Insulin vitamin D conjugates

• US 9,616,109 B2
• Filed: 10/21/2015
• Issued: 04/11/2017
• Est. Priority Date: 10/22/2014
• Status: Active Grant

• Current Assignee: Extend Biosciences, Inc.
• Original Assignee: Extend Biosciences, Inc.
• Inventors: Soliman, Tarik, Hales, Laura M., Hall, Daniel B., Sard, Howard, Hegde, Vishnumurthy
• Primary Examiner(s): Alstrum Acevedo, James H
• Assistant Examiner(s): MARTINEZ, TARA L
• Application Number:
  US14/919,572
• Publication Number:
  US 20160114001A1
• Time in Patent Office: 538 Days
• Field of Search: None
• CPC Class Codes: A61K 38/28 Insulins
• 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: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: C07K 14/62 Insulins

Abstract

The invention provides non-hormonal vitamin D conjugated to insulin peptides that result in the peptides having increased absorption, bioavailability or circulating half-life when compared to non-conjugated forms. The vitamin D targeting groups are coupled to the insulin peptides via the third carbon on the vitamin D backbone.

Claims

1. A carrier-drug conjugate, comprising a targeting group that is a non-hormonal vitamin D not hydroxylated at the carbon 1 position, conjugated to an insulin peptide at the carbon 3 position of said non-hormonal vitamin D targeting group.

2. The carrier-drug conjugate of claim 1, wherein said targeting group is conjugated to said insulin peptide via a scaffold that is poly(ethylene glycol).

3. A pharmaceutical composition, comprising a carrier-drug conjugate comprising a targeting group that is a non-hormonal vitamin D not hydroxylated at the carbon 1 position, conjugated via a scaffold at the carbon 3 position to an insulin comprising a first peptide having an amino acid sequence with at least a 90% sequence identity to SEQ ID NO:

1 and a second peptide having an amino acid sequence with at least a 90% sequence identity to SEQ ID NO;

2.

4. The pharmaceutical composition of claim 3, wherein said first peptide has the amino acid sequence of SEQ ID NO:

1.

5. The pharmaceutical composition of claim 3, wherein said first peptide has the amino acid sequence of SEQ ID NO:

5.

6. The pharmaceutical composition of claim 3, wherein said second peptide has the amino acid sequence of SEQ ID NO:

2.

7. The pharmaceutical composition of claim 3, wherein said second peptide has the amino acid sequence of SEQ ID NO:

6.

8. The pharmaceutical composition of claim 3, wherein said second peptide has the amino acid sequence of SEQ ID NO:

7.

9. The pharmaceutical composition of claim 3, wherein said second peptide has the amino acid sequence of SEQ ID NO:

8.

10. The pharmaceutical composition of claim 3, wherein said scaffold is poly(ethylene glycol).

11. A pharmaceutical composition, comprising:

a) an insulin peptide,

b) a stably attached scaffold,

c) a targeting group that is a non-hormonal vitamin D not hydroxylated at the carbon 1 position, conjugated at the carbon 3 position,

wherein after administration to a first test subject, said insulin peptide has a half-life measured by an enzyme immunoassay (EIA) of blood samples taken at a plurality of time points that is greater than a half-life of said insulin peptide administered to a second test subject without said stably attached scaffold moiety and targeting group as measured by said EIA 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 insulin peptide stably attached to said scaffold and targeting group retains about the same activity as said insulin peptide not stably attached to said scaffold and targeting group as measured by a functional assay.

14. The pharmaceutical composition of claim 11, wherein the scaffold has a mass of about 500 Da to 5,000 Da.

15. The pharmaceutical composition of claim 11, wherein said scaffold is approximately the same mass as the insulin peptide.

16. A carrier-drug conjugate, comprising a targeting group that is vitamin D that is not hydroxylate at the carbon 1 position non-releasably conjugated to a first insulin peptide, wherein said insulin peptide is conjugated at the carbon 3 position of said vitamin D targeting group.

17. The carrier-drug conjugate of claim 16, wherein said vitamin D is non-hormonal.

18. The carrier-drug conjugate of claim 16, wherein said insulin peptide retains about the same activity as said insulin peptide not conjugated to said targeting group as measured by a functional assay.

19. The carrier-drug conjugate of claim 16, further comprising a scaffold that is poly(ethylene glycol).

20. The carrier-drug conjugate of claim 19, wherein said scaffold is approximately the same mass as the insulin peptide.

21. The carrier-drug conjugate of claim 16, wherein said first insulin peptide has a 90% sequence identity to SEQ ID NO:

1.

22. The carrier-drug conjugate of claim 21, further comprising a second insulin peptide having a 90% sequence identity to SEQ ID NO:

2.