技术领域technical field
本发明属药物制剂领域，涉及含有难溶性药物的药物组合物，具体涉及含难溶性药物的固体制剂，特别涉及以固体形式存在的自微乳化制剂及其制备方法。The invention belongs to the field of pharmaceutical preparations, and relates to a pharmaceutical composition containing insoluble drugs, in particular to a solid preparation containing insoluble drugs, in particular to a self-microemulsifying preparation in solid form and a preparation method thereof.
背景技术Background technique
自微乳化给药系统（SMEDDS）是由天然的或合成的油相、表面活性剂及助表面活性剂组成的各向同性的混合物，口服后遇体液在胃肠道蠕动下即可自发形成粒径小于100nm的O/W型纳米乳。SMEDDS可保证难溶性药物在制剂中和小肠液中保持溶解状态，自乳化后具有极小的粒径，保证了较大的分散度，显著提高在胃肠液中的溶出速率或溶解度，进而提高难溶性药物的口服生物利用度。自微乳化给药系统已有文献报道，如：SX Cui, et al.Biol Pharm Bull, 2008, 31: 118-125. K Kawakami, et al.J Control Release, 2002, 81: 65-74.。Self-microemulsifying drug delivery system (SMEDDS) is an isotropic mixture composed of natural or synthetic oil phase, surfactant and co-surfactant. O/W type nanoemulsion with diameter less than 100nm. SMEDDS can ensure that insoluble drugs remain dissolved in the preparation and in the small intestinal fluid. After self-emulsification, it has a very small particle size, which ensures a large degree of dispersion and significantly improves the dissolution rate or solubility in the gastrointestinal fluid, thereby improving Oral bioavailability of poorly soluble drugs. Self-microemulsifying drug delivery systems have been reported in the literature, such as: SX Cui, et al.Biol Pharm Bull , 2008, 31: 118-125. K Kawakami, et al.J Control Release , 2002, 81: 65-74.
尽管SMEDDS是难溶性药物口服给药的优良载体，且已被广泛应用于促进难溶性药物的溶出，但在实际应用过程中仍存在许多问题，主要包括：（1）生产工艺和成本，至目前为止，所有SMEDDS制剂均以浓缩液的形式灌封于软胶囊中，对软胶囊壳要求较高，整个制备工艺十分复杂，生产成本高；（2）稳定性，传统的软胶囊胶壳处方含有一定量的水分，SMEDDS中含有大量表面活性剂，作为内容物将夺取胶壳水分，最终导致胶壳变硬，影响其崩解和自微乳化效果，进而影响制剂疗效；（3）刺激性，SMEDDS处方中的乳化剂占30%-60%，软胶囊剂口服后，局部浓度较高，可能带来极大的胃肠道刺激性。上述缺陷已引起本领域研究者的关注，选择合适的处方、工艺将SMEDDS制剂固态化，可避免液体状态的不利影响，促进SMEDDS制剂的推广应用，具有潜在的社会和经济效益。Although SMEDDS is an excellent carrier for oral administration of poorly soluble drugs and has been widely used to promote the dissolution of poorly soluble drugs, there are still many problems in the actual application process, mainly including: (1) production process and cost, so far So far, all SMEDDS preparations are encapsulated in soft capsules in the form of concentrated liquid, which requires high requirements for the soft capsule shell, the entire preparation process is very complicated, and the production cost is high; (2) Stability, the traditional soft capsule shell prescription contains A certain amount of water, SMEDDS contains a large amount of surfactant, as the content will take away the moisture of the rubber shell, and eventually cause the rubber shell to harden, affecting its disintegration and self-microemulsification effect, and then affecting the efficacy of the preparation; (3) irritation, The emulsifier in the SMEDDS prescription accounts for 30%-60%. After the soft capsule is taken orally, the local concentration is high, which may cause great gastrointestinal irritation. The above defects have attracted the attention of researchers in this field. Selecting a suitable prescription and process to solidify the SMEDDS preparation can avoid the adverse effects of the liquid state and promote the popularization and application of the SMEDDS preparation, which has potential social and economic benefits.
有研究（中国发明专利200910187307）公开了长春西汀口服自微乳化微丸制剂及其制备方法，其中将难溶性药物长春西汀制备成自微乳化浓缩液，然后将此浓缩液与常规辅料混匀后制备软材，进一步采用挤出滚圆法制备微丸。该自微乳微丸需加入大量辅料以制备软材，有可能对自微乳化能力造成较大影响，且后处理工艺复杂，不利于工业化连续生产。另外，挤出滚圆法制备微丸的影响因素很多，而且它们并不只是独立发生作用的，而是各种因素间协同作用的结果，如填充剂的种类及含量、药物种类及含量、黏合剂的种类及含量、挤出机设备因素、滚圆机设备因素、挤出速度、滚圆速度等等，该些因素对微丸粒径有较大影响，使得处方工艺重现性差。Some studies (Chinese Invention Patent 200910187307) disclosed vinpocetine oral self-microemulsifying pellet preparation and its preparation method, wherein the insoluble drug vinpocetine was prepared into a self-microemulsifying concentrate, and then the concentrate was mixed with conventional excipients After homogenizing, soft materials are prepared, and pellets are further prepared by extrusion and spheronization. The self-microemulsion pellets need to add a large amount of auxiliary materials to prepare soft materials, which may have a great impact on the self-microemulsification ability, and the post-treatment process is complicated, which is not conducive to industrial continuous production. In addition, there are many factors affecting the preparation of pellets by extrusion spheronization, and they do not act independently, but are the result of synergistic effects among various factors, such as the type and content of fillers, the type and content of drugs, and binders. The type and content of the pellets, extruder equipment factors, spheronizer equipment factors, extrusion speed, spheronization speed, etc., these factors have a greater impact on the particle size of the pellets, making the recipe process poor reproducibility.
中国发明专利200710027400公开了一种薏苡仁油自乳化制剂及其制备方法，其中：以薏苡仁油或以薏苡仁油与分散剂组成的混合物为油相，采用乳化剂、助乳化剂作为乳化相，以固体吸附剂作为载体制备固体自微乳化制剂；中国发明专利200610036351公开了一种灵芝孢子油自乳化制剂及其制备工艺，其中：该制剂由灵芝孢子油或灵芝孢子油和其载体作为油相、乳化剂、助乳化剂或／及固体吸附剂组成，可制成软胶囊、液体胶囊、硬胶囊、颗粒剂或其他口服剂型；中国发明专利200510042547公开了一种姜黄素自微乳化制剂及其制备工艺，其中，将所制得的姜黄素微乳浓缩液用固体吸附剂吸附后制成胶囊或颗粒剂用于口服给药。所述的三种方法存在入下缺陷：均需制备自微乳化浓缩液后经固体吸附剂吸附，再制成相应的固体制剂，其制备工艺步骤较多，后处理复杂；为了充分吸附，固体吸附剂的用量往往较大，载药量较低；而自微乳化浓缩液黏度较大，不易与吸附剂混合均匀；溶出速度受固体吸附剂性质影响较大。Chinese invention patent 200710027400 discloses a self-emulsifying preparation of coix seed oil and its preparation method, wherein: coix seed oil or a mixture of coix seed oil and dispersant is used as the oil phase, and emulsifiers and co-emulsifiers are used as the emulsifying phase , using solid adsorbent as carrier to prepare solid self-microemulsifying preparation; Chinese invention patent 200610036351 discloses a self-emulsifying preparation of ganoderma spore oil and its preparation process, wherein: the preparation consists of ganoderma spore oil or ganoderma spore oil and its carrier as oil Phase, emulsifier, co-emulsifier or/and solid adsorbent, can be made into soft capsules, liquid capsules, hard capsules, granules or other oral dosage forms; Chinese invention patent 200510042547 discloses a curcumin self-microemulsifying preparation and Its preparation process, wherein, the prepared curcumin microemulsion concentrate is absorbed by a solid adsorbent and made into capsules or granules for oral administration. The three methods described have the following disadvantages: they all need to be prepared from the microemulsion concentrate and then adsorbed by a solid adsorbent, and then made into a corresponding solid preparation. The preparation process has many steps and the post-treatment is complicated; in order to fully absorb, the solid The amount of adsorbent is often large and the drug loading is low; while the self-microemulsion concentrate has a high viscosity and is not easy to mix evenly with the adsorbent; the dissolution rate is greatly affected by the properties of the solid adsorbent.
中国发明专利200910012391公开了一种黄豆苷元自微乳化半固体骨架胶囊及其制备方法，它是由黄豆苷元、油相、乳化剂、助乳化剂、弱碱、半固体载体形成的均一的半固体骨架制剂，需先在60℃水浴中使载体熔融，各组分混合均匀，再放冷后成型；中国发明专利200810117846公开了一种双环醇的含表面活性剂的药物组合物及其自微乳化制剂，该制剂主要由在室温下呈半固体状物的表面活性剂、助表面活性剂、油类中的一种或几种成分组成的载药基质中形成；中国发明专利200710004942.7公开了一种含人参皂甙Rh2的自微乳组合物，包括人参皂甙Rh2和自微乳释药系统，该释药系统含有熔点较低的组分，需先在60℃水浴中使各组分混合均匀并溶解药物；中国发明专利200510015048公开了全反式维甲酸的口服自微乳化浓缩物，其中包含治疗剂量的全反式维甲酸及其类似物和熔点低于70℃的油相、表面活性剂、助表面活性剂及增粘剂组成，在80℃水浴中将各组分混合均匀，冷却至40℃，灌装胶囊，在室温下固体或半固体的自微乳化浓缩物形式存在。所述的四种方法均选用室温下为固态或半固态的脂质辅料制备SMEDDS，药物需在熔融状态下加入，药物在高温下的稳定性及在制剂辅料中的溶解度严重限制了这些方法的适用范围；此外，由于受到脂质辅料与胶囊壳相容性的限制，可选用的脂质辅料并不多，工业化程度较差。Chinese invention patent 200910012391 discloses a daidzein self-microemulsifying semi-solid skeleton capsule and its preparation method. For semi-solid skeleton preparations, the carrier needs to be melted in a 60°C water bath first, and the components are mixed evenly, and then let cool to shape; Chinese invention patent 200810117846 discloses a pharmaceutical composition containing a bicyclic alcohol and its own surfactant. Microemulsification preparation, which is mainly formed in a drug-loading matrix composed of one or more components of semi-solid surfactants, co-surfactants, and oils at room temperature; Chinese invention patent 200710004942.7 discloses A self-microemulsion composition containing ginsenoside Rh2, including ginsenoside Rh2 and a self-microemulsion drug delivery system, the drug delivery system contains components with a lower melting point, and the components need to be mixed in a water bath at 60°C Uniform and dissolve the drug; Chinese invention patent 200510015048 discloses the oral self-microemulsifying concentrate of all-trans retinoic acid, which contains a therapeutic dose of all-trans retinoic acid and its analogues and an oil phase with a melting point below 70°C, surface active It is composed of surfactant, co-surfactant and tackifier. Mix all components uniformly in 80°C water bath, cool to 40°C, fill capsules, and exist in the form of solid or semi-solid self-microemulsifying concentrate at room temperature. Described four kinds of methods all select for use at room temperature to be solid or semi-solid lipid adjuvant preparation SMEDDS, medicine needs to add under molten state, the stability of medicine at high temperature and the solubility in the preparation adjuvant severely limit these methods. Scope of application; In addition, due to the limitation of the compatibility of lipid excipients and capsule shells, there are not many lipid excipients available, and the degree of industrialization is poor.
中国发明专利200610070024公开了一种白藜芦醇抗肿瘤固体自微乳剂及其制备方法，其中，将所制得的白藜芦醇自微乳组合物的浓缩液加入支撑剂溶解后，冷冻干燥制备冻干乳，将其做成固体自微乳制剂。虽然制剂稳定性较好，但冷冻干燥工艺复杂，耗能，耗时，不利于工业化推广应用。Chinese invention patent 200610070024 discloses a resveratrol anti-tumor solid self-microemulsion and its preparation method, wherein, the prepared resveratrol self-microemulsion composition is added to the proppant to dissolve the concentrated solution, and then freeze-dried Prepare freeze-dried milk and make it into solid self-microemulsion preparation. Although the preparation has good stability, the freeze-drying process is complex, energy-consuming and time-consuming, which is not conducive to industrial promotion and application.
基于上述分析，目前尚无良好的适于工业生产的SMEDDS固态化成型技术，严重制约了SMEDDS这一优良的难溶性药物口服给药载体的推广应用。Based on the above analysis, there is still no good solid-state molding technology for SMEDDS suitable for industrial production, which seriously restricts the popularization and application of SMEDDS, an excellent carrier for oral administration of insoluble drugs.
发明内容Contents of the invention
本发明的目的在于克服现有技术中难溶性药物制备成口服固体自微乳制剂时所存在的问题，提供一种含难溶性药物的固体制剂，特别涉及以固体形式存在的自微乳化制剂及其制备方法。The object of the present invention is to overcome the problems existing in the preparation of insoluble drugs into oral solid self-microemulsion preparations in the prior art, and provide a solid preparation containing insoluble drugs, particularly related to self-microemulsification preparations in solid form and its preparation method.
本发明的含难溶性药物的固体制剂制成固体自微乳微丸，可供口服。该固体制剂制能快速溶出、高度稳定、生物利用度高、适于工业化生产；该制剂在水介质存在下自发乳化形成粒径小于100nm的水包油型微乳，促进难溶性药物的吸收，能提高其生物利用度及临床疗效。The solid preparation containing insoluble drugs of the present invention is made into solid self-microemulsion pellets and can be taken orally. The solid preparation can dissolve quickly, is highly stable, has high bioavailability, and is suitable for industrial production; the preparation spontaneously emulsifies in the presence of an aqueous medium to form an oil-in-water microemulsion with a particle size of less than 100 nm, which promotes the absorption of insoluble drugs. Can improve its bioavailability and clinical efficacy.
具体而言，本发明的含难溶性药物的固体制剂，其特征在于，含有难溶性药物、自微乳化辅料和亲水性载体材料，制成含难溶性药物的固体自微乳微丸，该自微乳微丸中，其内容物为球形微丸，由空白丸芯、含药物自微乳化层及保护层组成；Specifically, the solid preparation containing insoluble drugs of the present invention is characterized in that it contains insoluble drugs, self-microemulsifying adjuvants and hydrophilic carrier materials, and is made into solid self-microemulsion pellets containing insoluble drugs. In the self-microemulsion pellets, the content is a spherical pellet, which is composed of a blank core, a drug-containing self-microemulsion layer and a protective layer;
本发明中，球形微丸直径为0.5－2.0mm，优选介于0.7-1.5mm；In the present invention, the spherical pellets have a diameter of 0.5-2.0 mm, preferably 0.7-1.5 mm;
本发明中，保护层视情况亦可以去除；In the present invention, the protective layer can also be removed as the case may be;
本发明中，由难溶性药物、自微乳化辅料和亲水性载体材料组成含药物自微乳化层药物层；In the present invention, the medicine layer of the drug-containing self-microemulsifying layer is composed of insoluble drugs, self-microemulsifying auxiliary materials and hydrophilic carrier materials;
本发明中，“难溶性药物”指在水中或生理体液中溶解度较低，从而影响其口服生物利用度的药物，属于按目前已被普遍接受的生物药剂学分类系统分类II和IV的难溶性药物。按《中华人民共和国药典》2010年版关于药物溶解度的测定方法进行测定；In the present invention, "poorly soluble drugs" refer to drugs with low solubility in water or physiological body fluids, thereby affecting their oral bioavailability, and belong to the insoluble drugs classified into II and IV according to the currently generally accepted biopharmaceutical classification system. drug. Measured according to the determination method of drug solubility in the 2010 edition of the Pharmacopoeia of the People's Republic of China;
所述的难溶性药物选自在100毫升的25℃的水中溶解度小于1克的药物，优选自免疫抑制剂或他汀和贝特类降血脂药，最优选自环孢素A、非诺贝特、辛伐他汀，特别优选环孢素A；The insoluble drug is selected from drugs with a solubility of less than 1 gram in 100 ml of water at 25°C, preferably from immunosuppressants or statins and fibrates, most preferably from cyclosporine A, fenofibrate , simvastatin, particularly preferably cyclosporine A;
但必须指出的是药物本身的化学结构并不是影响本发明的固体制剂性质的决定因素，本发明适用于脂溶性强而在生理体液中难溶的药物。However, it must be pointed out that the chemical structure of the drug itself is not a decisive factor affecting the properties of the solid preparation of the present invention, and the present invention is suitable for drugs that are highly fat-soluble but poorly soluble in physiological body fluids.
本发明中，难溶性药物与自微乳辅料的比例为0.1/10-1.2/10，优选0.6/10-1.0/10；难溶性药物与自微乳化辅料质量和与亲水载体材料的比例为2/1-10/1，优选6/1-8/1。Among the present invention, the ratio of insoluble medicine and self-microemulsifying auxiliary material is 0.1/10-1.2/10, preferably 0.6/10-1.0/10; Insoluble medicine and self-microemulsifying auxiliary material quality and the ratio with hydrophilic carrier material are 2/1-10/1, preferably 6/1-8/1.
本发明中，自微乳辅料由油相、乳化剂和助乳化剂组成，乳化剂和助乳化剂质量比为1/1-4/1，优选1/1-3/1，最优选2/1-3/1；油相与乳化剂和助乳化剂质量和之比为4/6-1/9，优选4/6-2/8，最优选3/7-2/8；In the present invention, the self-microemulsion auxiliary material is composed of an oil phase, an emulsifier and a co-emulsifier, and the mass ratio of the emulsifier to the co-emulsifier is 1/1-4/1, preferably 1/1-3/1, most preferably 2/1 1-3/1; the mass ratio of oil phase to emulsifier and co-emulsifier is 4/6-1/9, preferably 4/6-2/8, most preferably 3/7-2/8;
其中，油相包含但不局限于油酸乙酯，亚油酸乙酯，LabrafilM1944CS，Arlacel 80，Arlacel 86，Capmul MCM，Captex 200，Captex 355，Miglyol 812，Myvacet，Myverol 18-92，Soybean oil，Peceol，Maisine，Gelucire 44/14或其混合物，优选LabrafilM1944CS，油酸乙酯，亚油酸乙酯或其混合物；Wherein, the oil phase includes but not limited to ethyl oleate, ethyl linoleate, LabrafilM1944CS, Arlacel 80, Arlacel 86, Capmul MCM, Captex 200, Captex 355, Miglyol 812, Myvacet, Myverol 18-92, Soybean oil, Peceol, Maisine, Gelucire 44/14 or mixtures thereof, preferably Labrafil M1944CS, ethyl oleate, ethyl linoleate or mixtures thereof;
乳化剂包含但不局限于Cremophor EL，Cremophor RH40，Labrafac CM10，Labrafil M2125CS，Tagat TO，Tween 80，Labrasol，Ophase 31或其混合物，优选Cremophor EL，Cremophor RH40，Tween 80或其混合物；Emulsifiers include but are not limited to Cremophor EL, Cremophor RH40, Labrafac CM10, Labrafil M2125CS, Tagat TO, Tween 80, Labrasol, Ophase 31 or their mixtures, preferably Cremophor EL, Cremophor RH40, Tween 80 or their mixtures;
助乳化剂包括但不局限于乙醇、乙二醇、丙二醇、甘油、聚乙二醇、Transcutol或其混合物，优选Transcutol，聚乙二醇，丙二醇或其混合物。Co-emulsifiers include but are not limited to ethanol, ethylene glycol, propylene glycol, glycerin, polyethylene glycol, Transcutol or mixtures thereof, preferably Transcutol, polyethylene glycol, propylene glycol or mixtures thereof.
本发明中，自微乳化辅料在含水介质中可以进行自微乳化，形成粒径小于100nm的微乳。In the present invention, the self-microemulsifying auxiliary material can be self-microemulsified in an aqueous medium to form a microemulsion with a particle size of less than 100 nm.
本发明中，亲水性载体材料包含但不局限于聚乙烯吡咯烷酮、聚乙二醇、丙烯酸树脂（EPO）、聚乙烯醇/聚乙二醇(3:1)接枝共聚物（Kollicoat IR）、羟丙基甲基纤维素、羟丙基纤维素、糖醇类或其混合物，优选聚乙烯吡咯烷酮、聚乙二醇、羟丙基甲基纤维素或其混合物。In the present invention, the hydrophilic carrier material includes but not limited to polyvinylpyrrolidone, polyethylene glycol, acrylic resin (EPO), polyvinyl alcohol/polyethylene glycol (3:1) graft copolymer (Kollicoat IR) , hydroxypropylmethylcellulose, hydroxypropylcellulose, sugar alcohols or mixtures thereof, preferably polyvinylpyrrolidone, polyethylene glycol, hydroxypropylmethylcellulose or mixtures thereof.
本发明提供了所述的含难溶性药物的固体制剂的制备方法，其包括步骤：The invention provides the preparation method of the described solid preparation containing insoluble drugs, which comprises the steps of:
将油相、乳化剂、助乳化剂混合均匀后，得一澄清油状溶液，在室温或升温情况下，加入药物超声使溶解；将所得含药自微乳浓缩液用蒸馏水稀释成微乳，加入亲水性载体材料，采用流化床喷雾包衣工艺喷载于空白丸芯表面。After mixing the oil phase, emulsifier, and co-emulsifier evenly, a clear oily solution is obtained. At room temperature or at elevated temperature, add the drug sonication to dissolve it; dilute the obtained drug-containing self-microemulsion concentrate with distilled water into a microemulsion, The hydrophilic carrier material is sprayed on the surface of the blank pellet core by a fluidized bed spray coating process.
本发明中，采用流化床包衣技术实现固体化自微乳制剂的“一步成型”， 将载药自微乳浓缩液稀释成微乳，加入一定亲水性载体材料制成包衣液，喷于流化床包衣室中，利用干燥气流使之共沉淀析出，并沉积在空白丸芯外层上，可直接制得载药固体自微乳微丸，而得到的微丸可以直接装入硬胶囊里成为最终的制剂，不需要进一步加工处理。In the present invention, the "one-step forming" of the solidified self-microemulsion preparation is realized by fluidized bed coating technology, the drug-loaded self-microemulsion concentrate is diluted into a microemulsion, and a certain hydrophilic carrier material is added to make a coating solution. Spray in the fluidized bed coating room, use the dry air to make it co-precipitate, and deposit on the outer layer of the blank core, so that the drug-loaded solid self-microemulsion pellets can be directly prepared, and the obtained pellets can be directly loaded Into hard capsules to become the final preparation, no further processing is required.
本发明的含难溶性药物的固体自微乳微丸中，可以空白丸芯为起始物，先包一层隔离衣后或直接将活性成分的固体分散体附着在丸芯表面而构成药物核芯。丸芯主要起支持作用，可主要由蔗糖、微晶纤维素、磷酸钙、碳酸钙、磷酸三钙或其混合物组成，还可以含有粘合剂和其它辅料。一般可根据通用工业包衣机械设备的要求选用，并无特殊的要求，可以从专业丸芯提供商处获得。例如，市售的微晶纤维素微丸、糖丸、玻璃珠、塑料颗粒等。一般粒径在0.3-1.2mm之间，优选0.5-1.0mm。微丸包衣增重可在100%-400%之间，优选100%-200%。载药微丸的大小视空白丸芯及自微乳层的厚度而定，一般介于0.5－2.0mm，优选介于0.7－1.5mm。In the solid self-microemulsion pellets containing insoluble drugs of the present invention, a blank pellet core can be used as a starting material, and a layer of isolation clothing is firstly coated, or a solid dispersion of active ingredients is directly attached to the surface of the pellet core to form a drug core. core. The ball core mainly plays a supporting role, and can be mainly composed of sucrose, microcrystalline cellulose, calcium phosphate, calcium carbonate, tricalcium phosphate or a mixture thereof, and can also contain binders and other auxiliary materials. Generally, it can be selected according to the requirements of general industrial coating machinery and equipment. There is no special requirement, and it can be obtained from professional pellet core suppliers. For example, commercially available microcrystalline cellulose pellets, sugar pellets, glass beads, plastic granules, and the like. Generally, the particle size is between 0.3-1.2 mm, preferably 0.5-1.0 mm. The pellet coating weight gain can be between 100%-400%, preferably 100%-200%. The size of the drug-loaded micropill depends on the thickness of the blank core and the self-microemulsion layer, generally between 0.5-2.0mm, preferably between 0.7-1.5mm.
本发明中，将自微乳微丸制剂装入胶囊、泡罩或药袋中以终产品的形式给予患者。所述胶囊壳可选用普通明胶甘油囊壳或肠溶胶囊壳，囊体大小可视内容的量选用普通0、1、2、3号胶囊。In the present invention, the self-microemulsion pellet preparation is packed into capsules, blisters or medicine bags and administered to patients in the form of a final product. The capsule shell can be selected from ordinary gelatin glycerin capsule shells or enteric-coated capsule shells, and the size of the capsule body can be selected from ordinary No. 0, 1, 2, and 3 capsules depending on the amount of content.
本发明的自微乳微丸，在水性介质中可自发形成粒径小于100nm的微乳。The self-microemulsion pellets of the present invention can spontaneously form microemulsions with a particle diameter of less than 100 nm in an aqueous medium.
本发明的自微乳微丸，在40℃和75%相对湿度加速试验条件下，能够保持24个月以上的良好稳定性。The self-microemulsion pellets of the present invention can maintain good stability for more than 24 months under the accelerated test conditions of 40° C. and 75% relative humidity.
按中国药典规定的方法，测定其再分散性。在0.1%SDS的SDS溶液中10分钟再分散度大于70%，优选大于75%，更优选地，大于80%，最优选大于85%。According to the method stipulated in the Chinese Pharmacopoeia, its redispersibility was measured. The 10-minute redispersibility in 0.1% SDS in SDS solution is greater than 70%, preferably greater than 75%, more preferably greater than 80%, most preferably greater than 85%.
在本发明的一个具体实施方式中，制备含难溶性药物固体自微乳微丸的方法包括以下步骤：In a specific embodiment of the present invention, the method for preparing solid self-microemulsion pellets containing insoluble drugs comprises the following steps:
（1）将油相、乳化剂、助乳化剂混合均匀后，得一澄清油状溶液，在室温或升温情况下，加入药物超声使溶解。(1) After mixing the oil phase, emulsifier, and co-emulsifier evenly, a clear oily solution is obtained, and the drug is ultrasonically dissolved at room temperature or at elevated temperature.
（2）将所得含药自微乳浓缩液用蒸馏水稀释成微乳，加入亲水性载体材料，用于流化床包衣操作。(2) The obtained drug-containing self-microemulsion concentrate is diluted with distilled water to form a microemulsion, and a hydrophilic carrier material is added for fluidized bed coating operation.
（3）上述溶液用于流化床包衣操作。一般地，流化床包衣可选择商业提供的任何一种类型的流化床设备。比如，在试验室小批量生产时，可采用Mini Glatt试验型流化床进行。其基本过程包括将空白丸芯置于流化床包衣机中，在热空气的作用下，呈沸腾（流化）状态；将（2）中待包衣溶液采用蠕动泵等设备输送到喷嘴处，在压缩气流的作用下，使料液物化成细小的液滴，并喷射至干燥腔中，遇悬浮的空白丸芯而附着，同时在干燥气流的作用下，使溶剂挥发，微乳呈固体沉积于丸芯表面，此过程反复进行，直至所有微乳沉积完毕。(3) The above solution is used for fluidized bed coating operation. Generally, any type of fluid bed equipment available commercially can be selected for fluid bed coating. For example, when producing small batches in the laboratory, the Mini Glatt experimental fluidized bed can be used. The basic process includes placing the blank pellet core in a fluidized bed coating machine, which is in a boiling (fluidized) state under the action of hot air; transporting the solution to be coated in (2) to the nozzle with a peristaltic pump and other equipment At the place, under the action of compressed air flow, the material liquid is made into fine liquid droplets, which are sprayed into the drying chamber and adhere to the suspended blank pellet core. At the same time, under the action of dry air flow, the solvent is volatilized, and the microemulsion is Solids are deposited on the surface of the core, and this process is repeated until all microemulsions are deposited.
相对于现有技术，本发明的制备方法具有下述突出的优点：①流化床内温度分布均匀，制备温度低，避免了产品的任何局部的过热，利于热敏物料制备；②工艺流程简单、可大幅度降低劳动强度、缩短工序的时间、可以进行连续操作，也可进行间歇操作，产品“一步成型”；③制备的微丸性能良好，含量均一；④工艺过程可控，且整个过程都在密闭状态下操作，可以有效地避免粉尘飞扬，保证生产环境符合GMP要求，便于工业化规模生产。Compared with the prior art, the preparation method of the present invention has the following outstanding advantages: ① uniform temperature distribution in the fluidized bed, low preparation temperature, avoiding any local overheating of the product, and being beneficial to the preparation of heat-sensitive materials; ② simple process flow , It can greatly reduce labor intensity, shorten the time of the process, and can be operated continuously or intermittently, and the product is "one-step forming"; ③The prepared pellets have good performance and uniform content; ④The process is controllable, and the whole process All are operated in a closed state, which can effectively avoid dust flying, ensure that the production environment meets the requirements of GMP, and facilitate industrial scale production.
附图说明Description of drawings
图1示出了实施例15微丸的表面和横断面形态。Figure 1 shows the surface and cross-sectional morphology of Example 15 pellets.
图2示出了实施例15、19以及市售制剂的溶出曲线。Figure 2 shows the dissolution profiles of Examples 15, 19 and commercially available formulations.
图3示出了高温、强光照射对实施例15微丸溶出的影响。Fig. 3 shows the impact of high temperature and strong light irradiation on the dissolution of the pellets of Example 15.
具体实施方式Detailed ways
实施例1-12含环孢素A自微乳浓缩液Embodiment1-12 contains cyclosporine A self-microemulsion concentrate
按下表1所示重量添加。Add the weight shown in Table 1 below.
表1 含环孢素A自微乳浓缩液配方Table 1 Formula of self-microemulsion concentrate containing cyclosporin A
将油相、乳化剂、助乳化剂混合均匀后，得一澄清油状溶液，在室温情况下，加入环孢素A超声使溶解，即得。After mixing the oil phase, emulsifier and co-emulsifier evenly, a clear oily solution is obtained. At room temperature, cyclosporin A is added to dissolve it by ultrasonic waves, and the product is obtained.
实施例13-19含环孢素A固体自微乳微丸Embodiment13-19 contains cyclosporine A solid self-microemulsion pellet
按下表2所示重量添加。Add the weight shown in Table 2 below.
表2 含环孢素A自微乳微丸配方Table 2 Cyclosporin A-containing self-microemulsion pellet formula
将含环孢素A自微乳浓缩液于搅拌状态下加入蒸馏水中，使分散均匀，加入处方量PVP K30，使溶解。将该混合溶液通过流化床喷载于空白蔗糖丸芯表面，制备固体分自微乳微丸。流化床包衣在以下条件下实施：喷嘴直径0.5mm，进风温度50℃，床体温度32-35℃，喷液速率1.0mL•min-1，流化风量0.4bar，雾化压力1.5-1.6bar。上述所得环孢素A自微乳微丸分装入普通硬胶囊，使每胶囊含25mg环孢素A。Add the cyclosporin A self-microemulsion concentrate into distilled water under stirring to make the dispersion uniform, and add the prescribed amount of PVP K30 to dissolve. The mixed solution is sprayed on the surface of a blank sucrose pellet core through a fluidized bed to prepare solid fraction self-microemulsion pellets. The fluidized bed coating is carried out under the following conditions: nozzle diameter 0.5mm, air inlet temperature 50°C, bed temperature 32-35°C, liquid spray rate 1.0mL•min-1 , fluidization air volume 0.4bar, atomization pressure 1.5 -1.6 bar. The cyclosporine A obtained above is divided into ordinary hard capsules from the microemulsion pellets, so that each capsule contains 25 mg of cyclosporine A.
测试实例1形态观察Test Example1 Morphology Observation
本实施例配方15的含有环孢素A固体自微乳微丸经喷金处理后，在扫描电子显微镜下观察，其表面和横切面形态如附图1。从横切面可以明确地看到本发明微丸的结构，即空白核芯外包被固体自微乳的结构。其表面含有一定裂缝，有利于水分迅速进入微丸内部，促进药物溶出。 The cyclosporin A-containing solid self-microemulsion pellets of formula 15 in this example were subjected to gold spraying treatment, and observed under a scanning electron microscope, the surface and cross-sectional morphology of which are shown in Figure 1. The structure of the pellets of the present invention can be clearly seen from the cross-section, that is, the structure of a blank core surrounded by a solid self-microemulsion. There are certain cracks on the surface, which is conducive to the rapid entry of water into the interior of the pellets and the dissolution of drugs.
测试实例2含量测定Test example2 content determination
色谱柱：Venusil XBP-C18（150×4.6mm, 5μm, Agela公司），加Alltech充填式预柱，1.0mm×20mm，柱前连接Φ0.25nm×1000mm长的不锈钢管；流动相：乙腈/水/四丁基甲醚/磷酸=61/34/5/0.1(v/v/v/v)；检测波长：226nm；柱温：70℃；流速：1.0ml/min；进样量：20μl。取20粒胶囊内容物，研细混匀后，精密称取相当于环孢素A 25mg粉末置50ml容量瓶中，加入适量甲醇超声提取30min，定容至刻度，过滤（Millex®AP, Milipore, 0.45μm），取续滤液进样测定，代入含量测定的标准曲线方程计算微丸的含量。 Chromatographic column: Venusil XBP-C18 (150×4.6mm, 5μm, Agela Company), plus Alltech packed pre-column, 1.0mm×20mm, connected to a Φ0.25nm×1000mm long stainless steel tube before the column; mobile phase: acetonitrile/water /tetrabutylmethyl ether/phosphoric acid=61/34/5/0.1(v/v/v/v); detection wavelength: 226nm; column temperature: 70°C; flow rate: 1.0ml/min; injection volume: 20μl. Take the contents of 20 capsules, grind and mix well, accurately weigh 25mg powder equivalent to cyclosporine A, put it into a 50ml volumetric flask, add an appropriate amount of methanol for ultrasonic extraction for 30min, dilute to the mark, filter (Millex®AP, Milipore, 0.45 μm), take the subsequent filtrate for sample injection, and substitute into the standard curve equation for content determination to calculate the content of the pellets.
测试实例3溶出度比较Test Example3 Dissolution Comparison
按中国药典2010版规定的转篮法，对实施例15获得的胶囊剂与市售新山地明软胶囊Sandimmum Neoral®进行溶出度比较。以0.1%SDS 水溶液500ml为再分散介质，温度为37 ±0.5 ℃，转速为100 r/min，分别在5，10，20，30，45和60 min取样5ml，同时迅速补充等量同温的溶剂。样品经10000转离心15min，取0.5ml加0.5ml甲醇涡旋混合后，经HPLC法测定，通过标准曲线计算溶出量，并计算药物的累计溶出百分数（P）。结果如附图2所示。According to the basket method stipulated in the Chinese Pharmacopoeia 2010 edition, the capsules obtained in Example 15 were compared with the commercially available SandmmumNeoral® soft capsules for dissolution. Use 500ml of 0.1% SDS aqueous solution as the redispersion medium, the temperature is 37 ± 0.5 ℃, and the rotation speed is 100 r/min. Take 5ml of samples at 5, 10, 20, 30, 45 and 60 minutes respectively, and quickly replenish the same amount of the same temperature solvent. The sample was centrifuged at 10,000 rpm for 15 minutes, 0.5ml was taken and 0.5ml methanol was vortex mixed, and then determined by HPLC, the dissolution amount was calculated by the standard curve, and the cumulative dissolution percentage (P) of the drug was calculated. The results are shown in Figure 2.
环孢素A是难溶性药物，但实施例15、19在0.1%SDS中均能快速、完全溶出，10min时在介质中的累积溶出度均可达到80％以上，表明固体自微乳小丸在水性介质能够迅速乳化成细小乳滴，并将药物包裹。实施例15的溶出速度相对于实施例19要更快一些，是因为其包衣增重（200%）低于实施例19（400%），微丸粒径相对更小，根据Noyes-Whitney方程，溶出速度更快。参比制剂Neoral®5min没有乳滴再分散，10min也只有少许分散，而20min即再分散完全，这可能和软胶囊壳有关，软胶囊壳破裂需要的时间相比于硬胶囊壳要更长一些，也说明参比制剂再分散性能非常好，只要囊壳一破裂就能迅速再分散。Cyclosporine A is a poorly soluble drug, but Examples 15 and 19 can be dissolved quickly and completely in 0.1% SDS, and the cumulative dissolution rate in the medium can reach more than 80% in 10 minutes, showing that the solid self-microemulsion pellets in The aqueous medium can be quickly emulsified into fine emulsion droplets and encapsulate the drug. The dissolution rate of Example 15 is faster than that of Example 19, because its coating weight gain (200%) is lower than that of Example 19 (400%), and the particle size of the pellets is relatively smaller, according to the Noyes-Whitney equation , the dissolution rate is faster. The reference preparation Neoral® did not redisperse the emulsion droplets in 5 minutes, and only a little dispersed in 10 minutes, but it was completely redispersed in 20 minutes. This may be related to the soft capsule shell, which takes longer to break than the hard capsule shell. , which also shows that the redispersibility of the reference preparation is very good, as long as the capsule shell is broken, it can be quickly redispersed.
测试实例4再分散后粒径Particle size aftertest example4 redispersion
分别取各处方样品2g 置于烧杯中，用50 ml 蒸馏水稀释（37 ℃），充分乳化后经0.8μm微孔滤膜过滤。用NICOMP-380/ ZLS测定乳液的粒径分布，所测得粒径为强度径。结果如表3所示。Take 2g samples of each recipe and place them in a beaker, dilute with 50 ml distilled water (37 ℃), fully emulsify and filter through a 0.8 μm microporous membrane. Use NICOMP-380/ZLS to measure the particle size distribution of the emulsion, and the measured particle size is the intensity diameter. The results are shown in Table 3.
表3 实施例13-19再分散后粒径Table 3 Example 13-19 Particle size after redispersion
固体自微乳微丸再分散后，粒径均在100nm内，呈双峰分布，分别为几个纳米和几十个纳米，和固体化之前的液态自微乳液再分散在水中相比，粒径有所增大，但和液态自微乳液再分散在不同浓度的PVP k30中，粒径分布呈现同一趋势，即双峰分布。固体化的微丸再分散后，随着自微乳液量的增加，小粒径逐渐增大，可能自微乳液受PVP k30水溶液的影响，有一部分水化过程中与PVP k30形成了胶束。After the redispersion of the solid self-microemulsion pellets, the particle size is within 100nm, showing a bimodal distribution, which is several nanometers and tens of nanometers respectively. Compared with the liquid self-microemulsion redispersion in water before solidification, the particle size However, when the liquid self-microemulsion is redispersed in different concentrations of PVP k30, the particle size distribution presents the same trend, that is, bimodal distribution. After the solidified pellets were redispersed, the small particle size gradually increased with the increase of the amount of self-microemulsion. It may be that the self-microemulsion was affected by the PVP k30 aqueous solution, and a part of the self-microemulsion formed micelles with PVP k30 during the hydration process.
测试实例5稳定性试验Test example5 Stability test
稳定性试验：对实施例15固体自微乳微丸的稳定性进行了考察。按《中华人民共和国药典》2010年版二部附录XIX C原料药与药物制剂稳定性指导原则进行。首先在较为剧烈的条件下不加包装进行了影响因素试验（高温60℃；恒温25℃，高湿92.5%RH和75%RH；恒温25℃，强光4500±500Lx），分别于第0、5、10天取样，测定固体自微乳微丸的含量及溶出度。Stability test: The stability of the solid self-microemulsion pellets in Example 15 was investigated. According to the "Pharmacopoeia of the People's Republic of China" 2010 edition two appendix XIX C stability guidelines for raw materials and pharmaceutical preparations. First, the influence factor test was carried out without packaging under more severe conditions (high temperature 60°C; constant temperature 25°C, high humidity 92.5%RH and 75%RH; constant temperature 25°C, strong light 4500±500Lx), respectively at 0, 5. Take samples in 10 days, and measure the content and dissolution rate of the solid self-microemulsion pellets.
高温、高湿及强光等条件对实施例15固体自微乳微丸胶囊的含量影响结果如表4所示，对溶出的影响见附图3。高温60℃放置后，微丸外观仍圆整，但包衣层变脆，敲击或碰撞容易剥落。以0时含量为100%计，60℃条件下，微丸5天，10天时药物含量为(99±0.3)%，没有显著变化，再分散性能和0天比较，ƒ2值5天，10天分别为87%和67%，无显著性差异。湿度为75%的条件下放置10天，微丸粘结，5天、10天吸湿分别为14.06%和16.57%，微丸已经不完整，融溶在一起，丸芯清晰可见。在湿度为92.5%的条件下，5天吸湿就达到22.29%，10天吸湿达32.76%，且胶囊壳变软，微丸已经不完整，融溶在一起，丸芯模糊可见。未对其湿度75%和92.5%条件下微丸作含量与再分散性能分析。照度为(4500±500)lx的条件下，5天、10天药物含量与0时相比没有显著变化，光照对再分散性能无显著影响。The results of the effects of high temperature, high humidity and strong light on the content of solid self-microemulsion pellet capsules in Example 15 are shown in Table 4, and the effects on dissolution are shown in Figure 3. After being placed at a high temperature of 60°C, the appearance of the pellets is still round, but the coating layer becomes brittle, and it is easy to peel off when knocked or collided. Based on the content of 100% at 0, under the condition of 60 °C, the drug content of the pellets was (99±0.3)% for 5 days and 10 days, no significant change, and the redispersibility was compared with that of 0 days. The value of ƒ2 was 5 days, 10 Days were 87% and 67%, no significant difference. Placed under the condition of 75% humidity for 10 days, the pellets were bonded, and the moisture absorption was 14.06% and 16.57% in 5 days and 10 days respectively. The pellets were incomplete and melted together, and the core of the pellets was clearly visible. Under the condition of a humidity of 92.5%, the moisture absorption reached 22.29% in 5 days and 32.76% in 10 days, and the capsule shell became soft, the pellets were incomplete and melted together, and the pellet core was vaguely visible. The content and redispersion performance of the pellets under the conditions of 75% and 92.5% humidity were not analyzed. Under the condition of illuminance of (4500±500) lx, there was no significant change in drug content at day 5 and day 10 compared with time 0, and light had no significant effect on redispersion performance.
表4 实施例15稳定性影响因素实验考察结果Table 4 Example 15 Stability Influencing Factors Experimental Investigation Results
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110085318.0ACN102727446B (en) | 2011-04-06 | 2011-04-06 | Solid preparation containing poorly soluble drug and preparation method thereof |
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110085318.0ACN102727446B (en) | 2011-04-06 | 2011-04-06 | Solid preparation containing poorly soluble drug and preparation method thereof |
| Publication Number | Publication Date |
|---|---|
| CN102727446A CN102727446A (en) | 2012-10-17 |
| CN102727446Btrue CN102727446B (en) | 2015-06-17 |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110085318.0AExpired - Fee RelatedCN102727446B (en) | 2011-04-06 | 2011-04-06 | Solid preparation containing poorly soluble drug and preparation method thereof |
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| CN (1) | CN102727446B (en) |
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| CN103961316B (en)* | 2014-05-13 | 2020-01-07 | 浙江工商大学 | A kind of microemulsion containing enramycin and preparation method thereof |
| CN113679749A (en)* | 2021-08-17 | 2021-11-23 | 沈阳化工大学 | Preparation method of plant extract self-microemulsion sustained-release antibacterial anti-inflammatory buccal tablets |
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| EP1340497A1 (en)* | 2002-03-01 | 2003-09-03 | Novagali Sas | Self emulsifying drug delivery systems for poorly soluble drugs |
| CN1682701A (en)* | 2005-03-09 | 2005-10-19 | 山东大学 | Curcumin self-microemulsifying preparation and preparation method thereof |
| CN101647782A (en)* | 2009-09-10 | 2010-02-17 | 沈阳药科大学 | Vinpocetine oral administration self-microemulsifying pellet as well as preparation method and application thereof |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1340497A1 (en)* | 2002-03-01 | 2003-09-03 | Novagali Sas | Self emulsifying drug delivery systems for poorly soluble drugs |
| CN1682701A (en)* | 2005-03-09 | 2005-10-19 | 山东大学 | Curcumin self-microemulsifying preparation and preparation method thereof |
| CN101647782A (en)* | 2009-09-10 | 2010-02-17 | 沈阳药科大学 | Vinpocetine oral administration self-microemulsifying pellet as well as preparation method and application thereof |
| Publication number | Publication date |
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| CN102727446A (en) | 2012-10-17 |
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| CF01 | Termination of patent right due to non-payment of annual fee | Granted publication date:20150617 Termination date:20180406 |