热熔喷雾冷冻技术制备掩味头孢呋辛酯干混悬剂的研究

发布时间：2018-08-09 20:49

【摘要】：头孢呋辛（Cefuroxime），属于第二代头孢菌素，由英国GlaxoSmithKline公司首先开发成功并获得专利，并于1978年在英国、爱尔兰、德国和意大利率先上市，商品名为“Zinacef”，随后在全球许多国家地区销售。其对β-内酰胺酶高度稳定，对大多数G-和G+具有较高活性，安全性好，，成为临床上颇具价值的广谱抗生素。头孢呋辛口服后胃肠道对其吸收极少，据GlaxoSmithKline公司申请的专利4267320披露[1]，在头孢呋辛的C4羧基上引入酯基，得到头孢呋辛酯（Cefuroxime Axetil,CFA），可增强其亲酯性和在胃肠道中的稳定性，大大地提高了口服吸收率。头孢呋辛酯本身并不具有抗菌活性，口服吸收后迅速被体液和血液中的非特异性酶水解生成头孢呋辛而发挥抗菌作用，从而得到广泛地应用。国内已上市的的头孢呋辛酯剂型有片剂、胶囊剂、颗粒剂和干混悬剂。干混悬剂由于具有吸收良好、便于携带、易于服用，适合婴幼儿、儿童、老人及其他吞服困难的患者使用等优势，在临床应用中起到不可或缺的重要地位。然而，头孢呋辛酯味极苦，采用普通工艺制备的干混悬剂严重影响患者服药顺应性。对此，需采用现代化掩味技术解决这一缺陷。目前常用的掩味技术有添加矫味剂或甜味剂、药物微囊化、离子交换法、固体分散体法、包合法、喷雾干燥包衣等方法。但头孢呋辛酯具有味极苦、服用剂量大、湿热不稳定等特点，上述掩味方法对该药并不适用。国内目前采用的掩味手段为，以硬脂酸作为掩味包衣材料，将头孢呋辛酯与熔融状态的硬脂酸混合在一起，冷却后粉碎成具有一定粒度的颗粒。该方法由于破坏了包衣层的完整性而无法达到掩味的要求。现在热熔喷雾冷冻包衣这一新技术面世并已成功应用于药物制剂的生产。热熔喷雾冷冻包衣是在一定温度下（温度通常高于热熔材料的熔点而低于其他物料的熔点）将混合均匀的熔融辅料和其他物料通过雾化器分散成雾状液滴，并在冷冻室内与冷空气充分接触进行热交换，使雾状液滴迅速凝固，在高效旋风分离器内完成气固分离得到极细粉体或细颗粒半成品或成品的一种特殊包衣手段。本文采用热熔喷雾冷冻技术制备出掩味的头孢呋辛酯微粒，并将该微粒及其他辅料通过流化床顶喷制粒制备干混悬剂，成功实现头孢呋辛酯苦味的掩盖，并且提高头孢呋辛酯包衣微粒的溶出度。该方法对设备技术要求低，操作简便易行，可实现工业化连续生产，且能很好掩盖头孢呋辛酯的苦味。用头孢呋辛酯包衣微粒制备的干混悬剂冲服方便，口感好，患者顺应性高，尤其适用婴幼儿、儿童、老人及其他吞服困难的患者服用。本课题在参考大量掩味技术、热熔喷雾冷冻方面的专利、文献，充分了解头孢呋辛酯的理化性质、分析方法、制剂工艺等信息的基础上，设计一系列实验，对热熔喷雾冷冻制备头孢呋辛酯包衣微粒所用的热熔包衣材料、致孔剂、工艺参数进行考察研究，并采用一系列方法对所制备的头孢呋辛酯包衣微粒进行表征。初步制备了掩味的头孢呋辛酯干混悬剂，并对其进行质量考察和稳定性考察。全文共分为八部分：第一章：对头孢呋辛酯、掩味技术及评价方法、热熔喷雾冷冻技术进行概述。第二章：简要概述热熔喷雾冷冻的实验原理和工艺流程。第三章：建立头孢呋辛酯的溶出紫外分光光度测定法和含量测定的高效液相色谱法。第四章：采用热熔喷雾冷冻技术制备头孢呋辛酯包衣微粒。考察了包括脂质包衣材料与药物比例、致孔剂的种类、致孔剂与脂质包衣材料比例、雾化压力、冷冻温度等处方工艺因素对掩味的头孢呋辛酯微粒的影响。第五章：对热熔喷雾冷冻技术制备头孢呋辛酯包衣微粒的处方工艺进行优化。第六章：头孢呋辛酯微粒的特征测定。第七章：确定头孢呋辛酯干混悬剂的处方工艺，并对其进行了质量考察，考察结果符合规定，掩味效果优于市售产品。第八章：初步考察头孢呋辛酯干混悬剂的稳定性。
[Abstract]:Cefuroxime (Cefuroxime), belonging to the second generation cephalosporin, was first developed and patented by British GlaxoSmithKline company. In 1978, it was first listed in the UK, Ireland, Germany and Italy. The goods were called "Zinacef" and were sold in many countries around the world. They were highly stable to beta lactamases, most of the G- and G +, with high activity and good safety, has become a valuable broad-spectrum antibiotic in clinic.
The absorption of cefuroxime after oral administration of the gastrointestinal tract is very small. According to the patent applied by GlaxoSmithKline company 4267320 [1], the ester group is introduced on the C4 carboxyl group of cefuroxime, and cefuroxime ester (Cefuroxime Axetil, CFA) can be obtained, which can enhance its transesterification and the stability in the gastrointestinal tract, greatly improving the oral absorption rate. It does not have antibacterial activity. After oral absorption, it is quickly used to produce cefuroxime by nonspecific enzyme hydrolysis in body fluid and blood, which is widely used.
Cefuroxime ester (cefuroxime ester), which has been listed in China, has tablets, capsules, granules and dry suspension. Dry suspension has the advantages of good absorption, easy to carry and easy to take. It is suitable for infants, children, old people and other patients who have difficulty in swallowing. However, cefuroxime ester is an indispensable part. It is very bitter that the dry suspension prepared by ordinary technology seriously affects the compliance of the patients. In order to solve this problem, modern masking technology is needed to solve this defect. The commonly used masking techniques include adding flavoring agent or sweetener, drug microencapsulation, ion exchange, solid dispersion, encapsulation, spray drying and so on. But cefuroxime Octyl ester has the characteristics of extremely bitter taste, large dosage and unstable heat and humidity. The above-mentioned masking method is not suitable for this drug.
At present, stearic acid is used as a masking coating material in China. Cefuroxime ester is mixed with the stearic acid in molten state. After cooling, the stearic acid is crushed into particles with a certain granularity. This method can not meet the requirements of the taste mask because of destroying the integrity of the coating layer.
Now the new technology of hot melt spray freezing coating has been developed and successfully applied to the production of pharmaceutical preparations. The hot melt spray freezing coating is dispersed into foggy droplets by the atomizer at a certain temperature (the temperature is usually higher than the melting point of the hot-melt material but below the melting point of other materials) and is dispersed into a fog droplet through the atomizer. The freezing room is fully exposed to the cold air for heat exchange, which makes the fog droplets solidify rapidly. In the high efficiency cyclone separator, a special coating method for fine powder or fine particles or finished products is obtained by separating the gas and solid from the high efficiency cyclone separator.
In this paper, the masked cefuroxime ester particles were prepared by hot melt spray freezing technology, and the particles and other auxiliary materials were prepared by a fluidized bed top spray to prepare the dry suspension. It successfully realized the mask of the bitter taste of cefuroxime ester and improved the dissolution of cefuroxime coated particles. This method is low in equipment technology and easy to operate. It can achieve continuous industrial production, and can well cover the bitterness of cefuroxime ester. The dry suspension, prepared with cefuroxime ester coated particles, is convenient, good taste and high compliance, especially for infants, children, old people and other patients who have difficulty in swallowing.
On the basis of information about the physical and chemical properties of cefuroxime ester, analysis method and preparation technology, a series of experiments are designed on the basis of information of the physical and chemical properties of cefuroxime ester, analysis method, preparation technology and so on. A series of methods were used to characterize the coated particles of cefuroxime ester coated particles. The flavored Cefuroxime Axetil for Suspension was preliminarily prepared, and its quality was investigated and the stability was investigated. The full text is divided into eight parts:
Chapter 1: Cefuroxime ester, odor masking technology and evaluation methods, hot-melt spray freezing technology are summarized.
Chapter 2: The experimental principle and technological process of hot-melt spray freezing are briefly summarized.
Chapter 3: A dissolution ultraviolet spectrophotometric method and a high performance liquid chromatography method for the determination of cefuroxime ester were established.
The fourth chapter: the coating particles of cefuroxime ester were prepared by hot melt spray freezing technology. The effects of the proportion of lipid coating materials and drugs, the types of pore agent, the proportion of pore agent and lipid coating material, the pressure of atomization and the freezing temperature on the masked cefuroxyl ester particles were investigated.
Chapter 5: The formulation of cefuroxime ester coated particles prepared by hot-melt spray freezing was optimized.
The sixth chapter: the determination of the characteristics of cefuroxime ester particles.
Chapter 7: The formulation technology of cefuroxime axetil dry suspension was determined, and the quality of cefuroxime axetil dry suspension was investigated. The results showed that the flavor masking effect was better than that of commercial products.
Chapter 8: The stability of cefuroxime ester suspension was investigated.
【学位授予单位】：广东药学院
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R943

【参考文献】