CN101862297B - Water-insoluble medicine sustained-release pellet, sustained-release orally disintegrating tablet thereof and preparation method thereof - Google Patents
Water-insoluble medicine sustained-release pellet, sustained-release orally disintegrating tablet thereof and preparation method thereofDownload PDFInfo
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Abstract
Translated fromChineseDescription
Translated fromChinese技术领域technical field
本发明属于药物制剂领域，特别涉及一种非水溶性药物的缓释微丸、其缓释口腔崩解片及其制备方法。The invention belongs to the field of pharmaceutical preparations, in particular to a water-insoluble sustained-release pellet, its sustained-release orally disintegrating tablet and a preparation method thereof.
背景技术Background technique
现有的非水溶性药物的缓释制剂的缓慢释放时间短，不能实现长效释放，最长只有6小时。如布洛芬缓释速崩片以磷脂为阻滞剂，Kollicoat SR 30D为包衣材料，采用制粒包衣工艺制备缓释速崩片，但由于制粒工艺的限制，包衣不完全，使得缓释时间只有1.5小时(Fast dispersible/slow releasingibuprofen tablets.Adamo Fini，Valentina Bergamante，Gian Carlo Ceschel，A.Fini et al./European Journal of Pharmaceutics and Biopharmaceutics 69(2008)335-341)。而体内缓慢释药达8小时以上的药物，可以保持平稳的血药浓度，降低副作用，而且可以减少服用次数，大大方便了药物的服用，特别为长期服用药物的人群带来便利，但是一直未能实现。The existing sustained-release preparations of water-insoluble drugs have a short slow-release time and cannot achieve long-acting release, the longest being only 6 hours. For example, ibuprofen sustained-release and fast-disintegrating tablets use phospholipids as blockers and Kollicoat SR 30D as coating material. The slow-release and fast-disintegrating tablets are prepared by granulation and coating process, but due to the limitation of granulation process, the coating is incomplete. The sustained release time is only 1.5 hours (Fast dispersible/slow releasingibuprofen tablets.Adamo Fini, Valentina Bergamante, Gian Carlo Ceschel, A.Fini et al./European Journal of Pharmaceutics and Biopharmaceutics 69(2008) 335-341). And the medicine that releases medicine slowly in the body reaches more than 8 hours, can keep stable blood drug concentration, reduce side effect, and can reduce the frequency of taking, greatly facilitates the taking of medicine, especially brings convenience for the crowd of taking medicine for a long time, but has not been can achieve.
发明内容Contents of the invention
因此，本发明要解决的技术问题就是针对现有的非水溶性药物存在的缓释时间较短，一般不到8小时的不足，提供一种非水溶性药物的缓释微丸、其缓释口腔崩解片及其制备方法。该缓释口腔崩解片能够达到在口腔中快速崩解的要求，又能在体内缓慢释药8～13小时，保持平稳的血药浓度，降低副作用，减少服用次数。Therefore, the technical problem to be solved in the present invention is exactly that the slow-release time that existing water-insoluble medicine exists is shorter, generally less than 8 hours deficiency, a kind of slow-release pellet of water-insoluble medicine, its sustained-release Orally disintegrating tablet and its preparation method. The sustained-release orally disintegrating tablet can meet the requirement of rapid disintegration in the oral cavity, and can release the drug slowly in the body for 8-13 hours, maintain a stable blood drug concentration, reduce side effects, and reduce the number of times of taking.
因为缓释层是缓释微丸的释放速率的决定因素，因此，为了使缓释微丸的释药在8～13小时之间，本发明人对缓释层所需的成分和含量进行了大量的试验研究，终于完成了本发明。Because the sustained-release layer is the determinant of the release rate of the sustained-release pellets, therefore, in order to make the release of the sustained-release pellets between 8 to 13 hours, the inventors have carried out the required composition and content of the sustained-release layer A large amount of experimental research has finally accomplished the present invention.
本发明提供的解决上述技术问题的技术方案之一是，一种非水溶性药物的缓释微丸，包括空白丸芯、药物层、隔离层和缓释层，所述的缓释层包括以下组分：54～88％的缓释材料、2～30％的抗粘剂和1～30％的致孔剂，所述的百分比为占缓释层的质量百分比；其中，所述的缓释材料选自丙烯酸乙酯和甲基丙烯酸甲酯的共聚物、聚醋酸乙烯酯和乙基纤维素中的任何一种或多种。One of the technical solutions provided by the present invention to solve the above-mentioned technical problems is that a sustained-release pellet of a water-insoluble drug comprises a blank core, a drug layer, an isolation layer and a sustained-release layer, and the sustained-release layer includes the following Components: 54-88% of sustained-release material, 2-30% of anti-sticking agent and 1-30% of pore-forming agent, the percentages are the mass percentages of the sustained-release layer; wherein, the sustained-release The material is selected from any one or more of copolymers of ethyl acrylate and methyl methacrylate, polyvinyl acetate and ethyl cellulose.
本发明的缓释层中，所述的缓释材料选自丙烯酸乙酯和甲基丙烯酸甲酯的共聚物、聚醋酸乙烯酯类和乙基纤维素中的任何一种或多种都适合本发明。其中，所述的丙烯酸乙酯和甲基丙烯酸甲酯的共聚物较佳的是EudragitNE30D。所述的聚醋酸乙烯酯较佳的是Kollicoat SR30D。所述的乙基纤维素较佳的是全水乙基纤维素分散体。缓释材料是形成缓释层的最主要物质，其含量太少，则不能控制释药速度且重现性比较差，反之，则不能达到理想的释药效果。所述的缓释材料的含量为54～88％(wt)，较佳的为62～80％(wt)。In the slow-release layer of the present invention, any one or more of the slow-release materials selected from copolymers of ethyl acrylate and methyl methacrylate, polyvinyl acetates and ethyl cellulose are suitable for this invention. invention. Wherein, the copolymer of ethyl acrylate and methyl methacrylate is preferably Eudragit NE30D. The preferred polyvinyl acetate is Kollicoat SR30D. The ethyl cellulose is preferably full water ethyl cellulose dispersion. Sustained-release material is the most important substance to form the sustained-release layer. If its content is too small, the drug release rate cannot be controlled and the reproducibility is relatively poor. On the contrary, the desired drug release effect cannot be achieved. The content of the slow-release material is 54-88% (wt), preferably 62-80% (wt).
本发明的缓释层中，较佳的还进一步包括肠溶材料，所述的肠溶材料选自阴离子聚合物与甲基丙烯酸的聚合物。所述的阴离子聚合物与甲基丙烯酸的聚合物较佳的选自Eudragit L30D-55和Eudragit L100-55。肠溶材料的含量为0～8％(wt)，较佳的为1～8％(wt)。肠溶材料可以加速缓释层的溶解，参与控制药物的释放。In the sustained-release layer of the present invention, it is preferable to further include an enteric material selected from an anionic polymer and a polymer of methacrylic acid. The polymer of described anionic polymer and methacrylic acid is preferably selected from Eudragit L30D-55 and Eudragit L100-55. The content of the enteric material is 0-8% (wt), preferably 1-8% (wt). Enteric-coated materials can accelerate the dissolution of the sustained-release layer and participate in the controlled release of drugs.
本发明的缓释层中，所述的抗粘剂可为本领域常用抗粘剂，优选滑石粉和/或单硬脂酸甘油酯。抗粘剂的含量为2～30％(wt)，较佳的为15～25％(wt)。In the sustained-release layer of the present invention, the anti-adhesive agent can be a common anti-adhesive agent in the field, preferably talcum powder and/or glyceryl monostearate. The content of the anti-sticking agent is 2-30% (wt), preferably 15-25% (wt).
本发明的缓释层中，所述的致孔剂可为本领域常用致孔剂，较佳的选自乳糖、聚维酮、聚乙二醇、聚山梨酯80和羟丙基甲基纤维素中的任何一种或多种都适合本发明，更佳的是选自乳糖、聚维酮和羟丙基甲基纤维素。所述的致孔剂的含量为1～30％(wt)，较佳的为5～15％(wt)。In the sustained-release layer of the present invention, the porogen can be a common porogen in the art, preferably selected from lactose, povidone, polyethylene glycol,
如本领域常规，本发明的缓释层中还可以加入其他，较佳的如增塑剂。所述的增塑剂可为本领域常用增塑剂，较佳的是选自甘油、邻苯二甲酸二丁酯、邻苯二甲酸二乙酯、硬脂酸、聚乙二醇、丙二醇、柠檬酸三乙酯和三醋酸甘油酯中的任何一种或多种都适合本发明，较佳的是选自甘油和枸橼酸三乙酯。所述的增塑剂的含量为1～20％(wt)，较佳的为2～8％(wt)。As usual in the field, other, preferably plasticizers, can also be added to the slow-release layer of the present invention. Described plasticizer can be common plasticizer in this field, is preferably selected from glycerin, dibutyl phthalate, diethyl phthalate, stearic acid, polyethylene glycol, propylene glycol, Any one or more of triethyl citrate and triacetin are suitable for the present invention, preferably selected from glycerin and triethyl citrate. The content of the plasticizer is 1-20% (wt), preferably 2-8% (wt).
如本领域常规，本发明的缓释层中还可以加入色素，色淀和调味剂等。As usual in the field, pigments, lakes and flavoring agents can also be added to the sustained-release layer of the present invention.
本发明的非水溶性药物的缓释微丸中，所述的缓释层的含量占缓释微丸总质量的10～80％(wt)，较佳的是20～50％(wt)。In the sustained-release pellets of water-insoluble drugs of the present invention, the content of the sustained-release layer accounts for 10-80% (wt) of the total mass of the sustained-release pellets, preferably 20-50% (wt).
本发明的非水溶性药物的缓释微丸中，所述的空白丸芯可以是本领域所有的常规的空白丸芯，较佳的选自蔗糖丸芯、淀粉丸心和微晶纤维素丸心的一种或多种。空白丸芯作为本发明缓释微丸的核芯，也可根据最终微丸所需达到的粒径来选择其粒径大小，各种大小空白丸芯有市售，或根据现有技术自制。所述的空白丸芯的平均粒径在0.1～0.3毫米(mm)范围内较佳，更佳的是0.15～0.25mm。选择了粒径小的蔗糖丸心的理由是粒径小能够提高微丸的抗压性，并且制成口崩片降低沙砾感。空白丸芯的含量占缓释微丸总质量的5～50％(wt)，较佳的是20～40％(wt)。In the sustained-release pellets of water-insoluble drugs of the present invention, the blank cores can be all conventional blank cores in the art, preferably selected from sucrose cores, starch cores and microcrystalline cellulose cores. One or more types of hearts. As the core of the sustained-release pellets of the present invention, blank cores can also be selected according to the required particle size of the final pellets. Blank cores of various sizes are commercially available, or self-made according to the prior art. The average particle diameter of the blank pellet core is preferably in the range of 0.1-0.3 mm, more preferably 0.15-0.25 mm. The reason for choosing the sucrose core with small particle size is that the small particle size can improve the compression resistance of the pellets, and it can be made into orally disintegrating tablets to reduce the gritty feeling. The content of the blank pellet core accounts for 5-50% (wt) of the total mass of the sustained-release pellets, preferably 20-40% (wt).
本发明的非水溶性药物的缓释微丸，所述的非水溶性药物可以是对乙酰氨基酚、双氯芬酸钠、布洛芬或氢氯噻嗪。本发明的非水溶性药物的缓释微丸中，所述的药物层由药物活性成分和辅助成分组成，所述的药物活性成分可以是以下非水溶性药物：对乙酰氨基酚、双氯芬酸钠、布洛芬或氢氯噻嗪。所述的辅助成分包括粘合剂。粘合剂是指适宜将药物活性成分配成上药悬浮液，并有助于药物活性成分粘附包覆于空白丸芯上的物质，其含量太少，特别是小于微丸重量的1.5％，则上药率低；反之，如含量太高，则上药悬浮液粘度太高而上药不均。所述的粘合剂可以是药剂领域常规的粘合剂，优选羟丙甲基纤维素和聚乙烯吡咯烷酮中的任何一种或两种都适合本发明。药物活性成分和粘合剂的质量比较佳的是3∶1～14∶1。所述的药物层的含量占缓释微丸总质量的5～50％(wt)，较佳的为10～30％(wt)。In the sustained-release pellets of water-insoluble drugs of the present invention, the water-insoluble drugs may be acetaminophen, diclofenac sodium, ibuprofen or hydrochlorothiazide. In the sustained-release pellets of water-insoluble drugs of the present invention, the drug layer is composed of drug active ingredients and auxiliary ingredients, and the drug active ingredients can be the following water-insoluble drugs: acetaminophen, diclofenac sodium, ibuprofen or hydrochlorothiazide. Said auxiliary components include binders. Adhesive refers to the substance that is suitable for distributing the active ingredient of the drug into a drug suspension, and helps the active ingredient of the drug adhere to the blank pellet core, and its content is too small, especially less than 1.5% of the weight of the pellet , the drug application rate is low; on the contrary, if the content is too high, the drug suspension viscosity is too high and the drug application is uneven. The binder may be a conventional binder in the pharmaceutical field, preferably any one or both of hydroxypropylmethylcellulose and polyvinylpyrrolidone are suitable for the present invention. The mass ratio of active pharmaceutical ingredients and binder is preferably 3:1-14:1. The content of the drug layer accounts for 5-50% (wt) of the total mass of the sustained-release pellets, preferably 10-30% (wt).
本发明的非水溶性药物的缓释微丸中，所说的隔离层是指在药物层和缓释层之间形成一种屏障，隔离两者的物质，以免药物层与缓释层发生反应或是药物向包衣层渗透而影响微丸的稳定性；其含量太少，则隔离效差，反之，则影响释药速度。所述的隔离层可以是本领域所有的常规隔离层。较佳的可以选自羟丙甲基纤维素和聚乙烯吡咯烷酮。隔离层的含量占缓释微丸总质量的1～5％(wt)，较佳的是1～3％(wt)。In the sustained-release pellets of water-insoluble drugs of the present invention, said isolation layer refers to a barrier that forms a barrier between the drug layer and the sustained-release layer to isolate the two substances, so as to prevent the drug layer from reacting with the sustained-release layer. Or the drug penetrates into the coating layer and affects the stability of the pellets; if its content is too small, the isolation effect will be poor, otherwise, the drug release rate will be affected. The isolation layer can be all conventional isolation layers in the art. Preferable ones can be selected from hydroxypropylmethylcellulose and polyvinylpyrrolidone. The content of the isolation layer accounts for 1-5% (wt) of the total mass of the sustained-release pellets, preferably 1-3% (wt).
本发明的非水溶性药物的缓释微丸可用于压片制备缓释口腔崩解片，或者用于制备缓释混悬剂。The sustained-release pellets of water-insoluble drugs of the present invention can be used for tableting to prepare sustained-release orally disintegrating tablets, or for preparing sustained-release suspensions.
本发明提供的解决上述技术问题的技术方案之二是，一种所述的非水溶性药物的缓释微丸的制备方法，包括以下步骤：采用切喷流化床，将空白丸芯依次用上药液、2％～8％的隔离材料水溶液、缓释包衣液喷涂包覆，制成本发明的缓释微丸；其中所述的上药液含有10～35％非水溶性药物活性成分和1.0～5.5％黏合剂，所述的缓释包衣液包括20～50％的缓释材料、2～15％的抗粘剂、1～10％的增塑剂、1～15％的致孔剂，所述的百分比为质量百分比。The second technical solution for solving the above-mentioned technical problems provided by the present invention is a preparation method of the sustained-release pellets of water-insoluble drugs, comprising the following steps: using a cutting-jet fluidized bed, using blank pellet cores in sequence The drug solution, 2% to 8% aqueous solution of the isolation material, and the slow-release coating solution are sprayed and coated to make the sustained-release pellets of the present invention; wherein the drug solution contains 10 to 35% of the active water-insoluble drug composition and 1.0-5.5% binder, the sustained-release coating solution includes 20-50% of sustained-release material, 2-15% of anti-adhesive agent, 1-10% of plasticizer, 1-15% of Porogen, said percentage is mass percent.
本发明提供的解决上述技术问题的技术方案之三是，一种非水溶性药物的缓释口腔崩解片，其包含20～50％权利要求1所述的缓释微丸、5～10％的崩解剂、36～70％的填充剂、0.2～5％的润滑剂和0.1～0.5％的矫味剂，所述的百分比为占缓释口腔崩解片的质量百分比。The third technical solution to solve the above technical problems provided by the present invention is a sustained-release orally disintegrating tablet of a water-insoluble drug, which comprises 20-50% of the sustained-release pellets described in claim 1, 5-10% disintegrant, 36-70% filler, 0.2-5% lubricant and 0.1-0.5% flavoring agent, the percentages are the mass percentages of the sustained-release orally disintegrating tablet.
本发明的非水溶性药物的缓释口腔崩解片中，所述的填充剂是选自甘露醇、乳糖和微晶纤维素中的任何一种或多种都适合本发明。所述的甘露醇较佳的选自甘露醇200SD和甘露醇100SD。所述的微晶纤维素较佳的选自微晶纤维素PH102、KG-801和KG-802等。所述的填充剂的含量为36～70％(wt)，较佳的为48～55％(wt)，所述的百分比为占缓释口腔崩解片的质量百分比。In the sustained-release orally disintegrating tablet of water-insoluble drug of the present invention, the filler is any one or more selected from mannitol, lactose and microcrystalline cellulose, which is suitable for the present invention. The mannitol is preferably selected from mannitol 200SD and mannitol 100SD. The microcrystalline cellulose is preferably selected from microcrystalline cellulose PH102, KG-801, KG-802 and the like. The content of the filler is 36-70% (wt), preferably 48-55% (wt), and the said percentage is the mass percentage of the sustained-release orally disintegrating tablet.
本发明的非水溶性药物的缓释口腔崩解片中，所述的崩解剂是选自交联聚乙烯吡咯烷酮、羟丙纤维素、羧甲基淀粉钠、羧甲基纤维素钠和丙氨酸中的任何一种或多种都适合本发明，较佳的选自交联聚乙烯吡咯烷酮、羟丙纤维素和丙氨酸，最佳的为质量比3∶1∶1的交联聚乙烯吡咯烷酮、羟丙纤维素和丙氨酸。崩解剂的含量为5～10％(wt)，较佳的为5～8％(wt)，所述的百分比为占缓释口腔崩解片的质量百分比。In the slow-release orally disintegrating tablets of water-insoluble drugs of the present invention, the disintegrating agent is selected from crosslinked polyvinylpyrrolidone, hydroxypropyl cellulose, sodium carboxymethyl starch, sodium carboxymethyl cellulose and acetone Any one or more of amino acids are all suitable for the present invention, preferably selected from cross-linked polyvinylpyrrolidone, hydroxypropyl cellulose and alanine, the best being cross-linked polyvinylpyrrolidone with a mass ratio of 3:1:1 Vinylpyrrolidone, hydroxypropylcellulose and alanine. The content of the disintegrant is 5-10% (wt), preferably 5-8% (wt), and the said percentage is the mass percentage of the sustained-release orally disintegrating tablet.
本发明的非水溶性药物的缓释口腔崩解片中，所述的润滑剂是选自微分硅胶、硬脂酸镁和滑石粉中的任何一种或多种都适合本发明，较佳的选自微分硅胶和硬脂酸镁。所述的润滑剂的含量为0.2～5％(wt)，较佳的为1～2％(wt)，所述的百分比为占缓释口腔崩解片的质量百分比。In the sustained-release orally disintegrating tablets of water-insoluble drugs of the present invention, the lubricant is any one or more selected from microsilica gel, magnesium stearate and talcum powder, and is suitable for the present invention, preferably Selected from microscopic silica gel and magnesium stearate. The content of the lubricant is 0.2-5% (wt), preferably 1-2% (wt), and the said percentage is the mass percentage of the sustained-release orally disintegrating tablet.
本发明的非水溶性药物的缓释口腔崩解片中，所述的矫味剂可以是本领域常规的矫味剂，较佳的选自阿司帕坦、橘子香精、薄荷香精和苹果香精中的任何一种或多种都适合本发明，较佳的是选自阿司帕坦和薄荷香精。所述的矫味剂的含量为0.1～0.5％(wt)，较佳的为0.1～0.3％，所述的百分比为占缓释口腔崩解片的质量百分比。In the slow-release orally disintegrating tablet of water-insoluble drug of the present invention, the flavoring agent can be a conventional flavoring agent in the art, preferably selected from aspartame, orange essence, mint essence and apple essence Any one or more of them are suitable for the present invention, preferably selected from aspartame and peppermint essence. The content of the flavoring agent is 0.1-0.5% (wt), preferably 0.1-0.3%, and the percentage is the mass percentage of the sustained-release orally disintegrating tablet.
本发明所述的非水溶性药物的缓释口腔崩解片中，较佳的还进一步包括泡腾剂，所述的百分比为占缓释口腔崩解片的质量百分比。所述的泡腾剂可以是本领域常规的泡腾剂，较佳的为质量比1∶1～3∶1的碳酸氢钠和柠檬酸。所述的泡腾剂的含量为0～3％(wt)，较佳的为1～3％(wt)，所述的百分比为占缓释口腔崩解片的质量百分比。The sustained-release orally disintegrating tablet of the water-insoluble drug in the present invention preferably further includes an effervescent agent, and the percentage is the mass percentage of the sustained-release orally disintegrating tablet. The effervescent agent may be a conventional effervescent agent in the art, preferably sodium bicarbonate and citric acid in a mass ratio of 1:1 to 3:1. The content of the effervescent agent is 0-3% (wt), preferably 1-3% (wt), and the said percentage is the mass percentage of the sustained-release orally disintegrating tablet.
本发明提供的解决上述技术问题的技术方案之四是，一种所述的非水溶性药物的缓释口腔崩解片的制备方法，包括如下步骤：将所述的非水溶性药物的缓释微丸与填充剂、崩解剂、泡腾剂、矫味剂和润滑剂混合，用压片机压片，即得。The fourth technical solution provided by the present invention to solve the above-mentioned technical problems is that a method for preparing the sustained-release orally disintegrating tablet of the water-insoluble drug includes the following steps: The pellets are mixed with fillers, disintegrants, effervescent agents, flavoring agents and lubricants, and compressed into tablets with a tablet machine.
本发明所用的原料或试剂除特别说明之外，均市售可得。The raw materials or reagents used in the present invention are commercially available unless otherwise specified.
相比于现有技术，本发明的有益效果如下：本发明提供了一种非水溶性药物的缓释口腔崩解片。特别是优选了粒径小的蔗糖丸心和合适的包衣材料Eudragit NE30D，乙基纤维素，或者Kollicoat SR 30D组合，实现如下效果：第一，通过调整包衣组合以及填充辅料压成的口崩片可以缓慢释放8-13小时以上，从而保持平稳的血药浓度，降低副作用，具有优良的安全性，减少服用次数，服用方便，提高了服药患者顺应性。第二：本发明的非水溶性药物的缓释口腔崩解片经体外溶出试验表明更符合零级释放，而且最终累计释药量也高于普通缓释口崩片，具有功效大，选择性强的特点。第三：由于本发明的缓释微丸粒径小，强度较强，优选的包衣材料具有一定的韧性，采用其制备口崩片时，即可在较小的压力下压片成型，且口感好。第四：本发明制备缓释微丸的方法，可在切线喷流化床中同时实现上药与包衣工艺，生产步骤简单，效率较高，可应用于大规模生产。Compared with the prior art, the beneficial effects of the present invention are as follows: the present invention provides a slow-release orally disintegrating tablet of a water-insoluble drug. In particular, the combination of sucrose core with small particle size and suitable coating material Eudragit NE30D, ethyl cellulose, or Kollicoat SR 30D is preferred to achieve the following effects: First, the mouth formed by adjusting the coating combination and filling auxiliary materials The disintegrating tablet can be slowly released for more than 8-13 hours, thereby maintaining a stable blood drug concentration, reducing side effects, having excellent safety, reducing the number of times of taking, being convenient to take, and improving the compliance of patients taking medicine. Second: The sustained-release orally disintegrating tablet of the non-water-soluble drug of the present invention is more consistent with zero-order release through in vitro dissolution tests, and the final cumulative drug release is also higher than that of ordinary sustained-release orally disintegrating tablets, which has high efficacy and selectivity. strong features. Third: due to the small particle size and strong strength of the sustained-release pellets of the present invention, the preferred coating material has certain toughness. When it is used to prepare orally disintegrating tablets, it can be compressed into tablets under a relatively small pressure, and Good taste. Fourth: The method for preparing sustained-release pellets of the present invention can realize the drug application and coating process in a tangential jet fluidized bed at the same time, with simple production steps and high efficiency, and can be applied to large-scale production.
附图说明Description of drawings
以下结合附图说明本发明的特征和有益效果。The features and beneficial effects of the present invention will be described below in conjunction with the accompanying drawings.
图1是对乙酰氨基酚缓释微丸口腔崩解片在水中的释放曲线。Figure 1 is the release curve of acetaminophen sustained-release pellets orally disintegrating tablets in water.
具体实施方式Detailed ways
下面用实施例来进一步说明本发明，但本发明并不受其限制。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。The present invention is further illustrated below with examples, but the present invention is not limited thereto. For the experimental methods without specific conditions indicated in the following examples, the conventional conditions or the conditions suggested by the manufacturer are usually followed.
实施例1 制备对乙酰氨基酚缓释微丸Example 1 Preparation of Paracetamol Sustained-release Pellets
1.丸心上药1. pill heart medicine
将聚乙烯吡咯烷酮PVP S630 17g与对乙酰氨基酚100g加入75％(v/v)乙醇560ml中制成上药液，其中对乙酰氨基酚浓度15g/100ml，粘合剂PVPS630浓度2.5％(wt)。将平均粒径为0.15mm蔗糖丸心置流化床中流化10分钟，将上药液缓慢喷于丸心表面。上药增重：45.0～50.0％。切线喷流化床的操作条件为：风机频率为20～23Hz；物料温度为33～35℃；转盘的转动频率为100～150rpm；雾化喷枪的雾化压力为0.10～0.15MPa；包衣液的喷液速度为12～15g/min。Add 17g of polyvinylpyrrolidone PVP S630 and 100g of paracetamol to 560ml of 75% (v/v) ethanol to make a medicinal solution, wherein the concentration of paracetamol is 15g/100ml, and the concentration of binder PVPS630 is 2.5% (wt) . Put the sucrose ball core with an average particle size of 0.15 mm in a fluidized bed for 10 minutes, and slowly spray the drug solution on the surface of the ball core. Weight gain after taking medicine: 45.0-50.0%. The operating conditions of the tangential jet fluidized bed are: the fan frequency is 20-23Hz; the material temperature is 33-35°C; the rotation frequency of the turntable is 100-150rpm; the atomization pressure of the atomizing spray gun is 0.10-0.15MPa; The liquid spray speed is 12~15g/min.
2.包隔离层2. Package isolation layer
将羟丙甲基纤维素(HPMC)15g溶于300ml纯水中，用切喷流化床缓慢喷于步骤1中所得的上药丸心上。切线喷流化床的操作条件为：风机频率为20～23Hz；物料温度为33～35℃；转盘的转动频率为100～150rpm；雾化喷枪的雾化压力为0.10～0.15MPa；包衣液的喷液速度为12～15g/min。Dissolve 15 g of hydroxypropyl methylcellulose (HPMC) in 300 ml of pure water, and slowly spray it on the upper pill core gained in step 1 with a cutting jet fluidized bed. The operating conditions of the tangential jet fluidized bed are: the fan frequency is 20-23Hz; the material temperature is 33-35°C; the rotation frequency of the turntable is 100-150rpm; the atomization pressure of the atomizing spray gun is 0.10-0.15MPa; The liquid spray speed is 12~15g/min.
3.包缓释层3. Package slow release layer
将尤特奇丙烯酸树脂Eudragit NE30D 170g，肠溶型丙烯酸树脂EudragitL30D-5520g，乙基纤维素20g，纯水200g，过千目滑石粉50g和乳糖4.5g用高速剪切搅拌混匀制成包衣液，用切喷流化床将该液缓慢喷于步骤2得到的微丸表面上。切线喷流化床的操作条件为：风机频率为20～23Hz；物料温度为23～25℃；转盘的转动频率为100～150rpm；雾化喷枪的雾化压力为0.10～0.15MPa；包衣液的喷液速度为6～10g/min。所得缓释微丸过60目筛。Mix Eudragit acrylic resin Eudragit NE30D 170g, enteric-coated acrylic resin Eudragit L30D-5520g, ethyl cellulose 20g, pure water 200g, talc powder 50g and lactose 4.5g with high-speed shearing to make a coating The liquid is slowly sprayed on the surface of the pellets obtained in
实施例2 片制备对乙酰氨基酚缓释微丸口腔崩解片Example 2 Preparation of acetaminophen sustained-release pellets orally disintegrating tablets
压片制备口腔崩解片，一片量(mg)Tablet preparation orally disintegrating tablet, one piece (mg)
对乙酰氨基酚缓释微丸 225Acetaminophen sustained-release pellets 225
甘露醇 178Mannitol 178
微晶纤维素 87Microcrystalline Cellulose 87
交联聚乙烯吡咯烷酮 22Cross-linked polyvinylpyrrolidone 22
羟丙纤维素 11Hydroxypropyl Cellulose 11
阿司帕坦 2
硬脂酸镁 1Magnesium stearate 1
微分硅胶 1Micro silica gel 1
滑石粉 15Talc powder 15
制备方法如下：The preparation method is as follows:
将实施例1所得的对乙酰氨基酚缓释微丸过60目筛，将可直接压片的辅料：甘露醇、微晶纤维素、交联聚乙烯吡咯烷酮、羟丙纤维素、硬脂酸镁、滑石粉、微分硅胶和阿斯帕坦用压片机直接压片，片剂硬度3kg。Pass the acetaminophen sustained-release pellets obtained in Example 1 through a 60-mesh sieve, and the auxiliary materials that can be directly compressed: mannitol, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, hydroxypropyl cellulose, magnesium stearate , talcum powder, micro-silica gel and aspartame are directly compressed with a tablet machine, and the hardness of the tablet is 3kg.
取该缓释微丸口腔崩解片，按照《中华人民共和国药典》(2005年版二部附录)溶出度测定法浆法的装置，以纯水900mL为溶出介质，转速为100r/min，定时取溶出液5mL，滤过，并及时补加5mL水，稀释，摇匀，照紫外分光光度法(《中华人民共和国药典》附录IV A)，在243nm处测定吸光度，根据标准曲线方程计算检出量，求出释放度和绘制释药曲线。对乙酰氨基酚缓释微丸口腔崩解片的溶出曲线见图1，图中纵坐标表示药物释放百分率(Q)，横坐标表示时间(t)。可见该对乙酰氨基酚缓释微丸口腔崩解片崩解迅速，在50秒内崩解，在水中缓慢释放可达13小时。Get this sustained-release pellet orally disintegrating tablet, according to the device of " Pharmacopoeia of the People's Republic of China " (2005 edition two appendices) dissolution method slurry method, with pure water 900mL as dissolution medium, rotating speed is 100r/min, take regularly Eluate 5mL, filter, and add 5mL water in time, dilute, shake up, according to ultraviolet spectrophotometry ("Pharmacopoeia of the People's Republic of China" appendix IV A), measure absorbance at 243nm, calculate detection amount according to standard curve equation , Calculate the release rate and draw the release curve. The dissolution curve of acetaminophen sustained-release pellets orally disintegrating tablets is shown in Figure 1, in which the ordinate represents the drug release percentage (Q), and the abscissa represents time (t). It can be seen that the acetaminophen sustained-release pellet orally disintegrating tablet disintegrates rapidly within 50 seconds, and can be slowly released in water for up to 13 hours.
实施例3 制备双氯芬酸钠缓释微丸Example 3 Preparation of Diclofenac Sodium Sustained Release Pellets
1.丸心上药1. pill heart medicine
将聚乙烯吡咯烷酮PVP VA64 17g与对双氯芬酸钠100g加入75％(v/v)乙醇560ml，其中双氯芬酸钠浓度：15g/100ml，粘合剂浓度：2.5％(wt)。将平均粒径为0.10mm蔗糖丸芯置流化床中流化10分钟，将上述药液缓慢喷于丸心表面。上药增重：45.0～50.0％。切线喷流化床的操作条件为：风机频率为20～23Hz；物料温度为33～35℃；转盘的转动频率为100～150rpm；雾化喷枪的雾化压力为0.10～0.15MPa；包衣液的喷液速度为12～15g/min。Add 17g of polyvinylpyrrolidone PVP VA64 and 100g of diclofenac sodium to 560ml of 75% (v/v) ethanol, wherein the concentration of diclofenac sodium: 15g/100ml, the concentration of binder: 2.5% (wt). Put the sucrose ball core with an average particle size of 0.10 mm in a fluidized bed for 10 minutes, and slowly spray the above-mentioned medicinal solution on the surface of the core. Weight gain after taking medicine: 45.0-50.0%. The operating conditions of the tangential jet fluidized bed are: the fan frequency is 20-23Hz; the material temperature is 33-35°C; the rotation frequency of the turntable is 100-150rpm; the atomization pressure of the atomizing spray gun is 0.10-0.15MPa; The liquid spray speed is 12~15g/min.
2.包隔离层2. Package isolation layer
将羟丙甲基纤维素13g溶于300ml纯水中，用切喷流化床缓慢喷于上药丸心上。切线喷流化床的操作条件为：风机频率为20～23Hz；物料温度为33～35℃；转盘的转动频率为100～150rpm；雾化喷枪的雾化压力为0.10～0.15MPa；包衣液的喷液速度为12～15g/min。Dissolve 13 g of hydroxypropyl methylcellulose in 300 ml of pure water, and slowly spray it on the core of the last pill with a cutting jet fluidized bed. The operating conditions of the tangential jet fluidized bed are: the fan frequency is 20-23Hz; the material temperature is 33-35°C; the rotation frequency of the turntable is 100-150rpm; the atomization pressure of the atomizing spray gun is 0.10-0.15MPa; The liquid spray speed is 12~15g/min.
3.包缓释层3. Package slow release layer
将聚醋酸乙烯酯(Kollicoat SR30D巴斯夫)100g，乙基纤维素20g，纯水150g，单硬脂酸甘油酯3g和羟丙甲纤维素1.5g用高速搅拌，混匀，用切喷流化床将该液缓慢喷于步骤2得到的微丸表面上。切线喷流化床的操作条件为：风机频率为20～23Hz；物料温度为23～25℃；转盘的转动频率为100～150rpm；雾化喷枪的雾化压力为0.10～0.15MPa；包衣液的喷液速度为6～10g/min。所得缓释微丸过60目筛。Stir 100g of polyvinyl acetate (Kollicoat SR30D BASF), 20g of ethyl cellulose, 150g of pure water, 3g of glyceryl monostearate and 1.5g of hypromellose at high speed, mix well, and use a cutting jet fluidized bed Slowly spray the liquid on the surface of the pellets obtained in
实施例4 制备双氯芬酸钠缓释微丸口腔崩解片Example 4 Preparation of Diclofenac Sodium Sustained Release Pellets Orally Disintegrating Tablets
压片制备口腔崩解片，一片量(mg)Tablet preparation orally disintegrating tablet, one piece (mg)
双氯芬酸钠缓释微丸 225Diclofenac Sodium Sustained Release Pellets 225
甘露醇 178Mannitol 178
微晶纤维素 87Microcrystalline Cellulose 87
交联聚乙烯吡咯烷酮 25Cross-linked polyvinylpyrrolidone 25
羟丙纤维素 8
丙氨酸 8
阿司帕坦 2
硬脂酸镁 1Magnesium stearate 1
微分硅胶 1Micro silica gel 1
滑石粉 15Talc powder 15
制备方法如下：The preparation method is as follows:
将实施例3所制备的双氯芬酸钠缓释微丸过60目筛，将可直接压片的辅料：甘露醇，微晶纤维素，交联聚乙烯吡咯烷酮，羟丙纤维素、丙氨酸、微分硅胶、硬脂酸镁、滑石粉和阿斯帕坦用压片机直接压片，片剂硬度3kg。取该缓释微丸口腔崩解片，同实施例2的方法测定溶出度。该片剂崩解迅速，在50秒内崩解，在水中缓慢释放8小时。The diclofenac sodium sustained-release pellets prepared in Example 3 were passed through a 60-mesh sieve, and the auxiliary materials that could be directly compressed were: mannitol, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, hydroxypropyl cellulose, alanine, micronutrient Silica gel, magnesium stearate, talc and aspartame are directly compressed with a tablet machine, and the hardness of the tablet is 3kg. Get the sustained-release pellet orally disintegrating tablet, and measure the dissolution rate with the method of Example 2. The tablet disintegrates rapidly, disintegrating in 50 seconds with a slow release in water for 8 hours.
实施例5 制备布洛芬缓释微丸口腔崩解片Example 5 Preparation of ibuprofen sustained-release pellets orally disintegrating tablets
1.丸心上药1. pill heart medicine
将PVP S630 17g与布洛芬60g加入75％(v/v)乙醇560ml中制成上药液，其中布洛芬浓度：10g/100ml，粘合剂PVP S630浓度：2.5％(wt)。将平均粒径为0.20mm蔗糖丸心置流化床中流化10分钟，将上药液缓慢喷于丸心表面。上药增重：45.0～50.0％。切线喷流化床的操作条件为：风机频率为20～23Hz；物料温度为33～35℃；转盘的转动频率为100～150rpm；雾化喷枪的雾化压力为0.10～0.15MPa；包衣液的喷液速度为12～15g/min。Add 17g of PVP S630 and 60g of ibuprofen to 560ml of 75% (v/v) ethanol to make a medicinal solution, wherein the concentration of ibuprofen: 10g/100ml, the concentration of PVP S630 of the adhesive: 2.5% (wt). Put the sucrose ball core with an average particle size of 0.20 mm in a fluidized bed for 10 minutes, and slowly spray the drug solution on the surface of the core ball. Weight gain after taking medicine: 45.0-50.0%. The operating conditions of the tangential jet fluidized bed are: the fan frequency is 20-23Hz; the material temperature is 33-35°C; the rotation frequency of the turntable is 100-150rpm; the atomization pressure of the atomizing spray gun is 0.10-0.15MPa; The liquid spray speed is 12~15g/min.
2.包隔离层2. Package isolation layer
将羟丙甲基纤维素15g溶于300ml纯水中，用切喷流化床缓慢喷于步骤1中所得的上药丸心上。切线喷流化床的操作条件为：风机频率为20～23Hz；物料温度为33～35℃；转盘的转动频率为100～150rpm；雾化喷枪的雾化压力为0.10～0.15MPa；包衣液的喷液速度为12～15g/min。Dissolve 15 g of hydroxypropyl methylcellulose in 300 ml of pure water, and slowly spray it on the upper pill core gained in step 1 with a cutting jet fluidized bed. The operating conditions of the tangential jet fluidized bed are: the fan frequency is 20-23Hz; the material temperature is 33-35°C; the rotation frequency of the turntable is 100-150rpm; the atomization pressure of the atomizing spray gun is 0.10-0.15MPa; The liquid spray speed is 12~15g/min.
4.包缓释层4. Package slow release layer
将尤特奇丙烯酸树脂(Eudragit NE30D)170g，肠溶型丙烯酸树脂Eudragit L30D-55 20g，乙基纤维素20g，纯水200g，过千目滑石粉50g和乳糖4.5g用高速剪切搅拌混匀制成包衣液，用切喷流化床将该液缓慢喷于步骤2得到的微丸表面上。切线喷流化床的操作条件为：风机频率为20～23Hz；物料温度为23～25℃；转盘的转动频率为100～150rpm；雾化喷枪的雾化压力为0.10～0.15MPa；包衣液的喷液速度为6～10g/min。所得缓释微丸过60目筛。Mix Eudragit acrylic resin (Eudragit NE30D) 170g, enteric acrylic resin Eudragit L30D-55 20g, ethyl cellulose 20g, pure water 200g, talcum powder 50g and lactose 4.5g with high-speed shearing Make a coating solution, and slowly spray the solution on the surface of the pellets obtained in
实施例6 制备布洛芬缓释微丸口腔崩解片Example 6 Preparation of ibuprofen sustained-release pellets orally disintegrating tablets
压片制备口腔崩解片，一片量(mg)Tablet preparation orally disintegrating tablet, one piece (mg)
布洛芬缓释微丸 225Ibuprofen Sustained Release Pellets 225
甘露醇 178Mannitol 178
微晶纤维素 87Microcrystalline Cellulose 87
阿司帕坦 2
交联聚乙烯吡咯烷酮 25Cross-linked polyvinylpyrrolidone 25
羟丙纤维素 8
丙氨酸 8
柠檬酸 3Citric acid 3
碳酸氢钠 3Sodium bicarbonate 3
硬脂酸镁 1Magnesium stearate 1
微分硅胶 1Micro silica gel 1
滑石粉 15Talc powder 15
制备方法如下：The preparation method is as follows:
将实施例5所制备的布洛芬缓释微丸过60目筛，将可直接压片的辅料：甘露醇、微晶纤维素、交联聚乙烯吡咯烷酮、羟丙纤维素、丙氨酸、微分硅胶、硬脂酸镁、滑石粉、碳酸氢钠、柠檬酸和阿斯帕坦用压片机直接压片，片剂硬度3kg。取该缓释微丸口腔崩解片，同实施例2的方法测定溶出度。该片剂崩解迅速，在50秒内崩解，在水中缓慢释放13小时。The ibuprofen sustained-release pellets prepared in Example 5 are passed through a 60-mesh sieve, and the auxiliary materials that can be directly compressed: mannitol, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, hydroxypropyl cellulose, alanine, Differential silica gel, magnesium stearate, talc, sodium bicarbonate, citric acid and aspartame are directly compressed with a tablet machine, and the hardness of the tablet is 3kg. Get the sustained-release pellet orally disintegrating tablet, and measure the dissolution rate with the method of Example 2. The tablet disintegrates rapidly, disintegrating in 50 seconds, and releases slowly in water for 13 hours.
实施例7 制备氢氯噻嗪缓释微丸Example 7 Preparation of hydrochlorothiazide sustained-release pellets
1.丸心上药1. pill heart medicine
将PVP S630 10g与氢氯噻嗪50g加入75％(v/v)乙醇440ml中制成上药液，其中氢氯噻嗪浓度10g/100ml，粘合剂PVP S630浓度2％(wt)。将平均粒径为0.30mm蔗糖丸心置流化床中流化10分钟，将上药液缓慢喷于丸心表面。上药增重：45.0～50.0％。切线喷流化床的操作条件为：风机频率为20～23Hz；物料温度为33～35℃；转盘的转动频率为100～150rpm；雾化喷枪的雾化压力为0.10～0.15MPa；包衣液的喷液速度为12～15g/min。Add 10g of PVP S630 and 50g of hydrochlorothiazide into 440ml of 75% (v/v) ethanol to make a medicinal solution, wherein the concentration of hydrochlorothiazide is 10g/100ml, and the concentration of adhesive PVP S630 is 2% (wt). Put the sucrose ball core with an average particle size of 0.30 mm in a fluidized bed for 10 minutes, and slowly spray the drug solution on the surface of the ball core. Weight gain after taking medicine: 45.0-50.0%. The operating conditions of the tangential jet fluidized bed are: the fan frequency is 20-23Hz; the material temperature is 33-35°C; the rotation frequency of the turntable is 100-150rpm; the atomization pressure of the atomizing spray gun is 0.10-0.15MPa; The liquid spray speed is 12~15g/min.
2.包隔离层2. Package isolation layer
将羟丙甲基纤维素15g溶于300ml纯水中，用切喷流化床缓慢喷于步骤1中所得的上药丸心上。切线喷流化床的操作条件为：风机频率为20～23Hz；物料温度为33～35℃；转盘的转动频率为100～150rpm；雾化喷枪的雾化压力为0.10～0.15MPa；包衣液的喷液速度为12～15g/min。Dissolve 15 g of hydroxypropyl methylcellulose in 300 ml of pure water, and slowly spray it on the upper pill core gained in step 1 with a cutting jet fluidized bed. The operating conditions of the tangential jet fluidized bed are: the fan frequency is 20-23Hz; the material temperature is 33-35°C; the rotation frequency of the turntable is 100-150rpm; the atomization pressure of the atomizing spray gun is 0.10-0.15MPa; The liquid spray speed is 12~15g/min.
3.包缓释层3. Package slow release layer
将尤特奇丙烯酸树脂(Eudragit NE30D)170g，肠溶型丙烯酸树脂Eudragit L30D-55 20g，乙基纤维素20g，纯水200g，过千目滑石粉50g和乳糖4.5g用高速剪切搅拌混匀制成包衣液，用切喷流化床将该液缓慢喷于步骤2得到的微丸表面上。切线喷流化床的操作条件为：风机频率为20～23Hz；物料温度为23～25℃；转盘的转动频率为100～150rpm；雾化喷枪的雾化压力为0.10～0.15MPa；包衣液的喷液速度为6～10g/min。所得缓释微丸过60目筛。Mix Eudragit acrylic resin (Eudragit NE30D) 170g, enteric acrylic resin Eudragit L30D-55 20g, ethyl cellulose 20g, pure water 200g, talcum powder 50g and lactose 4.5g with high-speed shearing Make a coating solution, and slowly spray the solution on the surface of the pellets obtained in
实施例8 制备氢氯噻嗪缓释微丸口腔崩解片Example 8 Preparation of hydrochlorothiazide sustained-release pellets orally disintegrating tablets
压片制备口腔崩解片，一片量(mg)Tablet preparation orally disintegrating tablet, one piece (mg)
氢氯噻嗪缓释微丸 150Hydrochlorothiazide extended-release pellets 150
甘露醇 178Mannitol 178
微晶纤维素 87Microcrystalline Cellulose 87
阿司帕坦 2
交联聚乙烯吡咯烷酮 25Cross-linked polyvinylpyrrolidone 25
羟丙纤维素 8
丙氨酸 8
柠檬酸 3Citric acid 3
碳酸氢钠 3Sodium bicarbonate 3
硬脂酸镁 1Magnesium stearate 1
微分硅胶 1Micro silica gel 1
滑石粉 15Talc powder 15
制备方法如下：The preparation method is as follows:
将实施例7所制备的氢氯噻嗪缓释微丸过60目筛，将可直接压片的辅料：甘露醇、微晶纤维素、交联聚乙烯吡咯烷酮、羟丙纤维素、丙氨酸、微分硅胶、硬脂酸镁、滑石粉、碳酸氢钠、柠檬酸和阿斯帕坦用压片机直接压片，片剂硬度3kg。取该缓释微丸口腔崩解片，同实施例2的方法测定溶出度。该片剂崩解迅速，在50秒内崩解，在水中缓慢释放13小时。Pass the hydrochlorothiazide sustained-release pellets prepared in Example 7 through a 60-mesh sieve, and the auxiliary materials that can be directly compressed: mannitol, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, hydroxypropyl cellulose, alanine, microsilica gel , magnesium stearate, talcum powder, sodium bicarbonate, citric acid and aspartame are directly compressed with a tablet machine, and the tablet hardness is 3kg. Get the sustained-release pellet orally disintegrating tablet, and measure the dissolution rate with the method of Example 2. The tablet disintegrates rapidly, disintegrating in 50 seconds, and releases slowly in water for 13 hours.
实施例9 制备对乙酰氨基酚缓释微丸Example 9 Preparation of Paracetamol Sustained-release Pellets
1.丸心上药1. pill heart medicine
将羟丙甲基纤维素92g与对乙酰氨基酚278g加入75％(v/v)醇1700ml中制成上药液。将平均粒径为0.15mm蔗糖丸心置流化床中流化10分钟，将上药液缓慢喷于丸心表面。上药增重：43％。切线喷流化床的操作条件为：风机频率为20～23Hz；物料温度为33～35℃；转盘的转动频率为100～150rpm；雾化喷枪的雾化压力为0.10～0.15MPa；包衣液的喷液速度为12～15g/min。Add 92g of hydroxypropylmethylcellulose and 278g of acetaminophen into 1700ml of 75% (v/v) alcohol to prepare the medicinal solution. Put the sucrose ball core with an average particle size of 0.15 mm in a fluidized bed for 10 minutes, and slowly spray the drug solution on the surface of the ball core. Medicated weight gain: 43%. The operating conditions of the tangential jet fluidized bed are: the fan frequency is 20-23Hz; the material temperature is 33-35°C; the rotation frequency of the turntable is 100-150rpm; the atomization pressure of the atomizing spray gun is 0.10-0.15MPa; The liquid spray speed is 12~15g/min.
2.包隔离层2. Package isolation layer
将聚乙烯吡咯烷酮30g溶于380ml纯水中，用切喷流化床缓慢喷于步骤1中所得的上药丸心上。切线喷流化床的操作条件为：风机频率为20～23Hz；物料温度为33～35℃；转盘的转动频率为100～150rpm；雾化喷枪的雾化压力为0.10～0.15MPa；包衣液的喷液速度为12～15g/min。Polyvinylpyrrolidone 30g was dissolved in 380ml pure water, and slowly sprayed on the upper pill core gained in step 1 with a cutting jet fluidized bed. The operating conditions of the tangential jet fluidized bed are: the fan frequency is 20-23Hz; the material temperature is 33-35°C; the rotation frequency of the turntable is 100-150rpm; the atomization pressure of the atomizing spray gun is 0.10-0.15MPa; The liquid spray speed is 12~15g/min.
3.包缓释层3. Package slow release layer
将全水乙基纤维素分散体54g，Eudragit L100-55 10g，纯水220g，甘油1g，单硬脂酸甘油酯20g，滑石粉10g，聚维酮3g和聚乙二醇2g用高速剪切搅拌混匀制成包衣液，用切喷流化床将该液缓慢喷于步骤2得到的微丸表面上。切线喷流化床的操作条件为：风机频率为20～23Hz；物料温度为23～25℃；转盘的转动频率为100～150rpm；雾化喷枪的雾化压力为0.10～0.15MPa；包衣液的喷液速度为6～10g/min。所得缓释微丸过60目筛。Mix 54g of whole water ethyl cellulose dispersion, Eudragit L100-55 10g, pure water 220g, glycerin 1g, glyceryl monostearate 20g, talcum powder 10g, povidone 3g and polyethylene glycol 2g with high speed shear Stir and mix to make a coating solution, and spray the solution slowly on the surface of the pellets obtained in
实施例10 压片制备对乙酰氨基酚缓释微丸口腔崩解片Example 10 Tablet preparation of paracetamol sustained-release pellets orally disintegrating tablets
压片制备口腔崩解片，一片量(mg)Tablet preparation orally disintegrating tablet, one piece (mg)
缓释微丸 对乙酰氨基酚缓释微丸 250Sustained-release pellets Paracetamol sustained-release pellets 250
填充剂 甘露醇 126Bulking agent Mannitol 126
填充剂 微晶纤维素 54Filler Microcrystalline Cellulose 54
崩解剂 羧甲基淀粉钠 50Disintegrant Sodium Starch Carboxymethyl 50
矫味剂 薄荷香精 0.2Flavoring Agent Peppermint Flavor 0.2
矫味剂 阿司帕坦 0.3Flavoring agent Aspartame 0.3
润滑剂 硬脂酸镁 15Lubricant Magnesium Stearate 15
润滑剂 滑石粉 4.5Lubricant Talc 4.5
制备方法如下：The preparation method is as follows:
将实施例9所得的对乙酰氨基酚缓释微丸过60目筛，将可直接压片的辅料：甘露醇、微晶纤维素、羧甲基淀粉钠、薄荷香精、阿斯帕坦、硬脂酸镁和滑石粉用压片机直接压片，片剂硬度3kg。取该缓释微丸口腔崩解片，同实施例2的方法测定溶出度。该片剂崩解迅速，在50秒内崩解，在水中缓慢释放11小时。Pass the acetaminophen sustained-release pellets obtained in Example 9 through a 60-mesh sieve, and the auxiliary materials that can be directly compressed: mannitol, microcrystalline cellulose, sodium carboxymethyl starch, mint flavor, aspartame, hard Magnesium fatty acid and talcum powder are directly compressed into tablets with a tablet machine, and the tablet hardness is 3kg. Get the sustained-release pellet orally disintegrating tablet, and measure the dissolution rate with the method of Example 2. The tablet disintegrates rapidly, disintegrating in 50 seconds with a slow release in water for 11 hours.
实施例11 制备对乙酰氨基酚缓释微丸Example 11 Preparation of Paracetamol Sustained Release Pellets
1.丸心上药1. pill heart medicine
将羟丙甲基纤维素2.6g与对乙酰氨基酚18.4g加入75％(v/v)乙醇53ml中制成上药液。将平均粒径为0.15mm蔗糖丸心置流化床中流化10分钟，将上药液缓慢喷于丸心表面。上药增重：20％。切线喷流化床的操作条件为：风机频率为20～23Hz；物料温度为33～35℃；转盘的转动频率为100～150rpm；雾化喷枪的雾化压力为0.10～0.15MPa；包衣液的喷液速度为12～15g/min。Add 2.6 g of hydroxypropyl methylcellulose and 18.4 g of acetaminophen into 53 ml of 75% (v/v) ethanol to prepare a medicinal solution. Put the sucrose ball core with an average particle size of 0.15 mm in a fluidized bed for 10 minutes, and slowly spray the drug solution on the surface of the ball core. Medicated weight gain: 20%. The operating conditions of the tangential jet fluidized bed are: the fan frequency is 20-23Hz; the material temperature is 33-35°C; the rotation frequency of the turntable is 100-150rpm; the atomization pressure of the atomizing spray gun is 0.10-0.15MPa; The liquid spray speed is 12~15g/min.
2.包隔离层2. Package isolation layer
将聚乙烯吡咯烷酮4g溶于70ml纯水中，用切喷流化床缓慢喷于步骤1中所得的上药丸心上。切线喷流化床的操作条件为：风机频率为20～23Hz；物料温度为33～35℃；转盘的转动频率为100～150rpm；雾化喷枪的雾化压力为0.10～0.15MPa；包衣液的喷液速度为12～15g/min。Polyvinylpyrrolidone 4g was dissolved in 70ml pure water, and slowly sprayed on the upper pill core gained in step 1 with a cutting jet fluidized bed. The operating conditions of the tangential jet fluidized bed are: the fan frequency is 20-23Hz; the material temperature is 33-35°C; the rotation frequency of the turntable is 100-150rpm; the atomization pressure of the atomizing spray gun is 0.10-0.15MPa; The liquid spray speed is 12~15g/min.
3.包缓释层3. Package slow release layer
将全水乙基纤维素分散体88g，纯水180g，单硬脂酸甘油酯5g，聚山梨酯80 2g和甘油5g用高速剪切搅拌混匀制成包衣液，用切喷流化床将该液缓慢喷于步骤2得到的微丸表面上。切线喷流化床的操作条件为：风机频率为20～23Hz；物料温度为23～25℃；转盘的转动频率为100～150rpm；雾化喷枪的雾化压力为0.10～0.15MPa；包衣液的喷液速度为6～10g/min。所得缓释微丸过60目筛。With full water ethyl cellulose dispersion 88g, pure water 180g, glyceryl monostearate 5g,
实施例12 压片制备对乙酰氨基酚缓释微丸口腔崩解片Example 12 Tablet preparation of paracetamol sustained-release pellets orally disintegrating tablets
压片制备口腔崩解片，一片量(mg)Tablet preparation orally disintegrating tablet, one piece (mg)
缓释微丸 对乙酰氨基酚缓释微丸 150Sustained-release pellets Paracetamol sustained-release pellets 150
填充剂 甘露醇 147Bulking agent Mannitol 147
填充剂 微晶纤维素 147Filler Microcrystalline Cellulose 147
崩解剂 羧甲基纤维素钠 25Disintegrant Sodium Carboxymethylcellulose 25
矫味剂 阿司帕坦 1Flavoring Aspartame 1
矫味剂 薄荷香精 0.5Flavoring Agent Peppermint Flavor 0.5
润滑剂 硬脂酸镁 15Lubricant Magnesium Stearate 15
润滑剂 微分硅胶 10Lubricant
泡腾剂 碳酸氢钠 3.8Effervescent Sodium Bicarbonate 3.8
泡腾剂 柠檬酸 1.3Effervescent agent citric acid 1.3
制备方法如下：The preparation method is as follows:
将实施例11所得的对乙酰氨基酚缓释微丸过60目筛，将可直接压片的辅料：甘露醇、微晶纤维素、羧甲基纤维素钠、阿斯帕坦、薄荷香精、硬脂酸镁、微分硅胶、碳酸氢钠和柠檬酸用压片机直接压片，片剂硬度3kg。取该缓释微丸口腔崩解片，同实施例2的方法测定溶出度。该片剂崩解迅速，在50秒内崩解，在水中缓慢释放9小时。The acetaminophen sustained-release pellets obtained in Example 11 were passed through a 60-mesh sieve, and the auxiliary materials that could be directly compressed into tablets: mannitol, microcrystalline cellulose, sodium carboxymethyl cellulose, aspartame, mint essence, Magnesium stearate, micro silica gel, sodium bicarbonate and citric acid are directly compressed with a tablet machine, and the hardness of the tablet is 3kg. Get the sustained-release pellet orally disintegrating tablet, and measure the dissolution rate with the method of Example 2. The tablet disintegrates rapidly, disintegrating in 50 seconds with a slow release in water for 9 hours.
实施例13 制备对乙酰氨基酚缓释微丸Example 13 Preparation of Paracetamol Sustained Release Pellets
1.丸心上药1. pill heart medicine
将羟丙甲基纤维素9g与对乙酰氨基酚117g加入75％(v/v)乙醇550ml中制成上药液。将平均粒径为0.15mm蔗糖丸心置流化床中流化10分钟，将上药液缓慢喷于丸心表面。上药增重：99％。切线喷流化床的操作条件为：风机频率为20～23Hz；物料温度为33～35℃；转盘的转动频率为100～150rpm；雾化喷枪的雾化压力为0.10～0.15MPa；包衣液的喷液速度为12～15g/min。Add 9 g of hydroxypropyl methylcellulose and 117 g of acetaminophen into 550 ml of 75% (v/v) ethanol to prepare a medicinal solution. Put the sucrose ball core with an average particle size of 0.15 mm in a fluidized bed for 10 minutes, and slowly spray the drug solution on the surface of the ball core. Medicated weight gain: 99%. The operating conditions of the tangential jet fluidized bed are: the fan frequency is 20-23Hz; the material temperature is 33-35°C; the rotation frequency of the turntable is 100-150rpm; the atomization pressure of the atomizing spray gun is 0.10-0.15MPa; The liquid spray speed is 12~15g/min.
2.包隔离层2. Package isolation layer
将聚乙烯吡咯烷酮0.8g溶于40ml纯水中，用切喷流化床缓慢喷于步骤1中所得的上药丸心上。切线喷流化床的操作条件为：风机频率为20～23Hz；物料温度为33～35℃；转盘的转动频率为100～150rpm；雾化喷枪的雾化压力为0.10～0.15MPa；包衣液的喷液速度为12～15g/min。Polyvinylpyrrolidone 0.8g was dissolved in 40ml pure water, and slowly sprayed on the upper pill core gained in step 1 with a cutting jet fluidized bed. The operating conditions of the tangential jet fluidized bed are: the fan frequency is 20-23Hz; the material temperature is 33-35°C; the rotation frequency of the turntable is 100-150rpm; the atomization pressure of the atomizing spray gun is 0.10-0.15MPa; The liquid spray speed is 12~15g/min.
3.包缓释层3. Package slow release layer
将全水乙基纤维素分散体60g，Eudragit L30D 1g，纯水200g，单硬脂酸甘油酯4g，羟丙甲纤维素15g和枸橼酸三乙酯20g用高速剪切搅拌混匀制成包衣液，用切喷流化床将该液缓慢喷于步骤2得到的微丸表面上。切线喷流化床的操作条件为：风机频率为20～23Hz；物料温度为23～25℃；转盘的转动频率为100～150rpm；雾化喷枪的雾化压力为0.10～0.15MPa；包衣液的喷液速度为6～10g/min。所得缓释微丸过60目筛。Mix 60g of whole water ethyl cellulose dispersion, 1g of Eudragit L30D, 200g of pure water, 4g of glyceryl monostearate, 15g of hypromellose and 20g of triethyl citrate with high-speed shearing and mixing. For the coating solution, slowly spray the solution on the surface of the pellets obtained in
实施例14 压片制备对乙酰氨基酚缓释微丸口腔崩解片Example 14 Tablet preparation of paracetamol sustained-release pellets orally disintegrating tablets
压片制备口腔崩解片，一片量(mg)Tablet preparation orally disintegrating tablet, one piece (mg)
缓释微丸 对乙酰氨基酚缓释微丸 200Sustained-release pellets Acetaminophen sustained-release pellets 200
填充剂 微晶纤维素 100
填充剂 甘露醇 128Bulking agent Mannitol 128
崩解剂 交联聚乙烯吡咯烷酮 30Disintegrant Cross-linked polyvinylpyrrolidone 30
崩解剂 羟丙纤维素 10
崩解剂 丙氨酸 10
矫味剂 阿司帕坦 2.5Flavoring agent Aspartame 2.5
润滑剂 硬脂酸镁 20
制备方法如下：The preparation method is as follows:
将实施例13所得的对乙酰氨基酚缓释微丸过60目筛，将可直接压片的辅料：甘露醇、交联聚乙烯吡咯烷酮、羟丙纤维素、丙氨酸、硬脂酸镁和阿斯帕坦用压片机直接压片，片剂硬度3kg。取该缓释微丸口腔崩解片，同实施例2的方法测定溶出度。该片剂崩解迅速，在50秒内崩解，在水中缓慢释放12小时。The acetaminophen sustained-release pellets obtained in Example 13 were passed through a 60-mesh sieve, and the auxiliary materials that could be directly compressed into tablets: mannitol, cross-linked polyvinylpyrrolidone, hydroxypropyl cellulose, alanine, magnesium stearate and Aspartame is directly compressed into tablets with a tablet machine, and the tablet hardness is 3kg. Get the sustained-release pellet orally disintegrating tablet, and measure the dissolution rate with the method of Example 2. The tablet disintegrates rapidly, disintegrating in 50 seconds, and releases slowly in water for 12 hours.
实施例15 制备对乙酰氨基酚缓释微丸Example 15 Preparation of Paracetamol Sustained Release Pellets
1.丸心上药1. pill heart medicine
将羟丙甲基纤维素0.6g与对乙酰氨基酚5.7g加入75％(v/v)乙醇57ml中制成上药液。将平均粒径为0.15mm蔗糖丸心置流化床中流化10分钟，将上药液缓慢喷于丸心表面。上药增重：26％。切线喷流化床的操作条件为：风机频率为20～23Hz；物料温度为33～35℃；转盘的转动频率为100～150rpm；雾化喷枪的雾化压力为0.10～0.15MPa；包衣液的喷液速度为12～15g/min。Add 0.6 g of hydroxypropyl methylcellulose and 5.7 g of acetaminophen into 57 ml of 75% (v/v) ethanol to prepare a medicinal solution. Put the sucrose ball core with an average particle size of 0.15 mm in a fluidized bed for 10 minutes, and slowly spray the drug solution on the surface of the ball core. Medicated weight gain: 26%. The operating conditions of the tangential jet fluidized bed are: the fan frequency is 20-23Hz; the material temperature is 33-35°C; the rotation frequency of the turntable is 100-150rpm; the atomization pressure of the atomizing spray gun is 0.10-0.15MPa; The liquid spray speed is 12~15g/min.
2.包隔离层2. Package isolation layer
将聚乙烯吡咯烷酮1.3g溶于30ml纯水中，用切喷流化床缓慢喷于步骤1中所得的上药丸心上。切线喷流化床的操作条件为：风机频率为20～23Hz；物料温度为33～35℃；转盘的转动频率为100～150rpm；雾化喷枪的雾化压力为0.10～0.15MPa；包衣液的喷液速度为12～15g/min。Polyvinylpyrrolidone 1.3g was dissolved in 30ml pure water, and slowly sprayed on the upper pill core gained in step 1 with a cutting jet fluidized bed. The operating conditions of the tangential jet fluidized bed are: the fan frequency is 20-23Hz; the material temperature is 33-35°C; the rotation frequency of the turntable is 100-150rpm; the atomization pressure of the atomizing spray gun is 0.10-0.15MPa; The liquid spray speed is 12~15g/min.
3.包缓释层3. Package slow release layer
将全水乙基纤维素分散体60g，Eudragit L30D 4g，纯水200g，单硬脂酸甘油酯4g，乳糖30g和枸橼酸三乙酯2g用高速剪切搅拌混匀制成包衣液，用切喷流化床将该液缓慢喷于步骤2得到的微丸表面上。切线喷流化床的操作条件为：风机频率为20～23Hz；物料温度为23～25℃；转盘的转动频率为100～150rpm；雾化喷枪的雾化压力为0.10～0.15MPa；包衣液的喷液速度为6～10g/min。所得缓释微丸过60目筛。Mix 60g of whole water ethyl cellulose dispersion, Eudragit L30D 4g, pure water 200g, glyceryl monostearate 4g, lactose 30g and triethyl citrate 2g with high-speed shear stirring to make coating liquid, Slowly spray the liquid on the surface of the pellets obtained in
实施例16 压片制备对乙酰氨基酚缓释微丸口腔崩解片Example 16 Tablet preparation of paracetamol sustained-release pellets orally disintegrating tablets
压片制备口腔崩解片，一片量(mg)Tablet preparation orally disintegrating tablet, one piece (mg)
缓释微丸 对乙酰氨基酚缓释微丸 100Sustained-release pellets Paracetamol sustained-
填充剂 微晶纤维素 50Filler Microcrystalline Cellulose 50
填充剂 甘露醇 100Bulking
填充剂 乳糖 100
崩解剂 羧甲基淀粉钠 40Disintegrant
矫味剂 阿司帕坦 1Flavoring Aspartame 1
润滑剂 硬脂酸镁 1Lubricant Magnesium Stearate 1
泡腾剂 碳酸氢钠 5.33Effervescent Sodium Bicarbonate 5.33
泡腾剂 柠檬酸 2.67Effervescent citric acid 2.67
制备方法如下：The preparation method is as follows:
将实施例15所得的对乙酰氨基酚缓释微丸过60目筛，将可直接压片的辅料：微晶纤维素、羧甲基淀粉钠、阿斯帕坦、硬脂酸镁、碳酸氢钠和柠檬酸用压片机直接压片，片剂硬度3kg。取该缓释微丸口腔崩解片，同实施例2的方法测定溶出度。该片剂崩解迅速，在50秒内崩解，在水中缓慢释放12小时。The acetaminophen sustained-release pellets obtained in Example 15 were passed through a 60-mesh sieve, and the auxiliary materials that could be directly compressed were: microcrystalline cellulose, sodium carboxymethyl starch, aspartame, magnesium stearate, bicarbonate Sodium and citric acid are directly compressed with a tablet machine, and the tablet hardness is 3kg. Get the sustained-release pellet orally disintegrating tablet, and measure the dissolution rate with the method of Example 2. The tablet disintegrates rapidly, disintegrating in 50 seconds, and releases slowly in water for 12 hours.
下面通过试验例来进一步说明本发明的有益效果。The beneficial effects of the present invention will be further illustrated below through test examples.
效果实施例1 药物加速稳定性实验Effect Example 1 Drug Accelerated Stability Test
将实施例1所制备的对乙酰氨基酚口腔崩解片包装于密封的双层铝塑袋中，于40℃±2℃、RH 75％±5％的条件下，放置3个月，于0、1、2、3个月分别取样，进行片剂性状、崩解时间、硬度、含量、释放度的测定，结果见表1。The acetaminophen orally disintegrating tablets prepared in Example 1 were packaged in a sealed double-layer aluminum-plastic bag, placed for 3 months at 40°C ± 2°C, and RH 75% ± 5%. , 1, 2, and 3 months were sampled respectively, and the tablet properties, disintegration time, hardness, content, and release were measured. The results are shown in Table 1.
表1.对乙酰氨基酚口腔崩解片加速稳定性实验(n＝3)Table 1. Accelerated stability test of acetaminophen orally disintegrating tablets (n=3)
由加速稳定性实验结果可以看出，于双层铝塑袋中保存的样品3个月的性状、含量与0天时相比基本无变化，崩解时间略有延长，硬度略有下降。本品应密封保存在阴凉干燥的环境中。From the results of the accelerated stability test, it can be seen that the properties and content of the samples stored in double-layer aluminum-plastic bags for 3 months are basically unchanged compared with those at 0 days, the disintegration time is slightly prolonged, and the hardness is slightly decreased. This product should be sealed and stored in a cool and dry environment.
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