COMPOSITION FOR LONG-ACTING PEPTIDE ANALOGS

• US 20090088387A1
• Filed: 07/31/2008
• Published: 04/02/2009
• Est. Priority Date: 08/03/2007
• Status: Active Grant

• Current Assignee: Pharmain Corporation
• Original Assignee: Pharmain Corporation
• Inventors: CASTILLO, GERARDO M., CHAN, ELAINE K., BOLOTIN, ELIJAH M.
• Granted Patent: US 7,960,336 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• 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, 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 imidodiacetic acid group, or 4) a moiety of formula (Z_yHis_w)_p, 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 having a general formula:

A-(Cm)_x-peptide, wherein;

(a) the peptide is a biologically active peptide having no more than 100 amino acids;

(b) Cm is;

(i) a Gly moiety, wherein x is an integer from 0-6;

(ii) a Ala moiety, wherein x is an integer from 0-6;

(iii) a Arg moiety, wherein x is an integer from 0-6;

(iv) a Lys moiety, wherein x is an integer from 0-6;

(v) a moiety of formula (N)_q-Arg, wherein N is any amino acid and q is 0 or 1 and x is an integer from 0-6;

or

(vi) a moiety of formula (N)_q-Lys, wherein N is any amino acid and q is 0 or 1×

is an integer from 0-6; and

(c) A is;

(i) an alkyl group having 6 to 36 carbons and x is an integer from 2-6;

(ii) a nitrilotriacetic acid moiety;

(iii) an iminodiacetic acid moiety;

or

(iv) a moiety of formula (Z_yHis_w,)_p, wherein Z is an amino acid residue other than histidine, His is histidine, y is an integer from 0-6, w is an integer from 1-6, p is an integer from 1-6, and x is an integer from 2-6.

2. The composition of claim 1, wherein Cm is Gly and A-(Gly)_x is attached to the peptide through an amide bond at the N-terminus.

3. The composition of claim 1, wherein Cm is Gly and A-(Gly)_x is attached to the peptide through a side chain of an amino acid of the peptide.

4. The composition of claim 1, wherein Cm is Gly and A-(Gly)_x is attached to the peptide through an amide bond at the C-terminus.

5. The composition of claim 1, having a general formula:

A-(Cm)_x-peptide, wherein;

(a) (Cm)_x is Gly-Gly-Gly-;

(b) A- is amide bonded to the amino terminus of -Gly-Gly-Gly-; and

(c) A-Gly-Gly-Gly- is amide bonded to any amino group of the peptide.

6. The composition of claim 5 wherein the peptide is a vasopressin analog having the general formula:

Cys-Tyr-Phe-Gln-Asn-Cys-Pro-B-C-D, wherein

Cys is cystine or cysteine;

Tyr is yrosine;

Phe is penylalanine;

Gln is gutamine;

Asn is apargine;

Pro is proline;

B is lysine or arginine;

C is glycine or alanine; and

D is NH₂ or H.

7. The composition of claim 5, wherein A is a linear alkyl carbonyl group with formula CH₃(CH₂)_n—

CO—

, wherein n is an integer between 4-34.

8. The composition of claim 6, wherein A is a linear alkyl carbonyl group with formula CH₃(CH₂)_n—

CO—

, wherein n is an integer between 4-34.

9. The composition of claim 8, wherein n is 6 and Cm is Gly-Gly-Gly-.

10. The composition of claim 8, wherein n is 10 and Cm is Gly-Gly-Gly-.

11. The composition of claim 6, having the formula:

CH₃(CH₂)₆CO—

OCH(CH₃)CO-Gly-Gly-Gly-Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly-NH₂.

12. The composition of claim 6, having the formula:

His-His-His-His-His-His-Gly-Gly-Gly-Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly-NH₂.

13. The composition of claim 1, wherein A is a branched alkyl carbonyl group with 6-36 carbon units attached through the carbon of the carbonyl group.

14. The composition of claim 5, wherein A is a branched alkyl carbonyl group with 6-36 carbon units attached through the carbon of the carbonyl group.

15. The composition of claim 6, wherein A is a branched alkyl carbonyl group with 6-36 carbon units attached through the carbon of the carbonyl group.

16. The composition of any of claims 6-11, 13-15 further comprising a polymeric carrier with multiple alkyl chains of 6-36 carbon units wherein the alkyl carbonyl groups of a plurality of peptide analogs are non-covalently bound to the multiple alkyl chains of the polymeric carrier by hydrophobic interaction.

17. The composition of claim 1, wherein A is nitrilotriacetic acid group or imidodiacetic acid group.

19. The composition of claim 1, wherein the peptide is GLP and A-(Cm)_n—

is not attached to the N terminus of the peptide.

20. The composition of claim 19, wherein A is chemical group or moiety containing 1) nitrilotriacetic acid group, 2) iminodiacetic acid group, or 3) (Z_yHis_w)_p.

21. The composition of claim 20, further comprising a polymeric carrier with covalently linked metal binding domain and a chelated metal ion.

22. The composition of claim 19, wherein A is chemical group or moiety containing alkyl group with 6 to 36 carbon units.

23. The composition of claim 22 further comprising a polymeric carrier with multiple alkyl chains of 6-36 carbon units.

24. The composition of claim 1, wherein A is His₆.

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

26. A method comprising administering a composition of claim 1 to a subject.

27. A method for treatment of diabetes in a subject comprising administering to the subject a composition selected from any one of claims 19-24.

28. A method for treatment of hypovolemia, splanchnic vasodilation, systemic vasodilation, hypotension, esophageal variceal hemorrhage, hepatorenal syndrome, or sepsis in a subject comprising administering to the subject a composition of claim 1 wherein the peptide is a vasopressin analog of the formula:

Cys-Tyr-Phe-Gln-Asn-Cys-Pro-B-C-D, wherein

Cys is cystine or cysteine;

Tyr is tyrosine;

Phe is phenylalanine;

Gln is glutamine;

Asn is aspargine;

Pro is proline;

B is Lysine or arginine;

C is Glycine or alanine; and

D is NH₂ or H.

29. The method of claim 28, wherein A is a linear alkyl carbonyl group with formula CH₃(CH₂)_n—

CO—

;

wherein n is an integer between 4-34.

30. The method of claim 28, wherein (Cm)_x is Gly-Gly-Gly-.

31. The method of claim 28, wherein hypovolemia or hypotension is being treated.

32. The method of claim 31, wherein hypotension is due to paracentesis

33. The method of claim 28, wherein esophageal variceal hemorrhage is being treated.

34. The method of claim 28, wherein hepatorenal syndrome is being treated.

35. The method of claim 28, wherein sepsis is being treated.

36. The method of claim 28, wherein hepatorenal syndrome is caused by liver cirrhosis.

37. The method of claim 36, wherein liver cirrhosis is caused by alcohol or hepatitis.

18. The composition of 12 or 17, further comprising a polymeric carrier with covalently linked metal binding domain and a chelated metal ion.

38. A composition comprising:

(a) a polymeric carrier comprising;

(i) a polymeric core;

(ii) a plurality of first hydrophobic groups covalently bound to the polymeric core;

(iii) a plurality of protective side chains, wherein each protective side chain is covalently bound to the polymeric core and has a molecular weight between about 400 and 20,000 Daltons independent of the polymeric core weight; and

(b) a plurality of peptide analogs, each comprising a peptide covalently bound to a second hydrophobic group,

wherein said peptide analogs are non-covalently bound to the polymeric carrier through a hydrophobic interaction between the first hydrophobic groups and the second hydrophobic groups.

39. The composition of claim 38, wherein the peptide is a vasopressin analog having the general formula:

Cys-Tyr-Phe-Gln-Asn-Cys-Pro-B-C-D, wherein

Cys is cystine or cysteine;

Tyr is tyrosine;

Phe is phenylalanine;

Gln is glutamine;

Asn is aspargine;

Pro is proline;

B is lysine or arginine;

C is glycine or alanine; and

D is NH₂ or H.

40. The composition of claim 38, wherein the hydrophobic group is a linear alkyl carbonyl group with formula CH₃(CH₂)_n—

CO—

;

wherein n is an integer between 4-34.

41. The composition of claim 40, having the formula:

CH₃(CH₂)_nCO—

OCH(CH₃)CO-Gly-Gly-Gly-Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly-NH₂.

42. The composition of claim 38, wherein the peptide is GLP.

43. The composition of claim 38, wherein the peptide analog is GLP-Gly-Gly-Gly wherein Gly-Gly-Gly- is attached to the C terminus or a side chain of the peptide.

44. A composition comprising:

(a) a polymeric carrier comprising;

(i) a polymeric core;

(ii) a plurality of first chelating groups covalently bound to the polymeric core, wherein the first chelating groups are coordinately bonded to a transition metal ion;

(iii) a plurality of first protective side chains, wherein each first protective side chain is covalently bound to the polymeric core and has a molecular weight between about 400 and 20,000 Daltons independent of the polymeric core weight; and

(b) a plurality of peptide analogs, each comprising a peptide covalently bound to a second chelating group, wherein said peptide analogs are non-covalently bound to the polymeric carrier through a coordinate bond to the transition metal ion.

45. The composition of claim 44, wherein the peptide is a vasopressin analog having the general formula:

Cys-Tyr-Phe-Gln-Asn-Cys-Pro-B-C-D, wherein

Cys is cystine or cysteine;

Tyr is tyrosine;

Phe is phenylalanine;

Gln is glutamine;

Asn is aspargine;

Pro is proline;

B is lysine or arginine;

C is glycine or alanine; and

D is NH₂ or H.

46. The composition of claim 44, wherein the peptide analog has the formula:

His-His-His-His-His-His-Gly-Gly-Gly-Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly-NH₂.

47. The composition of claim 44, wherein the peptide analog has the formula:

His-His-His-His-His-His-Gly-Gly-Gly-Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly-NH₂.

48. The composition of claim 44, wherein the peptide is GLP.

49. The composition of claim 44, wherein the peptide analog is GLP-Gly-Gly-Gly wherein Gly-Gly-Gly- is attached to the C terminus or a side chain of the peptide.