WO2022034944A1 - Formulation composite pour le traitement du diabète sucré de type 2 - Google Patents

Formulation composite pour le traitement du diabète sucré de type 2 Download PDF

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Publication number
WO2022034944A1
WO2022034944A1 PCT/KR2020/010841 KR2020010841W WO2022034944A1 WO 2022034944 A1 WO2022034944 A1 WO 2022034944A1 KR 2020010841 W KR2020010841 W KR 2020010841W WO 2022034944 A1 WO2022034944 A1 WO 2022034944A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
acceptable salt
type
diabetes
metformin
Prior art date
Application number
PCT/KR2020/010841
Other languages
English (en)
Korean (ko)
Inventor
안재순
윤덕일
김동민
이선
Original Assignee
주식회사 엘지화학
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 주식회사 엘지화학 filed Critical 주식회사 엘지화학
Priority to PE2023000275A priority Critical patent/PE20231638A1/es
Priority to BR112023002559A priority patent/BR112023002559A2/pt
Priority to PCT/KR2020/010841 priority patent/WO2022034944A1/fr
Priority to MX2023001785A priority patent/MX2023001785A/es
Publication of WO2022034944A1 publication Critical patent/WO2022034944A1/fr
Priority to CL2023000415A priority patent/CL2023000415A1/es
Priority to CONC2023/0002829A priority patent/CO2023002829A2/es

Links

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
    • A61K31/13—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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 a combination preparation for effectively treating type 2 diabetes, and more particularly, to a first layer comprising metformin or a pharmaceutically acceptable salt thereof, an aqueous polyvinyl acetate dispersion, and a cellulose excipient; And by providing a combination formulation comprising a second layer including gemigliptin or a pharmaceutically acceptable salt thereof and an excipient, the size of the tablet is minimized to improve patient compliance and at the same time, blood glucose in type 2 diabetes patients to improve control.
  • the International Diabetes Federation estimated that there were 366 million people with diabetes worldwide. It was reported that 80% of them are concentrated in developing countries, and about 36% belong to the Western Pacific region including Korea. However, considering about 183 million people who are currently diabetic but not diagnosed with diabetes, the actual number of diabetic patients worldwide is expected to exceed 549 million, and in 2011 alone, 4.6 It was reported that 100,000 people died due to diabetes.
  • Diabetes mellitus is a metabolic disease in which blood sugar rises due to a defect in insulin secretion, a defect in insulin action, or a defect in both.
  • Type 1 diabetes is a result of the destruction of pancreatic beta cells ( ⁇ -cells), which is a serious disease that can lead to ketosis if not treated. It usually develops in childhood, but sometimes it can also develop in adults who are not obese and whose first symptoms of hyperglycemia appear later in life.
  • Type 2 diabetes which is currently on the rise, accounts for 90 to 95% of all diabetes, and it is a complex disease whose mechanism is not clearly elucidated. Symptoms are not severe and appear in various forms, which are complexly involved in beta cell dysfunction, peripheral insulin resistance, and hepatic glucose metabolism abnormalities.
  • Existing oral drugs used to treat diabetes include insulin-secreting agents such as sulfonylureas and meglitinides, biguanides, thiazolidinediones, and alpha -Glucosidase inhibitors ( ⁇ -glucosidase inhibitors) can be broadly divided into 4 groups.
  • Sulfonylureas and biguanides have been used for a long time as a treatment for type 2 diabetes.
  • sulfonylurea promotes insulin secretion from beta cells, the beta cell function gradually decreases, leading to treatment with other drugs or insulin.
  • Metformin is a representative drug belonging to the biguanide, and it is a safe drug with few side effects of hypoglycemia and is widely used as the first drug prescribed for the treatment of type 2 diabetes. Because type 2 diabetes is a progressive disease, long-term treatment cannot control blood sugar sufficiently, and combination therapy is required within a few years after diagnosis.
  • Korean Patent Application Laid-Open No. 10-2014-0045271 it is a double-layered pharmaceutical formulation composed of a first layer containing metformin and a second layer containing gemigliptin, which alleviates the side effects of the existing single formulation and provides more Disclosed are those showing improved preventive and therapeutic effects on diabetes and complex diseases thereof.
  • the present invention provides a first layer comprising metformin or a pharmaceutically acceptable salt thereof, an aqueous polyvinyl acetate dispersion, and a cellulose excipient; And it provides a combination formulation for the treatment of type 2 diabetes comprising a second layer comprising a gemigliptin or a pharmaceutically acceptable salt thereof and an excipient.
  • Metformin is a drug belonging to the group of biguanides, which blocks glucose production in the liver, reduces glucose absorption in the intestine, and improves the body's sensitivity to insulin.
  • pharmaceutically acceptable salts of metformin include, for example, hydrochloric acid, acetylsalicylate, fumarate, succinate, and the like, and hydrochloric acid salt may be preferably used.
  • Gemigliptin is a relatively recently developed potent and selective dipeptidyl peptidase IV (DPP-IV) inhibitor, and the DPP-IV inhibitor is GLP-1 (glucagon-like pepetide-1). It is a drug designed to inhibit degradation by IV. GLP-1 is an incretin that promotes insulin secretion from beta cells, increases glucose utilization in peripheral tissues, suppresses glucagon secretion in alpha cells, and reduces glucose production in the liver.
  • DPP-IV dipeptidyl peptidase IV
  • compositions of gemigliptin include, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, trifluoroacetic acid, citric acid, formic acid, maleic acid, oxalic acid (oxalic acid), succinic acid, benzoic acid, There are tartaric acid, fumaric acid, manderic acid, ascorbic acid, malic acid, methanesulfonic acid, etc., and preferably tartaric acid salt 1.5 hydrate can be used.
  • the first layer including metformin or a pharmaceutically acceptable salt thereof includes an aqueous dispersion of polyvinyl acetate and a cellulose-based excipient.
  • polyvinyl acetate aqueous dispersion is used in the form of a solid content.
  • the polyvinyl acetate aqueous dispersion may be included in a weight ratio of 10 to 40 parts by weight, 12 to 35 parts by weight, or 15 to 30 parts by weight based on 100 parts by weight of metformin or a pharmaceutically acceptable salt thereof. there is.
  • hydroxypropyl methylcellulose hyperromellose
  • hydroethyl methylcellulose hydroxyethyl methylcellulose
  • hydropropyl methyl cellulose may be used as the cellulosic excipient.
  • the cellulosic excipient may be included in a weight ratio of 3 to 20 parts by weight, 4 to 15 parts by weight, or 5 to 12 parts by weight based on 100 parts by weight of metformin or a pharmaceutically acceptable salt thereof.
  • the first layer containing metformin or a pharmaceutically acceptable salt thereof is formed by forming a matrix with an aqueous polyvinyl acetate dispersion and a cellulose-based excipient in a first layer containing metformin or a pharmaceutically acceptable salt thereof, and the first layer containing metformin or a pharmaceutically acceptable salt thereof is sustained-release Make it possible to implement the type dissolution pattern.
  • the combination formulation comprises a first layer containing metformin or a pharmaceutically acceptable salt thereof, and a second layer containing gemigliptin or a pharmaceutically acceptable salt thereof in the form of a double-layered tablet. It can be manufactured by tableting with
  • the second layer containing gemigliptin or a pharmaceutically acceptable salt thereof may include microcrystalline cellulose as an excipient.
  • the combination preparation is to be prepared by coating a first layer containing metformin or a pharmaceutically acceptable salt thereof with a second layer containing gemigliptin or a pharmaceutically acceptable salt thereof.
  • the second layer containing gemigliptin or a pharmaceutically acceptable salt thereof may include a coating agent as an excipient, and , the coating agent may be, for example, AquariusTM (Ashland Speficalty Ingredients), but is not limited thereto.
  • the second layer containing gemigliptin or a pharmaceutically acceptable salt thereof may further include tartaric acid.
  • tartaric acid is additionally included, the stability of gemigliptin or a pharmaceutically acceptable salt thereof may be improved.
  • the combination preparation may further include a pharmaceutically acceptable additive as needed.
  • Pharmaceutically acceptable additives may include binders, disintegrants, lubricants, and the like.
  • the binder may include polyvinyl acetate, vinylpyrrolidone-vinyl acetate copolymer, hydroxypropyl methylcellulose, polyvinylpyrrolidone, copovidone, gelatin, alginate, corn starch, potato starch, etc. It is not limited.
  • the disintegrant may include, but are not limited to, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, sodium starch glycolate, and the like.
  • lubricant examples include, but are not limited to, colloidal silicon dioxide, hydrous silicon dioxide, magnesium stearate, sodium stearyl fumarate, glyceryl behenate, calcium stearate, stearic acid, talc (talc), and the like.
  • the combination preparation may include 200 to 2,000 mg, 300 to 1,500 mg, or 400 to 1,200 mg of metformin or a pharmaceutically acceptable salt thereof.
  • the combination preparation may contain 10 to 200 mg, 15 to 150 mg, or 20 to 100 mg of gemigliptin or a pharmaceutically acceptable salt thereof.
  • the combination preparation is, for example, 25 mg of gemigliptin and 500 mg of metformin or a pharmaceutically acceptable salt thereof, 50 mg of gemigliptin and 1,000 mg of metformin or a drug thereof a pharmaceutically acceptable salt, 50 mg of gemigliptin and 500 mg of metformin or a pharmaceutically acceptable salt thereof, or 50 mg of gemigliptin and 1,000 mg of metformin or a pharmaceutically acceptable salt thereof.
  • the composite formulation may be coated with a film
  • the usable coating agent includes a coating agent commonly used in the art, for example, polyvinylpyrrolidone, copovidone, Opadry series, oil It may include, but is not limited to, a drag series.
  • a combination formulation with a minimized tablet size comprising metformin or a pharmaceutically acceptable salt thereof and gemigliptin or a pharmaceutically acceptable salt thereof is provided to improve patient compliance and control blood sugar can effectively treat type 2 diabetes.
  • a double-layer tablet having a layer of gemigliptin in an immediate-release pattern and metformin in a sustained-release pattern was prepared.
  • the double-layered tablets of Examples 1 to 4 were coated with Opadry II after obtaining tablets.
  • the metformin layer was granulated by spraying an aqueous dispersion of polyvinyl acetate on a mixture of metformin hydrochloride, hypromellose, and carboxymethylcellulose sodium, and then magnesium stearate was mixed with the dried product to be used as a metformin layer.
  • the gemigliptin layer was prepared by simply mixing all additives including gemigliptin tartrate 1.5 hydrate. Each layer was compressed with a double-layer tablet press to obtain a double-layer tablet, which was then coated using Opadry II.
  • gemigliptin of an immediate-release pattern was prepared by a coating process on a metformin tablet of a sustained-release pattern.
  • composition of Table 2 After granulation by spraying an aqueous dispersion of polyvinyl acetate on a mixture of metformin hydrochloride, hypromellose, and carboxymethyl cellulose sodium, magnesium stearate was mixed with the dried product.
  • the mixture was tableted with a tablet press to obtain tablets. It was prepared by dispersing gemigliptin tartrate 1.5 hydrate, Aquarius and tartaric acid in purified water. It was prepared by putting a tablet containing metformin hydrochloride in a tablet coating machine and coating it with a solution in which gemigliptin was dispersed.

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

Abstract

La présente invention concerne une formulation composite pour le traitement efficace du diabète sucré de type 2 et, plus spécifiquement, l'invention concerne une formulation composite comprenant : une première couche comprenant de la metformine ou un sel pharmaceutiquement acceptable de celle-ci, une dispersion aqueuse d'acétate de polyvinyle, et un excipient à base de cellulose ; et une seconde couche comprenant de la gémigliptine ou un sel pharmaceutiquement acceptable et un excipient, la formulation étant un comprimé à taille réduite conçu pour améliorer la compliance au traitement ainsi que la régulation du glucose chez les patients atteints du diabète sucré de type 2.
PCT/KR2020/010841 2020-08-14 2020-08-14 Formulation composite pour le traitement du diabète sucré de type 2 WO2022034944A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
PE2023000275A PE20231638A1 (es) 2020-08-14 2020-08-14 Formulacion compuesta para tratamiento de diabetes mellitus tipo 2
BR112023002559A BR112023002559A2 (pt) 2020-08-14 2020-08-14 Preparação de combinação para tratar diabetes tipo 2
PCT/KR2020/010841 WO2022034944A1 (fr) 2020-08-14 2020-08-14 Formulation composite pour le traitement du diabète sucré de type 2
MX2023001785A MX2023001785A (es) 2020-08-14 2020-08-14 Formulacion compuesta para tratamiento de diabetes mellitus tipo 2.
CL2023000415A CL2023000415A1 (es) 2020-08-14 2023-02-10 Formulación compuesta para tratamiento de diabetes mellitus tipo 2
CONC2023/0002829A CO2023002829A2 (es) 2020-08-14 2023-03-08 Formulación compuesta para tratamiento de diabetes mellitus tipo 2

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/KR2020/010841 WO2022034944A1 (fr) 2020-08-14 2020-08-14 Formulation composite pour le traitement du diabète sucré de type 2

Publications (1)

Publication Number Publication Date
WO2022034944A1 true WO2022034944A1 (fr) 2022-02-17

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PCT/KR2020/010841 WO2022034944A1 (fr) 2020-08-14 2020-08-14 Formulation composite pour le traitement du diabète sucré de type 2

Country Status (6)

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BR (1) BR112023002559A2 (fr)
CL (1) CL2023000415A1 (fr)
CO (1) CO2023002829A2 (fr)
MX (1) MX2023001785A (fr)
PE (1) PE20231638A1 (fr)
WO (1) WO2022034944A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100074950A1 (en) * 2008-03-14 2010-03-25 Nectid Inc. Anti-diabetic combinations
WO2012049566A1 (fr) * 2010-10-14 2012-04-19 Japan Tobacco Inc. Polythérapie pour l'utilisation dans le traitement du diabète
KR20130136718A (ko) * 2012-06-05 2013-12-13 한미약품 주식회사 메트포르민 서방성 장용제제 및 이의 제조방법
KR20140045271A (ko) * 2012-10-08 2014-04-16 주식회사 엘지생명과학 제미글립틴 및 메트포르민을 포함하는 복합 제제 및 이의 제조방법
KR20180002460A (ko) * 2016-06-29 2018-01-08 주식회사 엘지화학 제2형 당뇨병 및 당뇨성 이상지질혈증 치료용 조성물, 키트 및 병용 요법
KR20200135095A (ko) * 2019-05-24 2020-12-02 주식회사 엘지화학 제2형 당뇨병 치료용 복합제제

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100074950A1 (en) * 2008-03-14 2010-03-25 Nectid Inc. Anti-diabetic combinations
WO2012049566A1 (fr) * 2010-10-14 2012-04-19 Japan Tobacco Inc. Polythérapie pour l'utilisation dans le traitement du diabète
KR20130136718A (ko) * 2012-06-05 2013-12-13 한미약품 주식회사 메트포르민 서방성 장용제제 및 이의 제조방법
KR20140045271A (ko) * 2012-10-08 2014-04-16 주식회사 엘지생명과학 제미글립틴 및 메트포르민을 포함하는 복합 제제 및 이의 제조방법
KR20180002460A (ko) * 2016-06-29 2018-01-08 주식회사 엘지화학 제2형 당뇨병 및 당뇨성 이상지질혈증 치료용 조성물, 키트 및 병용 요법
KR20200135095A (ko) * 2019-05-24 2020-12-02 주식회사 엘지화학 제2형 당뇨병 치료용 복합제제

Also Published As

Publication number Publication date
CO2023002829A2 (es) 2023-03-27
CL2023000415A1 (es) 2023-10-13
PE20231638A1 (es) 2023-10-16
MX2023001785A (es) 2023-03-10
BR112023002559A2 (pt) 2023-03-14

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