Claims for Patent: 9,399,017

Summary for Patent: 9,399,017

Title:	Peptide pharmaceutical for oral delivery
Abstract:	Acid-containing oral pharmaceutical compositions are provided wherein the pharmaceutical active agents are peptide compounds (i.e., those that include a plurality of amino acids and at least one peptide bond in their molecular structures). Certain barrier layers and/or particulate coated acid are used to reduce any adverse interactions that might otherwise occur between the acid of the compositions and other components of the composition. Use of these barrier layers and/or use of particulate coated acid is believed to promote a more simultaneous release of the components of the composition than is achieved by prior art acid-protection techniques, thus enhancing, and making more consistent, the bioavailability of the active peptide compounds.
Inventor(s):	Stern; William (Tenafly, NJ), Consalvo; Angelo P. (Monroe, NY)
Assignee:	Enteris BioPharma, Inc. (Boonton, NJ)
Application Number:	14/158,029
Patent Claims:	1. A pharmaceutical composition for oral delivery of a physiologically active peptide agent comprising: (A) said peptide agent; (B) at least one pharmaceutically acceptable acid particle that is coated with a pharmaceutically acceptable protective coating that is non-acidic, wherein said acid is present in said pharmaceutical composition in a quantity which, if said composition were added to 10 milliliters of 0.1M aqueous sodium bicarbonate solution, would be sufficient to lower the pH of said solution to no higher than 5.5; (C) 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; (D) a water soluble barrier layer that separates said acid from said protective vehicle; and (E) an absorption enhancer wherein either (a) said barrier layer adds 3-6% to the weight of the pharmaceutical composition, exclusive of any acid-protective vehicle, or (b) said barrier layer comprises a material having water solubility in excess of 11 grams per 100 milliliters of water at room temperature, or (c) said peptide agent and said acid are in the same or only layer of said composition. 2. The pharmaceutical composition of claim 1, wherein said barrier layer adds at least 3% to the weight of the pharmaceutical composition, exclusive of the barrier layer or any layer external thereto. 3. The pharmaceutical composition of claim 1, wherein said barrier layer is present in an amount which adds between 3 and 6% to the weight of the pharmaceutical composition, exclusive of the barrier layer or any layer external thereto. 4. The pharmaceutical composition of claim 1, wherein said absorption enhancer is a surface active agent. 5. The pharmaceutical composition of claim 1, wherein said absorption enhancer is an acyl carnitine. 6. The pharmaceutical composition of claim 1, wherein said absorption enhancer is L-lauroyl carnitine. 7. The pharmaceutical composition of claim 1, wherein said acid has a pKa no higher than 4.2 and has a solubility in water of at least 30 grams per 100 milliliters of water at room temperature. 8. The pharmaceutical composition of claim 1, wherein the acid is selected from the group consisting of citric acid, tartaric acid and an acid salt of an amino acid. 9. The pharmaceutical composition of claim 1, wherein said pharmaceutical composition further comprises a pharmaceutical binder and, uniformly dispersed in said binder, said acid, an absorption enhancer, and said peptide active agent. 10. The pharmaceutical composition of claim 1, wherein said active peptide is selected from the group consisting of salmon calcitonin, natural parathyroid hormone, a para thyroid hormone truncate, and an amidated parathyroid hormone truncate. 11. The pharmaceutical composition of claim 10, wherein said active peptide is PTH1-31-amide. 12. The pharmaceutical composition of claim 1, wherein said acid comprises acid particles coated with glucose. 13. The pharmaceutical composition of claim 1, wherein said acid comprises acid particles coated with sodium citrate. 14. The pharmaceutical composition of claim 1, wherein said acid comprises glucose-coated citric acid particles. 15. The pharmaceutical composition of claim 14, wherein average particle size of said coated acid particles is between 30 mesh and 140 mesh. 16. The pharmaceutical composition of claim 1 further comprising a cellulose filler, wherein said composition has been compressed into tablet form such that the maximum weight loss during friability testing is no greater than 1%. 17. The pharmaceutical composition of claim 1 further comprising a pharmaceutical binder for dry compression. 18. The pharmaceutical composition of claim 1 further comprising a pharmaceutical disintegrant. 19. The pharmaceutical composition of claim 1, further comprising a sufficient amount of an antioxidant to substantially prevent oxidation of the peptide agent. 20. The pharmaceutical composition of claim 19, wherein the antioxidant is selected from the group consisting of sodium pyruvate, derivatives of sodium pyruvate, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, sodium bisulfite, and sodium metabisulfite. 21. A pharmaceutical composition for oral delivery of a physiologically active peptide agent comprising: (A) said active peptide agent, (B) pharmaceutically acceptable acid particles that are coated with a pharmaceutically acceptable protective coating that is non-acidic and has a solubility in water of at least one gram per 100 milliliters of water at room temperature, wherein total acid in said pharmaceutical composition is 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, (C) a water soluble barrier layer that separates said acid from said protective vehicle; and (D) an absorption enhancer. 22. The pharmaceutical composition of claim 21, wherein said protective coating is glucose. 23. The pharmaceutical composition of claim 21, wherein said protective coating is sodium citrate. 24. The pharmaceutical composition of claim 21, wherein said acid particles are glucose-coated citric acid. 25. The pharmaceutical composition of claim 21, wherein said absorption enhancer is a surface active agent. 26. The pharmaceutical composition of claim 21, wherein said absorption enhancer is an acyl carnitine. 27. The pharmaceutical composition of claim 21, wherein said absorption enhancer is L-lauroyl carnitine. 28. The pharmaceutical composition of claim 21, wherein said acid has a pKa no higher than 4.2 and has a solubility in water of at least 30 grams per 100 milliliters of water at room temperature. 29. The pharmaceutical composition of claim 21, wherein the acid 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 21, wherein said pharmaceutical composition further comprises a pharmaceutical binder and, uniformly dispersed in said binder, said acid particles, said absorption enhancer, and said peptide active agent. 31. The pharmaceutical composition of claim 21, wherein said active peptide is selected from the group consisting of salmon calcitonin, natural parathyroid hormone, a parathyroid hormone truncate, and an amidated parathyroid hormone truncate. 32. The pharmaceutical composition of claim 31, wherein said active peptide is PTH1-31-amide. 33. The pharmaceutical composition of claim 21 further comprising cellulose filler, wherein said composition has been compressed into tablet form such that the maximum weight loss during friability testing is no greater than 1%. 34. The pharmaceutical composition of claim 21 further comprising a pharmaceutical binder for dry compression. 35. The pharmaceutical composition of claim 21, wherein average particle size of said coated acid particles is between 30 mesh and 140 mesh. 36. A pharmaceutical composition for oral delivery of a physiologically active peptide agent comprising: (A) said peptide agent; (B) at least one pharmaceutically acceptable acid wherein said acid is present in said pharmaceutical composition in a quantity which, if said composition were added to 10 milliliters of 0.1M aqueous sodium bicarbonate solution, would be sufficient to lower the pH of said solution to no higher than 5.5, wherein said acid comprises acid particles that are coated with a pharmaceutically acceptable protective coating that is non-acidic and has a solubility in water of at least one gram per 100 milliliters of water at room temperature; (C) 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; and (D) a water soluble barrier layer that separates said coated acid from said protective vehicle; and (E) an absorption enhancer, wherein either (a) said barrier layer adds at least 3% to the weight of the pharmaceutical composition, exclusive of any acid-protective vehicle, or (b) said barrier layer comprises a material having water solubility in excess of 11 grams per 100 milliliters of water at room temperature, or (c) said peptide agent and said acid are in the same or only layer of said composition. 37. The pharmaceutical composition of claim 36, wherein said barrier layer adds at least 3% to the weight of the pharmaceutical composition, exclusive of any acid-protective vehicle, and wherein said peptide agent and said acid are in the same or only layer of said composition. 38. A pharmaceutical composition for oral delivery of a physiologically active peptide agent comprising: (A) said peptide agent; (B) an absorption enhancer; (C) at least one pharmaceutically acceptable acid selected from the group consisting of citric acid, tartaric acid and an acid salt of an amino acid, wherein said acid is present in said pharmaceutical composition in a quantity which, if said composition were added to 10 milliliters of 0.1M aqueous sodium bicarbonate solution, would be sufficient to lower the pH of said solution to no higher than 5.5, wherein said acid comprises acid particles that are coated with a protective coating, said protective coating being comprised of either glucose or sodium citrate; (D) 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; and (E) a water soluble barrier layer that separates said coated acid from said protective vehicle, wherein either said barrier layer adds at least 3% to the weight of the pharmaceutical composition, exclusive of any acid-protective vehicle, and wherein said peptide agent and said acid are in the same or only layer of said composition. 39. A pharmaceutical tablet for oral delivery of a physiologically active peptide agent comprising: (A) said peptide agent; (B) L-lauroyl carnitine; (C) glucose-coated citric acid particles, wherein total citric acid, exclusive of glucose, exceeds 200 milligrams per tablet; (D) a cellulose filler; (E) a pharmaceutical binder for dry compression; (F) an outer layer of an acid-resistant enteric coating effective to transport said pharmaceutical composition through the stomach of a patient while preventing contact between said active peptide agent and stomach proteases; and (G) a water soluble barrier layer beneath said outer layer of enteric coating that separates said enteric coating from said coated acid, said barrier layer being comprised of a compound selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and polyvinylpyrrolidone and being present in an amount higher than three percent by weight relative to the total weight of the pharmaceutical composition, exclusive of said outer layer and said barrier layer. 40. The tablet of claim 39, wherein said peptide agent is selected from the group consisting of salmon calcitonin, natural parathyroid hormone, a parathyroid hormone truncate, and an amidated parathyroid hormone truncate. 41. The pharmaceutical composition of claim 40, wherein said active peptide is PTH1-31-amide. 42. A pharmaceutical tablet for oral delivery of a physiologically active peptide agent comprising: (A) said peptide agent; (B) L-lauroyl carnitine; (C) glucose-coated citric acid particles, wherein total citric acid, exclusive of glucose, exceeds 200 milligrams per tablet; (D) a cellulose filler; (E) a pharmaceutical binder for dry compression; (F) an outer layer of an acid-resistant enteric coating effective to transport said pharmaceutical composition through the stomach of a patient while preventing contact between said active peptide agent and stomach proteases; and (G) a water soluble barrier layer beneath said outer layer of enteric coating that separates said enteric coating from said coated acid, said barrier layer being comprised of a compound selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, methyl cellulose and polyvinylpyrolidone, and being present in an amount higher than three percent by weight relative to the total weight of the pharmaceutical composition, exclusive of said outer layer and said barrier layer; wherein said composition has been compressed into tablet form such that the maximum weight loss during friability testing is no greater than 1%. 43. A pharmaceutical tablet for oral delivery of a physiologically-active peptide agent comprising: (A) salmon calcitonin; (B) a lauroyl carnitine absorption enhancer; (C) glucose-coated citric acid particles, wherein total citric acid, exclusive of glucose, exceeds 200 milligrams per tablet; (D) a cellulose filler; (E) a pharmaceutical binder for dry compression; (F) an outer layer of an acid-resistant enteric coating effective to transport said pharmaceutical composition through the stomach of a patient while preventing contact between said active peptide agent and stomach proteases; and (G) a water soluble barrier layer beneath said outer layer of enteric coating that separates said enteric coating from said coated acid; said barrier layer being comprised of a compound selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and polyvinylpyrolidone, and being present in an amount higher than three percent by weight relative to the total weight of the pharmaceutical composition, exclusive of said outer layer and said barrier layer; wherein said composition has been compressed into tablet form such that the maximum weight loss during friability testing is no greater than 1%. 44. A pharmaceutical composition for oral delivery of a physiologically active peptide agent comprising: (A) said peptide agent; (B) an absorption enhancer; (C) a pharmaceutical binder for dry compression; (D) a disintegrant; (E) a glidant; (F) a lubricant; (G) at least one pharmaceutically acceptable acid wherein said acid is present in said pharmaceutical composition in a quantity which, if said composition were added to 10 milliliters of 0.1M aqueous sodium bicarbonate solution, would be sufficient to lower the pH of said solution to no higher than 5.5, wherein said acid comprises acid particles that are coated with a pharmaceutically acceptable protective coating that is non-acidic and has a solubility in water of at least one gram per 100 milliliters of water at room temperature; (H) 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; and (I) a water soluble barrier layer that separates said coated acid from said protective vehicle; wherein materials of paragraphs (A) through (G) are thoroughly intermixed in a single layer. 45. The pharmaceutical composition of claim 1, wherein the composition is a single tablet or capsule. 46. The pharmaceutical composition of claim 21, wherein the composition is a single tablet or capsule. 47. The pharmaceutical composition of claim 36, wherein the composition is a single tablet or capsule. 48. The pharmaceutical composition of claim 38, wherein the composition is a single tablet or capsule. 49. The tablet of claim 39, wherein the average particle size of said coated acid particles is between 30 mesh and 140 mesh. 50. The tablet of claim 43, wherein the average particle size of said coated acid particles is between 30 mesh and 140 mesh. 51. The tablet of claim 44, wherein the average particle size of said coated acid particles is between 30 mesh and 140 mesh. 52. The pharmaceutical composition of claim 36, wherein the average particle size is between 30 mesh and 140 mesh. 53. The pharmaceutical composition of claim 38, wherein the average particle size is between 30 mesh and 140 mesh. 54. The pharmaceutical composition of claim 1, wherein the peptide agent is a luteinizing hormone-releasing factor. 55. The pharmaceutical composition of claim 1, wherein the peptide agent is leuprolide. 56. The pharmaceutical composition of claim 21, wherein the peptide agent is a luteinizing hormone-releasing factor. 57. The pharmaceutical composition of claim 21, wherein the peptide agent is leuprolide. 58. The pharmaceutical tablet of claim 39, wherein the peptide agent is a luteinizing hormone-releasing factor. 59. The pharmaceutical tablet of claim 39, wherein the peptide agent is leuprolide.

Details for Patent 9,399,017

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2027-05-29