Vitamin D-ghrelin conjugates

• US 9,173,950 B2
• Filed: 11/15/2014
• Issued: 11/03/2015
• Est. Priority Date: 05/17/2012
• Status: Active Grant

• Current Assignee: Extend Biosciences, Inc.
• Original Assignee: Extend Biosciences, Inc.
• Inventors: Soliman, Tarik, Hales, Laura M., Sard, Howard P., Amere, Mukkanti
• Primary Examiner(s): Alstrum Acevedo, James H
• Assistant Examiner(s): MARTINEZ, TARA L
• Application Number:
  US14/542,581
• Publication Number:
  US 20150065420A1
• Time in Patent Office: 353 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 38/22 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• CPC Class Codes: A61K 47/551 one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• 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 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system

Abstract

The invention provides carriers that enhance the absorption, half-life or bioavailability of Ghrelin peptides. The carriers comprise targeting groups that bind the Vitamin D Binding protein (DBP), conjugation groups for coupling the targeting groups to the therapeutic compounds, and optionally scaffolding moieties.

Claims

1. A carrier-drug conjugate, comprising a targeting group that is vitamin D that is not hydroxylated at the Carbon 1 position stably linked to a therapeutic peptide having Ghrelin activity comprising an amino acid sequence with at least a 90% sequence identity to SEQ ID NO:

5.

2. The carrier-drug conjugate of claim 1, wherein said targeting group is linked to said therapeutic peptide via a scaffold.

3. The carrier drug conjugate of claim 2, wherein said scaffold is between about 100 Da. and 200,000 Da.

4. A pharmaceutical composition comprising the carrier-drug conjugate of claim 1.

5. A pharmaceutical composition comprising the carrier-drug conjugate of claim 2.

6. A pharmaceutical composition comprising the carrier-drug conjugate of claim 3.

7. The pharmaceutical composition of claim 4, wherein said carrier increases the absorption, bioavailability, or half-life of said therapeutic peptide in circulation.

8. The pharmaceutical composition of claim 6, wherein said therapeutic peptide has the sequence of SEQ ID NO:

5.

9. The pharmaceutical composition of claim 6, wherein said scaffold is poly(ethylene glycol).

10. The pharmaceutical composition of claim 9, wherein said therapeutic peptide has the sequence of SEQ ID NO:

5.

11. A pharmaceutical composition, comprising:

(a) a therapeutic peptide having Ghrelin activity comprising an amino acid sequence with at least a 90% sequence identity to SEQ ID NO;

5,

(b) a stably attached scaffold,

(c) a targeting group that is vitamin D that is not hydroxylated at the Carbon 1 position,

wherein after administration to a first subject, said therapeutic peptide has a half life measured by an Enzyme Linked Immunosorbant Assay (ELISA) analysis of blood samples taken at a plurality of time points that is greater than a half life of said therapeutic peptide administered to a second subject without said attached scaffold and targeting group as measured by said ELISA analysis of blood samples taken at said plurality of time points.

12. The pharmaceutical composition of claim 11, wherein said administration to said first and second subjects is accomplished by subcutaneous injection.

13. The pharmaceutical composition of claim 11, wherein said therapeutic peptide retains at least about the same activity as said therapeutic peptide not attached to said scaffold and targeting group as measured by a Ghrelin receptor binding assay.

14. A carrier-drug conjugate, comprising a stably linked targeting group that is vitamin D that binds a vitamin D binding protein with a higher affinity than said carrier-drug conjugate binds to a vitamin D receptor, wherein said carrier-drug conjugate comprises a therapeutic peptide having Ghrelin activity further comprising an amino acid sequence with at least a 90% sequence identity to SEQ ID NO:

5.

15. The carrier-drug conjugate of claim 14, wherein said targeting group is linked to said therapeutic peptide via a scaffold.

16. The carrier drug conjugate of claim 15, wherein said scaffold is between about 100 Da. and 200,000 Da.

17. A pharmaceutical composition comprising the carrier-drug conjugate of claim 14.

18. A pharmaceutical composition comprising the carrier-drug conjugate of claim 15.

19. A pharmaceutical composition comprising the carrier-drug conjugate of claim 16.

20. The pharmaceutical composition of claim 19, wherein said carrier increases the nasal absorption, topical absorption, dermal absorption, bioavailability, or half-life of said therapeutic peptide in circulation.

21. The pharmaceutical composition of claim 19, wherein said therapeutic peptide has the sequence of SEQ ID NO:

5.

22. The pharmaceutical composition of claim 21, wherein said scaffold is poly(ethylene glycol).

23. A pharmaceutical composition, comprising:

(a) a therapeutic peptide having Ghrelin activity comprising an amino acid sequence with at least a 90% sequence identity to SEQ ID NO;

5,

(b) a stably attached scaffold,

(c) a targeting group that is Vitamin D,

wherein after administration to a first subject, said therapeutic peptide has a half life measured by an ELISA analysis of blood samples taken at a plurality of time points that is greater than a half life of said therapeutic peptide administered to a second subject without said attached scaffold and targeting group as measured by said ELISA analysis of blood samples taken at said plurality of time points.

24. The pharmaceutical composition of claim 23, wherein said administration to said first and second subjects is accomplished by subcutaneous injection.

25. The pharmaceutical composition of claim 23, wherein said therapeutic peptide retains at least about the same activity as said therapeutic peptide not attached to said scaffold and targeting group as measured by a Ghrelin receptor binding assay.