Granted Patent B2

US 6,906,030 · App. 10/443,713 · Granted Jun 14, 2005

Abstract

Claims (47)

1. A delivery composition comprising:

(a) a peptide; and

(b) at least one diketopiperazine having the formula:

wherein R 1 and R 2 are C 1 -C 24 alkyl or C 1 -C 24 alkenyl and have at least one functional group selected from the group consisting of oxygen, amide, and carboxyl groups;

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

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

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 μm.

5. The delivery composition as defined in claim 1 , wherein said peptide is selected from the group consisting of human growth hormone, bovine growth hormone, growth hormone-releasing hormone, an interferon, interleukin-I, interleukin-II, insulin, heparin, calcitonin, erythropoietin, atrial naturetic factor, a monoclonal antibody, somatostatin, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, vasopressin, vancomycin, or any combination of any of the foregoing.

6. A delivery composition as defined in claim 1 , wherein said peptide is selected from the group consisting of an interferon, interleukin-I, interleukin-II, insulin, heparin, calcitonin, oxytocin, vasopressin, vancomycin, or any combination of any of the foregoing.

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

8. A delivery composition as defined in claim 7 , wherein said two α-amino acids from which said diketopiperazine is derived are the same.

9. A delivery composition as defined in claim 7 , wherein said diketopiperazine is prepared by the thermal condensation of said two α-amino acids from which said diketopiperazine is derived.

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

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

12. A delivery composition as defined in claim 1 , wherein at least one functional group in R 1 and R 2 is carboxyl.

13. A delivery composition as defined in claim 11 , wherein at least one functional group in R 1 and R 2 is carboxyl.

14. A delivery composition as defined in claim 1 , wherein the peptide is insulin.

15. A delivery composition as defined in claim 1 , wherein the peptide is calcitonin.

16. A delivery composition as defined in claim 1 , wherein the delivery composition is a solution comprising from about 10 to about 2000 mg of the diketopiperazine per ml of solution.

17. The delivery composition of claim 16 , wherein the solution comprises from about 75 to about 500 mg of the diketopiperazine per ml of solution.

18. A pharmacological composition comprising:

(a) a peptide; and

(b) at least one diketopiperazine having the formula:

wherein R 1 and R 2 are C 1 -C 24 alkyl or C 1 -C 24 alkenyl and have at least one functional group selected from the group consisting of oxygen, amide, and carboxyl groups;

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

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

19. 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.

20. A dosage unit form as defined in claim 19 , comprising an oral dosage unit form.

21. A method for administering a peptide to an animal in need thereof, said method comprising administering orally to said animal, a composition as defined in claim 1 .

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

(A) forming a diketopiperazines solution by solubilizing, in a solvent, at least one diketopiperazine having the formula:

wherein R 1 and R 2 are C 1 -C 24 alkyl or C 1 -C 24 alkenyl and have at least one functional group selected from the group consisting of oxygen, amide, and carboxyl groups;

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

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

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

23. A method as defined in claim 22 , 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.

Assignments (6)