介孔碳(CMK-3)载体用于提高非诺贝特溶出速率及物理稳定性的研究

目的以制备的介孔碳(CMK-3)为载体载入非诺贝特制备纳米药物分散体系,以期提高非诺贝特的溶出速率和纳米分散药物的稳定性。方法采用吸附平衡法将模型药物非诺贝特载入到碳载体中,应用扫描电子显微镜(SEM)来表征制备载体的形貌,透射电子显微镜(TEM)和氮吸附曲线表征载体的内部孔道结构,差示扫描量热(DSC)和X射线衍射(XRD)研究药物在载体中的存在状态,采取溶出度测定方法研究所制备的载药体系的药物溶出速度,并测定其长期稳定性。结果药物已载入碳载体的纳米孔道中,且药物粒子的高度分散和晶型的转变,显著提高了难溶性药物非诺贝特的溶出速率,并且碳载体的刚性结构有效阻止了分散药物粒子的再聚集,物理稳定性大大提高。结论制备的非诺贝特-CMK-3载药体系,为提高难溶性药物的生物利用度以及解决纳米分散药物的物理稳定性等问题,提供了一种可能。     

非诺贝特片和胶囊的溶出度评价

目的利用光纤药物溶出度仪(FODT-601)实时测定非诺贝特片(胶囊)的溶出度,并通过比较溶出曲线评价其制剂工艺和内在质量的差异。方法采用FODT-601仪,以《中国药典》2010年版规定的溶出度测定条件实时监测非诺贝特制剂的溶出曲线;并采用直观分析、Weibull分布模型拟合以及f2相似因子法比较不同剂型、不同厂家、不同批号间的溶出曲线。结果《中国药典》2010年版规定非诺贝特片及胶囊溶出度标准是:60min时取样,其限度为标示量的60%,所选的所有药物均在20min时就满足其限度规定。非诺贝特片与胶囊原创厂家的溶出行为较为一致,但国产厂家的非诺贝特片与胶囊溶出行为不一致;非诺贝特片国产厂家的溶出行为与原创厂家溶出行为差异较大,但非诺贝特胶囊国产厂家的溶出行为与原创厂家溶出行为较为一致;Weibull分布模型拟合法和f2相似因子法评价结果基本一致。结论用FODT-601仪测定非诺贝特制剂,操作简单,得到的数据信息完整,其溶出曲线用Weibull分布模型或f2相似因子法评价均可。     

非诺贝特体外溶出度考察及其微粉化制剂的研究

目的考察不同厂家非诺贝特固体制剂体外溶出度以及微粉化对非诺贝特溶出度的影响。方法分别以 40 % (φ)乙醇溶液、5 0 % (φ)乙醇溶液、5g/L十二烷基硫酸钠溶液、1 0g/L十二烷基硫酸钠溶液为溶出介质 ,对 4种市售非诺贝特固体制剂的体外溶出度进行考察。采用球磨机制备微粉化非诺贝特 ,对其溶出度进行测定。结果 1 0 g/L十二烷基硫酸钠溶液中微粉化制剂的溶出速率明显快于其余 3种非微粉化制剂 ,初步探讨了非诺贝特固体制剂体外溶出度标准。用相似因子法对自制微粉化胶囊和法国生产的微粉化胶囊的溶出实验数据进行统计分析 ,结果表明两者溶出行为相似 ,相似因子f2 =72 4(5 0≤f2 ≤ 1 0 0 )。结论不同厂家非诺贝特固体制剂的溶出度差异较大 ,微粉化工艺能显著提高非诺贝特的溶出度     

介孔二氧化硅纳米粒增溶型非诺贝特片剂的制备及体内外研究

目的 制备介孔二氧化硅纳米粒(mesoporous silica nanoparticles,HK)增溶型非诺贝特(fenofibrate,FNB)片剂并进行体内外研究。方法 用吸附法以HK为FNB的载体制成固体分散体(FNB-HK)。采用差示扫描量热法、X射线衍射法和傅里叶红外光谱法分析非诺贝特在FNB-HK中的存在状态。通过考察体外溶出度,优化处方并制片。将自制片和市售片分别对家兔单剂量口服给药,采用高效液相色谱法测定家兔血浆药物浓度。结果 FNB-HK表征表明HK能够抑制非诺贝特的结晶。经过处方优化,乳糖做填充剂,8%羧甲基淀粉钠为崩解剂时,片剂能够达到最理想的溶出速率。自制片与市售片相比,体内达峰时间提前,达峰浓度增大,相对生物利用度为149.95%。结论 本研究研制的片剂能显著改善FNB的溶出速率,提高其口服生物利用度。     

复方水飞蓟素丹参素自乳化半固体胶囊的制备及性质考察

目的：制备复方水飞蓟素丹参素自乳化半固体胶囊剂,以期提高水飞蓟素和丹参素溶出度及生物利用度。方法：通过测定溶解度和绘制三元相图对自乳化处方进行筛选,应用单纯形网格法进行处方优化;采用熔融法制备半固体胶囊并对该半固体胶囊进行稳定性影响因素考察及药物溶出度测定。结果：制备了高载药量的水飞蓟素丹参素自乳化半固体胶囊剂,自制制剂中水飞蓟素和丹参素的溶出度超过80%,而市售参比制剂中水飞蓟素和丹参素的溶出度不超过50%。结论：复方水飞蓟素丹参素自乳化半固体胶囊剂能够显著提高水飞蓟素和丹参素的溶出度。     

非诺贝特纳米混悬剂溶出度测定与体内吸收的相关性评价

目的考察非诺贝特纳米混悬剂、原料药粉、微粉化原料药粉的体外溶出特性,研究比较三者在大鼠体内的生物利用度,并对其体内外相关性作出评价。方法以紫外分光法测定体外溶出度;以高效液相色谱法测定大鼠灌胃给药后的血药浓度;以Wagner-Nelson法计算体内吸收分数,考察体内吸收与体外溶出的相关性。结果纳米组AUC0-36h和Cmax分别为原料组、微粉组的10倍和2倍,纳米混悬剂组体内吸收分数fa与体外溶出速率ft的关系为：fa=4.407 9ft？303.31,r=0.983 8。结论与原料和微粉组相比,非诺贝特制成纳米混悬剂后,药物的溶出速度和生物利用度均有显著提高,体外溶出与体内吸收相关性良好。     

非诺贝特纳米混悬剂溶出度测定与体内吸收的相关性评价

目的 考察非诺贝特纳米混悬剂、原料药粉、微粉化原料药粉的体外溶出特性,研究比较三者在大鼠体内的生物利用度,并对其体内外相关性作出评价。方法 以紫外分光法测定体外溶出度;以高效液相色谱法测定大鼠灌胃给药后的血药浓度;以Wagner-Nelson法计算体内吸收分数,考察体内吸收与体外溶出的相关性。结果 纳米组AUC0-36h 和Cmax分别为原料组、微粉组的10倍和2倍,纳米混悬剂组体内吸收分数fa与体外溶出速率ft的关系为：fa=4.407 9ft- 303.31,r=0.983 8。结论 与原料和微粉组相比,非诺贝特制成纳米混悬剂后,药物的溶出速度和生物利用度均有显著提高,体外溶出与体内吸收相关性良好。     

复方自乳化半固体珍菊降压胶囊剂的制备及其性质考察

目的制备复方自乳化半固体珍菊降压胶囊剂,以期提高其主要成分(芦丁和氢氯噻嗪)溶出度及生物利用度。方法通过溶解度实验和绘制伪三元相图的方法进行自乳化处方的筛选,以载药量、载油量及粒径等为指标应用单纯形网格法优化处方;采用熔融法制备半固体胶囊并对该半固体胶囊进行稳定性影响因素考察及药物溶出度测定。结果复方自乳化半固体珍菊降压胶囊剂最优处方为泊洛沙姆188-油酸乙酯-聚乙二醇辛基苯基醚-聚乙二醇400(质量比28.6∶8.4∶44.1∶19.1),该制剂中主要成分芦丁和氢氯噻嗪载药量为128.8、57.7 mg.g-1;60℃、光照下含量明显下降;复方自乳化半固体胶囊剂和市售胶囊剂1 h药物溶出度分别为100%、48.1%。结论所制备的复方自乳化半固体胶囊剂具有载药量高、溶出度好的特点。     

非诺贝特固体分散片的试制

以PEG4000和十二烷基硫酸钠为载体，采用溶剂—熔融法制备了非诺贝特固体分散体，再与适当辅料混合压片制得非诺贝特固体分散片。用正交设计表L9(3^4)筛选处方。溶出度实验表明自制片较市售两种制剂溶出快。     

茴三硫固体分散体的体内外评价

目的采用热熔挤出技术制备茴三硫固体分散体,用于提高其溶出度和口服生物利用度。方法以水溶性聚合物Plasdone S630为载体,用热熔挤出技术制备茴三硫固体分散体。采用差示扫描量热法和X射线粉末衍射法对固体分散体进行表征,并评价其溶出度及犬体内药动学行为。结果药物以无定形或分子状态存在于固体分散体中,溶出速率明显高于参比制剂与物理混合物,在40℃,湿度75%加速6个月,溶出曲线和固体分散体中茴三硫存在状态未发生变化。犬体内药动学研究结果表明,茴三硫固体分散体的Cmax和口服生物利用度是参比制剂的1.66倍和1.57倍。结论采用热熔挤出技术制备的茴三硫固体分散体为热力学稳定体系,能明显提高茴三硫的体外溶出度和口服生物利用度。     

非洛贝特纳米混悬剂的制备及其体外溶出性考察

目的:制备非洛贝特纳米混悬剂,以促进药物溶出。方法:以非洛贝特为主药,采用熔融乳化法联合高压均质法制备纳米混悬剂;选取处方中表面活性剂泊洛沙姆188(Poloxamer188)与聚乙烯吡咯烷酮(PVP)K30用量比、均质压力、均质次数为考察因素,药物粒径为指标设计正交试验筛选制备工艺,并进行验证试验;同时考察制剂溶出速率和溶出浓度。结果:最佳制备工艺为Poloxamer188:PVPK30用量比2:1、均质压力800bar,均质次数为9。所制纳米粒平均粒径为356nm,多分散系数为0.19,平均Zeta电位为-39mV。制剂5min时溶出浓度可达20.10mg·L-1,4h时达25.46mg·L-1,接近完全溶出。结论:将难溶药物非诺贝特制成纳米混悬剂可以显著改善其溶出作用。     

介质研磨法制备他达拉非纳米混悬液研究

目的:采用介质研磨法制备他达拉非纳米混悬液,以提高他达拉非的溶出度和生物利用度。方法:以粒径、多分散指数(PDI)、Zeta电位和物理稳定性为评价指标,优化处方和工艺参数;采用扫描电镜(SEM)、X-射线粉末衍射法(XRPD)、差示扫描量热法(DSC)对样品进行表征,HPLC法测定他达拉非纳米混悬液体外溶出度,UPLC-MS/MS法检测大鼠中他达拉非的血药浓度。结果:他达拉非纳米混悬液最优处方为他达拉非质量分数2%、HPC 1%和SDS 0.1%;最优工艺为粒径0.1 mm氧化锆珠,转速3 000 r·min^-1,研磨时间30 min。制备的他达拉非纳米混悬液PDI为0.173±0.013,Zeta电位为(－22.6±0.4) mV,纳米颗粒为棒状结晶,粒径为(218.2±1.3) nm,分布均匀,晶型稳定;体外溶出度10 min内达到99%,大鼠体内生物利用度为原料药的4.01倍,在室温条件下放置6个月稳定性良好。结论:介质研磨法制备他达拉非纳米混悬液方法简单,产品稳定性好,能显著提高他达拉非溶出度和生物利用度。     

Pharmacokinetic evaluation of oral fenofibrate nanosuspensions and SLN in comparison to conventional suspensions of micronized drug

An increasing number of newly developed drugs show bioavailability problems due to poor water solubility. Formulating the drugs as nanosuspensions may help to overcome these problems by increasing saturation solubility and dissolution velocity. In the present study the bioavailability of the poorly soluble fenofibrate following oral administration was investigated in rats. Four formulations were tested: a nanosuspension type DissoCube(R), one solid lipid nanoparticle (SLN) preparation and two suspensions of micronized fenofibrate as reference formulations, one suspension in sirupus simplex and a second in a solution of hydroxyethy-cellulose in physiological saline. Both colloidal drug delivery systems showed approximately two-fold bioavailability enhancements in terms of rate and extent compared to the reference formulations. No significant differences were found in AUC(0-22 h) as well as in C(max) and t(max) between the two colloidal delivery systems. In conclusion, nanosuspensions may be a suitable delivery system to improve the bioavailability of drugs with low water solubility.     

In vitro and in vivo evaluation of a self-microemulsifying drug delivery system for the poorly soluble drug fenofibrate

Fenofibrate is indicated in hypercholesterolemia and hypertriglyceridemia alone or combined (types IIa, IIb, III, IV, and V dyslipidemias). However, due to its low solubility in water, it has low bioavailability after oral administration. In order to improve the dissolution rate, fenofibrate was formulated into a self-microemulsifying drug delivery system (SMEDDS). We used pseudoternary phase diagrams to evaluate the area of microemulsification, and an in vitro dissolution test was used to investigate the dissolution rate of fenofibrate. The optimized formulation for in vitro dissolution and bioavailability assessment consisted of propylene glycol laurate (Lauroglycol FCC) (60 %), macrogol-15-hydroxystearate (Solutol HS 15) (27 %), and diethylene glycol monoethyl ether (Transcutol-P) (13 %). The mean droplet size of the oil phase in the microemulsion formed by the SMEDDS was 131.1 nm. The dissolution rate of fenofibrate from SMEDDS was significantly higher than that of the reference tablet. In vivo pharmacokinetics study of fenofibrate in beagles administered SMEDDS-A form resulted in a 3.7-fold increase in bioavailability as compared with the reference drug. Our studies suggested that the fenofibrate containing SMEDDS composition can effectively increase the solubility and oral bioavailability of poorly water-soluble drugs.     

基于纳米混悬技术盐酸齐拉西酮胶囊的制备及质量评价

目的：制备盐酸齐拉西酮纳米混悬剂,提高其体外溶出度,并对其进行质量评价。方法：采用超声辅助沉淀法制备纳米混悬剂,以粒径、多分散性指数为评价指标。通过单因素考察初步优化纳米混悬剂的处方和制备工艺,采用拟中心复合设计,对处方用量进行优化设计。采用扫描电镜、差式扫描量热法和粉末X射线衍射法对固化后的粉末进行表征,高效液相法测定盐酸齐拉西酮体外溶出度。结果：基于纳米混悬技术制备的盐酸齐拉西酮胶囊的体外溶出度与市售胶囊相比得到显著的提高。结论：以Soluplus和SDS为稳定剂成功制备盐酸齐拉西酮纳米混悬剂,提高其体外溶出度,具有较好的应用前景。     

熔融法制备非诺贝特缓释胶囊的处方工艺研究

目的 采用熔融法固体分散体技术代替微丸技术制备非诺贝特缓释胶囊。 方法 将主药与辅料熔融制备缓释颗粒,装入胶囊,以进口品为对照,按国家颁布的质量标准中释放度检查条件考查其释放。 结果 两者体外释放基本一致。 结论 熔融法固体分散体技术制备非诺贝特缓释胶囊较微丸技术简单方便,适合工业生产。     

Development of a New Method to Assess Nanocrystal Dissolution Based on Light Scattering

Purpose

Nanocrystals exhibit enhanced dissolution rates and can effectively increase the bioavailability of poorly water soluble drug substances. However, methods for in vitro characterization of dissolution are unavailable. The objective of this study was to develop an in situ noninvasive analytical method to measure dissolution of crystalline nanosuspensions based on light scattering.

Methods

Fenofibrate nanosuspensions were prepared by wet media milling. Their solubilities and dissolution profiles in simulated gastric fluid supplemented with 0.1% Tween^? 80 were measured in a small scale setup with an instrument for dynamic light scattering and the intensity of scattered light as readout parameter.

Results

A good correlation was achieved between the dissolution profile of a nanosuspension measured in the light scattering setup and a conventional dissolution experiment. Nanosuspensions of 120–270?nm size could be distinguished by the light scattering method. The suspensions dissolved within 1.9–12.3?min. Over a concentration range of 40–87% of the solubility dissolution profiles of a nanosuspension with 140?nm were monitored and the determined total dissolution times were in good agreement with the Noyes-Whitney dissolution model.

Conclusions

A noninvasive, sensitive and reproducible method is presented to assess nanocrystal dissolution. In situ measurements based on light scattering allow a straightforward experimental setup with high temporal resolution.     

Micronization of drugs using supercritical carbon dioxide.

Particles from gas saturated solutions, a novel method for high pressure material processing, has been used for micronization of practically insoluble calcium-channel blockers nifedipine and felodipine and the hypolipidemic agent fenofibrate with the aim of increasing their dissolution rate and hence their bioavailability. Dependent on the pre-expansion conditions, a mean particle size of between 15 and 30 microm was achieved for micronized nifedipine and 42 microm for micronized felodipine. The particle size of processed fenofibrate, on the other hand, increased due to agglomeration. The highest dissolution rate was achieved by preparation of drug coprecipitates with PEG 4000. Copyright