WO2017219453A1 - 一种缬沙坦分散片及其制备方法 - Google Patents

一种缬沙坦分散片及其制备方法 Download PDF

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WO2017219453A1
WO2017219453A1 PCT/CN2016/093517 CN2016093517W WO2017219453A1 WO 2017219453 A1 WO2017219453 A1 WO 2017219453A1 CN 2016093517 W CN2016093517 W CN 2016093517W WO 2017219453 A1 WO2017219453 A1 WO 2017219453A1
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valsartan
dispersible tablet
sodium
lubricant
cassia
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PCT/CN2016/093517
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English (en)
French (fr)
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张丛
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深圳市樊溪电子有限公司
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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
    • 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
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/482—Cassia, e.g. golden shower tree
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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 invention relates to the field of medicines, in particular to a valsartan dispersible tablet and a preparation method thereof.
  • Valsartan (N-(L-pentanoyl)-N44-[2-(1H-tetrazolium-5-yl)phenyl]benzyl)-L-proline), molecular formula C24H29N5O3, among which effective therapeutic ingredients It is used for the treatment of various types of hypertension and has a good protective effect on heart, brain and kidney.
  • Valsartan is a specific angiotensin II (AngII) receptor antagonist, and is another new type of antihypertensive drug following angiotensin-converting enzyme inhibitors.
  • AngII angiotensin II
  • hypoglycemic reaction no first dose of hypoglycemic reaction, excellent tolerance, not only reduce blood, but also protect target organs from damage, reduce proteinuria, reduce overall cardiovascular disease incidence, prevent cardiovascular The potential role of complications and the low incidence of adverse reactions. Since the dispersible tablet has the characteristics of rapid disintegration and high bioavailability, it is particularly suitable for patients who have difficulty swallowing.
  • CN101732270A discloses a valsartan dispersible tablet and a preparation method thereof, comprising a therapeutically effective amount of valsartan and a medicinal auxiliary material, and solving the problem of low bioavailability of valsartan in human body, using amorphous, Hydrolyzyl- ⁇ -cyclodextrin which is highly soluble in water, uses its hydrophobic cavity to encapsulate the drug, increases the solubility and stability of the drug, reduces the side effects of the drug, promotes the release of the drug in the body, and increases absorption.
  • the composition of valsartan is single, and the antihypertensive effect on specific individuals is sometimes not obvious.
  • the dispersible tablet is made of at least one disintegrating agent and a water-swelling high-viscosity swelling auxiliary material, and the proportion of the prescription auxiliary material is changed, and the disintegration time limit of the tablet can be adjusted within a certain range to meet the requirements of the dispersing tablet.
  • the deviation and disintegration degree of valsartan dispersible tablets are required to meet the requirements of the Chinese Pharmacopoeia. Therefore, other projects need to meet the internal control standards of the company, so the possibility of change of disintegrants and other excipients of valsartan decomposition tablets is relatively small.
  • Cassia contains emodin, chrysophanol, physcion, obtusin, obtusifolin and its anthraquinones, aqueous leachate, ethanol-water extract And ethanol leaching solution, have the effect of lowering blood pressure, the antihypertensive effect of infusion is not obvious, and with cassia seed ⁇ 5ml, the antihypertensive effect is more obvious, and the duration is longer, intravenous injection with the same amount of dilute alcohol, can also reduce blood pressure, And can be restored immediately.
  • valsartan drugs For the efficacy of valsartan drugs, patients with hypertension such as myocardial infarction, heart failure, proteinuria, diabetes, etc. can be used routinely, and combined with hydrochlorothiazide to prepare tablets - valsartan hydrochlorothiazide tablets.
  • hydrochlorothiazide for the efficacy of valsartan drugs, patients with hypertension such as myocardial infarction, heart failure, proteinuria, diabetes, etc. can be used routinely, and combined with hydrochlorothiazide to prepare tablets - valsartan hydrochlorothiazide tablets.
  • the present invention is generally considered to be a combination only when monotherapy cannot achieve satisfactory results.
  • cassia seed Chinese medicine ingredients to valsartan tablets.
  • the valsartan dispersible tablets of the present invention have the following advantages and significant progress:
  • cassia contains organic substances such as emodin and chrysophanol, it can be used for laxatives. It is effective for high blood pressure and constipation. It also reduces the intra-abdominal pressure caused by severe exertion due to high blood pressure and constipation. Increased pressure, and the incidence of complications such as cerebral hemorrhage.
  • a valsartan dispersible tablet composed of valsartan, hydroxypropyl- ⁇ -cyclodextrin, a pharmaceutically acceptable excipient, a binder, a glidant, a flavoring agent and a cassia seed, wherein: pharmaceutically Acceptable excipients are one or more of a filler, a lubricant, a disintegrant selected from the group consisting of lactose, compressible starch, microcrystalline cellulose, mannitol, dextrin, and pregelatinized starch.
  • the lubricant is selected from one or more of magnesium stearate, talc, silica and magnesium lauryl sulfate
  • the disintegrant is selected from the group consisting of Gelatinized starch, sodium starch glycolate, microcrystalline cellulose, crospovidone, sodium carboxymethyl starch, sodium carboxymethylcellulose, low-substituted hydroxypropylcellulose and croscarmellose sodium One or more of them;
  • Cassia can choose one or two of Black Cassia or White Cassia.
  • the ratio of valsartan, filler, disintegrant, binder, lubricant, glidant and flavoring agent and cassia seed according to weight is: valsartan 100 parts; filler 100-200 parts 5-30 parts of disintegrant; 150-500 parts of binder; 0.1-8 parts of lubricant; 0.1-10 parts of glidant and flavoring agent; 10-50 parts of cassia seed.
  • the weight ratio of valsartan to hydroxypropyl- ⁇ -cyclodextrin is 1:1.5-1:4.
  • the present invention also provides a vegetation method for valsartan dispersible tablets, the following steps:
  • hydroxypropyl- ⁇ -cyclodextrin is dissolved in an appropriate amount of water to make a saturated aqueous solution, valsartan is passed through a 100 mesh sieve, dissolved in an appropriate amount of ethanol, and the valsartan ethanol solution is slowly added to the hydroxy group under magnetic stirring.
  • Propyl- ⁇ -cyclodextrin In the refined saturated aqueous solution, after all the melting, stirring is continued for 2-4 hours at room temperature, and 90% or more of ethanol is removed by rotary evaporation at room temperature, and then placed in a shallow tray, and the temperature is frozen at -50 ° C in a refrigerator freezer. 12 hours, then sublimed and dried under vacuum for 24 hours to form a clathrate;
  • step (2) The inclusion compound is mixed with microcrystalline cellulose, sodium carboxymethyl starch, magnesium stearate and the like, and the external disintegrating agent is placed at a temperature of 20 ° C to 25 ° C to uniformly mix. Afterwards, the amide methyl ester, sodium azide and the reactant are mixed, the catalyst enters, and the chemical reaction is performed by heating, and the reaction process is strictly controlled during the period, and the time cannot be more than three minutes, thereby minimizing the side effects, step (2) After the white solid valsartan methyl ester is obtained, the microcrystalline cellulose can increase the compressibility of the drug, and has a certain help-disintegrating effect, which is beneficial to the subsequent process steps;
  • the obtained solid raw material was hydrolyzed, acidified in a hydrochloric acid solution having a concentration of 0.1 mol/L, and extracted to obtain a novel valsartan dispersible tablet.
  • the clinical pharmaceutical results showed that the preparation process of valsartan had the longest absorption wavelength of 270 nm at a certain concentration, that is, 0.1 mol/L hydrochloric acid solution, and the other excipients prepared had no loss and absorption at this wavelength, so attention should be paid to concentration control.
  • concentration control the temperature and time required for disintegration are strict, and the general temperature is controlled at 20+25 ° C for less than 3 minutes. At this time, the disintegrating sheet disintegrates uniformly and easily.
  • FIG. 1 A chromatogram of an embodiment of the present invention measured under selected conditions.
  • A indicates the condition Blank plasma chromatogram for inclusion of internal standard (IS);
  • B indicates blank plasma chromatogram with valsartan;
  • C indicates conditions for plasma chromatogram of test sample spiked with internal standard (IS) .
  • hydroxypropyl- ⁇ -cyclodextrin is dissolved in an appropriate amount of water to make a saturated aqueous solution, valsartan is passed through a 100 mesh sieve, dissolved in an appropriate amount of ethanol, and the valsartan ethanol solution is slowly added to the hydroxy group under magnetic stirring.
  • a saturated aqueous solution of propyl- ⁇ -cyclodextrin after all the fusion, stirring was continued for 3 hours at room temperature, and 90% or more of ethanol was removed by rotary evaporation at room temperature, and then placed in a shallow dish, and the temperature was in the refrigerator freezer. Freezing at -50 ° C for 12 hours, then sublimation drying in a vacuum environment for 24 hours to form a clathrate;
  • the inclusion compound is mixed with microcrystalline cellulose, sodium carboxymethyl starch, magnesium stearate 100 mesh sieve, and the external disintegrating agent is placed at a temperature of 20 ° C to 25 ° C to be uniformly mixed.
  • the amide methyl ester, sodium azide and the reactant are mixed, the catalyst enters, and the temperature is heated to carry out the chemical reaction, and the reaction process is strictly controlled during the period, the time cannot be more than three minutes, and the side effects can be minimized, after the step (2) Get white solid laksa Tanthanum methyl ester, because microcrystalline cellulose can increase the compressibility of the drug, and has a certain help-disintegrating effect, which is of great benefit to the subsequent process steps;
  • the obtained solid raw material was hydrolyzed, acidified in a hydrochloric acid solution having a concentration of 0.1 mol/L, and extracted to obtain a novel valsartan dispersible tablet.
  • the preparation method was similar to that of Example 1.
  • the preparation method was the same as that of Example 1 and Example 2.
  • Study subjects 20 healthy male volunteers were selected, age: (24.0 ⁇ 2.35) years old, height: (1.70 ⁇ 0.06) m, body weight: (66.0 ⁇ 5.5) kg. All subjects passed the physical examination before the test. During the first half of the trial, no medication was used; during the trial, alcohol-free drinks and caffeinated beverages were avoided; avoid strenuous exercise. Sign the informed consent form.
  • Method of administration The test design was carried out by a random cross test method. At 8:00 pm on the 1st day before the administration, the subjects entered the clinical phase I trial ward; after 12 hours of fasting, the next morning, a single oral test drug, 10 oral compound valsartan dispersible tablets, 10 oral compound ⁇ The Shatan capsules were all dosed at 160 mg/25 mg, swallowed with 200 ml of 5% dextrose water and 200 ml of warm boiled water; the subjects were tested by cross-administration after one week of taking the drug.
  • Preparation of stock solution accurately weigh 20mg of valsartan dispersible tablet, place it in a 40ml volumetric flask, dissolve it into a standard stock solution of 0.5mg/ml with ethanol, and then accurately absorb 2ml in a 100ml volumetric flask and dissolve it with acetonitrile.
  • Sample treatment The blood sample was directly added with four volumes of acetonitrile for precipitation, and mixed. After centrifugation at 12000 r/min, the supernatant was taken directly for 20 ul, the flow rate was 2 ml/min, the detection wavelength was 250 nm, and the sensitivity was 0.005 AUFS.

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Abstract

本发明提供了一种缬沙坦分散片，是由缬沙坦、羟丙基-β-环糊精、药学上可以接受的辅料，粘合剂，助流剂，矫味剂和决明子组成，其中：药学上可以接受的辅料为填充剂、润滑剂、崩解剂中的一种或多种，所述填充剂选自乳糖、可压性淀粉、微晶纤维素、甘露醇、糊精和预胶化淀粉中的一种或多种；所述的润滑剂选自硬脂酸镁、滑石粉、二氧化硅和十二烷基硫酸镁中的一种或多种；所述的崩解剂选自预胶化淀粉、淀粉羟基乙酸钠、微晶纤维素、交联聚维酮、羧甲基淀粉钠、羟甲基纤维素钠、低取代羟丙基纤维素和交联羧甲基纤维素钠中的一种或多种；决明子可以选择黑决明子或者白决明子中的一种或两种。还提供一种缬沙坦分散片的制备方法。

Description

一种缬沙坦分散片及其制备方法 技术领域
本发明涉及药物领域，特别涉及一种缬沙坦分散片及其制备方法。
背景技术
缬沙坦类(N-(L-戊酰基)-N44-[2-(1H-四氮唑-5-基)苯基]苄基)-L缬氨酸)，分子式C24H29N5O3，其中有效治疗成分为缬沙坦，用于各种类型的高血压治疗，并对心脑肾有较好的保护作用。缬沙坦(Valsartan)是一种特异性血管紧张素II(AngII)受体拮抗剂，是继血管紧张素转换酶抑制剂后又一类新型降压药，其降压效果平稳，服用简单(每日一次)，无首剂低血糖反应，耐受性极好，不仅具有降低血药，还有保护靶器官不受损害，降低蛋白尿，全面降低心血管疾病发生率，预防各种心血管并发症的潜在作用，且不良反应发生率低的特点。由于分散片具有崩解快、生物利用度高的特点，因此特别适合于吞咽困难的患者。
CN101732270A公开了一种缬沙坦分散片及其制备方法，含有治疗有效量的缬沙坦和药用辅料，并且解决了缬沙坦在人体中口服吸收生物利用度低的问题，采用无定形，极易溶于水的羟丙基-β-环糊精，采用其疏水腔对药物包合，增加了药物溶解度和稳定性，降低了药物的毒副作用，促进了药物在体内的释放，增加吸收，提高生物利用度，然而，缬沙坦药物的成分单一，对特殊个体降压效果有时并不明显。
目前分散片由至少1种崩解剂和遇水形成高粘度的溶胀性辅料而制成，改变处方辅料组成比例，可在一定范围内调节片剂的崩解时限，使之符合分散片的要求，另外，目前缬沙坦分散片的偏差和崩解度均要求符合《中国药典》要 求，其他项目需要符合企业内控标准，因此对缬沙坦分解片的崩解剂和其他辅料的改变可能性比较小。
决明子含大黄素(emodin)、大黄酚(chrysophanol)、大黄素甲醚(physcion)、决明素(obtusin)、钝叶决明素(obtusifolin)及其甙类，其水浸出液、乙醇-水浸出液和乙醇浸出液，均有降低血压的作用，浸剂降压作用不明显，而用决明子酊5ml，降压作用较明显，且持续时间较长，用同量稀醇静脉注射，亦可降压，并可立即恢复。实验表明，决明子可使自发性遗传性高血压大鼠收缩压明显降低，同时使舒张压明显降低，但对心率和呼吸无明显影响。决明子对自发性遗传性高血压大鼠的降压作用和持续时间，均显著强于利血平。决明子脂溶部分在10mg/ml/kg开始有缓慢的降压效应；醇溶、水溶部分15mg/ml/kg开始出现明显的降压效应。三者降压效应均无快速耐受现象，与迷走神经无关，不能抑制肾上腺素的升压效应，不能加强乙酰胆碱的降压效应，但能被阿托品所阻断，提示与胆碱能神经、外周M-受体有关。因此，决明子对血压升高也有一定的治疗作用。
对于缬沙坦药物的药效，既往心肌梗塞、心力衰竭及蛋白尿、糖尿病等高血压病人可作为常规使用，既往与氢氯噻嗪合用制备成片剂—缬沙坦氢氯噻嗪片。但是临床表明，通常只在单药治疗不能达到满意效果时，因此本发明考虑联合用药。根据服用缬沙坦分散片病人其他病情的统计分析，我们于缬沙坦片剂里加入决明子中药成分，相比现有技术，本发明涉及的缬沙坦分散片具有如下优点和显著进步：
在临床试验中表明，该种新的缬沙坦分散片在心血管调节中起重要作用，而且降低血压的过程中，并不影响心率。中药成分决明子不仅可以降低血压，明显降低低密度脂蛋白成分，对于防止或者延缓动脉粥样硬化的形成有至关重要的作用。在长期治疗中，降压疗程缩短，半衰期长，疗效持续时间长，治疗1-3周后达最大降压疗效，并得以维持。与决明子联合应用显著地增强缬沙坦的降压作用，突然终止新型缬沙坦分散片的服用，也改变了以往高血压“反跳” 或其他副作用。研究证明，决明子中药成分入药可以减轻单纯应用缬沙坦所带来的咳嗽鼻炎等上呼吸道症状，并且缓解少数人皮疹、瘙痒及其他超敏反应的副作用。新加入的中药成分不仅针对老年人降压效果奇佳，更加对于青年型血压异常增高疾病有显著效果。由于决明子中含有大黄素、大黄酚等有机物，可润肠通便，对于高血压兼便秘者疗效显著，同时降低了由于血压增高，排便习惯差的便秘者由于剧烈用力，导致的腹压颅内压增加，进而脑出血等并发症的发生率。
发明内容
为了实现本发明的目的，其解决方案在于如下：
一种缬沙坦分散片，是由缬沙坦、羟丙基-β-环糊精、药学上可以接受的辅料，粘合剂，助流剂，矫味剂和决明子组成，其中：药学上可以接受的辅料为填充剂、润滑剂、崩解剂中的一种或多种，所述填充剂选自乳糖、可压性淀粉、微晶纤维素、甘露醇、糊精和预胶化淀粉中的一种或多种；所述的润滑剂选自硬脂酸镁、滑石粉、二氧化硅和十二烷基硫酸镁中的一种或多种；所述的崩解剂选自预胶化淀粉、淀粉羟基乙酸钠、微晶纤维素、交联聚维酮、羧甲基淀粉钠、羟甲基纤维素钠、低取代羟丙基纤维素和交联羧甲基纤维素钠中的一种或多种；决明子可以选择黑决明子或者白决明子中的一种或两种。
优选的，缬沙坦、填充剂、崩解剂、粘合剂，润滑剂，助流剂和矫味剂以及决明子按照重量分的配比为：缬沙坦100份；填充剂100-200份；崩解剂5-30份；粘合剂150-500份；润滑剂0.1-8份；助流剂和矫味剂0.1-10份；决明子10-50份。
优选的，所述的缬沙坦与羟丙基-β-环糊精的重量比为1：1.5-1：4。
为此，本发明还提供一种缬沙坦分散片的植被方法，如下步骤：
(1)取羟丙基-β-环糊精溶于适量水中制成饱和水溶液，缬沙坦过100目筛，溶于适量乙醇，在磁力搅拌下，将缬沙坦乙醇溶液慢慢加入羟丙基-β-环糊 精的饱和水溶液中，全部溶合后在室温下继续搅拌2-4小时，室温下旋转蒸发除去90％以上乙醇后，装入浅盘，至于冰箱冷冻室内，使其温度在-50℃下冷冻12小时，然后在真空环境下升华干燥24小时形成包合物；
(2)取包合物与微晶纤维素，羧甲基淀粉钠，硬脂酸镁等100目筛混匀，20℃-25℃温度下，将外崩解剂置入使其混合均匀，后将酰胺甲酯、叠氮化钠与反应剂相混，催化剂进入，加温使其进行化学反应，期间严密控制反应进程，时间不能超过三分钟，可最大程度降低其副作用，步骤(2)后得到白色固体缬沙坦甲酯，因微晶纤维素可增加药物的可压性，且有一定助崩作用，对于之后的工艺步骤大有裨益；
(3)决明子适量翻炒，煎煮后滤去药渣，研磨成粉，加入外渗崩解剂及润滑剂，与所得缬沙坦固体混合均匀，放置密闭容器压片；
(4)继续蒸除溶剂，重结晶回收固体原料；
(5)将所得固体原料水解，放入浓度为0.1mol/L的盐酸溶液中酸化，萃取得到新型缬沙坦分散片。
临床制药结果表明：缬沙坦制备过程，在一定浓度下，即0.1mol/L盐酸溶液中的最长吸收波长为270nm，制备的其余辅料在此波长处无耗损与吸收，故注意浓度控制。另外，崩解要求温度与时间较为严格，一般温度控制于20+25℃,时间不超过3分钟，此时的分散片崩解均匀易混。
根据下文结合附图对本发明具体实施例的详细描述，本领域技术人员将会更加明了本发明的上述以及其他目的、优点和特征。
附图说明
后文将参照附图以示例性而非限制性的方式详细描述本发明的一些具体实施例。附图中相同的附图标记标示了相同或类似的部件或部分。本领域技术人员应该理解，这些附图未必是按比例绘制的。附图中：
【图1】本发明的实施例在选定条件下测得的色谱图。其中A表示的条件 为掺入内标物(IS)的空白血浆色谱图；B表示的条件为掺入缬沙坦的空白血浆色谱图；C表示的条件为掺入内标物(IS)的受试血浆色谱图。
具体实施方式
以下实施例进一步描述本发明的制备过程和有益效果，实施例仅用于例证的目的，不限制本发明的范围，同时本领域普通技术人员根据本发明所做的显而易见的改变和修饰也包含在本发明范围之内。
实施例1：
缬沙坦20g
羟丙基-β-环糊精30g
微晶纤维素20g；
羧甲基淀粉钠1g；
粘合剂40g；
硬脂酸镁0.05g；
助流剂和矫味剂2g；
决明子10g。
制备工艺：
(1)取羟丙基-β-环糊精溶于适量水中制成饱和水溶液，缬沙坦过100目筛，溶于适量乙醇，在磁力搅拌下，将缬沙坦乙醇溶液慢慢加入羟丙基-β-环糊精的饱和水溶液中，全部溶合后在室温下继续搅拌3小时，室温下旋转蒸发除去90％以上乙醇后，装入浅盘，至于冰箱冷冻室内，使其温度在-50℃下冷冻12小时，然后在真空环境下升华干燥24小时形成包合物；
(2)取包合物与微晶纤维素，羧甲基淀粉钠，硬脂酸镁100目筛混匀，20℃-25℃温度下，将外崩解剂置入使其混合均匀，后将酰胺甲酯、叠氮化钠与反应剂相混，催化剂进入，加温使其进行化学反应，期间严密控制反应进程，时间不能超过三分钟，可最大程度降低其副作用，步骤(2)后得到白色固体缬沙 坦甲酯，因微晶纤维素可增加药物的可压性，且有一定助崩作用，对于之后的工艺步骤大有裨益；
(3)决明子适量翻炒，煎煮后滤去药渣，研磨成粉，加入外渗崩解剂及润滑剂，与所得缬沙坦固体混合均匀，放置密闭容器压片；
(4)继续蒸除溶剂，重结晶回收固体原料；
(5)将所得固体原料水解，放入浓度为0.1mol/L的盐酸溶液中酸化，萃取得到新型缬沙坦分散片。
实施例2：
缬沙坦20g
羟丙基-β-环糊精35g
乳糖40g；
微晶纤维素1g；
粘合剂40g；
十二烷基硫酸镁0.06g；
助流剂和矫味剂2g；
决明子10g。
制备方法类似实施例1。
实施例3：
缬沙坦20g
羟丙基-β-环糊精35g
甘露醇20g；
交联羧甲基纤维素钠5g；
粘合剂40g；
二氧化硅0.05g；
助流剂和矫味剂2g；
决明子10g。
制备方法同实施例1和实施例2。
以上三种配比制成的缬沙坦分散片为受试制剂，采用HPLC法分析其在健康人体内的药代动力学和生物等效性的特点。
1、仪器与试剂：采用Aglient1200高效液相色谱系统，该系统具有自动进样器和二极管阵列检测器，四元梯度泵，AT-130柱温箱等，并采用北京医用离心机场生产的台式高速微量离心机以及BT25S精密电子分析天平，微型漩涡混合仪，YGL系列氮吹仪，纯水机和缬沙坦分散片，其中内标物采用纯度98％以上的尼美舒利内标物，工作台软件采用N2000色谱数据工作台，
2、研究对象：选择20例健康男性志愿者，年龄：(24.0±2.35)岁，身高：(1.70±0.06)m，体重：(66.0±5.5)kg。试验前，所有受试者均经体检合格。试验前半年，未使用任何药物；试验期间，禁烟酒和含咖啡因饮料；避免剧烈运动。签署知情同意书。
3、给药方法：用随机交叉试验方法进行试验设计。于给药前1日晚8时，受试者进入临床I期试验病房；禁食12h后，次日清晨，单次口服试验药品，10名口服复方缬沙坦分散片，10名口服复方缬沙坦胶囊，剂量均为160mg/25mg，用5％葡萄糖水200ml和温开水200ml吞服；受试者在服药1周后，自身交叉给药进行试验。
4、制备储备液：精密称取缬沙坦分散片20mg，置于40ml容量瓶中，以乙醇溶解定容成0.5mg/ml标准储备液，再从中精密吸取2ml于100ml容量瓶中用乙腈溶解制成含缬沙坦10000ng/ml的对照品储备液；精密称取尼美舒利内标物40mg，置于1000ml容量瓶中，采用乙腈溶解定容成0.4mg/ml标准储备液，再从中精密吸取1ml于1000ml容量瓶中，采用乙腈溶解制备成含尼美舒利400ng/ml的内标储备液，所有标准储备液于0℃以上温度的冰箱中保存。
5、样本处理：血样直接加四倍体积的乙腈进行沉淀，混匀，采用12000r/min离心后，取上清20ul直接进行，流速为2ml/min，检测波长为250nm，灵敏度为0.005AUFS。
6、试验结果：从图1可见，缬沙坦与尼美舒利的保留时间为4.48，5.56分钟，两者分离完全，无杂质峰值干扰。
至此，本领域技术人员应认识到，虽然本文已详尽示出和描述了本发明的多个示例性实施例，但是，在不脱离本发明精神和范围的情况下，仍可根据本发明公开的内容直接确定或推导出符合本发明原理的许多其他变型或修改。因此，本发明的范围应被理解和认定为覆盖了所有这些其他变型或修改。

Claims (4)

  1. 一种缬沙坦分散片，其特征在于：它是由缬沙坦、羟丙基-β-环糊精、药学上可以接受的辅料，粘合剂，助流剂，矫味剂和决明子组成，其中：药学上可以接受的辅料为填充剂、润滑剂、崩解剂中的一种或多种，所述填充剂选自乳糖、可压性淀粉、微晶纤维素、甘露醇、糊精和预胶化淀粉中的一种或多种；所述的润滑剂选自硬脂酸镁、滑石粉、二氧化硅和十二烷基硫酸镁中的一种或多种；所述的崩解剂选自预胶化淀粉、淀粉羟基乙酸钠、微晶纤维素、交联聚维酮、羧甲基淀粉钠、羟甲基纤维素钠、低取代羟丙基纤维素和交联羧甲基纤维素钠中的一种或多种；决明子可以选择黑决明子或者白决明子中的一种或两种。
  2. 根据权利要求1所述的缬沙坦分散片，其特征在与所述的缬沙坦、填充剂、崩解剂、粘合剂，润滑剂，助流剂和矫味剂以及决明子按照重量分的配比为：
    缬沙坦  100份
    填充剂  100-200份
    崩解剂  5-30份
    粘合剂  150-500份
    润滑剂  0.1-8份
    助流剂和矫味剂  0.1-10份
    决明子  10-50份。
  3. 如权利要求1所述的缬沙坦分散片，其特征在于所述的缬沙坦与羟丙基-β-环糊精的重量比为1：1.5-1：4。
  4. 一种缬沙坦分散片的制备方法，其特征在于，包括如下步骤：
    (1)取羟丙基-β-环糊精溶于适量水中制成饱和水溶液，缬沙坦过100目 筛，溶于适量乙醇，在磁力搅拌下，将缬沙坦乙醇溶液慢慢加入羟丙基-β-环糊精的饱和水溶液中，全部溶合后在室温下继续搅拌2-4小时，室温下旋转蒸发除去90％以上乙醇后，装入浅盘，至于冰箱冷冻室内，使其温度在-50℃下冷冻12小时，然后在真空环境下升华干燥24小时形成包合物；
    (2)取包合物与微晶纤维素，羧甲基淀粉钠，硬脂酸镁等100目筛混匀，20℃-25℃温度下，将外崩解剂置入使其混合均匀，后将酰胺甲酯、叠氮化钠与反应剂相混，催化剂进入，加温使其进行化学反应，期间严密控制反应进程，时间不能超过三分钟，可最大程度降低其副作用，步骤(2)后得到白色固体缬沙坦甲酯；
    (3)决明子适量翻炒，煎煮后滤去药渣，研磨成粉，加入外渗崩解剂及润滑剂，与所得缬沙坦固体混合均匀，放置密闭容器压片；
    (4)继续蒸除溶剂，重结晶回收固体原料；
    (5)将所得固体原料水解，放入浓度为0.1mol/L的盐酸溶液中酸化，萃取得到新型缬沙坦分散片。
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