Absorption enhancers such as e.g. bht, bha or propyl gallate

• US 20060223740A1
• Filed: 04/15/2004
• Published: 10/05/2006
• 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 7,651,995 B2
• Time in Patent Office: Days
• US Class Current: 514/5.900
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• 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 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/28 Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• 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: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/4891 Coated capsules; Multilayered drug free capsule shells with drug coating for immediate release A61K9/4808; osmotic devices A61K9/0004
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/18 of the parathyroid hormones
• CPC Class Codes: A61P 5/48 of the pancreatic hormones

Abstract

The invention provides a pharmaceutical composition comprising a mixture of (a) an active macromolecular principle, and (b) an aromatic alcohol absorption enhancer chosen from butylated hydroxy toluene, butylated hydroxy anisole and analogues and derivatives thereof, wherein the aromatic alcohol absorption enhancer is present in an amount by weight greater than or equal to that of the active macromolecular principle, and further comprises a pharmaceutical composition comprising a mixture of (a) an active macromolecular principle, (b) an aromatic alcohol absorption enhancer chosen from propyl gallate, butylated hydroxy toluene, butylated hydroxy anisole and analogues and derivatives thereof, wherein the aromatic alcohol absorption enhancer is present in an amount by weight greater than or equal to that of the active macromolecular principle, and (c) a solubilisation aid capable of increasing the solubility of the aromatic alcohol absorption enhancer in aqueous media.

Claims

1. A pharmaceutical composition comprising a mixture of:

(a) an active macromolecular principle, and

(b) an aromatic alcohol absorption enhancer chosen from butylated hydroxy toluene, butylated hydroxy anisole and analogues and derivatives thereof, wherein the aromatic alcohol absorption enhancer is present in an amount by weight greater than or equal to that of the active macromolecular principle.

3. A composition according to claim 1, wherein the mixture comprises less than 5% by weight of water.

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

5. A composition according to claim 1, wherein the mixture comprises at least 1% by weight of the aromatic alcohol absorption enhancer.

6. A composition according to claim 1, wherein the ratio by weight of the aromatic alcohol absorption enhancer to active macromolecular principle is at least 5:

1.

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

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

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

10. A composition according to claim 1, wherein the aromatic alcohol absorption enhancer is chosen from BHT, BHA and analogues and derivatives thereof, including analogues and derivatives of hydroxy toluene or 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, C1-12 alkylthio or C_2-12 alkenyl, either unsubstituted or substituted in any position, especially by halogen atoms.

13. A composition according to claim 1, where the active macromolecular principle is insulin, calcitonin, growth hormone, parathyroid hormone, or erythropoeitin, and derivatives and analogues, either synthetic or from natural sources, conforming to structures derived from either human or animal origin.

14. A composition according to claim 1, where the active macromolecular principle is insulin, calcitonin, parathyroid hormone or a derivative or an analogue thereof, either synthetic or from natural sources, conforming to structures derived from either human or animal origin.

15. A composition according to claim 14, where the active macromolecular principle is insulin or a derivative or an 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.

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

28. 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.

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

2. A pharmaceutical composition comprising a mixture of:

(a) an active macromolecular principle,

(b) an aromatic alcohol absorption enhancer chosen from propyl gallate, butylated hydroxy toluene, butylated hydroxy anisole and analogues and derivatives thereof, wherein the aromatic alcohol absorption enhancer is present in an amount by weight greater than or equal to that of the active macromolecular principle, and

(c) a solubilisation aid capable of increasing the solubility of the aromatic alcohol absorption enhancer in aqueous media.

11. A composition according to claim 2, wherein the aromatic alcohol absorption enhancer is 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 alLylthio 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.

12. A composition according to claim 2, where the solubilisation aid is chosen from a bile acid or salt, benzyl alcohol, phenyl ethanol, phenoxyethanol, transcutol and isopropanol.

17. Use, in a pharmaceutical composition, of an aromatic alcohol chosen from butylated hydroxy toluene, butylated hydroxy anisole and analogues and derivatives thereof as an enhancer for the absorption of a macromolecule across the intestinal wall.

21. Use according to claim 17, wherein the composition comprises less that 5% by weight of water.

24. Use according to claim 17, wherein the macromolecule to be absorbed/active macromolecular principle is a polypeptide or protein, polynuclcotide, polysaccharide or a mixture thereof.

25. Use according to claim 24, wherein the macromolecule to be absorbed/active macromolecular principle to be absorbed is chosen from insulin, calcitonin, growth hormone, parathyroid hormone and erythropoeitin, and derivatives and analogues thereof, either synthetic or from natural sources, conforming to structures derived from either human or animal origin.

26. Use according to claim 25, wherein the macromolecule to be absorbed/active macromolecular principle to be absorbed is insulin, calcitonin, parathyroid hormone or a derivative or an analogue thereof, either synthetic or from natural sources, conforming to structures derived from either human or animal origin.

27. Use according to claim 26, wherein the macromolecular principle is insulin or a derivative or an 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.

18. Use of an aromatic alcohol chosen from butylated hydroxy toluene, butylated hydroxy anisole and analogues and derivatives 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.

23. Use according to claim 18, wherein the medicament is provided in the form of a solution, as a microparticulate dispersion or as a solid.

19. Use, in a pharmaceutical composition, of an aromatic alcohol chosen from propyl gallate, butylated hydroxy toluene, butylated hydroxy anisole and analogues and derivatives thereof together with a solubilisation aid capable of increasing the solubility of the aromatic alcohol absorption enhancer in aqueous media as an enhancer for the absorption of macromolecules across the intestinal wall.

22. Use according to claim 19, wherein the solubilisation aid is chosen from a conjugated bile acid or salt, benzylalcohol, phenylethanol, phenoxyethanol, transcutol and isopropanol.

20. Use of an aromatic alcohol chosen from propyl gallate, butylated hydroxy toluene, butylated hydroxy anisole and analogues and derivatives thereof together with a solubilisation aid capable of increasing the solubility of the aromatic alcohol absorption enhancer in aqueous media 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.