CN105213316A - Enteric-coated solid preparation containing lycopene, resveratrol or melatonin and preparation method of enteric-coated solid preparation - Google Patents

Enteric-coated solid preparation containing lycopene, resveratrol or melatonin and preparation method of enteric-coated solid preparation Download PDF

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CN105213316A
CN105213316A CN 201510713742 CN201510713742A CN105213316A CN 105213316 A CN105213316 A CN 105213316A CN 201510713742 CN201510713742 CN 201510713742 CN 201510713742 A CN201510713742 A CN 201510713742A CN 105213316 A CN105213316 A CN 105213316A
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enteric
carrier
solid
soluble
solid preparation
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顾茂健
郑启兰
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上海宣泰医药科技有限公司
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The invention relates to the field of medicinal preparation, in particular to an enteric-coated solid preparation containing lycopene, resveratrol or melatonin and a preparation method of the enteric-coated solid preparation. The enteric-coated solid preparation comprises the melatonin serving as an active component, water-soluble and/or enteric-coated carrier accessories and other pharmaceutic adjuvants, wherein the water-soluble carrier accessory can be used as a water-soluble solid dispersion carrier; the enteric-coated carrier accessory is an enteric-coated polymer and can be used as an enteric-coated solid dispersion carrier or enteric-coated coating membrane material; the enteric-coated solid preparation containing the melatonin has good solubility in enteric canal and enables a medicament to be quickly dissolved and released in the enteric canal, so that the absorption of the melatonin is improved and the bioavailability of the melatonin is improved. The melatonin solid dispersion composition disclosed by the invention can be suitable for application and industrial production of oral dosage forms such as tablets, granules, pellets, capsules, enteric capsules, enteric coating tablets, enteric coating pellets and enteric coating granules.

Description

-种含番茄红素、白黎芦醇或视黑素的肠溶固体制剂及其制备方法 - Species containing enteric solid preparation and preparation method lycopene, resveratrol or melanin depending

[oow] 相关申请 [Oow] RELATED APPLICATIONS

[0002] 本申请是申请日为2010年10月27日,发明名称为"一种含番茄红素、白襲芦醇或稱黑素的肠溶固体制剂及其制备方法"的中国发明专利申请No. 201010528511. 2的分案申请。 [0002] This application is filed October 27, 2010, entitled "containing lycopene, an enteric solid formulations white resveratrol or hit called melanin and its preparation method," the Chinese invention patent application No. divisional application 201,010,528,511.2 of.

技术领域 FIELD

[0003] 本发明设及一种含番茄红素、白襲芦醇和/或稱黑素作为活性成分的肠溶固体制剂及其制备方法。 [0003] The present invention is provided, and one containing lycopene, white passage Lo alcohol and / or said enteric solid preparation and preparation method as an active ingredient of melanin. 具体而言,本发明的肠溶固体制剂通过结合使用固体分散体和肠溶释放载体,使上述含有番茄红素、白襲芦醇和/或稱黑素的制剂增加了活性成分的溶解度和/或吸收度,提高了活性成分的生物利用度。 More specifically, a solid enteric-coated formulations of the invention by using a solid dispersion of an enteric release carrier and binding the lycopene-containing formulations, white passage Lo alcohol and / or said melanocytes increases the solubility of the active ingredient and / or absorption, increased bioavailability of the active ingredient.

背景技术 Background technique

[0004] 随着自动化合成、组合化学及高通量筛选技术的发展,越来越多的新活性药物同时也是难溶性药物摆在了制药工程的流水线上。 [0004] With the development of automated synthesis, combinatorial chemistry and high-throughput screening technology, more and more new active drug is also poorly soluble drugs placed in the pharmaceutical pipeline project. 据估计有大于40%的市售药物是难溶性药物,而在制药工业实验室中的难溶性药物约占总量的60%W上。 It is estimated that more than 40% of marketed drugs are poorly soluble drug, accounting for about 60% W and the total amount of poorly soluble drugs in the pharmaceutical industry laboratories. 对于低溶解度高通透性的药物,其吸收限速步骤是药物的低溶出速率。 For high permeability low solubility drugs, a low absorption rate-limiting step is the dissolution rate of the drug. 传统普通片剂很难提高运类药物的生物利用度,适当的工艺及剂型改造是该类药物产品成功开发的关键,因此工艺及剂型对于运类药物在胃肠道中的吸收起着决定性作用。 Traditional ordinary tablet is difficult to improve the bioavailability of drugs transported, the appropriate process and formulation of such reform is the key to successful development of the drug product, and therefore the process and formulation for transport drugs absorption in the gastrointestinal tract plays a decisive role. 近年来国内外针对难溶性药物给药策略的研究技术有许多,如微粉化技术、纳米技术、微乳技术、分子包合技术、脂质体技术、固体分散技术、嵌段共聚物胶束等,其中固体分散体技术由于增溶效果明显、工艺相对简单、成本低在工业界比较受青睐。 In recent years, many home and abroad, such as micronization, nanotechnology, microemulsion, molecular inclusion technology, liposome technology, solid dispersion, a block copolymer micelle technology for the study of administration of insoluble drugs strategy wherein the solid dispersion aRT solubilizing effect is obvious, the process is relatively simple, low cost in comparison popular industry. 目前的上市产品、研究论文或专利在固体分散体技术应用上主要偏重于解决药物的溶解度,W此来增加药物体内的吸收从而提高药物的生物利用度。 The current market, research papers or patent on a solid dispersion technology to solve major emphasis on the solubility of the drug, W to increase the absorption of this drug in the body and thus improve the bioavailability of the drug. 阳005]中国专利申请CN1981742A公开了HPMCAS作为难溶性药物的固体分散体载体的应用,但是该申请也列举了若干现有技术文献,显示当HPMCAS和某些难溶性药物制成固体分散体时,溶解度的提高效果并不好,如化kuzaigaku,53 (4),221-228 (1993)中T.Yamaguchi的关于MAT和HPMCAS或CMEC制成固体分散体时,CMEC的效果更好的描述。 Male 005] Chinese patent application CN1981742A discloses the use of HPMCAS as a solid dispersion carrier is poorly soluble drug, but this application also lists a number of prior art documents, when a display of certain poorly soluble drug and HPMCAS into a solid dispersion, solubility improvement effect is not good, such as of kuzaigaku, 53 (4), 221-228 (1993) with respect to time in T.Yamaguchi MAT CMEC and HPMCAS into a solid dispersion or, better description of the effect of CMEC.

[0006] 此外,PCT专利申请W0 2003/063831中还公开了一种含有固体药物分散体的即刻释放剂型,其含有至少30wt%的固体药物分散体、至少5wt%的崩解剂和porosigen,但是根据中国专利申请CN101057834A中的评述,该固体药物分散体的即刻释放剂型即使使所述片剂在胃中崩解,但由于固体分散体长时间处于消化液中而将使药物重结晶,造成药物溶解度降低。 [0006] In addition, the PCT Patent Application W0 2003/063831 discloses a further immediate release formulation containing a solid pharmaceutical dispersion which comprises at least 30wt% of the solid drug dispersion, at least 5wt% of a disintegrant and porosigen, but the Chinese patent application CN101057834A in comments, the immediate release solid pharmaceutical dosage form of dispersion even when the tablet disintegrates in the stomach, but since the solid dispersion will be a long time in digestive fluids pharmaceutical recrystallized resulting pharmaceutical solubility decreases.

[0007] 番茄红素化ycopene,分子式〔4。 [0007] Lycopene of ycopene, formula [4. 馬6,分子量536. 85,纯品为深红色针状结晶)是一种非环状的类胡萝h素,最早是从番茄中分离提取制得,人体内不能自行合成,必须从外界摄入。 Ma 6, molecular weight 536.85, is a pure dark red needle crystal) is a non-cyclic carotenoid pigment h, first isolated from tomato extract obtained, the human body can not be synthesized, it must be taken from outside into. 在所有的类胡萝h素中,番茄红素具有最强的消除单线态氧的功能和消除自由基的功能,属于强抗氧化剂,其对单线态氧的消除能力是胡萝h素的2倍,维生素E的100倍;番茄红素能够减缓低密度脂蛋白的氧化,降低血浆中的胆固醇,防止屯、血管病;它能够有效抑制癌细胞繁殖,具有抗癌防癌作用,特别对前列腺癌具有很好的治疗作用。 In all of the carotenoid pigment h lycopene with singlet oxygen to eliminate most of the functions and features eliminate free radicals, are strong antioxidants, which is the elimination of the ability of singlet oxygen carrot pigment 2 h fold, 100-fold vitamin E; lycopene slows oxidized LDL, lower plasma cholesterol, preventing village, angiopathy; which inhibit cancer cell reproduction, having anti-cancer effect, especially for prostate cancer has a very good therapeutic effect. 另外它具有活化免疫细胞的功能,可增强机体免疫力和抗衰老,具有重要的应用价值和广泛的市场前景。 In addition, it has the activation of immune cell function, can enhance immunity and anti-aging, has important application value and broad market prospects.

[0008] 番茄红素是具有11个碳-碳共辆双键和2个非共辆双键的不饱和脂肪族締控。 [0008] Lycopene is having 11 carbon - carbon double bond and two cars were non-conjugated double bonds vehicle unsaturated aliphatic associated control. 天然食物原料中的番茄红素W全反式构型为主,数量占番茄红素总量的95%W上,只有少量为顺式构型(主要是5-顺、9-顺、13-顺和15-顺式构型);在哺乳动物的器官、血液和组织中番茄红素W各种顺式异构体为主,顺式番茄红素易溶于胆酸微粒和乳糜微粒,口服后更易被人体吸收,因此其生物利用率明显高于全反式番茄红素。 Natural food material W in the all-trans lycopene-based configuration, which accounted for 95% W on total lycopene, only a small amount of the cis-configuration (mainly 5-cis, 9-cis, 13- cis 15 and cis-configuration); in a mammal organs, blood and various tissues lycopene W mainly cis isomer, cis lycopene is soluble in bile acids and chylomicron particles, after oral administration more easily absorbed by the body, and therefore its bioavailability was significantly higher than the all-trans-lycopene.

[0009] 番茄红素脂溶性强,烙点为174°C,几乎不溶于水,在水中的溶解度只有大约0. 002yg/ml,溶解度低限制了番茄红素在胃肠道内的吸收,导致口服生物利用度低。 [0009] The fat-soluble lycopene strong, branded point of 174 ° C, almost insoluble in water, solubility in water is only about 0. 002yg / ml, a low solubility limits the absorption of lycopene within the gastrointestinal tract, resulting in oral low bioavailability. 此外, 番茄红素在空气中光、热、氧、金属离子的作用下极不稳定,易氧化降解和异构化,从而使其功能降低或失效。 Furthermore, lycopene light in the air, under the action of heat, oxygen, metal ions are very unstable, easily oxidized and degraded isomerization, thereby reducing its function or failure. 现有的市售番茄红素制剂主要是填装成软胶囊的油混悬液,没有解决番茄红素在胃肠道中溶解度低的问题。 Existing commercial formulations of lycopene is mainly filled into a soft capsule dispersion in oil, it does not solve the lycopene low solubility in the gastrointestinal tract problems.

[0010] 目前,已公开的增加番茄红素溶解度的口服固体药物组合物专利申请包括: [0010] It has been disclosed increase oral solid pharmaceutical composition the solubility of the lycopene Patent Application comprises:

[0011] (l)Basf公司的授权专利CN1125601C公开了"粉状番茄红素制剂、其制法和其应用",设及水可分散的粉状番茄红素制剂的制备方法。 [0011] (l) Basf's granted patent CN1125601C discloses "pulverulent lycopene formulation, their preparation and their use", and a preparation method provided a water-dispersible powder formulations of lycopene. 阳01引似DSM公司的授权专利CN1173637C公开了"细粉状类胡萝h素制剂的制备",制备易溶于水的番茄红素细粉末。 01 like the male lead DSM's granted patent CN1173637C discloses "Preparation of finely powdered carotenoid pigment preparation h", lycopene fine powder soluble in water is prepared.

[0013] (3)W色列Lycoret公司申请的W0 03045167公开了"类胡萝h素制剂"。 [0013] (3) W Lycoret Israeli company application W0 03045167 discloses "h carotenoid pigment preparation."

[0014] (4)中国专利化200610037859. 5公开了"P-环糊精和径丙基-P-环糊精混合包合番茄红素的组合物及其制备方法",该方法用混合环糊精包合药物,使番茄红素溶解度增加为14yg/ml。 [0014] (4) of China Patent 200610037859.5 discloses "diameter and the P-cyclodextrin propyl -P- mixing cyclodextrin inclusion lycopene composition and its preparation method ', with which the mixing ring dextrin inclusion drugs that increase the solubility of lycopene is 14yg / ml.

[0015] (5)中国专利申请CN101439030公开了"一种含番茄红素的药物组合物及其制备方法",该方法采用泊洛沙姆188作为载体制备固体分散体,或将它们与环糊精制备成=元包合物,提高番茄红素在固体制剂中的溶出度。 [0015] (5) Chinese Patent Application No. CN101439030 discloses "a pharmaceutical composition and method of preparation of lycopene-containing", which was prepared using Poloxamer 188 as a solid dispersion carrier, or they may with cyclodextrins = prepared as fine element clathrate, enhance the dissolution of lycopene in the solid formulation.

[0016] (6)中国专利申请CN1485028公开了"番茄红素滴丸",用水溶性基质(PEG4000、 PEG6000、明胶、硬脂酸)将番茄红素油树脂制成了口服固态分散体的滴丸W提高其溶解度。 [0016] (6) Chinese Patent Application CN1485028 discloses a "lycopene Pill", with a water-soluble base (PEG4000, PEG6000, gelatin, stearic acid) made into a solid oral Pill W dispersion oleoresin improve its solubility.

[0017] 上述专利申请有一个共性就是虽然增加了番茄红素溶解度的,但由于番茄红素是在胃中大量快速释放,由于胃中吸收面积小易造成番茄红素反析出,从而导致生物利用度利用仍然很低;另一方面如Basf公司的授权专利CN1125601C专利报道的工艺存在生产成本高、工业化难度大等缺点。 [0017] the above-mentioned patent applications have one thing in common is that despite an increase in the solubility of lycopene, but lycopene is a lot of quick release in the stomach, because the stomach absorbs lycopene could easily lead to a small area of ​​anti-precipitation, resulting in bioavailability the degree of utilization is still low; on the other hand such as technology Basf company's patents CN1125601C patent reported the presence of high production costs, the difficulty of large industrialized and other shortcomings.

[0018] 白襲芦醇巧esveratrol)属于非黄酬类多酪化合物,结构类似雌激素己締雌酪, 为白色结晶粉末,化学名称为巧)-5-巧-(4-径苯基)-乙締基]-1,3-苯二酪,分子式。 [0018] White passage resveratrol Qiao esveratrol) are non-yellowing type multi-paid casein compounds, has estrogen-like structure associated estrogen casein as a white crystalline powder with the chemical name is clever) -5- Qiao - (4-phenyl diameter) - b associative-yl] -1,3-benzenedicarboxylic casein suppliers. 化2〇3,分子量228. 25,烙点256-257°C,脂溶性强,难溶于水,据报道在水中饱和溶解度约为30yg/ml,易溶于甲醇、乙醇、乙酸乙醋、丙酬等有机溶剂。 Of 2〇3, molecular weight 228.25, branded point 256-257 ° C, fat-soluble strong, insoluble in water, is reported to the saturated solubility of about 30yg / ml in water, soluble in methanol, ethanol, acetic acid ethyl ester, propan-pay and other organic solvents. 白襲芦醇是植物为抵抗外界刺激如紫外线、真菌、病毒感染或机械损伤而产生的一种植物抗毒素,它主要存在于虎杖、葡萄、花生、桑權、松树等70多种植物中,在葡萄中的含量尤为丰富,具有抗氧化性、抗自由基活性、保护屯、血管、抗癌、抗衰老等多项保健功能。 White passage resveratrol is a plant or plant to resist external stimuli such as ultraviolet light, fungal, or viral infections arising from mechanical damage antitoxin, it is mainly present in the 70 kinds of Polygonum cuspidatum, grapes, peanuts, mulberry right, like pines, in content in grapes is particularly rich, with antioxidant, anti-free radical activity, Tuen protection, blood vessels, anti-cancer, anti-aging and many other health functions. 白襲芦醇对光、热、氧不稳定,具有顺式、 反式两种同分异构体,白襲芦醇反式异构体的生物活性强于顺式异构体,在紫外光照射下反式白襲芦醇能够转化成顺式异构体。 White passage resveratrol light, heat, oxygen labile, cis, trans isomers two kinds of biologically active trans isomers of resveratrol stronger than the white passage cis isomer, ultraviolet irradiation of trans-resveratrol white attack can be converted to the cis isomer. 白襲芦醇口服吸收良好,但由于快速代谢和排泄导致生物利用度低,消除半衰期短,主要是发生II相代谢反应,经肝脏和小肠迅速代谢为两大相关的代谢物:白襲芦醇葡糖巧酸和硫酸白襲芦醇。 White passage resveratrol good oral absorption, but due to rapid metabolism and excretion leading to a low bioavailability, short elimination half-life, mainly phase II metabolic reactions occur, rapidly metabolized by the liver and small intestine for the two related metabolites: white attack resveratrol Qiao gluconic acid and sulfuric white passage resveratrol. 研究发现,十二指肠和空肠是反式白襲芦醇口服吸收的主要部位,多药耐药相关蛋白(Mrp-2)参与反式白襲芦醇的肠道外排过程,外排转运蛋白P-糖蛋白不参与反式白襲芦醇的吸收转运。 Found, duodenum and jejunum are the major sites of trans-resveratrol attack white oral absorption, multidrug resistance-associated protein (Mrp-2) involved in the passage of trans-resveratrol of white parenteral discharge process, efflux transporter P- glycoprotein transporter is not involved in the absorption of trans-resveratrol of white attack.

[0019] 有关白襲芦醇及其巧化合物的文献和专利较多,但绝大多数集中在提取、制备、用途方面,很少设及提高生物利用度及提高溶解度方面,寻找和研究改善白襲芦醇水溶性,并提高其在小肠的吸收具有非常重要的意义。 [0019] Qiao and white passage resveratrol and patent related compounds more, but most concentrated in the extraction, preparation, uses, and provided little increase bioavailability and solubility improved, and research to find improved white Lu hit a water-soluble alcohol, and increase its has a very important significance in intestinal absorption. 中国专利CN100453071C公开了一种白襲芦醇口服多相脂质体。 Chinese patent discloses a white CN100453071C passage oral resveratrol polyphase liposome. 中国专利CN100493497C公开了一种白襲芦醇固体自微乳制剂。 CN100493497C Chinese patent discloses the passage of a white solid SMEDDS resveratrol. 中国专利申请CN1951369A公开了一种白襲芦醇包衣纳米脂质体。 Chinese patent application CN1951369A discloses a nano-coated white passage resveratrol liposomes. 中国专利申请CN101317832A公开了一种由于白襲芦醇和载体材料小麦醇溶蛋白制成的口服纳米给药系统,利用在载体材料的生物粘附特性和高度分散特性提高白襲芦醇的溶出速度和程度,增加药物在小肠的吸收。 Chinese patent application CN101317832A discloses a nano-delivery system made since oral passage Lo white wheat gliadin alcohol carrier material, in use of bioadhesive properties of the carrier material and the highly dispersed dissolution rate characteristics are improved and the white passage resveratrol degree, increase the absorption of drugs in the small intestine. 中国公开专利申请CN101292966A公开了一种白襲芦醇及其固体分散体及其制备方法, W化loxamer、高分子量聚乙二醇为载体,用溶剂法和烙融法制备分散体,改善药物水溶性。 Chinese Patent Application Publication CN101292966A discloses a passage resveratrol and white solid dispersion and its preparation method, W of loxamer, high molecular weight polyethylene glycol as the carrier, with a solvent melting method and baked Preparation of dispersion, improvement of water-soluble drugs sex. 中国授权专利CN1220486C提供了白襲芦醇及其武和衍生物的径丙基-P-环糊精包合物W及制备方法,提高药物水溶性和稳定性。 Chinese patent CN1220486C provides authorization resveratrol and white passage diameter propyl cyclodextrin inclusion -P- preparation and W Wu and derivatives, water-soluble and improve drug stability.

[0020] 上述专利申请虽然部分设及到使白襲芦醇溶解度提高的方法,但运些发明增加白襲芦醇溶解度的程度依旧很小,脂质体、固体自微乳、包衣纳米脂质体等纳米制剂还存在稳定性差、对辅料和设备要求较高、生产成本高、难W工业化生产等缺点。 [0020] Although some of the above-mentioned patent application and is provided to enable the passage of white resveratrol improved solubility method, but increases the degree of white invention more transport passage solubility of resveratrol is still small, liposomes, solid self microemulsions, nano-coating fat nanoformulations plastid poor stability so there are higher requirements for the equipment and materials, high production costs, difficulties and other shortcomings W industrial production.

[0021] 稱黑素(Melatonin,MT),又名脑白金或松果体素,是哺乳动物和人类的松果体分泌的一种具有广泛生理和药理作用的神经内分泌激素,具有调整人体生物钟、镇静催眠和免疫调节等生理作用。 [0021] called melanocytes (Melatonin, MT), also known as melatonin or melatonin, a pineal gland in mammals and human neuroendocrine hormone with a wide range of physiological and pharmacological effects, have to adjust the body clock , the physiological role of sedative-hypnotic and immune regulation. 稱黑素为白色结晶粉末,化学名称为5-甲氧基-N-乙酷色胺,分子式。 Called melanin as a white crystalline powder with the chemical name 5-methoxy-tryptamine cool -N- B suppliers. 化6成〇2,分子量232. 27,烙点116-118。 Of 60% 〇2, molecular weight 232.27, branded point 116-118. 在水中溶解度不到lmg/ml(25°C),属于两亲性化合物,油水分配系数LogP为1. 19,略溶于水,易溶于热水和丙二醇,可溶于含水乙醇、 酸、碱中。 Solubility in water of less than lmg / ml (25 ° C), belonging to the amphiphilic compound, partition coefficient LogP of 1.19, slightly soluble in water, soluble in water and propylene glycol, soluble in aqueous alcohol, acid, soda. 健康志愿者口服MT绝对生物利用度仅15%且个体差异大,其在人体的吸收也很不稳定,首过效应明显,同一剂量的MT在不同个体中可有10-20倍的差异。 The absolute bioavailability of oral MT in healthy volunteers and only 15% of individual differences, and its absorption in the body is also very unstable, first-pass effect is obvious, the same dose of MT may have a 10-20 fold difference in different individuals. 口服MT后,MT 经被动扩散吸收入血,仅与血浆白蛋白结合,结合率约33 %,但其结合非常疏松且不饱和。 After oral administration of MT, MT absorbed into the bloodstream by passive diffusion, only plasma albumin binding, binding rate of about 33%, but it is loose and the unsaturated binding. 另有文献报道稱黑素口服吸收具有部位特异性,在大鼠直肠的吸收药量> 回肠>十二指肠=空肠=结肠> 胃。 Another reported oral absorption with melanin, said site-specific, dose absorption in the rat rectum> ileum> = colon duodenum jejunum => stomach. 也有研究表明其生物利用度与剂量有关,YeleswarowruKrishnaswamy、 Melau曲linLeeG等研究了MT不同给药途径的生物利用度。 Research has also shown that its bioavailability and dose-related, YeleswarowruKrishnaswamy, Melau song linLeeG other studies of bioavailability of different routes of administration MT. 给大鼠灌胃后,利用度为53. 5% ;给狗灌胃MTlOmg/kg时,利用度几乎为100%,但当Img/kg时,则降至16. 9%。 After gavage to rats, using the degree of 53.5%; dogs when fed MTlOmg / kg, almost 100% utilization, but Img / kg, the dropped to 16.9%.

发明内容 SUMMARY

[0022] 本发明一方面提供了一种肠溶固体制剂,其含有选自番茄红素、白襲芦醇和稱黑素中的一种或多种活性成分和肠溶性载体,其中所述肠溶性载体与所述活性成分W肠溶固体分散体形式存在于制剂中。 [0022] In one aspect the present invention provides a solid enteric preparation containing lycopene selected, said alcohol and white melanin Lo passage of one or more active ingredients and an enteric carrier, wherein said enteric W carrier and the active ingredient is enteric solid dispersion present in the formulation.

[0023] 在一个实施方案中,所述的活性成分是白襲芦醇,所述的肠溶性载体是乙酸班巧酸径丙基甲基纤维素化PMCA巧和/或邻苯二甲酸径丙基甲基纤维素化PMCP)。 [0023] In one embodiment, the active ingredient is resveratrol white passage, the carrier is a class enteric acetic acid Qiao diameter of PMCA clever methylcellulose and / or phthalic acid prop-diameter methylcellulose of PMCP).

[0024] 在又一个实施方案中,所述的活性成分是稱黑素,所述的肠溶性载体是乙酸班巧酸径丙基甲基纤维素化PMCA巧和/或甲基丙締酸/丙締酸乙醋共聚物如化化agit L100-55和/或邻苯二甲酸径丙基甲基纤维素化PMCP)。 [0024] In yet another embodiment, the active ingredient is called melanin, the carrier is a class enteric acetic acid Qiao diameter of PMCA clever methylcellulose and / or associated methylpropanesulfonic acid / propionic acid ethyl ester copolymers such as the association of of agit L100-55 and / or methylcellulose phthalate diameter of PMCP).

[0025] 在又一个实施方案中,所述的活性成分是番茄红素,所述的肠溶性载体是邻苯二甲酸径丙基甲基纤维素化PMCP)。 [0025] In yet another embodiment, the active ingredient is lycopene, the enteric carrier is methylcellulose phthalate diameter of PMCP).

[00%]另一方面,本发明提供所述含有肠溶固体分散体的肠溶固体制剂的制备方法,其包括将所述的活性成分和肠溶性载体溶于溶剂中,干燥除去溶剂W得到肠溶固体分散体。 [00%] another aspect, the present invention provides a method for preparing an enteric solid formulations of the enteric solid dispersion containing an active ingredient and which comprises an enteric carrier dissolved in the solvent, and drying to remove the solvent to give W enteric solid dispersion. [0027] 在一个实施方案中,所述肠溶固体制剂的制备方法包括将所述的活性成分和肠溶性载体混匀后加热至烙融,然后将其冷冻干燥或热烙挤出制得肠溶固体分散体。 Preparation Method [0027] In one embodiment, the enteric solid preparation comprising the active ingredient and the enteric carrier baked mix was heated to melt, then freeze-dried or hot extrusion to obtain intestinal branded soluble solid dispersion.

[00測又一方面,本发明提供一种肠溶固体制剂,其含有选自番茄红素、白襲芦醇和稱黑素中的一种或多种活性成分,W及肠溶性载体和水溶性载体,其中所述水溶性载体与所述活性成分W水溶固体分散体形式存在于制剂中,并且在该固体制剂外层包覆含有肠溶性载体的肠溶包衣层。 [00 measuring a further aspect, the present invention provides an enteric solid preparation selected from the group comprising lycopene, said one kind of alcohols and white passage Lo melanin or more active ingredients, W, and a carrier and an enteric soluble vector, wherein said water-soluble carrier with the active ingredient W water-soluble solid dispersion present in the formulation, and the enteric coating layer comprises an enteric coated carrier layer of the solid preparation.

[0029] 在一个实施方案中,所述的活性成分是番茄红素,所述的水溶性载体是Soluplus 和/或聚氧乙締-聚氧丙締共聚物(Poloxamer),所述的肠溶性载体是乙酸班巧酸径丙基甲基纤维素化PMCA巧。 [0029] In one embodiment, the active ingredient is lycopene, said water soluble carrier is Soluplus and / or associative polyoxyethylene - polyoxypropylene copolymer association (Poloxamer), the enteric acetic acid class clever carrier is methylcellulose diameter of PMCA clever.

[0030] 在又一个实施方案中,所述的水溶固体分散体活性成分番茄红素在P册.8憐酸盐缓冲液中的溶解度不低于10yg/ml,优选不低于20yg/ml。 [0030] In yet another embodiment, the aqueous dispersion of solid active ingredient in the solubility of lycopene P .8 volumes acetate buffer pity is not less than 10yg / ml, preferably not less than 20yg / ml.

[0031] 在又一个方面,本发明提供所述含有水溶固体分散体的肠溶固体制剂的制备方法,其包括将所述的活性成分和水溶性载体溶于溶剂中,干燥除去溶剂W得到水溶性固体分散体,并对所得的水溶性固体分散体进一步包肠溶衣。 [0031] In yet another aspect, the present invention provides a method for preparing aqueous enteric solid formulations containing solid dispersion comprising the active ingredient and a water-soluble carrier in a solvent, an aqueous solvent is removed by drying to obtain W solid dispersion, and a water soluble solid dispersion obtained is further enteric coated.

[0032] 在又一个实施方案中,所述的制备方法包括将所述的活性成分和水溶性载体混匀后加热至烙融,然后将其冷冻干燥或热烙挤出制得水溶性固体分散体,并对所得的水溶性固体分散体进一步包肠溶衣。 [0032] In yet another embodiment, the method comprises the preparation of the active ingredient and a water-soluble carrier is heated to bake melting after mixing, and then lyophilized to prepare extruded baked or heat-soluble solid dispersion body, and the resulting water-soluble solid dispersion further enteric coated.

[0033] 在又一个实施方案中,所述的包含肠溶固体分散体或水溶固体分散体的肠溶固体制剂中还可W进一步含有表面活性剂,优选化emo地or化和/或化emo地orRH40。 [0033] In yet another embodiment, the solid formulation comprising an enteric solid dispersion or aqueous enteric solid dispersion of W may further contain a surfactant, preferably of the emo or and / or of emo to orRH40.

[0034] 在一个优选的实施方案中,所述活性成分总重与所述表面活性剂的重量比为1 : 2-1 : 4。 [0034] In a preferred embodiment, the active ingredient the weight ratio of the total weight of the surfactant is 1: 2-1: 4.

[0035] 在又一个实施方案中,本发明提供含有肠溶性或水溶固体分散体的肠溶固体制剂,其还可进一步含有一种或多种选自下述的成分:花青素、姜黄素、叶黄素、P-胡萝h 素、胡萝h素、石恼提取水不溶物如较花酸和熊果酸、脂溶性维生素如维生素A、维生素D、 维生素K和维生素E。 [0035] In yet another embodiment, the present invention provides a solid formulation comprising an enteric water-soluble or enteric solid dispersion, which may further contain one or more components selected from: anthocyanin, curcumin , lutein, P- h carrot pigment, carrot pigment h, angry stone extract more water-insoluble substance such as ellagic acid and ursolic acid, fat-soluble vitamins such as vitamin A, vitamin D, vitamin K, and vitamin E.

[0036] 在又一个方面,本发明还提供一种保健组合物,其含有如上所述的肠溶固体制剂。 [0036] In yet another aspect, the present invention also provides a healthcare composition comprising an enteric solid formulation as described above.

[0037] 发明详述 [0037] DETAILED DESCRIPTION

[0038] 不希望被任何理论所束缚,本发明通过采用固体分散体技术和定位释放原理相结合,即通过采用固体分散体技术解决了药物的难溶性问题,同时通过对载体材料性质的选择,即采用在肠中才能溶解的肠溶性载体制备固体分散体或先制备成水溶性固体分散体, 再进行包覆肠溶衣膜W控制药物在胃中少量释放或不释放。 [0038] Without wishing to be bound by any theory, the present invention is released by using solid dispersion technique and positioning principle of combining, i.e., to solve the insoluble problem of a drug by using solid dispersion technique, through the choice of the carrier material properties, i.e. enteric preparation of the solid support employed can be dissolved in the intestine to prepare a dispersion or a water soluble solid dispersion, an enteric coating film which is then coated with a small amount of controlled drug release or W is not released in the stomach. 在肠中由于吸收表面积大,载体或衣膜迅速溶解,药物大量释放并迅速吸收,从而提高了生物利用度。 Since the absorption of large surface area, coating or film carrier rapidly dissolves in the intestine, a large amount of drug released and rapidly absorbed, thereby improving the bioavailability.

[0039] 根据本发明的肠溶固体制剂,作为活性成分可W依据要求含有选自番茄红素、白襲芦醇和稱黑素中的一种或多种活性成分。 [0039] The enteric solid formulations of the invention, as an active ingredient may be selected from the group comprising W according to the requirements of lycopene, said alcohol and white passage Lo melanin one or more active ingredients.

[0040] 其中,番茄红素分子式为[4。 [0040] wherein lycopene formula [4. 馬6,具有下述式所示的结构, Ma 6, having the structure represented by the following formula,

[0041 ] [0041]

Figure CN105213316AD00081

[0042] 本发明的番茄红素包括所有番茄红素的顺反异构体。 Lycopene [0042] The present invention includes all of the lycopene, cis and trans isomers.

[0043] 白襲芦醇的化学名称为巧)-5-巧-(4-径苯基)-乙締基]-1,3-苯二酪,分子式为。 [0043] The chemical name for white passage resveratrol clever) -5- Qiao - (4-phenyl diameter) - B associative yl] -1,3-benzenedicarboxylic casein, formula. 化2〇3。 Of 2〇3. W44] 稱黑素化学名称为5-甲氧基-N-乙酷色胺,分子式Ci3HieN2〇2。 W44] melanin said chemical name 5-methoxy-tryptamine cool -N- B, formula Ci3HieN2〇2.

[0045] 用于本发明的番茄红素、白襲芦醇和稱黑素均可商购得到。 [0045] The lycopene used in the present invention, the passage of the white pigment can be black, said reed alcohol commercially available.

[0046] 除上述=种活性组分外,本发明提供的包含肠溶或水溶固体分散体的肠溶固体制剂,还可含有一种或多种其他适宜的活性组分,例如:花青素、姜黄素、叶黄素、P-胡萝h 素、胡萝h素、石恼提取水不溶物如较花酸和熊果酸、和脂溶性维生素如维生素A、维生素D、维生素K、维生素E,优选花青素、姜黄素、叶黄素、P-胡萝h素、较花酸和/或胡萝h素。 [0046] In addition to the active component = species, the present invention provides a solid preparation comprising an enteric solid dispersion enteric or water-soluble, and may contain one or more other suitable active ingredients, for example: anthocyanin , curcumin, lutein, P- h carrot pigment, carrot pigment h, angry stone extract more water-insoluble substance such as ursolic acid and ellagic acid, and fat-soluble vitamins such as vitamin A, vitamin D, vitamin K, vitamin E, preferably anthocyanins, curcumin, lutein, P- h carrot pigment, more ellagic acid and / or carrot h Su.

[0047] 当使用肠溶性载体与所述活性成分形成肠溶固体分散体或者肠溶包衣时,所述肠溶性载体对于控制活性成分在胃中少量释放或者不释放是十分有利的。 [0047] When forming the active ingredient during the enteric solid dispersion or an enteric coating, the enteric carrier for the control of small amounts of the active ingredient is not released in the stomach or release it is advantageous to use an enteric carrier. 并且肠溶固体分散体和肠溶包衣内的水溶固体分散体的应用,进一步使药物活性成分在吸收表面积大的肠中得W被大量释放并吸收。 And water soluble solids in the application of the enteric solid dispersion, and the dispersion enteric coating, further pharmaceutically active ingredients have a large number of W is released and absorbed in the intestinal absorption of large surface area.

[0048] 本发明中,肠溶性载体是指一种水溶抑依赖型载体,其溶解具有抑依赖性,在人体肠液环境(约抑> 5. 5)中才能溶解,故称在人体肠液环境中才能溶解的载体为肠溶性载体。 [0048] In the present invention, an enteric soluble carrier refers to a carrier-dependent inhibition, which was dissolved with dependent suppression, in the human intestinal environment can be dissolved (about suppression> 5.5), the so called in the human intestinal environment to dissolve the enteric carrier to carrier.

[0049] 为提高溶解度,包含肠溶固体分散体或水溶固体分散体的肠溶固体制剂中还可W 进一步含有表面活性剂。 [0049] To improve solubility, a solid preparation comprising an enteric solid dispersion or aqueous enteric solid dispersion of W may further contain a surfactant. 表面活性剂既可W添加在固体分散体中也可W和其他载体辅料一起在固体分散体外添加。 Surface active agents may be added to the W solid dispersion and W may be added together with other adjuvants in a carrier solid dispersion vitro. 适宜的表面活性剂选自一种或多种W下组中的物质:十二烷基硫酸钢、聚氧乙締-聚氧丙締共聚物(Poloxamer)、吐溫类、司盘类、聚乙二醇类、聚氧乙締藍麻油类如化emo地orEL聚氧乙締氨化藍麻油类如化emo地or40,优选化emo地or化和/ 或化emo地or40。 Suitable surfactants are selected from one or more of the group W materials: steel dodecylsulfate, polyoxyethylene association - polyoxypropylene copolymer association (Poloxamer), Tweens, Spans, polyethylene glycols, polyoxyethylene association of hydrocarbons such as sesame oil blue emo association to orEL polyoxyethylene amides of hydrocarbons such as sesame oil blue emo to or40, or preferably of the emo and / or of the emo or40. 表面活性的添加量可根据需要调节,一个优选的比例范围是,所述活性成分重量与所述表面活性剂的重量比为1 : 2-1 : 4。 The amount of surfactant added can be adjusted as needed, a preferred ratio ranges are, by weight of the active ingredient the weight ratio of the surfactant is 1: 2-1: 4.

[0050] 根据本发明的一个实施方案,肠溶固体制剂中含有肠溶性载体与一种或多种所述活性成分形成的肠溶固体分散体。 [0050] According to an embodiment of the present invention, an enteric solid preparation comprising an enteric solid carrier and an enteric one or more active ingredients of the dispersion formed.

[0051] 作为用于所述肠溶固体分散体的肠溶性载体,一个优选的实施方案是所述的肠溶性载体为一种或多种选自W下组中的肠溶性聚合物:乙酸邻苯二甲酸纤维素(CAP)、乙酸偏苯=酸纤维素(CAT)、乙酸班巧酸纤维素(CA巧、邻苯二甲酸甲基纤维素、邻苯二甲酸乙基径甲基纤维素、邻苯二甲酸径丙基甲基纤维素化PMCP)、乙酸班巧酸径丙基甲基纤维素化PMCAS)、乙酸马来酸径丙基甲基纤维素、偏苯=酸径丙基甲基纤维素化PMCT)、簇甲基乙基纤维素、聚下酸乙締邻苯二甲酸醋、聚乙酸乙締醇邻苯二甲酸醋(PVAP)、甲基丙締酸/丙締酸乙醋共聚物和甲基丙締酸/甲基丙締酸甲醋共聚物。 [0051] As carrier for the enteric enteric solid dispersion, a preferred embodiment is the enteric carrier is one or more selected from the group of W enteric polymer: phthalic acid cellulose phthalate (CAP), cellulose acetate, trimellitic acid = (CAT), cellulose acetate Qiao classes acetate (CA Qiao, methylcellulose phthalate, methyl cellulose phthalate, ethyl diameter , methylcellulose phthalate diameter of PMCP), diameter class acetic acid coincidence of methylcellulose PMCAS), acetic acid, maleic diameter methylcellulose, trimellitic acid diameter = propyl of methylcellulose PMCT), cluster methyl ethyl cellulose, polyethylene association phthalic acid ethyl acetate, polyvinyl acetate phthalate, ethyl alcohol vinegar association (PVAP), associated methylpropanesulfonic acid / propionic acid associative ethyl ester copolymers and methacrylic acid associative / methylpropanesulfonic acid methyl ester associative copolymer. 更优选肠溶性载体为HPMCAS和/或甲基丙締酸/丙締酸乙醋共聚物如化化agitL100-55和/或HPMCP。 More preferably the carrier is HPMCAS enteric and / or associated methylpropanesulfonic acid / propionic acid ethyl ester association of agitL100-55 of such copolymers and / or HPMCP.

[0052] 用于肠溶固体分散体制剂的肠溶性载体和活性成分的比例没有特殊限制,可W根据本领域的常规要求添加。 The proportion of enteric carrier and an active ingredient [0052] The formulation for the enteric solid dispersion is not particularly limited, and W may be added in accordance with conventional requirements of the art. 优选地,所述活性成分总重量与所述肠溶性载体的重量比为1 : 1-1 : 20。 Preferably, the weight of the total weight of the active ingredient and the enteric carrier ratio of 1: 1-1: 20.

[0053] 由W上讨论可知,本发明的包含肠溶固体分散体的肠溶固体制剂可W使含有的活性成分在胃中少量释放或不释放。 [0053] W can be seen from the above discussion, an enteric solid preparation comprising an enteric solid dispersion of the present invention, the active ingredient may be W contained a small amount of released or not released in the stomach. 优选地,所述的活性成分白襲芦醇在0. 1M盐酸中的45分钟溶出度不大于20%,优选不大于10%,在抑6. 8憐酸盐缓冲液中的60分钟溶出度各不低于75 %,优选不低于80 %;稱黑素在0. 1M盐酸中的60分钟溶出度不大于25 %,优选不大于15 %,在抑6. 8憐酸盐缓冲液中的30分钟溶出度各不低于80 %,优选不低于90 %。 Preferably, the active constituents of the passage 45 minutes resveratrol dissolution in 0. 1M hydrochloric acid is less than 20%, preferably not more than 10% dissolution at 60 minutes 6.8 suppressing salt buffer pity each of not less than 75%, preferably not less than 80%; 60 minutes, said dissolution melanin in 0. 1M hydrochloric acid is not more than 25%, preferably no greater than 15% inhibition at 6.8 Rei formate buffer each 30 minutes of dissolution is not less than 80%, preferably not less than 90%. 在本发明中,所述包含肠溶固体分散体的肠溶固体制剂溶出度实验依据中国药典附录XD释放度测定第二法(用于肠溶制剂)测定,具体的测试方法参见试验例1-3。 In the present invention, a dissolution test comprising an enteric solid formulations enteric solid dispersion measuring method according to the second appendix XD release Chinese Pharmacopoeia (for enteric formulation) was measured, specific test methods see Test Example 1- 3.

[0054] 根据需要,本发明的包含肠溶固体分散体的肠溶固体制剂还可W进一步包含其它药用辅料W制成片剂、胶囊剂、颗粒剂、散剂或微丸等剂型。 [0054] If necessary, an enteric solid preparation comprising an enteric solid dispersion of the present invention may further comprise other pharmaceutically acceptable excipients W W form of tablets, capsules, granules, powders and pellets dosage form. 其中,所述的其它药用辅料包括稀释剂、崩解剂、润滑剂、抗氧剂中的一种或多种。 Wherein said additional pharmaceutical excipients include diluents, disintegrants, lubricants, one or more antioxidants. 所述的稀释剂,其可W是微晶纤维素、淀粉、预胶化淀粉、乳糖、甘露醇、憐酸氨巧中的一种或多种;崩解剂,其可W是低取代纤维素、 交联簇甲基纤维素钢、簇甲基淀粉钢、交联聚乙締化咯烧酬中的一种或多种;润滑剂,其可W是硬脂酸儀、滑石粉、微粉硅胶、硬脂酸、氨化植物油中的一种或多种;和抗氧剂,其可W 是抗坏血酸、抗坏血酸钢、维生素C栋桐酸醋、维生素E、维生素E班巧酸聚乙二醇醋灯PG巧中的一种或多种。 The diluents which may be W is microcrystalline cellulose, starch, pregelatinized starch, lactose, mannitol, ammonia, one or more clever in pity acid; disintegrants, which may be substituted with W is a low fiber one or more elements, crosslinked cellulose clusters steel, steel cluster starch, slightly crosslinked polyvinyl association of the burning paid; lubricant, which may be W is stearic instrument, talc, micronized silica, stearic acid, amides of one or more vegetable oils; and an antioxidant, which may be W is ascorbic acid, ascorbyl steel, vitamin C dong Tong vinegar, vitamin E, vitamin E polyethylene glycol acid classes Qiao vinegar light PG in one or more clever.

[0055] 根据本发明的又一个实施方案,肠溶固体制剂中含有选自番茄红素、白襲芦醇和稱黑素中的一种或多种活性成分,W及肠溶性载体和水溶性载体,其中所述水溶性载体与所述活性成分W水溶固体分散体形式存在于该固体制剂中,并且在该固体制剂外层包覆有含有肠溶性载体的肠溶包衣层。 [0055] According to yet another embodiment of the present invention, an enteric solid formulations containing lycopene selected, said one kind of alcohols and white passage Lo melanin or more active ingredients, W, and a carrier and an enteric water-soluble carrier wherein said water-soluble carrier with the active ingredient W water-soluble solid dispersion is present in the solid preparation, and coated with an enteric coating layer comprising an enteric carrier in the solid preparation of the outer layer.

[0056] 其中,所述的水溶性载体是指在水中能溶解的载体,它包括非抑依赖型和抑依赖型两种。 [0056] wherein said water-soluble carrier refers to a vector capable of dissolving in water, which comprises suppressing non-dependent and dependent suppression two. 其中非抑依赖型载体的溶解不受环境中溶液抑值的影响,在任何抑值溶液中均能溶解;抑依赖型载体的溶解取决于环境中溶液的抑值,当溶液的抑值大于该溶解抑值时,载体才能溶解。 Effects of inhibition values ​​wherein a solution dissolving a non-dependent type carrier suppression from the environment, the inhibition values ​​are soluble in any solution; carrier suppression dependent inhibition of dissolution depends on the value of the environment of the solution, when the solution is greater than the value of the suppression dissolution suppression value, in order to dissolve the carrier. 本发明中设及的另一种肠溶固体制剂即活性成分先制成水溶性固体分散体再在该固体制剂外层包覆含有肠溶性载体的肠溶包衣制剂中的水溶性载体优选水溶性非抑依赖型载体。 Another enteric solid formulations of the invention and is provided, i.e., first made soluble active ingredient water soluble carrier solid dispersion enteric coating comprising an enteric coated preparation is subdivided in the solid preparation of the carrier is preferably water-soluble outer layer non-carrier-dependent inhibition.

[0057] 一个优选的实施方案中,所述水溶性非抑依赖型载体为一种或多种选自W下组中的物质:甲基纤维素、径丙甲基纤维素(HPMC)、聚氧乙締-聚氧丙締共聚物(Poloxamer)、 聚乙締化咯烧酬(PVP)、聚氧乙締(PE0)、共聚维酬(Copovidone)、聚乙締醇(PVA)、聚乙二醇类、Soluplus、糖类、甘露醇和木糖醇,更优选化loxamer和/或Soluplus。 [0057] In a preferred embodiment, the water-soluble carrier is a non-dependent inhibition of one or more selected from the group of W materials: methyl cellulose, methyl cellulose, diameter (HPMC), poly oxyethylene associative - polyoxypropylene copolymer association (Poloxamer), polyethylene of slightly burned pay association (PVP), polyoxyethylene association (PE0), copovidone pay (copovidone), polyvinyl alcohol association (PVA), polyvinyl glycols, Soluplus, sugars, mannitol, and xylitol, and more preferably of loxamer / or Soluplus.

[0058] 所述的水溶性载体和活性成分的比例没有特殊限定,可W根据需要调整。 [0058] The ratio of the water-soluble carrier and the active ingredient is not particularly limited, and W can be adjusted as needed. 优选地, 所述活性成分总重与所述水溶性载体的重量比为1 : 1-1 : 20。 Preferably, the total weight of the active ingredient the weight ratio of the water-soluble carrier is 1: 1-1: 20.

[0059] 根据需要,所述的肠溶固体制剂还可包括其它药用辅料W制成包肠溶衣的肠溶片、胶囊、颗粒剂、散剂或微丸等成品供口服给药。 [0059] The desired, the enteric solid formulations may include other pharmaceutical excipients W enteric formed enteric coated tablets, capsules, granules, powders and the finished pellets for oral administration. 其中,所述的其它药用辅料包括稀释剂、 崩解剂、润滑剂、抗氧剂中的一种或多种。 Wherein said additional pharmaceutical excipients include diluents, disintegrants, lubricants, one or more antioxidants. 所述的稀释剂,其可W是微晶纤维素、淀粉、预胶化淀粉、乳糖、甘露醇、憐酸氨巧中的一种或多种;崩解剂,其可w是低取代纤维素、交联簇甲基纤维素钢、簇甲基淀粉钢、交联聚乙締化咯烧酬中的一种或多种;润滑剂,其可W是硬脂酸儀、滑石粉、微粉硅胶、硬脂酸、氨化植物油中的一种或多种;和抗氧剂,其可W是抗坏血酸、抗坏血酸钢、维生素C栋桐酸醋、维生素E、维生素E班巧酸聚乙二醇醋(TPG巧中的一种或多种。 W60] 对于所述的肠溶包衣层中含有的肠溶性载体,其优选为一种或多种选自W下组中的肠溶性聚合物:乙酸邻苯二甲酸纤维素(CAP)、乙酸偏苯S酸纤维素(CAT)、乙酸班巧酸纤维素(CA巧、邻苯二甲酸甲基纤维素、邻苯二甲酸乙基径甲基纤维素、邻苯二甲酸径丙基甲基纤维素化PMCP)、乙酸班巧酸径丙基甲基纤维素化PMCA巧、乙酸马来酸径丙基 The diluents which may be W is microcrystalline cellulose, starch, pregelatinized starch, lactose, mannitol, ammonia, one or more clever in pity acid; disintegrant is low-substituted fiber can w one or more elements, crosslinked cellulose clusters steel, steel cluster starch, slightly crosslinked polyvinyl association of the burning paid; lubricant, which may be W is stearic instrument, talc, micronized silica, stearic acid, amides of one or more vegetable oils; and an antioxidant, which may be W is ascorbic acid, ascorbyl steel, vitamin C dong Tong vinegar, vitamin E, vitamin E polyethylene glycol acid classes Qiao vinegar (TPG coincidence of one or more of W60] to support the enteric layer comprises enteric coating, which is preferably one or more selected from the group of W enteric polymer: cellulose acetate phthalate (CAP), cellulose acetate, trimellitic acid, S (CAT), cellulose acetate Qiao classes acetate (CA Qiao, phthalate, methylcellulose phthalate, methyl ethyl diameter cellulose, methylcellulose phthalate diameter of PMCP), diameter class acetic acid Qiao methylcellulose coincidence of PMCA, maleic acid, acetic acid propyl diameter 甲基纤维素、偏苯=酸径丙基甲基纤维素化PMCT)、簇甲基乙基纤维素、聚下酸乙締邻苯二甲酸醋、 聚乙酸乙締醇邻苯二甲酸醋(PVAP)、甲基丙締酸/丙締酸乙醋共聚物和甲基丙締酸/甲基丙締酸甲醋共聚物,更优选HPMCAS。 Methylcellulose, trimellitic acid = diameter of methylcellulose PMCT), cluster methyl ethyl cellulose, polyvinyl acetate association phthalic acid vinegar, ethyl alcohol, polyvinyl acetate phthalate associative vinegar ( PVAP), associated methylpropanesulfonic acid / propionic acid ethyl ester copolymer, associative and associative-methylpropanesulfonic acid / methyl-propionic acid methyl ester associative copolymer, more preferably HPMCAS.

[0061] 所述的肠溶包衣层中还可W进一步含有选自增塑剂、抗粘剂和稳定剂中的一种或多种载体。 [0061] The enteric coating layer may further contain W is selected from a plasticizer, a stabilizer, and anti-adherent in one or more carriers. 其中,增塑剂可选自一种或多种W下组中的物质:邻苯二甲酸二乙醋值EP)、癸二酸二下醋值BS)、巧樣酸S下醋灯BC)、巧樣酸S乙醋灯EC)、藍麻油、S醋酸甘油醋灯A)、 丙二醇、甘油、聚乙二醇、精制挪子油、油酸、締基班巧酸酢和聚乳酸(PLA),优选TEC;抗粘剂可选自一种或多种W下组中的物质:滑石粉、微粉硅胶、单硬脂酸甘油醋,优选滑石粉和微粉硅胶;稳定剂包括十二烷基硫酸钢。 Wherein the plasticizer is selected from one or more of the group W substances: vinegar, diethyl phthalate EP value), the BS value of vinegar sebacate), Qiao lamp BC acid like vinegar S) , Qiao sample S acid ethyl ester lamp EC), blue sesame oil, triacetin, vinegar lamp S A), propylene glycol, glycerin, polyethylene glycol, refined Norwegian oil, oleic acid, associative classes clever group of Health and polylactic acid (PLA ), preferably the TEC; optional anti-adherent material more of the group W from one or: talc, silica powder, glycerol monostearate vinegar, preferably micronized talc and silica; stabilizers include dodecyl sulfuric acid steel.

[0062] 对于所述的肠溶包衣层中含有各种成分的比例没有特殊限制,可W根据需要调整。 [0062] There is no particular limitation to the ratio of the enteric coating layer containing various ingredients, W can be adjusted as required. 优选地,所述的肠溶性载体为所述肠溶包衣层固含量的60-90重量%;所述的增塑剂为所述肠溶包衣层固含量的10-30重量% ;所述的抗粘剂为所述肠溶包衣层固含量的10-30 重量% ;所述的稳定剂为所述肠溶包衣层固含量重量的0.5-5重量%。 Preferably, the enteric carrier is 60-90 wt.% Of the solids content of the enteric coating layer; said plasticizer is 10-30% by weight of the solids content of the enteric coating layer; the said anti-sticking agent is 10-30 wt% solids content of the enteric coating layer; stabilizer according to the weight of the solids content of the enteric coating layer is 0.5 to 5 wt%. 更优选所述的肠溶性载体为所述肠溶包衣层固含量的70-80重量% ;所述的增塑剂为所述肠溶包衣层固含量的10-15重量%;所述的抗粘剂为所述肠溶包衣层固含量的15-20重量%;所述的稳定剂为所述肠溶包衣层固含量的3-5重量%。 More preferably, the carrier is the enteric coating layer of the enteric solids content 70-80% by weight; the plasticizer is 10-15% by weight of the solids content of the enteric coating layer; the the antisticking agent is 15-20 wt% solids content of the enteric coating layer; stabilizer according to the solids content of 3-5 wt% of an enteric coating layer.

[0063] 相对于包衣层中包覆的成分总重量,优选所述的肠溶包衣层重量为10-50重量%,更优选为15-25重量%。 [0063] with respect to the total weight of the composition coating layer coated, the enteric coating layer weight is preferably 10 to 50 wt%, more preferably 15-25 wt%.

[0064] 本发明的水溶/肠溶固体分散体的制备方法可采用常用的制备固体分散体的方法,包括烙融法、溶剂法、溶剂-烙融法、研磨法、溶剂-冷冻干燥法、溶剂-喷雾干燥法和热烙挤出法等,具体可参见化学工业出版社出版、朱盛山主编的《药物新剂型》第1版第26-29 页。 [0064] The method of preparing an aqueous / enteric solid dispersion of the present invention may be employed conventional methods for preparing solid dispersions including melt branded, solvent, solvent - branded melting method, a grinding method, a solvent - freeze-drying method, solvent - spray drying and hot branding extrusion method, reference may be made chemical industry Publishing House, "new drug formulations," first Edition, page 26-29 Sheng Zhu Shan editor.

[0065] 作为一个优选的实施方案,本发明提供了一种肠溶固体制剂,其含有番茄红素作为活性成分,肠溶性载体和/或水溶性载体;其中所述肠溶性载体与番茄红素W肠溶固体分散体形式存在于制剂中,或者所述水溶性载体与所述番茄红素W水溶固体分散体形式存在于该固体制剂中,并且在该固体制剂外层包覆含有肠溶性载体的肠溶包衣层。 [0065] As a preferred embodiment, the present invention provides an enteric solid formulations containing lycopene as an active ingredient, an enteric carrier and / or water soluble carrier; and wherein the enteric carrier lycopene W enteric solid dispersion present in the formulation, or the water-soluble carrier and the water-soluble lycopene W is present in the form of a solid dispersion of the solid formulation comprising an enteric coating and the solid formulation carrier layer enteric coating layer. 该肠溶固体制剂能够提高番茄红素的水溶性和稳定性,使药物在胃内少量释放或不释放,而在肠道大量释放,增加番茄红素生物利用度。 The enteric-coated solid preparation can be improved water solubility and stability of lycopene, a small amount of the drug released or not released in the stomach, and large in the intestinal tract, increase the bioavailability of lycopene.

[0066] 在本优选实施方案中,除有W下特殊说明,其适用对于前述实施方案的讨论。 [0066] In a preferred embodiment of the present embodiment, in addition to the special W that is applied to the discussion of the preceding embodiments.

[0067] 根据本优选实施方案的肠溶固体制剂,当其中所述肠溶性载体与番茄红素W肠溶固体分散体形式存在于制剂中时,优选的肠溶性载体是HPMCP。 [0067] The enteric-coated solid preparation of the present preferred embodiments, when the carrier and wherein the enteric lycopene W enteric solid dispersion is present in the formulation, the enteric carrier is preferably HPMCP.

[0068] 根据本优选实施方案的肠溶固体制剂,当其中所述水溶性载体与所述番茄红素W 水溶固体分散体形式存在于该固体制剂中,并且在该固体制剂外层包覆有含有肠溶性载体的肠溶包衣层时,优选的水溶性载体是Soluplus和/或化loxamer,更优选化loxamer,优选的肠溶性载体是HPMCAS,更优选HPMCASAS-LF。 [0068] The enteric-coated solid preparation of the present preferred embodiment, when the water-soluble carrier and wherein the solid lycopene W aqueous dispersion is present in the solid preparation, the solid formulation and coated with a layer when an enteric coating layer comprising an enteric carrier, preferably water-soluble carrier is Soluplus and / or of loxamer, more preferably of loxamer, preferably of HPMCAS enteric carrier is, more preferably HPMCASAS-LF. W例为提高溶解度,可在番茄红素固体肠溶制剂中添加表面活性剂。 Example W In order to improve the solubility, a surfactant may be added in an enteric solid formulations of lycopene. 适宜的表面活性剂包括十二烷基硫酸钢、聚氧乙締-聚氧丙締共聚物(Poloxamer)、吐溫类、司盘类、聚乙二醇类、聚氧乙締藍麻油类如化emo地orEL聚氧乙締氨化藍麻油类如化emo地or40或其组合,优选化emo地or化和/或化emo地or40。 Suitable surfactants include dodecyl sulfate steel association polyoxyethylene - polyoxypropylene copolymer association (Poloxamer), Tweens, Spans, polyethylene glycols, polyoxyethylene association hydrocarbons such as sesame oil blue emo orEL of the polyoxyethylene amide blue association of hydrocarbons such as sesame oil, or combinations thereof emo to or40, or preferably of the emo and / or of the emo or40. 表面活性的添加量可跟据需要调节,一个优选的比例范围是,所述活性成分重量与所述表面活性剂的重量比为1 : 2-1 : 4。 The amount of active surface may be added as required with the adjustment, a preferred ratio range, the weight ratio of the active ingredient by weight of the surfactant is 1: 2-1: 4.

[0070] 优选地,所述的水溶固体分散体活性成分番茄红素在添加表面活性剂后在pH6. 8 憐酸盐缓冲液中的溶解度不低于10yg/ml,优选不低于20yg/ml。 [0070] Preferably, the aqueous dispersion of solid active ingredient lycopene after adding the surfactant solubility in pH6. 8 pity salt buffer is not less than 10yg / ml, preferably not less than 20yg / ml .

[0071] 根据本优选实施方案的肠溶固体制剂,在番茄红素水溶或肠溶固体分散体中,番茄红素与所述肠溶性或水溶性载体的重量比优选为1 : 1-1 : 20,更优选1 : 8-1 : 16。 [0071] The enteric-coated solid preparation of the present preferred embodiment, the lycopene-soluble or enteric solid dispersion, the weight of the lycopene with an enteric or water-soluble carrier is preferably from 1: 1 to 1: 20, more preferably 1: 8-1: 16.

[0072] 番茄红素属于脂肪族締控,具有强还原性,易氧化降解,为了提高制剂稳定性,在处方中优选添加一定量的抗氧化剂,例如抗坏血酸、抗坏血酸钢、维生素C栋桐酸醋、维生素E、维生素E班巧酸聚乙二醇醋灯PG巧中的一种或多种。 [0072] Lycopene aliphatic or association control, having a strong reduction, oxidative degradation easily, in order to improve the stability of the formulation, the formulation in an amount of antioxidant added is preferably such as ascorbic acid, ascorbic steel, vitamin C Building Tong vinegar , vitamin E, vitamin E polyethylene glycol acetic acid classes Qiao lamp PG in one or more clever.

[0073] 所述番茄红素水溶性/肠溶固体分散体可W与其它药用辅料混合,进一步加工制备成片剂、胶囊剂、颗粒剂、散剂、微丸或包肠溶衣的肠溶片、胶囊、颗粒剂、散剂或微丸等成品供口服给药,制剂规格优选lmg-20mg。 [0073] The water-soluble lycopene / W enteric solid dispersion may be mixed with other pharmaceutically acceptable excipients, further processed prepared into tablets, capsules, granules, powders, pellets, or enteric coated enteric tablets, capsules, granules, powders, pellets, or other finished products for oral administration, the preparation, preferably lmg-20mg.

[0074] 本优选实施方式的番茄红素固体分散体的制备方法优选溶剂-喷雾干燥法。 [0074] The present production method is preferably a solvent lycopene preferred embodiment the solid dispersion - spray drying. 由于番茄红素的烙点高,为174°C,且不稳定,用热烙挤出法制备固体分散体时易出现载体发生分解和番茄红素发生降解现象,因此制备番茄红素固体分散体一般优选采用溶剂-喷雾干燥法。 Due to the high lycopene branded point of 174 ° C, and unstable, prone to hot extrusion when baked Preparation of solid dispersion carrier decomposition and degradation phenomena occur lycopene, thus preparing solid dispersions lycopene solvent is generally preferred - spray drying.

[00巧]作为一个具体的实施方案,溶剂-喷雾干燥法可选取肠溶或水溶性载体辅料和/ 或表面活性剂与番茄红素,将其加入可溶解上述物质且对上述物质惰性的有机溶剂中,如二氯甲烧或乙酸乙醋。 [Qiao 00] As a specific embodiment, the solvent - spray-drying method may be an enteric or water-soluble carrier selected adjuvant and / or surfactant and lycopene, which is added to the above material and the organic soluble substance inert to the above-described a solvent, such as dichloromethane or acetic acid ethyl ester burning. 然后,揽拌,溶解,采用喷雾干燥法除去有机溶剂,若有需要可置真空干燥箱中进一步干燥10-3化,即得本实施方案的水溶性/肠溶性载体固体分散体。 Then, embrace mixing, dissolving, spray drying the organic solvent is removed, if necessary, further dried in a vacuum oven of 10-3, to obtain the present embodiment is a water-soluble / enteric solid dispersion carrier.

[0076] 对于所得到的水溶性载体固体分散体,进一步对其肠溶包衣,W得到肠溶固体制剂。 [0076] For a solid water-soluble carrier obtained dispersion, it further enteric coating, W to give an enteric solid formulations.

[0077] 作为又一优选的实施方案,本发明提供了一种肠溶固体制剂,其含有白襲芦醇作为活性成分,肠溶性载体和/或水溶性载体;其中所述肠溶性载体与白襲芦醇W肠溶固体分散体形式存在于制剂中,或者所述水溶性载体与白襲芦醇W水溶固体分散体形式存在于该固体制剂中,并且在该固体制剂外层包覆有含有肠溶性载体的肠溶包衣层。 [0077] As still another preferred embodiment, the present invention provides a solid enteric preparation containing white passage of resveratrol as an active ingredient, an enteric carrier and / or water soluble carrier; and wherein the enteric carrier white W passage of the enteric solid dispersion resveratrol present in the formulation, the water-soluble or water-soluble solid carrier and dispersion W white passage resveratrol is present in the solid preparation, and there is a solid formulation comprising the sheath the enteric coating layer is an enteric carrier. 该固体制剂能够提高白襲芦醇的水溶性和稳定性,使药物在胃内少量释放或不释放,而在肠道大量释放,增加白襲芦醇的生物利用度。 The solid formulation can improve the water solubility and stability of the resveratrol white passage, a small amount of the drug released or not released in the stomach, and large in the intestinal tract, increase the bioavailability of resveratrol white passage.

[0078] 在本优选实施方案中,除有W下特殊说明,其适用对于前述实施方案的讨论。 [0078] In a preferred embodiment of the present embodiment, in addition to the special W that is applied to the discussion of the preceding embodiments.

[0079] 根据本优选实施方案的肠溶固体制剂,当其中所述肠溶性载体与白襲芦醇W肠溶固体分散体形式存在于制剂中时,优选的肠溶性载体是HPMCAS和/或HPMCP。 [0079] The enteric-coated solid preparation of the present preferred embodiments, when the carrier and wherein said enteric W enteric solid dispersion of white passage resveratrol present in the formulation, the preferred carrier is HPMCAS enteric and / or HPMCP .

[0080] 根据本优选实施方案的肠溶固体制剂,当其中所述水溶性载体与白襲芦醇W水溶固体分散体形式存在于该固体制剂中,并且在该固体制剂外层包覆有含有肠溶性载体的肠溶包衣层时,优选的水溶性载体是Soluplus和/或化loxamer,更优选化loxamer,优选的肠溶性载体是HPMCAS,更优选HPMCASAS-LF。 [0080] The enteric-coated solid preparation of the present preferred embodiment, when the water-soluble carrier and wherein the passage of resveratrol W white solid aqueous dispersion is present in the solid preparation, and the solid preparation coated with an outer layer comprising when the enteric coating layer is an enteric carrier, preferably water-soluble carrier is Soluplus and / or of loxamer, more preferably of loxamer, preferably of HPMCAS enteric carrier is, more preferably HPMCASAS-LF.

[0081] 根据本优选实施方案的肠溶固体制剂,在白襲芦醇水溶或肠溶固体分散体中白襲芦醇与所述肠溶性或水溶性载体的重量比优选为1 : 1-1 : 20,更优选1 : 2-1 : 8。 [0081] The enteric-coated solid preparation of the present preferred embodiment, the water-soluble or white passage resveratrol enteric solid dispersion with the white passage resveratrol enteric or water-soluble carrier weight ratio is preferably 1: 1-1 : 20, more preferably 1: 2-1: 8.

[0082] 白襲芦醇固体分散体与其它辅料混合,可进一步加工制备成片剂、胶囊剂、颗粒剂、散剂、微丸或包肠溶衣的肠溶片、胶囊、颗粒剂、散剂或微丸等成品供日服给药,制剂规格20mg-S00mg。 [0082] White solid dispersion attack resveratrol mixed with other excipients, be processed further prepared into tablets, capsules, granules, powders, pellets enteric or enteric coated tablets, capsules, granules, powders, or pellets and other products for daily buccal administration, the formulation specifications 20mg-S00mg.

[0083] 本优选实施方式的白襲芦醇固体分散体的制备方法优选溶剂-喷雾干燥法或热烙挤出法。 [0083] The preferred method of preparing the passage of the solvent the white solid resveratrol present preferred embodiment of the dispersion - spray drying or hot extrusion branded.

[0084] 作为一个具体的实施方案,溶剂-喷雾干燥法可选取肠溶或水溶性载体辅料和/ 或表面活性剂与白襲芦醇,将其加入可溶解上述物质且对上述物质惰性的有机溶剂中,如二氯甲烧或乙酸乙醋。 [0084] As a specific embodiment, the solvent - spray-drying method may be an enteric or water-soluble carrier selected adjuvants and / or surfactants and White passage of resveratrol, which is added to the above material and the organic soluble substance inert to the above-described a solvent, such as dichloromethane or acetic acid ethyl ester burning. 然后揽拌,溶解,采用喷雾干燥法除去有机溶剂,若有需要可置真空干燥箱中进一步干燥10-3化,即得本实施方案的水溶性/肠溶性载体固体分散体。 Then embrace mixing, dissolving, spray drying the organic solvent is removed, if necessary, further dried in a vacuum oven of 10-3, to obtain the present embodiment is a water-soluble / enteric solid dispersion carrier.

[0085] 作为又一具体的实施方案,热烙挤出法是将药物与载体混合加入热烙挤出机中, 经加热使药物和载体迅速达到烙融状态,再经螺杆混合元件和剪切元件的混合、剪切与挤压将物料输出,使药物颗粒更加均匀地分散。 [0085] As a further specific embodiment, the hot extrusion process branded drug mixed with a carrier is added to the hot branded extruder, by heating the drug and carrier baked quickly reach molten state, and then the screw mixing elements and shearing mixing elements, and pressing the material cut output, the drug particles are more uniformly dispersed.

[0086] 作为又一优选的实施方案,本发明提供了一种肠溶固体制剂,其含有稱黑素作为活性成分,肠溶性载体和/或水溶性载体;其中所述肠溶性载体与稱黑素W肠溶固体分散体形式存在于制剂中,或者所述水溶性载体与稱黑素W水溶固体分散体形式存在于该固体制剂中,并且在该固体制剂外层包覆有含有肠溶性载体的肠溶包衣层。 [0086] As still another preferred embodiment, the present invention provides a solid enteric-coated formulation comprising as an active ingredient called melanin, enteric carrier and / or water soluble carrier; and wherein the enteric carrier called black Su W enteric solid dispersion present in the formulation, or the water-soluble carrier with said aqueous melanin W solid dispersion is present in the solid preparation, and comprising a carrier coated with an enteric layer in the solid preparation enteric coating layer.

[0087] 在本优选实施方案中,除有W下特殊说明,其适用对于前述实施方案的讨论。 [0087] In a preferred embodiment of the present embodiment, in addition to the special W that is applied to the discussion of the preceding embodiments.

[0088] 根据本优选实施方案的肠溶固体制剂,当其中所述肠溶性载体与稱黑素W肠溶固体分散体形式存在于制剂中时,优选的肠溶性载体是HPMCAS、化化agitL100-55和/或HPMCPo [0088] The enteric-coated solid preparation of the present preferred embodiment, wherein when said carrier and said enteric melanin when W enteric solid dispersion is present in the formulation, the preferred carrier is of HPMCAS enteric, of agitL100- of 55 and / or HPMCPo

[0089] 根据本优选实施方案的肠溶固体制剂,当其中所述水溶性载体与所述稱黑素W水溶固体分散体形式存在于该固体制剂中,并且在该固体制剂外层包覆有含有肠溶性载体的肠溶包衣层时,优选的水溶性载体是Soluplus和/或化loxamer,更优选化loxamer,优选的肠溶性载体是HPMCAS。 [0089] The enteric-coated solid preparation of the present preferred embodiment, when the water-soluble carrier and wherein the said water-soluble melanin W solid dispersion is present in the solid preparation, the solid formulation and coated with a layer an enteric coating layer containing an enteric carrier, preferably water-soluble carrier is Soluplus and / or of loxamer, more preferably of loxamer, preferably enteric carrier is HPMCAS.

[0090] 根据本优选实施方案的肠溶固体制剂,在稱黑素水溶或肠溶固体分散体中,稱黑素与所述肠溶性或水溶性载体的重量比优选为1 : 1-1 : 20,更优选1 : 2-1 : 10。 [0090] The enteric-coated solid preparation of the present preferred embodiment, the water-soluble or enteric melanin said solid dispersion, the melanin weighed enteric or water-soluble carrier is preferably from 1: 1 to 1: 20, more preferably 1: 2-1: 10.

[0091] 本发明的稱黑素固体分散体与其它辅料混合,可进一步加工制备成片剂、胶囊剂、颗粒剂、散剂、微丸或包肠溶衣的肠溶片、胶囊、颗粒剂、散剂或微丸等成品供口服给药,控制稱黑素主要在小肠中释放,增加稱黑素的口服吸收,提高生物利用度。 [0091] The present invention melanosomes said solid dispersion is mixed with other excipients, be processed further prepared into tablets, capsules, granules, powders, pellets enteric or enteric coated tablets, capsules, granules, finished pellets or powders, etc. for oral administration, controlled release of said melanin mainly in the small intestine, said oral absorption increased melanin, improve bioavailability. 制剂规格Img-lOmg。 Preparation specifications Img-lOmg.

[0092] 本优选实施方案的稱黑素固体分散体的制备方法优选溶剂-喷雾干燥法或热烙挤出法。 Preparation preferred solvent [0092] called melanocytes present preferred embodiment of the solid dispersion - spray drying or hot extrusion branded. 具体方法可参见上述白襲芦醇固体分散体的制备方法。 Specific methods can be found in the passage of the above preparation method resveratrol white solid dispersion.

[0093] 本发明的特点是用简单的方法实现了难溶性药物的增溶和释放性能的调控。 [0093] The features of the present invention is to realize a solubilizing poorly soluble drug release properties and regulation in a simple manner. 采用肠溶聚合物作载体制备的肠溶固体分散体或水溶性载体制备水溶固体分散体并进一步包肠溶衣,使药物W无定形状态或/和分子状态存在于固体分散体中,同时又可具备肠溶特征。 Enteric polymer employed for preparing the support of the enteric solid dispersion or a water-soluble solid carrier prepared aqueous dispersion of enteric coating and further, amorphous drug or W / and molecules present in the solid state dispersion, while It may be provided with an enteric characteristics. 制剂工艺简单、自动化程度高,省时高效,是一种可工业化大生产的技术。 Preparation process is simple, high degree of automation, time-saving and efficient, is an industrial production technology.

[0094] 另外,采用热烙挤出法时整个过程无溶剂参与,因此无溶剂残留问题及溶剂干燥过程。 [0094] Further, the use of the whole process involved in solvent-free hot extrusion branded, so no solvent residues and solvent drying process. 热烙挤出技术和传统的烙融法都是在物料达到烙融状态的情况下制备固体分散体, 但前者通过螺杆混合元件和剪切元件的有机组合,实现了强烈的混合、剪切与挤压作用的协同,使药物更均匀、紧密地分散在载体中,更大程度地提高了药物的溶出度。 Thermal branding extrusion technology and traditional branded melting method solid dispersions are prepared in the case of branded material reaches a molten state, but the former by a screw mixing elements and shearing elements of the organic composition, to achieve the intensive mixing, with a shear cooperative pressing action, so that the drug is more uniform, intimately dispersed in the carrier, the greater the degree of improved drug dissolution. 通过优选载体,使药物W无定形状态分散在载体中或者分子状态溶解在载体中。 Preferably, the carrier through, W amorphous drug dispersed in the carrier state or dissolved in a carrier molecule.

具体实施方式 Detailed ways

[0095] W下通过实施例进一步说明本发明,但并不意图对本发明进行限制。 [0095], it is not intended to be limiting of the present invention in a W examples further illustrate the invention.

[0096] 实施例1-1 [0096] Example 1-1

[0097]称取HPMCAS AS-LF、HPMCP HP-55、Kollidone VA64、Poloxamerl88、Soluplus各lOg分别溶于lOOOg二氯甲烧中,再向上述溶液分别加入0.〇5g维生素C揽拌至全部溶解, 然后分别加入番茄红素(长沙惠瑞生物科技有限公司生产)lg,形成均一溶液。 [0097] Weigh HPMCAS AS-LF, HPMCP HP-55, Kollidone VA64, Poloxamerl88, Soluplus lOg each separately dissolved in dichloromethane lOOOg burning, followed by adding the above solution were added to the stirred 0.〇5g vitamin C embrace all dissolved and then were added lycopene (Changsha-Swiss biotechnology Co., Ltd.) lg, a uniform solution. 用Buchi mini spray化yer B-290喷雾干燥除去有机溶剂得到番茄红素固体分散体,喷雾干燥过程中,物料溫度控制在50-55 °C。 A Buchi mini spray of yer B-290 spray-dried to remove the organic solvent to give a solid dispersion lycopene, spray-drying process, the material temperature is controlled at 50-55 ° C. 阳09引实施例1-2 Example 09 Primer 1-2 male

[0099]分别称取Soluplus20g、16g分别溶于lOOOg二氯甲烧中,再向上述溶液分别加入0. 05g维生素C揽拌至全部溶解,然后分别加入番茄红素(长沙惠瑞生物科技有限公司生产)lg,形成均一溶液。 [0099] were weighed Soluplus20g, 16g of dichloromethane were dissolved lOOOg burning, followed by adding the above solution was added 0. 05g of vitamin C were mixed to embrace all dissolved and then were added lycopene (Swiss biotechnology Ltd. Changsha production) lg, a uniform solution. 用Buchiminispray化yerB-290喷雾干燥除去有机溶剂得到番茄红素固体分散体,喷雾干燥过程中,物料溫度控制在50-55°C。 Buchiminispray yerB-290 with spray drying of the organic solvent was removed to give a solid dispersion lycopene, spray-drying process, the material temperature is controlled at 50-55 ° C. 阳100]实施例1-3 阳1〇1]称取Cremo地orRH40、Cremo地or化各4g,分别溶于含有16gSoluplus、0. 05g维生素C的lOOOg二氯甲烧溶液中,再向上述溶液分别加入Ig番茄红素(长沙惠瑞生物科技有限公司生产),揽拌至全部溶解。 Male 100] Example 1-3 male 1〇1] Cremo weighed to orRH40, Cremo of the or each 4g, respectively containing dissolved 16gSoluplus, 0. LOOOg burning was 05g dichloromethane vitamin C, followed by adding to the solution Ig were added lycopene (Changsha-Swiss biotechnology Co., Ltd.), to embrace the mix is ​​completely dissolved. 用Buchiminispray化yerB-290喷雾干燥除去有机溶剂得到番茄红素固体分散体,喷雾干燥过程中,物料溫度控制在50-55°C。 Buchiminispray yerB-290 with spray drying of the organic solvent was removed to give a solid dispersion lycopene, spray-drying process, the material temperature is controlled at 50-55 ° C. 阳102]实施例1-4 Male 102] Example 1-4

[0103]称取HPMCPHP-55、Soluplus各8g,分别溶于含有0. 05g维生素C、2gCremo地or RH40的lOOOg二氯甲烧溶液中,再向上述溶液分别加入Ig番茄红素(长沙惠瑞生物科技有限公司生产),揽拌至全部溶解。 [0103] Weigh HPMCPHP-55, Soluplus each 8g, 0. 05g were dissolved containing vitamin C, 2gCremo to burn or lOOOg methylene RH40 solution, the above solution was added again Ig lycopene (Changsha-Swiss respectively biological Technology Co., Ltd.), to embrace the mix is ​​completely dissolved. 用Buchiminispray化yerB-290喷雾干燥除去有机溶剂得到番茄红素固体分散体,喷雾干燥过程中,物料溫度控制在50-55°C。 Buchiminispray yerB-290 with spray drying of the organic solvent was removed to give a solid dispersion lycopene, spray-drying process, the material temperature is controlled at 50-55 ° C. 阳104]实施例2-1 阳1化]取班巧酸乙酸径丙基甲基纤维素(HPMCAS AS-LF)lOg和15g分别溶于含Ig维生素C的2份丙酬溶液中,形成均一溶液;分别各称取5g白襲芦醇溶解于上述溶液中,用Buchi minispray化yer B-290喷雾干燥除去有机溶剂分别得到白色粉末即为白襲芦醇:HPMCAS AS-LF为1 : 2和1 : 3的肠溶固体分散体,喷雾干燥过程中,物料溫度控制在50-55°C。 Male 104] Example 1 of the male 2-1] acetic acid skillfully taking classes diameter methylcellulose (HPMCAS AS-LF) lOg and 2 parts of a solution of 15g were dissolved in propan-pay Ig containing vitamin C to form a homogenous solution; were each weighed passage 5g white resveratrol dissolved in the above solution, with a Buchi minispray of yer B-290 spray-dried to remove the organic solvent to give a white powder of each passage is the white resveratrol: HPMCAS aS-LF 1: 2 and 1: 3 enteric solid dispersion, spray-drying process, the material temperature is controlled at 50-55 ° C. [0106] 分别取本例中的肠溶固体分散体适量,按重量比白襲芦醇:微晶纤维素:低取代径丙基纤维素:硬脂酸儀=5 : 20 : 1 : 0.5的比例混合均匀,压制成片(旋转式压片机ZP-5,上海天和制药机械有限公司)。 [0106] respectively, according to the present embodiment taken in an appropriate amount of the enteric solid dispersion, the weight ratio of resveratrol white attack: microcrystalline cellulose: Low-substituted hydroxypropylcellulose Diameter: Instrument stearate = 5: 20: 1: 0.5 the proportion of mixed and compressed into tablets (a rotary tableting machine ZP-5, Shanghai pharmaceutical Machinery Co. days). 阳107]实施例2-2 Male 107] Example 2-2

[0108] 取班巧酸乙酸径丙基甲基纤维素(HPMCASAS-LF) 15g、白襲芦醇5g、维生素C栋桐酸醋Ig,研磨混匀,投入到同向双螺杆挤出机(赛默飞世尔科技公司MiniL油)加料斗内,螺杆挤出区段溫度已预热至230°C,螺杆转速为30rpm,物料由机头模孔挤出,挤出物室溫冷却,粉碎后过180ym孔径筛网即得肠溶固体分散体。 [0108] Qiao classes taken diameter methylcellulose acetic acid (HPMCASAS-LF) 15g, white resveratrol passage 5g, vitamin C, Building an Ig Tong vinegar, abrasive mix, into the same direction twin screw extruder ( Thermo Fisher Scientific company MiniL oil) inside the hopper, screw extruder zone temperatures had been preheated to 230 ° C, a screw speed of 30 rpm, the material extruded from head die orifice, cooling the extrudate at room temperature, pulverized 180ym sieve through the aperture i.e. enteric solid dispersion.

[0109] 取本例中的肠溶固体分散体适量,按重量比白襲芦醇:微晶纤维素:低取代径丙基纤维素:硬脂酸儀=5 : 20 : 1 : 0.5的比例混合均匀,压制成片(旋转式压片机ZP-5, 上海天和制药机械有限公司)。 [0109] Take this embodiment an appropriate amount of enteric solid dispersion, the weight ratio of resveratrol white attack: microcrystalline cellulose: cellulose low-substituted propyl diameter: Stearic acid analyzer = ratio of 5: 0.5: 20: 1 mixed well and compressed into tablets (a rotary tableting machine ZP-5, Shanghai pharmaceutical Machinery Co. days).

[0110] 实施例2-3 阳111] 取班巧酸乙酸径丙基甲基纤维素(HPMCASAS-LF) 25g和40g分别溶于Ig含维生素C的2份丙酬溶液中,形成均一溶液;分别称取5g白襲芦醇溶解于上述溶液中,用Buchi minispray化yerB-290喷雾干燥除去有机溶剂分别得到白色粉末即为白襲芦醇:HPMCAS AS-LF为1 : 5和1 : 8的肠溶固体分散体,喷雾干燥过程中,物料溫度控制在50-55°C。 [0110] Example 2-3 male 111] acetic acid opportunely take classes diameter methylcellulose (HPMCASAS-LF) 25g and 40g, respectively, were dissolved in propan-pay Ig 2 parts of a solution containing vitamin C to form a homogeneous solution; Weigh 5g white passage resveratrol dissolved in the above solution, with a Buchi minispray yerB-290 spray drying of the organic solvent were removed to give a white powder that is white attack resveratrol: HPMCAS aS-LF 1: 5 and 1: 8 enteric solid dispersion, spray-drying process, the material temperature is controlled at 50-55 ° C. [0112] 分别取本例中的肠溶固体分散体适量,按重量比白襲芦醇:微晶纤维素:低取代径丙基纤维素:硬脂酸儀=5 : 20 : 1 : 0.5的比例混合均匀,压制成片(旋转式压片机ZP-5,上海天和制药机械有限公司)。 [0112] respectively, according to the present embodiment taken in an appropriate amount of the enteric solid dispersion, the weight ratio of resveratrol white attack: microcrystalline cellulose: Low-substituted hydroxypropylcellulose Diameter: Instrument stearate = 5: 20: 1: 0.5 the proportion of mixed and compressed into tablets (a rotary tableting machine ZP-5, Shanghai pharmaceutical Machinery Co. days). 阳11引实施例2-4 Example 2-4 Primer 11 male

[0114] 取径丙基甲基纤维素邻苯二甲酸醋HP-55(HPMCPHP-55)25g和40g,分别溶于Ig 含维生素C的2份丙酬溶液中,形成均一溶液;分别称取5g白襲芦醇溶解于上述溶液中, 用Buchiminispray化yerB-290喷雾干燥除去有机溶剂分别得到白色粉末即白襲芦醇:HPMCPHP-55为1 : 5和1 : 8的肠溶固体分散体,喷雾干燥过程中,物料溫度控制在50-55 °C。 [0114] taken diameter methylcellulose acetate phthalate HP-55 (HPMCPHP-55) 25g and 40g, respectively, was dissolved in propan-pay Ig 2 parts of a solution containing vitamin C to form a homogeneous solution; Weigh 5g white passage resveratrol dissolved in the above solution, with Buchiminispray yerB-290 spray drying of the organic solvent was removed to give a white powder and white, respectively, the passage of resveratrol: HPMCPHP-55 is 1: 5 and 1: 8 of the enteric solid dispersion, spray-drying process, the material temperature is controlled at 50-55 ° C.

[0115] 分别取本例中的肠溶固体分散体适量,按重量比白襲芦醇:微晶纤维素:低取代径丙基纤维素:硬脂酸儀=5 : 20 : 1 : 0.5的比例混合均匀,压制成片(旋转式压片机ZP-5,上海天和制药机械有限公司)。 [0115] respectively, according to the present embodiment taken in an appropriate amount of the enteric solid dispersion, the weight ratio of resveratrol white attack: microcrystalline cellulose: Low-substituted hydroxypropylcellulose Diameter: Instrument stearate = 5: 20: 1: 0.5 the proportion of mixed and compressed into tablets (a rotary tableting machine ZP-5, Shanghai pharmaceutical Machinery Co. days).

[0116] 实施例2-5 [0116] Example 2-5

[0117] 取40gPoloxamer188、lg维生素C充分分散、溶解于丙酬中,形成均一溶液,称取5g白襲芦醇溶解于上述溶液中,用Buchiminispray化yerB-290喷雾干燥除去有机溶剂得到白色粉末即为水溶固体分散体,喷雾干燥过程中,物料溫度控制在50-55°C。 [0117] Take 40gPoloxamer188, lg vitamin C sufficiently dispersed and dissolved in propan-paid form a homogenous solution, weighed 5g White passage resveratrol was dissolved in the solution, removed and dried Buchiminispray of yerB-290 spray an organic solvent to give a white powder that is solid dispersion is water-soluble, spray-drying process, the material temperature is controlled at 50-55 ° C.

[0118] 取本例中的水溶性非抑依赖型固体分散体适量,按重量比白襲芦醇:微晶纤维素:低取代径丙基纤维素:硬脂酸儀=5 : 20 : 1 : 0. 5的比例混合均匀,压制成片(旋转式压片机ZP-5,上海天和制药机械有限公司),用含HPMCASAS-LF的肠溶包衣溶液包衣(OHARA实验型高效包衣机),包衣增重为15重量%,得肠溶包衣片剂。 [0118] Take this embodiment the water-soluble non-inhibiting amount dependent solid dispersion, the weight ratio of resveratrol white attack: microcrystalline cellulose: Low-substituted hydroxypropylcellulose Diameter: Instrument stearate = 5: 20: 1 : 0.5 ratio of the mixed and compressed into tablets (a rotary tableting machine ZP-5, days Shanghai pharmaceutical Machinery Co.), coated with an enteric coating solution (OHARA containing experimental efficiency of HPMCASAS-LF clothes dryers), coating weight 15% by weight, to give enteric coated tablets. 其中肠溶包衣溶液中HPMCASAS-LF、巧樣酸S乙醋灯EC)、滑石粉、十二烷基硫酸钢分别占包衣溶液固含量重量的72%、11%、15%、2%。 Wherein the enteric coating solution HPMCASAS-LF, like Qiao acid ethyl ester S lamp EC), talc, sodium lauryl sulfate, 72% of the steel weight of the solids content of the coating solution, 11%, 15%, 2% .

[0119] 实施例2-6 [0119] Example 2-6

[0120] 取40gHPMCE5、lg维生素C充分分散、溶解于丙酬中,形成均一溶液,称取5g白襲芦醇溶解于上述溶液中,用Buchiminispray化yerB-290喷雾干燥除去有机溶剂得到白色粉末即为水溶固体分散体,喷雾干燥过程中,物料溫度控制在50-55 °C。 [0120] Take 40gHPMCE5, lg vitamin C sufficiently dispersed and dissolved in propan-paid form a homogenous solution, weighed 5g White passage resveratrol was dissolved in the solution, removed and dried Buchiminispray of yerB-290 spray an organic solvent to give a white powder that is solid dispersion is water-soluble, spray-drying process, the material temperature is controlled at 50-55 ° C. 阳12U 取本例中的水溶性非抑依赖型固体分散体适量,按重量比白襲芦醇:微晶纤维素:低取代径丙基纤维素:硬脂酸儀=5 : 20 : 1 : 0. 5的比例混合均匀,压制成片(旋转式压片机ZP-5,上海天和制药机械有限公司),用含HPMCASAS-LF的肠溶包衣溶液包衣(OHARA实验型高效包衣机),包衣增重为15重量%,得肠溶包衣片剂。 Take the present embodiment the male 12U soluble in the non-suppressing amount dependent solid dispersion, the weight ratio of resveratrol white attack: microcrystalline cellulose: Low-substituted hydroxypropylcellulose Diameter: Instrument stearate = 5: 20: 1: ratio of 0.5 mixed and compressed into tablets (a rotary tableting machine ZP-5, days Shanghai pharmaceutical Machinery Co.), coated with an enteric coating solution containing the HPMCASAS-LF (OHARA experimental efficient coating machine), a coating weight gain of 15% by weight, to give enteric coated tablets. 其中肠溶包衣溶液中HPMCASAS-LF、TEC、滑石粉、十二烷基硫酸钢分别占包衣溶液固含量重量的72%、11 %、 15%、2%。 Wherein the enteric coating solution HPMCASAS-LF, TEC, talc, sodium lauryl sulfate, 72% of the steel weight of the solids content of the coating solution, 11%, 15%, 2%. 阳122] 实施例3-1 Male 122] Example 3-1

[0123] 取lOg班巧酸乙酸径丙基甲基纤维素(HPMCASAS-L巧充分分散、溶解于丙酬中, 形成均一溶液,称取5g稱黑素溶解于上述溶液中,用Buchiminispray化yerB-290喷雾干燥除去有机溶剂得到白色粉末即为肠溶固体分散体,喷雾干燥过程中,物料溫度控制在50-55 °C。 [0123] Qiao classes taking lOg diameter acetic acid methylcellulose (HPMCASAS-L Qiao sufficiently dispersed and dissolved in propan-paid form a homogenous solution, called melanocytes Weigh 5g dissolved in the above solution, with Buchiminispray of yerB -290 spray drying the organic solvent was removed to give a white powder that is an enteric solid dispersion, spray-drying process, the material temperature is controlled at 50-55 ° C.

[0124] 取本例中的肠溶固体分散体适量,按重量比稱黑素:微晶纤维素:低取代径丙基纤维素:硬脂酸儀=5 : 20 : 1 : 1的比例混合均匀,压制成片(旋转式压片机ZP-5,上海天和制药机械有限公司)。 [0124] Take this embodiment an appropriate amount of enteric solid dispersion, the weight ratio of said melanin: microcrystalline cellulose: Low-substituted hydroxypropylcellulose Diameter: Instrument stearate = 5: 20: 1: 1 ratio uniform and compressed into tablets (a rotary tableting machine ZP-5, Shanghai pharmaceutical Machinery Co. days). 阳125] 实施例3-2 阳1%] 取15g班巧酸乙酸径丙基甲基纤维素(HPMCASAS-L巧充分分散、溶解于丙酬中, 形成均一溶液,称取5g稱黑素溶解于上述溶液中,用Buchiminispray化yerB-290喷雾干燥除去有机溶剂得到白色粉末即为肠溶固体分散体,喷雾干燥过程中,物料溫度控制在50-55 °C。 Male 125] Example 3-2 1% male] Take 15g acetic acid classes Qiao diameter methylcellulose (HPMCASAS-L Qiao sufficiently dispersed and dissolved in propan-paid form a homogenous solution, weighed called melanin dissolved 5g in the solution, with Buchiminispray yerB-290 spray drying of the organic solvent was removed to give a white powder that is an enteric solid dispersion, spray-drying process, the material temperature is controlled at 50-55 ° C.

[0127] 取本例中的肠溶固体分散体适量,按重量比稱黑素:微晶纤维素:低取代径丙基纤维素:硬脂酸儀=5 : 20 : 1 : 1的比例混合均匀,压制成片(旋转式压片机ZP-5,上海天和制药机械有限公司)。 [0127] Take this embodiment an appropriate amount of enteric solid dispersion, the weight ratio of said melanin: microcrystalline cellulose: Low-substituted hydroxypropylcellulose Diameter: Instrument stearate = 5: 20: 1: 1 ratio uniform and compressed into tablets (a rotary tableting machine ZP-5, Shanghai pharmaceutical Machinery Co. days). 阳12引实施例3-3 Example 3-3 Primer 12 male

[0129] 取25g班巧酸乙酸径丙基甲基纤维素(HPMCASAS-L巧充分分散、溶解于丙酬中, 形成均一溶液,称取5g稱黑素溶解于上述溶液中,用Buchiminispray化yerB-290喷雾干燥除去有机溶剂得到白色粉末即为肠溶固体分散体,喷雾干燥过程中,物料溫度控制在50-55 °C。 [0129] Take 25g acetic acid classes Qiao diameter methylcellulose (HPMCASAS-L Qiao sufficiently dispersed and dissolved in propan-paid form a homogenous solution, called melanocytes Weigh 5g dissolved in the above solution, with Buchiminispray of yerB -290 spray drying the organic solvent was removed to give a white powder that is an enteric solid dispersion, spray-drying process, the material temperature is controlled at 50-55 ° C.

[0130] 取本例中的肠溶固体分散体适量,按重量比稱黑素:微晶纤维素:低取代径丙基纤维素:硬脂酸儀=5 : 20 : 1 : 1的比例混合均匀,压制成片(旋转式压片机ZP-5,上海天和制药机械有限公司)。 [0130] Take this embodiment an appropriate amount of enteric solid dispersion, the weight ratio of said melanin: microcrystalline cellulose: Low-substituted hydroxypropylcellulose Diameter: Instrument stearate = 5: 20: 1: 1 ratio uniform and compressed into tablets (a rotary tableting machine ZP-5, Shanghai pharmaceutical Machinery Co. days).

[0131] 实施例3-4 阳132] 取25g班巧酸乙酸径丙基甲基纤维素(HPMCASAS-LF)、5g稱黑素,研磨混匀,投入到同向双螺杆挤出机(赛默飞世尔科技公司MiniL油)加料斗内,螺杆挤出区段溫度已预热至150°C,螺杆转速为30rpm,物料由机头模孔W透明条状物挤出,盛接于不诱钢盘中,室溫冷却,粉碎后过180ym孔径筛网即得固体分散体。 [0131] Example 3-4 male 132] Take 25g acetic acid classes Qiao diameter methylcellulose (HPMCASAS-LF), 5g said melanin, grinding and mix into the same direction twin screw extruder (Race Thermo Fisher Scientific MiniL oil) within the hopper, screw extruder zone temperatures had been preheated to 150 ° C, a screw speed of 30 rpm, the material W by the head die orifice strips extruded transparent, not connected to Sheng induced steel plate, cooled to room temperature, pulverized to obtain a mesh aperture through 180ym solid dispersion.

[0133] 取本例中的肠溶固体分散体适量,按重量比稱黑素:微晶纤维素:低取代径丙基纤维素:硬脂酸儀=5 : 20 : 1 : 1的比例混合均匀,压制成片(旋转式压片机ZP-5,上海天和制药机械有限公司)。 [0133] Take this embodiment an appropriate amount of enteric solid dispersion, the weight ratio of said melanin: microcrystalline cellulose: Low-substituted hydroxypropylcellulose Diameter: Instrument stearate = 5: 20: 1: 1 ratio uniform and compressed into tablets (a rotary tableting machine ZP-5, Shanghai pharmaceutical Machinery Co. days). 阳134] 实施例3-5 Male 134] Example 3-5

[0135] 取50g班巧酸乙酸径丙基甲基纤维素(HPMCASAS-L巧充分分散、溶解于丙酬中, 形成均一溶液,称取5g稱黑素溶解于上述溶液中,用Buchiminispray化yerB-290喷雾干燥除去有机溶剂得到白色粉末即为肠溶固体分散体,喷雾干燥过程中,物料溫度控制在50-55 °C。 [0135] Take 50g acetic acid classes Qiao diameter methylcellulose (HPMCASAS-L Qiao sufficiently dispersed and dissolved in propan-paid form a homogenous solution, called melanocytes Weigh 5g dissolved in the above solution, with Buchiminispray of yerB -290 spray drying the organic solvent was removed to give a white powder that is an enteric solid dispersion, spray-drying process, the material temperature is controlled at 50-55 ° C.

[0136] 取本例中的肠溶固体分散体适量,按重量比稱黑素:微晶纤维素:低取代径丙基纤维素:硬脂酸儀=5 : 20 : 1 : 1的比例混合均匀,压制成片(旋转式压片机ZP-5,上海天和制药机械有限公司)。 [0136] Take this embodiment an appropriate amount of enteric solid dispersion, the weight ratio of said melanin: microcrystalline cellulose: Low-substituted hydroxypropylcellulose Diameter: Instrument stearate = 5: 20: 1: 1 ratio uniform and compressed into tablets (a rotary tableting machine ZP-5, Shanghai pharmaceutical Machinery Co. days). 阳137] 实施例3-6 Male 137] Example 3-6

[0138] 取25g化化agitL100-55充分分散、溶解于丙酬中,形成均一溶液,称取5g稱黑素溶解于上述溶液中,用Buchiminispray化yerB-290喷雾干燥除去有机溶剂得到白色粉末即为肠溶固体分散体,喷雾干燥过程中,物料溫度控制在50-55°C。 [0138] Take 25g of agitL100-55 of well dispersed and dissolved in propan-paid form a homogenous solution, called melanocytes Weigh 5g dissolved in the solution, removed and dried Buchiminispray yerB-290 spray of the organic solvent to give a white powder that is enteric solid dispersion, spray-drying process, the material temperature is controlled at 50-55 ° C.

[0139] 取本例中的肠溶固体分散体适量,按重量比稱黑素:微晶纤维素:低取代径丙基纤维素:硬脂酸儀=5 : 20 : 1 : 1的比例混合均匀,压制成片(旋转式压片机ZP-5,上海天和制药机械有限公司)。 [0139] Take this embodiment an appropriate amount of enteric solid dispersion, the weight ratio of said melanin: microcrystalline cellulose: Low-substituted hydroxypropylcellulose Diameter: Instrument stearate = 5: 20: 1: 1 ratio uniform and compressed into tablets (a rotary tableting machine ZP-5, Shanghai pharmaceutical Machinery Co. days). 阳140] 实施例3-7 阳141] 取25g径丙基甲基纤维素邻苯二甲酸醋HP-55(HPMCPHP-55)充分分散、溶解于丙酬中,形成均一溶液,称取5g稱黑素溶解于上述溶液中,用Buchiminispray化yerB-290 喷雾干燥除去有机溶剂得到白色粉末即为肠溶固体分散体,喷雾干燥过程中,物料溫度控制在50-55 °C。 Male 140] Example 3-7 male 141] 25g embodiment taken diameter methylcellulose acetate phthalate HP-55 (HPMCPHP-55) sufficiently dispersed and dissolved in propan-paid form a homogenous solution, said Weigh 5g melanin is dissolved in the solution, with Buchiminispray yerB-290 spray drying of the organic solvent was removed to give a white powder that is an enteric solid dispersion, spray-drying process, the material temperature is controlled at 50-55 ° C.

[0142] 取本例中的肠溶固体分散体适量,按重量比稱黑素:微晶纤维素:低取代径丙基纤维素:硬脂酸儀=5 : 20 : 1 : 1的比例混合均匀,压制成片(旋转式压片机ZP-5,上海天和制药机械有限公司)。 [0142] Take this embodiment an appropriate amount of enteric solid dispersion, the weight ratio of said melanin: microcrystalline cellulose: Low-substituted hydroxypropylcellulose Diameter: Instrument stearate = 5: 20: 1: 1 ratio uniform and compressed into tablets (a rotary tableting machine ZP-5, Shanghai pharmaceutical Machinery Co. days). 阳143] 实施例3-8 Male 143] Example 3-8

[0144] 取25g阳G4000分散、溶解于丙酬中,形成均一溶液,称取5g稱黑素溶解于上述溶液中,用Buchiminispray化yerB-290喷雾干燥除去有机溶剂得到白色粉末即为水溶性非pH依赖型固体分散体,喷雾干燥过程中,物料溫度控制在50-55°C。 [0144] Take 25g male G4000 dispersed and dissolved in propan-paid form a homogenous solution, called melanocytes Weigh 5g dissolved in the above solution, with Buchiminispray yerB-290 Spray drying of the organic solvent was removed to give a white powder that is water soluble non- pH-dependent solid dispersion, spray-drying process, the material temperature is controlled at 50-55 ° C.

[0145] 取本例中的水溶性非抑依赖型固体分散体适量,按重量比稱黑素:微晶纤维素:低取代径丙基纤维素:硬脂酸儀=5 : 20 : 1 : 1的比例混合均匀,压制成片(旋转式压片机ZP-5,上海天和制药机械有限公司),用含HPMCASAS-LF的肠溶包衣溶液包衣(OHARA实验型高效包衣机),包衣增重为15重量%,得肠溶包衣片剂。 [0145] Take this embodiment the water-soluble non-inhibiting amount dependent solid dispersion, the weight ratio of said melanin: microcrystalline cellulose: Low-substituted hydroxypropylcellulose Diameter: Instrument stearate = 5: 20: 1: 1 ratio mixed and compressed into tablets (a rotary tableting machine ZP-5, days Shanghai pharmaceutical Machinery Co.), coated with an enteric coating solution containing the HPMCASAS-LF (OHARA experimental efficiency coating machine) , a coating weight gain of 15% by weight, to give enteric coated tablets. 其中肠溶包衣溶液中HPMCASAS-LF、TEC、滑石粉、十二烷基硫酸钢分别占包衣溶液固含量重量的72%、11 %、 15%、2%。 Wherein the enteric coating solution HPMCASAS-LF, TEC, talc, sodium lauryl sulfate, 72% of the steel weight of the solids content of the coating solution, 11%, 15%, 2%. 阳146] 试验例1 阳147] 由于番茄红素在0. 1M盐酸、水、pH6. 8憐酸盐缓冲液介质中几乎不溶解,首先测定其固体分散体的水溶解度。 Male 146] Test Example 1 147 male] Since lycopene in 0. 1M hydrochloric acid, water, pH6. 8 pity medium salt buffer practically insoluble, first determining water-solubility of a solid dispersion.

[0148] 实验方法如下:取过量的番茄红素固体分散体置于10ml0. 1M盐酸或抑6.8 憐酸盐缓冲液,于37 °C水浴超声30min,用0. 45ym孔径尼龙滤膜滤头过滤,续滤液HPLC(Agilent1200高效液相色谱仪)进样测定。 [0148] Experiment method is as follows: taking an excess of solid dispersion was placed lycopene 10ml0 1M hydrochloric acid buffer suppressor 6.8 Rei, 30min, filtered through a nylon filter pore size of 0. 45ym frit bath sonicator at 37 ° C. , the filtrate HPLC (Agilent1200 HPLC) assay sample.

[0149] 含量和溶解度测定方法采用高效液相色谱法,流动相为100%乙腊,检测波长为472皿,流速2.Oml/min,柱溫30°C,色谱柱是柱(150X4. 6mm,5ym),番茄红素色谱保留时间为13min。 [0149] content and solubility determination by HPLC, mobile phase B was 100% wax, the detection wavelength was 472 dish, a flow rate of 2.Oml / min, column temperature 30 ° C, the column is a column (150X4. 6mm , 5ym), lycopene retention time of 13min. 采用外标法计算。 Calculated using the external standard method. 测定结果见表1-1。 The measurement results are shown in Table 1-1.

[0150] 表1-1不同的肠溶固体制剂中番茄红素在P册.8憐酸盐缓冲液的溶解度(HPLC法测定) [0150] Table 1-1 different enteric solid formulations of lycopene in the P register .8 pity solubility salt buffer (HPLC method)

[0151] [0151]

Figure CN105213316AD00171

[0152] 由表1-1的溶解度结果可知,固体分散体技术对番茄红素具有增溶作用,由于载体的不同,增溶效果也不一样,HPMCASAS-LF对番茄红素的增溶作用较差,而载体Soluplus、HPMCPHP-55的增溶效果较好;加入表面活性剂后增溶效果更明显。 [0152] Solubility is apparent from the results of Table 1-1, the solid dispersion technology solubilization of lycopene, due to the different carriers, solubilizing effect is not the same, HPMCASAS-LF solubilization of lycopene than difference and the carrier Soluplus, solubilizing effect is preferably HPMCPHP-55; after addition of the surfactant is more effective solubilization. 阳153] 分别取表1-1中实施例1-4的2个固体分散体样品,按番茄红素:微晶纤维素: 低取代径丙基纤维素:硬脂酸儀=5 : 2 : 1 : 0.5的比例混合压片(旋转式压片机ZP-5, 上海天和制药机械有限公司),用含HPMCASAS-LF的肠溶包衣溶液包衣(OHARA实验型高效包衣机),包衣增重为15重量%,得到样品1和样品2,待测溶出度。 Male 153] were collected in Table 1-4 Example 2 The solid dispersion of Sample 1-1, lycopene by: microcrystalline cellulose: Low-substituted hydroxypropylcellulose Diameter: Instrument stearate = 5: 2: 1: 0.5 ratio mixture of tableting (rotary tableting machine ZP-5, days Shanghai pharmaceutical Machinery Co.), coated with an enteric coating solution containing the HPMCASAS-LF (OHARA experimental efficiency coating machine), coating weight gain of 15% by weight, to give 2, the test samples 1 and dissolution. 其中肠溶包衣溶液中HPMCASAS-LF、TEC、滑石粉、十二烷基硫酸钢分别占包衣溶液固含量重量的72%、11 %、 15%、2%。 Wherein the enteric coating solution HPMCASAS-LF, TEC, talc, sodium lauryl sulfate, 72% of the steel weight of the solids content of the coating solution, 11%, 15%, 2%.

[0154] 本发明采用体外溶出度实验模拟药物在胃肠道内的溶出过程,实验方法如下:参照中国药典附录2005版XD释放度测定第二法(用于肠溶制剂)测定,溶出介质为750ml0. 1M盐酸,转速为l(K)r/min,溫度为37°C±0. 5°C,于溶出45分钟时取样5ml,过滤弃去1ml初滤液,取续滤液,HPLC法进样测定在0. 1M盐酸的溶出度(Agilent1200高效液相色谱仪),并迅速补充同溫等体积溶出介质,同时加入250ml0. 2M憐酸钢溶液,用2M氨氧化钢溶液调节抑至6. 8 + 0. 05,于60min时间点取样5ml并迅速补充同溫同体积抑6. 8憐酸盐缓冲液,测定在抑6. 8憐酸盐缓冲液的溶出度。 [0154] The present invention employs the stripping process, the experimental methods in vitro dissolution experiments simulated medicament in the gastrointestinal tract as follows: determining a second method with reference to Chinese Pharmacopoeia 2005 Appendix XD release (enteric preparation for) determining the dissolution medium 750ml0 . 1M hydrochloric acid, the rotation speed of l (K) r / min, a temperature of 37 ° C ± 0. 5 ° C, the sample 5ml in 45 minutes elution, filtered discarded early to 1ml filtrate, the filtrate, HPLC method the sample measured dissolution in 0. 1M hydrochloric acid (Agilent 1200 high performance liquid chromatography), and quickly added with an equal volume of dissolution medium temperature, while adding 250ml0. 2M steel pity acid solution, adjusted with 2M ammonia to suppress oxidation of the steel was 6.8 + 0.05, sampled at the time point 60min and quickly added 5ml same temperature and 6.8 volume suppression pity salt buffer, measured in dissolution suppressing salt Rei 6.8 buffer. 结果见表1-2。 The results are shown in Table 1-2. 阳155] 表1-2番茄红素肠溶固体制剂的累积溶出度标示百分含量(% )测定结果表阳巧6] Male 155] Table 1-2 Fan cumulative dissolution of lycopene enteric solid formulations indicated percentages (%) The measurement results in Table 6 male clever]

Figure CN105213316AD00181

阳157]试验例2 Male 157] Test Example 2

[0158] 本发明采用体外溶出度实验模拟白襲芦醇在胃肠道内的溶出过程,实验方法如下:参照中国药典附录XD释放度测定第二法(用于肠溶制剂)测定,溶出介质为750ml 0. 1M盐酸,转速为l(K)r/min,溫度为37°C±0. 5°C,于溶出45分钟时取样5ml,过滤弃去1ml初滤液,取续滤液,HPLC法进样测定在0. 1M盐酸的溶出度(Agilent1200高效液相色谱仪),并迅速补充同溫等体积溶出介质,同时加入250ml0. 2M憐酸钢溶液,用2M氨氧化钢溶液调节抑到6. 8 + 0. 05,分别于0.化、Ih时间点取样5ml并迅速补充同溫同体积抑6. 8 憐酸盐缓冲液,测定在P册.8憐酸盐缓冲液的溶出度。 [0158] The present invention, in vitro dissolution experiments simulated the dissolution process resveratrol white attack, the experimental methods in the gastrointestinal tract as follows: with reference to Appendix XD Pharmaceutical China second release determination method (for enteric formulation) was measured, as the dissolution medium 750ml 0. 1M hydrochloric acid, the rotation speed of l (K) r / min, a temperature of 37 ° C ± 0. 5 ° C, in 45 minutes eluted sample 5ml, 1ml filtrate was filtered to discard First, the filtrate, HPLC method into sample dissolution measured at 0. 1M hydrochloric acid (Agilent 1200 high performance liquid chromatography), and quickly added with an equal volume of dissolution medium temperature, while adding 250ml0. 2M steel pity acid solution, adjusted with 6 to suppress oxidation of the steel 2M ammonia solution. 8 + 0.05, respectively, of 0.5, Ih is the sampling time and quickly added 5ml same temperature and 6.8 volume suppression pity salt buffer, dissolution measured P .8 volumes of salt buffer at Rei. 结果见表2-1。 The results are shown in Table 2-1.

[0159] 白襲芦醇的含量和溶出度测定方法采用高效液相色谱法,流动相为27/73 (v/v) 乙腊/7长,检测波长为303nm,流速1.0ml/min,柱溫30°C,色谱柱是Cl迪(250X4. 6mm, 5ym),白襲芦醇色谱保留时间为10. 356min。 [0159] Determination of Content and dissolution white passage resveratrol HPLC using a mobile phase of 27/73 (v / v) acetic wax / 7 long, the detection wavelength was 303nm, flow rate 1.0ml / min, Column temperature 30 ° C, the column is Cl di (250X4. 6mm, 5ym), white passage resveratrol chromatographic retention time of 10. 356min. 采用外标法计算。 Calculated using the external standard method.

[0160] 表2-1白襲芦醇肠溶固体制剂的累积溶出度标示百分含量(% )测定结果表 [0160] Table 2-1 cumulative dissolution rate of the enteric solid formulations white passage resveratrol Flag percentage (%) Results of measurement table

[0161] [0161]

Figure CN105213316AD00191

阳162] 由表2-1的溶出度结果可知:相同载体和相同比例下不同制备方法即喷雾干燥法与热烙法制备增溶效果相似,如见实施例2-1和2-2的溶出结果;当载体为HPMCASAS-LF、 HPMCPHP-55、化loxamer188时,白襲芦醇的肠溶固体制剂既能增溶又能控制白襲芦醇在酸中少量释放;药物与肠溶载体HPMCASAS-LF重量比在1 : 2至1 : 8均能很好地达到对白襲芦醇增溶的作用;HPMCE5作为载体有增溶作用但增溶效果不明显。 Male 162] can be seen from the dissolution results of Table 2-1: the same carrier and the same proportion of Preparation Method i.e. thermal spray drying method similar to Preparation baked solubilizing effects, such as dissolution see Examples 2-1 and 2-2 result; when the carrier is HPMCASAS-LF, HPMCPHP-55, time of loxamer188, enteric solid formulations of resveratrol white passage solubilizing both white and can control the passage of a small amount of resveratrol in acid release; pharmaceutical carrier and an enteric HPMCASAS- LF weight ratio of 1: 2 to 1: 8 were well achieve the passage of white resveratrol effect solubilization; HPMCE5 solubilization as carriers are, but solubilizing effect is not obvious.

[0163] 表2-2白襲芦醇肠溶固体制剂的稳定性考察有关物质测定结果表 [0163] TABLE 2-2 Stability of enteric white solid formulation passage resveratrol measurement result table related substances

[0164] [0164]

Figure CN105213316AD00192

阳1化]由表2-2考察数据可看出,白襲芦醇与载体HPMCASAS-LF、HPMCPHP-55、 Poloxamer188制备的肠溶固体制剂稳定性好,同时也表明白襲芦醇与载体HPMCASAS-LF、HPMCPHP-55、化loxamer188 相容性均很好。 1 of the male] As can be seen from Table 2-2 inspection data, the passage of white resveratrol carrier HPMCASAS-LF, HPMCPHP-55, Poloxamer188 enteric solid formulations produced good stability, but also the passage of the table to understand the carrier resveratrol HPMCASAS -LF, HPMCPHP-55, of loxamer188 compatibility are very good.

[0166] 试验例3 [0166] Test Example 3

[0167] 本发明采用体外溶出度实验模拟药物在胃肠道内的溶出度,实验方法如下: [0167] The present invention employs the dissolution experiment vitro dissolution experiments simulated medicament in the gastrointestinal tract as follows:

[0168] 本发明采用体外溶出度实验模拟稱黑素在胃肠道内的溶出过程,实验方法如下: 参照中国药典附录XD释放度测定第二法(用于肠溶制剂)测定,溶出介质为750ml0. 1M 盐酸,转速为l(K)r/min,溫度为37°C±0. 5°C,于溶出60分钟时取样5ml,过滤弃去1ml初滤液,取续滤液,HPLC法进样测定在0. 1M盐酸的溶出度(Agilent1200高效液相色谱仪), 并迅速补充同溫等体积溶出介质,同时加入250ml0. 2M憐酸钢溶液,用2M氨氧化钢溶液调节抑到6. 8 + 0. 05,分别于30分钟、60分钟时间点取样5ml并迅速补充同溫同体积抑6. 8 憐酸盐缓冲液,测定在抑6. 8憐酸盐缓冲液的溶出度。 [0168] The present invention is simulated in vitro dissolution test known as the dissolution process of melanin, the experimental methods in the gastrointestinal tract as follows: Determination of determining a second reference to Appendix XD release Chinese Pharmacopoeia (for enteric formulation), as dissolution medium 750ml0 . 1M hydrochloric acid, the rotation speed of l (K) r / min, a temperature of 37 ° C ± 0. 5 ° C, the sample 5ml in 60 minutes elution, filtered discarded early to 1ml filtrate, the filtrate, HPLC method the sample measured dissolution in 0. 1M hydrochloric acid (Agilent 1200 high performance liquid chromatography), and quickly added with an equal volume of dissolution medium temperature, while adding 250ml0. 2M steel pity acid solution, adjusted with 2M ammonia to suppress oxidation of the steel was 6.8 + 0.05, respectively, at 30 minutes, 60 minutes 5ml sampling time point and the volume of the same temperature and quickly added 6.8 Rei suppression salt buffer, measured in dissolution suppressing salt Rei 6.8 buffer. 实验结果见表3-1。 The results are shown in Table 3-1.

[0169] 表3-1稱黑素固体分散体累积溶出度标示百分含量(% )测定结果表阳170] [0169] Table 3-1 called melanosomes accumulation of solid dispersions dissolution Flag and percent (%) positive measurement results in Table 170]

Figure CN105213316AD00201

阳171]由表3-1的溶出度结果可知:相同载体和相同比例(实施例3-3与3-4)下不同制备方法即喷雾干燥法与热烙法制备增溶效果一样;当载体为HPMCASAS-LF、化化agit L100-55、HPMCPHP-55、Poloxamer188时,稱黑素的肠溶固体制剂既能增溶又能控制稱黑素在酸中少量释放;药物与肠溶载体HPMCASAS-LF重量比在1 : 2到1 : 10均能很好地达到对稱黑素增溶的作用。 Male 171] can be seen from the dissolution results of Table 3-1: the same carrier and the same proportion (Example 3-3 and 3-4) Preparation Method i.e. spray drying method and the heat seared the same legal effect solubilization standby; when the vector is HPMCASAS-LF, technology of agit L100-55, HPMCPHP-55, Poloxamer188, the said enteric solid formulations of melanin can control both solubilizing said melanocytes in a small amount of acid release; pharmaceutical carrier and an enteric HPMCASAS- LF weight ratio of 1: 2 through 1:10 can achieve a good solubilization of the melanin symmetrical effect. 阳172]表3-2稱黑素肠溶固体制剂的稳定性考察有关物质测定结果表阳173] Male 172] Table 3-2 Stability of enteric solid formulations known melanocyte related substances determination result table 173 male]

Figure CN105213316AD00211

阳174] 由表3-2考察数据可看出,稱黑素与载体HPMCAS AS-LF、HPMCP HP-55制备的肠溶固体制剂稳定性好,同时也表明白襲芦醇与载体HPMCAS AS-LF、HPMCP HP-55相容性均很好。 Male 174] As can be seen from Table 3-2 inspection data, said carrier melanin HPMCAS AS-LF, enteric solid formulations HPMCP HP-55 prepared in good stability, but also the passage of the table to understand the carrier resveratrol HPMCAS AS- LF, HPMCP HP-55 compatibility are very good.

[01巧]本发明实施例和试验例中所使用的药物、载体辅料和其它辅料均是市售可得的, 其中番茄红素原料购自华北制药有限公司的产品(批号100503)、白襲芦醇原料购自长沙惠瑞生物科技有限公司的产品(批号100125)、稱黑素原料为浙江黄岩延年稱黑素有限公司生产的赠送样品(批号100920);化化agitL10055是Degussa公司生产的赠送样品(批号B060904025);HPMCASAS-LF购自日本信越化学工业株式会社生产的产品HPMCAS AS-LF(批号9013010),HPMCPHP-55购自日本信越化学工业株式会社生产的产品HPMCP HP-55 (批号7091249),KollidoneVA64 为BASF公司生产的赠送样品KollidoneVA64, 阳G4000购自国药集团化学试剂有限公司的产品阳G4000 (批号T20090312),Po1oxamer188 为BASF公司生产的赠送样品Poloxame;rl88(批号WPMD507C)、Soluplus、Cremo地orRH40、 化emo地or化均为BASF公司生产的赠送样品(批号分别为20777268E0、8968907化0 [Qiao 01] Test Examples and Examples drugs used in the embodiment of the present invention, the carrier and other adjuvants are commercially available materials, wherein the product obtained from the lycopene source (lot 100503) North China Pharmaceutical Co., Ltd., white passage resveratrol raw materials purchased from Changsha-Swiss biotechnology Co., Ltd. products (lot number 100125), called melanocytes presented samples of raw materials in Zhejiang Huangyan Yan said the production of melanin, Ltd. (lot number 100920); technology of agitL10055 is produced by Degussa gift samples (batch number B060904025); HPMCASAS-LF purchased from Shin-Etsu chemical Co., Ltd. products HPMCAS AS-LF (lot number 9013010), HPMCPHP-55 was purchased from Shin-Etsu chemical Co., Ltd. products HPMCP HP-55 (lot 7091249), KollidoneVA64 is manufactured by BASF presented sample KollidoneVA64, Yang G4000 purchased from Sinopharm chemical reagent Co., Ltd. Yang G4000 product (batch number T20090312), Po1oxamer188 is manufactured by BASF presented sample Poloxame; rl88 (lot WPMD507C), Soluplus, Cremo to orRH40, of land or of emo are available from BASF AG presented sample (lot number were 20777268E0,8968907 of 0 92273309T0),微晶纤维素购自山东曲阜天利药用辅料有限公司生产的产品(批号080904),低取代径丙基纤维素为湖州展望药业有限公司赠送的产品(批号20100221),硬脂酸儀购自安徽山河药用辅料有限公司生产的产品(批号090401),其它所使用的辅料也是本领域技术人员已知的。 92273309T0), microcrystalline cellulose available from Qufu Tianli medicinal materials Co., Ltd. products (lot 080904), low-substituted hydroxypropylcellulose diameter Prospect Get Pharmaceutical Co. product (batch 20100221) Huzhou, stearyl acid analyzer available from rivers Anhui pharmaceutical product materials Co. (lot 090401), are also used with other materials to the skilled artisan.

Claims (24)

  1. 1. 一种肠溶固体制剂,其含有作为活性成分的褪黑素和肠溶性载体,其中所述肠溶性载体与所述活性成分以肠溶固体分散体形式存在于制剂中。 An enteric solid formulations containing melatonin as an active ingredient and an enteric carrier, wherein the enteric carrier and the active ingredient is present in the formulation in an enteric solid dispersion.
  2. 2. 根据权利要求1所述的肠溶固体制剂,其中所述肠溶性载体为一种或多种选自以下组中的肠溶性聚合物:乙酸邻苯二甲酸纤维素、乙酸偏苯三酸纤维素、乙酸琥珀酸纤维素、 邻苯二甲酸甲基纤维素、邻苯二甲酸乙基羟甲基纤维素、邻苯二甲酸羟丙基甲基纤维素、乙酸琥珀酸羟丙基甲基纤维素、乙酸马来酸羟丙基甲基纤维素、偏苯三酸羟丙基甲基纤维素、 羧甲基乙基纤维素、聚丁酸乙烯邻苯二甲酸酯、聚乙酸乙烯醇邻苯二甲酸酯、甲基丙烯酸/ 丙烯酸乙酯共聚物和甲基丙烯酸/甲基丙烯酸甲酯共聚物,优选乙酸琥珀酸羟丙基甲基纤维素、EudragitL100-55和/或邻苯二甲酸羟丙基甲基纤维素。 2. enteric solid preparation according to claim 1, wherein the enteric carrier is one or more selected from the group of enteric polymer: acetate phthalate, cellulose acetate trimellitate cellulose, cellulose acetate succinate, methylcellulose phthalate, hydroxymethyl ethyl cellulose phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate cellulose, hydroxypropyl methyl cellulose acetate, maleic acid, trimellitic acid, hydroxypropyl methyl cellulose, carboxymethyl ethyl cellulose, polyvinyl butyrate phthalate, polyvinyl acetate alcohol phthalate, methacrylic acid / ethyl acrylate copolymer and methacrylic acid / methyl methacrylate copolymer, hydroxypropyl methylcellulose acetate succinate, preferably, Eudragit L100-55 and / or phthalimido acid hydroxypropyl methylcellulose.
  3. 3. 根据权利要求1所述的肠溶固体制剂,其中所述肠溶性载体是乙酸琥珀酸羟丙基甲基纤维素和/或邻苯二甲酸羟丙基甲基纤维素。 3. enteric solid preparation according to claim 1, wherein said carrier is an enteric hydroxypropyl methylcellulose acetate succinate and / or hydroxypropylmethylcellulose phthalate.
  4. 4. 根据权利要求1或2所述的肠溶固体制剂,其中所述活性成分与所述肠溶性载体的重量比为1 : 1-1 : 20。 The enteric-coated solid preparation of claim 1 or claim 2, wherein said active ingredient by weight of the enteric carrier ratio of 1: 1-1: 20.
  5. 5. 根据权利要求1或2所述的肠溶固体制剂,其中所述活性成分褪黑素在0.IM盐酸中的60分钟溶出度不大于25%,优选不大于15%,在pH6. 8磷酸盐缓冲液中的30分钟溶出度各不低于80 %,优选不低于90 %。 The enteric-coated solid preparation of claim 1 or claim 2, wherein the active ingredient melatonin 60 minutes 0.IM dissolution in hydrochloric acid is not more than 25%, preferably not more than 15%, at pH6. 8 dissolution of 30 minutes each in phosphate buffered saline is not less than 80%, preferably not less than 90%.
  6. 6. 根据权利要求1所述的肠溶固体制剂,其进一步包含其它药用辅料以制成片剂、胶囊剂、颗粒剂、散剂或微丸。 The enteric-coated solid preparation according to claim 1, which further comprises other pharmaceutical excipients in the form of tablets, capsules, granules, powders or pellets.
  7. 7. 根据权利要求6所述的肠溶固体制剂,其中所述的其它药用辅料包括稀释剂、崩解剂、润滑剂、抗氧剂中的一种或多种。 7. enteric solid preparation according to claim 6, wherein said other pharmaceutical excipients include one or more diluents, disintegrants, lubricants, antioxidants in.
  8. 8. 根据权利要求1所述肠溶固体制剂的制备方法,其包括将所述的活性成分和肠溶性载体溶于溶剂中,除去溶剂以得到肠溶固体分散体。 8. The method of claim 1 prepared according to claim enteric solid formulation which comprises the active ingredient and an enteric carrier dissolved in a solvent, the solvent was removed to give an enteric solid dispersion.
  9. 9. 根据权利要求1所述的肠溶固体制剂的制备方法,其包括将所述的活性成分和肠溶性载体混匀后加热至熔融,然后将其冷冻干燥或热熔挤出制得肠溶固体分散体。 9. A method for preparing an enteric solid preparation according to claim 1, comprising the active ingredient and the enteric heated to a molten carrier, after mixing, and then lyophilized to obtain an enteric or hot melt extrusion Solid dispersion.
  10. 10. -种肠溶固体制剂,其含有作为活性成分的褪黑素,以及肠溶性载体和水溶性载体,其中所述水溶性载体与所述活性成分以水溶固体分散体形式存在于所述制剂中,并且在固体制剂外层包覆含有肠溶性载体的肠溶包衣层。 10. - kind of enteric solid formulations containing melatonin as an active ingredient, and a carrier and an enteric water-soluble carrier, wherein the water-soluble carrier and the active ingredient is present in the solid dispersion in the aqueous formulation , and the enteric coating layer in the solid preparation comprising an enteric coating layer of the carrier.
  11. 11. 根据权利要求10所述的肠溶固体制剂,其中所述的水溶性载体为一种或多种选自以下组中的物质:甲基纤维素、羟丙甲基纤维素、聚氧乙烯-聚氧丙烯共聚物、聚乙烯吡咯烷酮、聚氧乙烯、共聚维酮、聚乙烯醇、聚乙二醇类、Soluplus、糖类、甘露醇和木糖醇,优选聚氧乙烯-聚氧丙烯共聚物。 11. The enteric solid formulation of claim 10, wherein said water-soluble carrier is one or more selected from the group of materials: methyl cellulose, hydroxypropyl methylcellulose, polyoxyethylene - polyoxypropylene copolymers, polyvinyl pyrrolidone, polyethylene oxide, copovidone, polyvinylalcohol, polyethylene glycols, Soluplus, sugars, mannitol, and xylitol, preferably a polyoxyethylene - polyoxypropylene copolymers .
  12. 12. 根据权利要求10所述的肠溶固体制剂,其中所述的水溶固体分散体中,所述活性成分与所述水溶性载体的重量比为1 : 1-1 : 20。 12. The enteric solid preparation according to claim 10, wherein said aqueous dispersion of the solid, the active ingredient the weight ratio of the water-soluble carrier was 1: 1-1: 20.
  13. 13. 根据权利要求10所述的肠溶固体制剂,其中所述的肠溶性载体为一种或多种选自以下组中的肠溶性聚合物:乙酸邻苯二甲酸纤维素、乙酸偏苯三酸纤维素、乙酸琥珀酸纤维素、邻苯二甲酸甲基纤维素、邻苯二甲酸乙基羟甲基纤维素、邻苯二甲酸羟丙基甲基纤维素、乙酸琥珀酸羟丙基甲基纤维素、乙酸马来酸羟丙基甲基纤维素、偏苯三酸羟丙基甲基纤维素、羧甲基乙基纤维素、聚丁酸乙烯邻苯二甲酸酯、聚乙酸乙烯醇邻苯二甲酸酯、甲基丙烯酸/丙烯酸乙酯共聚物和甲基丙烯酸/甲基丙烯酸甲酯共聚物,优选乙酸琥珀酸羟丙基甲基纤维素。 13. The enteric solid preparation according to claim 10, wherein said enteric carrier is one or more selected from the group of enteric polymer: acetate phthalate, cellulose acetate trimellitate cellulose acetate, cellulose acetate succinate, methylcellulose phthalate, hydroxymethyl ethyl cellulose phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate cellulose, hydroxypropyl methyl cellulose acetate, maleic acid, trimellitic acid, hydroxypropyl methyl cellulose, carboxymethyl ethyl cellulose, polyvinyl butyrate phthalate, polyvinyl acetate alcohol phthalate, methacrylate / ethyl acrylate copolymer and methacrylic acid / methyl methacrylate copolymer, hydroxypropyl methylcellulose acetate succinate is preferable.
  14. 14. 根据权利要求10所述的肠溶固体制剂,其中所述的肠溶包衣层还含有选自增塑剂、抗粘剂和稳定剂中的一种或多种载体。 14. The enteric solid preparation according to claim 10, wherein the enteric coating layer further contains a plasticizer selected, anti-tack agents, and stabilizers of one or more carriers.
  15. 15. 根据权利要求14所述的肠溶固体制剂,其中在肠溶包衣层中,所述的肠溶性载体为所述肠溶包衣层固含量的60-90重量% ;所述的增塑剂为所述肠溶包衣层固含量的10-30重量% ;所述的抗粘剂为所述肠溶包衣层固含量的10-30重量% ;所述的稳定剂为所述肠溶包衣层固含量的0. 5-5重量% ;优选所述的肠溶性载体为所述肠溶包衣层固含量的70-80重量% ;所述的增塑剂为所述肠溶包衣层固含量的10-15重量% ;所述的抗粘剂为所述肠溶包衣层固含量的15-20重量% ;所述的稳定剂为所述肠溶包衣层固含量的3-5重量%。 The increase; 15. enteric solid preparation according to claim 14, wherein the enteric coating layer of the enteric carrier is 60-90 wt.% Of the solids content of the enteric coating layer the plasticizer is 10-30% by weight of the solids content of the enteric coating layer; said anti-tack agent is 10-30 wt% solids content of the enteric coating layer; stabilizer according to the 0. 5-5% by weight of the solids content of the enteric coating layer;% preferably said carrier is an enteric coating layer of the enteric solids content of 70-80 weight; the plasticizer is of the intestine 10-15 wt% solids solution of the coating layer; said anti-tack agent is 15-20 wt% solids content of the enteric coating layer; said stabilizer for said solid enteric coating layer content of 3-5% by weight.
  16. 16. 根据权利要求10、14或15所述的肠溶固体制剂,其中所述的肠溶包衣层重量与其所包覆的成分总重的重量比为10-50重量%,优选为15-25重量%。 10, 14 or 16. The enteric solid preparation according to claim 15, wherein the total weight of the enteric coating layer of the coated weight of its content weight ratio of 10 to 50% by weight, preferably 15 25% by weight.
  17. 17. 根据权利要求10所述的肠溶固体制剂,其进一步包括其它药用辅料以制成片剂、 胶囊剂、颗粒剂、散剂或微丸。 17. The enteric solid preparation according to claim 10, further comprising other pharmaceutical excipients in the form of tablets, capsules, granules, powders or pellets.
  18. 18. 根据权利要求17所述的肠溶固体制剂,其中所述的其它药用辅料包括稀释剂、崩解剂、润滑剂、抗氧剂中的一种或多种。 18. The enteric solid preparation according to claim 17, wherein said other pharmaceutical excipients include one or more diluents, disintegrants, lubricants, antioxidants in.
  19. 19. 根据权利要求10所述的肠溶固体制剂的制备方法,其包括将所述的活性成分和水溶性载体溶于溶剂中,除去溶剂以得到水溶性固体分散体,并对所得的水溶性固体分散体进一步包肠溶衣。 19. A method for preparing an enteric solid preparation according to claim 10, comprising the active ingredient and a water-soluble carrier in a solvent, the solvent was removed to give a dispersion of water-soluble solid, and the resulting water-soluble The solid dispersion further enteric coated.
  20. 20. 根据权利要求10所述的肠溶固体制剂的制备方法,其包括将所述的活性成分和水溶性载体混匀后加热至熔融,然后将其冷冻干燥或热熔挤出制得水溶固体分散体,并对所得的水溶性固体分散体进一步包肠溶衣。 20. A method for preparing an enteric solid preparation according to claim 10, comprising the active ingredient and the water-soluble carrier is heated to melt and mix, and then freeze-drying or hot melt extrusion to obtain a solid water-soluble dispersion, and the resulting water-soluble solid dispersion further enteric coated.
  21. 21. 根据权利要求1或10所述的肠溶固体制剂,其中还包含表面活性剂,优选CremophorEL和/ 或CremophorRH40 〇 21. The enteric-coated solid preparation of claim 1 or claim 10, which further comprises a surfactant, preferably CremophorEL and / or square CremophorRH40
  22. 22. 根据权利要求21所述的肠溶固体制剂,其中所述活性成分重量与所述表面活性剂的重量比为1 : 2-1 : 4。 22. The enteric solid preparation according to claim 21, wherein said active ingredient by weight of the surfactant the weight ratio of 1: 2-1: 4.
  23. 23. 根据权利要求1或10所述的肠溶固体制剂,其还进一步含有一种或多种选自下述的成分:花青素、姜黄素、叶黄素、胡萝卜素、胡萝卜素、石榴提取水不溶物和脂溶性维生素。 23. The enteric-coated solid preparation of claim 1 or claim 10, which further comprises one or more components selected from: anthocyanin, curcumin, lutein, carotene, carotene, pomegranate The insoluble matter was extracted and fat soluble vitamins.
  24. 24. -种保健组合物,其含有权利要求1-7、10-18和20-23中任一项所述的肠溶固体制剂。 24. - Three Health composition comprising an enteric solid formulation as claimed in claim 1-7,10-18 and 20-23 according to any one of the.
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