卡马西平口腔速崩片的研制
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摘要
卡马西平(carbamazepine,CBZ)是一种三环类抗癫痫药,其主要的作用机制是一种电压依赖性钠通道阻断剂,阻滞各种可兴奋细胞膜的Na~+通道,抑制丘脑腹前核至额叶的神经冲动的传导,故能明显抑制异常高频放电的发生和扩散。其在肝脏代谢,能诱发自身代谢,主要代谢产物10,11-环氧化卡马西平(carbamazepine-10,11-epoxide)的药理活性与原形药相似,其在血浆和脑内的浓度可达原形药的50%。给药量的72%经肾脏排出,28%随粪便排出。口服生物利用度较低,在58%～85%之间。
为了方便老人、儿童和吞咽困难的患者服药,提高卡马西平的生物利用度,本文采用直接压片法(DCM)制备卡马西平口腔速崩片,并对其体外及体内速释效果进行评价。
在进行口腔速崩片的处方筛选过程中,以片剂的崩解时间和口感为主要评价指标。首先进行单因素实验,确定影响药物崩解的主要因素:填充剂、崩解剂、润滑剂。在此基础上,选取对崩解时间影响大的微晶纤维素、交联羧甲基纤维素钠、乳糖的含量为变量,进行三因素四水平的L_(16)(4~3)正交试验设计,以崩解时间和口感为主要评价指标确定最优处方。
在体外药物溶出度实验中,采用紫外分光光度法(UV)测定口腔速崩片中药物的累积溶出度;人体内药代动力学和生物利用度研究中,采用高效液相色谱法(HPLC)测定人体内的血药浓度。这两种方法专属性强,准确可靠,方便快捷,能够满足测定方法要求。
从片剂硬度、重量差异、脆碎度、崩解时限、溶出度、含量均匀度方面对卡马西平口腔速崩片的质量控制进行了研究。同时对原料药和口腔速崩片进行高温实验、高湿实验、光照实验影响因素考察,提示该制剂应在低温干燥环境中贮存。
在口腔速崩片的体内研究中,采用随机交叉试验设计,以市售卡马西平普通片剂为参比制剂,进行了人体内的药代动力学和相对生物利用度研究。药时曲线经用3p97软件处理,当权重均为w=1/cc时相关系数(R square)最大,拟合结果为单室模型,AUC采用统计矩原理计算。结果显示,口腔速崩片的C_(max)明显升高,T_(max)明显提前,相对生物利用度为115.84%。仅用5名健康志愿者为受试对象,但在一定程度上能说明自制口腔速崩片具有速释特性。
总之,本实验制备的卡马西平口腔速崩片工艺简单,可行,体外溶出快。药物的体外、体内分析测定方法准确、可靠;人体内药代动力学研究表明,该口腔速崩片具备速释效果,体内相对生物利用度较高。
Carbamazepine(CBZ) is a tricyclic anti-epilepsy drug,the main mechanism is a voltage-dependent sodium channel blocker,which can block a variety of cell membrane are excited by Na~+ channels and inhibit nerve impulse conduction from the hypothalamus ventral anterior nucleus to the frontal lobe,so obviously it can inhibit the abnormal high frequency electric discharge of occurrence and diffusion.It is metabolized in the liver which can induce its own metabolism.The main metabolite 10,11-epoxide carbamazepine's pharmacological activity similar to the prototype drug, its plasma and brain concentration is up to 50%of prototype drugs.72%dosage is excreted by the kidney and 28%with the feces.Its oral bioavailability is lower between 58%and 85%.
For the convenience of the elderly,children and patients with difficulty swallowing to take medicine,increase the bioavailability of carbamazepine,through experiments, direct compression method(DCM) was choose to prepare carbamazepine orally disintegrating tablets,evaluate its effects of immediate-release in vitro and in vivo at the same time.
Combined disintegrating time and taste as the main evaluation in the process of prescription selection.In the first single factor experiment revealed the main factor which can influence the disintegrating time are fillers,disintegrants,lubricants.On this basis of testing,using the amount of microcrystalline cellulose,cross-linked croscarmellose sodium and lactose as variance to carry out L_(16)(4~3) orthogonal experimental design of third factor and four levels.On the basis of the orthogonal experiment to optimize pharmaceutical formulation with disintegrating time and taste as criteria.
Ultraviolet spectrophotometry(UV) was developed for determination of carbamazepine in vitro drug release testing.A high performance liquid chromatography(HPLC) method was established for determination of carbamazepine in human plasma.These two methods were validated in accordance with requirements and found to be specific,accurate and precise.
The quality standard control of carbamazepine orally disintegrating tablets were studied by the tablet hardness,weight variation,friability,disintegrating time,dissolution,content uniformity aspects.At the same time,the impact factors experiment of raw materials and orally disintegrating tablets were tested in the high-temperature experiment,humidity experimente,illumination test,suggesting that the preparation should be stored at low temperature and dry environment.
In vivo study,the pharmacokinetic and relative bioavailability in human were investigated by comparing carbamazepine orally disintegrating tablets(CBZ-ODT) with carbamazepine conventional reference tablets with randomized crossover experimental design.The data were processed with 3p97 pharmacokinetic program. The area under the curve(AUC) was processed by statistical moment theory.
The data indicated that the absorption profile fitted the one-compartment model and R square was better when weight coefficient(w) was choose l/cc.From the results was concluded the C_(max) was increased,T_(max) was advanceed,relative bioavailability (F_r) is 115.84%,which indicated that drug release from CBZ-ODT has the characteristics of rapidly-release.Only five healthy volunteers for the subjects,but to some extent,illustrate self-made orally disintegrating tablets with immediate-release characteristics.
In a word,the pharmaceutical processing of CBZ-ODT is simple and feasible.The dissolution in vitro is rapid.The assays of CBZ in vitro and in vivo are accurate, reliable.The study on the pharmacokinetics of CBZ in human indicated the CBZ-ODT has the characteristics of immediate-release and a higher relative bioavailability.
为了方便老人、儿童和吞咽困难的患者服药,提高卡马西平的生物利用度,本文采用直接压片法(DCM)制备卡马西平口腔速崩片,并对其体外及体内速释效果进行评价。
在进行口腔速崩片的处方筛选过程中,以片剂的崩解时间和口感为主要评价指标。首先进行单因素实验,确定影响药物崩解的主要因素:填充剂、崩解剂、润滑剂。在此基础上,选取对崩解时间影响大的微晶纤维素、交联羧甲基纤维素钠、乳糖的含量为变量,进行三因素四水平的L_(16)(4~3)正交试验设计,以崩解时间和口感为主要评价指标确定最优处方。
在体外药物溶出度实验中,采用紫外分光光度法(UV)测定口腔速崩片中药物的累积溶出度;人体内药代动力学和生物利用度研究中,采用高效液相色谱法(HPLC)测定人体内的血药浓度。这两种方法专属性强,准确可靠,方便快捷,能够满足测定方法要求。
从片剂硬度、重量差异、脆碎度、崩解时限、溶出度、含量均匀度方面对卡马西平口腔速崩片的质量控制进行了研究。同时对原料药和口腔速崩片进行高温实验、高湿实验、光照实验影响因素考察,提示该制剂应在低温干燥环境中贮存。
在口腔速崩片的体内研究中,采用随机交叉试验设计,以市售卡马西平普通片剂为参比制剂,进行了人体内的药代动力学和相对生物利用度研究。药时曲线经用3p97软件处理,当权重均为w=1/cc时相关系数(R square)最大,拟合结果为单室模型,AUC采用统计矩原理计算。结果显示,口腔速崩片的C_(max)明显升高,T_(max)明显提前,相对生物利用度为115.84%。仅用5名健康志愿者为受试对象,但在一定程度上能说明自制口腔速崩片具有速释特性。
总之,本实验制备的卡马西平口腔速崩片工艺简单,可行,体外溶出快。药物的体外、体内分析测定方法准确、可靠;人体内药代动力学研究表明,该口腔速崩片具备速释效果,体内相对生物利用度较高。
Carbamazepine(CBZ) is a tricyclic anti-epilepsy drug,the main mechanism is a voltage-dependent sodium channel blocker,which can block a variety of cell membrane are excited by Na~+ channels and inhibit nerve impulse conduction from the hypothalamus ventral anterior nucleus to the frontal lobe,so obviously it can inhibit the abnormal high frequency electric discharge of occurrence and diffusion.It is metabolized in the liver which can induce its own metabolism.The main metabolite 10,11-epoxide carbamazepine's pharmacological activity similar to the prototype drug, its plasma and brain concentration is up to 50%of prototype drugs.72%dosage is excreted by the kidney and 28%with the feces.Its oral bioavailability is lower between 58%and 85%.
For the convenience of the elderly,children and patients with difficulty swallowing to take medicine,increase the bioavailability of carbamazepine,through experiments, direct compression method(DCM) was choose to prepare carbamazepine orally disintegrating tablets,evaluate its effects of immediate-release in vitro and in vivo at the same time.
Combined disintegrating time and taste as the main evaluation in the process of prescription selection.In the first single factor experiment revealed the main factor which can influence the disintegrating time are fillers,disintegrants,lubricants.On this basis of testing,using the amount of microcrystalline cellulose,cross-linked croscarmellose sodium and lactose as variance to carry out L_(16)(4~3) orthogonal experimental design of third factor and four levels.On the basis of the orthogonal experiment to optimize pharmaceutical formulation with disintegrating time and taste as criteria.
Ultraviolet spectrophotometry(UV) was developed for determination of carbamazepine in vitro drug release testing.A high performance liquid chromatography(HPLC) method was established for determination of carbamazepine in human plasma.These two methods were validated in accordance with requirements and found to be specific,accurate and precise.
The quality standard control of carbamazepine orally disintegrating tablets were studied by the tablet hardness,weight variation,friability,disintegrating time,dissolution,content uniformity aspects.At the same time,the impact factors experiment of raw materials and orally disintegrating tablets were tested in the high-temperature experiment,humidity experimente,illumination test,suggesting that the preparation should be stored at low temperature and dry environment.
In vivo study,the pharmacokinetic and relative bioavailability in human were investigated by comparing carbamazepine orally disintegrating tablets(CBZ-ODT) with carbamazepine conventional reference tablets with randomized crossover experimental design.The data were processed with 3p97 pharmacokinetic program. The area under the curve(AUC) was processed by statistical moment theory.
The data indicated that the absorption profile fitted the one-compartment model and R square was better when weight coefficient(w) was choose l/cc.From the results was concluded the C_(max) was increased,T_(max) was advanceed,relative bioavailability (F_r) is 115.84%,which indicated that drug release from CBZ-ODT has the characteristics of rapidly-release.Only five healthy volunteers for the subjects,but to some extent,illustrate self-made orally disintegrating tablets with immediate-release characteristics.
In a word,the pharmaceutical processing of CBZ-ODT is simple and feasible.The dissolution in vitro is rapid.The assays of CBZ in vitro and in vivo are accurate, reliable.The study on the pharmacokinetics of CBZ in human indicated the CBZ-ODT has the characteristics of immediate-release and a higher relative bioavailability.
引文
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