WO2004096266A1 - Stabilite physique amelioree de preparations d'insuline - Google Patents

Stabilite physique amelioree de preparations d'insuline Download PDF

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Publication number
WO2004096266A1
WO2004096266A1 PCT/DK2004/000300 DK2004000300W WO2004096266A1 WO 2004096266 A1 WO2004096266 A1 WO 2004096266A1 DK 2004000300 W DK2004000300 W DK 2004000300W WO 2004096266 A1 WO2004096266 A1 WO 2004096266A1
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WO
WIPO (PCT)
Prior art keywords
insulin
human insulin
lys
des
human
Prior art date
Application number
PCT/DK2004/000300
Other languages
English (en)
Other versions
WO2004096266A8 (fr
Inventor
Dorthe Bruun
Christian Poulsen
Original Assignee
Novo Nordisk A/S
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Publication of WO2004096266A1 publication Critical patent/WO2004096266A1/fr
Publication of WO2004096266A8 publication Critical patent/WO2004096266A8/fr

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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
    • 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

Definitions

  • the present invention relates to stabilised pharmaceutical compositions comprising insulin or an analogue or derivative thereof.
  • the invention also relates to formulations comprising such insulin compositions and to a method for improving the physical stability of insulin compositions.
  • the stability of formulations of therapeutic agents is of particular importance to assure proper biological potency of the drug during storage and use.
  • the stability of the formulation can be divided into at least two categories - chemical stability (chemical modifications) and physical stability (formation of insoluble insulin fibrils). Again using insulin as an example, various chemical modifications can occur including deamidation and higher molecular weight transformation products.
  • chemical stability of insulin is given by Jens Brange in "Stability of Insulin", Kluwer Academic Publishers, 1994.
  • insulin products are subject to the formation of insoluble aggregates (fibrils) as a result of exposure to high mechanical stress and/or high temperatures e.g. when carried in the pocket of a patient.
  • the insulin drug substance is dissolved by addition of acid. Addition of acid reduce pH (pH ⁇ 2) which is sufficiently far from the iso-electric point of the drug substance where the solubility of the drug substance is rather low. Later in the formulation process, pH is raised by mixing with an alkaline sub-solution containing base.
  • the invention provides a process for improving the physical stability of an insulin formulation.
  • the invention provides an insulin preparation comprising human insulin or an analogue or derivative thereof with improved physical stability.
  • the invention also provides the use of such a formulation for treating diabetes.
  • insulin as used herein is intended to refer to not only human insulin as such, but also insulin analogues and derivatives.
  • analogue of human insulin refers to a polypeptide having the amino acid sequence of human insulin in which one or more amino acids have been deleted and/or replaced by other amino acids, including amino acids not encoded by the genetic code, or comprising additional amino acids, i.e. more than the 51 amino acids of human insulin.
  • derivative of human insulin refers to human insulin or an analogue thereof in which at least one organic substituent is bound to one or more of the amino acids.
  • acid refers to an aqueous dissolvable substance capable of decreasing pH. Nonlimiting examples of such substances could be hydrochloric acid, acetic acid, sulphuric acid and phosphoric acid, preferably hydrochloric acid.
  • base refers to an aqueous dissolvable substance capable of increasing pH.
  • Nonlimiting examples of such substances could be sodium hydroxide, potassium hydroxide, lithium hydroxide, preferably sodium hydroxide.
  • chemical stability refers to the tendency of an insulin composition to form soluble degradation products during storage under static conditions.
  • physical stability refers to the tendency of an insulin composition to form insoluble aggregates as a result of a physical action such as shaking of an insulin composition.
  • Insulin compositions according to the invention have been shown to have a high physical stability, which is reflected in a reduction in the formation of insoluble aggregates after storage and/or shaking.
  • the present invention is particularly advantageous in connection with compositions comprising analogues and/or derivatives of human insulin.
  • Dissolution of the insulin drug substance is performed by addition of base for instance sodium hydroxide (to pH > 8), which is sufficiently far from the iso-electric point of the drug substance to assure full solubility. Later on in the process, pH is reduced by mixing with an acid solution such as hydrochloric acid. Alternatively, pH of the alkaline insulin solution (pH > 8) is reduced by addition of an acid such as hydrochloric acid (to pH - 2) and subsequently raised by addition of an alkaline solution containing a base such as sodium hydroxide. Since insulin preparations comprising fast-acting analogues of human insulin generally show a rather low physical stability, the present invention is particularly advantageous in connection with preparations comprising such analogues.
  • base for instance sodium hydroxide
  • the insulin preparations according to the present invention comprises one or more fast-acting analogues of human insulin, in particular analogues wherein position B28 is Asp, Lys, Leu, Val or Ala and position B29 is Lys or Pro; or B3 is Lys and B29 is Glu; or des(B28-B30), des(B27) or des(B30) human insulin.
  • the insulin preparation according to the invention comprises an insulin derivative having a protracted profile of action such as insulins having one or more lipophilic substituents or where certain amino acids has been replaced or added (for instance Gly in A21 and Arg in B31 and B32).
  • the preferred lipophilic insulins are acylated insulins, including those described in WO 95/07931 (Novo Nordisk A/S), e.g. human insulin derivatives wherein the ⁇ -amino group of Lys B29 contain an acyl substituent which comprises at least 6 carbon atoms.
  • Preferred insulin derivatives are the following:
  • B29-N ⁇ -myristoyl-des(B30)-human insulin B29-N ⁇ -myristoyl-human insulin, B29-N 8 - palmitoyl human insulin, B28-N ⁇ - Lys B28 Pro B29 human insulin, B28-N ⁇ -palmitoyl Lys B28 Pro B29 human insulin, B30-N ⁇ -myristoyl-Thr B29 Lys B30 human insulin, B30-N ⁇ - palmitoyl-Thr B29 Lys B30 -human insulin, B29-N ⁇ -(N-palmitoyl- ⁇ -glutamyl)-des(B30)-human insulin, B29-N ⁇ -(N-litocholyl- ⁇ -glytamyl)-des(B30)-human insulin, B29-N ⁇ -( ⁇ - carboxyheptadecanoyl)-des(B30)-human insulin, N ⁇ B29 -tetrade
  • the insulin compositions used according to the present invention may be administered parenterally to patients in need of such a treatment.
  • Parenteral administration may be performed by subcutaneous, intramuscular or intravenous injection by means of a syringe, optionally a pen-like syringe.
  • parenteral administration can be performed by means of an infusion pump.
  • a further option is a composition which may be a powder or a liquid for the administration of the human insulin derivative in the form of a nasal or pulmonary spray.
  • the insulin compositions may be prepared by conventional techniques, e.g. as described in
  • injectable insulin compositions can be prepared using the conventional techniques of the pharmaceutical industry which involves dissolving and mixing the ingredients as appropriate to give the desired end product.
  • the desired insulin or insulin derivative is dissolved in an amount of water which is somewhat less than the final volume of the composition to be prepared.
  • Isotonic agents, preservative agents, buffers, optionally a protracting agent and if needed a zinc salt or other metal salt is added as required and the pH value of the solution is adjusted - if necessary - using an acid, e.g. hydrochloric acid, or a base, e.g. aqueous sodium hydroxide as needed.
  • the volume of the solution is adjusted with water to give the desired concentration of the ingredients.
  • isotonic agents are sodium chloride, mannitol, sorbitol, glycerol, propylene glycol and dimethyl sulfone.
  • preservatives examples include phenol, m-cresol, methyl p-hydroxybenzoate and benzyl alcohol.
  • protracting agents examples include protamine and zinc.
  • Suitable buffers are sodium acetate and sodium phosphate.
  • a composition for nasal administration of an insulin may, for example, be prepared as described in European Patent No. 272097 (to Novo Nordisk A/S).
  • Crystals for pulmonal administration of an insulin may, for example, be prepared as described in US patent No. 6,310,038 (to Novo Nordisk A/S).
  • Aqueous solutions for pulmonal administration of an insulin may, for example, be prepared as described in WO 00/23098, WO 00/23099 or WO 00/29013 (all to Novo Nordisk A/S).
  • the optimal dose level for any patient will depend on a variety of factors including the efficacy of the specific insulin derivative and other anti-diabetic agent employed, the age, the body weight, the physical activity, and the diet of the patient, on a possible combination with other drugs, and on the severity of the case of diabetes. It is recommended that the daily dosage of the medicaments used in the regimen according to this invention be determined for each individual patient by those skilled in the art.
  • Two batches of insulin formulation were manufactured based on human insulin and with glycerol, phenol, m-cresol, phosphate, protamine and zinc as excipients and pH of the final product was adjusted to 7.3.
  • One of the batches (#1 ) was manufactured by dissolving the insulin drug substance at alkaline conditions (pH 11.3 at 5°C for 15 minutes by addition of 0.2 N NaOH) where after pH was adjusted to pH 3 and the formulation process was continued in the normal way.
  • a second batch (#2) was manufactured according to the same procedure; however, the insulin drug substance was dissolved at acidic conditions as prescribed in the current process. The two batches were produced in exactly the same way (except for the dissolution process of the drug substance - alkaline vs.
  • the batches were filled in 2 ml vials (5 vials per batch) and subjected to physical stability testing by application of high mechanical stress and temperature (shaking in water bath at 37°C) to promote the formation of insoluble insulin aggregates (fibrils) that were detected by turbidity measurements on a daily basis.
  • the time (referred to as lag-time) until a steep increase in turbidity was observed (fibrillation is associated with an increase in turbidity) was used as a measure of the relative physical stability of the four batches.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Diabetes (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une méthode d'amélioration de la stabilité de préparations d'insuline.
PCT/DK2004/000300 2003-05-02 2004-05-03 Stabilite physique amelioree de preparations d'insuline WO2004096266A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US46780303P 2003-05-02 2003-05-02
DKPA200300662 2003-05-02
US60/467,803 2003-05-02
DKPA200300662 2003-05-02

Publications (2)

Publication Number Publication Date
WO2004096266A1 true WO2004096266A1 (fr) 2004-11-11
WO2004096266A8 WO2004096266A8 (fr) 2005-03-17

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PCT/DK2004/000300 WO2004096266A1 (fr) 2003-05-02 2004-05-03 Stabilite physique amelioree de preparations d'insuline

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007135118A1 (fr) * 2006-05-24 2007-11-29 Novo Nordisk A/S Formules solubles stables contenant de l'insuline
WO2011003820A1 (fr) 2009-07-06 2011-01-13 Sanofi-Aventis Deutschland Gmbh Préparations d'insuline stables à la chaleur et aux agitations

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4476118A (en) * 1982-02-05 1984-10-09 Novo Industri A/S Stabilized insulin preparations
WO1995007931A1 (fr) * 1993-09-17 1995-03-23 Novo Nordisk A/S Insuline acylee
US5506203A (en) * 1993-06-24 1996-04-09 Ab Astra Systemic administration of a therapeutic preparation
US20030004096A1 (en) * 2001-03-23 2003-01-02 Peter Boderke Zinc-free and low-zinc insulin preparations having improved stability

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4476118A (en) * 1982-02-05 1984-10-09 Novo Industri A/S Stabilized insulin preparations
US5506203A (en) * 1993-06-24 1996-04-09 Ab Astra Systemic administration of a therapeutic preparation
US5506203C1 (en) * 1993-06-24 2001-02-06 Astra Ab Systemic administration of a therapeutic preparation
WO1995007931A1 (fr) * 1993-09-17 1995-03-23 Novo Nordisk A/S Insuline acylee
US20030004096A1 (en) * 2001-03-23 2003-01-02 Peter Boderke Zinc-free and low-zinc insulin preparations having improved stability

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007135118A1 (fr) * 2006-05-24 2007-11-29 Novo Nordisk A/S Formules solubles stables contenant de l'insuline
WO2011003820A1 (fr) 2009-07-06 2011-01-13 Sanofi-Aventis Deutschland Gmbh Préparations d'insuline stables à la chaleur et aux agitations

Also Published As

Publication number Publication date
WO2004096266A8 (fr) 2005-03-17

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