Design and evaluation of an extended-release matrix tablet formulation; the combination of hypromellose acetate succinate and hydroxypropylcellulose

The purpose of this study was to develop an extended-release(ER) matrix tablet that shows robust dissolution properties able to account for the variability of pH and mechanical stress in the GI tract using a combination of enteric polymer and hydrophilic polymer. Hypromellose acetate succinate(HPMCAS) and hydroxypropylcellulose(HPC) were selected as ER polymers for the ER matrix tablet(HPMCAS/HPC ER matrix tablet). Oxycodone hydrochloride was employed as a model drug. Dissolution properties of the HPMCAS/HPC ER matrix tablets were evaluated and were not affected by the pH of the test medium or paddle rotating speed.In a USP apparatus 3(bio-relevant dissolution method), dissolution profiles of the HPMCAS/HPC ER matrix tablets containing oxycodone hydrochloride were similar to that of the reference product(OxyC ontin). Moreover, in vivo performance after oral administration of the HPMCAS/HPC ER matrix tablets to humans was simulated by GastroP lus based on dissolution profiles from the USP apparatus 3. The plasma concentration-time profile simulated was similar to that of the reference product. These results suggest that the combination of HPMCAS and HPC shows a robust dissolution profile against pH and paddle rotating speed and indicates the appropriate extended-release profile in humans.

Development and <i>in Vitro-in Vivo</i>Evaluation of Controlled Release Matrix Tablets of Desvenlafaxine

The objective of this investigation was to prepare extended release tablet containing matrix granules of Desvenlafaxine succinate monohydrate and to study its in vitro release and in vivo absorption. The design of dosage form was performed by choosing hydrophilic hydroxypropyl methyl cellulose (HPMC K100M), sodium carboxyl methyl cellulose (Blanose), microcrystalline cellulose (MCC) and lactose monohydrate polymers as matrix builders and polyvinyl pyrolidine (Kollidon K30) as granulating polymers. Granules were prepared by composing drug with HPMC K100M, sodium CMC, MCC and lactose monohydrate by spray drying method. Optimized formulation of Desvenlafaxine succinate monohydrate was formed by using 20% HPMC K100M, 26.6% MCC, 6.6% of sodium CMC (Blanose), 13.3% of lactose monohydrate and 5% ratio of Kollidon K30 as binder. Tablets were compressed with free flowing optimized granules of uniform drug content. This extended the release period up to 24 h in vitro study. Similarity factor and mean dissolution time were also reported to compare various dissolution profiles. The network formed by HPMC, MCC and Blanose had been coupled satisfactorily with the controlled resistance. Biopharmaceutical study of this optimized dosage form in rabbit model showed 24 h prolonged drug release in vivo. A close correlation (R2 = 0.9833) was established between the in vitro release and the in vivo absorption of drug. The results suggested that wet granulation with spray dried technique, is a suitable method to formulate sustained release Desvenlafaxine succinate monohydrate and it can Perform therapeutically better than conventional immediate release dosage form.

Evaluation Procedure for Quality Consistency of Generic Nifedipine Extended-Release Tablets Based on the Impurity Profile

A procedure to evaluate the quality consistency of generic drugs based on the impurity profile and the similarity analysis methods was presented in this paper. Nifedipine extended-release tablets from six generic factories of China were used to evaluate the uniformity with the original drug in the study. The procedure includes: choice of chromatographic methods, data collection and conformity test, evaluation of intra-batch similarity of drugs, evaluation of generic drugs with the original drug and weighted similarity evaluation of generic drugs. The data were collected via high-performance liquid chromatography (HPLC), and then calculated by correlation coefficient, cosine, principal component analysis (PCA) and hierarchical clustering analysis (HCA). It is more suitable to use peak areas as the vector when calculating the similarity of impurity profile. After weighting the peak areas of the unspecified impurities in further evaluation of the generic quality, the generic level of different factories was differentiated and the best generic factory was picked out.

Extended tacrolimus release via the combination of lipid-based solid dispersion and HPMC hydrogel matrix tablets

The objective of this study is to evaluate the feasibility of obtaining extended release of tacrolimus by a novel combination of lipid-based solid dispersion and matrix-type extended release tablet techniques. Tacrolimus solid dispersion was prepared using glycerylbehenate(Compritol~?ATO888) and Pluronic F127 as the carrier materials with hot-melt method, which was then blended with hydrogel matrix materials, such as HPMC and lactose, the powders were directly compressed into tablets. In vitro drug release tests were carried out to evaluate the performance of the solid dispersions and the tablets. The dissolution rate of tacrolimus was significantly improved by the lipid-based solid dispersion, and the incorporation of HPC into the solid dispersion obviously improved its stability after storage. Extended release tablets loaded with tacrolimus solid dispersion showed prolonged drug release patterns over 24 h, the release patterns of the tablets can be tailored by the compositions of the matrix materials, including the types and content of HPMCs. A modified processing method that directly mixed the melted solid dispersion with HPMC powders improved the uniformity of the solid dispersion inside the tablet matrix and release profile. The release data of the extended release tablet fitted well to the Korsmeyer–Peppas model with n value of 0.85, which suggested diffusion-and erosion-controlled release mechanism. The combination of lipid-based solid dispersion and HPMC hydrogel matrix may find wide applications in the extended release dosage forms of high potent, water-insoluble drugs.

Effect of formulation variables on in vitro release of a water-soluble drug from chitosanesodium alginate matrix tablets

The objective of this study is to investigate the feasibility of using chitosanesodium alginate(CSeSA)based matrix tablets for extended-release of highly water-soluble drugs by changing formulation variables.Using trimetazidine hydrochloride(TH)as a water-soluble model drug,influence of dissolution medium,the amount of CSeSA,the CS:SA ratio,the type of SA,the type and amount of diluents,on in vitro drug release from CSeSA based matrix tablets were studied.Drug release kinetics and release mechanisms were elucidated.In vitro release experiments were conducted in simulated gastric fluid(SGF)followed by simulated intestinal fluid(SIF).Drug release rate decreased with the increase of CSeSA amount.CS:SA ratio had only slight effect on drug release and no influence of SA type on drug release was found.On the other hand,a large amount of water-soluble diluents could modify drug release profiles.It was found that drug release kinetics showed the best fit to Higuchi equation with Fickian diffusion as the main release mechanism.In conclusion,this study demonstrated that it is possible to design extended-release tablets of watersoluble drugs using CSeSA as the matrix by optimizing formulation components,and provide better understanding about drug release from CSeSA matrix tablets.

帕利哌酮缓释片与利培酮治疗精神分裂症的对照研究

目的为了比较帕利哌酮缓释片与利培酮治疗精神分裂症患者的疗效及安全性的差异。方法选取某精神病院60例精神分裂症患者,随机分成帕利哌酮组和利培酮组各30例,分别采用帕利哌酮缓释片和利培酮进行治疗,观察8周。以阳性及阴性症状量表(PANSS)减分率评定疗效,用治疗中出现的症状量表(TESS)评定不良反应,以个人和社会功能量表(PSP)评定社会功能。结果帕利哌酮组与利培酮组的总显效率(痊愈+显效)和总有效率(痊愈+显效+有效)的差异不显著(P>0.05)。患者治疗后,两组的PANSS总分及各因子分明显降低(P<0.05)。与利培酮组比较,帕利哌酮组的不良反应出现频率低、程度轻微,个人和社会功能恢复快。结论帕利哌酮缓释片是一种安全有效的新型抗精神病药,可以明显改善精神分裂症和分裂样精神病患者的精神病性症状及社会功能。

琥珀酸去甲文拉法辛缓释片的质量检测

目的建立琥珀酸去甲文拉法辛缓释片释放度、含量、含量均匀度及有关物质检测方法,并进行方法学验证。方法采用紫外分光光度法测定释放度,高效液相色谱法测定含量、含量均匀度及有关物质,分别考察专属性、线性、回收率、精密度及稳定性等,进行方法学验证。结果释放度方法学验证结果显示,该方法专属性好,在10~200μg/ml范围内线性关系良好,回收率、重复性及中间精密度均符合要求;含量、含量均匀度检测方法验证结果显示,该方法专属性良好,在5~400μg/ml范围内线性关系良好,回收率、重复性及中间精密度均符合要求,溶液在24 h内稳定;有关物质方法学验证结果显示,该方法专属性好,灵敏度高,线性、回收率均符合要求,且溶液在室温条件下放置24 h稳定性良好。结论释放度检测方法简单、灵敏、专属性好、准确度高,含量及含量均匀度检测方法准确可靠,有关物质检测方法准属性好、灵敏度高,均可用于琥珀酸去甲文拉法辛缓释片的质量控制。

Quantitative analysis of 3-isopropylamino-1,2-propanediol as a degradation product of metoprolol in pharmaceutical dosage forms by HILIC-CAD

Aryloxypropanolamine is an essential structural scaffold for a variety of b-adrenergic receptor antagonists such as metoprolol.Molecules with such a structural motif tend to degrade into α,β ehydroxypropanolamine impurities via a radicaleinitiated oxidation pathway.These impurities are typically polar and nonchromophoric,and are thus often overlooked using traditional reversed phase chromatography and UV detection.In this work,stress testing of metoprolol confirmed the generation of 3-isopropylamino-1,2-propanediol as a degradation product,which is a specified impurity of metoprolol in the European Pharmacopoeia(impurity N).To ensure the safety and quality of metoprolol drug products,hydrophilic interaction chromatography(HILIC)methods using Halo Penta HILIC column(150mm×4.6 mm,5 μm)coupled with charged aerosol detection(CAD)were developed and optimized for the separation and quantitation of metoprolol impurity N in metoprolol drug products including metoprolol tartrate injection,metoprolol tartrate tablets,and metoprolol succinate extended-release tablets.These HILIC-CAD methods were validated per USP validation guidelines with respect to specificity,linearity,accuracy,and precision,and have been successfully applied to determine impurity N in metoprolol drug products.

HPLC法测定琥珀酸去甲文拉法辛缓释片中去甲文拉法辛含量

建立高效液相色谱法测定琥珀酸去甲文拉法辛缓释片中去甲文拉法辛含量。采用Inertsil ODS-3 C18色谱柱(150 mm×4.6 mm,5μm),流动相为磷酸二氢钾缓冲液(取4.86g磷酸二氢钾,用水溶解并稀释至1000m L,加10m L三乙胺,用磷酸调节pH值至3.0±0.05)-乙腈(830∶170),柱温为30℃,流速为1.0 m L·min^(-1),检测波长为225 nm。去甲文拉法辛在40.57~60.85μg·m L^(-1)范围内与峰面积呈良好的线性关系(r=0.9991),低、中、高浓度平均回收率分别为99.85%、99.81%、99.83%,RSD分别为0.52%、0.24%、0.27%(n=3),检出限为0.25ng,日内、日间精密度RSD分别为0.43%和0.56%(n=6)。该方法灵敏、准确,专属性强,可作为琥珀酸去甲文拉法辛缓释片中的去甲文拉法辛含量测定方法。

更年期潮热非激素药物疗法的研发成败案例分析

本文深入分析了去甲文拉法辛缓释片、艾司米氮平片和甲磺酸帕罗西汀胶囊3种非激素药物治疗更年期潮热的临床研发历程。去甲文拉法辛缓释片和艾司米氮平片均由于疗效不足和存在安全性问题,被监管机构以获益风险平衡欠佳为理由拒绝批准。相比之下,甲磺酸帕罗西汀胶囊通过设置安慰剂导入期、更保守的样本量估计和预先规定对2项Ⅲ期试验的主要疗效指标进行荟萃分析等措施有效降低了药物研发失败的风险,不仅展示了对潮热频率和潮热程度的疗效,也通过多个Ⅱ期试验探索到耐受性最佳的剂量,最终获得了美国食品药品监督管理局的批准。非激素药物在更年期潮热治疗的研发中面临诸多挑战,包括药物安全性特征与在精神科疾病患者不同、药物疗效偏弱、临床前药效模型与临床症状缓解的关联度弱,以及剂量探索试验需要较大样本量等。以上案例分析为后续类似适应证的药物研发提供了优化试验设计、降低研发风险的策略借鉴。

琥珀酸去甲文拉法辛缓释片的制备及体外释药特性研究

目的制备琥珀酸去甲文拉法辛(desvenlafaxine succinate,DVS)缓释片,确定最佳处方及制备工艺,并进行体外释放特性研究。方法建立紫外分光光度法测定DVS缓释片的体外释放度,以体外释放度为评价指标,通过单因素考察,确定DVS缓释片的最佳处方及制备工艺。结果最佳处方及工艺:以HPMC K15M为骨架材料,用量50%;MCC为填充剂;硬脂酸镁为润滑剂,用量8%;湿法制粒后,以70 k N的压力压片。制备的DVS缓释片体外释放行为良好,可持续释药24 h,符合试验要求。结论 DVS缓释片的制备工艺稳定可靠,体外释放度测定方法简便易行。

ICP-MS法测定盐酸安舒法辛缓释片中7个元素杂质含量

目的:建立电感耦合等离子体质谱(ICP-MS)法测定盐酸安舒法辛缓释片中铅(Pb)、镉(Cd)、砷(As)、汞(Hg)、钴(Co)、钒(V)、镍(Ni)7个元素杂质含量。方法:用微波消解进行样品前处理;以^(73)Ge,^(115)In,^(209)Bi为内标,采用ICP-MS进行测定,测量模式为碰撞池模式(KED),碰撞气流速4.35 mL·min^(-1),采样深度5.0 mm,辅助气流速0.8 L·min^(-1),雾化器流速1.075 L·min^(-1);对所建立的方法进行了方法学验证。结果:7个元素标准曲线的相关系数均大于0.99;加样回收率在92.2%～104.4%之间;重复性试验RSD≤1.2%(n=6);中间精密度试验RSD≤3%,均满足USP<233>方法学验证的要求。样品检测的结果远小于国际人用药物注册技术协调会议《元素杂质指南Q3D》(ICHQ3D)中各元素杂质的每日允许暴露量(PDE)。结论:本文建立的方法样品用量少,分析速度快,灵敏度高,可用于盐酸安舒法辛缓释片中元素杂质的质量研究。

自研琥珀酸去甲文拉法辛缓释片与参比制剂体外溶出度一致性评价

目的:评价2种规格的自研琥珀酸去甲文拉法辛缓释片与参比制剂Pristiq^R体外溶出行为的一致性。方法:采用高效液相色谱法,色谱柱为Kromasil 100-5C_8(250 mm×4.6 mm,5μm),流动相为0.1 mol·L^(-1)磷酸二氢铵溶液(pH 4.4)-乙腈(80∶20),检测波长为226 nm,柱温为30℃,根据仿制药一致性评价要求,并参考PristiqR在FDA溶出数据库中的条件(0.9%氯化钠溶液,篮法和转速100 r·min^(-1))分别考察自研制剂与参比制剂在5种不同介质(水、0.9%氯化钠溶液、pH 1.0盐酸溶液、pH 4.5磷酸盐缓冲液及pH 6.8磷酸盐缓冲液)中的体外释放行为及其相似性,并采用乙醇倾泻和转速强力变化进一步考察两者缓释片的相似性。结果:自研制剂与参比制剂在5种不同介质中溶出曲线均相似;在强力变化的不同转速下溶出曲线相似;在乙醇倾泻实验中溶出曲线相似(f_2因子均>50%)。结论:2种规格的自研制剂与参比参比制剂体外溶出行为具有一致性。