Rapid-acting insulin composition comprising a substituted citrate
Inventors
Soula, Olivier • Charvet, Richard • Alluis, Bertrand
Assignees
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Publication Number
US-10792335-B2
Publication Date
2020-10-06
Expiration Date
Abstract
A composition, in the form of an aqueous solution, including an insulin in hexameric form and at least one substituted citrate of formula I: in which: R1, R2, R3, identical or different, represent OH or AA, at least one of the R1, R2, R3 is an AA radical, AA is a radical resulting from a natural or synthetic aromatic amino acid comprising at least one phenyl group or indole group, substituted or not substituted, said AA radical having at least one free carboxylic acid function, and the carboxylic acid functions are in the form of a salt of an alkali metal selected from Na+ and K+.
Core Innovation
The invention relates to a rapid-acting aqueous insulin formulation comprising insulin in hexameric form together with at least one substituted citrate of formula I. The substituted citrate contains substituent radicals R1, R2, and R3 that are identical or different and represent OH or AA, with at least one of R1, R2, or R3 being an AA radical.
AA is a radical resulting from a natural or synthetic aromatic amino acid comprising at least one phenyl group or indole group, substituted or not substituted, and having at least one free carboxylic acid group. The carboxylic acid groups are in the form of a salt of an alkali metal selected from Na+ and K+, and the composition is free of EDTA.
The formulation is characterized as being free of EDTA, distinguishing it from prior-art approaches in which EDTA and/or citric acid are used to destabilize insulin hexamers. Reported in vivo kinetics comparisons and structural characterization, including circular dichroism, support the association of insulin with substituted citrates versus EDTA controls, and the substituted citrates remain soluble at high concentrations in aqueous conditions.
Claims Coverage
The independent claims cover an aqueous insulin composition defined by insulin in hexameric form, at least one substituted citrate of formula I with aromatic-amino-acid-derived AA radicals in alkali-metal carboxylate form, and the requirement that the composition is free of EDTA.
Aqueous hexameric insulin with substituted citrate
A composition in the form of an aqueous solution comprising insulin in hexameric form and at least one substituted citrate of formula I, wherein R1, R2, and R3 are OH or AA and at least one of R1, R2, R3 is an AA radical.
Aromatic amino-acid-derived AA as alkali-metal carboxylate
AA is a radical resulting from a natural or synthetic aromatic amino acid comprising at least one phenyl group or indole group, substituted or not substituted, and having at least one free carboxylic acid group, with the carboxylic acid groups in the form of a salt of an alkali metal selected from Na+ and K+.
EDTA-free composition
The composition is free of EDTA.
Substituted citrate molar ratio range to insulin
The composition as claimed has a substituted citrate/insulin molar ratio between 3 and 400.
Substituted citrate mass ratio range to insulin
The composition as claimed has a substituted citrate/mass ratio between 0.5 and 30.
Substituted citrate concentration range
The composition has a concentration of the substituted citrate between 1.8 and 100 mg/mL.
Insulin concentration range for a pharmaceutical composition
A pharmaceutical composition comprises the composition, wherein the insulin concentration is between 240 and 3000 μM (40 to 500 IU/mL).
Named insulin analog selection
The composition includes insulin that is an insulin analog selected from insulin lispro, insulin aspart, and insulin glulisine.
Across the covered independent claim scope, the inventive concept is the combination of hexameric insulin with an EDTA-free substituted citrate defined by formula I, using AA radicals derived from aromatic amino acids and present as alkali-metal (Na+ or K+) salts. Dependent refinements specify substituent-ratio constraints, substituted citrate concentration, insulin concentration expressed in μM and IU/mL, and restriction of the insulin component to named insulin analogs.
Stated Advantages
Improved insulin kinetics, including a faster glycemic response and more rapid insulin absorption compared with market products such as Humalog®, Novolog®, Apidra®, and Humulin® R.
Preserved insulin hexamer stability by using substituted citrate while avoiding EDTA-associated destabilization.
Substituted citrate mixtures do not significantly disrupt insulin hexamer structure, as indicated by circular dichroism hexameric R6 signal at 240 nm.
Substituted citrates remain soluble at high concentrations in aqueous conditions.
Faster glucose-lowering in the pig model compared with commercial Humalog for insulin lispro formulations containing substituted citrate.
Faster insulin absorption in the pig model compared with commercial Humalog, as indicated by pharmacokinetic endpoints.
Documented Applications
Use as a pharmaceutical composition for administering insulin, including subcutaneous administration and pump-based administration routes, as referenced in the disclosed context.
In vivo pharmacodynamics and pharmacokinetics assessment in a pig model for insulin lispro formulations containing substituted citrate, compared to Humalog.
Aqueous formulation and preparation for insulin solutions using substituted citrate molecules and characterization by LC/MS and NMR, with conversion to acid/base forms.
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