Uptake of macromolecules

• US 8,314,058 B2
• Filed: 04/15/2004
• Issued: 11/20/2012
• Est. Priority Date: 04/15/2003
• Status: Active Grant

• Current Assignee: Axcess Limited
• Original Assignee: Axcess Limited
• Inventors: New, Roger R. C.
• Primary Examiner(s): Ha, Julie
• Application Number:
  US10/553,169
• Publication Number:
  US 20060122097A1
• Time in Patent Office: 3,141 Days
• Field of Search: None
• US Class Current: 514/1.1
• 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 solid pharmaceutical composition comprising a mixture of:

(a) an active macromolecular principle which is a polypeptide or protein, polynucleotide or polysaccharide;

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

(c) an additive chosen from

(i) propyl gallate or a linear or branched chain C_1-12 alkyl, C_1-12 alkyloxy, C_1-12 alkylthio or C_2-12 alkenyl ester of gallic acid which is optionally substituted with one or more groups which are the same or different and are selected from halogen and linear or branched chain C_1-12 alkyl, C_1-12 alkyloxy, C_1-12 alkylthio or C_2-12 alkenyl;

(ii) butyl hydroxy anisole, or hydroxy anisole wherein the methoxy group linked to the aromatic ring and/or the hydrogen ortho to the hydroxyl group is/are replaced by one or more groups which are the same or different and are selected from linear or branched chain C_1-12 alkyl, C_1-12 alkyloxy, C_1-12 alkylthio and C_2-12 alkenyl, either unsubstituted or substituted in any position by one or more halogen atoms; and

(iii) a mixture of (i) and (ii)

wherein the mixture comprises at least 1% by weight of the additive (c), wherein the ratio by weight of the non-conjugated bile salt+additive (b+c) to the active macromolecular principle is at least 3;

1 and wherein the composition, when introduced into the intestine, does not raise the pH of the intestinal fluid above pH 7.0.

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 ratio by weight of the non-conjugated bile salt+additive (b+c) to the active macromolecular principle is at least 5:

1.

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

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

6. A composition according to claim 1, where the active macromolecular principle is chosen from insulin, calcitonin, growth hormone, parathyroid hormone, erythropoietin, GLP1 and GCSF, or is single, double or triple-stranded RNA.

7. A composition according to claim 6, where the active macromolecular principle is insulin, calcitonin or parathyroid hormone.

8. A composition according to claim 7, where the active macromolecular principle is insulin and the composition further comprises an insulin sensitizing agent.

9. A composition according to claim 1, wherein component (b) is chenodeoxycholate.

10. A composition according to claim 1, wherein the additive is propyl gallate or a linear or branched chain C_1-12 alkyl, C_1-12 alkyloxy, C_1-12 alkylthio or C_2-12 alkenyl ester of gallic acid which is optionally substituted with one or more groups which are the same or different and are selected from halogen and linear or branched chain C_1-12 alkyl, C_1-12 alkyloxy, C_1-12 alkylthio or C_2-12 alkenyl.

11. A composition according to claim 1, wherein the additive is butyl hydroxy anisole or hydroxy anisole where 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_1-12 alkylthio or C_2-12 alkenyl, either unsubstituted or substituted in any position by one or more halogen atoms.

12. 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.

13. A pharmaceutical composition according to claim 12, wherein the enteric coating becomes permeable at a pH from 5.5 to 7.

14. A pharmaceutical composition according to claim 13, wherein the enteric coating becomes permeable at a pH from 5.5 to 6.5.

15. A composition according to claim 1, wherein the composition, when introduced into the intestine, enhances absorption of the active macromolecular principle due to the additive improving solubility of the bile salt.

16. A composition according to claim 1, which is water soluble.

17. A composition according to claim 1, which is an oral pharmaceutical composition, and wherein, when the composition is introduced into the intestines, the additive (c) enhances the solubility of the non-conjugated bile salt.

18. A composition according to claim 1, wherein the additive allows the non-conjugated bile acid or salt to remain in solution when added to intestinal fluids at pH levels between 5 and 6.5.

19. A composition according to claim 1, which does not comprise an agent which, when introduced into the intestine, raises the pH of the intestinal fluid above pH 7.5.

20. 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.

21. A method of enhancing the absorption of an active macromolecular principle which is polypeptide or protein, polynucleotide or polysaccharide across the intestinal wall in a human or animal body, which method comprises administering a non-conjugated bile acid or salt, together with an additive chosen from:

(i) propyl gallate or a linear or branched chain C_1-12 alkyl, C_1-12 alkyloxy, C_1-12 alkylthio or C_2-12 alkenyl ester of gallic acid which is optionally substituted with one or more groups which are the same or different and are selected from halogen and linear or branched chain C_1-12 alkyl, C_1-12 alkyloxy, C_1-12 alkylthio or C_2-12 alkenyl;

(ii) butyl hydroxy anisole, or hydroxy anisole wherein the methoxy group linked to the aromatic ring and/or the hydrogen ortho to the hydroxyl group is/are replaced by one or more groups which are the same or different and are selected from linear or branched chain C_1-12 alkyl, C_1-12 alkyloxy, C_1-12 alkylthio and C_2-12 alkenyl, either unsubstituted or substituted in any position by one or more halogen atoms; and

(iii) a mixture of (i) and (ii)

together with the active macromolecular principle in a solid pharmaceutical composition, wherein the additive accounts for at least 1% by weight of the total weight of (a) the active macromolecular principle, (b) the non-conjugated bile acid or salt, plus (c) the additive, wherein the ratio by weight of the non-conjugated bile salt+additive (b+c) to the active macromolecular principle is at least 3;

1 and wherein the composition, when introduced into the intestine, does not raise the pH of the intestinal fluid above pH 7.0, which method enhances the absorption of the active macromolecular principle due to the additive improving the solubility of the bile salt.

22. A method according to claim 21 wherein the active macromolecular principle to be absorbed is chosen from insulin, calcitonin, growth hormone, parathyroid hormone, erythropoietin, GLP1 and GCSF, or is single, double or triple-stranded RNA.

23. A method according to claim 22, wherein the active macromolecular principle to be absorbed is insulin, calcitonin or parathyroid hormone.

24. A method according to claim 23, wherein the active macromolecular principle to be absorbed is insulin and an insulin sensitizing agent is also present.

25. A method according to claim 21, wherein the composition comprises less than 5% by weight of water.

26. A method according to claim 21, wherein the active macromolecular principle, which is a polypeptide or protein, polynucleotide or polysaccharide, the non-conjugated bile acid or salt and the additive are formulated as a solution, a microparticulate dispersion or a solid.

27. A method according to claim 21, wherein the composition is coated with an enteric coating which becomes permeable at a pH from 3 to 7.

28. A method according to claim 27, wherein the enteric coating becomes permeable at a pH from 5.5 to 7.

29. A method according to claim 28, wherein the enteric coating becomes permeable at a pH from 5.5 to 6.5.

30. A method according to claim 21, wherein the composition is water soluble.

31. A method according to claim 21, wherein the additive allows the non-conjugated bile acid or salt to remain in solution when added to intestinal fluids at pH levels between 5 and 6.5.

32. A method according to claim 21, wherein the composition does not comprise an agent which, when introduced into the intestine, raises the pH of the intestinal fluid above pH 7.5.