Oral drug delivery compositions and methods

• US 6,461,643 B2
• Filed: 05/21/2001
• Issued: 10/08/2002
• Est. Priority Date: 04/22/1993
• Status: Expired due to Fees

• Current Assignee: NOVO Nordisk North America Operations A/S
• Original Assignee: Emisphere Technologies, Inc. (Novo Nordisk A/S)
• Inventors: Barantsevitch, Evgueni N., Leone-Bay, Andrea, Sarubbi, Donald J., Milstein, Sam J., Paton, Duncan R.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Channavajjala, Lakshmi
• Application Number:
  US09/862,063
• Publication Number:
  US 20020052422A1
• Time in Patent Office: 505 Days
• Field of Search: 424/489, 424/451, 424/464, 424/490, 424/491, 424/499, 514/553, 514/561
• US Class Current: 424/489
• CPC Class Codes: A61K 2039/5252 inactivated (killed)
• CPC Class Codes: A61K 2039/542 oral/gastrointestinal
• CPC Class Codes: A61K 2039/552 Veterinary vaccine
• CPC Class Codes: A61K 2039/55544 Bacterial toxins
• CPC Class Codes: A61K 2039/55555 Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
• 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 38/25 Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
• CPC Class Codes: A61K 38/27 Growth hormone [GH], i.e. somatotropin
• CPC Class Codes: A61K 39/12 Viral antigens
• CPC Class Codes: A61K 39/39 characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• 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: C12N 2720/10034 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Abstract

The present invention relates to an oral drug delivery system, and in particular to modified amino acids and modified amino acid derivatives for use as a delivery system of sensitive agents such as bioactive peptides. The modified amino acids and derivatives can form non-covalent mixtures with active biological agents and in an alternate embodiment can releasably carry active agents. Modified amino acids can also form durg containing microspheres. These mixtures are suitable for oral administration of biologically active agents to animals. Methods for the preparation of such amino acids are also disclosed.

Claims

1. A composition comprising:

(A) at least one biologically-active agent; and

(B) a compound having the formula;

2. The composition according to claim 1, wherein

Ar is substituted or unsubstituted phenyl;

R³ is C₁ to C₂₄ alkyl, (C₁ to C₁₀ alkyl) phenyl, or phenyl (C₁ to C₁₀ alkyl); and

n is equal to 1.

3. The composition according to claim 1, wherein said biologically-active agent is selected from the group consisting of a peptide, a polysaccharide, a mucopolysaccharide, a carbohydrate, a lipid, or any combination thereof.

4. The composition according to claim 1, wherein said biologically-active agent is a peptide.

5. The composition according to claim 1, wherein said biologically-active agent is a mucopolysaccharide.

6. The composition according to claim 1, wherein said biologically-active agent is a lipid.

7. 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-I, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, erythropoietin, atrial naturetic factor, an antigen, a monoclonal antibody, somatostatin, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, vasopressin, cromolyn sodium, vancomycin, desferrioxamine, or any combination thereof.

8. The composition according to claim 7, wherein said biologically-active agent is an interferon.

9. The composition according to claim 7, wherein said biologically-active agent is insulin.

10. The composition according to claim 7, wherein said biologically-active agent is human growth hormone.

11. The composition according to claim 7, wherein said biologically-active agent is heparin.

12. The composition according to claim 7, wherein said biologically-active agent is low molecular weight heparin.

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

14. The composition according to claim 7, wherein said biologically-active agent is cromolyn sodium.

15. 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,

(e) a dosing vehicle, or

(h) any combination thereof.

16. The dosage unit form according to claim 15, comprising a tablet, a capsule, or a liquid.

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

19. A dosage unit form as defined in claim 15, wherein said biologically-active agent is selected from the group consisting of a peptide, a polysaccharide, a mucopolysaccharide, a carbohydrate, a lipid, a pesticide, or any combination thereof.

20. The dosage unit form as defined in claim 19, wherein the biologically-active agent is a mucopolysaccharide.

21. The dosage unit form as defined in claim 20, wherein the mucopolysaccharide is heparin.

22. The dosage unit form as defined in claim 20, wherein the mucopolysaccharide is low molecular weight heparin.

23. The dosage unit form as defined in claim 19, wherein the biologically-active agent is a peptide.

24. The dosage unit form as defined in claim 23, wherein said peptide is selected from the group consisting of human growth hormone, bovine growth hormone, growth hormone-releasing hormone, an interferon, interleukin-1, interleukin-II, insulin, calcitonin, erythropoietin, atrial naturetic factor, an antigen, a monoclonal antibody, somatostatin, adrenoctorticotropin, gonadotropin releasing hormone, oxytocin, vasopressin, and any combination thereof.

25. The dosage unit form as defined in claim 24, wherein the peptide is insulin.

26. The dosage unit form as defined in claim 24, wherein the peptide is interferon.

27. The dosage unit form as defined in claim 24, wherein the peptide is human growth hormone.

28. The dosage unit form as defined in claim 24, wherein the peptide is calcitonin.

29. The dosage unit form as defined in claim 24, wherein the peptide is an antigen.

30. The dosage unit form as defined in claim 15, wherein the biologically-active agent is cromolyn sodium.

31. The dosage unit form as defined in claim 19, comprising a tablet, a capsule, or a liquid.

32. The dosage unit form as defined in claim 31, wherein said dosing vehicle is selected from the group consisting of water, 1,2-propane diol, ethanol, and any combination thereof.

33. 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 19.

34. The method for administering as defined in claim 33, wherein the biologically-active agent is a mucopolysaccharide.

35. The method for administering as defined in claim 33, wherein the mucopolysaccharide is heparin.

36. The method for administering as defined in claim 33, wherein the mucopolysaccharide is low molecular weight heparin.

37. The method as defined in claim 33, wherein said biologically-active agent is a peptide.

38. The method as defined in claim 37, wherein said peptide is selected from the group consisting of human growth hormone, bovine growth hormone, growth hormone- releasing hormone, an interferon, interleukin-1, interleukin-II, insulin, calcitonin, erythropoietin, atrial naturtic factor, an antigen, a monoclonal antibody, sommatostatin, adrenoctorticotropin, gonadotropin releasing hormone, oxytocin, vasopressin, and any combination thereof.

39. The method as defined in claim 37, wherein the peptide is insulin.

40. The method as defined in claim 37, wherein the peptide is interferon.

41. The method as defined in claim 37, wherein the peptide is growth hormone.

42. The method as defined in claim 37, wherein the peptide is calcitonin.

43. The method as defined in claim 37, wherein the peptide is an antigen.

44. The method as defined in claim 33, wherein the biologically-active agent is cromolyn sodium.

45. The composition of claim 7, wherein the biologically active-agent is an antigen.

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

(A) at least one biologically-active agent; and

(B) a compound having the formula;