Composition for long-acting peptide analogs

• US 9,657,078 B2
• Filed: 06/15/2015
• Issued: 05/23/2017
• Est. Priority Date: 08/03/2007
• Status: Active Grant

• Current Assignee: Pharmain Corporation
• Original Assignee: Pharmain Corporation
• Inventors: Castillo, Gerardo M., Bolotin, Elijah
• Primary Examiner(s): Russel, Jeffrey E
• Application Number:
  US14/739,312
• Publication Number:
  US 20150307578A1
• Time in Patent Office: 708 Days
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/02 Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07K 14/485 Epidermal growth factor [EGF], i.e. urogastrone
• CPC Class Codes: C07K 14/575 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695
• CPC Class Codes: C07K 14/57563 Vasoactive intestinal peptide [VIP]; Related peptides
• CPC Class Codes: C07K 7/16 Oxytocins; Vasopressins; Related peptides

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)_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_yHis_w)_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.

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.

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.

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(CH₃)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).

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.

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.