KR20220165346A - Formulation comprising evogliptin with improved stability - Google Patents
Formulation comprising evogliptin with improved stability Download PDFInfo
- Publication number
- KR20220165346A KR20220165346A KR1020210073866A KR20210073866A KR20220165346A KR 20220165346 A KR20220165346 A KR 20220165346A KR 1020210073866 A KR1020210073866 A KR 1020210073866A KR 20210073866 A KR20210073866 A KR 20210073866A KR 20220165346 A KR20220165346 A KR 20220165346A
- Authority
- KR
- South Korea
- Prior art keywords
- evogliptin
- coating layer
- coating
- tablet
- present
- Prior art date
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- LCDDAGSJHKEABN-MLGOLLRUSA-N Evogliptin Chemical compound C1CNC(=O)[C@@H](COC(C)(C)C)N1C(=O)C[C@H](N)CC1=CC(F)=C(F)C=C1F LCDDAGSJHKEABN-MLGOLLRUSA-N 0.000 title claims abstract description 59
- 229950011259 evogliptin Drugs 0.000 title claims abstract description 58
- 239000000203 mixture Substances 0.000 title claims description 18
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- 239000010410 layer Substances 0.000 claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229960003105 metformin Drugs 0.000 claims abstract description 20
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- 230000008646 thermal stress Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 1
- 229960001254 vildagliptin Drugs 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Images
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- 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
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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)
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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
- A61K31/33—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
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- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Abstract
Description
본 발명은 디펩티딜펩티다제 IV (DPP-IV) 억제제인 에보글립틴 또는 이의 허용가능한 염과 메트포르민을 포함하는 제제에 있어서, 에보글립틴의 안정성이 개선된 제제에 관한 것이다.The present invention relates to a formulation containing evogliptin or an acceptable salt thereof, a dipeptidylpeptidase IV (DPP-IV) inhibitor, and metformin, in which the stability of evogliptin is improved.
DPP-IV 저해제는 2형 당뇨병 환자의 치료 또는 치료 효과 증진을 위해 개발된 약물로서, 현재 국내에 시판중인 DPP-IV 저해제로는 시타글립틴(Sitagliptin), 빌다글립틴(Vildagliptin), 삭사글립틴(Saxagliptin), 에보글립틴(Evogliptin) 등이 있다. DPP-IV 저해제는 당 항상성 유지에 중요한 역할을 하는 GLP-1의 혈중농도를 높게 유지하여 혈당을 조절하는 기전을 가지며, 안정적인 혈당 강하 효과를 보일 뿐만 아니라 저혈당과 체중 증가 등 기존 당뇨병 치료제의 부작용을 개선하였다.DPP-IV inhibitors are drugs developed to treat or improve the therapeutic effect of
메트포르민은 비구아나이드계의 제2형 당뇨병 치료제로서 인간 말초 조직에서 인슐린에 대한 감수성을 증가시키고, 또한, 장에서 글루코오스의 흡수를 억제하고, 간 글루코오스합성(gluconeogenesis)을 억제하며, 지방산 산화를 억제하는데 관련되어 있어, 당뇨환자에게 투여되는 약물이다.Metformin is a
DPP-IV 억제제와 메트포르민은 당업계에 널리 알려진 당뇨병 치료용 의약 화합물로서, 상기 의약 화합물은 각기 다른 메커니즘을 통해 항당뇨 효과를 발휘하기 때문에, 두 약물의 조합은 당뇨환자의 치료에 있어 좋은 효과를 발휘한다는 것으로 알려져 있다.DPP-IV inhibitors and metformin are pharmaceutical compounds for the treatment of diabetes widely known in the art, and since the pharmaceutical compounds exert antidiabetic effects through different mechanisms, the combination of the two drugs has a good effect in the treatment of diabetic patients. It is known to perform.
이에, DPP-IV 저해제를 포함하는 복합제의 개발이 활발하게 이루어지고 있으며, 대표적으로 ‘메트포르민과 DPP-IV 저해제’, ‘TZD계열과 DPP-IV 저해제’, ‘SGLT-2 저해제와 DPP-IV 저해제’ 조합이 있으며, 최근에는 ‘메트포르민, DPP-IV 저해제 및 SGLT-2 저해제’ 조합의 3제 복합제, ‘로수바스타틴과 DPP-IV 저해제’의 당뇨/고지혈 복합제 개발 역시 활발히 진행 중이다.Accordingly, the development of complexes containing DPP-IV inhibitors is actively being carried out, and representatively 'metformin and DPP-IV inhibitors', 'TZD series and DPP-IV inhibitors', 'SGLT-2 inhibitors and DPP-IV inhibitors' ' combination, and recently, a three-drug combination of 'metformin, a DPP-IV inhibitor and a SGLT-2 inhibitor', and a diabetes/hyperlipidemia combination of 'rosuvastatin and a DPP-IV inhibitor' are also being actively developed.
그런데, DPP-IV 억제제를 복합제로 개발하던 중에 다른 약물과의 상호작용을 통해 DPP-IV 억제제의 안정성에 영향을 미친다는 사실 뿐만 아니라, DPP-IV 억제제의 접촉을 억제하는 격리층의 양 또는 비율이 DPP-IV 억제제의 안정성에 영향을 미친다는 사실이 발견되어, 장기간 저장에도 약물이 분해되지 않고 의약상 허용되지 않는 유연물질의 발생을 최소화시킬 수 있는 제형의 개발이 시도되었다.However, during the development of a DPP-IV inhibitor as a combination drug, not only the fact that the stability of the DPP-IV inhibitor is affected through interaction with other drugs, but also the amount or ratio of the isolation layer that inhibits the contact of the DPP-IV inhibitor It was discovered that this affects the stability of the DPP-IV inhibitor, and development of a formulation capable of minimizing the generation of pharmaceutically unacceptable related substances without decomposition even during long-term storage was attempted.
복합제 개발에 있어서는 약물이 체내에 흡수될 수 있을 정도로 적합한 방출을 발휘하여야 하지만, 각 물질의 물리·화학적 특성이 각기 다르기 때문에 복합제의 제형개발은 용이하지 않고, 바람직한 방출을 발휘하는 제형을 개발해도 잔류용매 등의 문제가 발생하여 적용이 어려운 경우가 있다. In the development of a combination drug, it is necessary to exhibit a release that is suitable for the drug to be absorbed into the body. There are cases in which application is difficult due to problems such as solvents.
상기 복합제제의 개발 방향은 약물 간 배합적합성 또는 방출 속도의 차이를 극복하기 위해 이층정 또는 약물코팅정의 제제형태로 개발되었는데, 약물코팅정은 정제 크기 감소를 통한 복약순응도 증진이라는 장점이 있어서 활발히 개발이 이뤄져왔으며, 임상적으로 널리 사용되고 있는 대표적인 예로는 자누메트엑스알서방정(Janumet®XR, WO 2009-099734 A1),콤비글라이즈(Kombiglyze®XR, WO 2005-117841 A1) 및 테넬리아엠서방정(Tenelia®MSR, 대한민국 등록특허 10-1526825)이 있다.The development direction of the combination preparation was developed in the form of a double-layer tablet or drug-coated tablet to overcome the difference in compatibility or release rate between drugs. Representative examples widely used clinically are Janumet XR, WO 2009-099734 A1, Kombiglyze ® XR , WO 2005-117841 A1, and Tenelia M sustained-release tablets. ® MSR, Korean Registered Patent No. 10-1526825).
본 발명의 발명자들 역시 이와 같은 약물코팅정의 장점을 활용하기 위하여 본 출원인이 개발한 DPP-IV 저해제 신약인 에보글립틴(Suganon®, 대한민국 등록특허 10-1007497)을 포함하는 약물코팅정을 개발하고자 하였다. 이를 위해, 본 발명의 발명자들은 WO 2009-099734 A1(자누메트엑스알 특허), WO 2005-117841 A1(콤비글라이즈 특허)의 실시예와 같이 코팅기제로서 범용적으로 사용되는 폴리비닐알코올 또는 하이드록시프로필메틸셀룰로오스를 적용하여 에보글립틴 약물코팅정을 개발하고자 하였는데, 연구 개발 과정 중에 에보글립틴이 코팅 시에 무정형으로 변화하며 안정성이 저하되어 유연물질이 빠른 속도로 증가하는 사실을 발견하였다. 장기간 저장에도 유연물질의 발생을 최소화할 수 있는 제형의 개발이 제약업계에서 필수적이라는 점을 고려할 때, 본 과제는 반드시 해결이 필요하다 할 수 있다.The inventors of the present invention also want to develop drug-coated tablets containing Evogliptin (Suganon ® , Korean Registered Patent No. 10-1007497), a new DPP-IV inhibitor developed by the present applicant, in order to utilize the advantages of such drug-coated tablets. did To this end, the inventors of the present invention are polyvinyl alcohol or hydride, which is universally used as a coating base, as in the examples of WO 2009-099734 A1 (Janumet XR patent) and WO 2005-117841 A1 (Combiglise patent) An attempt was made to develop evogliptin drug-coated tablets by applying hydroxypropylmethylcellulose. During the research and development process, it was found that evogliptin changes to an amorphous form during coating and decreases stability, resulting in a rapid increase in related substances. Considering that it is essential in the pharmaceutical industry to develop a formulation capable of minimizing generation of related substances even during long-term storage, it can be said that this problem must be solved.
특히, 상기 종래기술인 WO 2009-099734 A1(자누메트엑스알 특허)에서 개시하고 있는 시타글립틴의 속방층 제제화 기술은 휘발성이 낮은 용매를 사용하기 때문에 장시간의 코팅 공정을 거쳐야만 시타글립틴 속방층을 완성할 수 있다는 큰 문제점이 존재하는데, 대한민국 공개특허공보 10-2020-0021774 A에는 상기 문제점을 해결하기 위하여 고휘발성 유기용매에 용해하여 코팅액을 제조하는 방법을 제시하였으나, 이 기술은 잔류 용매 발생 가능성에 따른 독성 또는 허가 상의 문제를 야기할 수 있다는 문제점이 발생한다. 아울러 최근에는 작업자의 안전 및 친환경 공정을 위해 유기용매 사용을 지양하는 추세이다.In particular, the sitagliptin fast-release layer formulation technology disclosed in WO 2009-099734 A1 (Janumet XR patent), which is a prior art, uses a solvent with low volatility. There is a big problem that can be completed, but Korean Patent Publication No. 10-2020-0021774 A suggests a method of preparing a coating solution by dissolving in a highly volatile organic solvent to solve the above problem, but this technology has the possibility of generating residual solvent. There arises a problem that may cause toxicity or permission problems according to. In addition, in recent years, the use of organic solvents has been discouraged for the safety of workers and eco-friendly processes.
이에 본 발명의 발명자들은 ‘메트포르민과 에보글립틴’의 복합제를 개발하는 과정에서 에보글립틴의 안정성을 향상시키기 위한 연구를 수행하였으며, 코팅층 내에서 에보글립틴 유연물질 발생을 억제할 수 있는 고분자로서 에틸셀룰로오스를 도출하였다. 최종적으로, 안정성 개선을 위한 에틸셀룰로오스 및 적절한 코팅기제를 정제수에 용해 또는 분산시킨 에보글립틴 코팅 조성을 발견하여, 다양한 약물군과의 복합제제 개발에 활용성이 높은 본 발명을 완성하게 되었다.Accordingly, the inventors of the present invention conducted research to improve the stability of evogliptin in the process of developing a combination of 'metformin and evogliptin', and as a polymer capable of suppressing the generation of evogliptin related substances in the coating layer, Ethyl cellulose was derived. Finally, an evogliptin coating composition obtained by dissolving or dispersing ethyl cellulose and an appropriate coating agent in purified water for stability improvement was discovered, and the present invention, which is highly usable for the development of a combination preparation with various drug groups, was completed.
본 발명은 메트포르민 및 에보글립틴 또는 이의 허용가능한 염을 포함하는 복합제제에 있어서, 에보글립틴에서 유연물질이 생성되는 것을 억제함으로써 에보글립틴의 안정성이 개선된 복합제제를 제공하는 것을 목적으로 한다.An object of the present invention is to provide a combination preparation containing metformin and evogliptin or an acceptable salt thereof, in which the stability of evogliptin is improved by suppressing the formation of related substances in evogliptin. .
상기 과제를 해결하기 위하여, 본 발명은 메트포르민을 포함하는 내층; 및 내층을 코팅시킨 코팅층을 포함하고, 상기 코팅층에 에보글립틴 또는 이의 허용가능한 염과 에틸셀룰로오스를 포함하는 것인, 코팅층 내 에보글립틴의 안정성이 개선된 코팅된 정제를 제공한다.In order to solve the above problems, the present invention is an inner layer containing metformin; and a coating layer coated with an inner layer, wherein the coating layer contains evogliptin or an acceptable salt thereof and ethyl cellulose, and the stability of evogliptin in the coating layer is improved.
본 발명의 코팅된 정제는 내층에 메트포르민을 포함하며, 코팅층에 에보글립틴 또는 이의 허용가능한 염을 포함하고, 고분자인 에틸셀룰로오스를 함께 코팅시킨 것으로서, 본 발명의 코팅층에는 에보글립틴 또는 이의 허용가능한 염은 에보글립틴으로서 2.5 mg/T 내지 10 mg/T로 존재하고, 에틸셀룰로오스는 코팅층 총 중량의 25 내지 60 중량%로 존재한다.The coated tablet of the present invention contains metformin in the inner layer, evogliptin or an acceptable salt thereof in the coating layer, and ethyl cellulose, which is a polymer, is coated together, and the coating layer of the present invention contains evogliptin or an acceptable salt thereof. The salt is present as evogliptin at 2.5 mg/T to 10 mg/T, and ethyl cellulose is present at 25 to 60% by weight of the total weight of the coating layer.
본 발명에서, 에보글립틴의 ‘약학적으로 허용되는 염’은 무기 또는 유기 염기 및 무기 또는 유기산을 포함하는 약학적으로 허용되는 비독성 염기 또는 산으로부터 제조되는 염을 말한다. 무기 염기로부터 유도되는 염은 알루미늄, 암모늄, 칼슘, 구리, 제이철, 제일철, 리튬, 마그네슘, 망간 염, 망간, 칼륨, 나트륨, 아연 등을 포함한다. 특히 암모늄, 칼슘, 마그네슘, 칼륨 또는 나트륨 염이 바람직하다. 고형의 염은 하나 이상의 결정 구조로 존재할 수 있고, 또한 수화물 형태로 존재할 수 있다. 약학적으로 허용되는 비독성 유기 염기로부터 유도된 염은 일급, 이급 또는 삼급 아민, 천연적으로 치환된 아민을 포함하는 치환된 아민, 아민 환, 또는 아르기닌, 베타인, 카페인, 콜린, N,N'-디벤질에틸렌디아민, 디에틸아민, 2-디에틸아미노에탄올, 2-디메틸아미노에탄올, 에탄올아민, 에틸렌디아민, N-에틸몰폴린, N-에틸피페리딘, 글루카민, 글루코사민, 히스티딘, 하이드라바민, 이소프로필아민, 라이신, 메틸글루카민, 포폴린, 피페라진, 피페리딘, 폴리아민 수지, 프로카인, 퓨린, 테오브로민, 트리에틸아민, 트리메틸아민, 트리프로필아민, 트로메타민 등과 같은 염기성 이온 교환 수지를 포함한다. 무기 및 유기산으로부터 제조되는 염은 아세트산, 벤젠술폰산, 벤조산, 캄포르술폰산, 시트르산, 에탄술폰산, 퓨마르산, 글루콘산, 글루탐산, 하이드로브롬산, 염산, 이세티온산, 락트산, 말레산, 말산, 만델산, 메탄술폰산, 뮤크산, 질산, 파모산, 판토텐산, 인산, 숙신산, 황산, 타르타르산, p-톨루엔술폰산, 아디프산 등을 포함한다. 아세트산, 시트르산, 염산, 말산, 인산, 숙신산, 타르타르산 또는 아디프산이 특히 바람직하다.In the present invention, the 'pharmaceutically acceptable salt' of evogliptin refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid including an inorganic or organic base and an inorganic or organic acid. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese salts, manganese, potassium, sodium, zinc and the like. In particular, ammonium, calcium, magnesium, potassium or sodium salts are preferred. Solid salts may exist in one or more crystal structures and may also exist in the form of hydrates. Salts derived from pharmaceutically acceptable non-toxic organic bases include primary, secondary or tertiary amines, substituted amines including naturally substituted amines, amine rings, or arginine, betaine, caffeine, choline, N,N '-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, Hydrabamine, isopropylamine, lysine, methylglucamine, popolin, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. Basic ion exchange resins are included. Salts prepared from inorganic and organic acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, delic acid, methanesulfonic acid, muric acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, adipic acid and the like. Acetic acid, citric acid, hydrochloric acid, malic acid, phosphoric acid, succinic acid, tartaric acid or adipic acid are particularly preferred.
본 발명은 코팅층에 에보글립틴 또는 이의 허용가능한 염과 함께 에틸셀룰로오스를 포함시킴으로써, 에보글립틴 또는 이의 허용가능한 염의 안정성을 개선할 수 있는 것을 특징으로 한다.The present invention is characterized in that the stability of evogliptin or an acceptable salt thereof can be improved by including ethyl cellulose together with evogliptin or an acceptable salt thereof in a coating layer.
에보글립틴은 총 유연물질의 함량이 2.0 중량% 이하로 관리되고 있다. 그러므로 본 발명의 메트포르민 및 에보글립틴을 포함하는 복합제제는 열가혹 조건(60℃,HDPE bottle,Closed)에서 4주간 보관하는 경우, 에보글립틴 총 유연물질의 함량이 2.0 중량% 이하여야 하고, 바람직하게는 1.0 중량% 이하이다.Evogliptin has a total related substance content of 2.0% by weight or less. Therefore, when the combined preparation containing metformin and evogliptin of the present invention is stored for 4 weeks under heat-severe conditions (60°C, HDPE bottle, closed), the total related substance content of evogliptin should be 2.0% by weight or less, Preferably it is 1.0% by weight or less.
본 발명은 외층인 코팅층에 에보글립틴 및 에틸셀룰로오스를 포함시킴으로써 유연물질 생성이 촉진될 수 있는 에보글립틴 안정성 저하 문제를 해결하였다. 즉, 코팅액 내에 용해된 에보글립틴은 코팅 공정 중 급격한 고형화로 인해서 무정형으로 변할 수 있는데, 이로 인하여 에보글립틴 유연물질 생성을 촉진할 수 있다. 본 발명은 에틸셀룰로오스를 코팅액 내에 포함시켜 에보글립틴의 유연물질 생성을 억제하였다.The present invention solves the problem of deterioration in the stability of evogliptin, which can promote production of related substances, by including evogliptin and ethyl cellulose in the outer coating layer. That is, evogliptin dissolved in the coating solution may change into an amorphous form due to rapid solidification during the coating process, which may promote the production of evogliptin related substances. In the present invention, the production of related substances of evogliptin was suppressed by including ethyl cellulose in the coating solution.
본 발명은 상기 코팅액에 코팅기제를 포함할 수 있다. 에틸셀룰로오스를 코팅층에 적용할 경우, 에보글립틴 코팅층의 가소성을 최소화하여 유연물질의 발생을 억제할 수 있지만, 코팅층의 가소성이 낮아 코팅층 파손 등의 정제 불량이 나타날 수 있다. 본 발명에서 이러한 문제가 발생되지 않도록 코팅액에 특정 코팅기제를 포함한다. 바람직하게 본 발명의 코팅기제는 중쇄중성지방, 올레산, 폴리비닐알코올, 히드록시프로필메틸셀룰로오스, 탈크, 산화티탄, 글리세릴모노카프릴로카프레이트, 라우릴황산나트륨, 레시틴, 잔탄검, 폴리에틸렌글리콜 및 이들의 혼합물로 이루어진 군으로부터 선택될 수 있다.In the present invention, a coating agent may be included in the coating solution. When ethyl cellulose is applied to the coating layer, it is possible to suppress the generation of related substances by minimizing the plasticity of the evogliptin coating layer. In the present invention, a specific coating agent is included in the coating solution so that this problem does not occur. Preferably, the coating base of the present invention is medium chain triglyceride, oleic acid, polyvinyl alcohol, hydroxypropylmethylcellulose, talc, titanium oxide, glyceryl monocaprylocaprate, sodium lauryl sulfate, lecithin, xanthan gum, polyethylene glycol and these It may be selected from the group consisting of mixtures of.
또한, 본 발명의 내층은, 메트포르민 또는 그의 약학적으로 허용 가능한 염을 포함하며, ‘약학적으로 허용되는 염’은 무기 또는 유기 염기 및 무기 또는 유기산을 포함하는 약학적으로 허용되는 비독성 염기 또는 산으로부터 제조되는 염이면 가능하고, 바람직하게는 염산염이다. 본 발명의 내층에 포함되는 메트포르민 또는 그의 약학적으로 허용 가능한 염은 내층 총 중량의 약 75 내지 85 중량% 범위의 양으로 존재한다.In addition, the inner layer of the present invention includes metformin or a pharmaceutically acceptable salt thereof, and 'pharmaceutically acceptable salt' refers to a non-toxic pharmaceutically acceptable base including an inorganic or organic base and an inorganic or organic acid; A salt prepared from an acid is possible, and a hydrochloride salt is preferred. Metformin or a pharmaceutically acceptable salt thereof included in the inner layer of the present invention is present in an amount ranging from about 75 to 85% by weight of the total weight of the inner layer.
또한, 본 발명의 내층에는 임의로 1종 이상의 결합제, 바람직하게는 하이드록시프로필셀룰로오스가 내층 총 중량의 1 내지 10 중량% 범위의 양으로 존재할 수 있으며; 임의로 1종 이상의 방출조절제, 바람직하게는 메타아크릴산공중합체, 하이드록시프로필메틸셀룰로오스, 카보머 또는 이들의 혼합물이 내층 총 중량의 12 내지 25 중량% 범위의 양으로 존재할 수 있고; 임의로 1종 이상의 활택제, 바람직하게는 스테아린산 마그네슘이 내층 총 중량의 0.2 내지 2 중량% 범위의 양으로 존재할 수 있다.In addition, one or more binders, preferably hydroxypropylcellulose, may optionally be present in the inner layer of the present invention in an amount ranging from 1 to 10% by weight of the total weight of the inner layer; Optionally, at least one release controlling agent, preferably methacrylic acid copolymer, hydroxypropylmethylcellulose, carbomer or a mixture thereof, is present in an amount of 12 to 25% of the total weight of the inner layer. may be present in an amount in the range of weight percent; Optionally, one or more lubricants, preferably magnesium stearate, may be present in an amount ranging from 0.2 to 2% by weight of the total weight of the inner layer.
또한, 본 발명에서 내층은 에보그립틴의 안정성에 영향을 미치지 않는다. 그러므로 본 발명의 복합 제제의 내층에는 메트포르민 이외에 펜포르민 등의 빈구아니드; 아카르보스, 미글리톨 등의 글루코시다제 억제제; 인슐린, 인슐린 분비 촉진제 또는 인슐린 증감제; 레파글리니드, 나테글리니드 등의 메글리티니드; 글리메피리드, 글리부리드, 글리클라지드, 클로로프로프아미드, 글리피지드 등의 술포닐우레아계 약물; 글루코반스 등의 빈구아니드/글리부리드 조합물; 트리글리타존, 이사글리타존, 피오글리타존, 피라글리타자르, 엔글리타존, 다르글리타존, 이사글리타존, 레글리타자르, 리보글리타존, 리라글루티드 등의 티아졸리딘디온계 약물; PPAR-알파 효능제; PPAR-감마 효능제; PPAR 알파/감마 이중 효능제; 글리코겐 포스포릴라제; 지방산 결합 단백질(aP2)의 억제제; 글루카곤-유사펩티드(GLP-1), 또는 GLP-1 수용체의 다른 효능제; 및 다파글플로진 등의 SGLT-2 저해제를 비롯하여, 당업계에 공지된 다양한 종류의 당뇨병 치료제를 포함할 수 있다.In addition, the inner layer in the present invention does not affect the stability of evogriptin. Therefore, in addition to metformin, binguanides such as phenformin; glucosidase inhibitors such as acarbose and miglitol; insulin, insulin secretagogues or insulin sensitizers; meglitinides such as repaglinide and nateglinide; sulfonylurea drugs such as glimepiride, glyburide, gliclazide, chloropropamide, and glipizide; binguanide/glyburide combinations such as glucovans; thiazolidinedione drugs such as triglitazone, isaglitazone, pioglitazone, piraglitazar, englitazone, darglitazone, isaglitazone, leglitazar, rivoglitazone, and liraglutide; PPAR-alpha agonists; PPAR-gamma agonists; PPAR alpha/gamma dual agonists; glycogen phosphorylase; inhibitors of fatty acid binding protein (aP2); glucagon-like peptide (GLP-1), or other agonists of the GLP-1 receptor; and SGLT-2 inhibitors such as dapagleflozin and various types of antidiabetic agents known in the art.
또한, 본 발명은In addition, the present invention
a) 내층 정제를 제공하는 단계;a) providing an inner layer tablet;
b) 에보글립틴 또는 이의 허용가능한 염, 에틸셀룰로오스 및 코팅기제를 포함하는 코팅액으로 코팅층(의약 함유)을 형성시켜 코팅층 제형으로 정제를 코팅하는 단계; 및b) forming a coating layer (containing a drug) with a coating solution containing evogliptin or an acceptable salt thereof, ethyl cellulose and a coating agent, and coating the tablet with the coating layer formulation; and
c) 상기 코팅된 정제를 건조하여 본 발명의 코팅된 정제를 형성시키는 단계를 포함하는 코팅된 정제 제조 방법이 제공된다.c) there is provided a method for manufacturing a coated tablet comprising the step of drying the coated tablet to form the coated tablet of the present invention.
본 발명의 코팅된 정제에 사용되는 내층은 다양한 공정 및 부형제의 첨가 순서에 의해 제조될 수 있으며, 바람직하게는 습식 과립 공정 및 타정 공정을 통해 제조될 수 있다.The inner layer used in the coated tablet of the present invention may be prepared by various processes and the order of adding excipients, preferably through a wet granulation process and a tableting process.
본 발명에 따른 코팅액은 정제수에 에보글립틴 타르타르산염 및 에틸셀룰로오스 20cP를 포함하여 하기 [표 2]에 기재된 조성으로 하여 제조할 수 있다.The coating solution according to the present invention can be prepared with the composition shown in [Table 2], including evogliptin tartrate and 20 cP of ethyl cellulose in purified water.
본 발명의 코팅된 정제는 제II형 당뇨병에 대해 포유동물, 예를 들어 인간, 개과 동물 및 고양이과 동물의 치료에 유용하다.The coated tablets of the present invention are useful for the treatment of mammals, such as humans, canines and felines, for type II diabetes.
본 발명에 따른 코팅된 정제는 코팅층에 에틸셀룰로오스를 적용하여 에보글립틴의 유연물질 발생을 억제함으로써, 안정성 개선 및 충분한 유효기간을 확보할 수 있다는 장점이 있다. 또한, 에보글립틴을 코팅층에 적용시킴으로써 복합제제 내 에보글립틴부 비율 최소화를 통한 정제 크기 감소 효과를 얻을 수 있다.The coated tablet according to the present invention has the advantage of improving stability and securing a sufficient shelf life by suppressing generation of related substances of evogliptin by applying ethyl cellulose to the coating layer. In addition, by applying evogliptin to the coating layer, the tablet size reduction effect can be obtained through minimizing the ratio of the evogliptin part in the combination preparation.
도 1은 본 발명에 따른 실시예 및 비교예의 안정성 시험에서 에보글립틴의 유연물질을 분석한 결과를 나타낸 그래프이다.
도 2는 실시예 1의 실물 사진 및 정제 단면의 주사전자현미경 이미지이며, 코팅층이 형성된 것을 단면 이미지를 통해 확인할 수 있다.1 is a graph showing the results of analyzing related substances of evogliptin in the stability test of Examples and Comparative Examples according to the present invention.
2 is a scanning electron microscope image of a real photograph and a cross-section of a tablet of Example 1, and it can be confirmed through the cross-sectional image that a coating layer is formed.
이하, 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다.Hereinafter, examples will be described in detail to aid understanding of the present invention.
본 발명에서 사용되는 모든 용어는, 특별히 정의되지 않는 이상, 본 발명의 관련 분야에서 일반적으로 이해하는 바와 같은 의미로 사용된다. 또한, 본 발명의 이해를 돕기 위하여 수록된 실시예 및 실험예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 이에 한정되는 것은 아니다. 본 명세서에 기재된 바람직한 방법이나 시료 외에도 이와 유사하거나 동등한 것들 역시 본 발명의 범주에 포함된다.All terms used in the present invention, unless specifically defined, are used in the same meaning as commonly understood in the related field of the present invention. In addition, the examples and experimental examples recorded to aid understanding of the present invention are merely illustrative of the contents of the present invention, but the scope of the present invention is not limited thereto. In addition to the preferred methods or samples described herein, similar or equivalents thereof are also included in the scope of the present invention.
<실시예 1 내지 7> <Examples 1 to 7> 본 발명에 따른 복합제제의 제조Preparation of combination preparation according to the present invention
단계 1: 메트포르민을 포함하는 내층의 제조 Step 1: Preparation of inner layer containing metformin
1) 과립의 조제1) Preparation of granules
하기 표 1에 기재되어 있는 정제수와 에탄올의 혼합액에 메타아크릴산공중합체, 하이드록시프로필셀룰로오스 및 적색산화철을 잘 분산시킨 뒤, 유동층 과립기 내에서 메트포르민염산염에 분무하여 제립, 건조 및 정립하였다.After well dispersing methacrylic acid copolymer, hydroxypropyl cellulose and red iron oxide in a mixture of purified water and ethanol shown in Table 1 below, spraying on metformin hydrochloride in a fluid bed granulator was followed by granulation, drying and sizing.
2) 후혼합2) Post mixing
1)의 정립물을 혼합기에 넣고 하이드록시프로필메틸셀룰로오스 및 카보머를 혼합한 뒤, 체과한 스테아린산마그네슘으로 활택하여 최종 혼합물을 제조하였다.The sized product of 1) was put into a mixer, hydroxypropylmethylcellulose and carbomer were mixed, and sieved was lubricated with magnesium stearate to prepare a final mixture.
3) 타정3) tableting
2)의 최종 혼합물을 로타리 타정기(PR1000, PTK-GB, 한국)를 이용하여 타정하여 총 중량 1270.4mg의 정제(내층)를 제조하였다.The final mixture of 2) was compressed into tablets using a rotary tablet press (PR1000, PTK-GB, Korea) to prepare tablets (inner layer) having a total weight of 1270.4 mg.
단계 2: 에보글립틴을 포함하는 코팅층의 제조 Step 2: Preparation of a coating layer containing evogliptin
1) 코팅액의 제조1) Preparation of coating solution
정제수에 에보글립틴 타르타르산염 및 에틸셀룰로오스를 포함하여 하기 표 2의 조성 성분을 교반기에 넣고 완전히 분산시켜 코팅액을 제조하였다.A coating solution was prepared by putting the ingredients in Table 2 below, including evogliptin tartrate and ethyl cellulose, in purified water in a stirrer and completely dispersing them.
2) 외층(코팅층)의 코팅2) Coating of the outer layer (coating layer)
상기 1)에서 제조된 코팅액을 단계 1에서 제조된 메트포르민을 포함하는 내층 정제에 코팅기(Diosna, 독일) 내에서 분무, 건조하여 총 중량 1,330.4mg의 코팅된 정제를 수득하고 각각 실시예 1 내지 7로 하였다.The coating solution prepared in 1) was sprayed and dried on the inner-layer tablet containing metformin prepared in
상기 실시예 1 내지 7은 에보글립틴 타르타르산염, 에틸셀룰로오스, 탈크, 알루라레드 AC 알루미늄레이크, 글리세릴모노카프릴로카프레이트를 포함하고 있다. 실시예 1 내지 3은 에틸셀룰로오스의 양을 변화시킨 것이다. 실시예 4 내지 5는 실시예 1과 비교하여 각각 폴리비닐알코올 및 히드록시프로필메칠셀룰로오스를 추가적으로 포함하며, 실시예 6 내지 7은 실시예 1과 비교하여 에보글립틴의 양을 변화시킨 것이다.Examples 1 to 7 contained evogliptin tartrate, ethyl cellulose, talc, Allura Red AC aluminum lake, and glyceryl monocaprylocaprate. In Examples 1 to 3, the amount of ethyl cellulose was varied. Examples 4 to 5 additionally contain polyvinyl alcohol and hydroxypropylmethylcellulose, respectively, compared to Example 1, and Examples 6 to 7 are those in which the amount of evogliptin was changed compared to Example 1.
<비교예 1 내지 7> <Comparative Examples 1 to 7> 코팅층에 에틸셀룰로오스를 포함하지 않는 복합제제의 제조Preparation of composite preparations not containing ethyl cellulose in the coating layer
단계 1: 메트포르민을 포함하는 내층의 제조 Step 1: Preparation of inner layer containing metformin
상기 실시예 1의 단계 1과 동일한 방법으로 메트포르민을 포함하는 내층을 제조하였다.An inner layer containing metformin was prepared in the same manner as in
단계 2: 에보글립틴을 포함하는 코팅층의 제조 Step 2: Preparation of a coating layer containing evogliptin
하기 표 3에 기재된 조성으로 상기 본 발명에 따른 실시예 1의 단계 2와 동일한 방법으로 코팅된 정제를 수득하고 비교예 1 내지 7로 하였다.Tablets coated with the composition shown in Table 3 in the same manner as in
상기 비교예 1 내지 7은 약물코팅층에 포함되는 에틸셀루로오스가 에보글립틴의 안정성에 미치는 영향을 확인하기 위함이다. 즉, 비교예 1, 5 내지 7은 WO 2005-117841 A1(콤비글라이즈 특허)에서 약물 코팅층에 사용한 폴리비닐알코올을 포함하는 정제이고, 비교예 2는 WO 2009-099734 A1(자누메트엑스알 특허)에서 약물 코팅층에 사용한 하이드록시프로필메칠셀룰로오스를 포함하는 정제이다. 특히, 비교예 1 및 2는 각각 상기 실시예 4 및 5의 조성에서 에틸셀룰로오스를 제외한 것이다. 또한, 비교예 3은 히드록시프로필메칠셀룰로오스 아세테이트 숙시네이트, 비교예 4는 메타크릴레이트 공중합체 (Eudragit®E100)를 코팅층에 포함하는 정제이다.Comparative Examples 1 to 7 are for confirming the effect of ethyl cellulose included in the drug coating layer on the stability of evogliptin. That is, Comparative Examples 1 and 5 to 7 are tablets containing polyvinyl alcohol used in the drug coating layer in WO 2005-117841 A1 (CombiGlyze patent), and Comparative Example 2 is a tablet containing WO 2009-099734 A1 (JanumexR patent) ) is a tablet containing hydroxypropylmethylcellulose used in the drug coating layer. In particular, Comparative Examples 1 and 2 exclude ethyl cellulose from the compositions of Examples 4 and 5, respectively. Further, Comparative Example 3 is a tablet containing hydroxypropylmethylcellulose acetate succinate, and Comparative Example 4 is a tablet containing a methacrylate copolymer (Eudragit ® E100) in a coating layer.
<실험예 1> <Experimental Example 1> 안정성 시험 (열가혹 조건 및 가속 조건)Stability test (thermal stress conditions and accelerated conditions)
상기 실시예 1 내지 7, 비교예 1 내지 7에서 제조된 제제를 60℃밀폐된 HDPE bottle에 보관하고 개시시, 2주 및 4주 시점에서 총 유연물질의 양을 평가하여 표 4 및 도 1에 나타내었다.The preparations prepared in Examples 1 to 7 and Comparative Examples 1 to 7 were stored in a sealed HDPE bottle at 60° C., and the total amount of related substances was evaluated at the start, 2 weeks and 4 weeks, and shown in Table 4 and FIG. showed up
또한, 본 발명에 따른 실시예 1 및 4에서 제조된 제제를 40℃,75%RH 밀폐된 HDPE bottle에 보관하고 개시시, 1개월, 2개월 및 6개월 시점에서 총 유연물질의 양을 평가하여 그 결과를 표 5에 나타내었다.In addition, the preparations prepared in Examples 1 and 4 according to the present invention were stored in a sealed HDPE bottle at 40 ° C. and 75% RH, and the amount of total related substances was evaluated at the time of initiation, 1 month, 2 months and 6 months. The results are shown in Table 5.
상기 표 4에 기재된 결과에서 알 수 있는 바와 같이 코팅층의 에틸셀룰로오스 유무에 따라 유연물질 발생량이 큰 차이를 나타냄을 알 수 있다. 실시예 1 내지 3은 에틸셀룰로오스만을 주요 코팅기제로 포함하는 조성으로서 유연물질 발생 억제효과가 매우 뛰어나다. 즉, 실시예 1 내지 3은 열가혹 조건 하에서 충분히 안정함이 확인되었으며, 실시예 2는 에틸셀룰로오스 감량에 따라 유연물질 발생 속도가 다소 증가하였다. 실시예 3은 에틸셀룰로오스 증량에도 유의적인 변화를 보이지 않았다. 또한, 실시예 4는 에틸셀룰로오스 외에 폴리비닐알코올을 포함함에도 실시예 1과 유사한 유연물질 발생 속도를 나타내었으며, 가속시험 6개월에서도 충분히 안정함을 확인하였고, 실시예 6 및 7을 통해서는 코팅층 내 에보글립틴의 양을 변화시킬 경우에도 열가혹 조건 하에서 충분한 안정성을 확보할 수 있음을 확인하였다.As can be seen from the results in Table 4, it can be seen that the amount of related substances produced varies greatly depending on the presence or absence of ethyl cellulose in the coating layer. Examples 1 to 3 are compositions containing only ethyl cellulose as a main coating material, and have an excellent effect of inhibiting generation of related substances. That is, Examples 1 to 3 were confirmed to be sufficiently stable under heat stress conditions, and in Example 2, the generation rate of related substances slightly increased according to the amount of ethyl cellulose. Example 3 did not show a significant change even with the increase in ethyl cellulose. In addition, Example 4 showed a similar rate of generation of related substances to Example 1 even though polyvinyl alcohol was included in addition to ethyl cellulose, and it was confirmed that it was sufficiently stable even after 6 months of accelerated testing. It was confirmed that sufficient stability can be secured under heat stress conditions even when the amount of evogliptin is changed.
이에 대하여, 비교예 1, 2, 5 내지 7은 각각 폴리비닐알코올 또는 히드록시프로필메칠셀룰로오스만을 주요 코팅기제로 포함하는 조성으로서 높은 가소성에 의해 유연물질이 매우 빠르게 발생하므로, 에보글립틴 코팅 조성으로서 부적합하다. 또한, 비교예 3에서 히드록시프로필메칠셀룰로오스 아세테이트 숙시네이트를 코팅층에 포함하는 정제, 비교예 4에서 메타크릴레이트 공중합체 (Eudragit®E100)를 코팅층에 포함하는 정제 역시 유연물질이 매우 빠르게 발생하므로, 에보글립틴 코팅 조성으로서 부적합하다.In contrast, Comparative Examples 1, 2, and 5 to 7 are compositions containing only polyvinyl alcohol or hydroxypropylmethylcellulose as a main coating material, respectively, and related substances are generated very quickly due to high plasticity, so they are unsuitable as evogliptin coating compositions Do. In addition, the tablets containing hydroxypropylmethylcellulose acetate succinate in the coating layer in Comparative Example 3 and the tablets containing methacrylate copolymer (Eudragit ® E100) in the coating layer in Comparative Example 4 also generate related substances very quickly, Evogliptin is unsuitable as a coating composition.
그러므로 본 발명은 코팅층에 에틸셀룰로오스를 적용하여 에보글립틴의 유연물질 발생을 억제함으로써, 안정성 개선 및 충분한 유효기간을 확보할 수 있다.Therefore, in the present invention, by applying ethyl cellulose to the coating layer to suppress generation of related substances of evogliptin, it is possible to improve stability and secure a sufficient shelf life.
Claims (6)
내층을 코팅시킨 코팅층
을 포함하고, 상기 코팅층에 에보글립틴 또는 이의 허용가능한 염, 에틸셀룰로오스를 포함하는 것인, 코팅층 내 에보글립틴의 안정성이 개선된 코팅된 정제.an inner layer comprising metformin; and
Coating layer coated with the inner layer
A coated tablet with improved stability of evogliptin in the coating layer, comprising evogliptin or an acceptable salt thereof, or ethyl cellulose in the coating layer.
b) 에보글립틴 또는 이의 허용가능한 염, 에틸셀룰로오스 및 코팅기제를 포함하는 코팅액으로 코팅층을 형성시켜 코팅층 제형으로 정제를 코팅하는 단계; 및
c) 상기 코팅된 정제를 건조하여 본 발명의 코팅된 정제를 형성시키는 단계를 포함하는 코팅된 정제의 제조 방법.a) preparing granules containing metformin, mixing a binder, a release controlling agent and a lubricant and tableting to provide an inner-layer tablet;
b) forming a coating layer with a coating solution containing evogliptin or an acceptable salt thereof, ethyl cellulose and a coating agent, and coating the tablet with the coating layer formulation; and
c) a method for producing a coated tablet comprising the step of drying the coated tablet to form a coated tablet of the present invention.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005117841A1 (en) | 2004-05-28 | 2005-12-15 | Bristol-Myers Squibb Company | Coated tablet formulation and method |
| WO2009099734A1 (en) | 2008-02-05 | 2009-08-13 | Merck & Co., Inc. | Pharmaceutical compositions of a combination of metformin and a dipeptidyl peptidase-iv inhibitor |
| KR101007497B1 (en) | 2007-04-19 | 2011-01-12 | 동아제약주식회사 | DPP-IV inhibitor including ?-amino group, preparation method thereof and pharmaceutical composition containing the same for preventing and treating a diabetes or an obesity |
| KR20200021774A (en) | 2018-08-21 | 2020-03-02 | 대화제약 주식회사 | Methods of manufacturing formulations comprising sitagliptin immediate release layer, and the formulations manufactured by the methods, methods of sitagliptin immediate release layer coating, and compositions for sitagliptin immediate release layer coating |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005117841A1 (en) | 2004-05-28 | 2005-12-15 | Bristol-Myers Squibb Company | Coated tablet formulation and method |
| KR101007497B1 (en) | 2007-04-19 | 2011-01-12 | 동아제약주식회사 | DPP-IV inhibitor including ?-amino group, preparation method thereof and pharmaceutical composition containing the same for preventing and treating a diabetes or an obesity |
| WO2009099734A1 (en) | 2008-02-05 | 2009-08-13 | Merck & Co., Inc. | Pharmaceutical compositions of a combination of metformin and a dipeptidyl peptidase-iv inhibitor |
| KR20200021774A (en) | 2018-08-21 | 2020-03-02 | 대화제약 주식회사 | Methods of manufacturing formulations comprising sitagliptin immediate release layer, and the formulations manufactured by the methods, methods of sitagliptin immediate release layer coating, and compositions for sitagliptin immediate release layer coating |
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