WO2013100793A1 - Dérivé de l'insuline possedant une activite de réduction du taux de sucre et procede de sa production - Google Patents

Dérivé de l'insuline possedant une activite de réduction du taux de sucre et procede de sa production Download PDF

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Publication number
WO2013100793A1
WO2013100793A1 PCT/RU2011/001061 RU2011001061W WO2013100793A1 WO 2013100793 A1 WO2013100793 A1 WO 2013100793A1 RU 2011001061 W RU2011001061 W RU 2011001061W WO 2013100793 A1 WO2013100793 A1 WO 2013100793A1
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WO
WIPO (PCT)
Prior art keywords
insulin
derivative
derivative according
producing
insulin derivative
Prior art date
Application number
PCT/RU2011/001061
Other languages
English (en)
Russian (ru)
Inventor
Артур Викторович МАРТЫНОВ
Борис Славинович ФАРБЕР
Софья Борисовна ФАРБЕР
Original Assignee
Martynov Artur Viktorovich
Farber Boris Slavinovich
Farber Sof Ya Borisovna
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 Martynov Artur Viktorovich, Farber Boris Slavinovich, Farber Sof Ya Borisovna filed Critical Martynov Artur Viktorovich
Priority to EA201300207A priority Critical patent/EA023447B1/ru
Priority to IN1484MUN2014 priority patent/IN2014MN01484A/en
Priority to PCT/RU2011/001061 priority patent/WO2013100793A1/fr
Publication of WO2013100793A1 publication Critical patent/WO2013100793A1/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

  • the invention relates to pharmacy and medicine, namely, to orally, rectally, aerosol and parenterally administered compositions of a biologically active substance, in particular insulin oligopeptides for treating diabetes mellitus, its complications and for enhancing tissue regeneration in burns, diabetic foot syndrome.
  • a biologically active substance in particular insulin oligopeptides for treating diabetes mellitus, its complications and for enhancing tissue regeneration in burns, diabetic foot syndrome.
  • Diabetes mellitus is one of the most common serious diseases, which is based on an absolute or relative deficiency of the pancreatic hormone - insulin.
  • Insulin therapy insulin administration from the outside
  • the most common way to administer insulin is by subcutaneous injection. This method is inconvenient, it injures the psyche of patients (especially children), causes physical and moral suffering, but most importantly, it can exacerbate the pathology of the disease by itself. The latter is due to the fact that during subcutaneous injection of insulin, the normal concentration of glucose in the blood is achieved due to systematic hyperinsulinemia of peripheral tissues, while the liver (the main site of activity of the endogenous insulin produced in the body) lacks insulin.
  • the main obstacles to the creation of oral forms of insulin are the low resistance of the hormone to the action of proteolytic enzymes of the gastrointestinal tract, as well as the low permeability of insulin through the epithelial the intestinal wall tissue into the bloodstream, due to both low lipophilicity and the size of the hormone macromolecules.
  • Known solid insulin-containing drug consisting of a core containing insulin and excipients, and a shell of a biodegradable film-forming polymer material [1].
  • the preparation is prepared by introducing 1-40 mg of crystalline insulin and 200 mg of a stoichiometric mixture of 5-methoxysalicylic acid and sodium bicarbonate into a hard gelatin capsule or tablet. Then, the capsule (tablet) is coated with a copolymer of hydroxyethyl methacrylate and styrene crosslinked with divinylazobenzene.
  • the membrane is resistant to the action of the environment of the stomach and small intestine, but disintegrates in the large intestine under the influence of microorganisms present there.
  • the disadvantage of this tool is low efficiency and indefinite time to achieve maximum effect.
  • Oral administration to rats of said vehicle containing 1 unit. insulin leads to a decrease in blood glucose concentration by 20% 9 hours after administration.
  • subcutaneous administration of a solution of insulin in a dose of 0.1 or 1.0 units. leads to a decrease in blood glucose by 39 and 63%, respectively.
  • the maximum hypoglycemic effect for individual animals is achieved in the period from 1 to 9 hours, and in some animals there is no effect of a decrease in glucose concentration even after 10 hours after drug administration.
  • a solid insulin-containing drug is known in the form of nanocapsules, which are microparticles with a diameter of about 300 nm, consisting of bio-degradable (due to intestinal microflora) polyalkylcyanoacrylate with insulin immobilized inside it [2]. s
  • An object of the invention is to provide a supramolecular ensemble of excessively negatively charged oligopeptides of an insulin hydrolyzate having sugar-lowering activity when administered orally and dosage forms based on it that can reduce blood glucose to normal and maintain this level for at least a day.
  • the pharmaceutical composition as the main active substances, which contains a quasi-fluid self-acting the system to be organized is the supramolecular ensemble of peptides — products of enzymatic hydrolysis of insulin with trypsin, papain, chymotrypsin, which are then acylated with dicarboxylic acid anhydrides — succinic, acetic, maleic, and additionally contain pharmaceutically acceptable excipients.
  • a composition may be incorporated into an ointment, aerosol and used orally.
  • the content of acylated peptides can range from 0.0001 to 3.0 mass /%.
  • oligopeptides are resistant to enzymes, protected from further hydrolysis by acylation, and the small size of the peptides allows them to be freely absorbed.
  • a system of peptides that were previously intact (insulin molecule), but with altered charges is capable of self-organization on insulin receptors into an insulin-like supramolecular structure.
  • the negative charge of oligopeptides and their resistance to enzymatic hydrolysis contribute to the 24-hour (or more) prolongation of action and the maintenance of the level of glucose in the blood at the physiological level.
  • Example 1 Synthesis of a quasi-fluid system based on succinylated insulin peptides.
  • crystalline insulin 100 mg was dissolved in 1 ml of 0.1 M hydrochloric acid and then enzymatically hydrolyzed by incubation with proteinase K at room temperature for 1 hour. Then, while stirring the solution, succinic anhydride (7.5 mg), crushed to a powder, is slowly added and 60 minutes are incubated with stirring. The resulting peptides were purified from salts on a Sephadex G-25 chromatographic column, where TRIS-hydrochloride was used as an eluent. Protein yield was controlled by the absorption of the eluate in the ultraviolet region at 280 nm. Desalted peptides were poured into ampoules and lyophilized. The resulting peptides were further used to obtain various dosage forms and study their activity.
  • Example 2 Obtaining oral forms of succinylated insulin peptides.
  • Example 3 The study of the sugar-lowering effect of the supramolecular ensemble of insulin peptides (SMAI) when administered orally on a model of alloscan diabetes in rats
  • Example 4 The study of the sugar-lowering effect of the supramolecular ensemble of insulin peptides (SMAI) when administered orally on the model of alloscan diabetes in rats on the background of glucose load
  • the experiments were performed on sexually mature Wistar male rats.
  • the invention relates to pharmacy and medicine, namely, to orally, rectally, aerosol and parenterally administered formulations of a biologically active substance, in particular insulin oligopeptides for treating diabetes mellitus, its complications and for enhancing tissue regeneration in case of burns, diabetic foot syndrome.
  • a biologically active substance in particular insulin oligopeptides for treating diabetes mellitus, its complications and for enhancing tissue regeneration in case of burns, diabetic foot syndrome.
  • This system allows you to keep blood glucose levels at the physiological level for more than 24 hours with oral use, and the components of the system are resistant to enzymes and are small, easily absorbed from the intestines, through the skin and mucous with any method of application system.

Landscapes

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

Abstract

L'invention concerne la pharmacie et la médecine et notamment des composés administrés oralement d'une substance biologique active, y compris des ensembles supramoléculaires d'oligopeptides acylés de l'insuline pour traiter le diabète sucré et ses complications. Ce système permet de maintenir pendant 24 heures lors de l'utilisation pérorale unique le taux de glucose dans le sang à un niveau physiologique (supereffet), et les composés du système acquièrent une résistance à l'action des ferments et possèdent de faibles dimensions, ce qui permet leur absorption aisée de l'intestin. Essence de l'invention: on utilise en tant qu'agents principaux une composition supramoléculaire qui représente un ensemble d'oligopeptides acylés constituant des produits d'hydrolyse fermentative de l'insuline. La composition peut être produite par l'industrie dans des quantités suffisantes compte tenu de la disponibilité de tous ses composants.
PCT/RU2011/001061 2011-12-28 2011-12-28 Dérivé de l'insuline possedant une activite de réduction du taux de sucre et procede de sa production WO2013100793A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EA201300207A EA023447B1 (ru) 2011-12-28 2011-12-28 Производное инсулина, обладающее сахароснижающей активностью при пероральном применении, способ его получения и лекарственные формы на его основе
IN1484MUN2014 IN2014MN01484A (fr) 2011-12-28 2011-12-28
PCT/RU2011/001061 WO2013100793A1 (fr) 2011-12-28 2011-12-28 Dérivé de l'insuline possedant une activite de réduction du taux de sucre et procede de sa production

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/RU2011/001061 WO2013100793A1 (fr) 2011-12-28 2011-12-28 Dérivé de l'insuline possedant une activite de réduction du taux de sucre et procede de sa production

Publications (1)

Publication Number Publication Date
WO2013100793A1 true WO2013100793A1 (fr) 2013-07-04

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PCT/RU2011/001061 WO2013100793A1 (fr) 2011-12-28 2011-12-28 Dérivé de l'insuline possedant une activite de réduction du taux de sucre et procede de sa production

Country Status (3)

Country Link
EA (1) EA023447B1 (fr)
IN (1) IN2014MN01484A (fr)
WO (1) WO2013100793A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EA202090763A1 (ru) 2017-11-15 2020-08-03 Борис Славинович ФАРБЕР Фармацевтическая композиция для стимуляции деления стволовых клеток и подавления вирулентности бактерий

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1226104B1 (fr) * 1999-11-05 2009-04-08 Emisphere Technologies, Inc. Composes d'acide carboxylique phenoxy et compositions utilisees afin de diffuser des agents actifs
US20110293714A1 (en) * 2008-11-28 2011-12-01 Novo Nordisk A/S Pharmaceutical compositions suitable for oral administration of derivatized insulin peptides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1226104B1 (fr) * 1999-11-05 2009-04-08 Emisphere Technologies, Inc. Composes d'acide carboxylique phenoxy et compositions utilisees afin de diffuser des agents actifs
US20110293714A1 (en) * 2008-11-28 2011-12-01 Novo Nordisk A/S Pharmaceutical compositions suitable for oral administration of derivatized insulin peptides

Also Published As

Publication number Publication date
IN2014MN01484A (fr) 2015-05-01
EA023447B1 (ru) 2016-06-30
EA201300207A1 (ru) 2014-01-30

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