WO2013100793A1 - Производное инсулина, обладающее сахароснижающей активностью, и способ его получения - Google Patents
Производное инсулина, обладающее сахароснижающей активностью, и способ его получения Download PDFInfo
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- 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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- Prior art keywords
- insulin
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- insulin derivative
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- 238000004519 manufacturing process Methods 0.000 title claims description 14
- 238000000034 method Methods 0.000 title claims description 14
- 230000002058 anti-hyperglycaemic effect Effects 0.000 title 1
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical class N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims abstract description 156
- 102000004877 Insulin Human genes 0.000 claims abstract description 63
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- 102000004169 proteins and genes Human genes 0.000 claims description 4
- 108090000623 proteins and genes Proteins 0.000 claims description 4
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims description 3
- 108090000317 Chymotrypsin Proteins 0.000 claims description 3
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- 150000001413 amino acids Chemical class 0.000 claims 10
- 125000003277 amino group Chemical group 0.000 claims 10
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- 101000993800 Sus scrofa Insulin Proteins 0.000 claims 1
- 229940119528 pork insulin Drugs 0.000 claims 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 abstract description 28
- 239000008103 glucose Substances 0.000 abstract description 28
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- 239000003814 drug Substances 0.000 abstract description 7
- 229940088623 biologically active substance Drugs 0.000 abstract description 3
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- IZZIWIAOVZOBLF-UHFFFAOYSA-N 5-methoxysalicylic acid Chemical compound COC1=CC=C(O)C(C(O)=O)=C1 IZZIWIAOVZOBLF-UHFFFAOYSA-N 0.000 description 2
- 208000008960 Diabetic foot Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- HIMXGTXNXJYFGB-UHFFFAOYSA-N alloxan Chemical compound O=C1NC(=O)C(=O)C(=O)N1 HIMXGTXNXJYFGB-UHFFFAOYSA-N 0.000 description 2
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 229920002818 (Hydroxyethyl)methacrylate Polymers 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- AAUQLHHARJUJEH-UHFFFAOYSA-N 2-hydroxy-5-methoxybenzoic acid Natural products COC1=CC=CC(O)=C1C(O)=O AAUQLHHARJUJEH-UHFFFAOYSA-N 0.000 description 1
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- 102000003746 Insulin Receptor Human genes 0.000 description 1
- 108010001127 Insulin Receptor Proteins 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 102000052651 Pancreatic hormone Human genes 0.000 description 1
- 101800001268 Pancreatic hormone Proteins 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
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- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- AWKDEEXFAVIGAF-UHFFFAOYSA-N bis(4-ethenylphenyl)diazene Chemical compound C1=CC(C=C)=CC=C1N=NC1=CC=C(C=C)C=C1 AWKDEEXFAVIGAF-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
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- 238000013270 controlled release Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
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- 235000012631 food intake Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
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- 239000007903 gelatin capsule Substances 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
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- 239000004025 pancreas hormone Substances 0.000 description 1
- 229940032957 pancreatic hormone Drugs 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
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- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
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- 230000002035 prolonged effect Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 230000001012 protector Effects 0.000 description 1
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- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
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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)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Endocrinology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/RU2011/001061 WO2013100793A1 (ru) | 2011-12-28 | 2011-12-28 | Производное инсулина, обладающее сахароснижающей активностью, и способ его получения |
| IN1484MUN2014 IN2014MN01484A (cs) | 2011-12-28 | 2011-12-28 | |
| 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 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/RU2011/001061 WO2013100793A1 (ru) | 2011-12-28 | 2011-12-28 | Производное инсулина, обладающее сахароснижающей активностью, и способ его получения |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2013100793A1 true WO2013100793A1 (ru) | 2013-07-04 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/RU2011/001061 WO2013100793A1 (ru) | 2011-12-28 | 2011-12-28 | Производное инсулина, обладающее сахароснижающей активностью, и способ его получения |
Country Status (3)
| Country | Link |
|---|---|
| EA (1) | EA023447B1 (cs) |
| IN (1) | IN2014MN01484A (cs) |
| WO (1) | WO2013100793A1 (cs) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019098869A1 (ru) * | 2017-11-15 | 2019-05-23 | Борис Славинович ФАРБЕР | Фармацевтическая композиция для стимуляции деления стволовых клеток и подавления вирулентности бактерий |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1226104B1 (en) * | 1999-11-05 | 2009-04-08 | Emisphere Technologies, Inc. | Phenoxy carboxylic acid compounds and compositions for delivering active agents |
| US20110293714A1 (en) * | 2008-11-28 | 2011-12-01 | Novo Nordisk A/S | Pharmaceutical compositions suitable for oral administration of derivatized insulin peptides |
-
2011
- 2011-12-28 IN IN1484MUN2014 patent/IN2014MN01484A/en unknown
- 2011-12-28 WO PCT/RU2011/001061 patent/WO2013100793A1/ru active Application Filing
- 2011-12-28 EA EA201300207A patent/EA023447B1/ru not_active IP Right Cessation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1226104B1 (en) * | 1999-11-05 | 2009-04-08 | Emisphere Technologies, Inc. | Phenoxy carboxylic acid compounds and compositions for delivering active agents |
| 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 (cs) | 2015-05-01 |
| EA023447B1 (ru) | 2016-06-30 |
| EA201300207A1 (ru) | 2014-01-30 |
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