Claims for Patent: 6,004,583

Summary for Patent: 6,004,583

Title:	Protein-containing polymer composition for oral administration
Abstract:	A therapeutic-containing composition adapted for the oral administration of a biologically active material which comprises a water insoluble but water swellable polymer chemically modified with an enzyme inhibitor containing a chemical functionality which has an interactive affinity for target receptors located on the transport barrier walls of the digestive tract of the intended recipient, and at least one therapeutic of low oral bioavailability.
Inventor(s):	Plate ; Nikolai A. (Moscow, RU), Valuev; Lev I. (Moscow, RU), Valueva; Tatyana A. (Moscow, RU), Staroseltseva; Ludmila K. (Moscow, RU), Ametov; Alexander S. (Moscow, RU), Knyazhev; Vladimir A. (Moscow, RU), Henis; Jay M.S. (St. Louis, MO)
Assignee:	Orex Pharmaceutical Development Corp. (St. Louis, MO)
Application Number:	08/691,617
Patent Claims:	1. A therapeutic-containing composition adapted for the oral administration of a biologically active material comprising (a) a water insoluble, but water swellable, polymer which contains at least one enzyme inhibitor covalently bound to the polymer and a chemical functionality which has an interactive affinity for target receptors located on the transport barrier walls of the digestive tract of the intended human or animal specie, wherein said chemical functionality is either integral to the structure of said inhibitor or is covalently bound to the polymer and (b) one or more of therapeutic or biologically active agents. 2. A composition of claim 1 wherein said polymer is a gel forming hydrophilic polymer. 3. A composition of claim 2 wherein the gel forming polymer is partially crosslinked. 4. A composition of claim 3 wherein the crosslink density is about 0.01% to about 25%. 5. A composition of claim 3 wherein the crosslink density is about 0.01% to about 15%. 6. A composition of claim 2 wherein the inhibitor is an inhibitor of proteolytic enzymes. 7. A composition of claim 6 wherein the inhibitor is ovomucoid. 8. A composition of claim 7 wherein ovomucoid is functionalized by reacting ovomucoid with a polymerizable material. 9. A composition of claim 8 wherein the polymerizable material is acryloyl chloride. 10. A composition of claims 1, 4, 6, 7, or 9 wherein the polymeric hydrogel is a homopolymer or a copolymer prepared from one or more monomers selected from the group consisting of acrylic and methacrylic acids, acrylamide, methacrylamide, hydroxyethylacrylate and methacrylate, and vinylpyrrolidones, and the therapeutic is a protein or a peptide with a molecular weight of less than 100,000 daltons. 11. A composition of claim 10 wherein the protein is insulin. 12. A composition of claim 10 wherein the protein is a growth hormone or a somatotropin. 13. A composition of claim 12 wherein the protein is selected from the group consisting of human growth hormone (HGH), bovine growth hormone (BGH or BST), porcine growth hormone (PGH or PST), their analogues and derivatives and epidermal growth factor (FGF) and its analogues. 14. A composition of claim 10 wherein the protein is selected from the group consisting of interleukins, interleukin receptors and interleukin receptor agonists. 15. A composition of claim 10 wherein the protein is an interferon. 16. A composition of claim 10 wherein the protein is selected from the group consisting of blood cell growth stimulating factors and precursors and erithropoitin (EPO) and its analogues. 17. A composition of claim 10 wherein the protein is selected from the group consisting of parathyroid hormone (PTH), selenoprotein P, cystatin B and its liver thiol protease inhibitor analogues, endotoxin neutralizing protein, megakaryocyte simulatory factor (MGDF), granulocyte macrophage colony stimulating factor (GM-CSF), genofibrate, alpha calcitonin, beta calcitonin, tumor necrosis factor (TNF), tumor invasion inhibiting factors, transacting regulatory proteins (TAT's) of HIV and other retroviruses, protease inhibitors, and BPC 157, fat reducing hormones, and analogues and variants of these proteins. 18. A composition of claim 10 wherein the concentration of enzyme inhibitor is from 0.01 to 25 milligram of enzyme per gram of dry polymer. 19. A composition of claim 11 wherein the concentration of enzyme inhibitor is from 0.01 to 25 milligram of enzyme per gram of dry polymer. 20. A composition of claim 12 wherein the concentration of enzyme inhibitor is from 0.2 to 3 milligram of enzyme per gram of dry polymer. 21. The composition of claim 1 wherein the affinity functionality of the inhibitor of proteolytic enzymes is represented by lectin binding groups such as sugars or related glycosides and wherein these binding groups represent at least more than 3% of the weight of the unbound inhibitor. 22. A composition of claim 10 wherein the protein is of a molecular weight less than 65,000 daltons. 23. A composition of claims 1, 3, 4, 6, 7, 8, 9, which is enclosed within an enteric protective coating. 24. A composition of claim 23 additionally containing pharmacologically acceptable antimicrobial agents, stabilizers, salts and other formulation adjutants. 25. A composition of claim 10 wherein the inhibitor is ovomucoid. 26. A composition of matter adapted for the oral administration of insulin, said composition comprising (a) a polymeric hydrogel which is a homopolymer or a copolymer derived from one or more monomers selected from the group consisting of acrylic and methacrylic acids, acrylamide, methacrylamide, hydroxyethylacrylate or methacrylate, and vinylpyrrolidones; said hydrogel having been crosslinked with 5 to 20 weight percent of a crosslinking agent and said hydrogel containing in its polymer network covalently bonded ovomucoid derived from the white of the duck eggs, and (b) insulin. 27. A composition of claim 26, wherein the ovomucoid is functionalized prior to being covalently bonded to the polymer network. 28. A composition of claim 27 wherein the functionalizing agent is acryloyl chloride and the crosslinking agent is alkylene N,N-bis(acyl amide). 29. A composition of claim 28 wherein the polymeric hydrogel is a copolymer prepared from 40-99.5 weight percent of acrylamide and 0.5-60 weight percent of acrylic acid. 30. A composition of claim 29 wherein the polymeric hydrogel is a copolymer prepared from 40-90 weight percent of acrylamide and 10-60 weight percent of acrylic acid. 31. A composition of claim 29 wherein the polymeric hydrogel is a copolymer prepared from 95-99.5 weight percent of acrylamide and 0.5-5 weight percent of acrylic acid. 32. A composition of matter adapted for the oral administration of a growth hormone, said composition comprising (a) a polymeric hydrogel which is a homopolymer or a copolymer derived from one or more monomers selected from the group consisting of acrylic and methacrylic acids, acrylamide, methacrylamide, hydroxyethylacrylate or methacrylate, and vinylpyrrolidones; said hydrogel having been crosslinked with 5 to 20 weight percent of a crosslinking agent and said hydrogel containing in its polymer network covalently bonded ovomucoid derived from the white of the duck eggs, and (b) a growth hormone. 33. A composition of claim 32 wherein the ovomucoid is functionalized prior to being covalently bonded to the polymer network. 34. A composition of claim 33 wherein the functionalizing agent is acryloyl chloride and the crosslinking agent is alkylene N,N-bis(acyl amide). 35. A composition of claim 34 wherein the polymeric hydrogel is a copolymer prepared from 40-99.5 weight percent of acrylamide and 0.5-60 weight percent of acrylic acid. 36. A composition of claim 35 wherein the polymeric hydrogel is a copolymer prepared from 40-90 weight percent acrylamide and 10-60 weight percent of acrylic acid. 37. A composition of claim 35 wherein the polymeric hydrogel is a copolymer prepared from 95-99.5 weight percent acrylamide and 0.5-5 weight percent of acrylic acid. 38. A composition of claim 35 wherein the growth hormone is selected from the group consisting of human growth hormone, bovine growth hormone and porcine growth hormone. 39. A method of orally administering one or more biologically active materials comprising (a) preparing a composition for oral ingestion which contains a water insoluble, but water swellable, polymer having an enzyme inhibitor covalently bonded thereto, and a chemical functionality which has an interactive affinity for target receptors located on the transport barrier walls of the digestive tract of the intended human or animal specie, wherein said chemical functionality is either integral to the structure of said inhibitor or is covalently bound to the polymer and also containing one or more therapeutic or biologically active agents and (b) orally administering said composition to a human or animal specie. 40. A method of claim 39 wherein the polymer is partially crosslinked. 41. A method of claim 39 wherein the inhibitor is an inhibitor of proteolytic enzymes. 42. A method of claim 41 wherein the inhibitor is ovomucoid. 43. A method of claim 42 wherein ovomucoid is functionalized by reacting ovomucoid with a polymerizable material. 44. A method of claim 43 wherein the therapeutic is a protein. 45. A method of claim 44 wherein the protein is selected from the group consisting of insulin, a growth hormone and a somatotropin. 46. A therapeutic-containing composition adapted for the oral administration of a biologically active material comprising (a) a water insoluble, but water swellable, polymer which contains at least one enzyme inhibitor covalently bonded to said polymer, said inhibitor containing a chemical functionality which has an interactive affinity for target receptors located on the transport barrier walls of the digestive tract of the intended human or animal specie, and (b) one or more of therapeutic or biologically active agents, said composition having an oral therapeutic efficiency index (OTEI) of at least 0.05. 47. A composition of claim 46 wherein the gel forming polymer is partially crosslinked. 48. A composition of claim 47 wherein the biologically active agent is a protein. 49. A composition of claim 48 wherein the inhibitor is an inhibitor of proteolytic enzymes. 50. A composition of claim 49 wherein the inhibitor is ovomucoid. 51. A composition of claim 50 wherein ovomucoid is functionalized by reacting ovomucoid with a polymerizable material. 52. A composition of claim 51, wherein the protein is selected from the group consisting of insulin, growth hormone and a somatotropin. 53. A composition of claim 52 wherein protein is insulin and the OTEI is at least 0.1. 54. A composition of claim 53 wherein the OTEI is at least 0.5. 55. A therapeutic-containing composition adapted for the oral administration of a biologically active material comprising (a) a water insoluble, but water swellable, polymer containing within its matrix covalently bonded enzyme inhibitor and also containing a chemical functionality which has an interactive affinity for target receptors located on the transport barrier walls of the digestive tract of the intended human or animal specie, wherein said chemical functionality is either integral to the structure of said inhibitor or is covalently bound to the polymer and (b) one or more of therapeutic or biologically active agents. 56. A composition of claim 55 wherein the polymer is crosslinked and the inhibitor is entrapped within the polymer matrix. 57. A composition of claim 1 additionally containing water. 58. A composition of claim 6 wherein the chemical functionality which has an interactive affinity for target receptors on the transport barrier walls of the digestive tract is a glycoside. 59. A composition of claim 6 wherein the inhibitor is functionalized by reacting said inhibitor with a polymerizable material. 60. A composition of claim 59 wherein the polymerizable material is acryloyl chloride. 61. A composition of claim 6, wherein the chemical functionality that has an interactive affinity for target receptors located on the transport barrier walls of the digestive tract is covalently bonded to said polymer. 62. A composition of claim 6, wherein the chemical functionality that has an interactive affinity for target receptors located on the transport barrier walls of the digestive tract is part of the inhibitor of proteolytic enzymes. 63. A composition of claim 59, wherein the chemical functionality that has an interactive affinity for target receptors located on the transport barrier walls of the digestive tract is covalently bonded to said polymer. 64. A method of claim 39, wherein the chemical functionality that has an interactive affinity for target receptors located on the transport barrier walls of the digestive tract is covalently bonded to said polymer. 65. A method of claim 60 wherein the chemical functionality that has an interactive affinity for target receptors located on the transport barrier walls of the digestive tract is part of the inhibitor of proteolytic enzymes. 66. A composition of claim 1, wherein said chemical functionality is integral to the inhibitor. 67. A composition of claim 1, wherein said chemical functionality is covalently bound to the polymer. 68. A method of claim 39, wherein said chemical functionality is part integral to the inhibitor. 69. A method of claim 39, wherein said chemical functionality is covalently bound to the polymer.

Details for Patent 6,004,583

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2014-03-23