Modified amino acids for encapsulating active agents

• US 5,451,410 A
• Filed: 04/22/1993
• Issued: 09/19/1995
• Est. Priority Date: 04/22/1993
• 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: Barantsetvich, Evgueni N., Milstein, Sam J.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Benston, Jr., William E.
• Application Number:
  US08/051,019
• Time in Patent Office: 880 Days
• Field of Search: 424/490, 424/491, 424/489, 564/205
• US Class Current: 424/490
• 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 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

Modified amino acids and methods for their preparation and use as oral delivery systems for pharmaceutical agents are described. The modified amino acids are preparable by reacting single amino acids or mixtures of two or more kinds of amino acids with an amino modifying agent such as benzene sulfonyl chloride, benzoyl chloride, and hippuryl chloride. The modified amino acids form encapsulating microspheres in the presence of the active agent under sphere-forming conditions. Alternatively, the modified amino acids may be used as a carrier by simply mixing the amino acids with the active agent. The modified amino acids are particularly useful in delivering peptides, e.g. insulin or calmodulin, or other agents which are sensitive to the denaturing conditions of the gastrointestinal tract.

Claims

1. A composition comprising

(A) a biologically active agent;

and

(B) carrier comprising at least one modified amino acid selected from the group consisting of

(i) an acylated amino acid;

(ii) a sulfonated amino acid;

or

(iii) a combination of (i) and (ii).

2. A composition as defined in claim 1, wherein said acylated amino acid comprises an amino acid amide and said sulfonated amino acid comprises an amino acid sulfonamide.

3. A composition as defined in claim 1, wherein said carrier comprises a mixture of at least two of said modified amino acids.

4. The composition according to claim 1, wherein said modified amino acids are derived from reaction of an amino acid with an amino reactive modifying agent selected from the group consisting of benzene sulfonyl chloride, benzoyl chloride, hippuryl chloride, and amino acid carbodiimide.

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, interferon, interleukin-II, insulin, calcitonin, erythropoietin, atrial naturetic factor, antigens, and monoclonal antibody.

6. The composition according to claim 1, wherein said biologically active agent comprises at least one protein.

7. The composition according to claim 6, wherein said protein comprises erythropoietin.

8. The composition according to claim 6, wherein said protein comprises interferon.

9. The composition according to claim 6, wherein said protein comprises calcitonin.

10. The composition according to claim 6, wherein said protein comprises insulin.

11. The composition according to claim 6, wherein said protein comprises atrial naturetic factor.

12. The composition according to claim 6, wherein said protein comprises interleukin II.

13. The composition according to claim 6, wherein said protein comprises human growth factor.

14. The composition according to claim 6, wherein said protein comprises bovine growth factor.

15. The composition according to claim 1, wherein said biologically active agent comprises at least one polysaccharide.

16. The composition according to claim 15, wherein said polysaccharide comprises heparin.

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

18. The composition according to claim 1, wherein said biologically active agent comprises a monoclonal antibody.

19. A composition as defined in claim 1, wherein said composition comprises a microsphere.

20. A composition as defined in claim 1, wherein said microsphere comprises a microcapsule.

21. A composition as defined in claim 19, wherein said amino acid amide comprises a benzene amide of an amino acid and said amino acid sulfonamide comprises a benzene sulfonamide.