用渗滤理论研究乙基纤维素骨架片的最适压片力范围

目的　用渗滤理论研究制备阿司匹林-乙基纤维素骨架片的最适压片力范围。方法　使用不同的压片力(3～30 kN)制备了含阿司匹林40%的阿司匹林-乙基纤维素骨架片,测定了溶出曲线,用Higuchi方程和Ritger-Peppas方程对溶出数据进行拟合。将拟合的Higuchi方程的斜率b值和计算得到的片剂的孔隙率ε,代入渗滤理论推导出的公式中,可计算出表观扩散系数D和片剂溶出性能参数β,分别以D对ε及β对ε回归,可得到临界孔隙率ε_c,由β-ε,D-ε和β-ε₀曲线可推知最适压片力范围。结果　压片力在9～18 kN时,药物释放遵从Higuchi模型方程,片剂以骨架扩散机制释药,且释药速度适中,因此9～18 kN为最适压片力范围。低于9 kN时,片子的初始孔隙率太大,药物溶出过快;高于18 kN时,药物溶出过慢,呈异常扩散机制释放药物。结论　渗滤理论可较清楚地阐明阿司匹林骨架片的释药机制,并可得到制备阿司匹林片的最适压片力范围。     

阿司匹林壳聚糖-海藻酸钠微囊处方优化与释药机制研究

目的:制备阿司匹林壳聚糖-海藻酸钠微囊(ACSPM),并研究其处方优化与释药机制。方法:设计正交试验,以包封率为指标优化ACSPM处方并制备微囊,测定其释放度并通过释放动力学模型方程拟合探讨其释药机制。结果:所得微囊大小及含量均匀,最优处方中海藻酸钠浓度、壳聚糖浓度、海藻酸钠与阿司匹林比例分别为3.0%、1.0%、1∶4,体外释放符合Higuchi方程和Peppas方程。结论:该微囊制备工艺方法简单,释药机制以药物扩散为主兼有骨架溶蚀的non-Fickian过程。     

氨茶碱魔芋胶骨架片的释药机制研究

目的研究氨茶碱魔芋胶骨架片的体外释药机制。方法以氨茶碱为模型药物,采用粉末直接压片法制备氨茶碱魔芋胶骨架片,测定不同搅拌转速条件下骨架片的体外溶蚀度与释放度,分别采用零级方程和Peppas方程对释药过程中骨架片的溶蚀度和释放度数据进行处理。结果骨架片的溶蚀符合零级方程,溶蚀量随搅拌转速增加而增加;骨架片的药物释放为扩散和溶蚀协同作用,随搅拌转速增加或释药时间延长,骨架片释药过程中扩散释放所占比例下降,溶蚀释放所占比例增加。结论氨茶碱魔芋胶骨架片的释药机制为非Fick扩散,即药物扩散和骨架溶蚀协同作用。     

Box-Behnken效应面法优化对乙酰氨基酚魔芋胶骨架片的处方

目的:考察对乙酰氨基酚魔芋胶骨架片的制备处方,并考察其体外其释药机制。方法:以体外累积释放度为指标,通过单因素考察找出影响释放的主要因素,再采用Box-Behnken效应面优化法筛选出最佳处方。结果:通过体外释放度考察得到制备对乙酰氨基酚魔芋胶骨架片的最佳处方为药物20%、骨架材料17.95%、乳糖33.05%、淀粉28%、滑石粉1%。体外释放度试验表明其体外释药符合Ritger-Peppas动力学模型。结论:采用湿法制粒压片法制得对乙酰氨基酚魔芋胶骨架片,体外释放度试验表明具有较好的缓释特性。     

小剂量阿司匹林胃漂浮胶囊的制备及其体外释药特征的研究

目的:制备小剂量阿司匹林胃漂浮胶囊并研究其体外释药特征。方法:以阿司匹林为模型药物,以不同粘度和不同用量的羟丙基甲基纤维素(HPMC)和卡波姆为主要辅料制成阿司匹林胃漂浮胶囊,测定其释放度。结果:当HPMC K4M和HPMCK15M的最佳配比为3∶1时,阿司匹林胃漂浮胶囊在0h~10h内体外释药符合表观零级动力学过程,体外释放速度常数Kr=10.3%/h,释放参数n=0.6 173。结论:所制胶囊缓释效果明显,HPMC用量、粘度为影响阿司匹林胃漂浮胶囊释放速率的主要因素,其体外释药特征属于骨架溶蚀与药物扩散协同作用。     

奥沙西罗亲水凝胶骨架片制备及体外释药特性研究

目的制备奥沙西罗亲水凝胶骨架缓释片,考察处方、工艺以及释放条件对体外释药行为的影响,解析其机理。方法以羟丙甲纤维素(HPMC)为骨架材料,乙基纤维素(EC)为阻滞剂,采用湿颗粒压片法制备奥沙西罗亲水凝胶骨架片,考察HPMC用量、HPMC黏度、EC用量、制备方法、压片压力、释放介质及转速对奥沙西罗骨架片体外释药的影响。结果奥沙西罗骨架片体外释药符合Higuchi方程,药物释放机制是骨架溶蚀和药物扩散的综合效应;HPMC用量与黏度、阻滞剂用量、制备方法、压片压力对释放速率均有显著性影响;释放介质的pH值及转速对释放速率无显著性影响。结论调整处方HPMC用量可制得12 h给药1次的骨架缓释片。     

复方葡萄籽原花青素亲水凝胶骨架片的制备工艺及其释放度的研究

目的:研究复方葡萄籽花青素骨架片的处方工艺及其体外释药行为。方法:通过单因素试验,确定影响释药效果的主要因素,进行正交设计,以原花青素中单体成分儿茶素体外累积释放度为依据,优选出最佳工艺。结果:所制缓释片无突释现象,缓释周期12 h。采用零级、一级、Higuchi及Peppas方程判断儿茶素的释药机制,表明儿茶素释放行为符合Higuchi模型,释放机制为骨架溶蚀机制。结论:该法制备的复方葡萄籽花青素骨架片制备工艺简单易行,具有良好的释放机制。     

左羟丙哌嗪缓释骨架片的制备及体外释药行为评价

［摘要］　目的：制备左羟丙哌嗪缓释骨架片,考察其体外释放度,探讨其释药机制。方法：以亲水性高分子材料HPMC为骨架,采用湿法制粒,制备左羟丙哌嗪缓释骨架片,评价不同pH值条件下的释放度,并将释放数据拟合方程。结果：HPMC用量增加,左羟丙哌嗪释放速度下降;溶出介质pH对药物的释放特性有一定影响。在本实验条件下,HPMC用量对水溶液中药物的释放机制无明显影响,释药过程符合Higuchi方程(R2=0.988 9~0.990 4)或一级方程(R2=0.987 5~0.990 2),释药机制为非Fickian扩散(n=0.615 3~0.633 9)。结论：左羟丙哌嗪缓释骨架片的体外释放符合缓释要求,释放表现为药物扩散和凝胶溶蚀的协同作用。     

对乙酰氨基酚鼻用温敏凝胶的制备及其体外释药机制研究

目的：制备对乙酰氨基酚鼻用温敏凝胶,并对其体外释药机制进行研究。方法：以单用15%、16%、18%、20%、25%泊洛沙姆407（P407）,及5%、10%P407与1%、1.5%、2%、2.5%、3%、4%聚乙烯醇（PVA）混合为凝胶基质制备对乙酰氨基酚鼻用温敏凝胶,根据胶凝温度筛选P407和PVA的最佳处方浓度,考察该凝胶的体外累积溶蚀量和体外释药行为并进行释放模型零级动力学、一级动力学、Higuchi方程、Riguchi-Peppas方程拟合。结果：单独使用P407作为凝胶基质,最佳处方浓度为16%～20%,凝胶的溶蚀和体外释药行为均符合零级动力学方程特征;选择混合基质,最佳处方浓度P407为10%,PVA为3%、4%,凝胶的溶蚀符合零级动力学方程特征,而体外释药遵从Higuchi方程,为骨架扩散释放机制。结论：PVA可显著降低P407的用量。单独使用P407作为凝胶基质,药物体外释药受凝胶溶蚀控制;而对于混合基质凝胶,溶蚀对体外释药并非决定性影响因素。     

双氯芬酸钠甲基纤维素骨架片体外释药的影响因素研究

目的探讨影响甲基纤维素(MC)亲水凝胶骨架片体外释药的因素。方法以双氯芬酸钠(DS)为模型药物,选取MC为骨架材料,观察MC用量、黏合剂选择、压片压力大小对MC亲水凝胶骨架片体外释药的影响。结果 MC用量、压片压力对骨架片的体外释药有较大影响,而黏合剂性质对骨架片的体外释药影响不显著。结论 MC可作为DS骨架片的骨架材料;MC用量、压片压力均影响骨架片的体外释放。     

Matrix type controlled release systems: I. Effect of percolation on drug dissolution kinetics.

Matrix type controlled release tablets were prepared by compression of binary mixtures of a soluble brittle model drug (caffeine) and a plastic matrix substance (ethyl cellulose). The drug content of the tablets was varied from 10% to 100% (weight/weight) and the drug dissolution from one flat side of the tablets was studied. By means of percolation theory the release kinetics could be explained over the whole range of drug loadings. For low drug concentrations up to the lower percolation threshold the release was incomplete because most of the drug was encapsulated by the matrix substance. For drug loadings between the lower and the upper percolation threshold the release was matrix-controlled. For high drug loadings a change to zero order dissolution kinetics was observed. Close to the percolation threshold the diffusion coefficient obeys a scaling law, from which a simple equation to estimate the value of the lower percolation threshold was derived and applied to the measured dissolution data. The critical porosity (lower percolation threshold) was found to be 0.35, corresponding to a drug content of about 28% (weight/weight).     

Estimation of the percolation thresholds in acyclovir hydrophilic matrix tablets.

The principles of percolation theory were applied to design controlled release matrix tablets containing acyclovir. This statistical theory studies disordered or chaotic systems where the components are randomly distributed in a lattice. The application of this theory to study the release and hydration rate of hydrophilic matrices allows to explain the changes in release and hydration kinetics of swellable matrix type controlled delivery systems. The objective of the present paper is to estimate the percolation threshold of HPMC K4M in matrices of acyclovir and to apply the obtained result to the design of hydrophilic matrices for the controlled delivery of this drug. Matrix tablets have been prepared using acyclovir as drug and HPMC K4M as matrix forming material, employing five different excipient/drug percentages. Dissolution studies were carried out using the paddle method. Water uptake measurements were performed using a modified Enslin apparatus. In order to estimate the percolation threshold, the behaviour of the kinetic parameters with respect to the excipient volumetric fraction at time zero plus initial porosity was studied. According to percolation theory, the critical points observed in dissolution and water uptake studies can be attributed to the excipient percolation threshold. This threshold was situated between between 20.76% and 26.41% v/v of excipient plus initial porosity. The knowledge of the percolation threshold of the components of the matrix formulations contributes to improve their design. First, reducing the time to market and second, increasing their robustness when they are prepared at Industrial scale, avoiding the formulation in the nearby of the percolation threshold.     

Estimation of the percolation thresholds in acyclovir hydrophilic matrix tablets

The principles of percolation theory were applied to design controlled release matrix tablets containing acyclovir. This statistical theory studies disordered or chaotic systems where the components are randomly distributed in a lattice. The application of this theory to study the release and hydration rate of hydrophilic matrices allows to explain the changes in release and hydration kinetics of swellable matrix type controlled delivery systems. The objective of the present paper is to estimate the percolation threshold of HPMC K4M in matrices of acyclovir and to apply the obtained result to the design of hydrophilic matrices for the controlled delivery of this drug.Matrix tablets have been prepared using acyclovir as drug and HPMC K4M as matrix forming material, employing five different excipient/drug percentages. Dissolution studies were carried out using the paddle method. Water uptake measurements were performed using a modified Enslin apparatus. In order to estimate the percolation threshold, the behaviour of the kinetic parameters with respect to the excipient volumetric fraction at time zero plus initial porosity was studied. According to percolation theory, the critical points observed in dissolution and water uptake studies can be attributed to the excipient percolation threshold. This threshold was situated between between 20.76% and 26.41% v/v of excipient plus initial porosity.The knowledge of the percolation threshold of the components of the matrix formulations contributes to improve their design. First, reducing the time to market and second, increasing their robustness when they are prepared at Industrial scale, avoiding the formulation in the nearby of the percolation threshold.     

Determination of the percolation thresholds for polyethylene oxide and polyacrylic acid matrix tablets

The purpose of this study was to implement the concepts of percolation theory in the characterization of drug release from hydrophilic matrix tablets. Percolation theory is a powerful statistical tool that enables mathematical insight into geometrically complex and disordered systems. Matrix tablets are effective substrate for the implementation of percolation theory because of their inherent disordered structure. The objective was to predict percolation thresholds of polyethylene oxide and polyacrylic polymers in diclofenac sodium hydrophilic matrices. Matrix tablets were prepared using polyethylene oxide or polyacrylic acid as matrix forming materials and diclofenac sodium was used as a model drug substance. Ten formulations with different drug/excipient ratios were prepared using the direct compression method. Dissolution studies were performed using the paddle apparatus method. For estimating percolation threshold the change of the kinetic parameters in aspect to the volumetric fraction of excipient plus initial porosity of the tablets was studied. Observed critical points with sudden changes in behavior of kinetic parameters can be attributed to the percolation thresholds. Percolation threshold is found to be 60.22% v/v polyethylene oxide + initial porosity and 39.94% v/v polyacrylic acid + initial porosity. The results obtained demonstrate that percolation theory can be used to design and develop matrix tablet formulations. Determination of percolation threshold is a useful tool for preparing robust formulations.     

Study of morphine hydrochloride percolation threshold in Eudragit® RS–PM matrices

Percolation theory has been applied in the pharmaceutical field since 1987. The knowledge of the percolation thresholds of a system results in a clear improvement of the design of controlled release dosage forms such as inert matrices. In the present paper, the percolation thresholds of morphine hydrochloride inert matrices have been estimated and the obtained results have been applied to the design of controlled release inert matrices of this drug.

The tablets were prepared by compression of binary mixtures of morphine hydrochloride, as a drug of clinical interest to cancer patients, and Eudragit® RS–PM, a hydrophobic acrylic polymer as matrix forming material. Drug loadings between 10% and 90% (w/w) were prepared, keeping constant the drug and excipient particle sizes. The dissolution assay was carried out exposing only one side of the tablets to the dissolution medium. The drug percolation threshold was estimated following the method of Leuenberger and Bonny as 0.506±0.014 of total porosity, corresponding to ca. 40% (w/w) drug content. The scanning electron microscopy (SEM) micrographs corresponding to the tablet side facing the lower punch and to the cross-section of these matrices are in agreement with the estimated percolation range.On the other hand, according to the SEM study and to the tablet integrity after the release assays, the excipient percolation threshold is expected to range from 65 to 80% (w/w) of drug, i.e. from 29.5 to 17% (v/v) of excipient. The release profiles of the matrices situated above the percolation threshold of the swelling substances (more than 41% v/v of excipient) have shown practically linear release profiles, which appear to not be sensitive to the drug load.     

Release behaviour of clozapine matrix pellets based on percolation theory

The release behaviour of clozapine matrix pellets was studied in order to investigate if it is possible to explain it applying the concepts of percolation theory, previously used in the understanding of the release process of inert and hydrophilic matrix tablets. Thirteen batches of pellets with different proportions of clozapine/microcrystalline cellulose (MCC)/hydroxypropylmethyl cellulose (HPMC) and different clozapine particle size fractions were prepared by extrusion-spheronisation and the release profiles were studied. It has been observed that the distance to the excipient (HPMC) percolation threshold is important to control the release rate. Furthermore, the drug percolation threshold has a big influence in these systems. Batches very close to the drug percolation threshold, show a clear effect of the drug particle size in the release rate. However, this effect is much less evident when there is a bigger distance to the drug percolation threshold, so the release behaviour of clozapine matrix pellets is possible to be explained based on the percolation theory.     

The influence of polymer content on early gel-layer formation in HPMC matrices: The use of CLSM visualisation to identify the percolation threshold

Percolation theory has been used for several years in the design of HPMC hydrophilic matrices. This theory predicts that a minimum threshold content of polymer is required to provide extended release of drug, and that matrices with a lower polymer content will exhibit more rapid drug release as a result of percolation pathways facilitating the faster penetration of the aqueous medium. At present, percolation thresholds in HPMC matrices have been estimated solely through the mathematical modelling of dissolution data. This paper examines whether they can be also identified in a novel way: through the use of confocal laser scanning fluorescence microscopy (CLSM) to observe the morphology of the emerging gel layer during the initial period of polymer hydration and early gel formation at the matrix surface.In this study, matrices have been prepared with a polymer content of 5–30% w/w HPMC 2208 (Methocel K4M), with a mix of other excipients (a soluble drug (caffeine), lactose, microcrystalline cellulose and magnesium stearate) to provide a typical industrially realistic formulation. Dissolution studies, undertaken in water using USP apparatus 2 (paddle) at 50 rpm, provided data for the calculation of the percolation threshold through relating dissolution kinetic parameters to the excipient volumetric fraction of the dry matrix. The HPMC percolation threshold estimated this way was found to be 12.8% v/v, which was equivalent to a matrix polymer content of 11.5% w/w.The pattern of polymer hydration and gel layer growth during early gel layer formation was examined by confocal laser scanning fluorescence microscopy (CLSM). Clear differences in gel layer formation were observed. At polymer contents above the estimated threshold a continuous gel layer was formed within 15 min, whereas matrices with polymer contents below the threshold were characterised by irregular gel layer formation with little evidence of HPMC particle coalescence. According to percolation theory, this implies that a continuous cluster of HPMC particles was not formed.The images provide the first direct evidence of how the percolation threshold may be related to the success or failure of early gel layer development in HPMC matrices. It also shows how extended release characteristics are founded on the successful coalescence of hydrated polymer particles to form a continuous coherent diffusion barrier, which can then inhibit further percolation of the hydration medium. The correlation between percolation thresholds estimated from dissolution and imaging techniques suggests that confocal imaging may provide a more rapid method for estimating the percolation thresholds, facilitating the rational design of HPMC extended release matrices at lower polymer contents with minimal risk of dose dumping.     

盐酸尼卡地平控释片的释放度研究

采用羟丙甲纤维素制备了盐酸尼卡地平凝胶骨架控释片，其体外释入曲线符合一级动力学。     

In vitro controlled release of alfuzosin hydrochloride using HPMC-based matrix tablets and its comparison with marketed product

The present study is an attempt to formulate a controlled-release matrix tablet formulation for alfuzosin hydrochloride by using low viscous hydroxy propyl methyl cellulose (HPMC K-100 and HPMC 15cps) and its comparison with marketed product. Different batches of tablets containing 10 mg of alfuzosin were prepared by direct compression technique and evaluated for their physical properties, drug content, and in vitro drug release. All the formulations had a good physical integrity, and the drug content between the batches did not vary by more than 1%. Drug release from the matrix tablets was carried out for 12 hr and showed that the release rate was not highly significant with different ratios of HPMC K-100 and HPMC15cps. Similar dissolution profiles were observed between formulation F3 and the marketed product throughout the study period. The calculated regression coefficients showed a higher r2 value with zero-order kinetics and Higuchi model in all the cases. Although both the models could be applicable, zero-order kinetics seems to be better. Hence, it can be concluded that the use of low viscous hydrophilic polymer of different grades (HPMC K-100 and HPMC 15cps) can control the alfuzosin release for a period of 12 hr and was comparable to the marketed product.