Modified amino acids for drug delivery

• US 5,935,601 A
• Filed: 10/22/1996
• Issued: 08/10/1999
• Est. Priority Date: 04/22/1994
• Status: Expired due to Term

• Current Assignee: NOVO Nordisk North America Operations A/S (Novo Nordisk A/S)
• Original Assignee: Emisphere Technologies, Inc. (Novo Nordisk A/S)
• Inventors: Leone-Bay, Andrea, Wang, Nai Fang
• Primary Examiner(s): Kishore, Gollamudi S.
• Application Number:
  US08/732,404
• Time in Patent Office: 1,022 Days
• Field of Search: 424/489, 424/451, 424/464, 5/477, 5/491, 5/499, 5/490, 514/561, 514/553
• US Class Current: 424/489
• CPC Class Codes: A61K 31/16 Amides, e.g. hydroxamic acids
• CPC Class Codes: A61K 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 31/727 Heparin; Heparan
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 38/23 Calcitonins
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic 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 2601/08 the ring being saturated
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2601/18 with a ring being at least seven-membered
• CPC Class Codes: C07C 279/14 : being further substituted by carboxyl groups
• CPC Class Codes: C07K 1/1077 : by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids
• CPC Class Codes: C07K 5/06043 : Leu-amino acid
• CPC Class Codes: C07K 5/06095 : Arg-amino acid

Abstract

Compositions are provided which include (A) at least one biologically active agent, and (B) (a) at least one acylated amino acid; (b) at least one peptide comprising at least one acylated amino acid; or (c) a combination of (a) and (b); wherein said acylated amino acid is acylated by (I) a C₃ -C₁₀ cycloalkyl acylating agent substituted with C₁ -C₇ alkyl, C₂ -C₇ alkenyl, C₁ -C₇ alkoxy, hydroxy, phenyl, phenoxy, or --CO₂ R, wherein R is hydrogen, C₁ -C₄ alkyl or C₂ -C₄ alkenyl; (ii) an unsubstituted C₃ -C₁₀ cycloalkyl acylating agent; or (iii) a C₁ -C₆ alkyl acylating agent substituted with C₃ -C₁₀ cycloalkyl.

Claims

1. A composition comprising:

(A) at least one biologically active agent, and

(B) (a) at least one acylated amino acid;

(b) at least one peptide comprising at least one acylated amino acid;

or

(c) a combination of (a) and (b);

wherein said acylated amino acid is acylated by

(i) a C₃ -C₁₀ cycloalkyl acylating agent, substituted with C₁ -C₇ alkyl, C₂ -C₇ alkenyl, C₁ -C₇ alkoxy, hydroxy, phenyl, phenoxy, or --CO₂ R, wherein R is hydrogen, C₁ -C₄ alkyl or C₂ -C₄ alkenyl;

(ii) an unsubstituted C₃ -C₁₀ cycloalkyl;

or

(iii) a C₁ -C₆ alkyl acylating agent substituted with C₃ -C₁₀ cycloalkyl.

2. The composition according to claim 1, wherein said amino acid has the formula ##STR10## wherein:

R¹ is hydrogen, C₁ -C₄ alkyl, or C₂ -C₄ alkenyl;

R² is C₁ -C₂₄ alkyl, C₂ -C₂₄ alkenyl, C₃ -C₁₀ cycloalkyl, C₃ -C₁₀ cycloalkenyl, phenyl, naphthyl, (C₁ -C₁₀ alkyl) phenyl, (C₂ -C₁₀ alkenyl) phenyl, (C₁ -C₁₀ alkyl) naphthyl, (C₂ -C₁₀ alkenyl) naphthyl, phenyl (C₁ -C₁₀ alkyl), phenyl (C₂ -C₁₀ alkenyl), naphthyl (C₁ -C₁₀ alkyl), or naphthyl (C₂ -C₁₀ alkenyl);

R² being optionally substituted with C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₁ -C₄ alkoxy, --OH, --SH, --CO₂ R³, C₃ -C₁₀ cycloalkyl, C₃ -C₁₀ cycloalkenyl, heterocycle having 3-10 ring atoms wherein the hetero atom is one or more of N, O, S, or any combination thereof, aryl, (C₁ -C₁₀ alk)aryl, ar(C₁ -C₁₀ alkyl), or any combination thereof;

R² being optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and

R³ is hydrogen, C₁ -C₄ alkyl, or C₂ -C₄ alkenyl.

3. The composition according to claim 1, wherein said acylated amino acid has the formula ##STR11## wherein:

R⁴ is

(i) C₃ -C₁₀ cycloalkyl, optionally substituted with C₁ -C₇ alkyl, C₂ -C₇ alkenyl, C₁ -C₇ alkoxy, hydroxy, phenyl, phenoxy or --CO₂ R⁷, wherein R⁷ is hydrogen, C₁ -C₄ alkyl, or C₂ -C₄ alkenyl, or

(ii) C₃ -C₁₀ cycloalkyl substituted C₁ -C₆ alkyl;

R⁵ is hydrogen, C₁ -C₄ alkyl, or C₂ -C₄ alkenyl;

R⁶ is C₁ -C₂₄ alkyl, C₂ -C₂₄ alkenyl, C₃ -C₁₀ cycloalkyl, C₃ -C₁₀ cycloalkenyl, phenyl, naphthyl, (C₁ -C₁₀ alkyl) phenyl, (C₂ -C₁₀ alkenyl) phenyl, (C₂ -C₁₀ alkyl) naphthyl, (C₂ -C₁₀ alkenyl) naphthyl, phenyl (C₁ -C₁₀ alkyl), phenyl (C₂ -C₁₀ alkenyl), naphthyl (C₁ -C₁₀ alkyl), or naphthyl (C₂ -C₁₀ alkenyl);

R⁶ being optionally substituted with C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₁ -C₄ alkoxy, --OH, --SH, --CO₂ R⁷, C₃ -C₇ cycloalkyl, C₃ -C₇ cycloalkenyl, heterocycle having 3-10 ring atoms wherein the hetero atom is one or more atom of N, O, S or any combination thereof, aryl, C₁ -C₁₀ alk)aryl, ar(C₁ -C₁₀ alkyl) or any combination thereof;

R⁶ being optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and

R⁷ is hydrogen, C₁ -C₄ alkyl, or C₂ -C₄ alkenyl.

4. The composition according to claim 1, 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.

5. The composition according to claim 1, 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 thereof.

6. The composition according to claim 4, 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 thereof.

7. The composition according to claim 6, wherein said biologically-active agent is calcitonin.

8. The composition according to claim 1, wherein said amino acid is a naturally occurring amino acid.

9. The composition according to claim 1, wherein said amino acid is a synthetic amino acid.

10. The composition according to claim 1, wherein said amino acid is an α

-amino acid.

11. The composition according to claim 1, wherein said amino acid is a non-α

-amino acid.

12. The composition according to claim 2, wherein said amino acid is selected from the group consisting of alanine, arginine, asparagine, aspartic acid, citrulline, cysteine, cystine, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, phenylglycine, proline, serine, threonine, tryptophan tyrosine, valine, hydroxyproline, γ

-carboxyglutamate, O-phosphoserine, β

-alanine, α

-aminobutyric acid, γ

-aminobutyric acid, α

-aminoisobutyric acid, 4-(4-aminophenyl)butyric acid, (aminophenyl)acetic acid, aminobenzoic acid 4-aminohippuric acid, (aminomethyl)benzoic acid ε

-aminocaproic acid, 7-aminoheptanoic acid, β

-aspartic acid, γ

-glutamic acid, cysteine (acetomedomethyl), ε

-lysine, ε

-lysine alpha-9-fluroenylmethoxycarbonyl, methionine sulfone, norleucine, norvaline, ornithine, d-ornithine, p-nitro-phenylalanine, hydroxy proline, and thioproline.

13. The composition according to claim 12, wherein said amino acid is selected from the group consisting of arginine, leucine, lysine, phenylalanine, tyrosine, valine, phenylglycine, 4-(4-aminophenyl)butyric acid, 4-(4-aminophenyl)acetic acid and aminobenzoic acid.

14. The composition according to claim 1, wherein said peptide is selected from the group consisting of a di-peptide, a tri-peptide, a tetra-peptide, or a penta-peptide.

15. The composition according to claim 14, wherein said peptide comprises at least one naturally occurring amino acid.

16. The composition according to claim 14, wherein said peptide comprises at least one synthetic amino acid.

17. The composition according to claim 14, wherein said peptide comprises at least one α

-amino acid.

18. The composition according to claim 14, wherein said peptide comprises one or more amino acids selected from the group consisting of alanine, arginine, asparagine, aspartic acid, citrulline, cysteine, cystine, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, phenylglycine, proline, serine, threonine, tryptophan tyrosine, valine, hydroxy proline, γ

-carboxyglutamate, O-phosphoserine, β

-alanine, α

-amino butyric acid, γ

-amino butyric acid, α

-amino isobutyric acid, ε

-amino caproic acid, 7-amino heptanoic acid, β

-aspartic acid, γ

-glutamic acid, cysteine (acetomidomethyl), ε

-lysine, ε

-lysine, (alpha-9-fluorenylmethoxycarbonyl, methionine sulfone, norleucine, norvaline, ornithine, d-ornithine, p-nitro-phenylalanine, hydroxy proline, and thioproline.

19. The composition according to claim 18, wherein said peptide is formed from one or more amino acids selected from the group consisting of arginine, leucine, lysine, phenylalanine, tyrosine, valine, and phenylglycine.

20. The composition according to claim 1, wherein said acylating agent has the formula ##STR12## wherein R⁸ is (i) C₃ -C₁₀ cycloalkyl substituted with C₁ -C₇ alkyl, C₂ -C₇ alkenyl, C₁ -C₇ alkoxy, hydroxy, phenyl, phenoxy, or --CO₂ R⁹ wherein R⁹ is hydrogen, C₁ -C₄ alkyl or C₂ -C₄ alkenyl;

(ii) an unsubstituted C₃ -C₁₀ cycloalkyl;

or

(iii) a C₁ -C₁₆ alkyl substituted with C₃ -C₁₀ cycloalkyl; and

X is a leaving group.

21. The composition according to claim 20, wherein R is cyclohexyl, cyclopentyl, cyclopropyl, or cycloheptyl.

22. The composition according to claim 1, wherein component (b)(i) comprises a mixture of two or more acylated amino acids.

23. The composition according to claim 1, wherein said composition is in microsphere form.

24. A dosage unit form comprising

(A) a composition according to 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.

25. A dosage unit form according to claim 24 wherein said dosage unit is in the form of a tablet, a capsule, or a liquid.

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

27. A method for preparing a composition, said method comprising mixing:

(A) at least one biologically-active agent;

(B) (a) at least one acylated amino acid;

(b) at least one peptide comprising at least one acylated amino acid;

or

(c) a combination of (a) and (b);

wherein said acylated amino acid is acylated by

(i) a C₃ -C₁₀ cycloalkyl acylating agent substituted with C₁ -C₇ alkyl, C₂ -C₇ alkenyl, C₁ -C₇ alkoxy, hydroxy, phenyl, phenoxy, or --CO₂ R, wherein R is hydrogen, C₁ -C₄ alkyl or C₂ -C₄ alkenyl;

(ii) an unsubsituted C₃ -C₁₀ cyckloalkyl acylating agent;

or

(iii) a C₁ -C₆ alkyl acylating agent substituted with C₁₀ -C cycloalkyl; and

(C) optionally a dosing vehicle.

28. The method according to claim 27, further comprising a stabilizing additive.

29. The method according to claim 28, wherein the stabilizing additive is selected from the group consisting of gum acacia, gelatin, polyethylene glycol or polylysine.