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Details for Patent: 5,629,020

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Details for Patent: 5,629,020

Title: Modified amino acids for drug delivery
Abstract:The present invention relates to an oral delivery system, and in particular to modified amino acids or peptides for use as a delivery system of sensitive agents such as bioactive peptides. The modified amino acids or peptides can form non-covalent mixtures or microspheres with active biological agents. These mixtures or microspheres are suitable for oral administration of biologically active agents to animals. Methods for the preparation of such amino acids and peptides are also disclosed.
Inventor(s): Leone-Bay; Andrea (Ridgefield, CT), Wang; Nai F. (Long Island City, NY)
Assignee: Emisphere Technologies, Inc. (Hawthorne, NY)
Filing Date:Apr 22, 1994
Application Number:08/231,622
Claims:1. A composition comprising:

(A) at least one biologically active agent selected from the group consisting of a peptide, a mucopoly-saccharide, a carbohydrate, a lipid, a pesticide, or any combination thereof, 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

a C.sub.3 -C.sub.10 cycloalkyl acylating agent.

2. The composition according to claim 1, wherein said amino acid has the formula ##STR10## wherein: R.sup.1 is hydrogen, C.sub.1 -C.sub.4 alkyl, or C.sub.2 -C.sub.4 alkenyl;

R.sup.2 is C.sub.1 -C.sub.24 alkyl, C.sub.2 -C.sub.24 alkenyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.3 -C.sub.10 cycloalkenyl, phenyl, naphthyl, (C.sub.1 -C.sub.10 alkyl)phenyl, (C.sub.2 -C.sub.10 alkenyl)phenyl, (C.sub.1 -C.sub.10 alkyl)naphthyl, (C.sub.2 -C.sub.10 alkenyl)naphthyl, phenyl (C.sub.1 -C.sub.10 alkyl), phenyl (C.sub.2 -C.sub.10 alkenyl), naphthyl (C.sub.1 -C.sub.10 alkyl), or naphthyl (C.sub.2 -C.sub.10 alkenyl);

R.sup.2 being optionally substituted with C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.1 -C.sub.4 alkoxy, --OH, --SH, --CO.sub.2 R.sup.3, C.sub.3 -C.sub.10 cycloalkyl, C.sub.3 -C.sub.10 cycloalkenyl, heterocycle having 3-10 ring atoms wherein the hetero atom is one or more of N, O, S, or any combination thereof, aryl, (C.sub.1 -C.sub.10 alk)aryl, ar(C.sub.1 -C.sub.10 alkyl), or any combination thereof;

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

R.sup.3 is hydrogen, C.sub.1 -C.sub.4 alkyl, or C.sub.2 -C.sub.4 alkenyl.

3. The composition according to claim 1, wherein said acylated amino acid has the formula ##STR11## wherein: R.sup.4 is C.sub.3 -C.sub.10 cycloalky;

R.sup.5 hydrogen, C.sub.1 -C.sub.4 alkyl, or C.sub.2 -C.sub.4 ALKENYL;

R.sub.6 is C.sub.1 -C.sub.24 alkyl, C.sub.2 -C.sub.24 alkenyl, C.sub.3 -C.sub.10 cycloalky, C.sub.3 -C.sub.10 cycloalkenyl, phenyl, naphthyl, (C.sub.1 -C.sub.10 alkyl)phenyl, (C.sub.2 -C.sub.10 alkenyl)phenyl, (C.sub.2 -C.sub.10 alkyl)naphthyl, (C.sub.2 -C.sub.10 alkenyl)naphthyl, phenyl (C.sub.1 -C.sub.10 alkyl), phenyl (C.sub.2 -C.sub.10 alkenyl), naphthyl(C.sub.1 -C.sub.10 alkyl), or naphthyl (C.sub.2 -C.sub.10 alkenyl);

R.sub.6 being optionally substituted with C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.1 -C.sub.4 alkoxy, --OH, --SH, --CO.sub.2 R.sup.7, C.sub.3 -C.sub.7 cycloalkyl, C.sub.3 -C.sub.7 cycloalkenyl, heterocycle having 3-10 ring atoms wherein the hereto atom is one or more atom of N, O, S or any combination thereof, aryl, (C.sub.1 -C.sub.10 alk)aryl, ar(C.sub.1 -C.sub.10 alkyl) or any combination thereof; and

R.sup.6 being optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof.

4. A composition comprising:

(A) at least one biologically active agent 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, a monoclonal antibody, somatostatin, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, vasopressin, cromolyn sodium, vancomycin, desferrioxamine (DFO), or any combination therof, 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

a C.sub.3 -C.sub.10 cycloalkyl acylating agent.

5. 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.

6. The composition according to claim 5, wherein said biologically-active agent is calcitonin.

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

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

9. The composition according to claim 1, wherein said amino acid is an .alpha.-amino acid.

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

11. 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, .gamma.-carboxyglutamate, O-phosphoserine, .beta.-alanine, .alpha.-aminobutyric acid, .gamma.-aminobutyric acid, .alpha.-aminoisobutyric acid, 4-(4-aminophenyl)butyric acid, (aminophenyl)acetic acid, aminobenzoic acid, 4-aminohippuric acid, (aminomethyl)benzoic acid .epsilon.-aminocaproic acid, 7-aminoheptanoic acid, .beta.-aspartic acid, .gamma.-glutamic acid, cysteine(ACM), .epsilon.-lysine, .epsilon.-lysine (A-Fmoc), methionine sulfone, norleucine, norvaline, ornithine, d-ornithine, p-nitro-phenylalanine, hydroxy proline, and thioproline.

12. The composition according to claim 11, 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.

13. 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.

14. The composition according to claim 13, wherein said peptide comprises at least one naturally occurring amino acid.

15. The composition according to claim 13, wherein said peptide comprises at least one synthetic amino acid.

16. The composition according to claim 13, wherein said peptide comprises at least one .alpha.-amino acid.

17. The composition according to claim 13, 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, .gamma.-carboxyglutamate, O-phosphoserine, .beta.-alanine, .alpha.-amino butyric acid, .gamma.-amino butyric acid, .alpha.-amino isobutyric acid, .epsilon.-amino caproic acid, 7-amino heptanoic acid, .beta.-aspartic acid, .epsilon.-glutamic acid, cysteine (ACM), .epsilon.-lysine, .epsilon.-lysine (A-Fmoc), methionine sulfone, norleucine, norvaline, ornithine, d-ornithine, p-nitro-phenylalanine, hydroxy proline, and thioproline.

18. The composition according to claim 17, 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.

19. The composition according to claim 1, wherein said acylating agent has the formula ##STR12## wherein R.sup.1 is

C.sub.3 -C.sub.10 cycloalkyl; and

X is a leaving group.

20. The composition according to claim 19, wherein R.sup.8 is cyclohexyl, cyclopentyl, cyclopropyl, or cycloheptyl.

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

22. The composition according to claim 1, comprising a microsphere.

23. 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, or

(g) any combination thereof.

24. A dosage unit form according to claim 23 comprising a tablet, a capsule, or a liquid.

25. 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.

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

(A) at least one biologically-active agent selected from the group consisting of a peptide, a mucopoly-saccharide, a carbohydrate, a lipid, a pesticide, or any combination thereof;

(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

a C.sub.3 -C.sub.10 cycloalkyl acylating agent; and

(C) optionally a dosing vehicle.

27. The method according to claim 26, further comprising a stabilizing additive.

28. The method according to claim 27, wherein the stabilizing additive is selected from the group consisting of gum acacia, gelatin, polyethylene glycol or polylysine.

29. The composition according to claim 1, wherein said biologically active agent comprises an antigen.
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