發(fā)布時(shí)間：2018-08-09 20:49

【摘要】：頭孢呋辛（Cefuroxime），屬于第二代頭孢菌素，由英國(guó)GlaxoSmithKline公司首先開(kāi)發(fā)成功并獲得專利，并于1978年在英國(guó)、愛(ài)爾蘭、德國(guó)和意大利率先上市，商品名為“Zinacef”，隨后在全球許多國(guó)家地區(qū)銷售。其對(duì)β-內(nèi)酰胺酶高度穩(wěn)定，對(duì)大多數(shù)G-和G+具有較高活性，安全性好，，成為臨床上頗具價(jià)值的廣譜抗生素。 頭孢呋辛口服后胃腸道對(duì)其吸收極少，據(jù)GlaxoSmithKline公司申請(qǐng)的專利4267320披露[1]，在頭孢呋辛的C4羧基上引入酯基，得到頭孢呋辛酯（Cefuroxime Axetil,CFA），可增強(qiáng)其親酯性和在胃腸道中的穩(wěn)定性，大大地提高了口服吸收率。頭孢呋辛酯本身并不具有抗菌活性，口服吸收后迅速被體液和血液中的非特異性酶水解生成頭孢呋辛而發(fā)揮抗菌作用，從而得到廣泛地應(yīng)用。 國(guó)內(nèi)已上市的的頭孢呋辛酯劑型有片劑、膠囊劑、顆粒劑和干混懸劑。干混懸劑由于具有吸收良好、便于攜帶、易于服用，適合嬰幼兒、兒童、老人及其他吞服困難的患者使用等優(yōu)勢(shì)，在臨床應(yīng)用中起到不可或缺的重要地位。然而，頭孢呋辛酯味極苦，采用普通工藝制備的干混懸劑嚴(yán)重影響患者服藥順應(yīng)性。對(duì)此，需采用現(xiàn)代化掩味技術(shù)解決這一缺陷。目前常用的掩味技術(shù)有添加矯味劑或甜味劑、藥物微囊化、離子交換法、固體分散體法、包合法、噴霧干燥包衣等方法。但頭孢呋辛酯具有味極苦、服用劑量大、濕熱不穩(wěn)定等特點(diǎn)，上述掩味方法對(duì)該藥并不適用。 國(guó)內(nèi)目前采用的掩味手段為，以硬脂酸作為掩味包衣材料，將頭孢呋辛酯與熔融狀態(tài)的硬脂酸混合在一起，冷卻后粉碎成具有一定粒度的顆粒。該方法由于破壞了包衣層的完整性而無(wú)法達(dá)到掩味的要求。 現(xiàn)在熱熔噴霧冷凍包衣這一新技術(shù)面世并已成功應(yīng)用于藥物制劑的生產(chǎn)。熱熔噴霧冷凍包衣是在一定溫度下（溫度通常高于熱熔材料的熔點(diǎn)而低于其他物料的熔點(diǎn)）將混合均勻的熔融輔料和其他物料通過(guò)霧化器分散成霧狀液滴，并在冷凍室內(nèi)與冷空氣充分接觸進(jìn)行熱交換，使霧狀液滴迅速凝固，在高效旋風(fēng)分離器內(nèi)完成氣固分離得到極細(xì)粉體或細(xì)顆粒半成品或成品的一種特殊包衣手段。 本文采用熱熔噴霧冷凍技術(shù)制備出掩味的頭孢呋辛酯微粒，并將該微粒及其他輔料通過(guò)流化床頂噴制粒制備干混懸劑，成功實(shí)現(xiàn)頭孢呋辛酯苦味的掩蓋，并且提高頭孢呋辛酯包衣微粒的溶出度。該方法對(duì)設(shè)備技術(shù)要求低，操作簡(jiǎn)便易行，可實(shí)現(xiàn)工業(yè)化連續(xù)生產(chǎn)，且能很好掩蓋頭孢呋辛酯的苦味。用頭孢呋辛酯包衣微粒制備的干混懸劑沖服方便，口感好，患者順應(yīng)性高，尤其適用嬰幼兒、兒童、老人及其他吞服困難的患者服用。 本課題在參考大量掩味技術(shù)、熱熔噴霧冷凍方面的專利、文獻(xiàn)，充分了解頭孢呋辛酯的理化性質(zhì)、分析方法、制劑工藝等信息的基礎(chǔ)上，設(shè)計(jì)一系列實(shí)驗(yàn)，對(duì)熱熔噴霧冷凍制備頭孢呋辛酯包衣微粒所用的熱熔包衣材料、致孔劑、工藝參數(shù)進(jìn)行考察研究，并采用一系列方法對(duì)所制備的頭孢呋辛酯包衣微粒進(jìn)行表征。初步制備了掩味的頭孢呋辛酯干混懸劑，并對(duì)其進(jìn)行質(zhì)量考察和穩(wěn)定性考察。全文共分為八部分： 第一章：對(duì)頭孢呋辛酯、掩味技術(shù)及評(píng)價(jià)方法、熱熔噴霧冷凍技術(shù)進(jìn)行概述。 第二章：簡(jiǎn)要概述熱熔噴霧冷凍的實(shí)驗(yàn)原理和工藝流程。 第三章：建立頭孢呋辛酯的溶出紫外分光光度測(cè)定法和含量測(cè)定的高效液相色譜法。 第四章：采用熱熔噴霧冷凍技術(shù)制備頭孢呋辛酯包衣微粒�？疾炝税ㄖ|(zhì)包衣材料與藥物比例、致孔劑的種類、致孔劑與脂質(zhì)包衣材料比例、霧化壓力、冷凍溫度等處方工藝因素對(duì)掩味的頭孢呋辛酯微粒的影響。 第五章：對(duì)熱熔噴霧冷凍技術(shù)制備頭孢呋辛酯包衣微粒的處方工藝進(jìn)行優(yōu)化。 第六章：頭孢呋辛酯微粒的特征測(cè)定。 第七章：確定頭孢呋辛酯干混懸劑的處方工藝，并對(duì)其進(jìn)行了質(zhì)量考察，考察結(jié)果符合規(guī)定，掩味效果優(yōu)于市售產(chǎn)品。 第八章：初步考察頭孢呋辛酯干混懸劑的穩(wěn)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.
【學(xué)位授予單位】：廣東藥學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R943

【參考文獻(xiàn)】

相關(guān)期刊論文 前1條

1 康建磊;徐冰珠;;速釋口服固體制劑溶出度研究驗(yàn)證中需注意的問(wèn)題[J];解放軍藥學(xué)學(xué)報(bào);2010年04期

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