WO2021258851A1 - Composition pharmaceutique pour le traitement du diabète et son procédé de préparation - Google Patents

Composition pharmaceutique pour le traitement du diabète et son procédé de préparation Download PDF

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Publication number
WO2021258851A1
WO2021258851A1 PCT/CN2021/090963 CN2021090963W WO2021258851A1 WO 2021258851 A1 WO2021258851 A1 WO 2021258851A1 CN 2021090963 W CN2021090963 W CN 2021090963W WO 2021258851 A1 WO2021258851 A1 WO 2021258851A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
hydrochloride
treating diabetes
tyaggliflozin
diabetes according
Prior art date
Application number
PCT/CN2021/090963
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English (en)
Chinese (zh)
Inventor
高悦译
张倩
卢江
刘恩桂
Original Assignee
广州市力鑫药业有限公司
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Application filed by 广州市力鑫药业有限公司 filed Critical 广州市力鑫药业有限公司
Publication of WO2021258851A1 publication Critical patent/WO2021258851A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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

  • This application relates to the technical field of hypoglycemic preparations, in particular to a pharmaceutical composition for treating diabetes and a preparation method thereof.
  • Diabetes is divided into many types, but nearly 90% of the affected population are type 2 diabetes patients. According to relevant reports, about 6% of the world’s 20-79 age group of adults suffer from type 2 diabetes. According to relevant statistics, the number of people suffering from type 2 diabetes will continue to increase. By 2025, the number of people suffering from the disease is expected to reach 380 million, which will account for 7.1 of all adults in the 20-79 age range in the world. %.
  • type 2 diabetes As a chronic metabolic disease, type 2 diabetes is characterized by high blood sugar, which is mainly caused by relatively insufficient insulin secretion and insulin resistance. In addition, a significant feature of type 2 diabetes is that its condition is irreversible, which eventually causes many 2 Patients with type 1 diabetes develop into type 1 diabetes patients. At present, there is no clinically effective drug that can cure type 2 diabetes. In the early stage of the disease, long-term strict lifestyle control such as diet control and physical exercise is often required to reduce blood sugar and increase insulin. Resistance is improved to achieve the goal of controlling the development of type 2 diabetes.
  • Sodium-glucose cotransporter 2 (SGLT2) inhibitors include dapagliflozin, repaggliflozin, sepagliflozin, apagliflozin, etc., among which dapagliflozin is the first approved and marketed in Europe The effect of SGLT2 inhibitors in the treatment of diabetes has been initially confirmed by clinical studies.
  • Tianagliflozin (Tianagliflozin) is a new SGLT2 inhibitor with 5 chiral centers and its chemical name is: (IS)-1,5-dehydrate-6-deoxy-1-C-[4-chloro- 3-[(4-Ethoxyphenyl)methyl]phenyl]-D-glucitol, molecular formula: C 21 H 25 ClO 5 , molecular weight: 392.87, structural formula:
  • the SGLT2 inhibitor dapagliflozin (dapagliflozin) and extended-release metformin hydrochloride have been combined.
  • the drug is used as an adjuvant drug, combined with diet and exercise. Control blood sugar.
  • EMEA approved Novartis's vildagliptin/metformin hydrochloride compound tablet on November 14, 2007, to treat type 2 diabetes, for the treatment of patients who cannot effectively control blood sugar with the maximum tolerated dose of metformin.
  • the compound tablet The dosage specification of the drug is vildagliptin/guanidine diformate hydrochloride 50mg/850mg/1000mg.
  • the application provides a pharmaceutical composition for treating diabetes and a preparation method thereof.
  • the pharmaceutical composition has stable curative effect, good effect on treating type 2 diabetes, good patient compliance, and can prevent recurrence, which meets the needs of modern people.
  • the present application provides a pharmaceutical composition for the treatment of diabetes.
  • the pharmaceutical composition comprises tyaggliflozin, guanidine diformate hydrochloride and additives, and the mass ratio of tyaggliflozin, guanidine diformate hydrochloride and additives is 1 :(100 ⁇ 250):(15 ⁇ 30).
  • the mass ratio of typagliflozin, guanidine diformate hydrochloride and additives is 1: (150-250): (15-25).
  • the mass ratio of tyaggliflozin, guanidine diformate hydrochloride and additives is 1:230:20.
  • the additive includes sodium hyaluronate.
  • the binder includes carboxymethyl cellulose, and the mass ratio of the carboxymethyl cellulose to sodium hyaluronate is 1: (1.5-4).
  • the filler includes one of microcrystalline cellulose and dibasic calcium phosphate.
  • the disintegrant includes one of calcium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose.
  • this application provides a method for preparing a pharmaceutical composition for treating diabetes, including the following steps:
  • step S2 Add binders and additives to the mixed liquid A of step S1 to obtain mixed liquid B, then heat and concentrate to obtain a clear paste with a relative density of 1.20 to 1.30, then add filler and disintegrant to mix, dry, and weigh , Get a pharmaceutical composition.
  • the net particle size of tyaglide is 10-18 ⁇ m.
  • This application uses an ethanol solution with a mass concentration of 35% to pre-treat guanidine diformate hydrochloride and typagliflozin to improve the dissolution of the active ingredients in the composition.
  • carboxymethyl cellulose is added to make the hydrochloric acid dicarboxylic acid Guanidine and typagliflozin bind relatively tightly, but in the previous experiment, in the process of forming the clear ointment, it was found that the concentration time of the clear ointment became longer. It may be that the existence of carboxymethyl cellulose hindered the formation of the clear ointment.
  • the pharmaceutical composition of this application is pre-treated with guanidine diformate hydrochloride and tyaggliflozin with a 35% ethanol solution, which improves the dissolution of the active ingredients in the composition and ensures that the subsequently prepared pharmaceutical composition can stably exert its efficacy effect;
  • the pharmaceutical composition of the application has stable curative effect, good effect in treating type 2 diabetes, good patient compliance, and can prevent recurrence, which meets the needs of modern people;
  • the preparation method of the pharmaceutical composition of the present application has controllable quality, simple operation, low cost, and can be industrially produced.
  • Embodiment 1 The pharmaceutical composition of the application and its preparation method
  • the formulation of the pharmaceutical composition of the application includes the following raw materials by weight:
  • the preparation method of the pharmaceutical composition of the present application includes the following steps:
  • step S2 Take the formulated amount of carboxymethyl cellulose through an 80-mesh sieve, add carboxymethyl cellulose and sodium hyaluronate to the mixed solution A of step S1 to obtain mixed solution B, and then heat and concentrate to obtain a relative density of 1.20 Then add calcium hydrogen phosphate and carboxymethyl cellulose calcium to mix, dry for 15 minutes, control the moisture content ⁇ 3.5%, and weigh to obtain the pharmaceutical composition.
  • Embodiment 2 The pharmaceutical composition of the application and its preparation method
  • the formulation of the pharmaceutical composition of the application includes the following raw materials by weight:
  • the preparation method of the pharmaceutical composition of the present application includes the following steps:
  • step S2 Take the formulated amount of carboxymethyl cellulose through an 80-mesh sieve, add carboxymethyl cellulose and sodium hyaluronate to the mixed solution A of step S1 to obtain mixed solution B, and then heat and concentrate to obtain a relative density of 1.20 Then add microcrystalline cellulose and carboxymethyl cellulose calcium to mix, dry for 20 minutes, control the moisture content ⁇ 3.5%, and weigh to obtain the pharmaceutical composition.
  • Embodiment 3 The pharmaceutical composition of the present application and its preparation method
  • the formulation of the pharmaceutical composition of the application includes the following raw materials by weight:
  • the preparation method of the pharmaceutical composition of the present application includes the following steps:
  • step S2 Take the formulated amount of carboxymethyl cellulose through an 80-mesh sieve, add carboxymethyl cellulose and sodium hyaluronate to the mixed liquid A of step S1 to obtain mixed liquid B, and then heat and concentrate to obtain a relative density of 1.25 Then add microcrystalline cellulose and carboxymethyl cellulose calcium to mix, dry for 20 minutes, control the moisture content ⁇ 3.5%, and weigh to obtain the pharmaceutical composition.
  • Embodiment 4 The pharmaceutical composition of the present application and its preparation method
  • the formulation of the pharmaceutical composition of the application includes the following raw materials by weight:
  • the preparation method of the pharmaceutical composition of the present application includes the following steps:
  • step S2 Take the formulated amount of carboxymethyl cellulose through an 80-mesh sieve, add carboxymethyl cellulose and sodium hyaluronate to the mixed liquid A of step S1 to obtain mixed liquid B, and then heat and concentrate to obtain a relative density of 1.30 Then add microcrystalline cellulose and carboxymethyl cellulose calcium to mix, dry for 30 minutes, control the moisture content to be ⁇ 3.5%, and weigh to obtain the pharmaceutical composition.
  • the formulation of the pharmaceutical composition of the application includes the following raw materials by weight:
  • the preparation method of the pharmaceutical composition of the present application includes the following steps:
  • step S2 Take the formulated amount of carboxymethyl cellulose through an 80-mesh sieve, add carboxymethyl cellulose and sodium hyaluronate to the mixed liquid A of step S1 to obtain mixed liquid B, and then heat and concentrate to obtain a relative density of 1.30 Then add microcrystalline cellulose and carboxymethyl cellulose calcium to mix, dry for 30 minutes, control the moisture content to be ⁇ 3.5%, and weigh to obtain the pharmaceutical composition.
  • Example 5 Similar to Example 5, the difference is that: Sodium hyaluronate is not added to the pharmaceutical composition, and other parameters are the same as Example 5.
  • Example 5 Similar to Example 5, the difference is that the mass ratio of carboxymethyl cellulose to sodium hyaluronate in the pharmaceutical composition is 1:8, and other parameters are the same as in Example 5.
  • Test example 1 Concentration time test
  • the pharmaceutical compositions prepared in Examples 1 to 5 and Comparative Examples 1 to 3 were prepared into capsules according to conventional methods. According to the dissolution test method (Chinese Pharmacopoeia 2015 Edition Sibu General Principle 0931 Method 1), 900 mL of 0.1 mol/L hydrochloric acid The solution is the dissolution medium, the rotating speed of the basket method is 50rpm, and the operation is carried out in accordance with the law.
  • the drug dissolution rates of the pharmaceutical compositions prepared in Examples 1 to 5 are all different, and the drug tyaggliflozin dissolution rates of the drug compositions prepared in Comparative Examples 1 to 3 are all less than 90% after 60 minutes.
  • the dissolution rate of guanidine diformate hydrochloride of the prepared pharmaceutical composition was less than 100% after 60 minutes, and it could not dissolve completely.
  • changing the mass concentration of ethanol had an impact on the dissolution of the drug.
  • Test materials 100 male rats with a body weight of 200-220g were selected.
  • the pharmaceutical compositions prepared in Examples 1 to 5 and Comparative Examples 1 to 3 were each set as one set, tyaggliflozin was set as one set, and dicarboxylic acid hydrochloride Guanidine is a group.
  • Test method The rats were fasted for 16 hours, the fasting blood glucose was measured, and the fasting blood glucose was randomly divided into 10 groups.
  • the dosage of 5mg/kg (Taigliflozin group), 250mg/kg (guanidine diformate hydrochloride) Group), the dosage of the pharmaceutical compositions prepared in Examples 1 to 5 and Comparative Examples 1 to 3 were 300 mg/kg respectively, and 4.5 g/kg of glucose was orally administered 0.5 hours after the administration, and the dose of each group was determined 0.5 hours after the administration.
  • Rat blood glucose value calculate the inhibition rate of lowering blood glucose of rats in each administration group, calculate the ratio P1, P2 of the drug combination prepared in each example and comparative example to the blood glucose inhibition rate of tyaggliflozin and metformin hydrochloride, and judge the decrease after administration The effect of sugar.
  • the pharmaceutical composition prepared in Examples 1 to 5 has a greater effect on the glucose tolerance of normal rats, and the pharmaceutical composition prepared in Example 5 has the greatest effect on the glucose tolerance of normal rats, and the blood glucose inhibition rate High, indicating that the intensity of glucose tolerance in rats is affected by the mass ratio of tyaggliflozin and guanidine diformate hydrochloride.
  • Comparative Example 1 Compared with Example 5, the pharmaceutical compositions prepared in Comparative Example 1 (lack of sodium hyaluronate) and Comparative Example 2 (the mass ratio of carboxymethyl cellulose to sodium hyaluronate is 1:8), the blood glucose inhibition rate is both
  • the pharmaceutical composition prepared in Examples 1 to 5 is not as high, indicating that changes in the raw materials or content in the pharmaceutical composition will affect the blood glucose inhibition rate.
  • Comparative Example 3 (the ethanol solution with a mass concentration of 70%) has a negative effect on the normal The rat glucose tolerance effect is relatively small and has an impact on the blood sugar inhibition rate. It shows that the ethanol solution with a mass concentration of 35% can increase the effective active ingredients in the pharmaceutical composition and make the blood sugar lowering effect better.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une composition pharmaceutique pour le traitement du diabète et son procédé de préparation, comprenant de la tianagliflozine, du chlorhydrate de metformine et un additif. Le rapport en masse de la tianagliflozine, du chlorhydrate de metformine et de l'additif est de 1 à (100-250) à (15-30). La composition pharmaceutique présente des effets curatifs stables, de bons effets thérapeutiques sur le diabète de type II, et favorise l'observance du patient.
PCT/CN2021/090963 2020-06-22 2021-04-29 Composition pharmaceutique pour le traitement du diabète et son procédé de préparation WO2021258851A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010575055.0 2020-06-22
CN202010575055.0A CN111588713B (zh) 2020-06-22 2020-06-22 一种治疗糖尿病的药物组合物及其制备方法

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WO2021258851A1 true WO2021258851A1 (fr) 2021-12-30

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Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111588713B (zh) * 2020-06-22 2021-03-09 广州市力鑫药业有限公司 一种治疗糖尿病的药物组合物及其制备方法

Citations (9)

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CN104586834A (zh) * 2014-12-12 2015-05-06 周连才 一种艾帕列净和二甲双胍的药物组合物及其制备方法
CN104958290A (zh) * 2015-06-05 2015-10-07 安徽联创生物医药股份有限公司 托格列净与二甲双胍复方制剂及其制备方法
WO2015173584A1 (fr) * 2014-05-16 2015-11-19 Astrazeneca Ab Méthode de suppression de la sécrétion de glucagon d'un inhibiteur de sglt2
CN106176718A (zh) * 2016-08-03 2016-12-07 上海延安药业有限公司 复方卡格列净二甲双胍片
CN106924237A (zh) * 2017-03-03 2017-07-07 杭州华东医药集团新药研究院有限公司 一种含有恩格列净和盐酸二甲双胍的药物组合物
CN109010293A (zh) * 2018-08-23 2018-12-18 成都新柯力化工科技有限公司 一种用于糖尿病的纳米组装恩格列净药片及制备方法
CN109528706A (zh) * 2017-09-21 2019-03-29 天津药物研究院有限公司 一种用于治疗糖尿病的药物组合物及其制备方法和用途
WO2019120162A1 (fr) * 2017-12-18 2019-06-27 Vitnovo, Inc. Compositions, trousses et méthodes pour traiter le diabète sucré de type ii
CN111588713A (zh) * 2020-06-22 2020-08-28 广州市力鑫药业有限公司 一种治疗糖尿病的药物组合物及其制备方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190183959A1 (en) * 2017-12-18 2019-06-20 Vitnovo, Inc. Compositions, kits and methods for treating type ii diabetes mellitus
WO2019162800A1 (fr) * 2018-02-21 2019-08-29 Glenmark Pharmaceuticals Limited Composition pharmaceutique comprenant de la remogliflozine et un agent antidiabétique

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015173584A1 (fr) * 2014-05-16 2015-11-19 Astrazeneca Ab Méthode de suppression de la sécrétion de glucagon d'un inhibiteur de sglt2
CN104586834A (zh) * 2014-12-12 2015-05-06 周连才 一种艾帕列净和二甲双胍的药物组合物及其制备方法
CN104958290A (zh) * 2015-06-05 2015-10-07 安徽联创生物医药股份有限公司 托格列净与二甲双胍复方制剂及其制备方法
CN106176718A (zh) * 2016-08-03 2016-12-07 上海延安药业有限公司 复方卡格列净二甲双胍片
CN106924237A (zh) * 2017-03-03 2017-07-07 杭州华东医药集团新药研究院有限公司 一种含有恩格列净和盐酸二甲双胍的药物组合物
CN109528706A (zh) * 2017-09-21 2019-03-29 天津药物研究院有限公司 一种用于治疗糖尿病的药物组合物及其制备方法和用途
WO2019120162A1 (fr) * 2017-12-18 2019-06-27 Vitnovo, Inc. Compositions, trousses et méthodes pour traiter le diabète sucré de type ii
CN109010293A (zh) * 2018-08-23 2018-12-18 成都新柯力化工科技有限公司 一种用于糖尿病的纳米组装恩格列净药片及制备方法
CN111588713A (zh) * 2020-06-22 2020-08-28 广州市力鑫药业有限公司 一种治疗糖尿病的药物组合物及其制备方法

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