Composition for long-acting peptide analogs

• US 7,960,336 B2
• Filed: 07/31/2008
• Issued: 06/14/2011
• Est. Priority Date: 08/03/2007
• Status: Active Grant

• Current Assignee: Pharmain Corporation
• Original Assignee: Pharmain Corporation
• Inventors: Chan, Elaine K., Castillo, Gerardo M., Bolotin, Elijah M.
• Primary Examiner(s): Russel; Jeffrey
• Application Number:
  US12/184,186
• Publication Number:
  US 20090088387A1
• Time in Patent Office: 1,048 Days
• Field of Search: None
• US Class Current: 514/1.4
• 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 exemplified by peptides derived from vasopressin, terlipressin, and GLP1 and others 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, wherein A is a hydrophobic moiety or a metal binding moiety, 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. A may be linked to Cm by a linker group. The peptide analogs are complexed with polymeric carrier to provide enhanced half-life.

Claims

1. A composition comprising a peptide analog with a general formula:

A-(Cm)_x-peptide, wherein;

(a) the peptide is a vasopressin, wherein the vasopressin comprises a general formula;

Cys-Tyr-Phe-Gln-Asn-Cys-Pro-B-C-D (SEQ ID NO;

     53), wherein

Cys is cystine or cysteine;

Tyr is tyrosine;

Phe is phenylalanine;

Gln is glutamine;

Asn is asparagine;

Pro is proline;

B is lysine or arginine;

C is glycine or alanine; and

D is NH₂;

(b) Cm is

a Gly moiety, wherein x is an integer from 2-6 (SEQ ID NO;

     58); and

(c) A comprises an alkyl carbonyl group having 8-12 carbons and a linker, wherein the linker is —

OCH(CH₃)CO—

.

2. The composition of claim 1, wherein A-(Cm)_x is attached to the peptide at the N-terminus.

3. The composition of claim 1, wherein the alkyl carbonyl group is branched.

4. The composition of claim 1, wherein the alkyl carbonyl group is linear.

5. The composition of claim 1, wherein the (Cm)_x is -Gly-Gly-Gly (SEQ ID NO:

58).

6. The composition of claim 1, wherein the peptide analog formula is:

CH₃(CH₂)₁₀CO—

OCH(CH₃)CO-Gly-Gly-Gly-Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly-NH₂ (SEQ ID NO;

     35).

7. The composition of claim 1, wherein the peptide analog formula is:

CH₃(CH₂)₆CO—

OCH(CH₃)CO-Gly-Gly-Gly-Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly-NH₂ (SEQ ID NO;

     37).

8. The composition of claim 1, wherein the peptide analog formula is:

CH₃(CH₂)₁₀CO—

OCH(CH₃)CO-Gly-Gly-Gly-Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH₂ (SEQ ID NO;

     79).

9. The composition of claim 1, wherein the peptide analog formula is:

CH₃(CH₂)₆CO—

OCH(CH₃)CO-Gly-Gly-Gly-Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH₂ (SEQ ID NO;

     80).

10. 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 interactions.

11. A pharmaceutical composition comprising the composition of claim 1 in a pharmaceutically acceptable carrier.

12. A method comprising administering a composition of claim 1 to a subject by injection or infusion.

13. A method for treatment of hypovolemia, splanchnic vasodilation, systemic vasodilation, hypotension, esophageal variceal hemorrhage, hepatorenal syndrome, or sepsis in a subject in need of such treatment comprising administering to the subject a composition of claim 1.

14. The method of claim 13, wherein hypovolemia or hypotension is being treated.

15. The method of claim 13, wherein the hypotension is due to paracentesis.

16. The method of claim 13, wherein esophageal variceal hemorrhage is being treated.

17. The method of claim 13, wherein hepatorenal syndrome is being treated.

18. The method of claim 13, wherein sepsis is being treated.

19. The method of claim 17, wherein the hepatorenal syndrome is caused by liver cirrhosis.

20. The method of claim 19, wherein the liver cirrhosis is caused by alcohol or hepatitis.