WO2012159511A1 - Dispersion solide d'azilsartan, son procédé de préparation et composition pharmaceutique la comprenant - Google Patents

Dispersion solide d'azilsartan, son procédé de préparation et composition pharmaceutique la comprenant Download PDF

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Publication number
WO2012159511A1
WO2012159511A1 PCT/CN2012/074162 CN2012074162W WO2012159511A1 WO 2012159511 A1 WO2012159511 A1 WO 2012159511A1 CN 2012074162 W CN2012074162 W CN 2012074162W WO 2012159511 A1 WO2012159511 A1 WO 2012159511A1
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WO
WIPO (PCT)
Prior art keywords
azilsartan
solid dispersion
povidone
sodium
group
Prior art date
Application number
PCT/CN2012/074162
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English (en)
Chinese (zh)
Inventor
徐坚
师帅
郭晓峰
杨闯
石晓磊
Original Assignee
江苏恒瑞医药股份有限公司
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
Priority claimed from CN2011101344667A external-priority patent/CN102793680A/zh
Application filed by 江苏恒瑞医药股份有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to CN201280003292.3A priority Critical patent/CN103260605B/zh
Publication of WO2012159511A1 publication Critical patent/WO2012159511A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a solid dispersion of azilsartan, a process for the preparation thereof, and a pharmaceutical composition comprising the same, and use thereof in the preparation of an antihypertensive drug. Background technique
  • Azisartan (English name Azilsartan) is an angiotensin-receptor antagonist drug in the development of hypertension that selectively blocks the binding of angiotensin II to vascular smooth muscle ATI receptors. Blocking the vasoconstrictor of angiotensin II, which is often used to treat hypertension, is also the only angiotensin II receptor antagonist (sartan) drug in the terminal clinical stage.
  • Azisartan is almost insoluble in water. When it is made into an oral preparation, only azilsartan can be quickly and efficiently dissolved or dispersed in water to absorb well in the gastrointestinal tract. Otherwise, it is absorbed. And there are big obstacles to bio-use. Therefore, it is important and meaningful to improve its water solubility and dissolution without changing the pharmacological properties of its compounds.
  • CN101528262A discloses a solid composition comprising a pharmaceutically active ingredient, a low melting point oleaginous substance and a low viscosity binder.
  • the technical problem mainly solved by the invention is that when a low melting point oily substance is used to improve the stability of the medicinal ingredient in the solid preparation, the dissolution property of the medicine in the solid preparation is lowered, and the dissolution is ensured by adding a low viscosity adhesive. characteristic.
  • this invention does not fundamentally solve the problem that the water solubility of azilsartan is poor and the bioavailability is low.
  • Solid dispersion refers to a dispersion system in the form of a solid which is formed by dispersing a drug in a solid carrier.
  • the drug is present in the carrier in a molecular state, a colloidal state, a metastable state, a microcrystalline state, and an amorphous state, and these drugs in an amorphous state (high energy state) have a solubility and a dissolution rate larger than those of other crystal states. Therefore, the present invention is the first attempt to prepare a solid dispersion of azilsartan to achieve a desired dissolution effect of the drug to improve the bioavailability of the drug. Summary of the invention
  • azilsartan Since azilsartan is almost insoluble in water, it is essential to improve its solubility in water without changing the pharmacological properties of its compounds.
  • the inventors discovered through research and practice that the selection of a suitable carrier to prepare azilsartan as a solid dispersion can solve the above problems well.
  • the present invention provides a solid dispersion of azilsartan containing as an active ingredient azilsartan and a carrier material.
  • the carrier material is selected from the group consisting of povidone, poloxamer, polyethylene glycol, hydroxypropyl cellulose, polyethylene oxide, and the like.
  • povidone is selected from the group consisting of povidone K-17, povidone ⁇ -25, povidone ⁇ -30, povidone ⁇ -90;
  • the poloxamer is selected from the poloxamer 188, Polo Sigma 407;
  • Hydroxypropyl cellulose is selected, for example, from the trade name Klucel® LF Klucel® JF Klucel® -EF Klucel® -EXF, polyoxyethylene selected as polyoxyethylene N80.
  • Povidone K-17, povidone oxime-25, povidone oxime-30, povidone oxime-90 are preferred, and povidone oxime-30 is most preferred.
  • the mass ratio of the active ingredient azilsartan to the carrier material in the present invention is in the range of 1:0.5 to 1:10, preferably 1:1 to 1:6, more preferably 1:2 to 1:6, more preferably 1 : 3 : 5 , most preferably 1: 3 - 1 : 4.
  • Another object of the present invention is to provide a process for preparing the above solid dispersion of azilsartan, which comprises a solvent method, a melting method and a grinding method, preferably a solvent method.
  • the solvent method includes the following steps:
  • the solvent used in the step 1 is one or more selected from the group consisting of methanol, ethanol, acetone, tetrahydrofuran, chloroform and methylene chloride, preferably methanol.
  • the weight ratio of azilsartan and the carrier as an active ingredient to the organic solvent is 1 : 5-1: 50, preferably 1 : 10-1: 30.
  • the method for removing the organic solvent in the step 2 is selected from the group consisting of reduced pressure distillation, reduced pressure drying, vacuum drying, freeze drying, spray drying, fluidized bed drying, and heat drying, preferably under reduced pressure.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the solid dispersion of azilsartan and a pharmaceutically acceptable, suitable pharmaceutical excipient.
  • the pharmaceutical composition may be prepared as a tablet, a capsule, a pill, a granule, a pellet, preferably a tablet.
  • the pharmaceutical excipients include, but are not limited to:
  • lactose lactose
  • mannitol sorbitol
  • microcrystalline cellulose starch, modified starch, dextrin, cyclodextrin and its derivatives, calcium phosphate, sucrose, pregelatinized starch, Xylitol, fructose, maltitol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate;
  • binder polyvinylpyrrolidone, starch slurry, methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, guar gum, xanthan gum Wait.
  • the pharmaceutical composition of the present invention consists of the solid dispersion of the present invention and mannitol, microcrystalline cellulose, croscarmellose or crospovidone, magnesium stearate.
  • the pharmaceutical composition of the invention consists of azilsartan, povidone, mannitol, microcrystalline cellulose, croscarmellose or crospovidone, magnesium stearate Composition; wherein azilsartan and povidone are made into a solid dispersion of azilsartan.
  • the weight ratio of each component is:
  • microcrystalline cellulose 10% to 30%, preferably 15% to 25%;
  • the pharmaceutical composition further contains a stabilizer selected from the group consisting of maleic acid and sodium hydroxide, fumaric acid and sodium hydroxide, citric acid and sodium hydroxide, and tartaric acid.
  • a stabilizer selected from the group consisting of maleic acid and sodium hydroxide, fumaric acid and sodium hydroxide, citric acid and sodium hydroxide, and tartaric acid.
  • sodium hydroxide monosodium maleate, monosodium fumarate, sodium tartrate, monosodium citrate, propyl gallate, ethylenediaminetetraacetic acid, disodium edetate, butylated hydroxyanisole
  • sodium sulfite, sodium hydrogen sulfite, sodium metabisulfite and/or ascorbic acid preferably sodium carbonate, sodium hydrogencarbonate, maleic acid and sodium hydroxide, fumaric acid and sodium hydroxide, and citric acid
  • sodium hydroxide monosodium maleate, monosodium fumarate and/or monosodium
  • Another object of the present invention is to provide a use of the solid dispersion of azilsartan and a pharmaceutical composition containing the solid dispersion for the preparation of an antihypertensive drug.
  • Figure 1 is an X-ray diffraction pattern of azilsartan bulk drug
  • Figure 2 is an X-ray diffraction diagram of a solid dispersion of azilsartan (Example 1)
  • Figure 3 is a PVP carrier X-ray diffraction pattern
  • FIG 4 shows the absorption peak of azilsartan bulk drug
  • Figure 5 shows the absorption peak of the solid dispersion of azilsartan (Example 1)
  • Figure 6 shows the absorption peak of the PVP carrier.
  • Figure 7 shows the effect of different carrier species on the dissolution rate of azartan solid dispersion.
  • Figure 8 shows the effect of different carrier ratios on the dissolution rate of azartan solid dispersion.
  • Figure 9 is a comparison of dissolution rates of Example 19 and Comparative Example 1 of the present invention.
  • Preparation method a prescribed amount of solid dispersion and an auxiliary material other than magnesium stearate. After mixing well, pass through the mesh and mix again and add the prescribed amount of magnesium stearate (using a 60 mesh sieve). After mixing, the mixture was compressed using an 8.5 L die at a weight of 250 mg and a pressure of 7 to 9 kg.
  • Preparation method a prescribed amount of solid dispersion and an auxiliary material other than magnesium stearate. After mixing well, pass through a 30 mesh sieve, mix again and add the prescribed amount of magnesium stearate. After mixing evenly, use 10.5 mm die to weight
  • Preparation method a prescribed amount of solid dispersion and an auxiliary material other than magnesium stearate. After mixing evenly, pass through a 30 mesh sieve, mix again, add the prescribed amount of magnesium stearate, mix well and use 9.5 mm die to weight
  • Preparation method a prescribed amount of solid dispersion and an auxiliary material other than magnesium stearate. After mixing evenly, a 30-mesh sieve was added, and after mixing, a prescribed amount of magnesium stearate was added, and after mixing, a 9.5 mm die was used, and the mixture was tableted at a weight of 350 mg and a pressure of 7 to 9 kg.
  • Example 21 a prescribed amount of solid dispersion and an auxiliary material other than magnesium stearate.
  • Preparation method a prescribed amount of solid dispersion and an auxiliary material other than magnesium stearate. After mixing evenly, pass through a 30 mesh sieve, mix again, add the prescribed amount of magnesium stearate, mix well and use a 9.5 mm die to weigh the mixture with a weight of 350 mg and a pressure of 7 to 9 kg.
  • Example 22 a prescribed amount of solid dispersion and an auxiliary material other than magnesium stearate. After mixing evenly, pass through a 30 mesh sieve, mix again, add the prescribed amount of magnesium stearate, mix well and use a 9.5 mm die to weigh the mixture with a weight of 350 mg and a pressure of 7 to 9 kg.
  • Preparation Method 1 According to the above formula, the first four solid powders were mixed through a 30 mesh sieve. Granulation was carried out using a 5% aqueous solution of hydroxypropylcellulose as a binder. After the wet granules passed through a 20 mesh sieve, they were placed in an oven at 40 ° C for drying. After drying, the granules were taken out and passed through a 20 mesh sieve. Then add the prescribed amount of cross-linked PVP and magnesium stearate and mix well. The mixture was compressed using a 8.5 mm die at a weight of 250 mg and a pressure of 7 to 9 kg.
  • Preparation Method 2 Azilsartan-Povidone PVP-K30 solid dispersion, mannitol, and microcrystalline cellulose in the above formulation were uniformly mixed and passed through a 30 mesh sieve to carry out dry granulation.
  • the formulation was cross-linked with PVP and magnesium stearate. After mixing evenly, the mixture was compressed using a 8.5 mm die at a weight of 250 mg and a pressure of 7 to 9 kg. Comparative example 1
  • Figure 1 is an X-ray diffraction pattern of azilsartan bulk drug
  • Figure 2 is an X-ray diffraction diagram of a solid dispersion of azilsartan (Example 1)
  • Figure 3 is a PVP carrier X-ray diffraction pattern
  • the drug has a distinct endothermic peak at 211.88 ° C, indicating that the drug substance is present in a crystalline state, and when the azisartan and the carrier form a solid dispersion, the crystallization peak of the drug disappears. It is indicated that the solid dispersion of azilsartan exists in an amorphous or molecular state.
  • Experimental Example 3 Effect of different carrier species on dissolution of solid dispersion of azilsartan
  • Example 6 Example 8, Example 9, Example 10, Example 11, Example 12, Example
  • the solid dispersion and the drug substance described in 13 were placed in a capsule, and the dissolution behavior was evaluated.
  • the dissolution conditions are as follows: Dissolution medium: pH 4.5 acetate buffer 900 mL
  • Dissolution method According to the Chinese Pharmacopoeia 2010 dissolution test method, the second method of dissolution measurement (ie, paddle method) was selected, and the rotation speed was 50 rpm.
  • the dissolution profile was determined by UV spectrophotometry as shown in Figure 7.
  • the dissolution profile was determined by UV spectrophotometry as shown in Fig. 8.
  • Example 19 of the present invention was compared.
  • the dissolution conditions were the same as in Experimental Example 4.
  • the dissolution profile was determined by ultraviolet spectrophotometry as shown in Fig. 9.
  • Fig. 9 Comparison of dissolution rates of Example 19 of the present invention and Comparative Example 1.
  • Example 19 The change of the related substances in the storage of the 19th, 30th, and 60% RH conditions of Example 19, Example 20, and Example 21 of the present invention was examined to evaluate the chemical stability of the solid dispersion of azilsartan. .
  • the experimental results are shown in Table 2.
  • Table 2 Example 19, Example 20, Example 21 and comparison of the related substances in the drug substance at 30 ° C / 60% RH for 1 month
  • Example 19 of the present invention under storage at 30 ° C / 60% RH for one month was examined.
  • the experimental results are shown in Figure 10. From the experimental results of Fig. 10, it was found that the dissolution behavior of Example 19 was almost unchanged after storage for one month at 30 ° C / 60% RH. It is indicated that the azilsartan solid dispersion tablets have no dissolution reduction during storage under accelerated conditions, which shows the good stability of the azilstan solid dispersion tablets.

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Abstract

La présente invention porte sur une dispersion solide d'azilsartan, son procédé de préparation et une composition pharmaceutique la comprenant. Cette disperson solide d'azilsartan contient de l'azilsartan et un véhicule, lequel est sélectionné dans povidone, poloxamère, polyéthylène glycol, hydroxypropylcellulose et polyoxyéthylène.
PCT/CN2012/074162 2011-05-23 2012-04-17 Dispersion solide d'azilsartan, son procédé de préparation et composition pharmaceutique la comprenant WO2012159511A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201280003292.3A CN103260605B (zh) 2011-05-23 2012-04-17 阿齐沙坦固体分散体及其制备方法和药物组合物

Applications Claiming Priority (4)

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CN201110134466.7 2011-05-23
CN2011101344667A CN102793680A (zh) 2011-05-23 2011-05-23 阿齐沙坦固体分散体及其制备方法和药物组合物
CN201210037032.X 2012-02-17
CN201210037032 2012-02-17

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104644632A (zh) * 2015-01-27 2015-05-27 美吉斯制药（厦门）有限公司 含有阿齐沙坦和苯磺酸氨氯地平的口服片剂及其制备方法
CN105078974A (zh) * 2014-05-23 2015-11-25 深圳信立泰药业股份有限公司 一种阿利沙坦酯固体分散体及药物组合物
CN111643461A (zh) * 2019-03-04 2020-09-11 鲁南制药集团股份有限公司 一种治疗高血压症的片剂及其制备方法
WO2022123592A1 (fr) * 2020-12-08 2022-06-16 Alkem Laboratories Ltd Composition pharmaceutique stable d'azilsartan médoxomil ou de sel pharmaceutiquement acceptable et procédés de préparation de celle-ci

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104490835B (zh) * 2014-12-23 2018-06-12 广东东阳光药业有限公司 一种阿齐沙坦酯片剂及其制备方法
KR102201396B1 (ko) * 2017-11-30 2021-01-11 보령제약 주식회사 피마살탄을 포함하는 약학적 조성물

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CN101066264A (zh) * 2007-06-12 2007-11-07 杨喜鸿 奥美沙坦酯的固体分散体及其制备方法和药物应用
WO2008149338A2 (fr) * 2007-06-06 2008-12-11 Dexcel Ltd. Procédé de formation de formes posologiques orales solides dans des antagonistes du récepteur de l'angiotensine ii
CN101862325A (zh) * 2009-04-20 2010-10-20 北京德众万全药物技术开发有限公司 一种含有坎地沙坦酯的药物组合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008149338A2 (fr) * 2007-06-06 2008-12-11 Dexcel Ltd. Procédé de formation de formes posologiques orales solides dans des antagonistes du récepteur de l'angiotensine ii
CN101066264A (zh) * 2007-06-12 2007-11-07 杨喜鸿 奥美沙坦酯的固体分散体及其制备方法和药物应用
CN101862325A (zh) * 2009-04-20 2010-10-20 北京德众万全药物技术开发有限公司 一种含有坎地沙坦酯的药物组合物

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105078974A (zh) * 2014-05-23 2015-11-25 深圳信立泰药业股份有限公司 一种阿利沙坦酯固体分散体及药物组合物
CN104644632A (zh) * 2015-01-27 2015-05-27 美吉斯制药（厦门）有限公司 含有阿齐沙坦和苯磺酸氨氯地平的口服片剂及其制备方法
CN111643461A (zh) * 2019-03-04 2020-09-11 鲁南制药集团股份有限公司 一种治疗高血压症的片剂及其制备方法
CN111643461B (zh) * 2019-03-04 2022-09-13 鲁南制药集团股份有限公司 一种治疗高血压症的片剂及其制备方法
WO2022123592A1 (fr) * 2020-12-08 2022-06-16 Alkem Laboratories Ltd Composition pharmaceutique stable d'azilsartan médoxomil ou de sel pharmaceutiquement acceptable et procédés de préparation de celle-ci

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TW201247201A (en) 2012-12-01
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