CA2295140A1 - Stable insulin formulations - Google Patents

Stable insulin formulations Download PDF

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Publication number
CA2295140A1
CA2295140A1 CA002295140A CA2295140A CA2295140A1 CA 2295140 A1 CA2295140 A1 CA 2295140A1 CA 002295140 A CA002295140 A CA 002295140A CA 2295140 A CA2295140 A CA 2295140A CA 2295140 A1 CA2295140 A1 CA 2295140A1
Authority
CA
Canada
Prior art keywords
formulation
insulin analog
monomeric insulin
tris
buffer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CA002295140A
Other languages
French (fr)
Other versions
CA2295140C (en
Inventor
Michael Rosario Defelippis
Michael Allen Dobbins
Bruce Hill Frank
Shun Li
Dawn Marie Rebhun
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Eli Lilly and Co
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Individual
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Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of CA2295140A1 publication Critical patent/CA2295140A1/en
Application granted granted Critical
Publication of CA2295140C publication Critical patent/CA2295140C/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Abstract

The present invention provides a monomeric insulin analog formulation stabilized against aggregation in which the buffering agent is either TRIS or arginine. The stable formulations of the present invention are useful for treating diabetes, and are particularly advantageous in treatment regimes requiring lengthy chemical and physical stability, such as, in continuous infusion systems.

Claims (28)

1. A solution formulation comprising:
a physiologically tolerated buffer selected from the group consisting of TRIS and arginine; a monomeric insulin analog;
zinc; and a phenolic preservative.
2. The formulation of Claim 1, wherein the monomeric insulin analog is LysB28ProB29-human insulin and the buffer is TRIS.
3. The formulation of Claim 1, wherein the monomeric insulin analog is AspB28-human insulin and the buffer is TRIS.
4. The formulation of Claim 2 further comprising an isotonicity agent and wherein the pH of the formulation is between pH 7.0 and pH 8.0 when measured at a temperature of 22°C.
5. The formulation of Claim 4, wherein the concentration of LysB28ProB29_human insulin is between about 100 and about 400 units per milliliter.
6. The formulation of Claim 5, wherein TRIS is present at a concentration of about 2 mg/mL; glycerol is the isotonicity agent and is present at a concentration of about 16 mg/mL; and m-cresol is present at a concentration of about 1.76 mg/mL and phenol is present at a concentration of about 0.715 mg/mL.
7. A stable, soluble formulation of a monomeric insulin analog for use in a continuous infusion system, consisting essentially of: an isotonicity agent; a buffer selected from the group consisting of TRIS and arginine; a monomeric insulin analog; zinc; and a phenolic preservative.
8. The insulin analog formulation of Claim 1 which further comprises protamine.
9. The formulation of Claim 8, wherein the insulin analog is LysB28ProB29,
10. The formulation of Claim 8, wherein the insulin analog is AspB28.
11. The formulation of any one of Claims 8 through 10 wherein the buffer is arginine.
12. The formulation of any one of Claims 1 through 7 for use in a continuous infusion system.
13. A method for treating diabetes comprising administering an effective dose of the formulation of any one of Claims 1 through 11 to a patient in need thereof.
14. A method for treating diabetes comprising administering an effective dose of the formulation of any, one of Claims 1 through 7, wherein the formulation is administered using a continuous infusion system.
15. A method for treating hyperglycemia comprising administering an effective dose of the formulation of any one of Claims 1 through 11 to a patient in need thereof.
16. A method for treating hyperglycemia comprising administering an effective dose of the formulation of any one of Claims 1 through 7, wherein the formulation is administered using a continuous infusion system.
17. The formulation of monomeric insulin analog as described in any one of Claims 1 through 11 for use as a medicament for the treatment of diabetes.
18. The formulation of monomeric insulin analog as described in any one of Claims 1 through 11 for use as a medicament for the treatment of hyperglycemia.
19. A formulation of monomeric insulin analog as hereinbefore described with reference to any one of the examples.
20. A process for preparing the monomeric insulin analog formulation of Claim 1 comprising the steps of mixing a physiologically-tolerated buffer selected from the group consisting of TRIS and arginine with a monomeric insulin analog; zinc; and a phenolic preservative.
21. The process of Claim 20, wherein the monomeric insulin analog is LysB28ProB29-human insulin and the buffer is TRIS.
22. The process of Claim 20, wherein the monomeric insulin analog is AspB28-human insulin and the buffer is TRIS.
23. A process for preparing a monomeric insulin analog formulation comprising the steps of mixing a buffer selected from the group consisting of TRIS and arginine with a monomeric insulin analog; zinc; protamine; and a phenolic preservative.
24. The process of Claim 23, wherein the monomeric insulin analog is LysB28ProB29.
25. The process of Claim 23, wherein the monomeric insulin analog is AspB28.
26. The process of any one of Claims 23 through 25, wherein the buffer is arginine.
27. The formulation of any one of Claims 1 through 7 when made by the process of Claim 20.
28. The formulation of any one of Claims 8 through 11 when made by the process of Claim 23.
CA2295140A 1997-06-13 1998-06-11 Stable insulin formulations Expired - Lifetime CA2295140C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US5308997P 1997-06-13 1997-06-13
US60/053,089 1997-06-13
PCT/US1998/012218 WO1998056406A1 (en) 1997-06-13 1998-06-11 Stable insulin formulations

Publications (2)

Publication Number Publication Date
CA2295140A1 true CA2295140A1 (en) 1998-12-17
CA2295140C CA2295140C (en) 2010-09-14

Family

ID=21981869

Family Applications (1)

Application Number Title Priority Date Filing Date
CA2295140A Expired - Lifetime CA2295140C (en) 1997-06-13 1998-06-11 Stable insulin formulations

Country Status (31)

Country Link
US (3) US6034054A (en)
EP (1) EP0884053B1 (en)
JP (1) JP2002504908A (en)
KR (1) KR100597500B1 (en)
CN (1) CN1293916C (en)
AR (1) AR012894A1 (en)
AT (2) ATE226088T1 (en)
AU (1) AU734781B2 (en)
BR (1) BR9810116B1 (en)
CA (1) CA2295140C (en)
CO (1) CO4750643A1 (en)
CZ (1) CZ299637B6 (en)
DE (2) DE69834956T2 (en)
DK (1) DK0884053T3 (en)
EA (1) EA002880B1 (en)
ES (2) ES2185113T3 (en)
HK (1) HK1030747A1 (en)
HU (1) HUP0002877A3 (en)
ID (1) ID24310A (en)
IL (1) IL133348A0 (en)
NO (1) NO996131L (en)
NZ (1) NZ501382A (en)
PE (1) PE79099A1 (en)
PL (1) PL194244B1 (en)
PT (2) PT1283051E (en)
SV (1) SV1998000065A (en)
TR (1) TR199903036T2 (en)
TW (1) TW577753B (en)
UA (1) UA61109C2 (en)
WO (1) WO1998056406A1 (en)
ZA (1) ZA984697B (en)

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