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Generated: August 17, 2017

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Title: Diketopiperazine-based delivery systems
Abstract:Compositions useful in the delivery of active agents are provided. These delivery compositions include (a) an active agent; and either (b)(1) a carrier of (i) at least one amino acid and (ii) at least one diketopiperazine or (b)(2) at least one mono-N-substituted, di-N-substituted, or unsubstituted 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:Apr 29, 1997
Application Number:08/841,101
Claims:1. A delivery composition comprising:

(a) an active agent; and

(b) a diketopiperazine having the formula: ##STR5## wherein R.sup.1, R.sup.2, or R.sup.1 and R.sup.2 independently are hydrogen, C.sub.1 -C.sub.24 alkyl, C.sub.1 -C.sub.24 alkenyl, phenyl, naphtyl, (C.sub.1 -C.sub.10 alkyl)phenyl, (C.sub.1 -C.sub.10 alkenyl)phenyl, (C.sub.1 -.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), and naphthyl (C.sub.1 -C.sub.10 alkenyl);

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

said phenyl, naphthyl, or phenyl and naphthyl groups, optionally, are independently substituted by 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; and

R.sup.1 and R.sup.2 are not both hydrogen.

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 independently selected from the group consisting of glutamic acid, aspartic acid, tyrosine, phenylalanine, and optical isomers thereof.

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

13. 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.

14. A pharmacological composition comprising:

(a) at least one pharmacologically active agent; and

(b) a diketopiperazine having the formula: ##STR6## wherein R.sup.1, R.sup.2, or R.sup.1 and R.sup.2 independently 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), and naphthyl (C.sub.1 -C.sub.10 alkenyl);

R.sup.1 or R.sup.2, or both R.sup.1 and R.sup.2, optionally, are independently 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 alkeny;

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

said phenyl, naphthyl, or phenyl and naghthyl groups, optionally, are independently substituted by 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; and

R.sup.1 and R.sup.2 are not both hydrogen.

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 dosage unit form as defined in claim 15, selected from the group consisting of a tablet, a capsule, and a liquid.

18. 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 11.

19. A method for preparing a delivery composition, said method comprising:

(A) mixing

(a) an active agent; and

(b) a diketopiperazine having the formula: ##STR7## wherein R.sup.1, R.sup.2, or R.sup.1 and R.sup.2 independently 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 alkeny), naphthyl (C.sub.1 -C.sub.10 alkyl), and naphthyl (C.sub.1 -C.sub.10 alkenyl);

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

said phenyl, naphthyl, or phenyl and naphthyl groups, optionally, are independently substituted by 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; and

R.sup.1 and R.sup.2 are not both hydrogen.

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

(A) solubilizing, in a solvent, a diketopiperazine having the formula: ##STR8## wherein R.sup.1, R.sup.2, or R.sup.1 and R.sup.2 independently 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 alkeny), naphthyl (C.sub.1 -C.sub.10 alkyl), and naphthyl (C.sub.1 -C.sub.10 alkenyl);

R.sup.1 or R.sup.2, or both R.sup.1 and R.sup.2, optionally, are independently 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; R.sup.3 is hydrogen, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkenyl;

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

said phenyl, naphthyl, or phenyl and naphthyl grougs, optionally, are independently substituted by 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; and

R.sup.1 and R.sup.2 are not both hydrogen, 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.

21. A method as defined in claim 20, 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.

22. A delivery composition comprising:

(a) an active agent; and

(b) a diketopiperazine having the formula ##STR9##

23. A delivery composition as defined in claim 22, comprising a microsphere.

24. A delivery composition as defined in claim 23, wherein said microsphere comprises a microcapsule.

25. A delivery composition as defined in claim 23, wherein said microsphere has a diameter of less than about 10 .mu.m.

26. A delivery composition as defined in claim 22, wherein said active agent comprises a fragrance.

27. A delivery composition as defined in claim 22, wherein said active agent comprises a biologically active agent.

28. A delivery composition as defined in claim 27, 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 of any of the foregoing.

29. A delivery composition as defined in claim 27, 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.

30. A delivery composition as defined in claim 29, 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.

31. A pharmacological composition comprising: (A) at least one pharmacologically active agent; and

(B) a carrier comprising a diketopiperazine having the formula: ##STR10##

32. A dosage unit form comprising: (A) a delivery composition as defined in claim 22; 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.

33. A dosage unit form as defined in claim 32, comprising an oral dosage unit form.

34. A dosage unit form as defined in claim 32, selected from the group consisting of a tablet, a capsule, and a liquid.

35. 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 delivery composition as defined in claim 22.

36. A method for preparing a delivery composition, said method comprising:

(A) mixing

(a) an active agent; and

(b) a carrier comprising a diketopiperazine having the formula ##STR11##

37. A method for preparing microspheres containing an active agent, said method comprising (A) solubilizing, in solvent, a carrier comprising a diketopiperazine having the formula ##STR12## and; (B) contacting said carrier solution with said active agent and a precipitator solution in which said carrier is insoluble.

38. A method as defined in claim 37, wherein said carrier 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.
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