Uptake of macromolecules

• US 20060122097A1
• Filed: 04/15/2004
• Published: 06/08/2006
• Est. Priority Date: 04/15/2003
• Status: Active Grant

• Current Assignee: Axcess Limited
• Original Assignee: Axcess Limited
• Inventors: New, Roger R. C.
• Granted Patent: US 8,314,058 B2
• Time in Patent Office: Days
• US Class Current: 514/5.900
• CPC Class Codes: A61K 38/1816 Erythropoietin [EPO]
• CPC Class Codes: A61K 38/23 Calcitonins
• CPC Class Codes: A61K 38/27 Growth hormone [GH], i.e. somatotropin
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 38/29 Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

The invention provides a pharmaceutical composition comprising a mixture of: (a) an active macromolecular principle; and (b) a non-conjugated bile acid or salt; and (c) an additive chosen from propyl gallate, butyl hydroxy anisole (BHA) and analogues and derivatives thereof, or mixtures thereof.

Claims

1. A pharmaceutical composition comprising a mixture of:

(a) an active macromolecular principle; and

(b) a non-conjugated bile acid or salt; and

(c) an additive chosen from propyl gallate, butyl hydroxy anisole (BHA) and analogues and derivatives thereof, or mixtures thereof.

2. A composition according to claim 1, which comprises less than 5% by weight of water.

3. A composition according to claim 1, wherein the composition is coated with an enteric coating which becomes permeable at a pH from 3 to 7.

4. A composition according to claim 1, wherein the mixture comprises at least 1% by weight of the additive (c).

5. A composition according to claim 1, wherein the ratio by weight of the non-conjugated bile salt/additive (b+c) to active macromolecular principle is at least 5:

1.

6. A composition according to claim 1, wherein the mixture is in the form of a solution or a microparticulate dispersion.

7. A composition according to claim 1, wherein the mixture is in solid form.

8. A composition according to claim 1, wherein the active macromolecular principle is a polypeptide or protein, polynucleotide, polysaccharide or a mixture thereof.

9. A composition according to claim 8, where the active macromolecular principle is chosen from insulin, calcitonin, growth hormone, parathyroid hormone, or erythropoeitin, and derivatives and analogues thereof, either synthetic or from natural sources, conforming to structures derived from either human or animal origin.

10. A composition according to claim 9, where the active macromolecular principle is insulin, calcitonin, parathyroid hormone or a derivative or analogue thereof, either synthetic or from natural sources, conforming to structures derived from either human or animal origin.

11. A composition according to claim 10, wherein the active macromolecular principle is insulin or a derivative or analogue thereof, either synthetic or from natural sources, conforming to structures derived from either human or animal origin, and the composition further comprises an insulin sensitizing agent.

12. A composition according to claim 1, wherein the non-conjugated bile acid or salt is chenodeoxycholate.

13. A composition according to claim 1, wherein the additive is chosen from propyl gallate or an analogue or a derivative thereof, including esters of gallic acid, where the esters may be linear or branched chain C_1-12 alkyl, C_1-12 alkyloxy, C_1-12 alkylthio or C_2-12 alkenyl esters, and the compounds are optionally substituted with halogen, linear or branched chain C_1-12 alkyl, C_1-12 alkyloxy, C_1-12 alkylthio or C_2-12 alkenyl esters.

14. A composition according to claim 1, wherein the additive is chosen from BHA or an analogue or derivative thereof, including analogues and derivatives of hydroxy anisole where the methyl group or the methoxy group linked to the aromatic ring and/or the hydrogen ortho to the hydroxyl group are replaced by linear or branched chain C_1-12 alkyl, C_1-12 alkyloxy, C_1-2 alkylthio or C_2-12 alkenyl, either unsubstituted or substituted in any position, especially by halogen atoms.

15. A composition according to claim 1, for use in the therapeutic or diagnostic treatment of the human or animal body.

24. A method of enhancing the absorption of an active macromolecular principle in a patient, which method comprises administering to said patient a composition as defined in claim 1.

25. A method of treating a patient suffering from a condition or disease treatable by administration of a composition according to claim 1.

16. Use, in a pharmaceutical composition, of a non-conjugated bile acid or salt, together with an additive chosen from propyl gallate and BHA and analogues and derivatives thereof, or mixtures thereof as an enhancer for the absorption of macromolecules across the intestinal wall.

18. Use according to claim 16, wherein the molecule (s)/active macromolecular principle to be absorbed is a polypeptide or protein, polynucleotide, polysaccharide or a mixture thereof.

19. Use according to claim 18 wherein the molecule (s)/active macromolecular principle to be absorbed is chosen form insulin, calcitonin, growth hormone, parathyroid hormone, or erythropoeitin, and derivatives and analogues thereof, either synthetic or from natural sources, conforming to structures derived from either human or animal origin.

20. Use according to claim 19, wherein the molecule (s)/active macromolecular principle to be absorbed is insulin, calcitonin, parathyroid hormone or a derivatives or analogue thereof, either synthetic or from natural sources, conforming to structures derived from either human or animal origin.

21. Use according to claim 20, wherein the molecule (s)/active macromolecular principle to be absorbed is insulin or a derivatives or analogue thereof, either synthetic or from natural sources, conforming to structures derived from either human or animal origin, and an insulin sensitizing agent is also present.

22. Use according to claim 16, wherein the composition comprises less than 5% by weight of water.

23. Use according to claim 16, which comprises incorporating the active macromolecular principle (s) to be absorbed into the aromatic alcohol in the form of a solution, as a microparticulate dispersion or as a solid.

17. Use of a non-conjugated bile acid or salt, together with an additive chosen from propyl gallate and BHA and analogues and derivatives thereof, or mixtures thereof in the manufacture of a medicament containing an active macromolecular principle, in order to enhance absorption of the active macromolecular principle into the human or animal body.