Sustained release donepezil loaded PLGA microspheres for injection:Preparation,in vitro and in vivo study

The purpose of this study was to develop a PLGA microspheres-based donepezil(DP)formulation which was expected to sustain release of DP for one week with high encapsulation efficiency(EE).DP derived from donepezil hydrochloride was encapsulated in PLGA microspheres by the O/W emulsion-solvent evaporation method.The optimized formulation which avoided the crushing of microspheres during the preparation process was characterized in terms of particle size,morphology,drug loading and EE,physical state of DP in the matrix and in vitro and in vivo release behavior.DP microspheres were prepared successfully with average diameter of 30m,drug loading of 15.92±0.31%and EE up to 78.79±2.56%.Scanning electron microscope image showed it has integrated spherical shape with no drug crystal and porous on its surface.Differential scanning calorimetry and X-ray diffraction results suggested DP was in amorphous state or molecularly dispersed in microspheres.The Tg of PLGA was increased with the addition of DP.The release profile in vitro was characterized with slow but continuous release that lasted for about one week and fitted well with first-order model,which suggested the diffusion governing release mechanism.After single-dose administration of DP microspheres via subcutaneous injection in rats,the plasma concentration of DP reached peak concentration at 0.50 d,and then declined gradually,but was still detectable at 15 d.A good correlation between in vitro and in vivo data was obtained.The results suggest the potential use of DP microspheres for treatment of Alzheimer’s disease over long periods.

Development of cryptotanshinone-loaded pellets for angina chronotherapy:In vitro/in vivo prediction and evaluation

The clinical manifestations of variant angina is unevenly distributed during the 24 h, thusthe in vivo performance of drugs should be tailored according to the angina circadianrhythm. Cryptotanshinone(CTN) is one of the representative bioactive lipid-soluble com-ponents of Danshen which has been commonly used for cardiovascular diseases such asangina pectoris. The aim of this study was to develop a novel CTN sustained-released pel-lets(CTN-SRPs) to precisely synchronize the CTN plasma concentrations with predictedoccurrence of angina pectoris for angina chronotherapy. A deconvolution-based methodwas applied to develop and optimize the CTN-SRPs. The plasma concentration-time curveof CTN immediate-released formulation after oral administration in rats was used as theweight function. The predicted plasma concentration-time curve of CTN-SRPs simulatedaccording to the incidence of variant angina during 24 h was used as the response func-tion. Then the desired drug release profile of CTN-SRPs was calculated based on deconvo-lution using weight function and response function, and subsequently used for guiding theformulation optimization. CTN-SRPs were prepared with the combinations of PVP, polox-amer 127 and EC as matrix using fluidized bed technology. An orthogonal design was em-ployed to obtain the optimal formulation with its release profile similar with the desiredone. Pharmacokinetic studies validated that the actual plasma concentration-time curve ofthese optimized CTN-SRPs was similar with the predicted one. In addition, the percent er-rors(%PE) of CTN plasma concentrations in 8–12 h were less than 10%. In conclusion, thisdeconvolution-based method could be applied to adjust the in vivo performance of drugs forangina chronotherapy.

Preparation and evaluation of sustained-release diltiazem hydrochloride pellets

In this study,diltiazem hydrochloride(DTZ)pellets were prepared successfully by extrusionespheronization method.Then methacrylic acid and ethylcellulose coating formulations were employed to make the DTZ pellets sustained release.The pellets with different coatings were investigated by in vitro dissolution tests.At last,the pellets with the best coating copolymer were subjected to pharmacokinetic studies in beagle dogs.The dissolution profiles of pellets coated with Eudragit
NE30D were similar to Herbesser
,one of the marketed sustained release capsules.In the bioavailability study,the principal pharmacokinetic parameters of self-made pellets and the marketed ones were comparable;the relative bioavailability of DTZ sustained release capsules compared with Herbesser
was 98.5
36.4%.All the data indicated self-made sustained pellets could prolong the release of DTZ,decrease the fluctuation of drug level in vivo,and increase the compliance of patients.

Taste masking of ofloxacin and formation of interpenetrating polymer network beads for sustained release

The objective of this study was to carry out taste masking of ofloxacin(Ofl) by ion exchange resins(IERs)followed by sustained release of Ofl by forming interpenetrating polymer network(IPN) beads. Drug-resin complexes(DRCs) with three different ratios of Ofl to IERs(1:1, 1:2, 1:4) were prepared by batch method and investigated for in vivo and in vitro taste masking. DRC of methacrylic acid-divinyl benzene(MD) resin and Ofl prepared at a ratio of 1:4 was used to form IPN beads. IPN beads of MD 1:4 were prepared by following the ionic cross-linking method using sodium carboxymethyl xanthan gum(SCMXG) and SCMXG-sodium carboxymethyl cellulose(SCMXG-SCMC). IPN beads were characterized with FT-IR and further studied on sustained release of Ofl at different pH. In vivo taste masking carried out by human volunteers showed that MD 1:4 significantly reduced the bitterness of Ofl. Characterization studies such as FT-IR, DSC, P-XRD and taste masking showed that complex formation took place between drug and resin. In vitro study at gastric pH showed complete release of drug from MD 1:4 within 30 min whereas IPN beads took 5 h at gastric pH and 10 h at salivary pH for the complete release of drug. As the crosslinking increased the release kinetics changed into non-Fickian diffusion to zero-order release mechanism. MD 1:4 showed better performance for the taste masking of Ofl and IPNs beads prepared from it were found useful for the sustained release of Ofl at both the pH, indicating a versatile drug delivery system.

Evaluation of the Controlled Release Ability of Theophylline from Xanthan/Chondroitin Sulfate Hydrogels

The xanthan/chondroitin sulfate (X/CS) hydrogels, obtained by a crosslinking technique, were evaluated in vitro and in vivo as matrices for theophylline release. The influence of pH of simulated physiological media on the X/CS swelling behaviour at 37°C was investigated. The hydrogels theophylline loading degree was evaluated by near infrared chemical imaging (NIR-CI) technique and confirmed also by FT-IR spectroscopy;the drug loading was about 77.5% based on PLS-DA prediction (Partial least squares-Discriminate Analysis). The release profiles of theophylline from X/CS hydrogels in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) depend on CS content. The release mechanisms were controlled by the drug solubility and ionic properties of the polymers. In vivo theophylline delivery was done by oral administration. Pharmacokinetic analysis revealed sustained-release characteristics for 50/50 X/CS theophylline-loaded formulation compared with raw theophylline which was rapidly absorbed, distributed and eliminated. A good in vitro-in vivo correlation was found.

不同包被缓释尿素的瘤胃缓释效果的评价

[目的]本文旨在通过体外批次发酵、瘤胃灌注和持续动态人工瘤胃模拟系统等不同方法评价包被缓释尿素的瘤胃缓释效果。[方法]体外发酵试验:选取1种普通尿素和4种商业包被缓释尿素,体外培养24 h,采集不同时间点(0、1、3、6、9、12、24 h)发酵液测定氨氮浓度,将筛选出缓释效果最好的缓释尿素用于进一步的研究。瘤胃灌注试验:12只体重(平均27.6 kg)相近的安装有瘤胃瘘管的育肥公湖羊,随机平均分为2组,分别向瘤胃中灌注剂量为日干物质采食量0.5%的普通尿素或日采食量0.55%的缓释尿素(等氮当量),灌注后不同时间点(0、1、3、6、9、12和24 h)采集瘤胃液,测定pH值和氨氮浓度。人工瘤胃试验:在基础日粮中分别添加3.5%的豆粕(普通日粮组)、0.5%的普通尿素(普通尿素组)和0.55%的缓释尿素(缓释尿素组),使用玉米补充普通尿素和缓释尿素组能量的缺乏;试验重复3次,每次持续7 d(4 d适应期和3 d采样期),采样期每天早上投料前后不同时间点采集发酵液和溢流液,测定发酵参数和微生物蛋白浓度。[结果]体外发酵试验:在发酵开始的9、12 h,缓释尿素A组的氨氮浓度显著低于普通尿素组和其余3个缓释尿素处理组(P<0.05)。体内瘤胃灌注试验:在灌注尿素后1 h,缓释尿素组瘤胃pH值和氨氮浓度显著低于普通尿素组(P<0.05),在灌注尿素后6 h,缓释尿素组的pH值显著高于普通尿素组(P<0.05)。人工瘤胃模拟试验:相比于其他2组,日粮添加缓释尿素显著提高了发酵液中丙酸和微生物蛋白的浓度(P<0.05);相比于普通日粮组,日粮添加缓释尿素显著降低了发酵液pH值(P<0.05)。[结论]不同包被缓释尿素的瘤胃缓释效果存在差异,体外发酵筛选出的缓释尿素A在动物瘤胃灌注条件下同样表现出较好的缓释效果。在人工瘤胃发酵试验中添加缓释尿素A能够改善瘤胃发酵,促进微生物蛋白的合成,但对生长性能和瘤胃菌群的影响仍需动物饲养试验做进一步的验证。

醋酸阿比特龙缓释微球的制备及其体内外释药特性的考察

目的制备一种具有较好缓释效果的醋酸阿比特龙微球,并确定其最佳处方与工艺。方法以可生物降解的聚乳酸-羟基乙酸(PLGA)为载体材料,二氯甲烷(DCM)为有机溶剂,采用O/W型乳化-溶剂挥发法制备醋酸阿比特龙微球,扫描电子显微镜观察其外观形态,激光粒度仪测定其粒径,高效液相色谱法测定其载药量和包封率,气相色谱法测定DCM残留量,摇床法考察载药微球的体外释药特性,SD大鼠肌内注射考察微球的体内缓释效果。结果醋酸阿比特龙微球呈圆整的球形粒子,平均粒径43.7μm,载药量39.27%,包封率98.15%,DCM残留量0.054%。体外加速释放结果表明药物释放以扩散机制为主,释药周期可稳定维持11 d,累积释药度为80.86%;体内释药周期可维持16 d。结论制备的醋酸阿比特龙微球能够克服由于食物摄入引起的药物暴露量增加、血药浓度不稳定的问题,减少给药次数,实现了较好的缓释效果,为其后续的产业化提供了一定的数据支持,对其他小分子药物微球的研发具有一定的参考价值。

盐酸羟考酮缓释片体外释药特性研究

目的研究盐酸羟考酮缓释片的体外释药特性。方法采用篮法进行溶出试验,分别测定盐酸羟考酮缓释片在pH 1.2氯化钠盐酸溶液、pH 4.5醋酸盐溶液、pH 6.8磷酸盐溶液介质中的溶出度,并作溶出曲线,对体外溶出曲线进行模型拟合,考察其释放动力学及释药机制;采用往复筒法进行溶出试验,对往复筒的关键设置参数进行考察。测定样品在含不同体积分数(0,5%,20%,40%)乙醇pH 1.2盐酸介质的溶出度,并作溶出曲线,评估剂量倾泻风险。结果盐酸羟考酮缓释片的体外释放呈一级动力学,释药机制为溶蚀与扩散相结合;往复频率与溶出速率呈正相关,筛网规格在20~40目之间对溶出行为的影响较小。且乙醇不会导致剂量倾泻。结论本研究中分别建立了篮法及往复筒法测定盐酸羟考酮缓释片体外溶出度,可为体外溶出评价提供更多的评估手段。并建立了体外溶出曲线模型拟合及乙醇剂量倾泻实验方法,为了解该药体外释放规律及行为提供了更多参考。

米拉贝隆缓释片的体内外相关性溶出方法研究

目的利用流通池模拟难溶性药物米拉贝隆缓释制剂的溶出,建立米拉贝隆体内和体外的相关性(IVIVC)模型,开发具有预测能力的体外溶出方法。方法经Loo-Riegelman法对三种不同释放速率制剂的体内血药浓度进行反卷积分获得相应的累积吸收百分数(Fabs%),建立体外溶出目标曲线。以纯水为试验介质,流速4.0 mL·min^(-1)的试验条件下进行制剂R(贝坦利^(■),50 mg)和制剂T1、T2(50 mg)的溶出试验,通过高效液相色谱法测定溶出度,梯形面积法获得制剂的累积溶出百分数(F_(diss)%)。结果建立了米拉贝隆缓释制剂体内累积吸收与体外溶出度之间的A级IVIVC(回归系数大于0.9),制剂的外部预测误差在规定范围内。结论本研究建立的米拉贝隆缓释制剂IVIVC模型经验证具有较好的预测能力,该方法拥有的良好区分力及线性模型也可以为质量控制提供参考。

富马酸喹硫平缓释片的体内外相关性溶出方法研究

目的通过流通池法模拟富马酸喹硫平缓释制剂的体内动力学过程,建立具有体内外相关性的溶出方法,并进行体内外相关性模型预测能力的评估。方法采用HPLC-MS/MS法测得T1、T2和R制剂的血药浓度数据,通过WinNonlin软件的非房室模型和反卷积模块解析参比制剂的体内特征,依据参比制剂的体内特征指导溶出方法的设计,用3种释放速率不同的制剂的体内和体外数据建立体内外相关性模型,并进行模型预测能力验证。结果建立了具有A级相关性(R^(2)=0.967)和C级相关性(R^(2)=0.996)的溶出方法,内部制剂预测和外部制剂预测的预测误差PE%<10%,符合标准。结论本方法具有良好的体内外相关性,其体内外相关性模型经验证预测误差符合标准,对于吸收速率不同的制剂均具有良好的区分力,可以为富马酸喹硫平缓释片的制剂评价提供参考。

水飞蓟素磷脂复合物微孔渗透泵控释片比格犬体内药动学及体内外相关性研究

目的 评价水飞蓟素磷脂复合物微孔渗透泵(SM-PC MPOP)控释片的体外释药特性、比格犬体内药动学及其体内外相关性。方法 释放介质为pH7.5的磷酸盐缓冲液(添加0.5%十二烷基硫酸钠),以高效液相色谱法(HPLC)检测SM-PC MPOP的体外释放特征。用6只比格犬进行双周期交叉对照实验,按照30 mg/kg的剂量给药。HPLC法测定比格犬血浆内水飞蓟素的主要成分水飞蓟宾的质量浓度,应用药动学软件进行数据分析。结果 SM-PC MPOP在12 h累积释放度超过85%。药动学研究情况表明,受试制剂(SM-PC MPOP)和参比制剂(市售水飞蓟素胶囊)在比格犬体内的主要药动学参数:T_(max)分别为(3.2±0.4)、(0.9±0.1)h,C_(max)分别为(0.298 6±0.068 9)、(0.629 9±0.076 5)μg/ml,AUC_(0→24)分别为(2.996 8±0.583 3)、(2.268 9±0.432 8) h·μg/ml,SM-PC-MPOP对市售水飞蓟素胶囊的相对生物利用度为(162.21±30.82)%。结论 自制的SM-PC MPOP实现了缓慢释药且增加生物利用度的目标,其体内吸收与体外释药具备相对较好的关联性(r=0.839 0)。

脱卷积法进行自制尼群地平缓释制剂体内外相关性研究

目的 用脱卷积法进行自制尼群地平缓释制剂体内外相关性的研究。方法 以自制尼群地平口服溶液剂的犬体内血药浓度数据为权函数,根据3种自制尼群地平缓释制剂试验犬体内血药浓度数据,采用脱卷积法计算体内释药特性,与相应的体外释药特性进行比较,考察体内外相关性。结果 用脱卷积法计算3种尼群地平缓释制剂的体内外释药相关性良好。结论 脱卷积法适用于自制尼群地平缓释制剂的体内外相关性研究。

尼莫地平胃内滞留漂浮型缓释片的研究

将尼莫地平先制成速释型固体分散体，再压制成胃内滞留漂浮型缓释片（ＮＭＦＳＲＴ）。均匀设计法优选处方，并考察处方因素对尼莫地平释放的影响，在人体内对ＮＭＦＳＲＴ进行了初步评价。结果表明优选处方于体外漂浮达１０ｈ，０１５～６ｈ释放符合零级动力学。ＨＰＭＣ量越大，药物释放越慢，ＰＥＧ６０００量越大，释放越快。饮食后ＮＭＦＳＲＴ于胃内滞留时间约５ｈ，空腹时约３ｈ；对照非漂浮片饭后服滞留时间为３ｈ，空腹２ｈ排空。体内相对生物利用度为３９１４６％，ＭＲＴ较普通片延长一倍多。

克拉霉素缓释胶囊释放度与体内吸收度相关性的研究

目的:研究两种释药机理的克拉霉素缓释胶囊试验制剂体内-体外相关性,建立与体内吸收相关的释放度测定法。方法:在不同pH介质中测定克拉霉素缓释胶囊的体外释放度。采用LC-MS-MS测定健康志愿者单剂量交叉口服250 mg克拉霉素胶囊(F-1和F-2)后血药浓度,以Wagner-Nelson法计算药物的体内吸收百分数。以体外释放百分率对体内吸收百分数在相应的时间点进行相关性分析。结果:表明缓释胶囊F-1在pH5.0介质中释放百分率与体内吸收百分数相关,相关系数为0.9984,缓释胶囊F-2在pH 6.0介质中释放百分率与体内吸收百分数相关,相关系数为0.9939.结论:经相关性检验,两种克拉霉素缓释胶囊的体外释放与体内吸收为水平A相关。F-1在体内的吸收程度高于F-2,为F-1的处方筛选提供了理论依据。

山楂叶总黄酮缓释片的制备及Beagle犬体内外相关性研究

以山楂叶总黄酮为模型药物,羟丙甲纤维素(HPMC)、乙基纤维素(EC)及丙烯酸树脂(EudragitL100)为混合骨架材料制备日服两次的缓释片,以牡荆素为指标成分,考察Beagle犬单剂量口服缓释片后的药代动力学特征。结果表明,本品缓释特征较好,体外释放较符合Weibull模型,本品体外释放度与Beagle犬体内药物吸收分数之间相关系数为0.98。

石杉碱甲缓释微球的体外释放度及其体内外相关性研究

目的建立体内外相关性良好的石杉碱甲缓释微球的体外释放度测定方法。方法采用直接释药法和透析释药法测定石杉碱甲缓释微球的体外释放度,考察加入吐温的量和透析袋内递质的体积对释药速度的影响;采用高效液相色谱法测定石杉碱甲缓释微球在大鼠注射部位的残留量,计算微球在体内的释药速度。通过相关性评价确定最佳的体外释放度测定方法。结果透析释药法可获得良好的体内外相关性(r=0.990 2)。结论透析释药法可用于测定石杉碱甲缓释微球的体外释放度。

中药口服缓控释制剂体内外相关性研究进展

介绍缓控释制剂的体外释放度测定方法,使其能更好地模拟体内状态,得到好的体内外相关性;对最近的国内外文献中有关缓控释制剂的体内评价、体内外相关性研究进行了综述。结果表明具有良好体内外相关性的体外评价方法的建立对中药缓控释给药制剂的研究具有重要的意义。

布洛芬缓释微丸的制备及其药物动力学研究

采用膜控法制备布洛芬缓释微丸,应用转篮法(50r/min,37±1℃)比较了缓释微丸和普通片剂的体外药物溶出速率,采用HPLC法测定了制剂的血药浓度,并研究了制剂在人体内的药物动力学。缓释微丸的体外药物溶出符合一级动力学过程(K_r=0.4505h^(-1));体内动力学过程符合一级吸收和一级消除的单室模型,k_a=0.27h^(-1),K=0.27h^(-1),V_d=7.54L,t_(max)=3.97h,C_(max)=19.52μg/ml。多剂量给药血药浓度测定及计算表明:缓释微丸具有维持有效血药浓度(8.5μg/ml)时间长,血药浓度波动范围小的特点。此外,缓释微丸的体内外数据具有显著的相关性(p<0.01)。

缓释制剂的体内外相关性试验及检验

目的 :探讨缓释制剂体内外相关试验方法。方法 :以植入用缓释依托泊苷为例 ,根据体内及体外预试验数据 ,求算对应时间点关联系数K ,按中华人民共和国药典要求作对应时间点的点对点相关试验及检验。结果 :成功进行植入用缓释依托泊苷的体内外相关试验并实现相关。结论 :此法为长效缓释制剂提供了一种体内外相关试验的参考方法。

缓释微球的释放度试验及体内外相关性研究进展

简述了生物可降解的聚乳酸及乳酸 羟基乙酸共聚物微球的体外释放度试验方法及体内外相关性等 ,指出通过体外释放条件的选择可以获得较好的体内外相关性 ,并对体外释放通常快于体内的原因进行了探讨。