动态pH条件下4种茶碱控释、缓释制剂的体外释放度

目的：建立茶碱控释、缓释制剂的体外释放度评价方法。方法：模拟胃肠道的动态ｐＨ 条件,对茶碱控释胶囊、茶碱缓释片进行了体外释放度测定。结果：药物的累积释放百分率均与中国药典１９９５ 年版二部茶碱缓释片标准相近。结论：茶碱控释胶囊、缓释片释放度均不受ｐＨ 值的影响,动态ｐＨ条件可对茶碱控释、缓释制剂的体外释放度作出正确的评价。     

非洛地平缓释制剂体外释放度比较

目的:对不同厂家非洛地平缓释制剂的体外释放度进行比较。方法:按照非洛地平的部颁标准,采用桨法测定非洛地平缓释制剂的释放度,通过选用数学模型线性拟合,求出参数,进行方差分析。结果:B样品释放度的均一性和重现性均好于A样品,A样品同一样品不同批号间释放度差异极具显著性(P<0.01),B样品有2个批号间差异具显著性(P<0.05)。结论:两个厂家的产品的释放度均符合部颁标准规定,B样品释放度好于A样品。     

Bioavailability of ambroxol sustained release preparations. Part I: In vitro dissolution studies

The in vitro dissolution of two ambroxol-HCl containing sustained release preparations (75 mg) and the effect of pH of the dissolution medium on the dissolution rats were investigated. The studies were carried out using the USP XXI paddle method. A new ambroxol HCl sustained release formulation based on a dialyzing membrane for controlled release shows a longer release action as compared to a standard sustained release preparation from commercial source which is based on spheroids constituted by a lipid matrix. The in vitro release rate of the latter product also appears to be more pH dependent.     

Quality assessment for sustained release pharmaceutical preparations by dissolution test using microdialysis-HPLC method

Dissolution testing is a core performance test in pharmaceutical development and quality control. The conventional HPLC dissolution method (batch-sampling method) has many steps such as the filtration, collection and replenishment of sample solutions. We previously reported the dissolution test by using microdialysis methods (microdialysis-HPLC method) that can omit many steps. In this study, we investigated whether the microdialysis-HPLC method can be applied to quality assessment for sustained release preparations by a dissolution test. Calcium-channel blockers nifedipine tablets (20 mg) were used, and the test solution used was 0.2 M hydrogen phosphate-citric acid buffer (pH 6.8) with or without 1% sodium lauryl sulfate. In both test solutions, the microdialysis-HPLC method is able to accomplish continuous sampling of sample solutions, and the dissolution behaviors of original nifedipine tablets by the microdialysis-HPLC method were similar to that of the batch-sampling method. In contrast, the dissolution behaviors by the microdialysis-HPLC method were different between original nifedipine tablets and generic products, and the dissolution behaviors in the microdialysis-HPLC method tend to reflect the pharmaceutical design in comparison with the batch-sampling method. In addition, standard deviation in the microdialysis-HPLC method was lower than that of the batch-sampling method. We found that the recovery rate of nifedipine by the microdialysis-HPLC method was increased with the decrease in flow rate through dialysis probe. These findings provide significant information that can be used in pharmaceutical development and quality assessment for original and generic pharmaceutical products, which are sustained release preparations.     

Comparative in vitro dissolution and in vivo bioequivalence of 2 pentoxifylline sustained release formulations

Pentoxifylline is a xanthine derivative that is indicated for the treatment of patients with intermittent claudication on the basis of chronic occlusive arterial disease of the limbs. In the present study, prior to the in vivo study, an in vitro comparative dissolution test was performed by the paddle method for 2 oral sustained release pentoxifylline tablets (400 mg) following the bioequivalence guidance of FDA. Metrics of peak exposure (Cmax) and total exposure to 24 h (AUC24) were compared using a randomized, single oral, open-label, 2-period, 2-sequence, 2 treatments crossover study in 24 healthy male volunteers under fasted conditions. After an overnight fast, the volunteers received 400 mg pentoxifylline and the blood samples were collected over a 24-h period following drug administration. Plasma drug concentrations were measured by a reverse-phase HPLC method with ultraviolet detection. In vitro dissolution tests requirements were met by both formulations. Observed exposure metrics for test and reference products were 140.6±51.5 and 132.6±48.5 ng/ml for Cmax and 986.4±350.7 and 1 035.8±350.3 ng.h/ml for AUC0-24 respectively. The confidence intervals (90%) around ratios (test/reference) of least squares means derived from logarithmic transformed exposure metrics were 0.9912-1.1564% for Cmax and 0.8886-1.0535% for AUC0-24. Therefore it can be concluded that both products are bioequivalent in terms of peak and total exposure and therefore interchangeable.     

Comparative studies on the in vitro dissolution and bioavailability of various acetylsalicylic acid preparations

For five different brands of acetylsalicylic acid (ASA) preparations the in vitro/in vivo data were determined and tested for comparability. The in vitro dissolution rates were determined by two different methods (Paddle, rotating basket) whereas the in vivo data were obtained from 15 volunteers in a 5-fold cross-over trial. The markedly worse in vitro dissolution (rotating basket) of one preparation is in contrast to the in vivo data which showed bioequivalency of all five preparations. It is doubled that in vitro measurements alone reveal sufficient informations for any predictions of the in vivo characteristics (e.g. bioavailability) of a preparation. It was possible to determine separately ASA and salicylic acid using a highly selective HPLC-method developed by us.     

Sources of variation during collaborative evaluation of in vitro dissolution tests for two solid preparations

Collaborative in vitro dissolution tests on a sample of commercial tolbutamide tablets and a sample of oxytetracycline capsules were carried out in eight laboratories. The two preparations tested showed differences between the products in release characteristics, particularly in the disintegration phase. This may have caused the difference in the pattern of variance in the two trials. In the case of tolbutamide tablets the value of the repeatability standard deviation was small, and therefore the major contribution to the variance was in the difference between laboratories. With oxytetracycline capsules the major contribution to the variance lies in the random errors common to all laboratories (i.e. the within-laboratory variance). One major source of inter-laboratory variance was identified as the level of vibration at the side of the dissolution flask. Another source of variation was found to be due to using a stated extinction coefficient instead of comparing the absorbances of the samples to those of a solution of a reference substance.     

Dissolution of theophylline from film-coated slow release mini-tablets in various dissolution media

The dissolution of an experimental formulation of film-coated slow release theophylline mini-tablets has been investigated using the USP paddle apparatus in test media at pH 1.2 (hydrochloric acid), pH 5.4 and 7.4 (phosphate buffers) at 37 degrees C. Monitoring of in-vitro theophylline release over 12 h, under identical hydrodynamic conditions, showed that the dissolution rate at pH 1.2 is substantially greater (95% of total drug content released in less than 10 h) than that in phosphate buffers. The maximum release after 12 h was approximately 20 and 30% of total drug content of the tablet at pH 5.4 and 7.4, respectively. However, in vivo bioavailability after oral administration of tablets to rabbits corresponded to over 95% of total drug, compared with the same dose administered intravenously. The retarded drug release during in-vitro dissolution in phosphate buffer was attributed to a possible interaction of phosphate ions with theophylline molecules at the tablet core-coat interface. These findings indicate that both rate and extent of theophylline release from the slow release coated mini-tablets are highly sensitive to phosphate buffers. The data also emphasize the usefulness of an animal model for assessment of in-vivo drug release and subsequent absorption, during the development of modified release dosage forms.     

Clinical evaluation of sustained release preparations of cefaclor in dental infections. Comparative double blind clinical studies of sustained release preparations with a regular preparation of cefaclor

In vitro viable cell count studies of sustained release preparations of cefaclor (CCL) conclude that the mixture of nonenteric and enteric coated granules of CCL in the ratio of 4 to 6 is the most appropriate form (4:6 form) for the sustained release preparation of CCL. In order to clinically confirm the above conclusion, comparative double blind clinical studies of 3 mixtures forms (2:8, 4:6 and 6:4 forms) with a regular preparation (CCL form) were conducted in dental infections regarding efficacy, safety, and usefulness of the 4 forms. Evaluable cases for efficacy and usefulness were 364 in total (96 cases for the 2:8 form group, 89 cases for the 4:6 form group, 89 cases for the 6:4 form group, and 90 cases for the CCL form group). Evaluable cases for safety were 404 cases in total (102 for the 2:8 form, 100 for the 4:6 form, 102 for the 6:4 form, and 100 for the CCL form). Daily dose of the 3 forms of sustained release preparations was 375 mg b.i.d. after breakfast and dinner and that of the CCL form 250 mg t.i.d. after breakfast, lunch and dinner. Following are the results of the clinical studies: There were no significant differences among the 4 patient-groups (2:8 form, 4:6 form, 6:4 form, and CCL form) regarding background factors of the patients and findings of their subjective and objective symptoms before the initiation of the administration, and it was therefore confirmed that there were no problems in conducting the comparative double blind clinical studies. Overall clinical effective rate determined by the efficacy evaluation criteria of the Japanese society of oral surgery (JSOS) were 89.5% at day 3 and 94.8% at day 5 in the 2:8 form group, 87.4% at day 3 and 95.5% at day 5 in the 4:6 form group, 86.4% at day 3 and 91.0% at day 5 in the 6:4 form group, and 93.3% at day 3 and 96.7% at day 5 in the CCL form group. The effective rate determined by the physicians who actually treated the patients were 84.4% in the 2:8 form group, 87.6% in the 4:6 form group, 84.1% in the 6:4 form group, and 87.8% in the CCL form group. In both judgments by the efficacy evaluation criteria of JSOS and the physicians, there were no significant differences among the 4 forms regarding overall clinical efficacy.(ABSTRACT TRUNCATED AT 400 WORDS)     

Sources of variation during collaborative evaluation of in vitro dissolution tests for two solid preparations.

Collaborative in vitro dissolution tests on a sample of commercial tolbutamide tablets and a sample of oxytetracycline capsules were carried out in eight laboratories. The two preparations tested showed differences between the products in release characteristics, particularly in the distintegration phase. This may have caused the difference in the pattern of variance in the two trials. In the case of tolbutamine tablets the value of the repeatability standard deviation was small, and therefore the major contribution to the variance was in the difference between laboratories. With oxytetracycline capsules the major contribution of the variance lies in the random errors common to all laboratories (i.e. the within-laboratory variance). One major source of inter-laboratory viance was identified as the level of vibration at the side of the dissolution flask. Another source of variation was found to be due to using a stated extinction coefficient instead of comparing the absorbances of the samples to those of a solution of a reference substance.     

Pharmacodynamic aspects of sustained release preparations

The sustained release (SR) mode of drug administration has certain features that have an important impact on the magnitude of the pharmacologic response: (a) it minimizes fluctuation in blood drug concentrations (i.e. between peak and trough). However, due to the pronounced non-linear relationship between drug concentration and pharmacologic effect (i.e. pharmacodynamics) the impact of this property differs considerably as a function of the shape of the pharmacodynamic profile and the position of the specific range of concentrations on the curve of this profile; (b) it produces a slow input rate which tends to minimize the body's counteraction to the drug's intervening effect on regulated physiological processes; and (c) it provides a continuous mode of drug administration. This important pharmacodynamic characteristic may produce, in certain cases, an opposite clinical effect than that attained by an intermittent (pulsatile) mode of administration of the same drug. For many drugs with non-concentration-dependent pharmacodynamics, the exposure time, rather than the AUC, is the relevant parameter and it can therefore be optimized by SR preparations. The slow input function may minimize hysteresis in cases where the site of action is not in a rapid equilibrium with the blood circulation. The pharmacodynamics of the desired effect(s) and/or adverse effect(s) may also be influenced by the site of administration, especially in cases where the drug is delivered directly to its site of action. These factors demonstrate the important influence of the mode of administration on the pharmacological and clinical outcomes. In addition, they highlight the need to include these pharmacodynamic considerations in all stages from drug development to the optimization of their clinical use.     

茶碱缓释片体内外试验的相关性

目的：评价茶碱缓释片的体外释放与体内吸收的相关性,为其质量控制提供实验依据。方法：用反相高效液相色谱法测定血浆中的茶碱浓度,按Ｗａｇｎｅｒ－Ｎｅｌｓｏｎ公式计算一定时间内２种茶碱缓释片的体内吸收百分率。在３种不同ｐＨ的介质中进行体外释放度试验,。计算相应时间内的累积释放百分率。结果：介质的ｐＨ变化对茶碱缓释片的体外释放度无明显影响。结论;茶碱缓释片的体内吸收百分率与体外释放百分率间存在良好的相关关     

茶碱透皮贴片的制备及其体外渗透性研究

目的:制备茶碱透皮贴片,并考察其体外经皮渗透性。方法:以丙烯酸酯压敏胶为骨架材料,月桂氮酮和丙二醇为促渗剂,用离体人皮和Franz扩散池作为体外经皮释药模型,研究茶碱贴片体外渗透性。结果:茶碱贴片中的药物经皮渗透符合零级动力学,4%月桂氮酮和20%丙二醇有较好的促进渗透作用,其增渗倍数分别为不含促渗剂的茶碱对照贴片的2.30和2.04倍。结论:茶碱贴片体外经皮渗透作用较好。     

Comparison of the in vitro dissolution properties and in vivo steady-state pharmacokinetics of two sustained-release theophylline preparations

The sustained-release properties and relative bioavailability of Theolin^® Retard and Pharphylline^® Retard were studied in eight healthy adults after treatment for five days with twice daily 450 mg, respectively 425 mg. During the day-time dosing interval on the fourth and fifth day theophylline plasma concentrations were assayed by HPLC. After intake of Theolin^® Retard, minimum theophylline plasma concentrations were significantly higher, fluctuations in theophylline plasma concentrations were significantly smaller andt ₇₅ (the period within a dosing interval during which the plasma concentration exceeds 75% of the maximal concentration) was significantly longer than after Pharphylline^® Retard. Maximal concentrations and AUC values were not significantly different. For both products the plasma concentration time-curves on day 5 were significantly lower than on day 4.In vitro dissolution tests confirmed the more sustained release of theophylline from Theolin^® Retard. These results indicate an equal extent of absorption from the two products but better sustained-release properties for Theolin^® Retard.     

In vitro evaluation of theophylline matrices using xyloglucan

Xyloglucan is a water soluble polysaccharide extracted from the beans of Tamarindus Indica. Very few publications are found related to its use for preparing oral sustained release swellable matrix. The purpose of this investigation was to prepare sustained release matrices using Xyloglucan and investigate the effects of polymer level, diluents type, pH and ionic strength of the dissolution medium, basket rotational speed, and swelling isotherms on drug release. Tablet formulations containing 50% theophylline as a drug model, Xyloglucan cold water soluble (20%, 30 and 40%) and different diluents (Avicel PH-101, lactose and dibasic calcium phosphate) were prepared. The formulation containing 30% Xyloglucan water soluble and Avicel was selected as best formulation because it gives controlled release profile and tested for swelling isotherms, drug release in different dissolution media, and different basket rotational speed. Percent drug release from formulations containing 50% theophylline, 30% Xyloglucan water soluble, and Avicel PH-101 was 34.2% at 6 hours, 35.6% with lactose, and 30.9% with Emcompress. ANOVA two-way analysis showed a change in drug release rate when polymer percent was increased at the 5% significance level. Different diluents, different dissolution media, and different basket rotational speeds did not significantly change the drug release. The mechanism of drug release appears to follow anomalous relaxation for swellable matrix.     

Reproducibility of saliva and plasma theophylline levels following single dose administration of two sustained release preparations.

1 Concomitant saliva and plasma theophylline concentrations were measured in six healthy male volunteers following single dose administration of two sustained release preparations (Nuelin SA and Phyllocontin Continus). 2 Using mean values, a good correlation was obtained between saliva and plasma drug concentrations. Prediction of plasma values using individual saliva was poor and varied widely. The ratio of saliva to plasma concentrations in the same individual, assessed under standardised conditions, was not always reproducible.