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CN1608621A - Fine bicyclic alcohol powder and oral bicyclic alcohol release controlling prepn - Google Patents

Fine bicyclic alcohol powder and oral bicyclic alcohol release controlling prepn Download PDF

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CN1608621A
CN1608621A CN 200310101891 CN200310101891A CN1608621A CN 1608621 A CN1608621 A CN 1608621A CN 200310101891 CN200310101891 CN 200310101891 CN 200310101891 A CN200310101891 A CN 200310101891A CN 1608621 A CN1608621 A CN 1608621A
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releasing
bicyclic
delayed
alcohol
micropowder
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CN 200310101891
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Chinese (zh)
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CN100542528C (en )
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刘玉玲
李燕
陈丙跃
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中国医学科学院药物研究所
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, 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
    • A61K9/2086Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36Compounds containing methylenedioxyphenyl groups, e.g. sesamin

Abstract

The present invention discloses micropowder of hard-to-dissolve bicyclic alcohol medicine, micropowder preparing process, orally taken bicyclic alcohol skeleton delayed releasing preparation and its preparation process. Making bicyclic alcohol into micropowder can improve the extracorporal leaching rate and intracorporal absorption. Utilizing bicyclic alcohol micropowder as active component and gel skeleton material can produce orally taken delayed releasing preparation with high bioavailability. The mixture of bicyclic alcohol micropowder, delayed releasing material and retardant may be prepared into orally taken delayed releasing tablet, delayed releasing micro pellet and other delayed releasing preparation. Or, the delayed releasing part and fast releasing part may be prepared into double-layer tablet, coated tablet or capsulized micro pellet to balance medicine concentration in blood and favor to the treatment of chromatic hepatitis B and resisting virus.

Description

双环醇微粉化及口服控释制剂 Bicyclic alcohol micronized and oral controlled-release formulation

技术领域 FIELD

本发明涉及难溶性药物双环醇的微粉,微粉的制备方法,和双环醇的口服骨架缓释制剂,这种缓释制剂的制备方法。 The present invention relates to a method of preparing a poorly soluble drug bicyclic alcohol powder, fine powder, sustained release formulations and oral skeleton of bicyclic alcohols, methods of making such sustained release formulations.

背景技术 Background technique

病毒性肝炎在我国发病率较高,是严重危害人民健康的常见病之一。 Higher prevalence of viral hepatitis in our country, is a common disease of serious harm to people's health. 根据血清流行病学调查,甲型肝炎病毒感染流行率为80.9%,乙型肝炎病毒感染流行率达57.6%,乙肝表面抗原(HBsAg)阳性率为9.75%,丙型肝炎病毒感染率为3.2%,丁型和戊型肝炎亦有流行。 The serological surveys, hepatitis A virus infection prevalence was 80.9% HBV infection prevalence rate of 57.6%, hepatitis B surface antigen (HBsAg) positive rate of 9.75%, hepatitis C virus infection was 3.2% , hepatitis D, and E are also popular. 病毒性肝炎在急性阶段,除丙型肝炎外,多为自限性疾病,尤其是甲型和戊型肝炎可以自愈。 In the acute phase of viral hepatitis, in addition to hepatitis C, mostly self-limiting disease, especially influenza and hepatitis can heal. 但乙型、丙型和丁型肝炎可以发展为慢性肝炎,经过10-20年的病程,约有20%左右将发展为肝硬化,1-5%转变成肝癌。 However, hepatitis B, hepatitis C and hepatitis D may develop chronic hepatitis, after 10--20 years of course, about about 20% will develop cirrhosis, 1-5% into liver cancer. 目前约有3000万慢性肝炎病人在社会上流动。 There are about 30 million patients with chronic hepatitis flowing in the community. 由于乙肝可通过母婴传播,影响下一代,故危害极大。 Because of mother to child transmission of hepatitis B can affect the next generation, it is lethal. 另外,重型肝炎虽发生率不高但病死率极高。 In addition, although the incidence of severe hepatitis is not high, but high mortality rate. 因此,慢性病毒性肝炎的治疗是急待解决的重大问题。 Therefore, the treatment of chronic viral hepatitis is a major problem need to be solved.

目前国内外用于治疗慢性肝炎药种类甚多,归纳起来可分为四大类:(1)抗肝炎病毒药,如干扰素和拉米夫定;(2)免疫调节剂,如胸腺素α1(日达仙),特异性免疫核糖核酸和转移因子;(3)改善肝功能药,如联苯双酯、甘草甜素;(4)中草药,如苦参素、抗肝纤维化中药复方“861”。 At home and abroad for the treatment of many types of chronic hepatitis agent, can be categorized into four categories: (1) an anti-hepatitis virus agent, such as interferon and lamivudine; (2) immunomodulatory agents such as thymosin alpha] l ( Zadaxin), specific immune RNA and transfer factor; (3) improve liver function drugs, such as DDB, glycyrrhizin; (4) Chinese herbal medicine, such as oxymatrine, hepatic fibrosis herbal compound "861 . " 上述药物各有一定疗效,亦都各有其一定的问题。 These drugs have a certain effect, it must also have their own problems.

干扰素和拉米夫定(Lamivudin)是目前国际公认的抗肝炎病毒药。 Interferon and lamivudine (Lamivudin) is an internationally recognized anti-hepatitis virus drugs. 干扰素治疗急性丙型肝炎使病毒HCV-RNA转阴的有效率可达到60%左右,治疗慢性丙型和乙型肝炎的有效率为30%左右,但停药后复发率高,副反应发生率较多较重,且价格昂贵,长期注射给药使用不方便。 Interferon treatment of acute hepatitis C virus is HCV-RNA negative efficiency can reach about 60%, treatment of chronic hepatitis B and the effective rate was 30%, but the high rate of recurrence after treatment, side reaction rate more heavy, and expensive, long-term injection inconvenient to use. 拉米夫定为核苷类药物,为DNA多聚酶抑制剂,治疗慢性乙型肝炎1年时HBV-DNA转阴率可达80%,但HBeAg转阴率仅20-30%左右,且停药后很快复发,长期用药乙肝病毒出现点突变,产生耐药性,每年发生率约20%递增,如治疗二年病毒变异率为40%左右。 Lamivudine is a nucleoside drugs, a DNA polymerase inhibitor, the treatment of chronic HBV-DNA negative rate of 80% at 1 year, but about 20-30% HBeAg seroconversion rate, drug withdrawal soon after relapse, long-term treatment of hepatitis B virus appears point mutation, drug resistance, the annual incidence of about 20% of the increase, such as the treatment of viral mutation rate two years about 40%. 免疫调节药应用较多的是日达仙,大多用在不能应用干扰素治疗的病人,或作为联合用药,治疗慢性乙型肝炎HBeAg转阴率在20-30%左右。 Immunomodulatory drug use is more Zadaxin, mostly used in patients who can not use interferon therapy, or as a combination therapy, the treatment of chronic hepatitis B HBeAg seroconversion rate is about 20-30%. 此类药物治疗肝炎的确切疗效还有待更多的验证,价格亦相当昂贵。 The exact effect of these drugs to treat hepatitis more remains to be verified, the price is also very expensive. 联苯双酯是八十年代初我国在研究中药五味子基础上创制成功的改善肝功能新药,对慢性乙型肝炎降ALT作用显著,价格便宜,副反应少。 DDB is the study of traditional Chinese medicine on the basis of Schisandra create successful early eighties improve liver function drugs, chronic hepatitis B ALT drop a significant effect, the price is cheaper, less side effects. 存在的问题是停药后回跳率高,虽然发现对乙肝病毒复制也有一定抑制效果,但缺乏多中心的临床验证,另外,联苯双酯没有专利保护,因此在国际上无竞争力。 The problem is after stopping bounce rate, although the discovery of the hepatitis B virus replication also has some inhibitory effect, but the lack of multi-center clinical validation, in addition, DDB is no patent protection, and therefore not competitive in the international arena. 据报道,不少中药复方及中草药制剂对慢性乙型肝炎有一定疗效,其中有的在动物模型上有抗肝炎病毒作用,有的临床应用亦观察到对HBeAg转阴有一定疗效,但是大多未经过临床多中心严格的双盲、随机、对照验证,制剂质量不稳定。 According to reports, many traditional Chinese medicine and Chinese herbal medicine for chronic hepatitis B have a certain effect, some of which have anti-hepatitis virus effect in animal models and some clinical applications also observed a certain effect on HBeAg loss, but most did not after a rigorous double-blind clinical multicenter, randomized, controlled verification, unstable quality of preparation.

总之,目前我国约有3000万肝炎病人急需治疗,虽然治疗慢性肝炎药物品种很多,但可供患者选择的药物有限,临床迫切需要安全、有效、价格便宜的治疗肝炎新药。 In short, China has about 30 million hepatitis patients in urgent need of treatment, although the treatment of chronic hepatitis varieties of drugs a lot, but limited the drug of choice for patients, clinical urgent need for safe, effective, inexpensive drugs to treat hepatitis.

双环醇是由中国医科院药物所研制出的抗肝炎创制新药,目前双环醇研究成果已在14个国家和地区获得专利保护,经北京、上海多家医院对500多例慢性乙肝、丙肝患者进行临床疗效观察,表明该药不但能降低血清谷丙转氨酶和谷草转氨酶,而且具有一定抑制肝病毒复制的作用,未发现明显副作用,其综合效果明显优于联苯双酯。 Bicyclol by the Chinese Medical drug developed resistance to hepatitis development of new medicines, currently bicyclic alcohol research has been patented in 14 countries and regions, via Beijing, Shanghai and a number of hospitals for more than 500 cases of chronic hepatitis B, hepatitis C patients clinical efficacy, indicating that the drug not only can reduce serum alanine aminotransferase and aspartate aminotransferase, and has a certain inhibition of viral replication in the liver and found no obvious side effects, their combined effect is superior to DDB.

双环醇原料药及其普通片剂被国家药品监督管理局批准生产。 Bicyclol pharmaceutical raw materials and the production of ordinary tablets are approved by the State Drug Administration. 由于双环醇水溶性差,其普通片体外溶出速率较慢,以蒸馏水为溶出介质时,在两小时内仅能溶出60%-70%,临床治疗过种中,患者口服后生物利用度较低,表现出较为显著的个体差异,不利于其疗效的发挥。 Because of poor water solubility bicyclic alcohol, its ordinary sheet slower dissolution rate in vitro, when distilled water as the dissolution medium, the dissolution in two hours only 60% -70%, clinical treated species, after oral administration in patients with low bioavailability, showed a more significant individual differences play a negative effect on their efficacy.

药物骨架型缓释制剂系由活性药物与一种或多种惰性材料通过压制或融合技术制成片状、小粒或其它形式的制剂。 Drug-based matrix type sustained-release preparation of the active drug with one or more inert materials by pressing or fusion into a sheet, pellet or other forms of formulation. 按骨架材料性质的不同,骨架型缓释制剂可分成生物溶蚀性骨架制剂、亲水凝胶(水溶蚀性)骨架制剂、不溶性骨架制剂和离子交换骨架制剂。 Skeleton by different material properties, can be divided into a matrix type sustained-release preparation bioerodable skeleton formulation, the hydrophilic gels (water-erodible) backbone formulation, an insoluble skeleton formulation and preparation of ion exchange backbone. 骨架制剂的临床应用有各种剂型,最常用的为口服剂型,其中制备骨架型片具有成本低、工艺简单的优点,且应用协带方便,受到人们的欢迎。 Clinical application of various formulations skeleton preparations are most commonly used oral dosage form, wherein the preparation of matrix type sheet having a low cost, the advantages of simple process, and easy application with RA, was welcomed.

发明内容 SUMMARY

为了克服现有技术中双环醇制剂中存在的问题,本发明提供一种微粉化双环醇。 In order to overcome the prior art bicyclic alcohol present in the formulation, the present invention provides a micronized bicyclic alcohols.

本发明的目的在于提供一种双环醇口服骨架缓释制剂。 Object of the present invention is to provide a scaffold for oral sustained release formulations bicyclic alcohol.

本发明的目的还在于提供双环醇口服骨架缓释制剂的制备方法。 Object of the present invention is to provide a method for preparing bicyclic skeleton oral sustained release formulation of an alcohol.

为实现本发明的目的,采用如下的技术方案:本发明提供一种药物骨架缓释制剂,其药物活性成分是微粉化双环醇并且双环醇粒径范围为1-200μm。 For purposes of this invention, the following technical solutions: The present invention provides a pharmaceutical sustained release formulation skeleton, a pharmaceutically active ingredient which is micronised bicyclic alcohols and bicyclic alcohols size range 1-200μm. 优选的微粉化双环醇的粒径范围为1-10μm。 The preferred particle size range micronized bicyclic alcohols 1-10μm. 微粉化双环醇在缓释制剂中的重量比例为5-30%;优选为14-16%。 Bicyclic alcohol weight ratio of micronized in a sustained release formulation from 5 to 30%; preferably 14-16%.

本发明的缓释制剂的骨架材料选自生物溶蚀性骨架、亲水凝胶骨架、不溶性骨架和离子交换骨架。 Framework material of the sustained-release formulation of the present invention is selected from bioerodable backbone, hydrophilic gel matrix, backbone, and the insoluble ion exchange backbone. 优选的亲水凝胶骨架材料包括羟丙基甲基纤维素、卡泊姆、羧甲基纤维素钠。 Preferred hydrophilic matrix materials include hydroxypropyl methyl cellulose, carbomers, sodium carboxymethylcellulose. 更优选的是羟丙基甲基纤维素。 More preferred is hydroxypropylmethylcellulose. 所述的羟丙基甲基纤维素在缓释制剂中的重量比例的用量范围为5-70%。 The weight ratio of hydroxypropyl methylcellulose in sustained release formulations in an amount ranging from 5-70%. 更优选的是羟丙基甲基纤维素是粘度为K4M、K15M、K100M的羟丙基甲基纤维素。 More preferred it is hydroxypropylmethylcellulose having a viscosity of K4M, K15M, K100M hydroxypropyl methylcellulose.

在本发明的药物骨架缓释制剂的优选实施方案中,骨架缓释制剂中含有阻滞剂。 In a preferred embodiment the sustained release pharmaceutical preparation of the present invention, the backbone, the backbone containing sustained release formulation blocker. 所述的阻滞剂优选是脂肪酸、脂肪醇。 The blockers are preferably fatty alcohols. 更优选的是阻滞剂是十八醇。 More preferred are stearyl alcohol blockers. 阻滞剂的用量范围为1-50%,更优选是25%。 Blocker in an amount ranging from 1 to 50%, more preferably 25%.

本发明的骨架缓释制剂包括骨架缓释片、缓释微丸、缓释胶囊。 Sustained Release formulation of the present invention comprises a Sustained Release tablets, sustained-release pellets, sustained release capsules. 并可与速释部分制成双层控释片、包芯控释片及微丸控释胶囊。 And immediate release and controlled release portion formed bilayer tablets, controlled release tablets and pellets Core controlled release capsule.

换言之,本发明的骨架缓释制剂,是以双环醇粗粉或微粉化双环醇作为活性成分。 In other words, the skeleton sustained release formulations of the invention, is coarse or micronized bicyclic alcohol bicyclic alcohols as an active ingredient. 双环醇粗粉可使用制药领域常用的过筛的方法制备,例如经100目筛的粒径范围为63-150μm,经300目筛的粒径小于47μm。 Bicyclic alcohol sieved meal may be prepared using conventional pharmaceutical art, for example by a particle size range of 100 mesh sieve was 63-150μm, through 300 mesh sieve particle size less than 47μm. 微粉化双环醇是用超细球磨设备处理,粒径为1-5μm。 Micronized bicyclic alcohol is treated with ultra-fine ball mill, a particle size of 1-5μm. 将不同粒径的双环醇进行对比,考察粒径对体外溶出的影响,结果表明,随着粒径越小,溶出速率越快。 The bicyclic alcohols of different particle sizes were compared to investigate the influence of particle size on in vitro dissolution results show that, as the smaller the particle size, the faster dissolution rate. 将100目筛原料和微粉化原料分别混悬后进行小鼠口服吸收试验,HPLC法测定血药浓度,绘制药时曲线,结果表明,两者相比,微粉化双环醇Cmax和AUC均提高1倍以上,而Tmax未发生变化。 After 100 mesh and micronized material were suspended material from mice oral absorption test, blood concentration was determined by HPLC, concentration-time curve when drawing The results show that, comparing the two, micronized Bicyclol Cmax and AUC are increased by 1 times more than the Tmax unchanged. 因此本发明中微粉化双环醇的粒径范围为1-200μm。 Thus the present invention is a particle size range micronized bicyclic alcohols 1-200μm. 优选的微粉化双环醇的粒径范围小于10μm。 The preferred particle size range is less than micronized bicyclic alcohols 10μm. 本发明的微粉化双环醇,可显著提高双环醇在生物体内生物吸收。 Micronized bicyclic alcohols of the present invention, can significantly increase the bicyclic alcohol absorbed in the living body organism. 本发明的微粉化双环醇在骨架缓释制剂中的重量比例为5-30%,优选为14-16%。 The weight ratio of micronized bicyclic alcohols of the present invention a sustained release formulation in the backbone of 5 to 30%, preferably 14-16%.

本发明的骨架缓释制剂选用的骨架材料包括生物溶蚀性骨架、亲水凝胶(水溶蚀性)骨架、不溶性骨架和离子交换骨架。 Sustained Release formulation of the invention comprises a reinforcing material selected bioerodable backbone, hydrophilic gels (water-erodible) skeleton, and a skeleton insoluble ion exchange backbone. 优选的骨架材料为亲水凝胶骨架,其中包括羟丙基甲基纤维素(HPMC),卡泊姆,羧甲基纤维钠,优选是羟丙基甲基纤维素。 Preferred backbone is a hydrophilic matrix material, which comprises hydroxypropyl methylcellulose (HPMC), carbomers, sodium carboxymethylcellulose fibers, preferably hydroxypropylmethylcellulose. 羟丙基甲基纤维素在处方中的用量范围为5-70%,优选是50%。 Hydroxypropyl methyl cellulose in an amount ranging from 5 to 70% in formulation, preferably 50%. 羟丙基甲基纤维素的粘度为K4M、K15M、K100M。 Viscosity hydroxypropyl methylcellulose is K4M, K15M, K100M. 本发明以微粉化双环醇为活性物质,选用不同粘度的羟丙基甲基纤维素混合体作为骨架材料,考察HPMC粘度对释药时间的影响。 The present invention is bicyclic alcohol is micronized active substance, a mixture of hydroxypropyl methylcellulose selected different viscosities as a skeletal material, the viscosity HPMC investigate the influence on the release time. 结果表明,随着HPMC粘度的增大,双环醇释药时间有所延长。 The results show that with the increase of the viscosity of the HPMC, the release time has been extended bicyclic alcohol. 因此优选的是K4M和K15M的羟丙基甲基纤维素联合使用。 It is therefore preferred K4M and K15M are hydroxypropyl methylcellulose used in combination. 选用不同粘度HPMC的混合物作骨架缓释材料制备骨架片,发现在体外可维持14小时恒速释放,符合零级动力学,与普通片相比,释药参数T50、Td分别由0.16h、0.2h延长至8.1h和10.5h;为获得释药时间更长、药效可持续20小时以上的缓释制剂,本发明的骨架缓释制剂还可以加入阻滞剂,例如脂肪酸,脂肪醇;优选的脂肪酸是硬脂酸,优选的脂肪醇是硬脂醇,更优选的是十八醇。 Mixtures of different viscosity HPMC is selected as the skeleton material prepared sustained release matrix tablets, found to be 14 hours of constant release in vitro, with zero order kinetics, compared with the conventional tablets, the release parameters T50, Td respectively, by 0.16h, 0.2 8.1h and 10.5h extended to h; to obtain a longer release time, and lasts up to 20 hours or more sustained release formulations, extended release formulations of the present invention, the skeleton may also be added blockers, such as fatty acids, fatty alcohols; preferably fatty acids are stearic acid, stearyl alcohol, fatty alcohols are preferred, and more preferably stearyl alcohol. 十八醇的用量范围为0-50%,优选是25%。 Stearyl alcohol in an amount ranging from 0 to 50%, preferably 25%. 体外释药测定结果表明,脂肪醇具有阻滞药物释放和胃漂浮作用,能够明显延缓药物体外释放时间,24小时释药曲线符合零级动力学。 The results show that the in vitro release assay, and fatty alcohols having gastric floating drug release retardation effect can be significantly delayed in vitro release time of 24 hours with zero order kinetics release profile.

本发明还提供了骨架缓释制剂的制备方法,包括粉末直接压片法和湿法制粒法。 The present invention further provides a method of preparing a sustained release formulation of the skeleton, including direct powder compression method and the wet granulation method.

粉末直接压片法:将HPMC(K4M)及乳糖过80目筛,与微粉化双环醇充分混合,加入微粉硅胶及硬脂酸镁混匀,压片,片重约355mg。 Direct powder compression method: The HPMC (K4M), and lactose are passed 80 mesh sieve, and mixed thoroughly micronized bicyclic alcohols, silica powder was added and mixed magnesium stearate, tabletting, tablets weighing approximately 355mg.

湿法制粒:将HPMC(K4M)及乳糖过80目筛,与微粉化双环醇充分混合均匀,加适量水制软材,16目筛制粒,湿颗粒于60℃条件下干燥2小时,用18目筛整粒,加入微粉硅胶及硬脂酸镁混匀,压片,片重约355mg。 Wet Granulation: the HPMC (K4M), and lactose are passed 80 mesh sieve and uniformly mixed micronized bicyclic alcohols, water was added q.s. made of soft material, 16-mesh sieve granulated, the wet granulation was dried under 60 ℃ 2 hours, 18 mesh sieve, silica powder was added and mixed magnesium stearate, tabletting, tablets weighing approximately 355mg.

体外释放度测定结果表明,使用湿法制粒压片比粉末直接压片工艺体外释放速率减慢。 In vitro release test showed that the use of wet granulation tableting slowing than direct powder tabletting vitro release rate.

活性成分在处方中的比例(载药量)、片剂硬度、片形等因素对释药时间无明显影响。 The proportion of active ingredient in the formulation (drug loading), tablet hardness, and other factors shaped sheet had no effect on release time.

Beagle狗体内试验表明,与普通片相比,缓释片体内释药时间明显延长,且生物利用度显著提高,释药参数MRT由4.12小时延长至9.32小时,相对生物利用度高达218%。 Beagle dogs vivo tests, in comparison with conventional tablets, sustained release tablets was significantly prolonged in vivo release time, and significantly improve the bioavailability, release parameters MRT extended from 4.12 to 9.32 hours, the relative bioavailability of as high as 218%.

总而言之,本发明将双环醇进行微粉化处理后,通过减小药物粒径、增大比表面积从而改善了药物的水溶性和水分散性。 After summary, the present invention will bicyclic alcohol micronization process, by reducing the drug particle size, the specific surface area is increased thereby improving the water soluble and water dispersible drug. 本发明提高了双环醇生物利用度、延缓释药时间、平稳血药浓度、减少服药次数,使病人一天服药1-2次,方便肝炎疾病的治疗。 The present invention improves the bioavailability of bicyclic alcohols, slow release time, stable blood concentration, reducing the number of medication, the patient taking one day 1-2 times, to facilitate the treatment of hepatitis diseases.

术语HPMC羟丙基甲基纤维素附图说明图1不同粒径双环醇体外溶出曲线比较图2微粉化双环醇与普通双环醇细粉体内药时曲线比较图3湿法制粒与粉末直接压片工艺体外释放曲线比较图4不同粘度HPMC骨架缓释片体外释放曲线图比较图5不同HPMC用量对双环醇缓释片释药影响图6不同粘度HPMC联合应用体外释药曲线图7不同载药量体外释药曲比较图8含凝胶骨架材料和阻滞剂的缓释片体外释药曲线图9Beagle获药时曲线(微粉化缓释片与普通片比较)具体实施方式实施例1:双环醇微粉化研究取双环醇原料药,分别制备粒径为63-150μ(100目筛处理)、<54μ(300目筛处理)和1-5μ(超细研磨设备微粉化处理,平均粒径为1.5μ)的双环醇细粉。 The term & hydroxypropyl methylcellulose HPMC 1 shows different particle sizes bicyclic alcohol 2 Comparative in vitro dissolution profile of micronized bicyclic alcohols with ordinary powder pharmacokinetics BICYCLOL graph comparing Figures 3 wet granulation and direct compression 4 process in vitro release profile of different viscosity HPMC matrix comparing FIG release tablets graph comparing different amount of HPMC FIG 5 7 6 different drug content of different viscosities bicyclic alcohol release from matrix tablets affect FIG HPMC combined in vitro release profile Comparative in vitro release curve of FIG. 8 in vitro release profile containing gel matrix material and a release sheet 9Beagle curve blockers (Comparative micronized sustained release tablets and conventional tablets) of the drug is eligible DETAILED DESCRIPTION Example 1: bicyclol Study bicyclol taken micronized drug, were prepared in a particle size of 63-150μ (100 mesh sieve), <54μ (300 mesh sieve) and 1-5μ (ultrafine milling apparatus micronized to an average particle size of 1.5 [mu]) bicyclol fines.

取100目筛细粉和微粉化细粉适量,照中国药典溶解度测定方法分别测定饱和水溶液中的溶解度,结果表明,100目筛细粉为28.72μg/ml,经微粉化处理后溶解度有所,为35.42μg/ml。 Take 100 mesh powder and micronized amount of powder, according to the solubility determination method of Chinese Pharmacopoeia saturated aqueous solubility were measured, the results showed that 100 mesh powder was 28.72μg / ml, after micronization process have solubility, It was 35.42μg / ml.

取上述三种粒径的双环醇细粉各2.5g,分别加入12.5g淀粉混匀压片(便于溶出度测定),以水900ml作溶剂,转速100rpm,照中国药典附录第一法进行溶出度测定,紫外分光光度法定量,结果表明,粒径越小,溶出速率越快,见附图1所示。 Take the three particle diameter of each powder bicyclic alcohol 2.5g, mixing starch were added 12.5g tabletting (to facilitate dissolution test), 900ml water as solvent, speed 100 rpm, the dissolution of a first method according to China Pharmacopoeia Appendix determination, quantitative UV spectrophotometry results showed that the smaller the particle size, the faster the dissolution rate, see Figure 1.

取100目筛细粉与微粉化细粉适量,加淀粉浆混悬,按25mg/kg剂量小鼠灌胃给药,于不同时间采集血样,依法测定血药浓度,结果经3P87软件处理,绘制药时曲线,结果表明,两种细粉达峰时间Tmax一致,但峰浓度和生物利用度显著不同,微粉化双环醇Cmax和AUC均比100目筛双环醇提高1倍以上。 Take 100 mesh sieve and fine micronized powder q.s. starch suspension, according to 25mg / kg dose of oral administration the mice, blood samples were collected at different times, measured blood concentration law, the results by software processing 3P87, drawing when drug curve, the results indicate that both fines peak time Tmax consistent, but the peak concentration and bioavailability significantly different, micronized bicyclol Cmax and AUC than 100 mesh bICYCLOL increase more than 1 times. 结果见附图2.。 The results are shown in Figure 2 ..

实施例2:不同制片方法对双环醇缓释片释药影响处方组成:原辅料 处方1微粉化双环醇 50mgHPMC(K4M) 55mg乳糖 240mg微粉硅胶 7mg硬脂酸镁 3mg粉末直接压片法:将HPMC(K4M)及乳糖过80目筛,与微粉化双环醇充分混合,加入微粉硅胶及硬脂酸镁混匀,压片,片重约355mg。 Example 2: Effect of Different Production Method bicyclol release from matrix tablets formulation composition: Formulation 1 micronised raw materials bicyclic alcohols 50mgHPMC (K4M) 55mg Lactose 240mg Aerosil powder 7mg Magnesium stearate 3mg direct compression method: HPMC (K4M), and lactose are passed 80 mesh sieve, and mixed thoroughly micronized bicyclic alcohols, silica powder was added and mixed magnesium stearate, tabletting, tablets weighing approximately 355mg.

湿法制粒:将HPMC(K4M)及乳糖过80目筛,与微粉化双环醇充分混合均匀,加适量水制软材,16目筛制粒,湿颗粒于60℃条件下干燥2小时,用18目筛整粒,加入微粉硅胶及硬脂酸镁混匀,压片,片重约355mg。 Wet Granulation: the HPMC (K4M), and lactose are passed 80 mesh sieve and uniformly mixed micronized bicyclic alcohols, water was added q.s. made of soft material, 16-mesh sieve granulated, the wet granulation was dried under 60 ℃ 2 hours, 18 mesh sieve, silica powder was added and mixed magnesium stearate, tabletting, tablets weighing approximately 355mg.

体外释放度测定结果表明,使用湿法制粒压片比粉末直接压片工艺体外释放速率减慢。 In vitro release test showed that the use of wet granulation tableting slowing than direct powder tabletting vitro release rate. 释药曲线见附图3所示。 See FIG. 3 release curve shown in FIG.

实施例3:不同HPMC粘度对双环醇缓释片释药影响处方组成:原辅料 处方1 处方2 处方3微粉化双环醇 50mg 50mg 50mgHPMC(K4M) 55mg -- --HPMC(K15M) -- 55mg --HPMC(K100M) -- 55mg乳糖 240mg 240mg 240mg微粉硅胶 7mg 7mg 7mg硬脂酸镁 3mg 3mg 3mg将HPMC(K4M)及乳糖过80目筛,与微粉化双环醇充分混合,加入微粉硅胶及硬脂酸镁混匀,压片,片重约355mg。 Example 3: Effect of different viscosity HPMC on the prescription form bicyclic alcohol release from matrix tablets: raw materials Formulation 1 formulation 2 formulation 3 BICYCLOL micronized 50mg 50mg 50mgHPMC (K4M) 55mg - --HPMC (K15M) - 55mg - -HPMC (K100M) - 55mg lactose 240mg 240mg 240mg Aerosil 7mg 7mg 7mg magnesium stearate 3mg 3mg 3mg the HPMC (K4M), and lactose are passed 80 mesh sieve, and mixed thoroughly micronized bicyclic alcohols, silica powder was added and stearyl magnesium mixing, tabletting, tablets weighing approximately 355mg.

体外释放度测定结果表明,处方中使用粘度为K4M的HPMC,释药较快,12小时释药在90%以上,释药曲线见附图4所示。 In vitro release test showed that the prescription of a viscosity of K4M HPMC, rapid drug release, release 12 hours more than 90%, see FIG. 4 curve release. 实施例4:不同HPMC用量对双环醇缓释片释药影响处方组成:原辅料 处方1 处方4 处方5微粉化双环醇 50mg 50mg 50mgHPMC(K4M) 35mg(10%) -- --HPMC(K4M) -- 55mg(15%) --HPMC(K4M) -- -- 75mg(20%)乳糖 240mg 240mg 240mg微粉硅胶 7mg 7mg 7mg硬脂酸镁 3mg 3mg 3mg将HPMC(K15M)及乳糖过80目筛,与微粉化双环醇充分混合,加入微粉硅胶及硬脂酸镁混匀,粉末直接压片,片重约355mg。 Example 4: Effect of different amount of HPMC on the prescription form bicyclic alcohol release from matrix tablets: Prescription 1 Prescription raw materials prescription 4-ol 5 micronized bicyclic 50mg 50mg 50mgHPMC (K4M) 35mg (10%) - --HPMC (K4M) - 55mg (15%) --HPMC (K4M) - - 75mg (20%) lactose micronized silica gel 240mg 240mg 240mg 7mg 7mg 7mg magnesium stearate 3mg 3mg 3mg the HPMC (K15M) and lactose are passed 80 mesh sieve, micronized bicyclol thorough mixing, aerosil and magnesium stearate are blended, direct compression, tablets weighing approximately 355mg. 考察释药特征。 Visits release characteristics.

体外释放度测定结果表明,HPMC用量越少,释放速度越快,用量增加,释放速度减慢。 In vitro release test showed that the smaller the amount of HPMC, the release faster, increasing the amount of the release rate slows down. 释药曲线见附图5(纸贴)所示。 Release curve see FIG. 5 (paper paste) shown in FIG.

实施例5:不同粘度HPMC联合应用对双环醇缓释制剂释药的影响处方组成: 原辅料 处方9 制备100片投料微粉化双环醇 50mg 3.5gHPMC(K4M) 75mg 7.5gHPMC(K15M) 75mg 7.5g乳糖 130mg 13g微粉硅胶 10mg 0.7g硬脂酸镁 3mg 0.3g将HPMC(K4M、K15M)及乳糖过80目筛,与微粉化双环醇充分混合,加适量水制软材,16目筛制粒,湿颗粒于60℃条件下干燥2小时,用18目筛整粒,加入微粉硅胶及硬脂酸镁混匀,压片,片重约343mg。 Example 5: HPMC of different viscosities in combination of sustained release formulations release of the bicyclic alcohol affect prescription form: Prescription 9 Preparation of raw materials feeding micronized 100 bicyclol 50mg 3.5gHPMC (K4M) 75mg 7.5gHPMC (K15M) 75mg 7.5g Lactose 130mg 13g Aerosil 10mg 0.7g magnesium stearate 3mg 0.3g the HPMC (K4M, K15M) and lactose are passed 80 mesh sieve, and mixed thoroughly micronized bicyclic alcohols, water was added q.s. made of soft material, 16-mesh sieve granulation, wet granules at 60 ℃ dried for 2 hours with a 18-mesh sieve, silica powder was added and mixed magnesium stearate, tabletting, tablets weighing approximately 343mg.

体外释放度测定结果表明,以不同粘度HPMC混合物(K4M∶K15M=1∶1)为骨架材料,14小时释药规律符合零级动力学方程,释药曲线见附图6所示。 In vitro release test showed that a mixture of different viscosity HPMC (K4M:K15M = 1:1) as matrix materials, 14 hours law with zero order release kinetics equation, see Fig release curve shown in Figure 6.

实施例6:不同载药量对双环醇缓释制剂释药的影响处方组成:原辅料 处方1 处方4 处方5微粉化双环醇 35mg 40mg 45mg10% 20% 30%HPMC(K4M) 55mg 55mg 55mg乳糖 240mg 240mg 240mg微粉硅胶 7mg 7mg 7mg硬脂酸镁 3mg 3mg 3mg将HPMC(K4M)及乳糖过80目筛,与微粉化双环醇充分混合,加入微粉硅胶及硬脂酸镁混匀,粉末直接压片,考察释药特征。 Example 6: Effect of different drug loading formulation of sustained release formulations release of the bicyclic alcohol composition: raw materials Prescription 1 Prescription 4 Prescription 5 micronized BICYCLOL 35mg 40mg 45mg10% 20% 30% HPMC (K4M) 55mg 55mg 55mg lactose 240mg 240mg 240mg Aerosil 7mg 7mg 7mg magnesium stearate 3mg 3mg 3mg the HPMC (K4M), and lactose are passed 80 mesh sieve, and mixed thoroughly micronized bicyclic alcohols, aerosil and magnesium stearate was added mixed, direct compression, visits release characteristics.

体外释放度测定结果表明,安10%,20%,30%的载药量设计处方,释药速率无明显改变。 The results show that the in vitro release assay, Ann 10%, 20%, 30% drug loading formulation design, no significant changes in the release rate. 释药曲线见附图7所示。 See release curve shown in Figure 7.

实施例7:阻滞剂对双环醇缓释制剂释药的影响分别以微粉化双环醇和100目筛双环醇粗粉为活性成分,按下列处方组成试验:处方组成: 原辅料 处方10 处方11微粉化双环醇 35mg -100筛双环醇粗粉 - 35mgHPMC(K4M) 50mg 50mgHPMC(K15M) 100mg 100mgHPMC(K100M) - -十八醇 30mg 30mg乳糖 55mg 55mg微粉硅胶 10mg 10mg硬脂酸镁 3mg 3mg将HPMC(K4M、K15M)、十八醇及乳糖过80目筛,与微粉化双环醇充分混合,加入微粉硅胶及硬脂酸镁混匀,压片,片重约340mg。 Example 7: BICYCLOL inhibitor on a sustained release formulation to release micronized respectively bicyclic alcohol coarse mesh 100 as the active ingredient bicyclic alcohols, the following test formulation composition: Composition Prescription: Prescription raw materials 10 11 Powder formulation bicyclic alcohols of 35mg -100 mesh bICYCLOL meal - 35mgHPMC (K4M) 50mg 50mgHPMC (K15M) 100mg 100mgHPMC (K100M) - - stearyl alcohol, lactose 55mg 55mg 30mg 30mg 10mg 10mg Aerosil magnesium stearate 3mg 3mg the HPMC (K4M , K15M), stearyl alcohol and lactose through a 80 mesh sieve, and mixed thoroughly micronized bicyclic alcohols, silica powder was added and mixed magnesium stearate, tabletting, tablets weighing approximately 340mg.

体外释放度测定结果表明,处方中加入适量十八醇,能进一步延缓释药时间,缓释片在体外释放2小时后能够漂浮。 In vitro release test showed that the prescription was added an appropriate amount of octadecanol, further delay the release time, sustained release tablets in vitro release after 2 hours can float.

与微粉化双环醇相比,100目筛双环醇粗粉制备的缓释片释药不完全,在相同的测定条件下,24小时仅释药60%。 Compared with micronized bicyclic alcohols, release from matrix tablets bicyclol coarse mesh 100 made incomplete under the same assay conditions, 24-hour release only 60%. 因此,表明,采用微粉化双环醇做活性成分,可改善药物体外释放度。 Thus, we showed that the micronized active ingredient bicyclic alcohols do, in vitro release of the drug can be improved. 释药曲线见附图8所示。 See FIG. 8 release curve.

实施例8:双环醇缓释片体内释药测定将实施例6制备的骨架缓释片,以25mg/kg剂量进行Beagle狗体内试验,以普通片剂作参比,分别于不同时间取血,样品处理后采用高效液相色谱法进行测定,绘制药时曲线。 Example 8: in vivo sustained release tablets Assay embodiment BICYCLOL Sustained Release Tablets prepared as in Example 6 to 25mg / kg dose test Beagle dogs, as reference ordinary tablets were bled at different times, after treatment the samples were determined by HPLC, concentration-time curve is drawn. 结果表明,体内释药时间明显延长。 The results showed significantly prolonged in vivo release time. 药时曲线见附图9所示。 See the curve shown in FIG. 9 medicine.

Claims (16)

  1. 1.一种药物骨架缓释制剂,其特征在于,药物活性成分是微粉化双环醇并且双环醇粒径范围为1-200μm。 1. A pharmaceutical sustained release formulation skeleton, wherein the pharmaceutically active ingredient is micronized and bicyclic alcohols bicyclol size range 1-200μm.
  2. 2.根据权利要求1的药物骨架缓释制剂,其特征在于,所述的微粉化双环醇的粒径范围为1-10μm。 2. The sustained-release pharmaceutical formulation skeleton according to claim 1, wherein said bicyclic alcohol is micronized to a particle size range 1-10μm.
  3. 3.根据权利要求1的药物骨架缓释制剂,其特征在于,所述的微粉化双环醇在缓释制剂中的重量比例为5-30%。 The sustained-release pharmaceutical formulation backbone of claim 1, wherein the weight ratio of micronized bicyclol sustained-release formulation is 5-30%.
  4. 4.根据权利要求1的药物骨架缓释制剂,其特征在于,所述的微粉化双环醇在缓释制剂中的重量比例为14-16%。 The sustained-release pharmaceutical formulation backbone of claim 1, wherein the weight ratio of micronized bicyclol sustained-release formulation was 14-16%.
  5. 5.根据权利要求1的药物骨架缓释制剂,其特征在于,骨架材料选自生物溶蚀性骨架、亲水凝胶骨架、不溶性骨架和离子交换骨架。 The sustained-release pharmaceutical formulation skeleton according to claim 1, characterized in that the framework material is selected from bioerodable backbone, hydrophilic gel matrix, backbone, and the insoluble ion exchange backbone.
  6. 6.根据权利要求5的药物骨架缓释制剂,其特征在于,所述的亲水凝胶骨架材料包括羟丙基甲基纤维素、卡泊姆、羧甲基纤维素钠。 6. A pharmaceutical sustained release formulation backbone according to claim 5, wherein said hydrophilic matrix materials include hydroxypropyl methyl cellulose, carbomers, sodium carboxymethylcellulose.
  7. 7.根据权利要求6的药物骨架缓释制剂,其特征在于,所述的亲水凝胶骨架材料是羟丙基甲基纤维素。 7. A pharmaceutical sustained release preparation skeleton according to claim 6, wherein said hydrophilic matrix material is hydroxypropyl methylcellulose.
  8. 8.根据权利要求7的药物骨架缓释制剂,其特征在于,所述的羟丙基甲基纤维素在缓释制剂中的重量比例为5-70%。 8. The sustained release pharmaceutical formulation skeleton of claim 7, wherein the weight ratio of said hydroxypropyl methylcellulose in sustained release formulation is 5-70%.
  9. 9.根据权利要求7的骨架缓释制剂,其特征在于,所述的羟丙基甲基纤维素的粘度为K4M、K15M、K100M。 9. The sustained-release formulation skeleton of claim 7, wherein the viscosity of the hydroxypropyl methyl cellulose is K4M, K15M, K100M.
  10. 10.根据权利要求7的药物骨架缓释制剂,其特征在于,骨架缓释制剂中含有阻滞剂。 10. A pharmaceutical sustained release formulation skeleton according to claim 7, wherein the extended release formulation containing the skeleton blocker.
  11. 11.根据权利要求11的药物骨架缓释制剂,其特征在于,所述的阻滞剂包括脂肪酸、脂肪醇。 11. The sustained release pharmaceutical formulation bobbin 11, wherein said blocker comprises fatty alcohols.
  12. 12.根据权利要求11的药物骨架缓释制剂,其特征在于,所述的阻滞剂是十八醇。 12. A pharmaceutical sustained release formulation bobbin according to claim 11, wherein said blocking agent is stearyl alcohol.
  13. 13.根据权利要求7的药物骨架缓释制剂,其特征在于,所述阻滞剂在缓释制剂中的重量比例1-50%。 13. A pharmaceutical sustained release formulation skeleton according to claim 7, wherein the weight ratio of said retarder in a sustained release formulation 1-50%.
  14. 14.根据权利要求15药物的骨架缓释制剂,其特征在于,所述阻滞剂在缓释制剂中的重量比例25%。 14. Sustained Release Drug formulation according to claim 15, wherein the weight ratio of said retarder in a sustained release formulation of 25%.
  15. 15.根据权利要求1的药物骨架缓释制剂,其特征在于,所述的骨架缓释制剂包括骨架缓释片、缓释微丸、缓释胶囊。 15. A pharmaceutical sustained release preparation skeleton according to claim 1, wherein said extended release formulation comprising a backbone skeleton sustained-release tablets, sustained-release pellets, sustained release capsules.
  16. 16.根据权利要求1的药物骨架缓释制剂,其特征在于,可与速释部分制成双层控释片、包芯控释片及微丸控释胶囊。 16. A pharmaceutical sustained release preparation skeleton according to claim 1, wherein the controlled release tablets can be made double, controlled release tablets and pellets Core controlled release capsule with immediate release portion.
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006015546A1 (en) * 2004-08-11 2006-02-16 Institute Of Mataria Medica, Chinese Academy Of Medical Sciences Use of bicyclol for manufacturing a medicament for preventing and/or treating acute alcoholism and acute or chronic alcoholic liver injury
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CN102058577B (en) 2008-08-06 2012-07-25 北京协和药厂 Medicament compound adopting bicyclo-ethanol as active component and preparation thereof
CN103230391A (en) * 2013-01-24 2013-08-07 辽宁亿灵科创生物医药科技有限公司 Bicyclol solid preparation
CN103284953A (en) * 2012-03-05 2013-09-11 辽宁亿灵科创生物医药科技有限公司 Bicyclol solid preparation and preparation method thereof
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WO2006015546A1 (en) * 2004-08-11 2006-02-16 Institute Of Mataria Medica, Chinese Academy Of Medical Sciences Use of bicyclol for manufacturing a medicament for preventing and/or treating acute alcoholism and acute or chronic alcoholic liver injury
CN100444865C (en) 2006-07-06 2008-12-24 陈红亮 Synergistic medicinal composition containing dicyclic alcohol
CN102058577B (en) 2008-08-06 2012-07-25 北京协和药厂 Medicament compound adopting bicyclo-ethanol as active component and preparation thereof
EP2471521A1 (en) * 2009-12-15 2012-07-04 Beijing Union Pharmaceutical Factory Double-layer osmotic pump controlled release tablet of bicyclol and preparation method thereof
CN102091052B (en) 2009-12-15 2012-11-07 北京协和药厂 Bicyclol double-layer osmotic pump control-released tablet and preparation method thereof
EP2471521A4 (en) * 2009-12-15 2013-07-10 Beijing Union Pharmaceutical Factory Double-layer osmotic pump controlled release tablet of bicyclol and preparation method thereof
CN103284953A (en) * 2012-03-05 2013-09-11 辽宁亿灵科创生物医药科技有限公司 Bicyclol solid preparation and preparation method thereof
CN103284953B (en) 2012-03-05 2014-08-13 辽宁亿灵科创生物医药科技有限公司 Bicyclol solid preparation and preparation method thereof
WO2013168179A2 (en) * 2012-04-03 2013-11-14 Rubicon Research Private Limited Controlled release pharmaceutical formulations of antiviral agents
WO2013168179A3 (en) * 2012-04-03 2014-01-30 Rubicon Research Private Limited Controlled release pharmaceutical formulations of antiviral agents
CN103230391A (en) * 2013-01-24 2013-08-07 辽宁亿灵科创生物医药科技有限公司 Bicyclol solid preparation
CN105434356A (en) * 2014-09-15 2016-03-30 北京协和药厂 Bicyclol-encapsulating PLGA nanoparticle, and preparation method and uses thereof

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