KR20170124999A - Method for producing amorphous linagliptin - Google Patents
Method for producing amorphous linagliptin Download PDFInfo
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Abstract
Description
본 발명은 약학적으로 이용되는 무정형 리나글립틴의 제조 방법에 관한 것이다.The present invention relates to a method for preparing amorphous linalooligin, which is used pharmacologically.
리나글립틴(linagliptin)은 하기 화학식 1로 표시되며, 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)크산틴의 일반명이다.Linagliptin is represented by the following formula 1 and is represented by the following formula 1: 1 - [(4-methyl-quinazolin-2-yl) methyl] (3- (R) -amino-piperidin-1-yl) xanthine.
[화학식 1][Chemical Formula 1]
Dipeptidyl peptidase-4(DPP-4) 효소는 인슐린 생성과 관련된 인크레틴 호르몬(incretin hormones) GLP-1 및 GIP를 분해시키는 물질로 알려져 있는 데, 리나글립틴은 DPP-4의 저해제(inhibitor)로 작용하여 제2형 당뇨병의 치료제로 이용되고 있다.Dipeptidyl peptidase-4 (DPP-4) enzyme is known to be involved in the formation of insulin-producing incretin hormones, GLP-1 and GIP, and linapliptin is an inhibitor of DPP-4 And is being used as a treatment for
리나글립틴은 베링거잉겔하임(Boehringer Ingelheim)사에서 개발되어, 베링거잉겔하임사와 일라이 릴리(Eli Lilly)사가 상품명 "Trajenta"TM으로 시판하고 있다. 리나글립틴 제제는 단독으로 사용되거나 메트포르민, 설포닐우레아, 피오글리타존과 같은 제2형 당뇨치료제와 병용으로 사용되기도 한다.Lena riptin article is developed in four Boehringer Ingelheim (Boehringer Ingelheim), and Boehringer Ingelheim Inc. and sold under the Eli Lilly (Eli Lilly) Inc. product name "Trajenta" TM. Linagliptin preparations may be used alone or in combination with a therapeutic agent for
리니글립틴은 국제특허공개 제WO 2004/018468호에 제조방법 및 약학적 용도가 기재되어 있고, 국제특허공개 제WO 2007/128721호에는 리니글립틴의 결정형으로서 무수 다형체(polymorph)A, 무수 다형체B, 다형체C, 다형체D, 다형체E가 개시되어 있다. 리니글립틴은 결정화 시 대부분의 경우 무수 다형체A의 결정형을 나타낸다.International Patent Publication No. WO 2004/018468 discloses a preparation method and pharmaceutical use, and International Patent Publication No. WO 2007/128721 discloses a method for producing an anhydrous polymorph A, Polymorph B, Polymorph C, Polymorph D, Polymorph E are disclosed. In most cases, lignigliptin shows a crystalline form of anhydrous polymorph A upon crystallization.
국제특허공개 제WO 2007/128721호에 따르면 무수 다형체 A는 (a) 순수 에탄올 중에 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)크산틴을 환류시키고, 임의로 이들의 혼합물을 여과하고, (b) 결정화될 때까지 고온 용액 또는 고온 여액을 냉각시키고, (c) 3급-부틸메틸에테르와 같은 용매로 희석시키고, (d) 용매 혼합물을 흡입 여과하고, (e) 45℃에서 진공건조시켜 제조된다.According to International Patent Publication No. WO 2007/128721, anhydrous polymorph A is prepared by reacting (a) 1 - [(4-methyl-quinazolin-2-yl) methyl] -3-methyl- -1-yl) -8- (3- (R) -amino-piperidin-1-yl) xanthine and optionally filtering the mixture, and (b) Cooling the filtrate, (c) diluting with a solvent such as tert-butyl methyl ether, (d) suction filtration of the solvent mixture, and (e) vacuum drying at 45 ° C.
그리고, 무수 다형체 B는 (a) 순수 에탄올 중에 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)크산틴을 용해시키고, 이들의 혼합물을 환류시키고, 임의로 여과하고, (b) 고온 용액 또는 고온 여액을 결정화되도록 10℃ 미만의 온도로 냉각시키고, (c) 3급-부틸메틸에테르와 같은 용매로 희석시키고, (d) 용매 혼합물을 흡입 여과하고, (e) 10℃ 미만의 온도에서 진공건조시켜 제조된다.The anhydrous polymorph B is obtained by reacting (a) 1 - [(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn- (B) dissolving the hot solution or hot filtrate at a temperature of less than 10 < 0 > C to crystallize, Cooling, (c) diluting with a solvent such as tert-butyl methyl ether, (d) suction filtration of the solvent mixture, and (e) vacuum drying at a temperature below 10 ° C.
그리고, 다형체 C는 (a) 1-[(4-메틸-퀴나졸린-2-일)메틸]-3-메틸-7-(2-부틴-1-일)-8-(3-(R)-아미노-피페리딘-1-일)크산틴을 메탄올에 용해시키고, 환류시키고, 임의로 활성탄의 존재하에 여과하고, (b) 상기 메탄올성 용액을 40 내지 60℃의 온도로 냉각시키고, (c) 3급-부틸메틸에테르 또는 디이소프로필에테르와 같은 용매를 첨가하고, (d) 수득된 현탁액을 먼저 15 내지 25℃로 냉각시키고, 이어서 0 내지 5℃로 냉각시키고, (e) 형성된 결정을 흡입 여과하고, 3급-부틸메틸에테르 또는 디이소프로필에테르로 다시 세척하고, (f) 수득된 결정을 70℃의 온도에서 진공 건조기에서 건조시켜 제조될 수 있다.The polymorph C is obtained by reacting (a) 1 - [(4-methyl-quinazolin-2-yl) methyl] -3-methyl- 7- (2-butyn- (B) cooling the methanolic solution to a temperature of 40-60 < 0 > C, ((b) c) adding a solvent such as tert-butyl methyl ether or diisopropyl ether, (d) cooling the resulting suspension to 15 to 25 ° C first, followed by cooling to 0 to 5 ° C, and (e) Is filtered off with suction and washed again with tert-butyl methyl ether or diisopropyl ether, and (f) the obtained crystals are dried in a vacuum drier at a temperature of 70 ° C.
그리고, 다형체 D는 다형체 C가 30 내지 100℃의 온도로 가열되고, 이 온도에서 건조되는 경우에 수득되며, 150±3℃에서 용융된다.Polymorph D is then obtained when polymorph C is heated to a temperature of 30 to 100 占 폚 and dried at this temperature and melted at 150 占 폚.
마지막으로, 무수 다형체 E는 다형체 D를 용융한 후 결정화하여 수득되며, 175±3℃의 온도에서 용융된다.Finally, the anhydrous polymorph E is obtained by melting polymorph D and crystallizing, and melting at a temperature of 175 3C.
리나글립틴은 황백색의 고체로서, 약간의 검습성(hygroscopic)을 가지며, 메탄올과 에탄올에는 잘 녹으나, 물에서는 양호하지 못하다. 이는 리나글립틴의 결정형에 따른 것으로 이해되며, 현재 시판되는 리나글립틴 제제의 생체이용율(bioavailability)은 약 30%로 보고되고 있다. Rinagliptin is a yellowish white solid with a slight hygroscopic character and is well soluble in methanol and ethanol but not in water. It is understood that this is due to the crystalline form of linalogliptin, and the bioavailability of currently commercially available linagliptin preparations is reported to be about 30%.
본 발명은 용해도가 높고 안정성이 우수한 무정형의 리나글립틴 제조 방법 및 이로부터 제조된 무정형 리나글립틴, 약학적 조성물을 제공하는 데 그 목적이 있다.It is an object of the present invention to provide amorphous linagliptin having high solubility and stability and amorphous linagliptin and pharmaceutical composition prepared therefrom.
본 발명은 무정형을 가지는 리나글립틴 분말을 제조하기 위한 방법을 제공한다.The present invention provides a method for preparing an amorphous linagliptin powder.
본 발명의 무정형 리나글립틴은 (a) 결정형 리나글립틴 또는 다형체 리나글립틴을 테트라하이드로퓨란에 용해시키는 단계; (b) 상기 용액을 50~70℃로 냉각시키고, 온도를 유지하면서 정제수를 천천히 적가하는 단계; (c) 상기 용액을 서서히 0~10℃까지 냉각하고 숙성시키는 단계; (d) 상기 용액을 여과하고 정제수로 세척후 건조하는 단계를 포함하여 이루어질 수 있다. 상기 제조방법에서 단계 (b)는 60℃에서 이루어지고, 단계 (c)는 5℃에서 이루어지는 것이 바람직하다.The amorphous linalyptin of the present invention comprises (a) dissolving crystalline lignagliptin or polymorphinagliptin in tetrahydrofuran; (b) cooling the solution to 50-70 < 0 > C and slowly adding dropwise purified water while maintaining the temperature; (c) slowly cooling the solution to 0-10 < 0 > C and aging; (d) filtering the solution, washing with purified water, and drying. In the above production process, step (b) is preferably carried out at 60 ° C, and step (c) is preferably carried out at 5 ° C.
본 발명에 따른 방법으로 제조된 리나글립틴은 무정형을 가지며, 종래 결정형(다형체) 리나글립틴에 비해 용해도가 높고, 대등한 안정성을 가지는 효과가 있다.Linagliptin produced by the method according to the present invention has an amorphous form and has an effect of having high solubility and comparable stability compared to conventional crystalline (polymorphic) lignagliptin.
도 1은 무수 다형체A 리나글립틴의 X-선 회절분석 결과를 나타낸 그래프이다.
도 2는 본 발명의 실시예 1에 따라 제조된 무정형 리나글립틴의 X-선 회절분석 결과를 나타낸 그래프이다.Fig. 1 is a graph showing the results of X-ray diffraction analysis of anhydrous polymorphic A rinagliptin.
FIG. 2 is a graph showing the results of X-ray diffraction analysis of amorphous linalglyptin prepared according to Example 1 of the present invention. FIG.
본 발명자들은 리나글립틴의 용해성, 생체흡수성을 향상시킬 목적으로, 결정형 리나글립틴(무수 다형체A)로부터 무정형의 리나글립틴으로 전환시키 위해 다양한 용매, 온도 조건에서 연구를 진행한 결과, 다음의 제조 방법을 통해 무정형의 특징을 가지는 리니글립틴 고체를 제조하여 본 발명을 완성하였다.The present inventors have conducted studies under various solvents and temperature conditions in order to convert crystalline lignagliptin (anhydrous polymorph A) to amorphous lignagliptin for the purpose of improving the solubility and bioabsorbability of lignagliptin. As a result, The present inventors completed the present invention by preparing a lignigliptin solid having amorphous characteristics.
본 발명의 무정형 리나글립틴의 제조 방법은 다음과 같다.The process for preparing amorphous linalooligitine of the present invention is as follows.
(a) 결정형 리나글립틴 또는 다형체 리나글립틴을 테트라하이드로퓨란(THF)에 넣고 승온환류 교반하면서 용해시킨다.(a) Crystalline linagliptin or polymorphic linagliptin is dissolved in tetrahydrofuran (THF) while stirring under reflux at elevated temperature.
(b) 상기 용해된 리나글립틴 용액을 서서히 50~70℃, 바람직하게는 60℃로 냉각시킨 다음, 온도를 유지하면서 과량의 정제수를 천천히 적가시킨다.(b) slowly cooling the dissolved linalglyptin solution to 50-70 째 C, preferably 60 째 C, followed by slowly dropping excess of purified water while maintaining the temperature.
(c) 상기 용액을 서서히 0~10℃, 바람직하게는 5℃로 냉각시킨 다음, 약 5시간 동안 숙성시킨다. (c) The solution is slowly cooled to 0 to 10 占 폚, preferably 5 占 폚, and aged for about 5 hours.
(d) 상기 숙성된 용액을 여과한 다음, 정제수로 세척한 후 약 45℃의 범위에서 약 12시간 정도 건조하면 무정형의 리나글립틴이 수득된다.(d) The aged solution is filtered, washed with purified water, and then dried at about 45 캜 for about 12 hours to obtain amorphous linalogliptin.
본 발명의 화합물은 경구 또는 비경구의 제형으로 제제화가 가능하며, 제형화에 사용되는 통상의 부형제(충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등)이 이용될 수 있으며, 경구 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등으로 제조될 수 있다. 통상의 부형제로는 전분, 호화전분, 옥수수전분, 만니톨, 수크로스, 락토오스, 젤라틴, 포비돈, 스테아린산 마그네슘, 탈크 등을 혼합하여 제조된다.The compound of the present invention can be formulated into oral or parenteral formulations, and conventional excipients (fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc.) used in the formulation can be used. , Pills, powders, granules, capsules and the like. Conventional excipients are prepared by mixing starch, starch, corn starch, mannitol, sucrose, lactose, gelatin, povidone, magnesium stearate, talc and the like.
이하, 본 발명을 실시예에 통해 상세히 설명한다. 다만, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited to the following examples.
A.재료준비: 리나글립틴은 Beijing Huikang Boyuan Chemical Tech 사로부터 공급받았으며, 제공된 리나글립틴의 특성은 다음과 같다. A. Materials Preparation : Linalogliptin was supplied by Beijing Huikang Boyuan Chemical Tech Co., Ltd. The characteristics of linalogliptin provided are as follows.
B.분석방법: X-선 회절분석은 PANAnalytical사(네덜란드)의 X'Pert PRO MRDTM를 이용하여 실시하였다. B. Analytical method : X-ray diffraction analysis was performed using X'Pert PRO MRD TM from PANAnalytical (Netherlands).
먼저, 제공받은 리나글립틴을 X-선 회절분석기로 분석하여, 그 결과를 도 1에 나타내었다. 도 1에 보이는 바와 같이, 제공받은 리나글립틴은 무수 다형체A(결정형)인 것으로 확인되었다.First, the supplied linalogliptin was analyzed by an X-ray diffractometer, and the results are shown in Fig. As shown in Fig. 1, it was confirmed that the supplied linagliptin was anhydrous polymorph A (crystal form).
실시예Example 1: 무정형 1: amorphous 리나글립틴의Linagliptin 제조 Produce
무수 다형체A 리나글립틴 88.0g에 테트라하이드로퓨란(THF) 200ml를 투입 승온환류 교반하여 용해시켰다. 용해 후 온도를 60℃로 냉각시키고 같은 온도를 유지하면서 정제수 800ml를 천천히 적가하였다. 적가 완료 후 서서히 5℃까지 냉각하고 같은 온도에서 5시간 교반하여 숙성시켰다.200 ml of tetrahydrofuran (THF) was added to 88.0 g of anhydrous polymorphic Alynagliptin, and the mixture was heated to reflux with stirring to dissolve it. After dissolution, the temperature was cooled to 60 DEG C, and 800 mL of purified water was slowly added dropwise while maintaining the same temperature. After completion of the dropwise addition, the mixture was slowly cooled to 5 캜 and aged for 5 hours at the same temperature.
상기 숙성된 용액을 여과하여 정제수 100ml로 세척 후 45℃에서 12시간 건조하여 리나글립틴 분말 63.4g(수율: 72.0%)을 수득하였다.(mp: 120~123℃)The aged solution was filtered, washed with 100 ml of purified water and dried at 45 ° C for 12 hours to obtain 63.4 g (yield: 72.0%) of linagliptin powder (mp: 120 to 123 ° C)
본 실시예 1에 따라 제조된 리나글립틴 분말의 X-선 회절분석 결과를 도 2에 나타내었다. 도 2에 보이는 바와 같이 본 실시예 1에 따른 리나글립틴은 특정 임계치의 피크를 나타내지 않아 무정형으로 확인되었다.Fig. 2 shows the X-ray diffraction analysis results of the linalglyptin powder prepared according to Example 1. Fig. As shown in Fig. 2, linagliptin according to Example 1 did not show a peak of a specific threshold value and was confirmed to be amorphous.
실시예Example 2: 무정형 2: amorphous 리나글립틴의Linagliptin 정제 제조 Tablet manufacture
상기 실시예 1에서 제조된 무정형 리나글립틴 5mg, 만니톨 10mg, 호화전분 80mg, 옥수수전분 10mg, 코포비돈 2mg, 스테아린산 마그네슘 2mg을 혼합하여 정제기를 사용하여 타정하여 무정형 리나글립틴 정제를 제조하였다.Amorphous linagliptin tablets were prepared by mixing 5 mg of amorphous linalglyptin prepared in Example 1, 10 mg of mannitol, 80 mg of starch, 10 mg of corn starch, 2 mg of copovidone and 2 mg of magnesium stearate and using a purifier.
실험예Experimental Example 1: 용해도 실험 1: Solubility experiment
용해도 실험은 대한약전에 소개된 분석법에 따라 각각의 화합물을 증류수에 포화 용해시키고 30분 경과한 다음, 액체 크로마토그라피로 용해된 양을 측정하여 그 결과를 하기 표 1에 나타내었다.The solubility test was carried out by dissolving each compound in distilled water according to the analytical method disclosed in Korean Pharmacopoeia and measuring the amount dissolved in liquid chromatography after 30 minutes elapsed. The results are shown in Table 1 below.
상기 표 1에 보이는 바와 같이, 본 발명에 따른 무정형 리나글립틴은 무수 다형체A 리나글립틴과 비교해 유의적으로 높은 용해도를 가지는 것이 확인되었다. 상기 결과는 생체흡수율의 증가 가능성을 제시한다.As shown in Table 1, it was confirmed that the amorphous linalyptin according to the present invention had a significantly higher solubility than the anhydrous polymorphic A. laminagliptin. These results suggest the possibility of increased bioabsorption.
실험예Experimental Example 2: 안정성 실험 2: Stability experiment
상기 실시예 2에서 제조된 무정형 리나글립틴 정제의 시간 경과에 따른 안정성을 시험하였다.The stability of the amorphous linaloolin tablet prepared in Example 2 over time was tested.
비교예로는 무수 다형체A 리나글립틴을 이용하여 상기 실시예 2와 동일 방법(동일 부형제)으로 정제를 제조하였다.As a comparative example, tablets were prepared in the same manner as in Example 2 (the same excipient) by using anhydrous polymorphic A-line and glyptin.
각각의 정제를 가속조건(40℃, 습도 75±5 %)에서 보관하면서 초기, 1개월, 2개월에 각각 활성물질의 초기 값에 대한 잔사율을 액체 크로마토그라피로 측정하였으며, 그 결과를 하기 표 2에 나타내었다.Each tablet was stored at accelerated conditions (40 ° C, humidity 75 ± 5%), and the residual rate with respect to the initial value of the active substance was measured by liquid chromatography at the beginning, one month and two months, Respectively.
상기 표 2에 보이는 바와 같이, 본 발명의 무정형 리나글립틴은 비교예의 무수 다형체A 리나글립틴과 비교해 대등한 안정성을 가지는 것이 확인되었다.As shown in Table 2, it was confirmed that the amorphous linalyptin of the present invention had comparable stability as compared with the anhydrous polymorphic A. glabridin of the comparative example.
Claims (3)
(b) 상기 용액을 50~70℃로 냉각시키고, 온도를 유지하면서 정제수를 천천히 적가하는 단계;
(c) 상기 용액을 서서히 0~10℃까지 냉각하고 숙성시키는 단계;
(d) 상기 용액을 여과하고 정제수로 세척후 건조하는 단계를 포함하는 것을 특징으로 하는,
무정형 리나글립틴의 제조 방법.
(a) dissolving crystalline lignagliptin or polymorphinagliptin in tetrahydrofuran;
(b) cooling the solution to 50-70 < 0 > C and slowly adding dropwise purified water while maintaining the temperature;
(c) slowly cooling the solution to 0-10 < 0 > C and aging;
(d) filtering the solution, washing with purified water, and drying.
Process for preparing amorphous linaloolin.
단계 (b)는 60℃에서 이루어지고,
단계 (c)는 5℃에서 이루어지는 것을 특징으로 하는,
무정형 리나글립틴의 제조 방법.
The method according to claim 1,
Step (b) is carried out at 60 < 0 > C,
Lt; RTI ID = 0.0 > 5 C, < / RTI >
Process for preparing amorphous linaloolin.
상기 무정형 리나글립틴은 하기와 같은 X-선 회절분석 다이어그램을 가지는 것을 특징으로 하는, 무정형 리나글립틴의 제조 방법.
Wherein the amorphous linalyptin has the following X-ray diffraction analysis diagram.
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