释放分割法体外评价释放特征符合Higuchi方程的缓释制剂药物动力学

提出一种Higuchi释放缓释制剂药物动力学体外评价方法 ,将Higuchi释放以高斯 牛顿法分割成零级释放、一级释放和速释部分 ,每部分释放对体内药物动力学的贡献值则通过经典的药物动力学计算获得。方法学研究证明了释放分割法与基于零级释放药物动力学的剂量分割法效果相当 ,释放分割法计算得到的血药浓度 (CRD)与剂量分割法计算得到的血药浓度 (CDD)间的相关方程为CDD=-0 2 5 88+1 0 1 4CRD(r=0 993 6)。由于任意Higuchi释放曲线可以通过归一化的Higuchi释放曲线线性化表达 ,所以归一化Higuchi释放曲线的分割系数可作为非归一化的Higuchi释放的体外评价的模数。释放分割法可以对制剂的体外释放行为进行经济的评价 ,适用于缓释制剂的处方筛选、体内外相关性研究等     

双氯芬酸钠—乙基纤维素固体分散物释放动力学研究

目的：研究双氯芬酸钠-乙基纤维素固体分散物颗粒及其缓释胶囊的药物释放动力学特征。方法：测定不同粒径、不同浓度的双氯芬酸钠-乙基纤维素固体分散物颗粒及其缓释胶囊在pH6.8磷酸盐缓冲液中的释放曲线,以零级动力学方程、一级动力学方程及Higuchi方程分别对释放曲线进行拟合,根据所得方程的相关系数,探讨不同粒径、不同浓度的固体分散物颗粒及其缓释胶囊的释放特征。结果：固体分散物颗粒释放动力学拟合优劣顺序为：Higuchi模型方程、一级动力学方程、零级动力学方程;缓释胶囊释放动力学拟合结果的优劣顺序为：Higuchi模型方程、零级动力学方程、一级动力学方程、零级动力学方程;缓释胶囊释放动力学拟合结果的优劣顺序为：Higuchi模型方程、零级动力学方程、零级动力学方程、一级动力学方程。结论：不同浓度、不同粒度的双氯芬酸钠-乙基纤维素固体分散物颗粒及缓释胶囊释放均遵从Higuchi方程,为骨架扩散机制。     

药物代谢动力学的基本概念Ⅲ.

单室开放模式(一级速度过程) 按照这个模式,所给药物并不立即分布到代表身体的房室中。在t时,只有部分(FD)药物到达体循环产生一个血药峰。吸收是按一级动力学速度进行的(图13)。在此模式中,排     

微孔渗透泵片的药物传递机制

口服渗透泵片以渗透压为驱动力，以零级释放动力学为释药特征，能在一定的时间内以恒定的释药速率释放药物，释药速率一般不受释放介质pH、搅拌速度及胃肠蠕动、食物等因素的影响，是理想的一种口服控释制剂。     

两室模型药物体内释放(溶出)速率估算的半参数随机模型

目的:为两室模型药物体内释放(溶出)速率估计提供一种半参数随机模型。方法:在生物药剂学意义上,同一药物的受试制剂(test preparation,TP)与参比制剂(reference preparation,RP)的纯吸收及处置过程相同,所需时间相等。将TP总驻留时间(Th)视为TP体内释放(溶出)时间(Tf)与RP总驻留时间(Tg)之和,Tf与Tg相互独立,Th、Tf及Tg均为非负且连续型随机变量。对TP:假设Tf概率分布未知,故Th亦服从由一次血管外给药后的血药浓度-时间数据用数值方法求得的概率密度函数(PDF)的数值解的某一未知概率分布(非参数模型)。对RP:由于无释放(溶出)过程或释放(溶出)过程可忽略不计(相对于TP),故假设药动学呈两室模型分布、一级动力学吸收、室间转运与消除特征,则可推导出Tg的PDF公式(参数模型)。根据卷积公式,得卷积型Volter-ra积分方程,运用数值反卷积分法求解,得到TP体内各时间间隔平均释放(溶出)速率值。结果:半参数随机模型可估计出TP体内释放(溶出)速率、TP的PDF之数值解及RP的PDF的函数形式与参数估计值。结论:半参数随机模型可用于两室模型药物体内释放(溶出)动力学研究。     

烟酸缓释片体内外释放特征研究

目的研究烟酸缓释片体外释放特征和体内药代动力学特征。方法采用体外释放度测定法和在体犬口服药代动力学参数测定法分别测定药物的体内外释放特征,对犬口服药代动力学特征和体内外释放度特征进行分析。结果烟酸缓释片与普通片比较具有缓释特征,药代动力学分析显示烟酸缓释片体内分布为单室模型,Wagner—Nelson法分析显示药物在体内的吸收呈现先慢后快的特征。结论烟酸缓释片具有缓释和释放先慢后快的特征。     

聚(甲基丙烯酸-co-泊洛沙姆)水凝胶的溶胀和药物释放性质

以自由基溶液聚合方法制备了聚 (甲基丙烯酸 co 泊洛沙姆 )共聚物水凝胶 ,研究凝胶的溶胀和模型药物氢溴酸右美沙芬 (DMP)和维生素B1 2 的释放性质。凝胶的溶胀和药物释放具有pH 依赖的特征 ,在中性或碱性介质中的溶胀和药物释放速率要高于酸性介质中。在中性或碱性介质中 ,凝胶的溶胀为非Fick或零级过程 ,对于组成适当的水凝胶 ,在数小时内以零级动力学过程释放药物。     

药物动力学的基本概念 Ⅱ.

药物的吸收和排除吸收和排除是决定体内全部药量的两个运动。下面描述的动力学模式是经常用来估计血管内或血管外给药以及估价药物由代谢降解或肾排泄的情况。同时也注意到对尿排药数据进行分析的可能性。静脉给药(单剂量) 单室开放模式(一圾速度过程):这种情况下,“人体”被看作单一的均匀小室,由静脉给药(剂量为D)后在体积V内,瞬间即达到平衡     

一室模型药物体内释放(溶出)速率估计的半参数随机模型

目的:为药物体内释放(溶出)动力学研究提供一种半参数随机模型。方法:在生物药剂学意义上,同一药物的受试制剂(test preparation,TP)与参比制剂(reference preparation,RP)的纯吸收及处置过程相同,所需时间相等。将TP总驻留时间(Th)视为TP体内释放(溶出)时间(Tf)与RP总驻留时间(Tg)之和,Tf与Tg相互独立,Th、Tf及Tg均为非负且连续型随机变量。对TP:假设Tf概率分布未知,故Th亦服从由一次血管外给药后的血药浓度-时间数据用数值方法求得的概率密度函数(PDF)的数值解的某一未知概率分布(非参数模型)。对RP:由于无释放(溶出)过程或释放(溶出)过程可忽略不计(相对于TP),故假设药动学呈一室模型分布、一级吸收(速率常数为Ka)与一级消除(速率常数为K)特征,即吸收时间与消除时间均服从指数分布,则Tg的PDF为{Ka K/(Ka-K){[exp(-Kt)-exp(-Ka t)]}(参数模型)。根据卷积公式,得卷积型Volterra积分方程,运用数值反卷积分法求解,得到TP体内各时间段平均释放(溶出)速率值。结果:半参数随机模型可估计出TP体内释放(溶出)速率、TP的PDF之数值解及RP的PDF的函数结构与参数估计值。结论:半参数随机模型可用于体内药物释放(溶出)与(或)吸收动力学研究。     

药物体内吸收动力学的随机模型

本文用随机模型分析零级兼一级并存的混合级吸收动力学特性,并将保证率曲线图的方法,用于判定体内吸收过程属于单纯零级或单纯一级吸收还是混合级吸收,同时通过概率的方法估计在混合级吸收过程中零级及一级吸收各占比例的范围。     

Pharmacokinetics of an immediate release, a controlled release and a two pulse dosage form in dogs.

Clinical studies have shown that circadian patterns influence the pharmacokinetics of certain drugs used in the treatment of different diseases. For such drugs, the bioavailability is influenced by the time of administration. The objective of this study was to investigate differences in the pharmacokinetic patterns between a pulsatile drug delivery system using a pulsatile capsule, an immediate release tablet and a controlled release tablet. Metoprolol was chosen as a model drug because of its high solubility and high permeability pattern throughout the GI tract. The dosage forms were administered to four dogs and the plasma levels were measured using LC-MS/MS. Pharmacokinetic parameters were determined for each dosage form. Fluctuations in the plasma time curves over the observation period indicated that physiological factors like motility have an influence on the drug absorption. The comparison of the plasma time curves of the dosage forms showed that each dosage form caused significant differences in the drug plasma levels. The pulsatile drug delivery capsule caused two defined C(max) values for each dose between 1-1.75 and 2.5-3.5h. Implications for the use of a pulsatile drug delivery device for chronopharmacotherapy are discussed. Pulsatile drug delivery offers a promising way for chronopharmacotherapy if the time of administration and pulse time are adjusted to the circadian pattern.     

Controlled release of nifedipine from gelatin microspheres and microcapsules: in vitro kinetics and pharmacokinetics in man

Nifedipine was embedded in a gelatin matrix to develop a prolonged release dosage form. The effects of polymer/drug ratio, size of the beads, cross-linking with formaldehyde and ethylcellulose coating of the gelatin microspheres on the in vitro release rate of the drug were investigated. The data were analysed according to different laws that can govern the release mechanism: first-order, Higuchi square root of time, spherical matrix and zero-order. The in vitro release kinetics of nifedipine from gelatin microspheres were mainly first-order; from formaldehyde hardened gelatin microspheres, complied with the diffusion model for a spherical matrix, and from ethylcellulose-coated gelatin microspheres, obeyed zero-order kinetics. These findings suggest the possibility of modifying the formulation in order to obtain the desired controlled release of the drug for a convenient oral sustained delivery system. The pharmacokinetic parameters of nifedipine, after administration of a single oral dose of nifedipine-loaded hardened gelatin microspheres to volunteers, suggest that the preparation can be considered as a sustained release delivery system for nifedipine.     

Controlled release of nifedipine from gelatin microspheres and microcapsules: in vitro kinetics and pharmacokinetics in man

Abstract

Nifedipine was embedded in a gelatin matrix to develop a prolonged release dosage form. The effects of polymer/drug ratio, size of the beads, cross-linking with formaldehyde and ethylcellulose coating of the gelatin microspheres on the in vitro release rate of the drug were investigated. The data were analysed according to different laws that can govern the release mechanism: first-order, Higuchi square root of time, spherical matrix and zero-order. The in vitro release kinetics of nifedipine from gelatin microspheres were mainly first-order; from formaldehyde hardened gelatin microspheres, complied with the diffusion model for a spherical matrix, and from ethylcellulose-coated gelatin microspheres, obeyed zero-order kinetics. These findings suggest the possibility of modifying the formulation in order to obtain the desired controlled release of the drug for a convenient oral sustained delivery system. The pharmacokinetic parameters of nifedipine, after adminstration of a single oral dose of nifedipine-loaded hardened gelatin microspheres to volunteers, suggest that the preparation can be considered as a sustained release delivery system for nifedipine.     

Blood levels following multiple oral dosing of chlorpheniramine conventional and controlled release preparations

An examination of steady-state performance of chlorpheniramine conventional versus controlled release products was conducted using 15 male subjects in a 3-way crossover study with a 2-week washout period between studies. The study was designed to determine if chlorpheniramine formulations provide consistent pharmacokinetic performance between individual units upon going from single dose to multiple dose therapy. In addition, the validity of predicting steady-state levels for these kinds of products using only single oral dose data was examined. The dosage forms evaluated were a conventional 4mg tablet, and 8 mg barrier coated-bead capsule, and an 8 mg repeat action tablet. Multiple doses of each product were orally administered to each subject for 6 days prior to the study day to achieve steady-state levels and on the actual study day. Serum samples were collected at specific time intervals on the study day, and chlorpheniramine levels assayed by HPLC. Pharmacokinetic analysis was based on a two-compartment open model. The mean plasma elimination half-lives of the various dosage forms were in the range 24.5–25.4h. There was no rapid release of drug from the controlled release products nor did they have drug release problems during the dosing interval. Good agreement was obtained between predicted average drug concentration at steady-state and drug concentration actually present for all the formulations studied. Based upon comparative examination of AUC, C_max, and fraction of dose absorbed data, the controlled release products administered every 12h were comparable in performance to a conventional release tablet administered every 6 h. Since the half-life of chlorpheniramine is approximately 1 day, therapeutic management may possibly be gained with dosing the patient once daily with a controlled release product or twice daily with a conventional tablet.     

Calculation of the dimensions of dosage forms with release controlled by diffusion for in vivo use.

Using numerical models and data obtained from in vitro experiments, the dimensions of diffusion controlled release dosage forms to achieve desired in vivo levels are predicted. Monolithic polymer-drug devices are considered, the release of the drug being controlled by transient diffusion with constant diffusivity. The dimensions of the devices are calculated for various shapes (e.g. spheres, parallelepipeds, cylinders), so that 85% of the drug is released within 6 or 24 h, respectively. Caffeine, diltiazem HCl, and theophylline are studied in ethylcellulose (EC), plasticized with dibutyl sebacate (DBS) or acetyltributyl citrate (ATBC), respectively. The dosage forms are to be administered orally once a day. The resulting drug levels in the plasma are calculated using a numerical model that takes into account: the kinetics of drug release and the pharmacokinetic data of these dosage forms and drugs. Plasma levels resulting from immediate release dosage forms are also calculated, serving as reference.     

Optimization of release kinetics from sustained-release formulations using model-independent pharmacokinetic simulation

In the present work, a single model-independent approach was developed to optimize the release kinetics of drugs from sustained-release formulations, using stavudine (d4T) as a model drug. This approach is based on the pharmacokinetic simulation of drug plasma levels through a semiparametric approach of the input function and on convolution with an empirical polyexponential unit impulse response function. Input functions were evaluated using different zero-order and first-order release constants. Optimum drug release to obtain a specific pharmacokinetic profile was approached using target model-independent pharmacokinetic parameters such as C(max)(SS), C(min)(SS), t(max)(SS), and peak-trough fluctuations. A Monte Carlo simulation was performed to estimate the fractional attainment of d4T plasma concentrations over therapeutic d4T levels. Zero-order (K(0) = 4 mg/h) and first-order (K(1) = 0.05 h(-1)) release constants were optimal for the formulation of sustained-release d4T tablets, plasma concentrations within the therapeutic range being achieved.     

Computer-Aided Dosage Form Design. II. Methods for Defining a Zero-Order Sustained-Release Delivery System of Maximum Formulating Flexibility

Classical methods employing pharmacokinetic data to calculate zero-order release rates for sustained release products require that a constant-rate drug delivery system must have a duration which is exactly equal to the desired dosage interval. This traditional approach fails to establish the minimum acceptable duration and also fails to provide any flexibility in the formulation goal. While it does calculate one pair of duration and dose values, there are infinite pairs of values capable of maintaining the desired plasma concentrations using the selected dosing interval. In the current method, computer simulations are used to establish the boundary conditions within which any pair of duration and dose values will maintain the desired levels when administered on the chosen dosing interval. By comparing the boundary conditions for every subject in a group, a single set of conditions which would work for the entire group can be selected. These final limits represent the broadest specifications for zero-order drug delivery system design for that particular drug combined with the plasma concentration goals and the desired dosing interval. The method is illustrated using theophylline pharmacokinetics.     

Development of oral extended release formulations of 6‐hydroxybuspirone

Reducing the maximum plasma concentration whilst maintaining the exposure was shown to ameliorate adverse events following the oral administration of 6‐hydroxybuspirone. This observation, along with a desire to provide for once daily dosing of this compound, provided the basis for the development of an extended release formulation. Hydrophilic matrix tablets based on hydroxypropyl methylcellulose and containing citric acid to provide for an acid microenvironment were prepared and evaluated by in vitro drug release studies and in vivo pharmacokinetic and scintigraphic studies using samarium oxide (¹⁵³Sm) labelled dosage forms. The dosage forms were found to release the contained drug by a predominantly diffusion mechanism and the release rate was relatively independent of environmental pH. Following administration of the extended release formulations to volunteers, comparative pharmacokinetic data indicated that the extended release formulations provided for a reduction in the maximum plasma concentration of 64–70% relative to that provided by the same dose given as an oral solution, whilst maintaining exposure relative to the oral solution. By examination of absorption curves derived by Wagner‐Nelson analysis of pharmacokinetic data it was noted that drug release in vivo correlated well with drug release observed in vitro and no marked change in rate of absorption was noted when dosage forms were located in and releasing drug in the colon. The robust control of drug release seen in vitro translated to a good in vivo performance. Copyright © 2012 John Wiley & Sons, Ltd.     

Pharmacokinetics of the CYP 3A Substrate Simvastatin following Administration of Delayed <Emphasis Type="BoldItalic">Versus</Emphasis> Immediate Release Oral Dosage Forms

PURPOSE: The study was designed to evaluate the effect of delayed release (DR) on absorption and bioavailability of intestinally metabolized drugs after oral dosing, using the HMG-CoA reductase inhibitor simvastatin, a CYP3A substrate, as a model drug. MATERIALS AND METHODS: To target drug release and to assess regional gastrointestinal absorption of the CYP 3A substrate simvastatin from the distal parts of the intestine, delayed release film coated tableted oral dosage forms were developed. Simvastatin delayed release tablet, simvastatin immediate release capsule and simvastatin immediate release tablet Zocor were administered as single doses (20 mg) to fasting healthy volunteers in a crossover design. RESULTS: Simvastatin bioavailability was increased by a factor of three, as compared to the reference formulation Zocor. The overall metabolite levels from the immediate release capsules tended to be higher throughout the period studied than the metabolite levels following administration of Zocor and simvastatin delayed release dosage form. CONCLUSIONS: The interplay between gastrointestinal physiology (lower CYP 3A expression in the distal ileum and the colon) and formulation design (zero-order controlled release after a predetermined lag-time) resulted in successful absorption and bioavailability improvement and represent a viable strategy to reduce the dose of CYP 3A drugs.     

孕二烯酮硅橡胶皮下埋植剂的长期体外释放研究

目的 对孕二烯酮硅橡胶皮下埋植剂进行长期体外释放考察,研究其初期药物爆破效应和药物释放的影响因素.方法 自制不同规格的孕二烯酮硅橡胶皮下埋植剂,采用蒸馏水为释放介质,考察防爆破处理和规格对药物释放的影响.结果 孕二烯酮硅橡胶皮下埋植剂在为期2年的体外释放实验中释放速度恒定,符合零级释放方程,其表面释放面积越大,孕二烯酮释放速度越快,防爆破处理可有效降低药物的突释.结论 孕二烯酮硅橡胶皮下埋植剂具有广阔的应用前景,为广大育龄妇女提供了一种更理想的避孕措施.