Diketopiperazine-based delivery systems

• US 5,976,569 A
• Filed: 04/29/1997
• Issued: 11/02/1999
• Est. Priority Date: 09/29/1994
• Status: Expired due to Term

• Current Assignee: NOVO Nordisk North America Operations A/S
• Original Assignee: Emisphere Technologies, Inc. (Novo Nordisk A/S)
• Inventors: Milstein, Sam J.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Spear, James M.
• Application Number:
  US08/841,101
• Time in Patent Office: 917 Days
• Field of Search: 424/451, 424/464, 424/489, 424/465, 424/405, 424/401, 514/2, 514/23, 514/54, 514/802, 514/805, 514/806, 514/807, 514/808, 514/889, 514/937, 514/951
• US Class Current: 424/451
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 38/23 Calcitonins
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: C07C 229/42 with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
• CPC Class Codes: C07C 233/55 having the carbon atom of the carboxamide group bound to a carbon atom of an unsaturated carbon skeleton
• CPC Class Codes: C07C 233/63 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 233/87 of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 235/38 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 235/64 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 235/84 with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 237/22 having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated peptides C07K
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2601/18 with a ring being at least seven-membered

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.

Claims

1. A delivery composition comprising:

(a) an active agent; and

(b) a diketopiperazine having the formula;

##STR5## wherein R¹, R², or R¹ and R² independently are hydrogen, C₁ -C₂₄ alkyl, C₁ -C₂₄ alkenyl, phenyl, naphtyl, (C₁ -C₁₀ alkyl)phenyl, (C₁ -C₁₀ alkenyl)phenyl, (C₁ -₁₀ alkyl)naphthyl, (C₁ -C₁₀ alkenyl)naphthyl, phenyl (C₁ -C₁₀ alkyl), phenyl (C₁ -C₁₀ alkenyl), naphthyl (C₁ -C₁₀ alkyl), and naphthyl (C₁ -C₁₀ alkenyl);

R¹ or R², or both R¹ and R², optionally, are independently substituted with C₁ -C₄ alkyl, C₁ -C₄ alkenyl, C₁ -C₄ alkoxy, --OH, --SH, and --CO₂ R³ or any combination thereof;

wherein R³ is hydrogen, C₁ -C₄ alkyl, or C₁ -C₄ alkenyl;

R¹, R², or R¹ and R², 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 C₁ -C₆ alkyl, C₁ -C₆ alkenyl, C₁ -C₆ alkoxy, --OH, --SH, or CO₂ R⁴ wherein R⁴ is hydrogen, C₁ -C₆ alkyl;

or C₁ -C₆ alkenyl; and

R¹ and R² 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 μ

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 α

-amino acids.

11. A delivery composition as defined in claim 10, wherein said two, α

-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 α

-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 α

-amino acids from which said diketopiperazine is derived.

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.

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.

14. A pharmacological composition comprising:

(a) at least one pharmacologically active agent; and

(b) a diketopiperazine having the formula;

##STR6## wherein R¹, R², or R¹ and R² independently are hydrogen, C₁ -C₂₄ alkyl, C₁ -C₂₄ alkenyl, phenyl, naphthyl, (C₁ -C₁₀ alkyl)phenyl, (C₁ -C₁₀ alkenyl)phenyl, (C₁ -C₁₀ alkyl)naphthyl, (C₁ -C₁₀ alkenyl)naphthyl, phenyl (C₁ -C₁₀ alkyl), phenyl (C₁ -C₁₀ alkenyl), naphthyl (C₁ -C₁₀ alkyl), and naphthyl (C₁ -C₁₀ alkenyl);

R¹ or R², or both R¹ and R², optionally, are independently substituted with C₁ -C₄ alkyl, C₁ -C₄ alkenyl, C₁ -C₄ alkoxy, --OH, --SH, and --CO₂ R³ or any combination thereof;

wherein R³ is hydrogen, C₁ -C₄ alkyl, or C₁ -C₄ alkeny;

R¹, R², or R¹ and R², 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 C₁ -C₆ alkyl, C₁ C₆ alkenyl, C₁ -C₆ alkoxy, --OH, --SH, or CO₂ R⁴ wherein R⁴ is hydrogen, C₁ -C₆ alkyl, or C₁ -C₆ alkenyl; and

R¹ and R² are not both hydrogen.

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

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 R¹, R², or R¹ and R² independently are hydrogen, C₁ -C₂₄ alkyl, C₁ -C₂₄ alkenyl, phenyl, naphthyl, (C₁ -C₁₀ alkyl)phenyl, (C₁ -C₁₀ alkenyl)phenyl, (C₁ -C₁₀ alkyl)naphthyl, (C₁ -C₁₀ alkenyl)naphthyl, phenyl (C₁ -C₁₀ alkyl), phenyl (C₁ -C₁₀ alkeny), naphthyl (C₁ -C₁₀ alkyl), and naphthyl (C₁ -C₁₀ alkenyl);

R¹ or R², or both R¹ and R², optionally, are independently substituted with C₁ -C₄ alkyl, C₁ -C₄ alkenyl, C₁ -C₄ alkoxy, --OH, --SH, and --CO₂ R³ or any combination thereof;

wherein R³ is hydrogen, C_1-C4 alkyl, or C₁ -C₄ alkenyl;

R¹, R², or R¹ and R², 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 C₁ -C₆ alkyl, C₁ -C₆ alkenyl, C₁ -C₆ alkoxy, --OH, --SH, or CO₂ R⁴ wherein R⁴ is hydrogen, C₁ -C₆ alkyl, or C₁ -C₆ alkenyl; and

R¹ and R² 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 R¹, R², or R¹ and R² independently are hydrogen, C₁ -C₂₄ alkyl, C₁ -C₂₄ alkenyl, phenyl, naphthyl, (C₁ -C₁₀ alkyl)phenyl, (C₁ -C₁₀ alkenyl)phenyl, (C₁ -C₁₀ alkyl)naphthyl, (C₁ -C₁₀ alkenyl)naphthyl, phenyl (C₁ -C₁₀ alkyl), phenyl (C₁ -C₁₀ alkeny), naphthyl (C₁ -C₁₀ alkyl), and naphthyl (C₁ -C₁₀ alkenyl);

R¹ or R², or both R¹ and R², optionally, are independently substituted with C₁ -C₄ alkyl, C₁ -C₄ alkenyl, C₁ -C₄ alkoxy, --OH, --SH, and --CO₂ R³ or any combination thereof;

R³ is hydrogen, C₁ -C₄ alkyl or C₁ -C₄ alkenyl;

R¹, R², or R¹ and R², 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 C₁ -C₆ alkyl, C₁ -C₆ alkenyl, C₁ -C₆ alkoxy, --OH, --SH, or CO₂ R⁴ wherein R⁴ is hydrogen, C₁ -C₆ alkyl, or C₁ -C₆ alkenyl; and

R¹ and R² 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 μ

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.

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.

31. A pharmacological composition comprising:

(A) at least one pharmacologically active agent; and

(B) a carrier comprising a diketopiperazine having the formula;

##STR10##

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.