In Vitro and in Vivo Evaluation of Whole and Half Tablets of Sustained-Release Adinazolam Mesylate

The mechanism of release from sustained-release adinazolam mesylate tablets was assessed by the Higuchi equation and by analysis of drug release profiles through 60% released using the Peppas equation. Computed values of the diffusional exponent, n, ranged from 0.59 to 0.66. Values of n in this range are consistent with a mixed mechanism of release, with diffusion of drug through the hydrated polymer matrix and relaxation of this matrix being the principal processes controlling release. The rate of in vitro drug release was increased for half tablets relative to whole tablets and is attributed to an increase in the surface to volume ratio of half tablets of about 16%. This increase in surface-to-volume ratio of half tablets was reflected by an increase in the constant, k, from the Peppas equation of 20–23% and by an increase in the slope of Higuchi plots of 12–18% for four lots of tablets. In vivo/in vitro relationships from two bioavailability studies were thoroughly evaluated. Using either a linear or a quadratic relationship, an in vivo/in vitro correlation exists for sustained-release adinazolam mesylate tablets.     

Development and in Vitro-in Vivo Evaluation of a Multiparticulate Sustained Release Formulation of Diltiazem

Purpose. To develop and evaluate the in vitro/in vivo performance of diltiazem sustained release pellets that were prepared by the Wurster column process. Methods. Pellets containing diltiazem were prepared by spraying a slurry of micronized diltiazem hydrochloride, pharmaceutical glaze and alcohol onto an appropriate mesh fraction of nonpareil seeds using the Wurster column. A two-step drug layering process was used to increase drug loading from 60% to 75%. The oven-dried diltiazem basic pellets were coated with eth-ylcellulose/dibutyl sebacate coating solution to yield diltiazem sustained release pellets. An open, randomized Latin square, three-way crossover clinical study was used to evaluate the in vivo performance of the coated product. Results. Altering the mesh fraction of the starting nonpareil seeds for this layering process was found to affect the release characteristics of drug from the pellets. An oven-drying step was required to stabilize the diltiazem basic pellets. The thicker the drug loading layer the longer the oven drying is needed to stabilize the pellets. The diltiazem sustained release pellets produced by these methods displayed sustained release dissolution profiles both in vitro and in vivo. Diltiazem basic pellets coated with a 0.6% ethylcellulose/dibutyl sebacate coating showed a different rate of absorption (lower C _max and higherT _max) and the same extent of absorption as compared to Cardizem^® tablets. Conclusions. Clinical data confirmed that this formulation approach is an effective means to produce a diltiazem sustained release product.     

Release and Absorption Characteristics of Novel Theophylline Sustained-Release Formulations: In Vitro-in Vivo Correlation

Five new experimental sustained-release (SR) formulations of theophylline, T-l, T-l-A, T-2, T-2-A, and T-2-E, in a matrix tablet form with a protein were developed. The in vitro release of theophylline from these novel experimental formulations and two commercial (Theotrim and Theo-Dur) SR formulations, was studied for 2 hr immersed in simulated gastric fluid TS, followed by an additional 10 hr immersed in simulated intestinal fluid TS. Like Theotrim and Theo-Dur, theophylline release profiles from all the novel experimental formulations were smooth, controlled, and unaffected by changes in the pH and the proteolytic enzyme content of the incubation media. Pharmacokinetic evaluation of T-l, T-l-A, T-2-A, Theotrim, and Theo-Dur was carried out in five dogs and six healthy human volunteers under fasting conditions, using immediate-release aminophylline tablets as controls. Pharmacokinetic analysis by the Wagner–Nelson procedure revealed sustained-release absorption characteristics for all the formulations with the exception of the immediate release aminophylline tablet. For each of the formulations tested, the regression analysis results of the percentage of theophylline absorbed in dogs or humans against the mean percentage released in vitro, at the corresponding times, indicated a high correlation. These data imply that the in vivo release profiles under fasting conditions in the gastrointestinal tract of dogs and humans may be similar to those in the in vitro studies.     

In Vivo/in Vitro Correlation of Experimental Sustained-Release Theophylline Formulations

A novel multiparticulate sustained-release theophylline formulation, which consisted of spherical drug pellets coated with a rate-controlling membrane, was evaluated in vivo. Two preparations that differ solely in the coat thickness, and hence rate of in vitro drug release, were studied in comparison with a solution of the drug. Both preparations produced serum concentration profiles that are reflective of a slow and sustained rate of absorption. The in vivo release versus time profiles calculated using a deconvolution procedure showed that the two preparations differed in the rate but not the extent of drug release. Satisfactory correlation was also obtained between the in vivo and the in vitro results. When the two preparations were further compared using the parameters, time to reach peak concentration (T _p), peak concentration (C _p), and total area under the serum concentration versus time curves (AUC), a statistically significant difference was observed in the T _p and C _p values but not the AUC values, suggesting that the preparations differed in the rate but not the extent of absorption. In addition, the extent of absorption from both preparations was comparable to that obtained with the drug solution.     

Formulation,Bioavailability, and Pharmacokinetics of Sustained-Release Potassium Chloride Tablets

The release of potassium chloride incorporated into hydrogenated vegetable oil and hydroxypropyl methylcellulose matrix tablets was studied in vitro. The formulations containing 20% hydrogenated vegetable oil and hydroxypropyl methylcellulose showed a sustained-release profile comparable to that of a standard commercially available sustained-release preparation, containing 8 mEq potassium chloride embedded in a wax material. The formulated and standard sustained-release potassium chloride tablets were compared to a conventional enteric-coated potassium chloride tablet in 10 healthy subjects. Mean recoveries in 24-hr urine potassium levels from four dosage forms (after subtracting normal urine potassium excretion levels) were 76 ± 32% from hydroxypropyl methylcellulose, 95 ± 22% from hydrogenated vegetable oil-incorporated matrix tablets, 91 ± 29% from commercially available sustained-release tablets, and 97 ± 13% from enteric-coated tablets. There was no significant difference (P > 0.05) in the time to reach maximum excretion rates among the three sustained-release tablets. No significant adverse effect was experienced with any of the preparations.     

Lack of In Vivo/In Vitro Correlations for 50 mg and 250 mg Primidone Tablets

Purpose. To determine if large differences in the in vitro dissolution profiles for primidone tablets would result in significant bioavailability differences. Methods. Two separate bioavailability studies were conducted. The first study used 18 healthy subjects and compared the bioavailability of an old 50 mg tablet formulation, a new 50 mg tablet formulation, and a suspension containing 50 mg/ml of primidone. The second study enrolled 24 subjects who were to receive a new 250 mg tablet formulation, two lots of an old 250 mg tablet formulation and a 250 mg tablet from a second manufacturer. In vitro dissolution was conducted over 90 minutes, using USP 23 Apparatus 2 at 50 rpm, with 900 ml of water. Results. Dissolution at 90 minutes for the old and new 50 mg tablets was approximately 20% and 100%, respectively. The dissolution of the four 250 mg tablets ranged from approximately 30% to 100%. The 50 mg tablet that dissolved slower had a longer Tmax and a 14% lower Cmax than the more rapidly dissolving tablet, but the AUC(0–) values differed by only 3%. Only nine subjects completed the 250 mg study because of side effects. The differences in Cmax and AUC(0–) among the four 250 mg tablets were less than 7%. Conclusions. Even though there were large differences in the in vitro dissolution of the 50 mg and the 250 mg primidone tablets, the two 50 mg tablets were shown to be bioequivalent, as were the four 250 mg tablets.     

Predictive Ability of Level A in Vitro-in Vivo Correlation for RingCap Controlled-Release Acetaminophen Tablets

Purpose. The goal of this study was to establish and validate an in vitro-in vivo correlation (IVIVC) for two sustained-release formulations (i.e., a matrix tablet and a RingCap banded matrix tablet) containing 750 mg of acetaminophen. Methods. The in vitro dissolution and in vivo disposition of these formulations were examined by using a USP type III dissolution apparatus and a single-dose, three-way, crossover study that included an immediate-release acetaminophen dosage form, respectively. An IVIVC was established by using the mean fraction dissolved (FD) and mean fraction absorbed (FA) and used to simulate the plasma concentation-time profile of acetaminophen after administration of the matrix tablet (i.e., internal validation) and RingCap banded matrix tablet (i.e., external validation). Results. A statistically significant relationship (r ² = 0.997, P < 0.001) existed between the FD and FA for matrix tablets and was best described by the equation (FA) = 0.984 × (FD) + 0.0133. The percent predictions errors in CMAX and AUCL were <10% when predicting the plasma concentration-time profiles for the two formulations, validating the internal and external predictability of the IVIVC. Conclusions. The data (i) show that in vitro dissolution data are a good predictor of in vivo fraction absorbed for acetaminophen, (ii) support the general use of in vitro dissolution data for readily soluble and readily absorbed drugs, (iii) suggest that acetaminophen may serve as a model drug for evaluating novel sustained-release delivery systems, and (iv) provide a tangible example of the limitations of current methods for predicting and validating IVIVC.     

碳酸锂片（缓释片）的质量分析

摘 要 目的：评价碳酸锂片（缓释片）的质量现状及存在问题。方法: 按照法定标准方法对样品进行检验,并进行了探索性研究,采用统计学分析方法对数据结果进行分析比较。结果: 按法定标准方法检验,120批次样品除1批溶出度不合格外,其余均符合规定,合格率为99.2%。结论:本品质量状况总体评价较好,另外现行质量标准有待提高。     

硝酸异山梨酯缓释胶囊的人体药物动力学及相对生物利用度

采用毛细管气相色谱法测定硝酸异山梨酯血药浓度 ,考察了国产及进口硝酸异山梨酯缓释胶囊多剂量口服达稳态过程和稳态药物动力学特征 ,研究硝酸异山梨酯缓释胶囊的人体药物动力学和相对生物利用度。结果表明 ,连续口服硝酸异山梨酯 4 0 mg缓释胶囊三天后 ,体内硝酸异山梨酯血药浓度基本达稳态水平。国产和进口缓释胶囊的稳态药物动力学参数 tmax分别为 4 .33± 0 .4 9和 3.83± 0 .72 h,Cmax分别为 2 4 .78± 8.2 9和 2 4 .4 2± 7.39ng/ ml,AUCss分别为 14 7.5± 18.4和 14 6 .9± 15 .7ng· h· m l- 1 ,波动度 DF分别为 3.5 4± 0 .82和 3.5 2± 0 .81。国产制剂的相对生物利用度为 10 0 .5 %± 8.1% ,经三因素方差分析和双单侧 t检验判定两种制剂具有生物等效性     

非洛地平-美托洛尔缓释片处方优化及体外释放一致性评价

目的 优化非洛地平-美托洛尔缓释片的处方,并评价其与市售制剂体外释放的一致性。方法 采用HPLC测定非洛地平-美托洛尔缓释片中非洛地平及美托洛尔的释放度;以体外释放度为评价指标,重点考察了固体分散体、微丸以及片芯中关键处方因素对非洛地平/美托洛尔释放行为的影响,进一步优化处方。结果 微丸组成、微丸粒径、微丸衣膜中致孔剂用量、微丸增重以及片芯中阻滞剂用量均影响药物释放;处方优化后自制的非洛地平-美托洛尔缓释片与市售制剂在0.3% SDS水溶液、含0.3% SDS的pH 4.0的柠檬酸缓冲液、含0.3% SDS的pH 6.8的磷酸盐缓冲液、含0.3% SDS的0.1 mol·L^-1 HCl中的体外释放行为一致。结论 自制非洛地平-美托洛尔缓释片与市售制剂的体外释放行为一致。     

醋氯芬酸缓释片和普通片体内外释药行为的相关性研究

目的对比研究醋氯芬酸缓释片和普通片的体外释放行为和Beagle犬体内的药动学,分析体内、体外释药行为的相关性。方法以紫外分光光度法测定两药的体外释放度,利用反相高效液相色谱法测定不同时间Beagle犬血浆中药物浓度,用DAS2.0统计软件计算有关药动学参数,Loo-Riegelman法计算体内吸收百分数,并对体内外相关性进行评价。结果醋氯芬酸缓释片体外恒速释放14h累积释放百分率在95%以上,普通片和缓释片的主要药动学参数达峰时间（tmax）为（2.833±1.169）h和（12.800±0.980）h,血浆半衰期（t1/2）为（2.650±0.261）h和（6.859±6.029）h,峰浓度（Cmax）为（23.457±8.881）μg/mL和（5.674±1.903）μg/mL,药时曲线下面积（AUC0-∞）为（113.171±16.529）μg.h/mL和（128.295±118.601）μg.h/mL,且体内外相关性较好。结论醋氯芬酸缓释片血药浓度平稳,与普通片相比可较长时间保持有效血药浓度。     

Controlled Release of Paracetamol from Amylodextrin Tablets: In Vitro and in Vivo Results

Amylodextrin is a suitable excipient for the design of solid controlled-release systems. The release of paracetamol from tablets containing 30% drug and 70% amylodextrin was studied in vitro and in vivo. In vitro dissolution profiles showed almost-constant drug release rates during 8 hr, when measured in 0.05 M buffer, pH 6.8. Peroral administration of the tablets to man showed almost-constant paracetamol plasma levels up to 14 hr, as compared to fast absorption and fast elimination of a reference paracetamol solution. The plasma profiles of eight volunteers demonstrated a small intersubject variability during the first day after tablet administration. Increasing variability and decreasing plasma levels during the second day were caused by excretion of tablets from the bodies. Cumulative input as a function of time showed near-zero-order drug release during the first day. The in vivo results indicate that amylodextrin tablets are not hydrolyzed by -amylase, present in the gastrointestinal tract.     

A Floating Controlled-Release Drug Delivery System: In Vitro-in Vivo Evaluation

A novel floating controlled-release drug delivery system was formulated in an effort increase the gastric retention time of the dosage form and to control drug release. The buoyancy was attributed to air and oil entrapped in the agar gel network. A floating controlled-release 300-mg theophylline tablet having a density of 0.67 was prepared and compared in vitro and in vivo to Theo-dur. The in vitro release rate of the floating tablet was slower. In vivo scintigraphic studies for a floating and a heavy nonfloating tablet, under fasting and nonfasting conditions, showed that the presence of food significantly increased the gastric retention time for both tablets, and tablet density did not appear to make a difference in the gastric retention time. However, the positions of the floating and nonfloating tablets in the stomach were very different. Bioavailability studies in human volunteers under both fasting and nonfasting conditions showed results comparable to those with Theo-dur. The floating controlled-release theophylline tablet maintained constant theophylline levels of about 2 mg/mL for 24 hr, which may be attributable to the release from the agar gel matrix and the buoyancy of the tablet in the stomach.     

In Vitro and in Vivo Evaluation in Dogs and Pigs of a Hydrophilic Matrix Containing Propylthiouracil

A hydrophilic matrix tablet containing 300 mg of propylthiouracil was formulated with several types of hydroxypropylmethylcellulose. The influence of polymer and drug granule particle size, polymer concentration, crystallinity and geometry of the polymer particles, the polymer incorporation outside or inside the granule, addition of a filler and tablet hardness were studied. Polymer concentration, polymer particle size and geometry, filler addition and type of the filler used had a major influence on in vitro drug dissolution profiles. The bioavailability of propylthiouracil in dogs from the hydrophilic matrices investigated was low, because of the short gastro-intestinal transit times of the matrix tablets in the dogs. The matrix tablets reached the colon in fasted dogs within 2–3 hours after administration. The results indicated the poor predictability of bioavailability experiments in dogs with hydrophilic matrices. Although the bioavailability data in pigs seemed promising, a transit time study revealed a long stomach residence time of the matrix tablets in pigs. These data suggested that pigs are an inappropriate animal model for bioavailability studies of erodible matrix tablets.     

沙丁胺醇包合物缓释片在家犬体内药动学研究

对沙丁胺醇包合物缓释片和市售普通片进行了家犬单剂量交叉口服给药的药动学研究 ,采用高效液相色谱 -荧光法测定血药浓度。缓释片和普通片药动学参数 Tmax分别为 7.0± 2 .6和 2 .2± 0 .8h,Cmax分别为 12 8.5± 2 4.1和 2 0 1.2± 10 .6 ng/ m l,AUC分别为 116 2 .2± 2 0 0 .9和 10 5 4.4± 15 7.3ng· h· ml- 1。缓释片相对于普通片的生物利用度为 110 .1% ,体内外相关性良好     

Formulation Design,Optimization and Pharmacodynamic Evaluation of Sustained Release Mucoadhesive Microcapsules of Venlafaxine HCl

The objective of present research work was to design and characterize the venlafaxine HCl-loaded sodium alginate-based mucoadhesive microcapsules by ionic gelation technique using HPMC K100M as mucoadhesive polymer. The Placket-Burman Design was applied for preliminary screening of the formulations and systematic optimization by using Box-Behnken Design. The prepared microcapsules were characterized for drug content, entrapment efficiency, micromeritic properties, particle size, swelling index, mucoadhesive strength, in vitro drug release and in vivo antidepressant activity. FTIR and differential scanning calorimetry studies showed no incompatibility. Surface morphology studies revealed spherical nature of the prepared microcapsules. In vitro drug release studies revealed sustained release by diffusion mechanism. Further, the microcapsules were effective in reducing the depression induced by forced swimming test in Sprague-Dawley rats compared to the pure drug. The microcapsules were found to be stable under accelerated stability conditions, which suggest them as better alternative delivery systems for enhanced therapeutic efficacy of antidepressant drug, venlafaxine HCl.     

单剂量口服法莫替丁缓释片的药代动力学

选择６名男性健康志愿者，通过ＨＰＬＣ法测定单剂量口服法莫替丁缓释片和普通市售片后的血药浓度，用３ｐ８７程序处理数据，研究该药缓释制剂的药代动力学和生物利用度，并考察了体内吸收率与体外溶出度的相关性．结果表明，两种剂型在体内血药浓度－时间曲线均符合一室模型．法莫替丁缓释片的主要药代动力学参数为：Ｔｍａｘ＝４．６ｈ，Ｃｍａｘ＝５０．９６μｇ／Ｌ，Ｔ１／２ｋｅ＝５．０４ｈ，ＡＵＣ＝６９６．８６μｇ·ｈ／Ｌ．其相对生物利用度为１１６％．     

甲硝唑胃内滞留型缓释片的研制

采用交联聚乙烯吡咯烷酮，卡波普，微晶纤维素等材料，直接压片，制得甲硝唑胃内滞留型缓释片，并进行了体外释放度的研究。结果显示，本品体外漂浮性良好，具有较好的缓释效果。体外释放行为符合一级释放动力学方程。     

Formulation and Evaluation of Rizatriptan Benzoate Mouth Disintegrating Tablets

The present investigation deals with development of mouth disintegrating tablets of rizatriptan benzoate to produce the intended benefits. Mouth disintegrating tablets of rizatriptan benzoate were prepared using superdisintegrants crospovidone, carboxymethylcellulose calcium, Indion 414 and Indion 234 using the direct compression method. The tablets prepared were evaluated for thickness, uniformity of weight, content uniformity, hardness, friability, wetting time, in vitro and in vivo disintegration time, mouth feel, in vitro drug release and assay by high performance liquid chromatography. The tablets disintegrated in vitro and in vivo within 4 to 7 s and 6 to 19 s, respectively. Almost 90% of drug was released from all formulations within 20 min. The drug release from the formulations followed first order kinetics. Stability studies of the tablets at 40±2°/75%±5% RH for 1 mo showed non significant drug loss. The formulation containing combination of crospovidone and Indion 234 was found to give the best results. Apart from fulfilling all official and other specifications, the tablets exhibited higher rate of release.     

氯氮平胃内漂浮片的研制

采用羟丙甲纤维素、十六醇等材料,湿法制颗粒压片,制备了氯氮平胃内漂浮片进行了体外漂浮性与体外释放度的研究。与普通氯氮平片比较,本品体外漂浮性良好,具有很好的缓释效果,其体外释放行为符合Higuchi方程。