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1. CA2512824 - IMPROVED ORAL DELIVERY OF PEPTIDES

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CLAIMS
WHAT IS CLAIMED IS:
1. An oral pharmaceutical composition for enhancing bioavailability and absorption of a physiologically active peptide in a patient, comprising: a therapeutically effective amount of an amidated active peptide, wherein the amidated active peptide has been amidated such that an amide group has been added at the C-terminus of an active peptide that is not found in nature with an amide group at its C-terminus, and wherein the amidated active peptide is human parathyroid hormone analog PTH 1-31NH2 or human parathyroid hormone analog PTH 1-34NH2; at least one pharmaceutically acceptable pH-lowering agent effective to lower the local intestinal pH substantially below the pH optima for proteases found in the intestine of the patient; and an absorption enhancer effective to promote bioavailability of said amidated active peptide, wherein the combination of the pH-lowering agent, the absorption enhancer, and the amidated active peptide enhances bioavailability and absorption of the amidated active peptide as compared with an oral pharmaceutical composition comprising the same active peptide having a free acid at its C-terminus instead of an amide group at its C- terminus.
2. The pharmaceutical composition of claim 1, further comprising at least one protease inhibitor.
3. The pharmaceutical composition of claim 1, further comprising an acid resistant protective vehicle effective to transport said pharmaceutical composition through the stomach of the patient while preventing contact between said amidated active peptide and stomach proteases.
4. The pharmaceutical composition of claim 1, wherein said amidated active peptide is prepared as a glycine-extended precursor and subsequently converted to a C-terminal amide group.
5. The pharmaceutical composition of claim 1, wherein said amidated active peptide further comprises an amino acid that contains an amidated side chain.
6. The pharmaceutical composition of claim 1, wherein said pH- lowering agent is present in said pharmaceutical composition 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 5.5.
7. The pharmaceutical composition of claim 1, wherein said pH- lowering agent is present in said pharmaceutical composition 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.
8. The pharmaceutical composition of claim 2, wherein said protease inhibitor is a stomach and/or intestine protease inhibitor.
9. The pharmaceutical composition of claim 2, wherein said protease inhibitor inhibits an enzyme selected from the group consisting of pepsin, trypsin, chymotrypsin, elastase, kallikrein, and carboxypeptidase.
10. The pharmaceutical composition of claim 1, wherein said amidated active peptide is linked to a membrane translocator which is at least partially cleavable in vivo by an enzyme.
11. 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.
12. 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.
13. 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.
14. The pharmaceutical composition of claim 3, wherein said protective vehicle is sufficient to prevent breakdown of said pharmaceutical composition in 0.1 N HC1 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.
15. The pharmaceutical composition of claim 1, wherein said absorption enhancer is a surface active agent.
16. The pharmaceutical composition of claim 15, wherein said surface active agent is absorbable or biodegradable.
17. The pharmaceutical composition of claim 15, wherein said surface active agent is selected from the group consisting of acylcarnitines, phospholipids, and bile acids.
18. The pharmaceutical composition of claim 17, wherein said enhancer is an acylcarnitine.
19. The pharmaceutical composition of claim 18, further comprising a sucrose ester.
20. The pharmaceutical composition of claim 1, wherein said 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.
21. The pharmaceutical composition of claim 1, wherein said absorption enhancer is selected from the group consisting of a cationic surfactant and an anionic surfactant that is a cholesterol derivative.
22. The pharmaceutical composition of claim 1, wherein said pharmaceutical composition comprises 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.
23. The pharmaceutical composition of claim 22, wherein said anionic surface active agent is an acid-soluble bile acid.
24. The pharmaceutical composition of claim 1, further comprising an amount of a second peptide effective to enhance bioavailability of said amidated active peptide, wherein said second peptide is not a physiologically active peptide.
25. The pharmaceutical composition of claim 3, further comprising a water soluble barrier that separates said pH-lowering agent from said protective vehicle.
26. The pharmaceutical composition of claim 1, wherein said pharmaceutical composition comprises at least one pH-lowering agent that has a pKa no higher than 4.2.
27. The pharmaceutical composition of claim 1, 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.
28. The pharmaceutical composition of claim 3, wherein all ingredients other than said protective vehicle are uniformly dispersed.
29. The pharmaceutical composition of claim 28, 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 amidated active peptide.
30. The pharmaceutical composition of claim 1, wherein said pharmaceutical composition is a solid dosage form in which a weight ratio of said pH-lowering agent to said absorption enhancer is between 3:1 and 20:1.
31. The pharmaceutical composition of claim 1, wherein said pharmaceutical composition is a solid dosage form in which the weight ratio of said pH-lowering agent to said absorption enhancer is between 5:1 and 10:1.
32. The pharmaceutical composition of claim 1, wherein said pH- lowering agent is selected from the group consisting of citric acid, tartaric acid, and an acid salt of an amino acid.
33. The pharmaceutical composition of claim 1, wherein said pH- lowering agent is present in an amount not less than 300 milligrams.
34. The pharmaceutical composition of claim 33, wherein said pH-lowering agent is present in an amount which is not less than 400 milligrams.
35. The pharmaceutical composition of claim 1, wherein said amidated active peptide is human parathyroid hormone analog PTH 1- 31NH2.
36. The pharmaceutical composition of claim 1, wherein said amidated active peptide is human parathyroid hormone analog PTH 1- 34NH2.
37. The pharmaceutical composition of claim 3, wherein said protective vehicle is a viscous protective syrup.
38. The pharmaceutical composition of claim 32, wherein a water soluble barrier separates said pH-lowering agent from said protective vehicle.
39. Use of amidation in the manufacture of a physiologically active peptide for oral delivery, wherein: said physiologically active peptide is not naturally amidated at its C-terminus; said active peptide is human parathyroid hormone analog PTH 1-31-
NH2 or human parathyroid hormone analog PTH 1-34-NH2; said amidation is carried out at the C-terminus of said active peptide; and said amidated peptide has enhanced bioavailability as compared to the free acid form of the active peptide.
40. The use of claim 39, wherein said active peptide is present in a pharmaceutical composition.
41. The use of claim 40, wherein said pharmaceutical composition further comprises at least one pH-lowering agent and/or protease inhibitor.
42. The use of claim 41, wherein said active peptide is for
selective release, together with said at least one pH-lowering agent and/or protease inhibitor, into a patient's intestine following passage of said active peptide and said pH-lowering agent and/or protease inhibitor through the patient's mouth and stomach under protection of an acid resistant protective vehicle which substantially prevents contact between stomach proteases and said active peptide.
43. The use of claim 39, wherein said active peptide is prepared as a glycine-extended precursor and subsequently converted to a C-terminal amide group.
44. The use of claim 39, wherein said active peptide is further amidated at an amino acid side chain.
45. The use of claim 42, wherein said pH-lowering agent is present in said pharmaceutical composition 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 5.5.
46. The use of claim 42, wherein said pH-lowering agent is present in said pharmaceutical composition 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.
47. The use of claim 42, wherein said protease inhibitor is a stomach and/or intestine protease inhibitor.
48. The use of claim 42, wherein said protease inhibitor inhibits an enzyme selected from the group consisting of pepsin, trypsin, chymotrypsin, elastase, kallikrein, and carboxypeptidase.
49. The use of claim 42, wherein said active peptide is for
release into a patient's intestine in the presence of at least one absorption enhancer effective to promote bioavailability of said active peptide.
50. The use of claim 39, wherein said active peptide is human parathyroid hormone analog PTH 1-31-NH2.
51. The use of claim 39, wherein said active peptide is human parathyroid hormone analog PTH 1-34-NH2.
52. The use of claim 39, wherein said enhanced bioavailability is the result of enhanced intestinal absorption.