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US-12622949-B2 - Compositions containing rapid-acting insulin analogues

US12622949B2US 12622949 B2US12622949 B2US 12622949B2US-12622949-B2

Abstract

A pharmaceutical composition comprises an effective amount of an insulin analogue comprising modified A-chain and B-chain polypeptides. The modified A chain comprises one or more substitutions relative to wild-type human insulin A-chain selected from a Gln, His or Glu substitution at position A8, a Glu or Ala substitution at position A14, and an Ala, Gln, Gly, or Thr substitution at position A21. The modified B-chain polypeptide comprises one or more modifications relative to wild-type human insulin B-chain selected from a deletion of the amino acid or amino acids at position B1, B1 and B2, or B1-B3, an Ala or Glu substitution at position B2, a Glu or Ala substitution at position B3, an Ala substitution at position B4; and a Glu or Lys substitution at position B29. The composition comprises one or more of iloprost, citrate, EDTA and a polyphosphate compound. The composition may be used to treat diabetes.

Inventors

  • Michael A. Weiss
  • Mentor MULAJ
  • Laurie A. BROADWATER
  • Thomas HATTIER
  • Richard BERENSON

Assignees

  • THERMALIN INC.
  • CASE WESTERN RESERVE UNIVERSITY

Dates

Publication Date
20260512
Application Date
20210302

Claims (13)

  1. 1 . A pharmaceutical composition comprising an effective amount of an insulin analogue comprising a modified A-chain polypeptide and a modified B-chain polypeptide, wherein the insulin analogue consists of the following modifications with respect to wild type human insulin: EA8, EA14, GA21, desB1, AB2, EB3, and EB29, and wherein the composition comprises one or more of iloprost, citrate, EDTA and a polyphosphate compound.
  2. 2 . The pharmaceutical composition of claim 1 , wherein the insulin analogue is monomeric or dimeric when formulated at U-500.
  3. 3 . The pharmaceutical composition of claim 2 , wherein the insulin analogue is formulated with a polyphosphate compound.
  4. 4 . The pharmaceutical composition of claim 3 , wherein the polyphosphate compound is one or more of a pyrophosphate, triphosphate, trimetaphosphate, and tetraphosphate.
  5. 5 . The pharmaceutical composition of claim 1 , wherein the insulin analogue is formulated with iloprost.
  6. 6 . The pharmaceutical composition of claim 5 , wherein the iloprost is present at a concentration of about 1 μg/mL to about 100 μg/mL.
  7. 7 . The pharmaceutical composition of claim 5 , wherein the insulin analogue is formulated with EDTA and citrate.
  8. 8 . The pharmaceutical composition of claim 1 , wherein the insulin analogue is formulated with less than 0.05 moles of zinc per mole of insulin.
  9. 9 . The pharmaceutical composition of claim 1 , wherein the insulin analogue is formulated with one or more of about 10 to about 100 mM Tris, about 0.1 mg/mL to about 10 mg/mL m-cresol, and about 0.1 mg/mL to about 25 mg/mL glycerin.
  10. 10 . The pharmaceutical composition of claim 7 , wherein the insulin analogue further comprises magnesium.
  11. 11 . The pharmaceutical composition of claim 1 , comprising iloprost at a concentration of about 5 μg/mL to about 50 μg/mL.
  12. 12 . A method for treating a subject with diabetes or prediabetes, the method comprising administering to the subject pharmaceutically effective amount of an insulin analogue comprising a modified A-chain polypeptide and a modified B-chain polypeptide, wherein the insulin analogue consists of the following modifications with respect to wild type human insulin: EA8, EA14, GA21, desB1, AB2, EB3, and EB29, and wherein the composition comprises one or more of iloprost, citrate, EDTA and a polyphosphate compound.
  13. 13 . The pharmaceutical composition of claim 1 , comprising iloprost at a concentration of about 10 μg/mL to about 25 μg/mL.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This is a national stage application of pending International Application No. PCT/US2021/020491 filed Mar. 2, 2021 which claims benefit of U.S. Provisional Application No. 62/984,165 filed on Mar. 2, 2020, the contents of which are incorporated by reference herein. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under grant numbers DK040949 and DK074176 awarded by the National Institutes of Health. The government has certain rights in the invention. TECHNICAL FIELD The present invention relates to insulin analogues and compositions thereof with rapid action as well as methods of treating diabetes or methods of managing blood glucose levels in a patient using the insulin analogues or compositions thereof. BACKGROUND Insulin has been used for more than 90 years to treat diabetes. Typically, the treatment involves multiple insulin injections every day. According to conventional regimen, patients are treated with one or two daily insulin injections of long-acting insulin to cover the basal insulin requirement supplemented with injections of a fast-acting insulin formulation (or fast-acting insulin analogue formulation) to cover the insulin requirement related to meals. However, even when properly and timely administered, insulin injections do not mimic the natural time-action profile of insulin. For example, commercially available rapid-acting insulin analogues enter into blood and the site of action too slowly and have too long an overall duration of action. This results in inadequate insulin levels at the initiation of a meal and too much insulin present between (and particularly immediately after) meals. In turn, this lag in insulin action causes hyperglycemia early after starting a meal and hypoglycemia after meals. In healthy individuals, insulin secretion is closely tied to blood glucose level. Increased blood glucose concentration, for example, after meals, is compensated by a rapid increase in insulin release directly into the bloodstream. In the fasting state, insulin levels fall to a basal level. The objective of insulin therapy is to replicate this natural time-action profile of insulin in diabetic patients, such that blood glucose levels can stay within the normal range characteristic of healthy individuals. However, current insulin products and delivery systems do not sufficiently meet this objective due to limitations in the absorption of the insulin or insulin analogue. For example, insulin formulations (or insulin analogue formulations) containing a predominance of protein molecules in the forms of monomers (which is the predominant form of insulin circulating in blood) and dimers have a strong tendency to aggregate and form inactive fibrils. For example, when insulin is solubilized in a buffer without zinc and stored at room temperature (25-30° C.), the insulin will form amyloid fibrils. To avoid this problem, currently available insulin products are typically formulated with zinc, which forms a complex with insulin called a zinc-insulin hexamer. Zinc-insulin hexamers can be stable in solution at room temperature for greater than 30 days, which is long enough to meet regulatory requirements for insulin formulation stability. However, zinc-insulin hexamers are too large to be readily absorbed by capillaries, and so the hexamers must disassemble in the subcutaneous interstitial fluid after injection before the insulin can be absorbed into the circulation. The hexameric formulation required for stabilization of the insulin in the vial prevents these formulations from being absorbed quickly enough to match physiological insulin secretion. Accordingly, rapid acting insulin analogues and compositions thereof are needed for better management of blood glucose levels in diabetic patients. SUMMARY OF THE INVENTION The present invention relates, in part, to insulin analogues or pharmaceutically acceptable compositions thereof that provide for rapid uptake of the analogue into the blood resulting in its rapid onset of action, for example, as compared to existing commercial insulin products and other similar insulin analogues. Further, in various embodiments, the insulin analogues and compositions have advantages in stability (e.g. as quantified by the rate of fibril formation, change in chemical stability after 7 and 28 days, and change in physical stability after 7 and 28 days), and mitogenicity (e.g. as quantified in cell-based proliferation assays). Formulation of the analogues with optimized selection and concentrations of excipients enhances the analogues' pharmacologic and thermodynamic stability advantages. Accordingly, in some embodiments, the present invention provides insulin analogues or pharmaceutically acceptable compositions thereof that exhibit a more rapid onset of insulin action (as compared to commercial insulin analogues or wild-type human insulin) without a decrease in stability (as c