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WO2017088812A1 - Composition et eutectique de saxagliptine et de metformine, et procédé pour les préparer et les utiliser - Google Patents

Composition et eutectique de saxagliptine et de metformine, et procédé pour les préparer et les utiliser Download PDF

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Publication number
WO2017088812A1
WO2017088812A1 PCT/CN2016/107251 CN2016107251W WO2017088812A1 WO 2017088812 A1 WO2017088812 A1 WO 2017088812A1 CN 2016107251 W CN2016107251 W CN 2016107251W WO 2017088812 A1 WO2017088812 A1 WO 2017088812A1
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WO
WIPO (PCT)
Prior art keywords
eutectic
saxagliptin
metformin
composition
hydrochloride
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2016/107251
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English (en)
Chinese (zh)
Inventor
陈敏华
张炎锋
杨朝惠
刘启月
张晓宇
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Crystal Pharmatech Co Ltd
Original Assignee
Crystal Pharmatech Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Crystal Pharmatech Co Ltd filed Critical Crystal Pharmatech Co Ltd
Publication of WO2017088812A1 publication Critical patent/WO2017088812A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole

Definitions

  • the invention relates to the field of chemical medicine, in particular to a composition, eutectic of saxagliptin and metformin, a preparation method thereof and use thereof.
  • the International Diabetes Federation (IDF) reports that people with diabetes worldwide are growing rapidly. According to the 2010 Guidelines for the Prevention and Treatment of Type 2 Diabetes in China, there are more than 92.4 million type 2 diabetes patients in China, and the prevalence rate is 9.42%. At present, China has become the world's largest diabetes country.
  • AACE American Association of Clinical Endocrinologists
  • EASD European Diabetes Research Association
  • ADA American Diabetes Association
  • CDS Chinese Medical Association Diabetes Association
  • Saxagliptin is a potent dipeptidyl peptidase-4 (DPP-4) inhibitor that increases endogenous glucagon-like peptide-1 (GLP-1) by selective inhibitory DPP-4. And glucose-dependent insulinotropic polypeptide (GIP) levels, thereby regulating blood sugar. Its structure is as shown in formula (Ia):
  • Metformin regulates blood glucose by reducing hepatic glucose synthesis and improving insulin sensitivity. It has multiple mechanisms of action, including delaying glucose uptake by the gastrointestinal tract, increasing peripheral glucose utilization by increasing insulin sensitivity, and inhibiting liver and kidney overgrowth.
  • the gluconeogenesis does not reduce blood sugar levels in non-diabetic patients. Its structure is as shown in formula (Ib):
  • Saxagliptin can be used in combination with metformin with a complementary effect.
  • Metformin regulates blood glucose primarily by reducing hepatic glucose synthesis and improving insulin sensitivity; while saxagliptin delays incretin inactivation, promotes insulin release, reduces glucagon release, and improves glucose in the islet beta cells.
  • the reaction regulates blood sugar.
  • the combination of the two can enhance the efficacy of hypoglycemic and improve islet ⁇ cells Function to improve blood sugar compliance rate.
  • Patent CN1213028C discloses that DPP-4 inhibitors can be used in combination with other types of anti-diabetic drugs, including biguanide hypoglycemic agents.
  • metformin hydrochloride is 500 mg, 1000 mg, while saxagliptin is only 2.5 mg, 5 mg, and metformin hydrochloride is too large. .
  • a eutectic is a crystal containing two molecules in the same crystal structure.
  • the interaction between the two molecules is a non-covalent bond (such as a hydrogen bond, a ⁇ - ⁇ conjugate, a halogen bond, etc.).
  • composition and the eutectic composition of metformin and saxagliptin provided by the invention have good stability and low wettability, and the dissolution rate of each component is faster and the solubility is higher than that of the prior art, and the composition provided by the invention has a total
  • the crystal preparation method is simple and the cost is low, which is of great value for the clinical optimization and development of the future combination drugs of metformin and saxagliptin.
  • the technical problem to be solved by the present invention is to provide a composition and eutectic of metformin and saxagliptin overcoming the deficiencies of the prior art.
  • the present invention provides a composition of metformin and saxagliptin characterized by wherein the molar ratio of metformin to saxagliptin is 1:1.
  • metformin may be in free form or in the form of the hydrochloride salt
  • saxagliptin may be in free form or in the form of the hydrochloride salt
  • composition of metformin and saxagliptin provided by the present invention is characterized in that the composition is a co-crystal of metformin and saxagliptin, and the molar ratio thereof is 1:1. Its structural formula is as shown in formula (I).
  • the eutectic provided by the present invention may be Form I, characterized in that the X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C is 17.8 ° ⁇ 0.2 °, 6.6 ° ⁇ 0.2 °, 24.4 ° ⁇ 0.2 at 2theta. There is a characteristic peak at °.
  • the X-ray powder diffraction pattern of Form I also has a diffraction peak at one or more of the 2theta values of 13.4 ° ⁇ 0.2 °, 22.2 ° ⁇ 0.2 °, and 23.1 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form I also has diffraction peaks at one or more of the 2theta values of 10.2 ° ⁇ 0.2 °, 20.2 ° ⁇ 0.2 °, and 15.5 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C has a characteristic peak at a value of 17.8 ° ⁇ 0.2 °, 6.6 ° ⁇ 0.2 °, 24.4 ° ⁇ 0.2 ° at 13.4 °.
  • the X-ray powder diffraction pattern of Form I is as shown in FIG. Further, a total of 26 diffraction peaks are shown in the X-ray diffraction pattern, and the positions and peak intensities of these diffraction peaks are shown in Table 1.
  • the crystalline form I provided by the present invention begins to exhibit an endothermic peak near heating to 210 ° C, and the differential scanning calorimetry chart is substantially as shown in FIG. 2 .
  • the crystalline form I provided by the present invention has a weight loss gradient of about 2.5% when heated to 120 ° C, and the thermogravimetric analysis chart is shown in FIG. 3 .
  • Form I is prepared by reacting metformin hydrochloride and saxagliptin hydrochloride in a nitrile solvent, or reacting metformin and saxagliptin in free form with hydrochloric acid in a nitrile solvent, stirring, and separating the solid to obtain .
  • the nitrile solvent is preferably acetonitrile.
  • the method of separating solids includes, but is not limited to, volatilization, filtration, centrifugation, etc., preferably centrifugation.
  • Another object of the invention is to provide a pharmaceutical composition comprising an effective amount of a compound of formula (I), and at least one pharmaceutically acceptable excipient.
  • the compound of the formula (I) can be used for the preparation of a medicament for treating diabetes.
  • the present invention has the following advantages compared with the prior art:
  • composition and the eutectic stability provided by the invention are good. It can well avoid drug storage and crystal transformation during development, thus avoiding changes in bioavailability and efficacy.
  • the crystal particles of the eutectic crystal form I provided by the invention are relatively small, which is beneficial to the improvement of solubility; the dispersion is relatively uniform, no agglomeration phenomenon, the residual solvent and the impurity encapsulation phenomenon are easily removed, and the quality of the process product is improved.
  • the eutectic hygroscopicity provided by the invention is low, and meets the storage requirements of the medicine.
  • Figure 1 is an XRPD pattern of eutectic crystal form I
  • Figure 2 is a DSC diagram of eutectic crystal form I
  • FIG. 3 is a TGA diagram of eutectic crystal form I
  • Figure 4 is a comparison of DVS of eutectic crystal form I with metformin hydrochloride and saxagliptin hydrochloride.
  • Figure 5 is a comparison of the stability of eutectic crystal form I at 25 ° C / 11.0% RH (the above figure shows the XRPD pattern before placement, the figure below shows the XRPD pattern after 3 months)
  • Figure 6 is a comparison of the stability of eutectic crystal form I at 25 ° C / 43.2% RH (the above figure shows the XRPD pattern before placement, the figure below shows the XRPD pattern after 3 months of placement)
  • Figure 7 is a PLM diagram of eutectic crystal form I
  • Figure 8 is a PLM diagram of saxagliptin hydrochloride
  • test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer.
  • X-ray powder diffraction pattern of the present invention in Panalytical Empyrean X-ray powder diffraction Collected on the instrument.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • the dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.).
  • the method parameters of the dynamic moisture adsorber are as follows:
  • Relative humidity range 0%RH-60%RH
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 1. Its XRPD diagram is shown in Figure 1, its DSC diagram is shown in Figure 2, and its TGA diagram is shown in Figure 3.
  • the molar ratio of Form I was determined by high performance liquid chromatography and ion mass spectrometry. The results showed that the molar ratio of metformin to saxagliptin and hydrochloric acid was 1:1:2.
  • the results are shown in Figures 7 and 8, respectively, as can be seen from the figure, the eutectic crystal form I particles are relatively small, which is favorable for solubility. Improve; more uniform dispersion, no agglomeration, easy to remove residual solvent and impurity encapsulation, improve the quality of process products.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition et un eutectique de saxagliptine et de metformine, et un procédé pour les préparer et les utiliser. En particulier, la présente invention concerne une composition et une forme eutectique dans lequel le rapport molaire de saxagliptine et de metformine est égal à 1/1, le profil de diffraction aux rayons X sur poudre (rayonnement CuK α) de sa forme cristalline eutectique I présente des pics caractéristiques aux valeurs 2 thêta 17,8° ± 0,2°, 6,6° ± 0,2° et 22,4° ± 0,2° à 25 °C. La composition et l'eutectique selon la présente invention ont une bonne stabilité, une faible mouillabilité et une solubilité répondant aux exigences médicales, toutes ces qualités étant de grande valeur pour l'optimisation et le développement de médicaments dans le futur.
PCT/CN2016/107251 2015-11-26 2016-12-12 Composition et eutectique de saxagliptine et de metformine, et procédé pour les préparer et les utiliser Ceased WO2017088812A1 (fr)

Applications Claiming Priority (2)

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CN201510835021.X 2015-11-26
CN201510835021 2015-11-26

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WO2017088812A1 true WO2017088812A1 (fr) 2017-06-01

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113354596A (zh) * 2021-06-01 2021-09-07 天津大学 依帕司他-二甲双胍盐丙酮溶剂化物及制备方法和应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102266325A (zh) * 2011-07-28 2011-12-07 海南锦瑞制药股份有限公司 一种二甲双胍晶体及其与沙格列汀的药用组合物与制备方法
WO2012090225A2 (fr) * 2010-12-29 2012-07-05 Nutracryst Therapeutics Private Limited Nouveaux co-cristaux/sels moléculaires de metformine et d'oléoyléthanolamide utiles en tant qu'agent antidiabétique et antiobésité efficace
WO2013160354A1 (fr) * 2012-04-25 2013-10-31 Enantia, S.L. Formes cristallines de la saxagliptine
CN104557944A (zh) * 2014-12-31 2015-04-29 北京瑞都医药科技有限公司 一种降糖药物及其制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012090225A2 (fr) * 2010-12-29 2012-07-05 Nutracryst Therapeutics Private Limited Nouveaux co-cristaux/sels moléculaires de metformine et d'oléoyléthanolamide utiles en tant qu'agent antidiabétique et antiobésité efficace
CN102266325A (zh) * 2011-07-28 2011-12-07 海南锦瑞制药股份有限公司 一种二甲双胍晶体及其与沙格列汀的药用组合物与制备方法
WO2013160354A1 (fr) * 2012-04-25 2013-10-31 Enantia, S.L. Formes cristallines de la saxagliptine
CN104557944A (zh) * 2014-12-31 2015-04-29 北京瑞都医药科技有限公司 一种降糖药物及其制备方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113354596A (zh) * 2021-06-01 2021-09-07 天津大学 依帕司他-二甲双胍盐丙酮溶剂化物及制备方法和应用

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