WO2022034944A1 - Composite formulation for treatment of type 2 diabetes mellitus - Google Patents

Composite formulation for treatment of type 2 diabetes mellitus 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
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Prior art keywords
pharmaceutically acceptable
acceptable salt
type
diabetes
metformin
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PCT/KR2020/010841
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French (fr)
Korean (ko)
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안재순
윤덕일
김동민
이선
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주식회사 엘지화학
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Priority to MX2023001785A priority Critical patent/MX2023001785A/en
Priority to BR112023002559A priority patent/BR112023002559A2/en
Priority to PE2023000275A priority patent/PE20231638A1/en
Priority to PCT/KR2020/010841 priority patent/WO2022034944A1/en
Publication of WO2022034944A1 publication Critical patent/WO2022034944A1/en
Priority to CL2023000415A priority patent/CL2023000415A1/en
Priority to CONC2023/0002829A priority patent/CO2023002829A2/en

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    • 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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Abstract

The present invention relates to a composite formulation for effectively treating type 2 diabetes mellitus and, more specifically, provides a composite formulation comprising: a first layer including metformin or a pharmaceutically acceptable salt thereof, an aqueous polyvinyl acetate dispersion, and a cellulose-based excipient; and a second layer including gemigliptin or a pharmaceutically acceptable salt and an excipient, wherein the formulation is a size-minimized tablet designed to improve medication compliance as well as glucose regulation in type 2 diabetes mellitus patients.

Description

제2형 당뇨병 치료용 복합제제Combination drug for the treatment of type 2 diabetes
본 발명은 제2형 당뇨병을 효율적으로 치료하기 위한 복합제제에 관한 것으로, 보다 상세하게는 메트포르민 또는 이의 약제학적으로 허용가능한 염, 폴리비닐아세테이트 수분산액 및 셀룰로오스계 부형제를 포함하는 제1층; 및 제미글립틴 또는 이의 약제학적으로 허용가능한 염 및 부형제를 포함하는 제2층을 포함하는 복합제제를 제공함으로써 정제의 크기를 최소화하여 환자의 복약 순응도를 개선함과 동시에 제2형 당뇨병 환자의 혈당조절을 개선하기 위한 것에 관한 것이다.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.
2011년 국제당뇨병연맹(IDF)은 전 세계 당뇨병 환자를 약 3억 6천 6백만명으로 추산하였다. 이 중 80%는 개발도상국에 집중되어 있고, 또한 약 36%는 우리나라가 포함되는 서태평양 지역에 속해 있는 것으로 보고하였다. 그러나 현재 당뇨병 상태에 있으나 당뇨병으로 진단되지 않은 약 1억 8천 3백만명의 환자들을 고려하면, 실제 당뇨병 환자는 전 세계적으로 5억 4천 9백만명 이상이 될 것으로 예상하였으며, 2011년에만 4백 6십만명이 당뇨병으로 인해 사망하였다고 보고하였다.In 2011, the International Diabetes Federation (IDF) 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.
당뇨병은 인슐린 분비의 결함, 인슐린 작용의 결함 또는 두 가지 모두의 결함으로 인하여 혈당이 높아지는 대사질환이다. 제1형 당뇨병은 췌장 베타세포(β-cell)가 파괴되어 나타나는 결과로, 치료하지 않으면 케톤혈증(ketosis)를 초래할 수 있는 중한 질환으로 인슐린 치료로 혈당 관리를 해야 한다. 보통 유년기에 발병하지만 때로는 비만하지 않으면서도 첫 고혈당 증상이 나이가 들어서 나타나는 성인에서도 발병할 수 있다. 현재 증가하고 있는 제2형 당뇨병은 전체 당뇨의 90 내지 95%를 차지하며, 그 기전이 명확하게 밝혀지지 않은 복합 질환으로 사춘기 때 나타날 수도 있지만 대개 성인에서 발생한다. 증상이 심하지 않으며 다양한 형태로 나타나는데, 이에는 베타세포의 기능부전, 말초 인슐린 저항, 간포도당 대사 이상 등이 복합적으로 관여하고 있다. 제2형 당뇨병의 경우 시간이 지날수록 혈당조절이 어려워져, 적절한 혈당조절을 위하여 평균 3~4년마다 새로운 혈당강하제를 투여해야 한다. 또한, 병용요법과 인슐린요법에도 불구하고 적절한 혈당 조절이 어렵다.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 (β-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. In the case of type 2 diabetes, as time goes by, blood sugar control becomes more difficult, and a new blood sugar-lowering agent needs to be administered on average every 3 to 4 years for proper blood sugar control. In addition, despite combination therapy and insulin therapy, proper blood sugar control is difficult.
기존에 당뇨병 치료에 이용되는 경구용 약물로는 설포닐요소제(sulfonylureas)와 메글리티나이드제(meglitinides)와 같은 인슐린 분비제, 비구아나이드제(biguanides), 티아졸리디네디온제(thiazolidinediones) 및 알파-글루코시데이즈 억제제(α-glucosidase inhibitor)등 크게 4군으로 나눌 수 있다. 설포닐요소제와 비구아나이드제는 제2형 당뇨병 치료약으로 오랫동안 사용되어 왔다. 그러나 설포닐요소제는 베타세포에서 인슐린 분비를 촉진하지만 결국은 베타세포의 기능은 점차 저하되어 다른 약물이나 인슐린 치료에 이르게 된다. 비구아나이드제에 속하는 약물로는 메트포르민(metformin)이 대표적인데, 저혈당의 부작용이 적은 안전한 약으로 제2형 당뇨병의 치료에 가장 처음으로 처방되는 약물로 많이 이용되고 있다. 제2형 당뇨병은 진행성 질환이기 때문에 장기 치료시 혈당을 충분히 제어할 수 없고 진단 후 몇 년 이내에 병용요법이 필요하게 된다.Existing oral drugs used to treat diabetes include insulin-secreting agents such as sulfonylureas and meglitinides, biguanides, thiazolidinediones, and alpha -Glucosidase inhibitors (α-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. However, although 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.
이와 관련하여 대한민국 공개특허공보 제10-2014-0045271호에서는 메트포르민을 포함하는 제1층 및 제미글립틴을 포함하는 제2층으로 구성된 이중층의 약제학적 제제로 기존 단일 제제의 부작용을 완화시키는 동시에 보다 향상된 당뇨병 및 이의 복합 질환에 대한 예방 및 치료 효과를 나타내는 것에 대하여 개시를 하고 있다.In this regard, in 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.
본 발명은 제2형 당뇨병 환자에 있어서 정제의 크기를 최소화하여 환자의 복약 순응도를 개선시키며, 약물 상호간의 상승작용에 의해서 효율적으로 제2형 당뇨병을 치료할 수 있는 복합 제제를 제공하는 것을 그 기술적 과제로 한다.It is a technical task of the present invention to provide a complex formulation that can minimize the size of the tablet in type 2 diabetes patients to improve the patient's medication compliance, and effectively treat type 2 diabetes by synergy between drugs. do it with
상기 과제를 해결하고자 본 발명은 메트포르민 또는 이의 약제학적으로 허용가능한 염, 폴리비닐아세테이트 수분산액, 및 셀룰로오스계 부형제를 포함하는 제1층; 및 제미글립틴 또는 이의 약제학적으로 허용가능한 염 및 부형제를 포함하는 제2층을 포함하는 제2형 당뇨병 치료용 복합제제를 제공한다.In order to solve the above problems, 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.
이하에서 본 발명에 대하여 상세히 설명한다.Hereinafter, the present invention will be described in detail.
메트포르민은 비구아나이드제(biguanides)에 속하는 약물로, 간에서 포도당이 생성되는 것을 막고 장에서 포도당 흡수를 감소시키며, 체내에서 인슐린에 대한 민감성을 개선시킨다.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.
메트포르민은 다양한 형태의 약제학적으로 허용가능한 염이 사용될 수 있다. 본 발명에서 메트포르민의 약제학적으로 허용가능한 염은, 예를 들면 염산, 아세틸살리실산염, 푸마르산염, 석신산염 등이 있으며, 바람직하게는 염산염이 사용될 수 있다.Various types of pharmaceutically acceptable salts of metformin may be used. In the present invention, pharmaceutically acceptable salts of metformin include, for example, hydrochloric acid, acetylsalicylate, fumarate, succinate, and the like, and hydrochloric acid salt may be preferably used.
제미글립틴은 비교적 최근에 개발된 강력하고 선택적인 디펩티딜 펩티다아제 IV 억제제(dipeptidyl peptidase IV (DPP-IV) inhibitor)로, DPP-IV 저해제는 GLP-1(glucagon-like pepetide-1)이 DPP-IV에 의해 분해되는 것을 저해하도록 설계된 약물이다. GLP-1은 베타세포로부터 인슐린 분비를 촉진하고, 말초조직에서 당 이용을 증가시키며, 알파세포에서 글루카곤 분비를 억제하고 간에서 당 생성을 감소시키는 역할을 하는 인크레틴(incretin)이다. 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.
제미글립틴은 다양한 형태의 약제학적으로 허용가능한 염이 사용될 수 있다. 본 발명에서 제미글립틴의 약제학적으로 허용가능한 염은, 예를 들면 염산, 브롬산, 인산, 황산, 아세트산, 트리플루오로아세트산, 구연산, 포름산, 말레인산, 수산(옥살산), 호박산, 벤조인산, 타르타르산, 푸말산, 만데린산, 아스코르빈산, 말린산, 메탄술폰산 등이 있으며, 바람직하게는 타르타르산 염 1.5 수화물이 사용될 수 있다.For gemigliptin, various types of pharmaceutically acceptable salts may be used. In the present invention, pharmaceutically acceptable salts 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.
본 발명에서, 메트포르민 또는 이의 약제학적으로 허용가능한 염을 포함하는 제1층은 폴리비닐아세테이트 수분산액 및 셀룰로오스계 부형제를 포함한다.In the present invention, the first layer including metformin or a pharmaceutically acceptable salt thereof includes an aqueous dispersion of polyvinyl acetate and a cellulose-based excipient.
본 발명에 따른 일 구체예에서 폴리비닐아세테이트 수분산액(polyvinyl acetate aqueous dispersion)은 고형분의 형태로 사용된다. 본 발명에 다른 일 구체예에서 폴리비닐아세테이트 수분산액은 메트포르민 또는 이의 약제학적으로 허용되는 염 100 중량부에 대하여 10 내지 40 중량부, 12 내지 35 중량부 또는 15 내지 30 중량부의 중량 비율로 포함될 수 있다.In one embodiment according to the present invention, polyvinyl acetate aqueous dispersion is used in the form of a solid content. In another embodiment of the present invention, 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.
본 발명에 따른 일 구체예에서 셀룰로오스계 부형제로는 하이드로프로필 메틸셀룰로오스(hydroxypropyl methylcellulose, hypromellose) 또는 하이드로에틸 메틸셀룰로오스(hydroxyethyl methylcellulose)가 사용될 수 있다. 본 발명에 따른 일 구체예에서 셀룰로오스계 부형제로는 하이드로프로필 메틸셀룰로오스가 사용될 수 있다. 본 발명에 따른 일 구체예에서 셀룰로오스계 부형제는 메트포르민 또는 이의 약제학적으로 허용되는 염 100 중량부에 대하여 3 내지 20 중량부, 4 내지 15 중량부 또는 5 내지 12 중량부의 중량 비율로 포함될 수 있다.In one embodiment according to the present invention, as the cellulosic excipient, hydroxypropyl methylcellulose (hypromellose) or hydroethyl methylcellulose (hydroxyethyl methylcellulose) may be used. In one embodiment according to the present invention, hydropropyl methyl cellulose may be used as the cellulosic excipient. In one embodiment according to the present invention, 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.
본 발명에서는 메트포르민 또는 이의 약제학적으로 허용가능한 염을 포함하는 제1층을 폴리비닐아세테이트 수분산액 및 셀룰로오스계 부형제로 매트릭스를 형성하여 메트포르민 또는 이의 약제학적으로 허용가능한 염을 포함하는 제1층이 서방형 용출 양상을 구현할 수 있도록 한다.In the present invention, 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.
본 발명에 따른 일 구체예에서, 복합제제는 메트포르민 또는 이의 약제학적으로 허용가능한 염을 포함하는 제1층, 및 제미글립틴 또는 이의 약제학적으로 허용가능한 염을 포함하는 제2층을 이층정의 형태로 타정하여 제조될 수 있다.In one embodiment according to the present invention, 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
본 발명에 따른 일 구체예에서, 복합제제가 이층정의 형태로 제조될 경우 제미글립틴 또는 이의 약제학적으로 허용가능한 염을 포함하는 제2층은 부형제로 미결정 셀룰로오스(microcrystalline cellulose)를 포함할 수 있다.In one embodiment according to the present invention, when the combination preparation is prepared in the form of a double-layered tablet, the second layer containing gemigliptin or a pharmaceutically acceptable salt thereof may include microcrystalline cellulose as an excipient.
본 발명에 따른 일 구체예에서, 복합제제는 메트포르민 또는 이의 약제학적으로 허용가능한 염을 포함하는 제1층을 제미글립틴 또는 이의 약제학적으로 허용가능한 염을 포함하는 제2층으로 코팅하여 제조될 수 있다.In one embodiment according to the present invention, 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. can
본 발명에 따른 일 구체예에서, 복합제제가 제1층을 제2층으로 코팅하여 제조될 경우 제미글립틴 또는 이의 약제학적으로 허용가능한 염을 포함하는 제2층은 부형제로서 코팅제를 포함할 수 있고, 코팅제는 예를 들면 Aquarius™(Ashland Speficalty Ingredients)를 사용할 수 있으나 이에 제한되는 것은 아니다.In one embodiment according to the present invention, when the combination preparation is prepared by coating the first layer with the second layer, 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, Aquarius™ (Ashland Speficalty Ingredients), but is not limited thereto.
본 발명에 따른 일 구체예에서, 복합제제가 제1층을 제2층으로 코팅하여 제조될 경우 제미글립틴 또는 이의 약제학적으로 허용가능한 염을 포함하는 제2층은 주석산을 추가로 포함할 수 있다. 주석산이 추가로 포함될 경우 제미글립틴 또는 이의 약제학적으로 허용가능한 염의 안정성을 개선시킬 수 있다.In one embodiment according to the present invention, when the combination preparation is prepared by coating the first layer with the second layer, the second layer containing gemigliptin or a pharmaceutically acceptable salt thereof may further include tartaric acid. . When tartaric acid is additionally included, the stability of gemigliptin or a pharmaceutically acceptable salt thereof may be improved.
본 발명에 따른 일 구체예에서, 복합제제는 그 필요에 따라 약제학적으로 허용가능한 첨가제를 추가로 포함할 수 있다. 약제학적으로 허용가능한 첨가제로는 결합제, 붕해제, 활택제 등을 포함할 수 있다. 상기 결합제의 예로는 폴리비닐아세테이트, 비닐피롤리돈-비닐 아세테이트 공중합체, 하이드록시프로필 메틸셀룰로오스, 폴리비닐피롤리돈, 코포비돈, 젤라틴, 알지네이트, 옥수수 전분, 감자 전분 등을 포함할 수 있으나 이에 제한되는 것은 아니다. 상기 붕해제의 예로는 카르복시메틸셀룰로오스 소듐, 크로스카르멜로스 소듐, 크로스포비돈, 전분글리콘산나트륨 등을 포함할 수 있으나 이에 제한되는 것은 아니다. 상기 활택제의 예로는 콜로이드성 이산화규소, 함수 이산화규소, 스테아린산 마그네슘, 소듐 스테아릴 푸마레이트, 글리세릴 베헤네이트, 스테아린산 칼슘, 스테아린산, 탈크(활석) 등을 포함할 수 있으나 이에 제한되는 것은 아니다.In one embodiment according to the present invention, the combination preparation may further include a pharmaceutically acceptable additive as needed. Pharmaceutically acceptable additives may include binders, disintegrants, lubricants, and the like. Examples of 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. Examples of the disintegrant may include, but are not limited to, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, sodium starch glycolate, and the like. Examples of the lubricant 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.
본 발명에 따른 일 구체예에서, 복합제제는 200 내지 2,000 mg, 300 내지 1,500 mg 또는 400 내지 1,200 mg의 메트포르민 또는 이의 약제학적으로 허용가능한 염을 포함할 수 있다.In one embodiment according to the present invention, 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.
본 발명에 따른 일 구체예에서, 복합제제는 10 내지 200 mg, 15 내지 150 mg 또는 20 내지 100 mg의 제미글립틴 또는 이의 약제학적으로 허용가능한 염을 포함할 수 있다.In one embodiment according to the present invention, 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.
본 발명에 따른 일 구체예에서, 복합제제는 예를 들면, 25 mg의 제미글립틴 및 500 mg의 메트포르민 또는 이의 약제학적으로 허용가능한 염, 50 mg의 제미글립틴 및 1,000 mg의 메트포르민 또는 이의 약제학적으로 허용가능한 염, 50 mg의 제미글립틴 및 500 mg의 메트포르민 또는 이의 약제학적으로 허용가능한 염 또는 50 mg의 제미글립틴 및 1,000 mg의 메트포르민 또는 이의 약제학적으로 허용가능한 염을 포함할 수 있다.In one embodiment according to the present invention, 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. .
본 발명에 따른 일 구체예에서, 복합제제는 필름으로 코팅될 수 있으며, 사용 가능한 코팅제로는 당 분야에서 통상적으로 사용되는 코팅제, 예를 들면 폴리비닐피롤리돈, 코포비돈, 오파드라이 시리즈, 유드라짓 시리즈 등을 포함할 수 있으나 이에 제한되는 것은 아니다.In one embodiment according to the present invention, the composite formulation may be coated with a film, and 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.
본 발명에 따르면, 메트포르민 또는 이의 약제학적으로 허용가능한 염 및 제미글립틴 또는 이의 약제학적으로 허용가능한 염을 포함하는 정제의 크기가 최소화된 복합제제를 제공하여 환자의 복약 순응도를 개선시키며, 혈당 조절을 통하여 효율적으로 제2형 당뇨병을 치료할 수 있다.According to the present invention, 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.
이하, 실시예를 통하여 본 발명을 보다 구체적으로 설명한다. 그러나 하기 실시예는 본 발명의 이해를 돕기 위하여 예시하는 것일 뿐, 본 발명의 범위가 이에 의하여 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through examples. However, the following examples are merely illustrative to aid the understanding of the present invention, and the scope of the present invention is not limited thereto.
실시예 1 내지 4: 이층정의 제조Examples 1 to 4: Preparation of bilayer tablets
다음의 표 1의 조성으로 속방형 용출 양상의 제미글립틴과 서방형 용출 양상의 메트포르민 층을 갖는 이층정을 제조하였다. 실시예 1 내지 4의 이층정은 정제를 얻은 후 이를 오파드라이 II를 사용하여 코팅하였다.With the composition shown in Table 1 below, 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.
[제조방법][Manufacturing method]
표 1의 조성 중 메트포르민 층은 메트포르민 염산염, 히프로멜로오스, 카르복시메틸셀룰로오스 소듐 혼합물에 폴리비닐아세테이트 수분산액을 분무하여 과립화한 후, 이의 건조물에 스테아린산마그네슘을 혼합하여 메트포르민 층으로 사용하였다. 제미글립틴 층은 제미글립틴 타르타르산염 1.5 수화물을 포함한 첨가제를 모두 단순 혼합하여 준비하였다. 각각의 층을 이층정 타정기로 타정하여 이층정 정제를 얻은 후 이를 오파드라이 II를 사용하여 코팅하였다.In the composition of Table 1, 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.
[표 1][Table 1]
Figure PCTKR2020010841-appb-I000001
Figure PCTKR2020010841-appb-I000001
실시예 5 및 6: 코팅정의 제조Examples 5 and 6: Preparation of coated tablets
다음의 표 2의 조성으로 서방형 용출 양상의 메트포르민 정제에 속방형 용출 양상의 제미글립틴을 코팅공정으로 제조하였다.With the composition shown in Table 2 below, gemigliptin of an immediate-release pattern was prepared by a coating process on a metformin tablet of a sustained-release pattern.
[제조방법][Manufacturing method]
표 2의 조성 중 메트포르민 염산염, 히프로멜로오스, 카르복시메틸셀룰로오스 소듐 혼합물에 폴리비닐아세테이트 수분산액을 분무하여 과립화 한 후, 이의 건조물에 스테아린산마그네슘을 혼합하였다. 이 혼합물을 타정기로 타정하여 정제를 얻었다. 제미글립틴 타르타르산염 1.5 수화물, Aquarius 및 주석산을 정제수에 분산시켜 준비하였다. 정제코팅기에 메트포르민 염산염을 함유한 정제를 넣고 제미글립틴이 분산된 용액으로 코팅하여 제조하였다.In the 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.
[표 2][Table 2]
Figure PCTKR2020010841-appb-I000002
Figure PCTKR2020010841-appb-I000002
실험예: 정제의 질량 및 크기 측정Experimental Example: Measurement of the mass and size of tablets
실시예 1 내지 4의 이층정 및 시판중인 자누메트 서방정(sitagliptin phosphate monohydrate와 메트포르민 염산염의 복합제) 및 콤비글라이즈 서방정(saxagliptin monohydrate와 메트포르민 염산염의 복합제)의 질량 및 크기를 측정하여 다음의 표 3에 정리하였다.The mass and size of the double-layered tablets of Examples 1 to 4 and the commercially available Janumet sustained-release tablet (combination of sitagliptin phosphate monohydrate and metformin hydrochloride) and Combi-Glyse sustained-release tablet (combination of saxagliptin monohydrate and metformin hydrochloride) were measured and shown in Table 3 below. arranged.
[표 3][Table 3]
Figure PCTKR2020010841-appb-I000003
Figure PCTKR2020010841-appb-I000003

Claims (14)

  1. 메트포르민 또는 이의 약제학적으로 허용가능한 염, 폴리비닐아세테이트 수분산액, 및 셀룰로오스계 부형제를 포함하는 제1층; 및a first layer comprising metformin or a pharmaceutically acceptable salt thereof, an aqueous polyvinyl acetate dispersion, and a cellulosic excipient; and
    제미글립틴 또는 이의 약제학적으로 허용가능한 염 및 부형제를 포함하는 제2층을 포함하는 제2형 당뇨병 치료용 복합제제.A combination formulation for the treatment of type 2 diabetes, comprising a second layer comprising gemigliptin or a pharmaceutically acceptable salt thereof and an excipient.
  2. 제1항에 있어서, 상기 셀룰로오스계 부형제가 하이드로프로필 메틸셀룰로오스 또는 하이드로에틸 메틸셀룰로오스인 것을 특징으로 하는 제2형 당뇨병 치료용 복합제제.According to claim 1, wherein the cellulosic excipient is hydropropyl methyl cellulose or hydroethyl methyl cellulose, type 2 diabetes treatment complex formulation, characterized in that.
  3. 제2항에 있어서, 상기 셀룰로오스계 부형제가 하이드로프로필 메틸셀룰로오스인 것을 특징으로 하는 제2형 당뇨병 치료용 복합제제.[Claim 3] The combination formulation for the treatment of type 2 diabetes according to claim 2, wherein the cellulosic excipient is hydropropyl methylcellulose.
  4. 제1항에 있어서, 상기 메트포르민의 약제학적으로 허용가능한 염이 염산염인 것을 특징으로 하는 제2형 당뇨병 치료용 복합제제.The combination formulation for the treatment of type 2 diabetes according to claim 1, wherein the pharmaceutically acceptable salt of metformin is hydrochloride.
  5. 제1항에 있어서, 상기 제미글립틴의 약제학적으로 허용가능한 염이 타르타르산염인 것을 특징으로 하는 제2형 당뇨병 치료용 복합제제.The combination formulation for the treatment of type 2 diabetes according to claim 1, wherein the pharmaceutically acceptable salt of gemigliptin is tartrate.
  6. 제1항에 있어서, 상기 폴리비닐아세테이트 수분산액이 메트포르민 또는 이의 약제학적으로 허용가능한 염 100 중량부에 대하여 10 내지 40 중량부로 포함되는 것을 특징으로 하는 제2형 당뇨병 치료용 복합제제.[Claim 2] The combination formulation for treating type 2 diabetes according to claim 1, wherein the polyvinyl acetate aqueous dispersion is included in an amount of 10 to 40 parts by weight based on 100 parts by weight of metformin or a pharmaceutically acceptable salt thereof.
  7. 제1항에 있어서, 상기 셀룰로오스계 부형제가 메트포르민 또는 이의 약제학적으로 허용가능한 염 100 중량부에 대하여 3 내지 20 중량부로 포함되는 것을 특징으로 하는 제2형 당뇨병 치료용 복합제제.According to claim 1, wherein the cellulosic excipient is 3 to 20 parts by weight based on 100 parts by weight of metformin or a pharmaceutically acceptable salt thereof, the type 2 diabetes complex formulation for treatment.
  8. 제1항에 있어서, 메트포르민 또는 이의 약제학적으로 허용가능한 염, 폴리비닐아세테이트 수분산액, 및 셀룰로오스계 부형제를 포함하는 제1층; 및 제미글립틴 또는 이의 약제학적으로 허용가능한 염 및 부형제를 포함하는 제2층이 이층정의 형태인 것을 특징으로 하는 제2형 당뇨병 치료용 복합제제.According to claim 1, wherein the first layer comprising metformin or a pharmaceutically acceptable salt thereof, polyvinyl acetate aqueous dispersion, and a cellulosic excipient; and a second layer comprising gemigliptin or a pharmaceutically acceptable salt thereof and an excipient in the form of a double-layered tablet.
  9. 제1항에 있어서, 메트포르민 또는 이의 약제학적으로 허용가능한 염, 폴리비닐아세테이트 수분산액, 및 셀룰로오스계 부형제를 포함하는 제1층이 제미글립틴 또는 이의 약제학적으로 허용가능한 염 및 부형제를 포함하는 제2층에 의해서 코팅된 형태인 것을 특징으로 하는 제2형 당뇨병 치료용 복합제제.According to claim 1, wherein the first layer comprising metformin or a pharmaceutically acceptable salt thereof, polyvinyl acetate aqueous dispersion, and a cellulosic excipient comprises gemigliptin or a pharmaceutically acceptable salt thereof and an excipient A combination formulation for the treatment of type 2 diabetes, characterized in that it is in a coated form by two layers.
  10. 제8항에 있어서, 상기 제2층에 포함되는 부형제가 미결정 셀룰로오스인 것을 특징으로 하는 제2형 당뇨병 치료용 복합제제.The combination formulation for treating type 2 diabetes according to claim 8, wherein the excipient included in the second layer is microcrystalline cellulose.
  11. 제9항에 있어서, 상기 제2층에 포함되는 부형제가 코팅제인 것을 특징으로 하는 제2형 당뇨병 치료용 복합제제.[10] The combination formulation for treating type 2 diabetes according to claim 9, wherein the excipient included in the second layer is a coating agent.
  12. 제9항에 있어서, 상기 제2층이 주석산을 추가로 포함하는 것을 특징으로 하는 제2형 당뇨병 치료용 복합제제.[10] The combination formulation for treating type 2 diabetes according to claim 9, wherein the second layer further comprises tartaric acid.
  13. 제1항에 있어서, 상기 메트포르민 또는 이의 약제학적으로 허용가능한 염을 200 내지 2,000 mg 포함하는 것을 특징으로 하는 제2형 당뇨병 치료용 복합제제.The combination formulation for treating type 2 diabetes according to claim 1, wherein the metformin or a pharmaceutically acceptable salt thereof is contained in an amount of 200 to 2,000 mg.
  14. 제1항에 있어서, 상기 제미글립틴 또는 이의 약제학적으로 허용가능한 염을 10 내지 200 mg 포함하는 것을 특징으로 하는 제2형 당뇨병 치료용 복합제제.[Claim 2] The combination formulation for the treatment of type 2 diabetes according to claim 1, comprising 10 to 200 mg of the gemigliptin or a pharmaceutically acceptable salt thereof.
PCT/KR2020/010841 2020-08-14 2020-08-14 Composite formulation for treatment of type 2 diabetes mellitus WO2022034944A1 (en)

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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 (en) * 2010-10-14 2012-04-19 Japan Tobacco Inc. Combination therapy for use in treating diabetes
KR20130136718A (en) * 2012-06-05 2013-12-13 한미약품 주식회사 Sustained release and enteric metformin formulation and method for preparation thereof
KR20140045271A (en) * 2012-10-08 2014-04-16 주식회사 엘지생명과학 Combination drug comprising gemigliptin and metformin and method for the preparation thereof
KR20180002460A (en) * 2016-06-29 2018-01-08 주식회사 엘지화학 Composition, kit and combination therapy for treating type 2 diabetes mellitus and diabetic dyslipidemia
KR20200135095A (en) * 2019-05-24 2020-12-02 주식회사 엘지화학 Combination preparation for treating type 2 diabetes mellitus

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 (en) * 2010-10-14 2012-04-19 Japan Tobacco Inc. Combination therapy for use in treating diabetes
KR20130136718A (en) * 2012-06-05 2013-12-13 한미약품 주식회사 Sustained release and enteric metformin formulation and method for preparation thereof
KR20140045271A (en) * 2012-10-08 2014-04-16 주식회사 엘지생명과학 Combination drug comprising gemigliptin and metformin and method for the preparation thereof
KR20180002460A (en) * 2016-06-29 2018-01-08 주식회사 엘지화학 Composition, kit and combination therapy for treating type 2 diabetes mellitus and diabetic dyslipidemia
KR20200135095A (en) * 2019-05-24 2020-12-02 주식회사 엘지화학 Combination preparation for treating type 2 diabetes mellitus

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