WO2006096079A2 - Composition pharmaceutique comprenant un analogue biosynthetique d'insuline humaine et son utilisation pour traiter le diabete sucre. - Google Patents

Composition pharmaceutique comprenant un analogue biosynthetique d'insuline humaine et son utilisation pour traiter le diabete sucre. Download PDF

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Publication number
WO2006096079A2
WO2006096079A2 PCT/PL2006/000016 PL2006000016W WO2006096079A2 WO 2006096079 A2 WO2006096079 A2 WO 2006096079A2 PL 2006000016 W PL2006000016 W PL 2006000016W WO 2006096079 A2 WO2006096079 A2 WO 2006096079A2
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
solution
composition according
human insulin
insulin
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Application number
PCT/PL2006/000016
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English (en)
Other versions
WO2006096079A3 (fr
Inventor
Piotr Borowicz
Jerzy Mikolajczyk
Monika Bogiel
Henryk Klukowski
Anna Krejer
Original Assignee
Instytut Biotechnologii I Antybiotykow
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.)
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Application filed by Instytut Biotechnologii I Antybiotykow filed Critical Instytut Biotechnologii I Antybiotykow
Publication of WO2006096079A2 publication Critical patent/WO2006096079A2/fr
Publication of WO2006096079A3 publication Critical patent/WO2006096079A3/fr

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Classifications

    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

  • composition comprising a biosynthetic analog of human insulin, and its use in the treatment of diabetes mellitus.
  • An object of the invention is a pharmaceutical composition comprising a biosynthetic analog of human insulin, and its use in the treatment of diabetes mellitus.
  • Insulin and its various derivatives are used in large amounts in the treatment of diabetes mellitus and are often manufactured on large industrial scale. Although there is a number of various modified derivatives of insulin and pharmaceutical formulations exhibiting various activity profiles, a search is being continued to find a drug that would maintain a constant glucose level in human body for a long time.
  • some formulations of typical human insulin include specific additives, e.g. various amounts of protamine, a protein forming with insulin an insoluble complex that deposits in the subcutaneous tissue, from which insulin is gradually released.
  • specific additives e.g. various amounts of protamine, a protein forming with insulin an insoluble complex that deposits in the subcutaneous tissue, from which insulin is gradually released.
  • various derivatives of human insulin used in the therapy of diabetes mellitus that include additional amino acids or an altered sequence of some amino acids. Alterations in the primary insulin structure affect its secondary and tertiary structure, which in turn induces changes in chemical and biological properties, and - as a consequence - results in pharmacokinetic and pharmacodynamic effects. These changes are of various nature. They lead to acceleration or delay and extension of action of the administered modified insulin.
  • An active form of insulin is its monomeric form, which readily penetrates into the blood upon subcutaneous injection.
  • the normal human insulin in the solution is in a form of hexamers, which upon administration dissociate into dimers, and, then, into monomers before penetrating the blood.
  • Insulin derivatives characterized by an accelerated action include lispro-lnsulin (Humalog®), where the sequence proline(28)-lysine(29) in B chain has been reversed. In such a case, formation of insulin dimers in the solution is difficult, because of steric effects.
  • proline in position 28 in B chain was replaced with aspartic acid. The negative charge introduced in this way hinders self-association of insulin monomers.
  • Lys-Arg insulin - of formula 1 we have found that chemical and biological properties similar to that of glargine derivative are exhibited by the human insulin derivative - referred to as Lys-Arg insulin - of formula 1 , in which lysine (B31 Lys) and arginine (B32Arg) residues have been added to C-terminus of B chain.
  • the above-mentioned compound can be prepared by a known method from a hybrid polypeptide of formula 2 - disclosed in Polish Patent No. 180 818 and obtained by expression in a bacteria cell - by digesting it with trypsin and, then, purifying it by known methods, e.g. such as chromatography and crystallization.
  • leader protein a hybrid polypeptide of formula 2 - disclosed in Polish Patent No. 180 818 and obtained by expression in a bacteria cell - by digesting it with trypsin and, then, purifying it by known methods, e.g. such as chromatography and crystallization.
  • the main physicochemical property of the insulin derivative B31Lys-32Arg distinguishing it from human insulin, is its isoelectric point value within the range from about 5 to about 8. This determines good solubility of the compound in solutions at acidic-to-slightly-acidic pH as well as at alkaline pH. Thanks to that property, it was possible to prepare B31 Lys-32Arg composition-solutions at acidic and alkaline pH, then subjected to biological activity testing.
  • the main aspect of the invention is a pharmaceutical composition comprising an effectively acting amount of biosynthetic analog of human insulin of formula 1 or its physiologically acceptable salt, and excipients.
  • the salt of biosynthetic analog of human insulin derivative of formula 1 should be for example metal alkaline or ammonium salt.
  • the composition is designed for administration in the solution or suspension form. It includes an effectively acting amount of the biosynthetic analog of human insulin of formula 1 , referred herein to as LysArg-insulin, or its physiologically acceptable salt, and excipients, such as isotonizing agents, preservatives, stabilizing agents and, optionally, a buffer substance.
  • excipients such as isotonizing agents, preservatives, stabilizing agents and, optionally, a buffer substance.
  • the amount of active substance used in the composition is about 1-1600
  • pH value of the solution of pharmaceutical composition according to the invention is from about
  • compositions of the invention are used in formulations comprising the normal recombinant human insulin.
  • a preferable isotonizing agent in the composition of the invention can be any substance, which makes it possible to prepare a solution isotonic with the human blood plasma.
  • Some typical isotonizing agents used in pharmacy include such agents as sodium chloride, mannitol, glycine and glycerol.
  • a use of glycerol is preferable.
  • Useful preservatives to be used in the compositions of the invention are compounds selected from the group consisting of m-cresol, phenol, methylparaben, propylparaben and their mixtures.
  • a choice of a preservative and/or an isotonizing agent can influence solubility of the insulin derivative. It has been found that the best preservatives for a formulation at pH 7.8 are 4- hydroxybenzoic acid derivatives (parabens).
  • Various additional excipients usually used in insulin preparations may also be components of pharmaceutical composition according to the invention.
  • buffer substance such as for example phosphate buffer, glycine buffer, TRIS, citrate buffer, whereas, the last one may take a function of buffer and/or zink ions complexing agent.
  • the Lys-Arg insulin like the normal recombinant human insulin, is stabilized by addition of zinc ions, introduced to the solution in a form of zinc chloride or oxide.
  • the zinc content can be from about 5 to about 150 mcg/mL
  • compositions according to the invention are nonionic surface-active agents such as for example polyoxyethylene and polyoxypropylene copolymers or various polysorbates.
  • Obtional, additional polysorbate content in composition according to the invention is 0,001 - 0,2 mg/mL.
  • the following content of the composition of the invention is proposed: 10-
  • composition of the invention Another following content of the composition of the invention is proposed: 10-500 IU/mL of the biosynthetic analog of human insulin of formula 1 , or its physiologically acceptable salt, 16 mg/mL of glycerol, 1 mg/mL of methylparaben- propylparaben mixture (7:3), 10-50 mcg/mL of zinc and water for injections up to 1 mL.
  • the composition includes phosphate buffer - pH 7.8-8.0.
  • a method of preparation of the pharmaceutical composition consisting in that (a) the biosynthetic analog of human insulin of formula 1 is dissolved while adjusting solution pH to about 3,5 -8,5 and the suitable amount of water is added to the volume; (b) a preservative, an isotonizing agent, a stabilizing agent and, optionally, a buffer substance are dissolved in an appropriate amount of water; and (c) the solutions (a) and (b) are mixed and, when necessary, the suitable amount of water is added to the volume.
  • a method of preparation of the basic pharmaceutical composition of the invention consists in that the biosynthetic analog of human insulin of formula 1 is dissolved in water with a use of acidifying agent, preferably diluted hydrochloric acid, and, then, pH of the solution is adjusted to about 3,5 - 5 with an alkalizing agent, preferably diluted sodium hydroxide solution, or it is dissolved in water with a use of an alkalizing agent, preferably phosphate buffer with pH 11 at a temperature below the room temperature, and, then, pH of the solution is adjusted to about 7.8 with phosphate buffer pH 5.5.
  • acidifying agent preferably diluted hydrochloric acid
  • pH of the solution is adjusted to about 3,5 - 5 with an alkalizing agent, preferably diluted sodium hydroxide solution, or it is dissolved in water with a use of an alkalizing agent, preferably phosphate buffer with pH 11 at a temperature below the room temperature, and, then, pH of the solution is adjusted to about 7.8 with phosphate buffer pH 5.5.
  • the further aspect of the invention is the medical use of the biosynthetic analog of human insulin derivative of formula 1 or its physiologically acceptable salt, of isoelectric point between 5 and 8, for preparation of a drug for the treatment of patients suffering from diabetes mellitus, and also a use of the pharmaceutical composition of the invention for preparation of the drug for the treatment of patients suffering from diabetes mellitus.
  • An aspect of the invention is also a method of treatment of patients suffering from diabetes mellitus, consisting in that to patients in a need of thereof is administered an effective amount of pharmaceutical composition of the invention.
  • Lys-Arg insulin corresponds to 28.82 I. U. (as in case of a normal human insulin).
  • the maximum activity of the formulation LAI-7.8i occurs after about 2 h, like in the case of the human insulin solution RHI-40 formulation and a decrease in glucose level has more mild nature and lasts much longer, about 1O h.
  • Comparison of activity of the analogue of human insulin LAI-5.0 with that of isophan-insulin (Gensulin N) NHI-40 has proved that LAI - 5.0 lowers a glucose level in blood serum of hyperglycemic rats more rapidly; that activity was observed in 10 minutes upon the administration and reached its maximum in 1 hour; long- term activity of both formulations is maintained for about 24 h.
  • a significant difference in activity of both formulations consists in an unexpected different nature of the biological action - the formulation LAI-5.0 reduces a glucose level immediately upon the administration and exhibits a weak maximum, indicating for permanent release of the active compound from a microdepot.
  • the stability examinations of preparations containing composition according to the invention show, the addition of stabilizer, especially polysorbate takes an advantage for the effect of stability during the storage.
  • the composition according to the invention stored during 6 months period was stable without any signs of changes.
  • Example I 362.3 mg of Lys-Arg insulin including 3.5% Zn was dissolved in 40 mL of 0.01 M hydrochloric acid. Then, to the resulting solution 0.01 M sodium hydroxide solution was added very slowly under stirring to reach pH 5.0. After that, water was added to the solution to the volume of 50 mL (Solution A). Separately, 0.3 g of m-cresol, 1.6 g of anhydrous glycerol and zinc chloride (the amount necessary to reach the final concentration of Zn ions of 30 mcg/mL) were dissolved in 45 mL of water. After that, water was added to the solution to the volume of 50 mL (Solution B). To Solution A, Solution B was added slowly under stirring, and the resulting mixture was filtered through a sterilizing filter. The resulting solution, including 100 IU/mL of Lys-Arg insulin, was distributed under aseptic conditions into vials (10 mL each).
  • Example II 362.3 mg of Lys-Arg insulin including 3.5% Zn was dissolved in 40 mL of 0.01 M hydrochloric acid. Then, to the resulting solution 0.01 M sodium hydroxide solution was added very slowly under stirring to reach pH 4.5. After that, water was added to the solution to the volume of 50 mL (Solution A). Separately, 150 mg of m-cresol, 65 mg phenol, 1.6 g of anhydrous glycerol and zinc chloride (the amount necessary to reach the final concentration of Zn ions of 30 mcg/mL) were dissolved in 45 mL of water. After that, water was added to the solution to the volume of 50 mL (Solution B). To Solution A, Solution B was added slowly under stirring, and the resulting mixture was filtered through a sterilizing filter. The resulting solution, including 100 IU/mL of Lys-Arg insulin, was distributed under aseptic conditions into vials (1O mL each).
  • Example III 362.3 mg of Lys-Arg insulin including 3.5% Zn was dissolved in 40 mL of 0.01 M hydrochloric acid. Then, to the resulting solution 0.01 M sodium hydroxide solution was added very slowly under stirring to reach pH 4.5. After that, water was added to the solution to the volume of 50 mL (Solution A). Separately, 0.3 g of m-cresol, 3.5 g of mannitol and zinc chloride (the amount necessary to reach the final concentration of Zn ions of 30 mcg/mL) were dissolved in 45 mL of water. After that, water was added to the solution to the volume of 50 mL (Solution B)
  • Solution B was added slowly under stirring, and the resulting mixture was filtered through an sterilizing filter.
  • the resulting solution including 100 IU/mL of Lys-Arg insulin, was distributed under aseptic conditions into vials (1O mL each).
  • Example IV 362.3 mg of Lys-Arg insulin including 3.5% Zn was dissolved in 40 mL of 0.01 M hydrochloric acid. Then, to the resulting solution 0.01 M sodium hydroxide solution was added very slowly under stirring to reach pH 4.5. After that, water was added to the solution to the volume of 50 mL (Solution A). Separately, 0.3 g of m-cresol, 1.6 g of anhydrous glycerol, 1 g polysorbate 80 and zinc chloride (the amount necessary to reach the final concentration of Zn ions of 30 mcg/mL) were dissolved in 45 mL of water. After that, water was added to the solution to the volume of 50 mL (Solution B).
  • Solution B was added slowly under stirring, and the resulting mixture was filtered through a sterilizing filter.
  • the resulting solution including 100 IU/mL of Lys-Arg insulin, was distributed under aseptic conditions into vials (10 mL each).
  • Example V 22 mg of zinc oxide was dissolved in 400 mL of 0.01 M hydrochloric acid, than 3,865 g of lizarg ⁇ insuline was added. Then, in the resulting solution 0.2
  • Solution B was added under stirring during 15 minutes, and after pH correction to the value 4,5 ⁇ 0,2, the resulting mixture was filtered through a sterilizing filter.
  • the resulting solution was distributed under aseptic conditions to injection pen cartridges (3,3 mL each).
  • Example Vl 724.6 mg of Lys-Arg insulin including 3.5% Zn was dissolved in 40 mL of 0.01 M hydrochloric acid and, then, 0.01 M sodium hydroxide solution was added very slowly under stirring to reach pH 4.1. Then, water was added to the solution up to the volume of 50 mL (Solution A).
  • Solution B was slowly added under stirring, and the resulting mixture was filtered through a sterilizing filter.
  • the resulting solution including 200 IU/mL of Lys-Arg insulin, was distributed into vials (10 ml_ each) under aseptic conditions.
  • Example VII 1086.9 mg of Lys-Arg insulin including 3.5% Zn was dissolved in 40 mL of 0.01 M hydrochloric acid and, then, 0.01 M sodium hydroxide solution was very slowly added under stirring to reach pH 5.0. Then, water was added up to the volume of 50 mL (Solution A).
  • Solution B was added slowly under stirring, and the resulting mixture was filtered through a sterilizing filter.
  • the resulting solution including 300 IU/mL of Lys-Arg insulin, was distributed under aseptic conditions to injection pen cartridges (3 mL each).
  • Example VIII 80 mg of Lys-Arg insulin including 3.5% Zn was dissolved in 40 mL of cooled (to a temperature below the room temperature) 0.25 M phosphate buffer solution (pH 11), and, then, under stirring pH was rapidly adjusted to 7.8 with 0.25 M phosphate buffer solution (pH 5.5). A precipitate appeared, which dissolved upon stirring within about 30 minutes.
  • Solution B was added slowly under stirring. Then, water was added to reach the volume of 100 mL and the mixture was filtered through a sterilizing filter. The resulting solution including 20 IU/mL Lys-Arg insulin was distributed under aseptic conditions into vials (10 mL each).

Abstract

L'invention concerne une composition pharmaceutique comprenant un dérivé d'insuline humaine de recombinaison, et une quantité efficacement active de ce dérivé représenté par la formule (I) ou des sels physiologiquement acceptables de celui-ci et des excipients. L'invention concerne également un procédé permettant de préparer ladite composition et son utilisation pour traiter le diabète sucré.
PCT/PL2006/000016 2005-03-10 2006-03-09 Composition pharmaceutique comprenant un analogue biosynthetique d'insuline humaine et son utilisation pour traiter le diabete sucre. WO2006096079A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PLP.373543 2005-03-10
PL373543A PL373543A1 (pl) 2005-03-10 2005-03-10 Kompozycja farmaceutyczna zawierająca biosyntetyczny analog insuliny ludzkiej, oraz jej zastosowanie w terapii cukrzycy

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WO2006096079A2 true WO2006096079A2 (fr) 2006-09-14
WO2006096079A3 WO2006096079A3 (fr) 2007-03-22

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010002283A2 (fr) * 2008-07-04 2010-01-07 Instytut Biotechnologii i Antybiotyków Nouveaux analogues d’insuline à une activité prolongée
WO2013176560A1 (fr) 2012-05-23 2013-11-28 Instytut Biotechnologii i Antybiotyków Analogue de l'insuline ou son sel pharmaceutiquement acceptable, composition pharmaceutique possédant un effet thérapeutique prolongé, utilisation de l'analogue d'insuline, procédé de dosage et méthode de traitement du diabète

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0133285B1 (fr) * 1983-07-29 1988-03-02 Hoechst Aktiengesellschaft Suspensions de cristaux de dérivés de l'insuline, procédé pour leur préparation et leur utilisation
EP0376156A2 (fr) * 1988-12-29 1990-07-04 Hoechst Aktiengesellschaft Nouveaux dérivés d'insuline, procédé de leur fabrication, leur utilisation et composés pharmaceutiques les contenant
WO1997031022A1 (fr) * 1996-02-21 1997-08-28 Novo Nordisk A/S Derives de l'insuline et leur utilisation
EP0925792A2 (fr) * 1997-12-23 1999-06-30 Eli Lilly And Company Compositions insolubles pour le contrôle du glucose sanguin

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0133285B1 (fr) * 1983-07-29 1988-03-02 Hoechst Aktiengesellschaft Suspensions de cristaux de dérivés de l'insuline, procédé pour leur préparation et leur utilisation
EP0376156A2 (fr) * 1988-12-29 1990-07-04 Hoechst Aktiengesellschaft Nouveaux dérivés d'insuline, procédé de leur fabrication, leur utilisation et composés pharmaceutiques les contenant
WO1997031022A1 (fr) * 1996-02-21 1997-08-28 Novo Nordisk A/S Derives de l'insuline et leur utilisation
EP0925792A2 (fr) * 1997-12-23 1999-06-30 Eli Lilly And Company Compositions insolubles pour le contrôle du glucose sanguin

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010002283A2 (fr) * 2008-07-04 2010-01-07 Instytut Biotechnologii i Antybiotyków Nouveaux analogues d’insuline à une activité prolongée
WO2010002283A3 (fr) * 2008-07-04 2010-04-29 Instytut Biotechnologii i Antybiotyków Nouveaux analogues d’insuline à une activité prolongée
CN102083855A (zh) * 2008-07-04 2011-06-01 生物技术及抗生素研究所 活性延长的新胰岛素类似物
EP2371853A2 (fr) 2008-07-04 2011-10-05 Instytut Biotechnologii I Antybiotykow Dérivés d'insuline ou ses sels pharmaceutiquement acceptables, composition pharmaceutique, utilisation du dérivé d'insuline et son sel pharmaceutiquement acceptable et procédé de traitement
JP2011526886A (ja) * 2008-07-04 2011-10-20 インスティト ビオテクノロギー イ アンテビオーテコフ 持効型活性を有する新規インスリン類似体
EP2371853A3 (fr) * 2008-07-04 2012-10-03 Instytut Biotechnologii I Antybiotykow Dérivés d'insuline ou ses sels pharmaceutiquement acceptables, composition pharmaceutique, utilisation du dérivé d'insuline et son sel pharmaceutiquement acceptable et procédé de traitement
US8618048B2 (en) 2008-07-04 2013-12-31 Instytut Biotechnologii i Antybiotyków Insulin analogues of prolonged activity
US20140121353A1 (en) * 2008-07-04 2014-05-01 Instytut Biotechnologii I Antybiotykow Insulin analogues of prolonged activity
EA023559B1 (ru) * 2008-07-04 2016-06-30 Институт Биотехнологии И Антибиотиков Аналоги инсулина человека с пролонгированной терапевтической активностью, стабильные в кислой среде
WO2013176560A1 (fr) 2012-05-23 2013-11-28 Instytut Biotechnologii i Antybiotyków Analogue de l'insuline ou son sel pharmaceutiquement acceptable, composition pharmaceutique possédant un effet thérapeutique prolongé, utilisation de l'analogue d'insuline, procédé de dosage et méthode de traitement du diabète

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PL373543A1 (pl) 2006-09-18
WO2006096079A3 (fr) 2007-03-22

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