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Details for Patent: 6,395,774

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Details for Patent: 6,395,774

Title: Carbon-substituted diketopiperazine delivery systems
Abstract:Compositions useful in the delivery of active agents are provided. These delivery compositions include (a) an active agent; and (b) a carrier of at least one mono-C-substituted or di-C-substituted diketopiperazine. Methods for preparing these compositions and administering these compositions are also provided.
Inventor(s): Milstein; Sam J. (Larchmont, NY)
Assignee: Emisphere Technologies, Inc. (Tarrytown, NY)
Filing Date:Aug 13, 2001
Application Number:09/929,530
Claims:1. A delivery composition comprising:

(a) an active agent; and

(b) at least one diketopiperazine having the formula: ##STR5##

wherein R.sup.1 and R.sup.2 are hydrogen, C.sub.1 -C.sub.24 alkyl, C.sub.1 -C.sub.24 alkenyl, phenyl, naphthyl, (C.sub.1 -C.sub.10 alkyl)phenyl, (C.sub.1 -C.sub.10 alkenyl)phenyl, (C.sub.1 -C.sub.10 alkyl)naphthyl, (C.sub.1 -C.sub.10 alkenyl)naphthyl, phenyl (C.sub.1 -C.sub.10 alkyl), phenyl (C.sub.1 -C.sub.10 alkenyl), naphthyl (C.sub.1 -C.sub.10 alkyl), or naphthyl (C.sub.1 -C.sub.10 alkenyl) and have at least one functional group selected from the group consisting of oxygen and amide groups;

both R.sup.1 and R.sup.2, optionally, are substituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkenyl, C.sub.1 -C.sub.4 alkoxy, --OH, --SH, and --CO.sub.2 R.sup.3 or any combination thereof; wherein R.sup.3 is hydrogen, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkenyl;

R.sup.1 and R.sup.2, optionally, are interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and

said phenyl or naphthyl group, optionally, is substituted with C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkenyl, C.sub.1 -C.sub.6 alkoxy, --OH, --SH, or CO.sub.2 R.sup.4 wherein R.sup.4 is hydrogen, C.sub.1 -C.sub.6 alkyl, or C.sub.1 -C.sub.6 alkenyl.

2. A delivery composition as defined in claim 1, comprising a microsphere.

3. A delivery composition as defined in claim 2, wherein said microsphere comprises a microcapsule.

4. A delivery composition as defined in claim 2, wherein said microsphere has a diameter of less than about 10 .mu.m.

5. A delivery composition as defined in claim 1, wherein said active agent comprises a fragrance.

6. A delivery composition as defined in claim 1, wherein said active agent comprises a biologically active agent.

7. A delivery composition as defined in claim 6, wherein said biologically active agent is selected from the group consisting of a peptide, a mucopolysaccharide, a carbohydrate, a lipid, a pesticide, or any combination thereof.

8. The delivery composition as defined in claim 7, wherein said biologically-active agent is selected from the group consisting of human growth hormone, bovine growth hormone, growth hormone-releasing hormone, an interferon, interleukin-II, insulin, heparin, calcitonin, erythropoietin, atrial naturetic factor, an antigen, a monoclonal antibody, somatostatin, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, vasopressin, cromolyn sodium, vancomycin, desferrioxamine (DFO), or any combination of any of the foregoing.

9. A delivery composition as defined in claim 8, wherein said biologically-active agent is selected from the group consisting of an interferon, interleukin-II, insulin, heparin, calcitonin, oxytocin, vasopressin, cromolyn sodium, vancomycin, DFO, or any combination of any of the foregoing.

10. A delivery composition as defined in claim 1, wherein said diketopiperazine is derived from two .alpha.-amino acids.

11. A delivery composition as defined in claim 10, wherein said two .alpha.-amino acids from which said diketopiperazine is derived are the same.

12. A delivery composition as defined in claim 10, wherein said diketopiperazine is prepared by the thermal condensation of said two .alpha.-amino acids from which said diketopiperazine is derived.

13. A delivery composition as defined in claim 1, further comprising (c) at least one enzyme inhibitor.

14. A pharmacological composition comprising:

(a) at least one pharmacologically active agent; and

(b) at least one diketopiperazine having the formula: ##STR6##

wherein R.sup.1 and R.sup.2 are hydrogen, C.sub.1 -C.sub.24 alkyl, C.sub.1 -C.sub.24 alkenyl, phenyl, naphthyl, (C.sub.1 -C.sub.10 alkyl)phenyl, (C.sub.1 -C.sub.10 alkenyl)phenyl, (C.sub.1 -C.sub.10 alkyl)naphthyl, (C.sub.1 -C.sub.10 alkenyl)naphthyl, phenyl (C.sub.1 -C.sub.10 alkyl), phenyl (C.sub.1 -C.sub.10 alkenyl), naphthyl (C.sub.1 -C.sub.10 alkyl), or naphthyl (C.sub.1 -C.sub.10 alkenyl) and have at least one functional group selected from the group consisting of oxygen and amide groups;

both R.sup.1 and R.sup.2, optionally, are substituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkenyl, C.sub.1 -C.sub.4 alkoxy, --OH, --SH, and --CO.sub.2 R.sup.3 or any combination thereof; wherein R.sup.3 is hydrogen, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkenyl;

R.sup.1 and R.sup.2, optionally, are interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and

said phenyl or naphthyl group, optionally, is substituted with C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkenyl, C.sub.1 -C.sub.6 alkoxy, --OH, --SH, or CO.sub.2 R.sup.4 wherein R.sup.4 is hydrogen, C.sub.1 -C.sub.6 alkyl, or C.sub.1 -C.sub.6 alkenyl.

15. A dosage unit form comprising:

(A) a delivery composition as defined in claim 1; and

(B) (a) an excipient,

(b) a diluent,

(c) a disintegrant,

(d) a lubricant,

(e) a plasticizer,

(f) a colorant,

(g) a dosing vehicle, or

(h) any combination thereof.

16. A dosage unit form as defined in claim 14, comprising an oral dosage unit form.

17. A method for administering a biologically active agent to an animal in need of such agent, said method comprising administering orally to said animal, a composition as defined in claim 1.

18. A method for preparing microspheres containing an active agent, said method comprising:

(A) solubilizing, in a solvent, at least one diketopiperazine having the formula: ##STR7##

wherein R.sup.1 and R.sup.2 are hydrogen, C.sub.1 -C.sub.24 alkyl, C.sub.1 -C.sub.24 alkenyl, phenyl, naphthyl, (C.sub.1 -C.sub.10 alkyl)phenyl, (C.sub.1 -C.sub.10 alkenyl)phenyl, (C.sub.1 -C.sub.10 alkyl)naphthyl, (C.sub.1 -C.sub.10 alkenyl)naphthyl, phenyl (C.sub.1 -C.sub.10 alkyl), phenyl (C.sub.1 -C.sub.10 alkenyl), naphthyl (C.sub.1 -C.sub.10 alkyl), or naphthyl (C.sub.1 -C.sub.10 alkenyl) and have at least one functional group selected from the group consisting of oxygen and amide groups;

both R.sup.1 and R.sup.2, optionally, are substituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkenyl, C.sub.1 -C.sub.4 alkoxy, --OH, --SH, and --CO.sub.2 R.sup.3 or any combination thereof; wherein R.sup.3 is hydrogen, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkenyl;

R.sup.1 and R.sup.2, optionally, are interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and

said phenyl or naphthyl group, optionally, is substituted with C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkenyl, C.sub.1 -C.sub.6 alkoxy, --OH, --SH, or CO.sub.2 R.sup.4 wherein R.sup.4 is hydrogen, C.sub.1 -C.sub.6 alkyl, or C.sub.1 -C.sub.6 alkenyl, to yield a diketopiperazine solution; and

(B) contacting said diketopiperazine solution with said active agent and a precipitator solution in which said diketopiperazine is insoluble.

19. A method as defined in claim 18, wherein said diketopiperazine solution has a pH within a first range and said precipitator solution has a pH within a second range, said first range being different than said second range.

20. A delivery composition as defined in claim 1, wherein R.sup.1 and R.sup.2 are C.sub.1 -C.sub.24 alkenyl and have at least one functional group selected from the group consisting of oxygen and amide groups; R.sup.1 and R.sup.2 are interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and R.sup.1 and R.sup.2 are substituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkenyl, C.sub.1 -C.sub.4 alkoxy, --OH, --SH, and --CO.sub.2 R.sup.3 or any combination thereof; wherein R.sup.3 is hydrogen, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkenyl.

21. A delivery composition as defined in claim 20, wherein R.sup.1 and R.sup.2 are interrupted by nitrogen.

22. A delivery composition as defined in claim 20, wherein R.sup.1 and R.sup.2 are substituted with --CO.sub.2 R.sup.3.

23. A delivery composition as defined in claim 22, wherein R.sup.3 is hydrogen.

24. A delivery composition as defined in claim 20, wherein the functional group is oxygen.

25. A delivery composition as defined in claim 20, wherein the functional group is an amide group.

26. A delivery composition as defined in claim 1, wherein R.sup.1 and R.sup.2 comprise an amide group.

27. A delivery composition as defined in claim 1, wherein the active agent is a hormone.

28. A delivery composition as defined in claim 1, wherein the active agent is insulin.

29. A delivery composition as defined in claim 1, wherein the active agent is calcitonin.

30. A pharmacological composition as defined in claim 14, wherein R.sup.1 and R.sup.2 are C.sub.1 -C.sub.24 alkenyl and have at least one functional group selected from the group consisting of oxygen and amide groups; R.sup.1 and R.sup.2 are interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and R.sup.1 and R.sup.2 are substituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkenyl, C.sub.1 -C.sub.4 alkoxy, --OH, --SH, and --CO.sub.2 R.sup.3 or any combination thereof; wherein R.sup.3 is hydrogen, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkenyl.

31. A pharmacological composition as defined in claim 30, wherein R.sup.1 and R.sup.2 are interrupted by nitrogen.

32. A pharmacological composition as defined in claim 30, wherein R.sup.1 and R.sup.2 are substituted with --CO.sub.2 R.sup.3.

33. A pharmacological composition as defined in claim 32, wherein R.sup.3 is hydrogen.

34. A pharmacological composition as defined in claim 30, wherein the functional group is oxygen.

35. A pharmacological composition as defined in claim 30, wherein the functional group is an amide group.

36. A pharmacological composition as defined in claim 14, wherein R.sup.1 and R.sup.2 comprise an amide group.

37. A pharmacological composition as defined in claim 14, wherein the active agent is a hormone.

38. A pharmacological composition as defined in claim 14, wherein the active agent is insulin.

39. A pharmacological composition as defined in claim 14, wherein the active agent is calcitonin.

40. A dosage unit form as defined in claim 15, wherein the active agent is insulin.

41. A method as defined in claim 18, wherein R.sup.1 and R.sup.2 are C.sub.1 -C.sub.24 alkenyl and have at least one functional group selected from the group consisting of oxygen and amide groups; R.sup.1 and R.sup.2 are interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and R.sup.1 and R.sup.2 are substituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkenyl, C.sub.1 -C.sub.4 alkoxy, --OH, --SH, and --CO.sub.2 R.sup.3 or any combination thereof; wherein R.sup.3 is hydrogen, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkenyl.

42. A method as defined in claim 41, wherein R.sup.1 and R.sup.2 are interrupted by nitrogen.

43. A method as defined in claim 41, wherein R.sup.1 and R.sup.2 are substituted with --CO.sub.2 R.sup.3.

44. A method as defined in claim 43, wherein R.sup.3 is hydrogen.

45. A method as defined in claim 41, wherein the functional group is oxygen.

46. A method as defined in claim 41, wherein the functional group is an amide group.

47. A method as defined in claim 18, wherein R.sup.1 and R.sup.2 comprise an amide group.

48. A method as defined in claim 18, wherein the active agent is a hormone.

49. A method as defined in claim 18, wherein the active agent is insulin.

50. A method as defined in claim 18, wherein the active agent is calcitonin.

51. A delivery composition comprising:

(a) an active agent; and

(b) at least one diketopiperazine having the formula: ##STR8##

wherein R.sup.1 and R.sup.2 are hydrogen, C.sub.1 -C.sub.24 alkyl, C.sub.1 -C.sub.24 alkenyl, phenyl, naphthyl, (C.sub.1 -C.sub.10 alkyl)phenyl, (C.sub.1 -C.sub.10 alkenyl)phenyl, (C.sub.1 -C.sub.10 alkyl)naphthyl, (C.sub.1 -C.sub.10 alkenyl)naphthyl, phenyl (C.sub.1 -C.sub.10 alkyl), phenyl (C.sub.1 -C.sub.10 alkenyl), naphthyl (C.sub.1 -C.sub.10 alkyl), or naphthyl (C.sub.1 -C.sub.10 alkenyl) and have at least one functional group oxygen;

both R.sup.1 and R.sup.2, optionally, are substituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkenyl, C.sub.1 -C.sub.4 alkoxy, --OH, --SH, and --CO.sub.2 R.sup.3 or any combination thereof; wherein R.sup.3 is hydrogen, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkenyl;

R.sup.1 and R.sup.2 are interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and

said phenyl or naphthyl group, optionally, is substituted with C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkenyl, C.sub.1 -C.sub.6 alkoxy, --OH, --SH, or CO.sub.2 R.sup.4 wherein R.sup.4 is hydrogen, C.sub.1 -C.sub.6 alkyl, or C.sub.1 -C.sub.6 alkenyl.
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