CN116115584A - Dextromethorphan sustained-release pellets and suspension - Google Patents

Abstract

The invention discloses a dextromethorphan sustained-release pellet and suspension, and the preparation method comprises the following steps: s1, taking dextromethorphan hydrobromide as a raw material drug and taking a microcrystalline cellulose pellet core as a drug carrying material, and obtaining a drug-containing pellet with the drug contained in the interior and the surface by adopting an adsorption drying method; s2, coating the drug-containing pellets by using a slightly soluble, insoluble or water-insoluble material in water as a slow-release coating material and using a water-soluble material as a plasticizer to obtain the dextromethorphan slow-release pellets. The dextromethorphan oral preparation can slowly release active substances in a human body, continuously exert the drug effect and improve the compliance of patients.

Description

Translated fromChinese

一种右美沙芬缓释微丸及混悬液A kind of dextromethorphan sustained-release pellets and suspension

技术领域technical field

本发明属于缓释制剂领域，尤其涉及一种右美沙芬缓释微丸及混悬液。The invention belongs to the field of sustained-release preparations, in particular to a dextromethorphan sustained-release pellet and suspension.

背景技术Background technique

咳嗽是呼吸系统疾病的一个主要症状，一种保护性反射，具有促进呼吸道的痰液和异物排出，保持呼吸道清洁与通畅的作用。轻微的咳嗽能帮助清除气管内的痰液与异物，且会自然缓解，一般不需服用止咳药；强烈而频繁的咳嗽，尤其是干咳，可影响休息和睡眠，甚至使病情加重而引起其他并发症，需要在针对病因治疗的同时加用止咳化痰药。Cough is a major symptom of respiratory diseases, a protective reflex that promotes the discharge of sputum and foreign matter in the respiratory tract, and keeps the respiratory tract clean and unobstructed. Mild cough can help remove sputum and foreign bodies in the trachea, and it will be relieved naturally. Generally, there is no need to take cough medicine; strong and frequent cough, especially dry cough, can affect rest and sleep, and even aggravate the condition and cause other complications. syndrome, it is necessary to add antitussive and expectorant drugs while treating the cause.

右美沙芬为吗啡类左吗喃甲基醚的右旋异构体，通过抑制延髓咳嗽中枢而发挥中枢性镇咳作用，其镇咳强度与可待因相等或略强；无镇痛作用，长期应用未见耐受性和成瘾性。治疗剂量不抑制呼吸。口服吸收好，15～30分钟起效，作用可维持3～6小时，血浆中原型药物浓度很低。Dextromethorphan is the dextro-isomer of morphine-like levomorphan methyl ether, which exerts a central antitussive effect by inhibiting the medullary cough center, and its antitussive strength is equal to or slightly stronger than codeine; it has no analgesic effect, Long-term application has no tolerance and addiction. Therapeutic doses do not inhibit respiration. Oral absorption is good, it takes 15-30 minutes to take effect, and the effect can be maintained for 3-6 hours. The concentration of the original drug in the plasma is very low.

普通的右美沙芬制剂，常需一日几次给药，如普通片剂一日给药3～4次，每次1-2片(15mg/片)。因怕麻烦等原因患者会有意无意改变服药方案，漏服一次或两次，血浆和组织中的药物水平浓度起伏大，即使继续用药，短期内也达不到治疗浓度，只能重复用药才能重建治疗水平，既浪费了药物又延误了治疗。因此，开发一种右美沙芬的缓释制剂是符合临床应用的前景和需求的。Ordinary dextromethorphan preparations often need to be administered several times a day, for example, ordinary tablets are administered 3 to 4 times a day, 1-2 tablets (15 mg/tablet) each time. For fear of trouble and other reasons, patients will intentionally or unintentionally change the medication regimen, and miss one or two doses. The concentration of the drug in plasma and tissue fluctuates greatly. treatment levels, both wasting drugs and delaying treatment. Therefore, the development of a sustained-release preparation of dextromethorphan is in line with the prospect and demand of clinical application.

发明内容Contents of the invention

基于上述技术问题，本发明提供了一种右美沙芬缓释微丸及混悬液，所述右美沙芬缓释制剂具有较高的载药量，并且能够在人体内缓慢释放药物，持续发挥药效，提高了患者的依从性。Based on the above technical problems, the present invention provides a dextromethorphan sustained-release pellet and suspension, the dextromethorphan sustained-release preparation has a higher drug loading, and can slowly release the drug in the human body, continuously efficacy and improved patient compliance.

本发明具体方案如下：Concrete scheme of the present invention is as follows:

本发明目的之一在于，提供了一种右美沙芬缓释微丸，其制备方法包括：S1、以氢溴酸右美沙芬为原料药、微晶纤维素微丸丸芯作为载药材料，采用吸附干燥法得到内部及表面均含药的含药微丸；S2、以在水中微溶、难溶或水不溶性材料作为缓释包衣材料，水溶性材料为增塑剂，对含药微丸包衣处理，得到右美沙芬缓释微丸。One of the objects of the present invention is to provide a kind of dextromethorphan sustained-release pellets, the preparation method of which comprises: S1, taking dextromethorphan hydrobromide as the raw material and microcrystalline cellulose pellet core as the drug-loading material, using The drug-containing pellets with drug-containing inside and on the surface are obtained by adsorption drying method; S2, using slightly soluble, insoluble or water-insoluble materials in water as sustained-release coating materials, and water-soluble materials as plasticizers, the drug-containing pellets Coating treatment to obtain dextromethorphan sustained-release pellets.

本发明具体选择了微晶纤维素微丸丸芯作为载药材料，首先，其特殊的微观特性决定了它容易形成多孔的结构，就为提高载药量提供了优势条件；其次，在吸附过程中，它优异的结构刚性保障了在吸附之后结构的稳定，有助于后续的包衣的进行；最后，微晶纤维素不溶于水但具有一定的亲水性，水更能顺利地进入到丸芯内部，从而释放其中的药物。进一步，在制备含药微丸时，选择吸附干燥法，得到内部及表面均含药的含药微丸，相对于现有包衣法得到仅表面含药的微丸，在很大程度上提高了载药量；并且通过将活性成分吸附在载药材料内部，也更有利于药物的缓慢释放。更进一步，在包衣时选择水溶性较好的增塑剂与在水中微溶/难溶/不溶的包衣材料配合，来改善包衣膜的成膜性、调节药物释放速率。The present invention specifically selects the microcrystalline cellulose pellet core as the drug-loading material. First, its special microscopic characteristics determine that it is easy to form a porous structure, which provides an advantageous condition for increasing the drug-loading capacity; secondly, in the adsorption process , its excellent structural rigidity ensures the stability of the structure after adsorption, which is helpful for the subsequent coating; finally, microcrystalline cellulose is insoluble in water but has a certain degree of hydrophilicity, and water can enter the pellets more smoothly. inside the core, thereby releasing the drug contained therein. Further, when preparing drug-containing pellets, the adsorption drying method is selected to obtain drug-containing pellets containing drugs both inside and on the surface. Compared with the existing coating method, which only contains drugs on the surface, the drug-containing pellets are greatly improved. The drug loading capacity is improved; and by adsorbing the active ingredient inside the drug-loaded material, it is also more conducive to the slow release of the drug. Furthermore, when coating, a plasticizer with better water solubility is selected to cooperate with coating materials that are slightly soluble/poorly soluble/insoluble in water to improve the film-forming properties of the coating film and adjust the drug release rate.

相对于现有采用阳离子树脂作为载药材料的右美沙芬微丸，本发明以微晶纤维素微丸丸芯与特定的包衣材料、辅料配合，在保证高载药量同时，延长了药物的释放。Compared with the existing dextromethorphan pellets that use cationic resins as drug-loading materials, the present invention uses microcrystalline cellulose pellet cores combined with specific coating materials and auxiliary materials to prolong the life of the drug while ensuring high drug loading. freed.

优选地，微晶纤维素微丸丸芯与氢溴酸右美沙芬原料药的重量比为1-2:2。Preferably, the weight ratio of microcrystalline cellulose pellet core to dextromethorphan hydrobromide bulk drug is 1-2:2.

优选地，微晶纤维素微丸丸芯D90粒径为100-200μm。Preferably, the D90 particle diameter of the microcrystalline cellulose pellet core is 100-200 μm.

本发明将微晶纤维素微丸丸芯的D90粒径控制在100-200μm，具有更大的比表面积以及更强的吸附能力，在该粒径条件下，微晶纤维素微丸丸芯的吸水率能够达到100-130％，并且有利于后期制备得到右美沙芬缓释混悬液。The present invention controls the D90 particle size of the microcrystalline cellulose pellet core at 100-200 μm, which has a larger specific surface area and stronger adsorption capacity. Under the particle size condition, the water absorption rate of the microcrystalline cellulose pellet core It can reach 100-130%, and is beneficial to the preparation of dextromethorphan sustained-release suspension in the later stage.

优选地，微晶纤维素微丸丸芯选自市售成品或自制得到；更优选地，微晶纤维素微丸丸芯制备方法包括：将微晶纤维素加入水中，均质处理，得到含水的微晶纤维素滤饼；对微晶纤维素滤饼干燥后，采用挤出滚圆法制备得到。Preferably, the microcrystalline cellulose pellet core is selected from commercially available finished products or obtained by self-made; more preferably, the preparation method of the microcrystalline cellulose pellet core includes: adding microcrystalline cellulose to water, and homogenizing treatment to obtain aqueous microcrystalline cellulose Crystalline cellulose filter cake: after drying the microcrystalline cellulose filter cake, it is prepared by extrusion and spheronization.

对于市售的微晶纤维素微丸丸芯不作具体限定，包括但不限于：目前已商业化的旭化成的

东辰制药的

等。There are no specific limitations on the commercially available microcrystalline cellulose pellet cores, including but not limited to: the currently commercialized Asahi Kasei

Dongchen Pharmaceutical's

wait.

优选地，含药微丸水分≤3％；含药微丸相对于微晶纤维素微丸丸芯增重55-65％。Preferably, the water content of the drug-containing pellets is ≤3%, and the weight of the drug-containing pellets increases by 55-65% relative to the core of the microcrystalline cellulose pellets.

优选地，吸附干燥法具体包括：将氢溴酸右美沙芬原料药溶解于溶剂中，得到含药溶液；将微晶纤维素微丸丸芯置于含药溶液中，搅拌4-6h，过滤干燥，得到含药微丸；更优选地，溶剂为50-80％乙醇；更优选地，含药溶液的浓度为10-50％；更优选地，搅拌速率为10-20rpm。Preferably, the adsorption drying method specifically includes: dissolving the dextromethorphan hydrobromide bulk drug in a solvent to obtain a drug-containing solution; placing microcrystalline cellulose pellet cores in the drug-containing solution, stirring for 4-6 hours, and filtering to dry , to obtain drug-containing pellets; more preferably, the solvent is 50-80% ethanol; more preferably, the concentration of the drug-containing solution is 10-50%; more preferably, the stirring rate is 10-20rpm.

本发明制备含药微丸时，选择合适的溶剂溶解原料药，既能保证很好地溶解原料药，又便于后续的干燥，更好地去除该溶剂；同时，溶剂还不能破坏微晶纤维素微丸丸芯的结构，保证在吸附原料药后能维持丸芯的完整性和刚性。When the present invention prepares drug-containing micropills, selecting a suitable solvent to dissolve the bulk drug can ensure that the bulk drug is well dissolved, facilitates subsequent drying, and better removes the solvent; at the same time, the solvent cannot destroy the microcrystalline cellulose The structure of the pellet core ensures that the integrity and rigidity of the pellet core can be maintained after absorbing the raw material drug.

本发明制备含药微丸时，优选乙醇作为溶剂，原料药氢溴酸右美沙芬在乙醇溶液中易溶，但微晶纤维素微丸丸芯在其中不溶，这就保障原料药溶液被充分吸附后，微丸丸芯依旧能保持球形结构，并且在干燥过程中溶剂更易挥发而被去除；在此过程中，微丸丸芯仅因为吸附有轻微溶胀现象，在干燥后立即恢复原状，其脆碎度并未受影响，能够较好的维持微丸丸芯的完整性和刚性。When the present invention prepares drug-containing pellets, ethanol is preferably used as a solvent, and the bulk drug dextromethorphan hydrobromide is easily soluble in the ethanol solution, but the microcrystalline cellulose pellet core is insoluble in it, which ensures that the bulk drug solution is fully absorbed After that, the pellet core can still maintain a spherical structure, and the solvent is more volatile and removed during the drying process; in this process, the pellet core returns to its original shape immediately after drying only because of the slight swelling phenomenon due to adsorption, and its friability It is not affected, and the integrity and rigidity of the pellet core can be better maintained.

本发明将微丸丸芯置于高浓度含药溶液中，通过低速、较长时间的搅拌，使得含药溶液与微丸丸芯接触，保障微晶纤维素微丸丸芯充分吸附原料药。In the present invention, the pellet core is placed in a high-concentration drug-containing solution, and the drug-containing solution contacts the pellet core through low-speed, long-time stirring to ensure that the microcrystalline cellulose pellet core fully absorbs the raw material drug.

对于干燥的方法不作具体限定，可以采用常规的干燥方法；如包括但不限于，热风循环烘箱干燥、流化床干燥等；优选地，采用流化床干燥，能够提高干燥效率以及均匀性。The drying method is not specifically limited, and conventional drying methods can be used; for example, including but not limited to, hot air circulation oven drying, fluidized bed drying, etc.; preferably, fluidized bed drying can improve drying efficiency and uniformity.

优选地，缓释包衣材料选自纤维素类、聚丙烯酸树脂及其衍生物类、聚二甲基硅氧烷及其类似物中的一种或多种的组合；更优选地，纤维素类包衣材料为醋酸纤维素或乙基纤维素。Preferably, the slow-release coating material is selected from one or more combinations of cellulose, polyacrylic acid resin and its derivatives, polydimethylsiloxane and the like; more preferably, cellulose The coating material is cellulose acetate or ethyl cellulose.

优选地，增塑剂选自聚乙二醇、枸橼酸三乙酯、邻苯二甲酸二乙酯中的一种或多种的组合；更优选地，包衣增重5-8％。Preferably, the plasticizer is selected from one or more combinations of polyethylene glycol, triethyl citrate, and diethyl phthalate; more preferably, the weight gain of the coating is 5-8%.

本发明目的之二在于，提供了一种右美沙芬混悬液，包括以上任一项所述的右美沙芬缓释微丸。The second object of the present invention is to provide a dextromethorphan suspension, including the dextromethorphan sustained-release pellets described in any one of the above.

优选地，所述右美沙芬混悬液按重量份包括：右美沙芬缓释微丸200-300份、增稠剂20-30份、pH调节剂6-10份、矫味剂5-10份、抑菌剂1-5份、水200-300份；更优选地，还包括食用香精1-2份、食用色素1-5份。Preferably, the dextromethorphan suspension comprises by weight: 200-300 parts of dextromethorphan sustained-release pellets, 20-30 parts of thickener, 6-10 parts of pH regulator, 5-10 parts of flavoring agent 1-5 parts of antibacterial agent, 200-300 parts of water; more preferably, 1-2 parts of food essence and 1-5 parts of food coloring are also included.

对于混悬液中，增稠剂、pH调节剂、矫味剂、抑菌剂、食用香精、食用色素不作具体限定。如增稠剂包括但不限于，羧甲基纤维素钠、羟丙甲纤维素、黄原胶、阿拉伯胶等；pH调节剂包括但不限于，柠檬酸、乳酸、酒石酸等；矫味剂包括但不限于，蔗糖、糖精钠、三氯蔗糖、阿司帕坦(阿斯巴甜)等；抑菌剂包括但不限于，苯甲酸钠、羟苯甲酯和羟苯乙酯等；食用色素和对应的食用香精进行搭配选择，包括但不限于，以黄色色素和柠檬香精或者菠萝香精搭配；红色色素则和西瓜香精或者草莓香精进行搭配使用。For the suspension, thickeners, pH regulators, flavoring agents, antibacterial agents, food flavors and food colorings are not specifically limited. Such as thickeners include but not limited to, sodium carboxymethylcellulose, hypromellose, xanthan gum, gum arabic, etc.; pH regulators include but not limited to, citric acid, lactic acid, tartaric acid, etc.; flavoring agents include But not limited to, sucrose, sodium saccharin, sucralose, aspartame (aspartame), etc.; bacteriostatic agents include, but not limited to, sodium benzoate, methylparaben and ethylparaben, etc.; food coloring and The matching of the corresponding food flavors is selected, including but not limited to, yellow pigment is used in combination with lemon flavor or pineapple flavor; red pigment is used in combination with watermelon flavor or strawberry flavor.

对于混悬液的制备方法不作具体限定，采用常规方法即可。如先将混悬液的其余辅料在搅拌的过程中溶解到溶剂中，然后投入制得的右美沙芬缓释微丸，最后经过灌装机均匀灌装到大小合适的HDPE瓶或玻璃瓶中，压盖后得到成品。The preparation method of the suspension is not specifically limited, and conventional methods can be used. For example, the rest of the auxiliary materials of the suspension are dissolved into the solvent during the stirring process, and then put into the prepared dextromethorphan sustained-release pellets, and finally evenly filled into HDPE bottles or glass bottles of appropriate size through the filling machine , and the finished product is obtained after capping.

本发明有益效果为：The beneficial effects of the present invention are:

本发明提供了一种右美沙芬缓释微丸及混悬液，所述右美沙芬缓释制剂制备工艺简单，能够在提高载药量的同时，减少突释，使药物在其用药周期内药物能够平稳释放，延长药物的作用时间，减少病人的服用次数，提高患者的依从性。The invention provides a dextromethorphan sustained-release pellet and a suspension. The preparation process of the dextromethorphan sustained-release preparation is simple, and can reduce burst release while increasing the drug loading, so that the drug can be used within its medication cycle. The drug can be released stably, prolonging the action time of the drug, reducing the number of times the patient takes it, and improving the patient's compliance.

附图说明Description of drawings

图1为本发明含药微丸的制备工艺流程图；Fig. 1 is the preparation process flowchart of drug-containing micropill of the present invention;

图2为本发明缓释微丸的制备工艺流程图；Fig. 2 is the preparation process flow chart of sustained-release pellet of the present invention;

图3为本发明混悬液的制备工艺流程图；Fig. 3 is the preparation process flowchart of suspension of the present invention;

图4为实施例2、3制备得到右美沙芬混悬液的体外释放曲线；Fig. 4 is the in vitro release curve of dextromethorphan suspension prepared byembodiment 2,3;

具体实施方式Detailed ways

下面，通过具体实施例对本发明的技术方案进行详细说明，但是应该明确提出这些实施例用于举例说明，但是不解释为限制本发明的范围。In the following, the technical solution of the present invention will be described in detail through specific examples, but these examples should be clearly set forth for illustration, but should not be construed as limiting the scope of the present invention.

实施例1Example 1

一种右美沙芬缓释微丸，其按照如下方法制备得到：A kind of dextromethorphan sustained-release pellets, which are prepared according to the following method:

S1、制备含药微丸：取200份氢溴酸右美沙芬原料药，加入到300份50％乙醇溶液中，在300rpm下搅拌30分钟，得到含药溶液；然后向含药溶液中投入150份微晶纤维素微丸丸芯(日本旭化成商业化生产CELPHERE

，型号：SCP-100，D90为100μm)，降低搅拌转速至20rpm，搅拌5小时后停止，再静置2小时；使用10μm孔径的滤纸/滤膜将上述药液过滤，收集含药微丸(湿)，置于流化床中，设置进风温度60℃，开启鼓风，开始干燥，待物料温度达到50℃后停止，得到235份含药微丸(干)；S1, preparation of drug-containing pellets: get 200 parts of dextromethorphan hydrobromide crude drug, join in 300 parts of 50% ethanol solution, stir at 300rpm for 30 minutes, obtain drug-containing solution; then drop 150 parts of drug-containing solution into drug-containing solution Part microcrystalline cellulose pellet core (Japan Asahi Kasei commercial production CELPHERE

, model: SCP-100, D90 is 100 μm), reduce the stirring speed to 20rpm, stop after stirring for 5 hours, and then let it stand for 2 hours; use filter paper/filter membrane with 10 μm pore size to filter the above medicinal solution, and collect the drug-containing pellets ( wet), placed in a fluidized bed, set the inlet air temperature to 60°C, turned on the blast, started drying, and stopped after the temperature of the material reached 50°C to obtain 235 parts of drug-containing pellets (dry);

测得含药微丸水分在2％以内，脆碎度为0，含药微丸相对于微晶纤维素微丸丸芯增重为57％。It is measured that the water content of the drug-containing pellets is within 2%, the friability is 0, and the weight gain of the drug-containing pellets relative to the microcrystalline cellulose pellet core is 57%.

S2、制备缓释微丸：取20份Asland的乙基纤维素(EC)Aqualon

(型号：N14)和2份枸橼酸三乙酯(TEC)，加入到378份80％乙醇溶液中，300rpm搅拌使之完全溶解，即得包衣液；取本实施例制得的含药微丸(干)200份，投入到带底喷装置的流化床中，在进风温度45℃下，喷入包衣液进行包衣；全部包衣液喷完后，调节进风温度为60℃，继续干燥30分钟，即得216份右美沙芬缓释微丸(包衣增重为8％)。S2, preparation of sustained-release pellets: get 20 parts of Asland's ethyl cellulose (EC) Aqualon

(model: N14) and 2 parts of triethyl citrate (TEC), join in 378 parts of 80% ethanol solution, stir at 300rpm and make it dissolve completely, obtain coating solution; 200 parts of pellets (dry) were put into a fluidized bed with a bottom spray device, and at an air inlet temperature of 45°C, sprayed into the coating liquid for coating; after all the coating liquid was sprayed, the air inlet temperature was adjusted to Continue drying at 60° C. for 30 minutes to obtain 216 parts of dextromethorphan sustained-release pellets (coating weight gain is 8%).

一种右美沙芬混悬液，包括：本实施例制备的右美沙芬缓释微丸216份、黄原胶20份、柠檬酸6份、阿司帕坦5份、羟苯甲酯1份、柠檬香精1份、柠檬黄1份、纯化水250份。A suspension of dextromethorphan, comprising: 216 parts of dextromethorphan sustained-release pellets prepared in this embodiment, 20 parts of xanthan gum, 6 parts of citric acid, 5 parts of aspartame, and 1 part of methylparaben , 1 part of lemon essence, 1 part of lemon yellow, 250 parts of purified water.

其制备方法为：先取20份黄原胶加入到250份纯化水中，搅拌使之溶解形成粘稠液体，然后再依次加入6份柠檬酸、5份阿司帕坦、1份羟苯甲酯、1份柠檬香精和1份柠檬黄，搅拌溶解完全；最后取216份本实施例制得的右美沙芬缓释微丸，投入到其中，300rpm下搅拌30分钟，使其形成均匀的混悬液；最后灌装至HDPE瓶中，压盖后得到成品。The preparation method is as follows: firstly take 20 parts of xanthan gum and add it to 250 parts of purified water, stir to dissolve it to form a viscous liquid, then add 6 parts of citric acid, 5 parts of aspartame, 1 part of methylparaben, 1 part of lemon essence and 1 part of tartrazine, stir and dissolve completely; finally take 216 parts of dextromethorphan sustained-release pellets prepared in this embodiment, put them into it, and stir for 30 minutes at 300 rpm to form a uniform suspension ; Finally, it is filled into HDPE bottles, and the finished product is obtained after capping.

实施例2Example 2

一种右美沙芬缓释微丸，其按照如下方法制备得到：A kind of dextromethorphan sustained-release pellets, which are prepared according to the following method:

S1、制备含药微丸：取300份氢溴酸右美沙芬原料药，加入到300份80％乙醇溶液中，在300rpm下搅拌30分钟，得到含药溶液；然后投入150份自制的微晶纤维素微丸丸芯，降低搅拌转速至15rpm，搅拌5小时后停止，再静置2小时；使用50μm孔径的滤纸/滤膜将上述药液过滤，收集含药微丸(湿)，置于流化床中，设置进风温度60℃，开启鼓风，开始干燥，待物料温度达到50℃后停止，得到240份含药微丸(干)；S1. Preparation of drug-containing pellets: Take 300 parts of dextromethorphan hydrobromide crude drug, add to 300 parts of 80% ethanol solution, stir at 300 rpm for 30 minutes to obtain drug-containing solution; then put 150 parts of self-made microcrystal For the core of cellulose pellets, reduce the stirring speed to 15rpm, stop after stirring for 5 hours, and then let it stand for 2 hours; use a filter paper/filter membrane with a pore size of 50 μm to filter the above medicinal solution, collect drug-containing pellets (wet), and place in the flow In the chemical bed, set the inlet air temperature to 60°C, turn on the blast, start drying, and stop after the temperature of the material reaches 50°C, and obtain 240 parts of drug-containing pellets (dry);

测得含药微丸的水分在1.5％以内，脆碎度为0，含药微丸相对于微晶纤维素微丸丸芯增重为60％。It is measured that the moisture content of the drug-containing pellets is within 1.5%, the friability is 0, and the weight gain of the drug-containing pellets relative to the microcrystalline cellulose pellet core is 60%.

S2、制备缓释微丸：取25份乙基纤维素和2份枸橼酸三乙酯，加入到243份75％乙醇中，搅拌使之完全溶解，得到固含量10％的包衣液；取本实施例制得的含药微丸(干)240份，投入到安装好底喷装置的流化床中，在进风温度为45℃，风量控制在1000m³/h，当物料温度达到42℃以上时，可以开启蠕动泵，转速保持在20rpm，可根据物料温度调节蠕动泵转速，整个包衣过程中物料温度不得低于32℃。包衣液消耗完毕后，关闭蠕动泵，调节进风温度至60℃，继续干燥35分钟，得到260份缓释微丸(包衣增重为8.0％)。S2. Preparation of sustained-release pellets: Take 25 parts of ethyl cellulose and 2 parts of triethyl citrate, add them to 243 parts of 75% ethanol, stir to dissolve them completely, and obtain a coating solution with a solid content of 10%; Get 240 parts of drug-containing pellets (dry) prepared in this example, and put them into the fluidized bed installed with the bottom spray device. The air inlet temperature is 45°C, and the air volume is controlled at 1000m³ /h. When the material temperature reaches When the temperature is above 42°C, the peristaltic pump can be turned on, and the speed can be kept at 20rpm. The speed of the peristaltic pump can be adjusted according to the temperature of the material. The temperature of the material during the entire coating process should not be lower than 32°C. After the coating solution was consumed, the peristaltic pump was turned off, the air inlet temperature was adjusted to 60° C., and the drying was continued for 35 minutes to obtain 260 parts of slow-release pellets (the weight gain of the coating was 8.0%).

其中，微晶纤维素微丸丸芯自制备得到，具体方法为：取100份微晶纤维素，加入到300份纯化水中，经高压均质机在1200bar压力下均质处理后真空抽滤，得到含水的微晶纤维素滤饼，含水量在40％，然后使用流化床进行干燥；最后投入到挤出滚圆机中，使用0.1mm的断面板，制备得到微晶纤维素微丸丸芯。通过激光粒度仪测得丸芯的粒径分布D90为130μm，测得其脆碎度为0。Among them, the microcrystalline cellulose pellet core is self-prepared, and the specific method is: take 100 parts of microcrystalline cellulose, add it to 300 parts of purified water, and vacuum filter it after homogenizing at a pressure of 1200 bar by a high-pressure homogenizer to obtain The water-containing microcrystalline cellulose filter cake has a water content of 40%, and then is dried using a fluidized bed; finally, it is put into an extrusion spheronizer, and a 0.1mm section plate is used to prepare a microcrystalline cellulose pellet core. The particle size distribution D90 of the pellet core measured by a laser particle size analyzer was 130 μm, and its friability was measured to be 0.

一种右美沙芬混悬液，包括：本实施例制备的右美沙芬缓释微丸260份、黄原胶20份、柠檬酸8份、三氯蔗糖5份、苯甲酸钠5份、草莓香精1份、胭脂红1份、纯化水200份。A dextromethorphan suspension, comprising: 260 parts of dextromethorphan sustained-release pellets prepared in this embodiment, 20 parts of xanthan gum, 8 parts of citric acid, 5 parts of sucralose, 5 parts of sodium benzoate, strawberry essence 1 part, 1 part of carmine, 200 parts of purified water.

其制备方法为：取20份黄原胶加入到200份纯化水中，搅拌使之溶解形成粘稠液体，然后再依次加入8份柠檬酸、5份三氯蔗糖、5份苯甲酸钠、1份草莓香精和1份胭脂红，搅拌溶解完全；最后取260份本实施例制得的右美沙芬缓释微丸，投入到其中，300rpm下搅拌30分钟，使其形成均匀的混悬液；最后灌装至白色或棕色的HDPE瓶中，压盖后得到成品。The preparation method is: take 20 parts of xanthan gum and add it to 200 parts of purified water, stir to dissolve it to form a viscous liquid, then add 8 parts of citric acid, 5 parts of sucralose, 5 parts of sodium benzoate, and 1 part of strawberry Essence and 1 part of carmine, stir and dissolve completely; finally take 260 parts of dextromethorphan sustained-release pellets prepared in this embodiment, put them into it, and stir for 30 minutes at 300 rpm to form a uniform suspension; finally pour Put it into white or brown HDPE bottle, and get the finished product after pressing the cap.

实施例3Example 3

一种右美沙芬缓释微丸，其按照如下方法制备得到：A kind of dextromethorphan sustained-release pellets, which are prepared according to the following method:

S1、制备含药微丸：与实施例2相同；S1, preparation of drug-containing pellets: the same as in Example 2;

S2、制备缓释微丸：取25份甲基丙烯酸-丙烯酸甲酯共聚物(1:1)和3份邻苯二甲酸二乙酯，加入到205份80％乙醇中，搅拌使之完全溶解，得到固含量12％的包衣液。然后取240份含药微丸(干)，投入到安装好底喷装置的流化床中，设置进风温度为45℃，风量控制在800m³/h，当物料温度达到42℃以上时，可以开启蠕动泵，转速保持在10rpm，可根据物料温度调节蠕动泵转速，整个包衣过程中物料温度不得低于32℃。包衣液消耗完毕后，关闭蠕动泵，调节进风温度至60℃，继续干燥30分钟，然后得到255份缓释微丸(包衣增重为6.25％)。S2. Preparation of sustained-release pellets: Take 25 parts of methacrylic acid-methyl acrylate copolymer (1:1) and 3 parts of diethyl phthalate, add them to 205 parts of 80% ethanol, stir to dissolve completely , to obtain a coating solution with a solid content of 12%. Then get 240 parts of drug-containing micropills (dry), drop into the fluidized bed that installs the bottom spray device, set the inlet air temperature as 45°C, and the air volume is controlled at 800m³ /h, when the material temperature reaches more than 42°C, The peristaltic pump can be turned on, and the speed can be kept at 10rpm. The speed of the peristaltic pump can be adjusted according to the temperature of the material. The temperature of the material during the entire coating process should not be lower than 32°C. After the coating solution was consumed, the peristaltic pump was turned off, the air inlet temperature was adjusted to 60° C., and the drying was continued for 30 minutes to obtain 255 parts of slow-release pellets (the coating weight gain was 6.25%).

一种右美沙芬混悬液，将右美沙芬缓释微丸替换为本实施例制备的右美沙芬缓释微丸，其它配方组成及制备方法均与实施例1相同。A dextromethorphan suspension, in which the dextromethorphan sustained-release pellets are replaced by the dextromethorphan sustained-release pellets prepared in this example, and other formulations and preparation methods are the same as in Example 1.

对比例1Comparative example 1

一种右美沙芬缓释微丸，其按照如下方法制备得到：A kind of dextromethorphan sustained-release pellets, which are prepared according to the following method:

S1、制备含药微丸：取300份氢溴酸右美沙芬原料药，加入到300份50％甲醇溶液中，在300rpm下搅拌30分钟；然后投入150份自制的微晶纤维素微丸丸芯，降低搅拌转速至15rpm，搅拌5小时后停止，再静置2小时；使用50μm孔径的滤纸/滤膜将上述药液过滤，收集含药微丸(湿)，置于流化床中，设置进风温度60℃，开启鼓风，开始干燥，待物料温度达到50℃后停止，得到247.5份含药微丸(干)；S1. Preparation of drug-containing pellets: take 300 parts of dextromethorphan hydrobromide crude drug, add them to 300 parts of 50% methanol solution, and stir at 300 rpm for 30 minutes; then put 150 parts of self-made microcrystalline cellulose pellet cores , reduce the stirring speed to 15rpm, stop after stirring for 5 hours, and then let stand for 2 hours; use the filter paper/filter membrane of 50 μm aperture to filter the above-mentioned medicinal solution, collect the drug-containing pellets (wet), place in the fluidized bed, set The air inlet temperature is 60°C, turn on the blower, start drying, and stop after the temperature of the material reaches 50°C, and obtain 247.5 parts of drug-containing pellets (dry);

测得含药微丸的水分在3％以内，脆碎度为0.2％，含药微丸相对于微晶纤维素微丸丸芯增重为65％。It is measured that the water content of the drug-containing pellets is within 3%, the friability is 0.2%, and the weight gain of the drug-containing pellets relative to the microcrystalline cellulose pellet core is 65%.

其中，微晶纤维素微丸丸芯采用与实施例2相同的方法自制得到。Wherein, the microcrystalline cellulose pellet core is self-produced by the same method as in Example 2.

S2、制备缓释微丸：与实施例2相同。S2. Preparation of sustained-release pellets: the same as in Example 2.

性能测试：Performance Testing:

对本发明实施例2、3制备的右美沙芬混悬液的体外释放曲线进行测定，测定方法参照《中国药典》2020年版通则0931第二法：精密量取样品约10ml，置于900ml已脱气处理的pH6.8磷酸盐缓冲液中，转速为100rpm，温度37℃；投入样品时开始计时，于设定的时间点取样10ml，同时补充等温等体积的释放介质，过滤得供试品溶液，每个时间点的样品检测右美沙芬含量。The in vitro release curve of the dextromethorphan suspension prepared in Examples 2 and 3 of the present invention is determined, and the determination method refers to the second method of "Chinese Pharmacopoeia" 2020 Edition General Rule 0931: Precisely measure about 10ml of the sample and place it in 900ml degassed In the treated pH6.8 phosphate buffer solution, the rotating speed is 100rpm, and the temperature is 37°C; when the sample is put in, start timing, take a sample of 10ml at the set time point, and supplement isothermal and equal-volume release medium at the same time, and filter to obtain the test solution. The samples at each time point were tested for dextromethorphan content.

实施例2、3右美沙芬混悬液的体外释放曲线如图4所示，可以看出，本发明制备的右美沙芬混悬液中的药物的释放无突释现象；从累积释放度上来看，释放曲线较为平缓，接近于“零级释放”；总体的释放时间大约在10～12小时左右，相对于常规的右美沙芬制剂，其药物释放周期延长将近一倍时间，良好的体外释放曲线是体内释药并维持良好药效基础。The in vitro release curve ofembodiment 2,3 dextromethorphan suspension is as shown in Figure 4, as can be seen, the release of the medicine in the dextromethorphan suspension prepared by the present invention has no sudden release phenomenon; Look, the release curve is relatively gentle, close to "zero-order release"; the overall release time is about 10 to 12 hours, compared with the conventional dextromethorphan preparation, the drug release period is nearly doubled, and the release in vitro is good. Curves are the basis for in vivo drug release and maintenance of good efficacy.

本发明所述右美沙芬混悬液具有良好体外释放曲线的关键，主要在于：(1)采用了具有丰富孔隙的微晶纤维素微丸丸芯作为载药材料，使用吸附干燥法，提高了药物载量；(2)采用在水中微溶、难溶或水不溶性材料作为缓释包衣材料，配合水溶性的增塑剂，对含药微丸进行包衣处理调节药物的释放速率。The dextromethorphan suspension of the present invention has the key of a good in vitro release curve, mainly in that: (1) microcrystalline cellulose pellet cores with abundant pores are used as the drug-loading material, and the adsorption drying method is used to improve the concentration of the drug. (2) Slightly soluble, poorly soluble or water-insoluble materials are used as sustained-release coating materials, and water-soluble plasticizers are used to coat the drug-containing pellets to adjust the release rate of the drug.

以上所述，仅为本发明较佳的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内，根据本发明的技术方案及其发明构思加以等同替换或改变，都应涵盖在本发明的保护范围之内。The above is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto, any person familiar with the technical field within the technical scope disclosed in the present invention, according to the technical solution of the present invention Any equivalent replacement or change of the inventive concepts thereof shall fall within the protection scope of the present invention.

Claims (10)

1. The dextromethorphan sustained-release pellet is characterized in that the preparation method comprises the following steps: s1, taking dextromethorphan hydrobromide as a raw material drug and taking a microcrystalline cellulose pellet core as a drug carrying material, and obtaining a drug-containing pellet with the drug contained in the interior and the surface by adopting an adsorption drying method; s2, coating the drug-containing pellets by using a slightly soluble, insoluble or water-insoluble material in water as a slow-release coating material and using a water-soluble material as a plasticizer to obtain the dextromethorphan slow-release pellets.

2. The dextromethorphan sustained release pellet of claim 1, wherein the weight ratio of microcrystalline cellulose pellet core to dextromethorphan hydrobromide bulk drug is 1-2:2.

3. Dextromethorphan sustained release pellets according to claim 1 or 2 wherein the microcrystalline cellulose pellet core D90 has a particle size of 100-200 μm.

4. Dextromethorphan sustained release pellets as set forth in any one of claims 1-3 wherein the microcrystalline cellulose pellet core is selected from a commercially available finished product or is self-made; preferably, the preparation method of the microcrystalline cellulose pellet core comprises the following steps: adding microcrystalline cellulose into water, and homogenizing to obtain an aqueous microcrystalline cellulose filter cake; and drying the microcrystalline cellulose filter cake, and adopting an extrusion spheronization method.

5. The dextromethorphan sustained-release pellet according to any one of claims 1-4, wherein the moisture of the drug-containing pellet is less than or equal to 3%; the weight of the drug-containing micropellets is increased by 55-65% relative to the microcrystalline cellulose micropellet core.

6. The dextromethorphan sustained release pellet as recited in any one of claims 1-5, wherein the adsorption drying process specifically comprises: dissolving dextromethorphan hydrobromide bulk drug in a solvent to obtain a drug-containing solution; placing microcrystalline cellulose pellet core into the drug-containing solution, stirring for 4-6h, filtering and drying to obtain drug-containing pellet; preferably, the solvent is 50-80% ethanol; preferably, the concentration of the drug-containing solution is 10-50%; preferably, the stirring rate is 10-20rpm.

7. Dextromethorphan sustained-release pellets as recited in any one of claims 1-6 wherein the sustained-release coating material is selected from the group consisting of one or more of celluloses, polyacrylic resins and derivatives thereof, polydimethylsiloxanes and analogs thereof; preferably, the cellulose-based coating material is cellulose acetate or ethylcellulose.

8. Dextromethorphan sustained release pellets as set forth in any one of claims 1-7 wherein the plasticizer is selected from the group consisting of polyethylene glycol, triethyl citrate, diethyl phthalate, and combinations thereof; preferably, the coating is weighted 5-8%.

9. Dextromethorphan suspension comprising dextromethorphan slow release pellets according to any one of claims 1-8.

10. Dextromethorphan suspension according to claim 9, comprising, in parts by weight: 200-300 parts of dextromethorphan sustained-release pellets, 20-30 parts of thickening agent, 6-10 parts of pH regulator, 5-10 parts of corrigent, 1-5 parts of bacteriostat and 200-300 parts of water; preferably, the food additive also comprises 1-2 parts of edible essence and 1-5 parts of edible pigment.

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