmol, 2.15 eq) in DMF (5 mL) was added diisopropylethylamine (1.63 g, 12.6 mmol, 6.00 eq) and 4-(dimethylamino)pyridine (25.7 mg, 211 umol) at 0° C., then stirred at 20° C. for 12 h. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate (2×50 mL), the organic layer was washed with brine (3×50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (column: Agela DuraShell C18 250*70 mm*10 um; mobile phase: [water (0.05% NH.sub.3H.sub.2O+10 mM NH.sub.4HCO.sub.3)-ACN]; B %: 68%-88%, 20 min) to give the product (1.00 g, 55% yield) as a light yellow solid. Melting point: 126° C. HPLC (Method 3) retention time: 8.3 min, ESI MS+ Found, C.sub.48H.sub.55N.sub.2O.sub.10.sup.+ Mass: 851.38 .sup.1H NMR (400 MHz, DMSO) δ 6.96 (d, J=8.33 Hz, 2H) 6.75 (d, J=8.11 Hz, 2H) 5.86 (ddt, J=16.96, 10.39, 6.17, 6.17 Hz, 2H) 5.25 (br d, J=17.32 Hz, 2H) 5.15 (br d, J=10.52 Hz, 2H) 5.08 (s, 2H) 4.96 (s, 2H) 3.99-4.18 (m, 4H) 3.07-3.22 (m, 6H) 2.86-3.02 (m, 4H) 2.52-2.65 (m, 4H) 2.32-2.45 (m, 2H) 2.10 (br d, J=14.03 Hz, 2H) 1.95 (td, J=12.06, 3.51 Hz, 2H) 1.76 (br d, J=8.11 Hz, 6H) 1.64 (br s, 2H) 1.37-1.56 (m, 4H) 1.28 (br d, J=10.74 Hz, 2H) 1.03 (br t, J=8.33 Hz, 2H).

Chemical Synthesis Example 16

bis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl) decanedioate (Naltrexone-Seb-Naltrexone, Compound 14)

[0348] ##STR00078##

[0349] To a stirred solution of naltrexone hydrochloride (378 mg, 1.00 mmol) in dry DCM (50 mL) under nitrogen was added 4-(dimethylamino)pyridine (244 mg, 2.0 mmol), sebacic acid (101 mg, 0.50 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (383 mg, 2.00 mmol) and the mixture was stirred overnight. The mixture was concentrated onto 2 g reverse phase silica. Purification was performed by reverse phase automated chromatography (aqueous-MeCN gradient). Product containing fractions were combined and concentrated to give the product as an off-white solid (294 mg, 69%). Melting point: 86° C. HPLC (Method 3) retention time: 8.9 min, ESI MS+ Found, C.sub.50H.sub.61N.sub.2O.sub.10.sup.+ Mass: 849.43 .sup.1H NMR (400 MHz, DMSO) δ 6.82 (d, J=8.2 Hz, 2H), 6.71 (d, J=8.2 Hz, 2H), 5.14 (s, 2H), 4.91 (s, 2H), 3.17 (d, J=5.6 Hz, 2H), 3.09 (s, 2H), 3.04 (s, 2H), 2.97-2.84 (m, 4H), 2.67 (dd, J=12.0, 5.0 Hz, 2H), 2.64-2.51 (m, 8H), 2.44-2.31 (m, 6H), 2.15-2.05 (m, 4H), 1.95 (td, J=12.1, 3.8 Hz, 2H), 1.79 (dd, J=13.6, 4.8 Hz, 2H), 1.63 (p, J=7.2 Hz, 4H), 1.46 (dd, J=14.0, 3.4 Hz, 2H), 1.34 (s, 4H), 0.55-0.42 (m, 4H), 0.14 (t, J=5.6 Hz, 4H).

Chemical Synthesis Example 17

bis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl) cyclohexane-1,4-dicarboxylate (Naltrexone-1,4-cyclohexyl-Naltrexone, Compound 15)

[0350] ##STR00079##

[0351] To a stirred solution of naltrexone hydrochloride (378 mg, 1.00 mmol) in dry DCM (50 mL) under nitrogen was added 4-(dimethylamino)pyridine (244 mg, 2.0 mmol), 1,4-cyclohexanedicarboxylic acid (86 mg, 0.50 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (383 mg, 2.00 mmol) and the mixture was stirred overnight. The mixture was concentrated onto 2 g reverse phase silica. Purification was performed by reverse phase automated chromatography (aqueous-MeCN gradient). Product containing fractions were combined and concentrated to give the product as an off-white solid (260 mg, 63%). Melting point: 145° C. HPLC (Method 3) retention time: 8.0 min, ESI MS+ Found, C.sub.48H.sub.55N.sub.2O.sub.10.sup.+ Mass: 819.39 .sup.1H NMR (400 MHz, DMSO) δ 6.83 (dd, =8.2, 1.9 Hz, 2H), 6.72 (dd, J=8.3, 2.2 Hz, 2H), 5.15 (s, 2H), 4.93 (d, J=5.8 Hz, 2H), 3.17 (d, J=5.5 Hz, 2H), 3.09 (s, 1H), 3.05 (s, 1H), 2.94 (s, 1H), 2.89 (dd, J=14.3, 5.0 Hz, 2H), 2.72-2.59 (m, 3H), 2.57 (d, J=5.9 Hz, 1H), 2.38 (tt, J=11.0, 6.2 Hz, 6H), 2.17-2.09 (m, 2H), 2.07 (s, 3H), 2.01-1.91 (m, 5H), 1.89-1.75 (m, 4H), 1.58 (s, 1H), 1.45 (t, J=14.2 Hz, 2H), 1.30 (d, J=12.1 Hz, 2H), 0.87 (q, J=7.3 Hz, 2H), 0.55-0.43 (m, 4H), 0.19-0.09 (m, 4H).

Chemical Synthesis Example 18

bis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl) terephthalate (Naltrexone-1,4-terephthalate-Naltrexone. Compound 16)

[0352] ##STR00080##

[0353] To a stirred solution of naltrexone hydrochloride (378 mg, 1.00 mmol) in dry DCM (50 mL) under nitrogen was added 4-(dimethylamino)pyridine (244 mg, 2.0 mmol), terephthalic acid (84 mg, 0.50 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (383 mg, 2.00 mmol) and the mixture was stirred overnight. The mixture was concentrated onto 2 g reverse phase silica. Purification was performed by reverse phase automated chromatography (aqueous-MeCN gradient). Product containing fractions were combined and concentrated to give the product as an off-white solid (180 mg, 44%). Melting point: 240° C. HPLC (Method 3) retention time: 8.9 min, ESI MS+ Found, C.sub.48H.sub.49N.sub.2O.sub.10.sup.+ Mass: 813.34 .sup.1H NMR (400 MHz, DMSO) δ 8.33 (d, J=2.2 Hz, 4H), 7.11-7.04 (m, 2H), 6.81 (d, J=8.0 Hz, 2H), 5.18 (s, 2H), 4.97 (d, J=2.2 Hz, 2H), 3.24-3.18 (m, 2H), 3.15 (s, 1H), 3.10 (s, 1H), 2.94 (d, J=2.2 Hz, 4H), 2.75-2.60 (m, 2H), 2.42 (d, J=6.9 Hz, 6H), 2.18-2.05 (m, 4H), 2.01 (t, J=11.7 Hz, 2H), 1.83 (d, J=13.2 Hz, 2H), 1.50 (t, J=13.8 Hz, 2H), 1.37 (d, J=12.5 Hz, 2H), 0.51 (d, J=8.1 Hz, 4H), 0.16 (d, J=5.0 Hz, 4H).

Chemical Synthesis Example 19

bis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl) tetradecanedioate (Naltrexone-dodecane-Naltrexone, Compound 17)

[0354] ##STR00081##

[0355] To a stirred solution of naltrexone hydrochloride (378 mg, 1.00 mmol) in dry DCM (50 mL) under nitrogen was added 4-(dimethylamino)pyridine (244 mg, 2.0 mmol), 1,12-dodecanedicarboxylic acid (129 mg, 0.50 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (383 mg, 2.00 mmol) and the mixture was stirred overnight. The mixture was concentrated onto 2 g reverse phase silica. Purification was performed by reverse phase automated chromatography (aqueous-MeCN gradient). Product containing fractions were combined and concentrated to give the product as an off-white solid (248 mg, 55%). Melting point: 73° C. HPLC (Method 3) retention time: 12.9 min, ESI MS+ Found, C.sub.54H.sub.69N.sub.2O.sub.10.sup.+ Mass: 905.50 .sup.1H NMR (400 MHz, DMSO) δ 6.81 (d, J=8.2 Hz, 21H), 6.71 (d, J=8.3 Hz, 2H), 5.14 (s, 2H), 4.90 (s, 2H), 3.17 (d, J=5.6 Hz, 2H), 3.09 (s, 1H), 3.04 (s, 1H), 2.97-2.85 (m, 2H), 2.67 (dd, J=12.0, 4.9 Hz, 2H), 2.64-2.50 (m, 6H), 2.44-2.31 (m, 6H), 2.10 (dt, J=14.1, 3.2 Hz, 2H), 1.96 (td, J=12.1, 3.8 Hz, 2H), 1.79 (dt, J 13.2, 4.2 Hz, 2H), 1.61 (p, J=7.3 Hz, 4H), 1.45 (td, J=13.9, 3.3 Hz, 2H), 1.39-1.21 (m, 18H), 0.92-0.84 (m, 2H), 0.55-0.42 (m, 4H), 0.14 (p, J=6.4 Hz, 4H).

Chemical Synthesis Example 20

bis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl) 3-ethyl-3-methylpentanedioate (Naltrexone-3-ethyl-3-methylglutaric acid-Naltrexone, Compound 18)

[0356] ##STR00082##

[0357] To a stirred solution of naltrexone hydrochloride (378 mg, 1.00 mmol) in dry DCM (50 mL) under nitrogen was added 4-(dimethylamino)pyridine (244 mg, 2.0 mmol), 3-Ethyl-3-methylglutaric acid (87 mg, 0.50 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (383 mg, 2.00 mmol) and the mixture was stirred overnight. The mixture was concentrated onto 2 g reverse phase silica. Purification was performed by reverse phase automated chromatography (aqueous-MeCN gradient). Product containing fractions were combined and concentrated to give the product as an off-white solid (157 mg, 38%). Melting point: 103° C. HPLC (Method 3) retention time: 8.8 min, ESI MS+ Found, C.sub.48H.sub.57N.sub.2O.sub.10.sup.+ Mass: 821.40 .sup.1H NMR (400 MHz, DMSO) δ 6.96-6.89 (m, 2H), 6.83 (d, J=8.2 Hz, 2H), 5.26 (s, 1H), 5.04 (d, J=2.3 Hz, 2H), 3.28 (d, J=5.6 Hz, 2H), 3.21 (s, 1H), 3.16 (s, 1H), 3.08-2.96 (m, 3H), 2.80 (d, J=16.3 Hz, 6H), 2.71 (dd, J=19.0, 5.9 Hz, 2H), 2.48 (s, 4H), 2.21 (dd, J=12.6, 2.5 Hz, 3H), 2.07 (t, J=12.2 Hz, 2H), 1.90 (d, J=13.4 Hz, 2H), 1.74 (d, J=8.0 Hz, 2H), 1.56 (t, J=13.9 Hz, 2H), 1.43 (d, J=12.7 Hz, 2H), 1.33 (s, 3H), 1.25 (d, =J=2.3 Hz, 2H), 1.09-0.94 (m, 4H), 0.60 (d, J=8.1 Hz, 4H), 0.25 (d, J=4.9 Hz, 4H).

Chemical Synthesis Example 21

bis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl) hexane-1,6-diyl bis(carbonate) (Naltrexone-Hex-Naltrexone, Compound 19)

[0358] ##STR00083##

[0359] To a solution of 1,6-hexanediol (59 mg, 0.50 mmol), triethylamine (348 uL, 2.5 mmol) and 4-(dimethylamino)pyridine (3.0 mg, 0.025 mmol) in DCM (10 mL) was added 4-nitrophenylchloroformate (222 mg, 1.1 mmol) and the mixture stirred for 2 d. Naltrexone hydrochloride (567 mg, 1.5 mmol) was added and the mixture stirred overnight. The mixture was concentrated onto 2 g reverse phase silica. Purification was performed by reverse phase automated chromatography (aqueous-MeCN gradient). Product containing fractions were combined and concentrated to give the product as an off-white solid (85 mg, 20%). Melting point: 102° C. HPLC (Method 3) retention time: 8.3 min, ESI MS+ Found, C.sub.48H.sub.57N.sub.2O.sub.12.sup.+ Mass: 853.39 .sup.1H NMR (400 MHz, DMSO) δ 6.82 (d, J=8.2 Hz, 2H), 6.71 (d, J=8.2 Hz, 2H), 5.14 (s, 2H), 4.91 (s, 2H), 4.18 (m, 4H), 3.17 (d, J=5.6 Hz, 2H), 3.09 (s, 2H), 3.04 (s, 2H), 2.97-2.84 (m, 4H), 2.67 (dd, J=12.0, 5.0 Hz, 2H), 2.64-2.51 (m, 8H), 2.44-2.31 (m, 6H), 2.15-2.05 (m, 4H), 1.95 (td, J=12.1, 3.8 Hz, 2H), 1.79 (dd, J=13.6, 4.8 Hz, 2H), 1.63 (p, J=7.2 Hz, 4H), 1.46 (dd, J=14.0, 3.4 Hz, 2H), 1.34 (s, 2H), 0.55-0.42 (m, 2H).

Chemical Synthesis Example 22

cyclohexane-1,4-diylbis(methylene) bis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl) bis(carbonate) (Naltrexone-CDM-Naltrexone, Compound 20)

[0360] ##STR00084##

[0361] To a solution of 1,4-cyclohexanedimethanol (72 mg, 0.50 mmol), triethylamine (348 uL, 2.5 mmol) and 4-(dimethylamino)pyridine (3.0 mg, 0.025 mmol) in DCM (10 mL) was added 4-nitrophenylchloroformate (222 mg, 1.1 mmol) and the mixture stirred for 2 d. Naltrexone hydrochloride (567 mg, 1.5 mmol) was added and the mixture stirred overnight. The mixture was concentrated onto 2 g reverse phase silica. Purification was performed by reverse phase automated chromatography (aqueous-MeCN gradient). Product containing fractions were combined and concentrated to give the product as an off-white solid (90 mg, 20%). Melting point: 131° C. HPLC (Method 3) retention time: 8.8 min, ESI MS+ Found, C.sub.50H.sub.5N.sub.2O.sub.12.sup.+ Mass: 879.41 .sup.1H NMR (400 MHz, DMSO) δ 6.81 (d, J=8.2 Hz, 2H), 6.70 (d, J=8.2 Hz, 2H), 5.14 (s, 2H), 4.91 (s, 2H), 3.98-4.17 (m, 4H) 3.07-3.22 (m, 6H) 2.86-3.02 (m, 4H) 2.52-2.65 (m, 4H) 2.32-2.45 (m, 2H) 2.10 (br d, J=14.03 Hz, 2H) 1.95 (td, J=12.06, 3.51 Hz, 2H) 1.76 (br d, J=8.11 Hz, 6H) 1.64 (br s, 2H) 1.37-1.56 (m, 4H) 1.28 (br d, J=10.74 Hz, 2H) 1.03 (br t, J=8.33 Hz, 2H), 0.87 (q, J=7.3 Hz, 2H), 0.55-0.43 (m, 4H), 0.19-0.09 (m, 4H).

Chemical Synthesis Example 23

bis((4R,4aR,7aR,12bS)-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl) adipate (Hydromorphone-Adip-Hydromorphone, Compound 21)

[0362] ##STR00085##

[0363] To a fine suspension of hydromorphone free base (456 mg, 1.60 mmol) in anhydrous THF (11.5 mL) was added 60% sodium hydride in mineral oil (64 mg, 1.60 mmol) portionwise and the mixture was stirred for 10 min under nitrogen. Adipoyl chloride (139 mg, 111 μL, 0.76 mmol) was added and stirring was continued overnight under nitrogen. The solution was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with dichloromethane (3×40 mL). The combined organic layers were washed with saturated brine (50 mL), dried (MgSO4) and concentrated to give a white solid (550 mg). Purification was performed by reverse phase automated chromatography (aqueous HCl-MeCN gradient). Product containing fractions were combined, concentrated to ˜50% volume, poured into saturated aqueous sodium bicarbonate (50 mL) and extracted with dichloromethane (4×50 mL). The combined organic layers were washed with saturated brine (50 mL), dried (MgSO.sub.4) and concentrated to give a white glassy solid (408 mg) containing ˜15% hydromorphone. A further purification was performed using reverse phase automated chromatography (aqueous HCl-MeCN gradient). Product containing fractions were combined, concentrated to ˜50% volume, poured into saturated aqueous sodium bicarbonate (25 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with saturated brine (20 mL), dried (MgSO.sub.4) and concentrated and concentrated to give the product as a white glassy solid (230 mg, 44%). Melting point: 112° C. HPLC (Method 3) retention time: 8.1 min, ESI MS+ Found, C.sub.40H.sub.45N.sub.2O.sub.8.sup.+ Mass: 681.32 .sup.1H NMR (400 MHz, DMSO-d6) δ 6.82 (d, J=8.0 Hz, 2H), 6.71 (d, J=8.0 Hz, 2H), 4.97 (s, 2H), 3.14 (d, J=5.6 Hz, 2H), 2.98 (td, J=14.3, 5.0 Hz, 2H), 2.54 (m, 10H), 2.32 (m, 8H), 2.17 (dt, J=12.6, 2.4 Hz, 2H), 2.03 (td, J=12.1, 3.8 Hz, 2H), 1.95 (td, J=12.1, 3.8 Hz, 2H), 1.74 (m, 6H), 1.48 (td, J=14.0, 3.4 Hz, 2H), 1.00 (m, 2H).

Chemical Synthesis Example 24

bis((4R,4aR,7S,7aR,12bS)-9-methoxy-3-methyl-2,3,4,4a,7,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl) adipate (Codeine-Adip-Codeine, Compound 22)

[0364] ##STR00086##

[0365] To a stirred solution of codeine free base (440 mg, 1.47 mmol) in anhydrous DMF (50 mL) was added adipic acid (102 mg, 0.70 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.55 g, 2.87 mmol) and 4-(dimethylamino)pyridine (385 mg, 3.15 mmol) and the mixture was stirred overnight. The resulting solution was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with dichloromethane (4×50 mL). The combined organic layers were washed with water (4×50 mL), saturated brine (50 mL), dried (MgSO4) and concentrated to give a white solid. Purification was performed by reverse phase automated chromatography (aqueous HCl-MeCN gradient). Product containing fractions were combined, concentrated to approximately 50% volume, poured into saturated aqueous sodium bicarbonate (100 mL) and extracted with dichloromethane (3×80 mL). The combined organic layers were washed with saturated brine (80 mL), dried (MgSO4) and concentrated to give the desired product as a white solid which was further purified by using an automated chromatography system under normal phase conditions (silica column, gradient of 2.fwdarw.30% methanol in dichloromethane) with detection at 254 nm to give the product (280 mg, 56%) as a white solid. Melting point: 209° C. HPLC (Method 3) retention time: 8.3 min, ESI MS+ Found, C.sub.42H.sub.49N.sub.2O.sub.8.sup.+ Mass: 709.35 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.58 (d, J=8.0 Hz, 2H), 6.47 (d, J=8.0 Hz, 2H), 5.56 (m, 2H), 5.35 (m, 2H), 5.10 (m, 2H), 5.01 (d, J=8.0 Hz, 2H), 3.76 (s, 6H), 3.28 (m, 2H), 2.97 (d, J=12.0 Hz, 2H), 2.68 (m, 2H), 2.54 (m, 2H), 2.41 (m, 10H), 2.25 (m, 4H), 2.01 (m, 2H), 1.77 (m, 2H), 1.71 (m, 4H).

III. Formation and Evaluation of Processable Conjugates

Example 1: Heat Processing of Compounds

[0366] Compounds that were collected as stable powders and/or gums were investigated for pellet formation by heat molding. Compounds were processed at a temperature ˜10-30° C. above their corresponding thermal transitions (glass transition temperature (Tg) for gums or amorphous powders or melting point (Tm) for crystalline powders) and pressed into a cylindrical mold of ˜1 mm in height×1 mm in diameter. Light microscopy was used to capture images of the heat-formed pellets. Temperatures used to achieve a melt for heat molding were in a range from 70° C. to 220° C.

[0367] Compound 3 and Compound 5 successfully formed glassy, mostly transparent pellets and had mechanical properties that allowed them to be easily handled without breaking. These pellets had the appropriate processing properties to be tested as articles for drug delivery applications. Compound 8 formed opaque yellow-tinted pellets that could be handled and assessed for drug release. Compound 2 formed a viscous liquid upon melting and flowed into the heat-mold template but displayed a softened state under ambient conditions and deformed during the process of removal from the mold. The recovered form was soft and tacky and could not be easily handled.

[0368] Compounds 9 and 11-22 successfully formed a (e.g., glassy, mostly transparent) pellet and provided mechanical properties that allowed the pellets to be handled without breaking. These pellets had the appropriate processing properties to be tested as articles for drug delivery applications. Compound 10 was yellow upon heating and didn't form a viscous liquid that could be pressed into a pellet. The recovered form of Compound 10 was brittle and did not have mechanical properties that allowed the pellet to be handled without breaking.

Example 2: Solvent Processing

[0369] Compound 9 was formed into a thin film coating on a polymer surface by solvent casting. Compound 9 was dissolved in acetone at 100 mg/ml and 10 μl of the solution was cast onto a Dacron coupon and left to air dry at room temperature overnight. Images of the thin, transparent coating were captured by light microscopy.

[0370] Compound 3 and Compound 5 were formed into a thin film coating on a polymer surface by solvent casting. Compounds were dissolved in acetone at 100 mg/ml and 10 μl of the solution was cast onto a Dacron coupon and left to air dry at room temperature overnight. Images of the thin, transparent coating were captured by light microscopy.

IV. Drug Release Evaluation

Example 1: Drug Release from Pellets

[0371] Drug release from heat-molded pellets of the compounds were assessed in phosphate buffered saline (PBS). Heat-molded pellets were placed in 20 ml glass vials and 2 ml of release buffer was added. Samples were incubated at 37° C. with constant agitation at 115 rpm. Release buffer was sampled and fully replaced with 2 ml of fresh buffer on days 1, 3, 7, 10, and 14. Samples were analyzed by high performance liquid chromatography (HPLC) to quantify drug products. Cumulative release was calculated as a percentage of total mass of starting pellets and was plotted over time.

[0372] Heat molded pellets of Compound 3, Compound 5, and Compound 8 were then placed in 20 mL glass vials and 4 mL of release buffer (phosphate buffered saline, PBS) was added. Samples were incubated at 37° C. on a shaker rotating at 115 rpm. Observations made after a 1-day incubation show mechanical collapse for Compound 3 and Compound 5 pellets under the test conditions and the pellet shape changed to a clear gel (Compound 3) or fragmented entirely to opaque particulates (Compound 5). Drug release from Compound 8 was assessed by HPLC from PBS release buffer weekly for 8 weeks with full buffer change at each time point. Minimal drug release was observed over the time period investigated.

Example 2: Drug Release from a Polymer Surface Coated

[0373] Compound-coated Dacron films were placed into 20 mL vials, 2 mL fetal bovine serum (FBS) was added, and the samples were incubated at 37 C. At day 1, 3, and 7, the FBS was removed, proteins were precipitated with the addition of MeCN (2:1 ratio), and the suspension was transferred to a centrifuge tube. The tubes were centrifuged at 10,000 rpm for 6 min and the supernatant was analyzed by HPLC to quantify the release products. A fresh 2 mL of FBS was added and the sample was incubation at 37° C. until the next timepoint.

CONTROLLED RELEASE DRUG DIMERS

Inventors

Cpc classification

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A61K31/485

HUMAN NECESSITIES

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A61K47/55

HUMAN NECESSITIES

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A61P25/04

HUMAN NECESSITIES

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A61K47/552

HUMAN NECESSITIES

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A61K9/0024

HUMAN NECESSITIES

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A61P25/36

HUMAN NECESSITIES

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A61K47/545

HUMAN NECESSITIES

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A61K9/1617

HUMAN NECESSITIES

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A61K47/542

HUMAN NECESSITIES

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C07D489/08

CHEMISTRY; METALLURGY

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C07D489/02

CHEMISTRY; METALLURGY

International classification

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A61K47/55

HUMAN NECESSITIES

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A61K47/54

HUMAN NECESSITIES

Abstract

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Description