Claims for Patent: 8,088,734

Summary for Patent: 8,088,734

Title:	Oral delivery of peptides
Abstract:	Bioavailability of peptide active agents to be administered orally is enhanced by a pharmaceutical composition providing an active peptide that is amidated at a site that is not naturally amidated.
Inventor(s):	Mehta; Nozer M. (Randolph, NJ), Stern; William (Tenafly, NJ), Gilligan; James P. (Union, NJ)
Assignee:	Unigene Laboratories Inc. (Fairfield, NJ)
Application Number:	10/761,481
Patent Claims:	1. An oral pharmaceutical composition comprising an active peptide agent that has an amide group at its C-terminus, and is not found in nature with an amide group at its C-terminus, wherein said active peptide agent is a human parathyroid hormone analog having the first 34 amino acids of human parathyroid hormone wherein the 34.sup.th amino acid is amidated at its C-terminus, said composition further comprising an absorption enhancer effective to promote bioavailability of said active peptide agent, or a pharmaceutically acceptable pH-lowering agent that is present in said pharmaceutical composition in a quantity which, if said composition were added to ten milliliters of 0.1M aqueous sodium bicarbonate solution, would be sufficient to lower the pH of said solution to no higher than 5.5. 2. The pharmaceutical composition of claim 1 comprising at least one pharmaceutically acceptable pH-lowering agent. 3. The pharmaceutical composition of claim 2 further comprising an acid resistant protective vehicle effective to transport said pharmaceutical composition through the stomach of a patient while preventing contact between said active peptide agent and stomach proteases. 4. The pharmaceutical composition of claim 1, wherein said active peptide agent is prepared by converting a glycine-extended precursor to said active peptide agent. 5. The pharmaceutical composition of claim 1, wherein said active peptide agent comprises an amino acid that contains an amidated side chain. 6. The pharmaceutical composition of claim 2, wherein said pH-lowering agent is present in a quantity which, if said composition were added to ten milliliters of 0.1M aqueous sodium bicarbonate solution, would be sufficient to lower the pH of said solution to no higher than 3.5. 7. The pharmaceutical composition of claim 1, wherein said active peptide agent is linked to a membrane translocator which is capable of being at least partially cleaved in vivo by an enzyme. 8. The pharmaceutical composition of claim 3, wherein said protective vehicle is present at a weight which is no more than 30% of the weight of the remainder of said pharmaceutical composition. 9. The pharmaceutical composition of claim 3, wherein said protective vehicle is present at a weight which is no more than 20% of the weight of the remainder of said pharmaceutical composition. 10. The pharmaceutical composition of claim 3, wherein said protective vehicle is present at a weight which is between 10% and 20% of the weight of the remainder of said pharmaceutical composition. 11. The pharmaceutical composition of claim 3, wherein said protective vehicle is sufficient to prevent breakdown of said pharmaceutical composition in 0.1N HCl for at least two hours, yet permits complete release of all contents of said pharmaceutical composition within 45 minutes after pH is increased to 6.3 in a dissolution bath in which said composition is rotating at 100 revolutions per minute. 12. The pharmaceutical composition of claim 1, comprising an absorption enhancer, wherein the absorption enhancer is a surface active agent. 13. The pharmaceutical composition of claim 12, wherein said surface active agent is absorbable or biodegradable. 14. The pharmaceutical composition of claim 12, wherein said surface active agent is selected from the group consisting of acylcarnitines, phospholipids and bile acids. 15. The pharmaceutical composition of claim 14, wherein said surface active agent is an acylcarnitine. 16. The pharmaceutical composition of claim 15, further including a sucrose ester. 17. The pharmaceutical composition of claim 1, comprising an absorption enhancer, wherein the absorption enhancer is a surface active agent selected from the group consisting of (i) an anionic agent that is a cholesterol derivative, (ii) a mixture of a negative charge neutralizer and an anionic surface active agent, (iii) non-ionic surface active agents, and (iv) cationic surface active agents. 18. The pharmaceutical composition of claim 1, comprising an absorption enhancer is selected from the group consisting of a cationic surfactant and an anionic surfactant that is a cholesterol derivative. 19. The pharmaceutical composition of claim 1, wherein said pharmaceutical composition includes at least two absorption enhancers, one of which is a cationic surface active agent, and another of which is an anionic surface active agent that is a cholesterol derivative. 20. The pharmaceutical composition of claim 19, wherein said anionic surface active agent is an acid-soluble bile acid. 21. The pharmaceutical composition of claim 1, further comprising an amount of a second peptide that is not physiologically active effective to enhance bioavailability of said peptide active agent. 22. The pharmaceutical composition of claim 3, further comprising a water soluble barrier that separates said pH-lowering agent from said protective vehicle. 23. The pharmaceutical composition of claim 2, wherein said composition includes at least one pH-lowering agent that has a pKa no higher than 4.2. 24. The pharmaceutical composition of claim 2, wherein at least one pH-lowering agent has a solubility in water of at least 30 grams per 100 milliliters of water at room temperature. 25. The pharmaceutical composition of claim 3, wherein all ingredients other than said protective vehicle are uniformly dispersed. 26. The pharmaceutical composition of claim 25, wherein said pharmaceutical composition comprises granules containing a pharmaceutical binder and, uniformly dispersed in said binder, said pH-lowering agent, said absorption enhancer and said peptide active agent. 27. The pharmaceutical composition of claim 1, comprising a pharmaceutically acceptable pH-lowering agent and an absorption enhancer wherein said composition is a solid dosage form wherein a weight ratio of said pH-lowering agent to said absorption enhancer is between 3:1 and 20:1. 28. The pharmaceutical composition of claim 1, comprising a pharmaceutically acceptable pH-lowering agent and an absorption enhancer wherein said composition is a solid dosage form wherein the weight ratio of said pH-lowering agent to said absorption enhancer is between 5:1 and 10:1. 29. The pharmaceutical composition of claim 2, wherein said pH-lowering agent is selected from the group consisting of citric acid, tartaric acid and an acid salt of an amino acid. 30. The pharmaceutical composition of claim 2, wherein said pH-lowering agent is present in an amount not less than 300 milligrams. 31. The pharmaceutical composition of claim 30, wherein said pH-lowering agent is present in an amount which is not less than 400 milligrams. 32. The pharmaceutical composition of claim 3, wherein said protective vehicle is a viscous protective syrup. 33. The pharmaceutical composition of claim 3, wherein a water soluble barrier separates said pH-lowering agent from said protective vehicle. 34. A method for modifying a physiologically active peptide to increase its oral bioavailability, while substantially maintaining its physiological activity, said method comprising: (A) amidating a physiologically active peptide that is not naturally amidated at its C-terminus at said C-terminus, wherein said amidated peptide is human parathyroid hormone analog PTH1-34-NH.sub.2; and (B) orally administering said amidated peptide in combination with (i) at least one absorption enhancer effective to promote bioavailability of said amidated peptide, or (ii) a pH-lowering agent that is present in a pharmaceutical composition comprising said amidated peptide in a quantity which, if said composition were added to ten milliliters of 0.1M aqueous sodium bicarbonate solution, would be sufficient to lower the pH of said solution to no higher than 5.5. 35. The method of claim 34 comprising an absorption enhancer, wherein said amidated peptide and said absorption enhancer are selectively released together with at least one pH-lowering agent and/or protease inhibitor into a patient's intestine following passage of said peptide active agent, absorption enhancer, pH-lowering agent and/or protease inhibitor through said patient's mouth and stomach under protection of an acid resistant protective vehicle which substantially prevents contact between stomach proteases and said peptide agent. 36. The method of claim 34, wherein said amidated peptide is prepared by converting a glycine-extended precursor to said amidated peptide. 37. The method of claim 34, wherein said amidated peptide further includes an amidated side chain. 38. The method of claim 34, wherein said pH-lowering agent and said absorption enhancer are both present. 39. The method of claim 34 comprising a pH-lowering agent, wherein said pH-lowering agent is present in a quantity which, if said composition were added to ten milliliters of 0.1 M aqueous sodium bicarbonate solution, would be sufficient to lower the pH of said solution to no higher than 3.5. 40. The method of claim 35, wherein said protease inhibitor is a stomach and/or intestine protease inhibitor. 41. The method of claim 35, wherein said protease inhibitor inhibits an enzyme selected from the group consisting of pepsin, trypsin, chymotrypsin, elastase, kallikrein and carboxypeptidase. 42. The method of claim 34, wherein said increase in oral bioavailability is the result of enhanced intestinal absorption of the amidated peptide.

Details for Patent 8,088,734

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2023-01-21