Patent US5359030A successfully refreshed from Google Patents.
US5359030A
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Conjugation-stabilized polypeptide compositions, therapeutic delivery and diagnostic formulations comprising same, and method of making and using the same
Assignee: LAI VENTURES Inc
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Filing: 1993-05-10
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Granted: 1994-10-25
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Expires: 2013-05-10
Abstract
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.
Inventors
- 👤 Nnochiri N. Ekwuribe
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 11:12
CPC Classifications
C; C12; C12N; C12N9/00; C12N9/96; A; A61; A61K; A61K47/00; A61K47/50; A61K47/51; A61K47/56; A61K47/59; A61K47/60; A61K9/00; A61K9/10; A61K9/107; A61K9/1075; A61P; A61P19/00; A61P19/08; A61P19/10; A61P3/00; A61P3/08; A61P3/10; A61P3/12; A61P3/14; A61P43/00; A61P5/00; A61P5/48; A61P5/50; C07; C07K; C07K1/00; C07K1/107; C07K1/1072; C07K1/1077; C07K14/00; C07K14/435; C07K14/575; C07K14/62; A61K38/00; A61K9/48; A61K9/4841; A61K9/4858
Claims Analysis
Total Claims: 42
Claim 1
Independent Claim
58 words
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.
Claim 2
Dependent Claim
58 words
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.
Claim 3
Dependent Claim
16 words
A peptide composition according to claim 1, wherein the peptide is a physiologically active therapeutic peptide.
Claim 4
Dependent Claim
32 words
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.
Claim 5
Dependent Claim
53 words
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.
Claim 6
Dependent Claim
53 words
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.
Claim 7
Dependent Claim
23 words
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.
Claim 8
Dependent Claim
77 words
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.
Claim 9
Dependent Claim
82 words
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.
Claim 10
Dependent Claim
82 words
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.
Claim 11
Dependent Claim
94 words
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.
Claim 12
Dependent Claim
94 words
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.
Claim 13
Dependent Claim
66 words
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.
Claim 14
Dependent Claim
66 words
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.
Claim 15
Dependent Claim
42 words
A multiligand conjugated peptide complex according to claim 9, wherein the α' and β 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.
Claim 16
Dependent Claim
67 words
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 α and α' carbons of the triglyceride backbone moiety, with the bioactive peptide being covalently coupled with the β-carbon of the triglyceride backbone moiety, either being directly covalently bonded thereto or indirectly bonded thereto through a polyalkylene spacer moiety.
Claim 17
Dependent Claim
46 words
A polysorbate complex comprising a polysorbate moiety including a triglyceride backbone having a fatty acid group covalently coupled to one of the α,α' and β carbon atoms thereof, and having a polyethylene glycol group covalently coupled to one of the α,α' and β carbon atoms thereof.
Claim 18
Dependent Claim
46 words
A polysorbate complex comprising a polysorbate moiety including a triglyceride backbone having a fatty acid group covalently coupled to one of the α,α' and β carbon atoms thereof, and having a polyethylene glycol group covalently coupled to one of the α,α' and β carbon atoms thereof.
Claim 19
Dependent Claim
19 words
A polysorbate complex according to claim 12, wherein the polysorbate moiety has a physiologically active moiety covalently bonded thereto.
Claim 20
Dependent Claim
20 words
A polysorbate complex according to claim 13, wherein the physiologically active moiety is covalently bonded to the polyethylene glycol group.
Claim 21
Dependent Claim
21 words
A stable, aqueously soluble, conjugated peptide complex comprising a peptide stabilizingly and conjugatively coupled to a polyethylene glycol modified glycolipid moiety.
Claim 22
Dependent Claim
21 words
A stable, aqueously soluble, conjugated peptide complex comprising a peptide stabilizingly and conjugatively coupled to a polyethylene glycol modified glycolipid moiety.
Claim 23
Dependent Claim
49 words
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.
Claim 24
Dependent Claim
18 words
A peptide complex according to claim 15, wherein the polyethylene glycol modified glycolipid moiety comprises a polysorbate polymer.
Claim 25
Dependent Claim
34 words
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.
Claim 26
Dependent Claim
56 words
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.
Claim 27
Dependent Claim
54 words
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.
Claim 28
Dependent Claim
50 words
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 α,α' and β carbon atoms thereof, and having a polyethylene glycol group covalently coupled to one of the α,α' and β carbon atoms thereof.
Claim 29
Dependent Claim
23 words
A peptide complex according to claim 21, wherein the peptide is covalently coupled with the triglyceride backbone at the β carbon atom thereof.
Claim 30
Dependent Claim
13 words
A peptide complex according to claim 15, wherein the peptide is a protein.
Claim 31
Dependent Claim
33 words
A peptide complex according to claim 21, wherein the triglyceride backbone comprises a biocompatible divalent spacer group between the β carbon atom and one of the α,α' carbon atoms of the triglyceride backbone.
Claim 32
Dependent Claim
48 words
A polysorbate complex comprising a polysorbate moiety including a triglyceride backbone having covalently coupled to carbon atoms independently selected from α,α' and β 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.
Claim 33
Dependent Claim
48 words
A polysorbate complex comprising a polysorbate moiety including a triglyceride backbone having covalently coupled to carbon atoms independently selected from α,α' and β 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.
Claim 34
Dependent Claim
24 words
A polysorbate complex according to claim 25, wherein the physiologically active moiety is covalently bonded to a terminal functionality of the polyethylene glycol group.
Claim 35
Dependent Claim
23 words
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.
Claim 36
Dependent Claim
54 words
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.
Claim 37
Dependent Claim
12 words
A peptide composition according to claim 1, wherein the peptide comprises insulin.
Claim 38
Dependent Claim
151 words
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 1 , R 2 and R 3 are each independently selected from the group consisting of lauric, oleic, palmitic, stearic acid radicals, and C 5 -C 18 alkyl; or R 1 and R 2 are each hydroxyl while R 3 is C 5 -C 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.
Claim 39
Dependent Claim
151 words
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 1 , R 2 and R 3 are each independently selected from the group consisting of lauric, oleic, palmitic, stearic acid radicals, and C 5 -C 18 alkyl; or R 1 and R 2 are each hydroxyl while R 3 is C 5 -C 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.
Claim 40
Dependent Claim
54 words
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.
Claim 41
Dependent Claim
13 words
A polymer peptide, conjugate according to claim 30, wherein said peptide is insulin.
Claim 42
Dependent Claim
13 words
A polymer peptide, conjugate according to claim 30, wherein said peptide is calcitonin.
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