Insulin vitamin D conjugates
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.
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.
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 —(CH 2 ) 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:
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.