Insulin vitamin D conjugates

• US 10,420,819 B2
• Filed: 03/23/2017
• Issued: 09/24/2019
• 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:
  US15/468,083
• Publication Number:
  US 20170252410A1
• Time in Patent Office: 915 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 method of treating a patient in need of insulin, comprising administering an effective amount of a pharmaceutical composition comprising said insulin conjugated to the carbon 3 position of a non-hormonal vitamin D targeting group that is not hydroxylated at the carbon 1 position.

2. The method of claim 1, wherein said pharmaceutical composition is delivered to said patient by a transdermal, oral, parenteral, subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intracranial injection, infusion, inhalation, ocular, topical, rectal, nasal, buccal, sublingual, vaginal, or implanted reservoir mode.

3. A method of manufacturing the pharmaceutical composition of claim 1, comprising conjugating said targeting group and said insulin, wherein said conjugating step utilizes a coupling group.

4. The method according to claim 3, wherein said coupling group is selected from the group consisting of an amine-reactive group, a thiol-reactive group, a maleimide group, a thiol group, an aldehyde group, an NETS-ester group, a haloacetyl group, an iodoacetyl group, a bromoacetyl groups, a SMCC group, a sulfo SMCC group, a carbodiimide group, bifunctional cross-linkers, NHS-maleimido, and combinations thereof.

5. The pharmaceutical composition resulting from the method of claim 3, wherein said composition comprises a carrier-drug compound containing a linkage selected from the group consisting of a thiol linkage, an amide linkage, an oxime linkage, a hydrazone linkage, and a thiazolidinone linkage.

6. The method according to claim 3, wherein said conjugating step is accomplished by cycloaddition reactions.

11. The carrier-drug conjugate of claim 5, wherein said insulin peptide retains substantially the same activity as said insulin peptide not conjugated to said targeting group as measured by a functional assay.

12. The method of claim 1, wherein said insulin comprises 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.

13. The method of claim 12, wherein said first peptide has the amino acid sequence of SEQ ID NO:

1.

14. The method of claim 12, wherein said first peptide has the amino acid sequence of SEQ ID NO:

5.

15. The method of claim 12, wherein said second peptide has the amino acid sequence of SEQ ID NO:

2.

16. The method of claim 12, wherein said second peptide has the amino acid sequence of SEQ ID NO:

6.

17. The method of claim 12, wherein said second peptide has the amino acid sequence of SEQ ID NO:

7.

18. The method of claim 12, wherein said second peptide has the amino acid sequence of SEQ ID NO:

8.

19. The method of claim 3, wherein said targeting group is conjugated to said insulin peptide via a scaffold that is selected from the group consisting of poly(ethylene glycol), polylysine, polyethyleneimine, poly(propyleneglycol), a peptide, serum albumin, thioredoxin, an immunoglobulin, an amino acid, a nucleic acid, a glycan, a modifying group that contains a reactive linker, a water-soluble polymer, a small carbon chain linker, and an additional therapeutic peptide.

20. The method of claim 19, wherein said scaffold is approximately the same mass as the insulin peptide.

7. A pharmaceutical carrier comprising a formula I:

B-(L)-^a S-(M)-^b-C 

 

I

Wherein;

B is a targeting group that is a vitamin D that is not hydroxylated at the carbon 1 position, conjugated at the carbon 3 position to (L)^a ;

S is a scaffold moiety, comprising poly(ethylene glycol), polylysine, polyethyleneimine, poly(propyleneglycol), a peptide, an amino acid, a nucleic acid, a glycan, a modifying group that contains a reactive linker, polylactic acid, a water-soluble polymer, a small carbon chain linker, or an additional therapeutic moiety;

C is an amine-reactive group, a thiol-reactive group, a maleimide group, a thiol group, a disulfide group, an aldehyde group, an NETS-ester group, a 4-nitrophenyl ester, an acylimidazole, a haloacetyl group, an iodoacetyl group, a bromoacetyl groups, a SMCC group, a sulfo SMCC group, a carbodiimide group and bifunctional cross-linkers such as NHS-Maleimido or combinations thereof;

(L)^a and (M)^b are linkers independently selected from —

(CH₂)_n—

, —

C(O)NH—

, —

HNC(O)—

, —

C(O)O—

, —

OC(O)—

, —

O—

, —

S—

S—

, —

S—

, —

S(O)—

, —

S(O)₂— and

—

NH—

;

a is an integer from 0-4;

b is an integer from 0-4; and

n is an integer from 0-3.

8. The pharmaceutical carrier of claim 7 comprising formula V:

9. The pharmaceutical carrier of claim 7 comprising formula VI:

10. The pharmaceutical carrier of claim 7 comprising formula VII: