Pharmacokinetics and Dynamic Response of Plain and Slow Release Isradipine Formulations in Moderately Hypertensive Patients

Abstract: The pharmacokinetic variables and antihypertensive effect of the calcium antagonist isradipine, were investigated in 30 hypertensive patients. Isradipine was given orally in parallel group design in plain and slow release formulations in doses of 2.5 mg twice daily and 5.0 mg once daily, respectively. Isradipine concentration in serum was measured by a sensitive RIA method after the first dose and after 6 weeks of treatment. The pharmacokinetics and concentration/effect relationship after the first dose and after 6 weeks of treatment were compared. No differences in pharmacokinetics were observed between single and multiple dosing. Data were in accordance with results from studies in healthy volunteers. Rate, but not extent of bioavailability differs between the two isradipine formulations. Antihypertensive efficacy of the two formulations was similar (16/11 and 19/15 mmHg), and a significant time dependent increase in E_max from 10/3 mmHg to 23/14 mmHg after 6 weeks of treatment was observed.     

Clinical Evaluation of Modified Release and Immediate Release Tacrolimus Formulations

The science of drug delivery has evolved considerably and has led to the development of multiple sustained release formulations. Each of these formulations can present particular challenges in terms of clinical evaluation and necessitate careful study to identify their optimal use in practice. Tacrolimus is an immunosuppressive agent that is widely used in organ transplant recipients. However, it is poorly soluble, has an unpredictable pharmacokinetic profile subject to important genetic polymorphisms and drug-drug interactions, and has a narrow therapeutic index. For these reasons, it represents an agent that could benefit from modified release formulations to overcome these limitations. The objective of this review is to discuss the clinical evaluation of immediate and modified release tacrolimus formulations in renal transplant recipients. Clinical trials from early development of immediate release tacrolimus to formulation-specific post-marketing trials of modified release tacrolimus formulations are reviewed with an emphasis on key elements relating to trial design end endpoint assessment. Particular elements that can be addressed with formulation alterations, such as pharmacokinetics, pharmacogenomics, and toxicity and corresponding clinical evaluations are discussed. In addition, current knowledge gaps in the clinical evaluation of immediate and modified release tacrolimus formulations are discussed to highlight potential avenues for the future development of different tacrolimus formulations with outcomes relevant to the regulators, the transplant community, and to transplant recipients. This review shows that new formulations may alter tacrolimus bioavailability, alleviate certain adverse events while potentially enhancing patient convenience.     

国产硝苯地平缓释制剂的研究进展

从制备工艺,释放度,药代动力学,降压谷峰比值几个方面介绍国产硝本地平缓释制剂的研究进展,国产硝苯地平缓释剂在技术指标上可以与进口同类产品相媲美,因其适合国情的价格,更适合国内患使用。     

Characteristics of rhVEGF Release from Topical Hydrogel Formulations

Purpose  

To study recombinant human vascular endothelial growth factor (rhVEGF), the release characteristics from topical gel formulations, and its interaction with the gelling agents.     

包膜缓释肥料养分释放速率评价方法的探讨

将巴氏滤液管置于直径２ｃｍ、高２０ｃｍ的圆柱状玻璃管中,制成一个封闭式的自动连续过滤系统,将肥料置于该系统中,使上端进水,下端收集滤液,检测各瞬间滤液中养分的浓度,即可得到时间与养分释放速率的相关曲线。Ｈａｕｋｅ描述的包膜缓释肥料养分释放的第二阶段可进一步划分为三个阶段,可望在短时间内完成定量检测包膜肥料质量。     

Design and Study of Rifampicin Oral Controlled Release Formulations

Oral controlled release formulations of rifampicin have been developed by using hydroxypropyl methylcellulose polymer at different ratios. From in vitro release data, we found that the release was extended with an increase of polymer proportion from 20% to 40%. However, increase in polymer beyond 40% resulted in no significant change in the release rate. There was a distinct difference in the release rate and release character due to variation in the compression force. The release kinetics were analyzed using Ritger and Peppas exponential equation. Stability studies at ambient storage conditions for 1 year showed that formulations were stable.     

Biopharmaceutical Evaluation and CMC Aspects of Oral Modified Release Formulations

This article discusses the range of outcomes from biopharmaceutical studies of specific modified release (MR) product examples in preclinical models and humans. It touches upon five major biopharmaceutical areas for MR drug products: (1) evidence for regional permeability throughout the GI tract, (2) susceptibility to food-effect, (3) susceptibility to pH-effect, (4) impact of chronopharmacology in designing MR products, and (5) implications to narrow therapeutic index products. Robust bioperformance requires that product quality is met through a thorough understanding of the appropriate critical quality attributes that ensure reliable and robust manufacture of a MR dosage form. The quality-by-design (QbD) aspects of MR dosage form design and development are discussed with the emphasis on the regulatory view of the data required to support dosage form development.     

Understanding and Managing the Impact of HPMC Variability on Drug Release from Controlled Release Formulations

The purpose of this study is to identify critical physicochemical properties of hydroxypropyl methylcellulose (HPMC) that impact the dissolution of a controlled release tablet and develop a strategy to mitigate the HPMC lot-to-lot and vendor-to-vendor variability. A screening experiment was performed to evaluate the impacts of methoxy/hydroxypropyl substitutions, and viscosity on drug release. The chemical diversity of HPMC was explored by nuclear magnetic resonance (NMR), and the erosion rate of HPMC was investigated using various dissolution apparatuses. Statistical evaluation suggested that the hydroxypropyl content was the primary factor impacting the drug release. However, the statistical model prediction was not robust. NMR experiments suggested the existence of structural diversity of HPMC between lots and more significantly between vendors. Review of drug release from hydrophilic matrices indicated that erosion is a key aspect for both poorly soluble and soluble drugs. An erosion rate method was then developed, which enabled the establishment of a robust model and a meaningful HPMC specification. The study revealed that the overall substitution level is not the unique parameter that dictates its release-controlling properties. Fundamental principles of polymer chemistry and dissolution mechanisms are important in the development and manufacturing of hydrophilic matrices with consistent dissolution performance. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1664–1672, 2014     

辐射聚合制备毛果芸香碱—水凝胶释放体系的研究

本文研究的药膜是在室温条件下将含药的单体放在模具中进行辐射交联聚合。该法工艺简便,药膜纯度高不带任何引发剂残余物。我们研究了基质含水率,药物含量、辐射剂量率及总剂量对药物释放速率的影响。结果表明:药物的释放量随着基质含水率及药含量的增加而增加;随着交联剂用量及辐照剂量率和总剂量的增加而降低。药物在剂量率为6.46×10~3Rad/sec及总剂量为1.28×10~6ad条件下辐照与未经辐照处理的药物进行了红外及紫外对比试验,结果表明;辐照对药物结构没有明显的影响。     

儿童口服缓控释制剂研究进展

口服缓控释制剂可减少给药次数、提高患者依从性、减少不良反应发生率,与特定年龄儿童的需求相匹配,是目前药物剂型研发的热点。本文通过调研国内外口服缓控释制剂发展现状及儿童可用的上市口服缓释制剂药品品种情况,对儿童口服缓控释制剂发展现状进行阐述和总结,以期为中国儿童用药研发和应用提供参考意见。     

Pharmaceutical Nanotechnology Nanoparticle-Based Topical Ophthalmic Formulations for Sustained Celecoxib Release

Celecoxib-loaded NPs were prepared from biodegradable polymers such as poly- e-caprolactone (PCL), poly(L-lactide) (PLA), and poly(D,L-lactide-co-glycolide) (PLGA) by spontaneous emulsification solvent diffusion method. Different concentrations of polymers, emulsifier, and cosurfactants were used for formulation optimization. Nanoparticles (NPs) were characterized regarding their particle size, PDI, zeta potential, shape, morphology, and drug content. Celecoxib-loaded NPs were incorporated into eye drops, in situ gelling system, and gel and characterized regarding their pH, viscosity, uniformity of drug content, in vitro release, and cytotoxicity. The results of optimized celecoxib-loaded PCL-, PLGA-, and PLA-NPs, respectively, are particle size 119 ± 4, 126.67 ± 7.08, and 135.33 ± 4.15 nm; zeta potential ? 22.43 ± 2.91, ? 25.46 ± 2.35, and ? 31.81 ± 2.54 mV; and encapsulation efficiency 93.44 ± 3.6%, 86.00 ± 1.67%, and 79.04 ± 2.6%. TEM analyses revealed that NPs have spherical shapes with dense core and distinct coat. Formulations possessed uniform drug content with pH and viscosity compatible with the eye. Formulations showed sustained release without any burst effect with the Higuchi non-Fickian diffusion mechanism. Cytotoxicity studies revealed that all formulations are nontoxic. Our formulations provide a great deal of flexibility to formulation scientist whereby sizes and zeta potentials of our NPs can be tuned to suit the need using scalable and robust methodologies. These formulations can thus serve as a potential drug delivery system for both anterior and posterior eye diseases. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1036–1053, 2013     

Encapsulation,Stability and In-vitro Release Characteristics of Liposomal Formulations of Colchicine

The severe toxicity and low therapeutic index of colchicine limit its therapeutic use. Encapsulation in liposomes might reduce these toxic effects. The objective of this study was to determine the factors influencing encapsulation of colchicine in liposomes and to optimize the encapsulation parameters. Colchicine was encapsulated in multilamellar liposomes and large unilamellar liposomes prepared using various phospholipids. The effects of method of preparation, type of vesicle, charge, and concentration of cholesterol on encapsulation of colchicine in liposomes were investigated. Also, stability of colchicine under stress conditions and at various temperatures, and in-vitro release characteristics were determined. A significant difference in encapsulation of colchicine in multilamellar liposomes was observed when prepared by two different methods. Induction of charge on the liposome surface increased encapsulation of colchicine in multilamellar liposomes, but did not affect large unilamellar liposomes. The liposome preparations could withstand simulated transport conditions and frequent changes in temperature. Particle size and concentration of colchicine did not change significantly during storage at various temperatures for six months. In order to retain encapsulated colchicine in liposomes, storage at or below room temperature was found to be suitable. In-vitro release of colchicine from large unilamellar liposomes was biphasic and was influenced by two rate-limiting barriers, the dialysis membrane and the liposome bi-layers. For optimum encapsulation and stability of colchicine liposomes were prepared from a mixture of 1,2-distearoyl-sn-glycero-3-phosphocholine, cholesterol and either stearylamine or dicetyl phosphate.     

尼莫地平固体分散体在速释制剂中的溶出性质

为了提高难溶性药物尼莫地平的溶出度,并在此基础上研制出其速释制剂,本研究选用PVP（k30)为载体制备了尼莫地平的固体分散体及机械混合物,比较了二者体外药物溶出度及药物的结晶形态,并考查了共沉淀物的稳定性,进而进行了尼莫地平速释片剂处方的筛选,并按最优处方制备了胶囊剂,比较了自制速释胶囊剂与市售片剂的释药情况,体外实验结果表明,固体分散体对尼莫地平溶出度的提高大大优于机械混合物,5分钟的释药量,前者为89％, 而后者仅为45％,X－射线衍射实验表明,尼莫地平在以PVP为载体的固体分散体中是以非晶体形式存在,并且在室温并密封于玻璃瓶中放置一年后仍无结晶出现,本研究制备的片剂和胶囊剂都具有速释性质,而以胶囊剂为优,说明压片压力可能影响溶出,速胶胶囊的释药速率大大高于市售普通片剂。     

尼莫地平固体分散体在速释制剂中的溶出性质(英)

为了提高难溶性药物尼莫地平的溶出度,并在此基础上研制出其速释制剂,本研究选用PVP（k30）为载体制备了尼莫地平的固体分散体及机械混合物,比较了二者体外药物溶出度及药物的结晶形态,并考查了共沉淀物的稳定性。进而进行了尼莫地平速释片剂处方的筛选,并按最优处方制备了胶囊剂。比较了自制速释胶囊剂与市售片剂的释药情况。体外实验结果表明,固体分散体对尼莫地平溶出度的提高大大优于机械混合物,5分钟的释药量,前者为89％,而后者仅为45％。X-射线衍射实验表明,尼莫地平在以PVP为载体的固体分散体中是以非晶体形式存在,并且在室温并密封于玻璃瓶中放置一年后仍无结晶出现。本研究制备的片剂和胶囊剂都具有速释性质,而以胶囊剂为优,说明压片压力可能影响溶出。速释胶囊的释药速率大大高于市售普通片剂。     

Investigations on the Mechanism of Magnesium Stearate to Modify Aerosol Performance in Dry Powder Inhaled Formulations

The potential of the force control agent magnesium stearate (MgSt) to enhance the aerosol performance of lactose-based dry powder inhaled (DPI) formulations was investigated in this study. The excipient-blends were investigated with analytical techniques including time-of-flight secondary ion mass spectrometry and single particle aerosol mass spectrometry (SPAMS), and particle size, morphology, and surface properties were evaluated. Excipient-blends were manufactured either by high-shear or low-shear blending lactose carrier with different amounts of MgSt in the range from 0% to 10% (w/w). Fluticasone propionate (FP) and salmeterol xinafoate (SX) used as model active pharmaceutical ingredients were added by low-shear mixing. The in vitro aerosol performance in terms of aerodynamic particle size distribution and fine particle fraction (FPF) of the FP and SX DPI formulations was evaluated with the Next Generation Impactor and also with SPAMS using a Breezhaler^® inhalation device. The distribution of MgSt on the lactose carrier in the blends was visualized and found to depend strongly on the blending method. This affected drug particle detachment from the carrier and thus impacted aerosol performance for FP and SX. Compared with blends without force control agent, low-shear blending of MgSt increases the FPF of the model drug SX, whereas high-shear blending significantly increased FPF of both SX and FP. The interactions between drug and carrier particles were substantially affected by the choice of blending technique of MgSt with lactose. This allows detailed control of aerosol performance of a DPI by an adequate choice of the blending technique. SPAMS successfully demonstrated that it is capable to distinguish changes in DPI formulations blended with different amounts of MgSt, and additional information in terms of dispersibility of fine particles could be generated.     

Use of Partial AUC to Demonstrate Bioequivalence of Zolpidem Tartrate Extended Release Formulations

Purpose  

FDA’s bioequivalence recommendation for Zolpidem Tartrate Extended Release Tablets is the first to use partial AUC (pAUC) metrics for determining bioequivalence of modified-release dosage forms. Modeling and simulation studies were performed to aid in understanding the need for pAUC measures and also the proper pAUC truncation times.     

Effect of Hydrophilic Diluents on the Release Profile of Griseofulvin from Tablet Formulations

Studies have shown that when compressing drugs with low aqueous solubility, the solubility of diluents selected is very crucial as it influences the disintegration, dissolution and bioavailability of such drugs. Based on these reports, the present study was undertaken to investigate the effect of some commonly used hydrophilic tablet diluents (lactose, sucrose, mannitol and dextrose) on the in vitro release properties of griseofulvin from compressed tablets. Griseofulvin granules and tablets were prepared using the wet granulation method. Tablet properties evaluated as a function of the diluents used include, hardness, friability, dissolution profile and dissolution efficiency at 60 min. Results obtained indicated variability in griseofulvin release in the presence of the diluents. The relative enhanced dissolution effects of the four hydrophilic diluents is in the order of dextrose>sucrose>lactose>mannitol. All the griseofulvin tablet batches produced exhibited a better drug release (in terms of rate and extent of release) than a commercially available tablet sample of griseofulvin (Fulcin^®). The results of the dissolution efficiency (DE_60min) are 91.7, 83.5, 48.7, 35.3 and 15.6% for dextrose, sucrose, lactose, mannitol and fulcin^®, respectively. The overall results indicated that dextrose or sucrose can be utilised to improve the in vitro release profile and hence in vivo bioavailability of griseofulvin from compressed tablets.     

Mechanism of Drug Release From Temperature-Sensitive Formulations Composed of Low-Melting-Point Microcrystalline Wax

It was reported that wax matrix (WM) particles composed of low-melting-point microcrystalline wax showed unique release behaviors; the particles released only a small amount of the entrapped drug (non–diffusion-controlled release) at 37°C, whereas it showed comparatively fast drug release in a diffusion-controlled manner at 25°C. However, the mechanism of the drug release is still unclear. The objective of this study was to determine the mechanism of drug release from the WM particles using X-ray computed tomography. In the WM particles collected during dissolution tests at 25°C, the void space derived from drug release increased with increasing time, and there was no change in the structure, indicating that the WM particles released drug while maintaining the particle shape at 25°C. In the WM particles collected during dissolution tests at 37°C, the void space was confirmed at initial time point; however, at subsequent time points, the void space was disappeared, and the roughness of the surface was evident. This structural change may have blocked the conveyance pathway of the outer medium, which would inhibit the drug release. The difference between the drug-release mechanisms of the WM particles at the 2 temperatures will be valuable for developing cooling-triggered, temperature-sensitive formulations.     

Statistical Comparison of Dissolution Profiles to Predict the Bioequivalence of Extended Release Formulations

Appropriate setting of dissolution specification of extended release (ER) formulations should include precise definition of a multidimensional space of complex definition and interpretation, including limits in dissolution parameters, lag time (t-lag), variability, and goodness of fit. This study aimed to set dissolution specifications of ER by developing drug-specific dissolution profile comparison tests (DPC tests) that are able to detect differences in release profiles between ER formulations that represent a lack of bioequivalence (BE). Dissolution profiles of test formulations were simulated using the Weibull and Hill models. Differential equations based in vivo–in vitro correlation (IVIVC) models were used to simulate plasma concentrations. BE trial simulations were employed to find the formulations likely to be declared bioequivalent and nonbioequivalent (BE space). Customization of DPC tests was made by adjusting the delta of a recently described tolerated difference test (TDT) or the limits of rejection of f2. Drug k _a (especially if k _a is small), formulation lag time (t-lag), the number of subjects included in the BE studies, and the number of sampled time points in the DPC test were the factors that affected the most these setups of dissolution specifications. Another recently described DPC test, permutation test (PT), showed excellent statistical power. All the formulations declared as similar with PT were also bioequivalent. Similar case-specific studies may support the biowaiving of ER drug formulations based on customized DPC tests.