Claims for Patent: 5,359,030

Summary for Patent: 5,359,030

Title:	Conjugation-stabilized polypeptide compositions, therapeutic delivery and diagnostic formulations comprising same, and method of making and using the same
Abstract:	A stabilized conjugated peptide complex comprising a peptide conjugatively coupled to a polymer including lipophilic and hydrophilic moieties, wherein the peptide may for example be selected from the group consisting of insulin, calcitonin, ACTH, glucagon, somatostatin, somatotropin, somatomedin, parathyroid hormone, erythropoietin, hypothalamic releasing factors, prolactin, thyroid stimulating hormones, endorphins, enkephalins, vasopressin, non-naturally occurring opioids, superoxide dismutase, interferon, asparaginase, arginase, arginine deaminease, adenosine deaminase, ribonuclease, trypsin, chymotrypsin, and papain. In a particular aspect, the invention comprises an insulin composition suitable for parenteral as well as non-parenteral administration, preferably oral or parenteral administration, comprising insulin covalently coupled with a polymer including (i) a linear polyalkylene glycol moiety and (ii) a lipophilic moiety, wherein the insulin, the linear polyalkylene glycol moiety and the lipophilic moiety are conformationally arranged in relation to one another such that the insulin in the composition has an enhanced in vivo resistance to enzymatic degradation, relative to insulin alone. One, two, or three polymer constituents may be covalently attached to the insulin molecule, with one polymer constituent being preferred. The conjugates of the invention are usefully employed in therapeutic as well as non-therapeutic, e.g., diagnostic, applications, and the peptide and polymer may be covalently coupled to one another, or alternatively may be associatively coupled to one another, e.g., by hydrogen bonding or other associative bonding relationship.
Inventor(s):	Ekwuribe; Nnochiri N. (Southfield, MI)
Assignee:	Protein Delivery, Inc. (Durham, NC)
Application Number:	08/059,701
Patent Claims:	1. A peptide composition comprising a peptide stabilizingly and covalently conjugatively coupled with one or more molecules of a non-naturally-occurring polymer, said polymer comprising a lipophilic moiety and a hydrophilic polymer moiety, thereby imparting balanced lipophilic and hydrophilic characteristics to the composition such that the composition is soluble in pharmaceutically acceptable solvents and able to interact with biological membranes. 2. A peptide composition according to claim 1, wherein the peptide is a physiologically active therapeutic peptide. 3. A peptide composition according to claim 1, wherein the peptide is a diagnostic peptide used for reactively determining the presence or absence of a condition or component in vitro or in vivo. 4. A peptide composition comprising a peptide stabilizingly and conjugatively coupled with one or more molecules of a non-naturally-occurring polymer comprising a lipophilic moiety and a hydrophilic polymer moiety wherein the peptide is soluble in aqueous solvents and active in prophylaxis or treatment of conditions or disease states in a plant or component thereof. 5. A peptide composition according to claim 1, wherein the non-naturally-occurring polymer comprises (i) a linear polyalkylene glycol moiety and (ii) a lipophilic moiety. 6. A peptide composition according to claim 1, wherein: the non-naturally-occurring polymer comprises (i) a linear polyalkylene glycol moiety and (ii) a lipophilic moiety; the peptide comprises a physiologically active peptide; and the physiologically active peptide, the linear polyalkylene glycol moiety and the lipophilic moiety are conformationally arranged in relation to one another such that the physiologically active peptide in the composition has an enhanced in vivo resistance to enzymatic degradation, relative to the physiologically active peptide alone. 7. A physiologically active peptide composition comprising a physiologically active peptide covalently coupled with one or more molecules of a polymer comprising (i) a linear polyalkylene glycol moiety and (ii) a lipophilic moiety, wherein the physiologically active peptide, the linear polyalkylene glycol moiety and the lipophilic moiety are conformationally arranged in relation to one another such that the physiologically active peptide in the physiologically active peptide composition has an enhanced in vivo resistance to enzymatic degradation, relative to the physiologically active peptide alone. 8. A physiologically active peptide composition of three-dimensional conformation comprising a physiologically active peptide covalently coupled with a polysorbate complex comprising (i) a linear polyalkylene glycol moiety and (ii) a lipophilic moiety, wherein the physiologically active peptide, the linear polyalkylene glycol moiety and the lipophilic moiety are conformationally arranged in relation to one another such that (a) the lipophilic moiety is exteriorly available in the three-dimensional conformation, and (b) the physiologically active peptide in the physiologically active peptide composition has an enhanced in vivo resistance to enzymatic degradation, relative to the physiologically active peptide alone. 9. A multiligand conjugated peptide complex comprising a triglyceride backbone moiety, having: a bioactive peptide covalently coupled with the triglyceride backbone moiety through a polyalkylene glycol spacer group bonded at a carbon atom of the triglyceride backbone moiety; and at least one fatty acid moiety covalently attached either directly to a carbon atom of the triglyceride backbone moiety or covalently joined through a polyalkylene glycol spacer moiety. 10. A multiligand conjugated peptide complex according to claim 9, wherein the .alpha.' and .beta. carbon atoms of the triglyceride backbone moiety have fatty acid moieties attached by covalently bonding either directly thereto, or indirectly covalently bonded thereto through polyalkylene glycol spacer moieties. 11. A multiligand conjugated peptide complex according to claim 9, wherein the fatty acid moiety is covalently attached either directly or through a polyalkylene glycol spacer moiety to the .alpha. and .alpha.' carbons of the triglyceride backbone moiety, with the bioactive peptide being covalently coupled with the .beta.-carbon of the triglyceride backbone moiety, either being directly covalently bonded thereto or indirectly bonded thereto through a polyalkylene spacer moiety. 12. A polysorbate complex comprising a polysorbate moiety including a triglyceride backbone having a fatty acid group covalently coupled to one of the .alpha.,.alpha.' and .beta. carbon atoms thereof, and having a polyethylene glycol group covalently coupled to one of the .alpha.,.alpha.' and .beta. carbon atoms thereof. 13. A polysorbate complex according to claim 12, wherein the polysorbate moiety has a physiologically active moiety covalently bonded thereto. 14. A polysorbate complex according to claim 13, wherein the physiologically active moiety is covalently bonded to the polyethylene glycol group. 15. A stable, aqueously soluble, conjugated peptide complex comprising a peptide stabilizingly and conjugatively coupled to a polyethylene glycol modified glycolipid moiety. 16. A peptide complex according to claim 15, wherein the peptide is covalently coupled to the polyethylene glycol modified glycolipid moiety by a labile covalent bond at a free are inc acid group of the polypeptide, wherein the labile covalent bond is scissionable in vivo by biochemical hydrolysis and/or proteolysis. 17. A peptide complex according to claim 15, wherein the polyethylene glycol modified glycolipid moiety comprises a polysorbate polymer. 18. A peptide complex according to claim 17, wherein the polysorbate polymer comprises fatty acid ester groups selected from the group consisting of monopalmitate, dipalmitate, monolaurate, dilaurate, trilaurate, monoleate, dioleate, trioleate, monostearate, distearate, and tristearate. 19. A peptide complex according to claim 15, wherein the polyethylene glycol modified glycolipid moiety comprises a polymer selected from the group consisting of polyethylene glycol ethers of fatty acids, and polyethylene glycol esters of fatty acids, wherein the fatty acids comprise a fatty acid selected from the group consisting of lauric, palmitic, oleic, and stearic acids. 20. A peptide complex according to claim 15, wherein the peptide is selected from the group consisting of insulin, calcitonin, ACTH, glucagon, somatostatin, somatotropin, somatomedin, parathyroid hormone, erythropoietin, hypothalmic releasing factors, prolactin, thyroid stimulating hormones, endorphins, enkephalins, vasopressin, non-naturally occurring opiods, superoxide dismutase, interferon, asparaginase, arginase, arginine deaminease, adenosine deaminase ribonuclease, trypsin, chymotrypsin, and papain. 21. A peptide complex according to claim 15, comprising a polysorbate moiety including a triglyceride backbone having a fatty acid group covalently coupled to one of the .alpha.,.alpha.' and .beta. carbon atoms thereof, and having a polyethylene glycol group covalently coupled to one of the .alpha.,.alpha.' and .beta. carbon atoms thereof. 22. A peptide complex according to claim 21, wherein the peptide is covalently coupled with the triglyceride backbone at the .beta. carbon atom thereof. 23. A peptide complex according to claim 15, wherein the peptide is a protein. 24. A peptide complex according to claim 21, wherein the triglyceride backbone comprises a biocompatible divalent spacer group between the .beta. carbon atom and one of the .alpha.,.alpha.' carbon atoms of the triglyceride backbone. 25. A polysorbate complex comprising a polysorbate moiety including a triglyceride backbone having covalently coupled to carbon atoms independently selected from .alpha.,.alpha.' and .beta. carbon atoms thereof, functionalizing groups including: (i) a fatty acid group; and (ii) a polyethylene glycol group having a physiologically active moiety covalently bonded thereto. 26. A polysorbate complex according to claim 25, wherein the physiologically active moiety is covalently bonded to a terminal functionality of the polyethylene glycol group. 27. A peptide composition according to claim 1, wherein the non-naturally-occurring polymer has a molecular weight of from about 500 to about 10,000 daltons. 28. A peptide composition according to claim 1, wherein the peptide is selected from the group consisting of insulin, calcitonin, ACTH, glucagon, somatostatin, somatotropin, somatomedin, parathyroid hormone, erythropoietin, hypothalamic releasing factors, prolactin, thyroid stimulating hormones, endorphins, enkephalins, vasopressin, non-naturally occurring opioids, superoxide dismutase, interferon, asparaginase, arginase, arginine deaminease, adenosine deaminase, ribonuclease, trypsin, chymotrypsin, and papain. 29. A peptide composition according to claim 1, wherein the peptide comprises insulin. 30. A polymer-peptide conjugate comprising a conjugating polymer selected from the group consisting of polymers of the formulae: ##STR19## wherein the sum of w, x, y, z is from 4 to 100 and R.sub.1, R.sub.2 and R.sub.3 are each independently selected from the group consisting of lauric, oleic, palmitic, stearic acid radicals, and C.sub.5 -C.sub.18 alkyl; or R.sub.1 and R.sub.2 are each hydroxyl while R.sub.3 is C.sub.5 -C.sub.18 alkyl, lauric, palmitic, oleic or stearic acid radical; ##STR20## where m has a value from 10 to 16, n+m is 8-240, or when more than one n is present, the sum of all n's+m is 8-240, and wherein the sugar portion of the glycolipid is optionally substituted with glycerol or aminoglycerol; ##STR21## wherein x=O and wherein: m and n are as specified above; and wherein said polymer is conjugatively coupled to a peptide. 31. A polymer-peptide conjugate according to claim 30, wherein said peptide is selected from the group consisting of insulin, calcitonin, ACTH, glucagon, somatostatin, somatotropin, somatomedin, parathyroid hormone, erythropoietin, hypothalmic releasing factors, prolactin, thyroid stimulating hormones, endorphins, enkephalins, vasopressin, non-naturally occurring opioids, superoxide dismutase, interferon, asparaginase, arginase, arginine deaminease, adenosine deaminase, ribonuclease, trypsin, chymotrypsin and papain. 32. A polymer peptide, conjugate according to claim 30, wherein said peptide is insulin. 33. A polymer peptide, conjugate according to claim 30, wherein said peptide is calcitonin.

Details for Patent 5,359,030

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2039-02-26
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2039-02-26