Claims for Patent: 9,657,078

Summary for Patent: 9,657,078

Title:	Composition for long-acting peptide analogs
Abstract:	The invention describes compositions of peptide analogs that are active in blood or cleavable in blood to release an active peptide. The peptide analogs have a general formula: A-(Cm).sub.x-Peptide (SEQ ID NO: 76), wherein A is hydrophobic moiety or a metal binding moiety, e.g., a chemical group or moiety containing 1) an alkyl group having 6 to 36 carbon units, 2) a nitrilotriacetic acid group, 3) an imidiodacetic acid group, or 4) a moiety of formula (Z.sub.yHis.sub.w).sub.p (SEQ ID NO: 50), wherein Z is any amino acid residue other than histidine, His is histidine, y is an integer from 0-6; w is an integer from 1-6; and p is an integer from 1-6; wherein if A has alkyl group with 6 to 36 carbon units x is greater than 0; and Cm is a cleavable moiety consisting of glycine or alanine or lysine or arginine or N-Arginine or N-lysine, wherein x is an integer between 0-6 and N may be any amino acid or none. The peptide analogs are complexed with polymeric carrier to provide enhanced half-life.
Inventor(s):	Castillo; Gerardo M. (Bothell, WA), Bolotin; Elijah (Bothell, WA)
Assignee:	PHARMAIN CORPORATION (Bothell, WA)
Application Number:	14/739,312
Patent Claims:	1. A composition comprising a peptide analog having a general formula: A-(Cm)x-peptide, wherein: a. Cm is independently selected from (i) Gly, (ii) Ala, (iii) Arg, (iv) Lys, (v) (N)q-Lys, wherein N is any amino acid, q is 0 or 1, and (vi) (N)q-Arg, wherein N is any amino acid, q is 0 or 1; b. x is an integer from 3-6; c. A is an alkyl group with 6 to 36 carbon units with a linker group selected from carbonyl and amino; and d. the peptide comprises glucagon-like peptide (GLP), leptin fragment, gastric inhibitory polypeptide (GIP), epidermal growth factor (EGF) receptor ligand, EGF, transforming growth factor alpha (TGF-alpha), gastrin/cholecystokinin receptor ligand, gastrin, cholecystokinin, auristatin, nisin, insulin, insulin-like growth factor, parathyroid hormone (PTH), atrial natriuretic factor, somatostatin, gonadotropin-releasing hormone, luteinizing-hormone-releasing-hormone, or vasoactive intestinal peptide (VIP). 2. The composition of claim 1, further comprising a polymeric carrier with a plurality of hydrophobic groups of 8-36 carbons each, wherein group A of the peptide analog is non-covalently bound to the plurality of hydrophobic groups of the polymeric carrier by hydrophobic interaction. 3. The composition of claim 2, wherein the peptide is atrial natriuretic factor, and A-(Cm)x- is attached to the N-terminus of the peptide. 4. The composition in claim 2, wherein the peptide is glucagon-like peptide (GLP) or atrial natriuretic factor. 5. The composition of claim 2, wherein the peptide is vasoactive intestinal peptide (VIP) or atrial natriuretic factor and A-(Cm)x- is attached to the N-terminus or the C-terminus of the peptide or a side chain. 6. The composition of claim 2, wherein A is a linear alkyl. 7. The composition of claim 3, wherein A is a linear alkyl. 8. The composition of claim 4, wherein A is a linear alkyl. 9. The composition of claim 5, wherein A is a linear alkyl. 10. The composition of claim 2, wherein A is a branched alkyl. 11. The composition of claim 3, wherein A is a branched alkyl. 12. The composition of claim 4, wherein A is a branched alkyl. 13. The composition of claim 5, wherein A is a branched alkyl. 14. The composition of claim 4, wherein the peptide is atrial natriuretic factor. 15. The composition of claim 1, wherein Cm is each independently selected from Ala, Arg, and Lys. 16. The composition of claim 1, wherein Cm is each independently selected from (i) Gly, (ii) (N)q-Lys, wherein N is any amino acid, q is 0 or 1, and (iii) (N)q-Arg, wherein N is any amino acid, q is 0 or 1. 17. The composition of claim 1, wherein the A-(Cm)x-(peptide) has lower biological activity in cell culture than a corresponding peptide lacking the A-(Cm)x in the absence of serum. 18. A composition comprising a peptide analog having a general formula: A-(Cm)x-peptide, wherein: a. Cm is independently selected from (i) Gly, (ii) Ala, (iii) Arg, (iv) Lys, (v) (N)q-Lys, wherein N is any amino acid, q is 0 or 1, and (vi) (N)q-Arg, wherein N is any amino acid, q is 0 or 1; b. x is an integer from 3-6; c. A is an alkyl group with 6 to 36 carbon units with a linker group selected from carbonyl, amino, and --OCH(CH.sub.3)CO--; wherein Cm has at least one Gly or one Ala linked directly to the peptide, wherein the A-(Cm)x-(peptide) has lower biological activity in cell culture than a corresponding peptide lacking the A-(Cm)x in the absence of serum, and wherein the peptide comprises glucagon-like peptide (GLP), leptin fragment, gastric inhibitory polypeptide (GIP), epidermal growth factor (EGF) receptor ligand, EGF, transforming growth factor alpha (TGF-alpha), gastrin/cholecystokinin receptor ligand, gastrin, cholecystokinin, auristatin, nisin, insulin, insulin-like growth factor, parathyroid hormone (PTH), atrial natriuretic factor, somatostatin, gonadotropin-releasing hormone, luteinizing-hormone releasing-hormone, or vasoactive intestinal peptide (VIP). 19. A method of making a peptide analog having a general formula: A-(Cm)x-peptide, wherein: a. Cm is independently selected from (i) Gly, (ii) Ala, (iii) Arg, (iv) Lys, (v) (N)q-Lys, wherein N is any amino acid, q is 0 or 1, and (vi) (N)q-Arg, wherein N is any amino acid, q is 0 or 1; b. x is an integer from 3-6; c. A is an alkyl group with 6 to 36 carbon units with a linker group selected from carbonyl and amino; and d. the peptide comprises glucagon-like peptide (GLP), leptin fragment, gastric inhibitory polypeptide (GIP), epidermal growth factor (EGF) receptor ligand, EGF, transforming growth factor alpha (TGF-alpha), gastrin/cholecystokinin receptor ligand, gastrin, cholecystokinin, auristatin, nisin, insulin, insulin-like growth factor, parathyroid hormone (PTH), atrial natriuretic factor, somatostatin, gonadotropin-releasing hormone, luteinizing-hormone releasing-hormone, or vasoactive intestinal peptide (VIP), the method comprising: step (i): forming a covalent bond between a resin and a reactive group on a first amino acid to provide a resin comprising a covalently bonded amino acid; step (ii): forming a covalent bond between the resin comprising the covalently bonded amino acid and a reactive group on a second amino acid; step (iii): repeating step (ii) to provide a (Cm)x-peptide; and forming a carbonyl or amino bond between the (Cm)x-peptide and an alkyl group with 6 to 36 carbon units to provide the peptide analog. 20. The composition of claim 1, wherein the peptide is an epidermal growth factor (EGF) receptor ligand. 21. The composition of claim 2, wherein the peptide is an epidermal growth factor (EGF) receptor ligand. 22. The composition of claim 18, wherein the peptide is an epidermal growth factor (EGF) receptor ligand. 23. The composition of claim 18, further comprising a polymeric carrier with a plurality of hydrophobic groups of 8-36 carbons each, wherein group A of the peptide analog is non-covalently bound to the plurality of hydrophobic groups of the polymeric carrier by hydrophobic interaction.

Details for Patent 9,657,078

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2027-08-03