Preparation of benznidazole pellets for immediate drug delivery using the extrusion spheronization technique

Abstract

Recent advances in the treatment of Chagas disease have followed combinations of drugs that act synergistically against infection, predominantly including benznidazole (BNZ) and azoles derivatives. Possible incompatibilities between these drugs, slow dissolution of BNZ and dose adjustment difficulties are technological obstacles to the development of multidrug formulations. Thus, in the present study, BNZ pellets were developed using extrusion spheronization for immediate drug delivery. Preformulation studies were then performed using thermal analysis and infrared spectroscopy and compatibility between the drug and selected excipients (polyethylene glycol 6000, sodium starch glycolate, microcrystalline cellulose and sodium croscarmellose) was investigated. No chemical decomposition of BNZ was observed, even in samples submitted to wet granulation and thermal stress. Subsequently, formulations were elaborated according to a simplex lattice experimental design using polyethylene glycol, sodium starch glycolate and sodium croscarmellose as disintegrating agents. In these experiments, BNZ pellets showed appropriate physicochemical characteristics, including high drug load capacity and excellent flow properties. The mixture experimental design allowed identification of adequate compositions of disintegrating agents and achieved rapid disintegration and dissolution of pellets. Optimum performance was achieved using polyethylene glycol and sodium croscarmellose at 5.0% w/w each. The present BNZ pellets are versatile alternatives to treat Chagas disease and provide insights into the preparation of multidrug systems.     

Shape-controlled synthesis of bare ZnO nanomaterials with improved photoactivity and photostability

ABSTRACT

Understanding the growth mechanisms of nanomaterials usually leads to the successful preparation of targeted micro-structures with excellent properties. In this paper, flower-like and roughly spherical ZnO nanocrystals have been successfully synthesised through facile wet chemical methods, i.e. hydrothermal pathways and homogeneous precipitation method. The photocatalytic activities of the prepared photocatalysts were evaluated by degradation of rhodamine B (RhB) and phenol under ultraviolet (UV) irradiation. Remarkably, the ZnO powder via homogeneous precipitation (urea/Zn²⁺?=?2.0) exhibited better photocatalytic performance and photostability than those of flower-like ZnO substrate. The enhanced photocatalytic properties could be attributed to more active catalytic sites and effective separation of carriers, which were confirmed by low-temperature nitrogen adsorption, photocurrent responses, and photoluminescence spectral analysis. A possible mechanism for the excellent photocatalytic activity of ZnO substrates was proposed.     

土壤中矮壮素、缩节胺的残留对番茄酱品质的影响

采用HPLC-MS/MS技术,同时测定土壤中的矮壮素和缩节胺残留。土壤样品经缓冲溶液提取后,经Agilent ZORBAX Rx-Si(l100mm×3.0mm,1.8μm)色谱柱分离,以含浓度10mmol/L NH4Ac+0.2%HCOOH的水溶液和甲醇(60:40,V/V)为流动相进行等度洗脱,经正离子多反应监测模式测定目标化合物。结果表明:两种化合物在1.0-50.0μg/L浓度范围内线性关系良好,定量限(LOQ)矮壮素为0.8μg/L,缩节胺为0.6μg/L;加标回收率平均在97.6%-99.5%;相对标准偏差(RSD)平均在2.5%-2.9%,适用于检测土壤中矮壮素和缩节胺。     

液相色谱-串联质谱法同时测定饲料中矮壮素和缩节胺的残留

本文采用高效液相色谱-串联质谱(HPLC-MS/MS)同时测定饲料中的矮壮素和缩节胺残留。样品先用正己烷脱除油脂,后用缓冲溶液(含0.2%甲酸-0.05mol/L乙酸铵)提取,离心上清液用乙腈沉淀净化后进行测试。结果表明:两种化合物在1.0~50.0μg/L范围内线性关系良好;定量限(S/N=10)矮壮素为0.32μg/L,缩节胺为0.45μg/L;加标回收率为91.7%~94.3%;相对标准偏差3.9%~6.1%;实测有30%的样品中含有矮壮素或缩节胺,含量范围为:矮壮素11.2μg/kg-78.4μg/kg;缩节胺9.7μg/kg-126.6μg/kg。该方法简便、快速、灵敏和准确,适合饲料中这两种农药残留的快速检测和定量分析。     

LC-MS/MS测定猪尿中盐酸克伦特罗不确定度的评定

建立了液相色谱-串联质谱法(LC-MS/MS)测定猪尿中盐酸克伦特罗残留量的不确定度评定数学模型,分析了影响样品测定结果的不确定度的主要来源,并计算出了各影响因素的不确定度分量.当猪尿中盐酸克伦特罗残留量的测定结果为3.6ng/mL时,其扩展不确定度为0.4ng/mL.     

金属包装罐双酚S迁移量测量不确定度评定

目的为提高金属包装罐双酚S迁移量测定的实验过程管理和报告评估水平,建立双酚S迁移量测量的不确定度评定方法。方法采用高效液相色谱-串联质谱法检测双酚S在体积分数为4%乙酸食品模拟物中的迁移量,结合JJF 1059.1—2012《测量不确定度评定与表示》规定的方法和步骤,建立不确定度评定的数学模型。根据测量模型,分析影响测量不确定度的主要输入量,对各不确定度分量的数值进行计算,对测量结果进行评估。结果实验中金属包装罐双酚S迁移量测量不确定度报告结果为(2.25±0.302)mg/g,k=2。结论不确定度评估分析表明,检测仪器分量、校准曲线拟合分量和标准溶液分量是最主要影响因素。     

Particle engineering at the drug substance,drug product interface: a comprehensive platform approach to enabling continuous drug substance to drug product processing with differentiated material properties

Direct compression offers a simple route to generate pharmaceutical dosage units and is core to the growing arena of continuous manufacturing. However, direct compression can be untenable for some active materials. This paper will outline three specific challenges API’s can present to direct (active pharmaceutical ingredients) compression. The first involves API’s having exceedingly high aspect ratio (“needles”) or small particle size resulting in low bulk density and poor flow properties. Two additional cases are relatively newer challenges to direct compression driven by the growing need for solubility enhancing formulations, and involve nano-crystalline materials and spray dried amorphous dispersions. Multiple approaches for managing high aspect ratio or micronized API’s have been implemented during the crystallization process or via particle coating downstream from API isolation. Fewer options have been reported for the successful conversion of nano-crystalline materials or spray dried amorphous dispersions into materials amenable to direct compression as these materials offer another specific set of challenges. One route that has not been explored that stands to allow continuous drug product processing across a broader product portfolio involves evaluating opportunities at the drug substance/drug product interface. Here, the options achieved through targeted introduction of excipients to the drug substance processing steps during product precipitation and/or isolation from a product slurry are discussed. This approach introduces new opportunities for designing multicomponent particles through productive and inherently continuous processes. This also offers a longer-term potential route to integrate across continuous drug substance processing to continuous drug product processing.     

Influence of lipid microparticle encapsulation on in vitro efficacy,photostability and water resistance of the sunscreen agents,octyl methoxycinnamate and butyl methoxydibenzoylmethane

Context: Essential requirements for the efficacy of sunscreen agents are optimal UV absorption, high photostability and resistance against water removal.

Objective: Aim of this study was to investigate the effect of encapsulation in lipid microparticles (LMs) on the overall performance of the two most commonly used sunscreen agents, octyl methoxycinnamate (OMC) and butyl methoxydibenzoylmethane (BMDBM).

Methods: LMs loaded with OMC and BMDBM were prepared by melt emulsification and characterized by optical microscopy, UV filter content and release studies. The LMs incorporating OMC and BMDBM or the nonencapsulated sunscreen agents were introduced into a model cream (oil-in-water emulsion).

Results: No significant differences were observed between the sun protection factor (SPF) of the formulations containing the free (SPF, 9.4?±?1.9) or microencapsulated (SPF, 9.6?±?1.3) UV filters. Irradiation of the creams with a solar simulator demonstrated that the photodecomposition of OMC and BMDBM was significantly decreased by encapsulation in LMs from 55.7?±?5.3% to 46.1?±?5.1% and 36.3?±?3.9% to 20.1?±?4.7%, respectively. However, in vitro water-resistance studies showed that entrapment in the LMs significantly enhanced the sunscreen agent removal caused by watering (the losses for OMC and BMDBM were 45.1?±?6.3% and 49.2?±?8.4%, respectively), as compared to the formulation with the nonencapsulated sunscreen agents (the losses for OMC and BMDBM were 26.7?±?6.1% and 28.0?±?6.7%, respectively).

Conclusion: Incorporation in LMs can have controversial effects on UV filter efficacy. In particular, the water-resistance properties of sun-care formulations containing sunscreens loaded in LMs should be verified to assure that the photoprotective activity is maintained during usage.     

A combination of complexation and self-nanoemulsifying drug delivery system for enhancing oral bioavailability and anticancer efficacy of curcumin

Abstract

Objective: Curcumin, the golden spice from Indian saffron, has shown chemoprotective action against many types of cancer including breast cancer. However, poor oral bioavailability is the major hurdle in its clinical application. In the recent years, self-nanoemulsifying drug delivery system (SNEDDS) has emerged as a promising tool to improve the oral absorption and enhancing the bioavailability of poorly water-soluble drugs. In this context, complexation with lipid carriers like phospholipid has also shown the tremendous potential to improve the solubility and therapeutic efficacy of certain drugs with poor oral bioavailability.

Methods: In the present investigation, a systematic combination of both the approaches is utilized to prepare the phospholipid complex of curcumin and facilitate its incorporation into SNEDDS. The combined use of both the approaches has been explored for the first time to enhance the oral bioavailability and in turn increase the anticancer activity of curcumin.

Results: As evident from the pharmacokinetic studies and in situ single pass intestinal perfusion studies in Sprague–Dawley rats, the optimized SNEDDS of curcumin–phospholipid complex has shown enhanced oral absorption and bioavailability of curcumin. The cytotoxicity study in metastatic breast carcinoma cell line has shown the enhancement of cytotoxic action by 38.7%. The primary tumor growth reduction by 58.9% as compared with the control group in 4T1 tumor-bearing BALB/c mice further supported the theory of enhancement of anticancer activity of curcumin in SNEDDS.

Conclusion: The developed formulation can be a potential and safe carrier for the oral delivery of curcumin.     

Effect of core size and excipients on the lag time and drug release from a pulsatile drug delivery system

Background: Pulsatile drug delivery system, based on a core-in-cup dry-coated tablet was examined and evaluated. The system consisted of three different parts: a core tablet (with increasing diameter), containing the active ingredient acting as reservoir; an impermeable outer shell; and a top cover layer barrier. The core tablet contained either caffeine or theophylline as model drugs. Objective: To investigate and evaluate how the geometrical characteristics of the core tablets, drugs, and excipients influence the behavior of the system presented, namely, lag time and drug release. Results and Discussion: Drug release exhibited a lag time period dependent on the core tablet size, drug solubility, and characteristics of polymer and polymer mixtures. The lag time was increased by increasing the core tablet diameter and the quantity of soluble lactose in the top cover layer. Conclusions: The quantity and characteristics of materials, the core tablet size, and the erosion of the top cover layer were found to be important factors in controlling the lag time and release. Increase in core tablet diameter resulted in lower lag times and greater release and release rates. Similarly, by increasing sufficiently the quantity of the soluble excipient lactose, in the top layer we observed a decrease of the lag times and an increase of release.     

SPE-HPLC-MS/MS检测地表水中的萘啶酸、吡哌酸、培氟沙星、氧氟沙星、司帕沙星和加替沙星残留

该实验建立全自动固相萃取-HPLC-MS/MS法检测地表水中的萘啶酸、吡哌酸、培氟沙星、氧氟沙星、司帕沙星和加替沙星残留的分析方法。随机采集地表水样并过滤,将pH调节至中性。将预处理好的地表水样品,以流量为8~10 mL/min的速度过已活化的固相萃取柱,再用10 mL 5%甲醇溶液淋洗、净化,弃去淋洗液,抽干小柱,最后用20 mL甲醇洗脱,收集洗脱液;洗脱液氮吹至近干,用乙腈定容至1 mL,涡旋混合1 min,上HPLC-MS/MS仪定量检测。结果表明吡哌酸、氧氟沙星、培氟沙星、司帕沙星、加替沙星和萘啶酸在质量浓度0.01~8.00μg/mL范围内线性关系良好,相关系数均大于0.995;检出限分别为1.82,1.39,2.41,1.49,1.93,1.12μg/L;方法加标回收率在84.2%~92.2%之间;重复性相对标准偏差(n=6)在5.0%以内。此方法具有处理速度快、检测结果可靠等特点,可以用于地表水等水系统中微量喹诺酮类抗生素残留的监测。     

A comparison of drug substance predicted chemical stability with ICH compliant stability studies

Objective: The aim of this study is to demonstrate the applicability of predictive stability studies to the degradation of drug substances.

Significance: The use of predicted stability studies during pharmaceutical development and in regulatory submissions is increasing, particularly in early phase to support an initial retest period/shelf life claim in the absence of standard stability data. These studies offer an alternative to standard stability testing and can facilitate clinical trials to be started earlier and medicines to reach patients faster. They involve a short-term stressed stability study, typically designed to degrade a drug substance or product to the specification level of the shelf life limiting attribute. The results are used to predict degradation under long-term storage conditions and enable stability understanding to be gained over a short time frame, using limited amounts of material.

Methods: In this work, Accelerated Stability Assessment Program (ASAP) studies were performed for 10 different drug substances and the predictions obtained for chemical degradation were compared to ICH compliant stability data.

Results: Across the studies good agreement was achieved, with the initial retest period predictions from the ASAP studies being conservative by design. When minimal degradation was observed during an ASAP study, it was demonstrated that at least a 12-month initial retest period could be supported.

Conclusion: This comparison of ASAP predictions and ICH compliant stability data has demonstrated the ability of well-designed ASAP studies to predict the long-term chemical stability of drug substances.     

Synthesis and pharmaceutical properties of N-acyloxymethyl prodrugs of Allop with potential anti-trypanosomal activity

Abstract

We report herein the synthesis, and the physicochemical and pharmacokinetic properties of N-acyloxymethyl prodrugs of allopurinol (Allop) (2a–f). Allop is a compound with activity against Trypanosoma cruzi, a causative agent of Chagas disease. Its pathology leads to a huge number of infections and deaths per year, because in addition to many sufferers only having limited access to health services only an inefficient chemotherapy is available. Relevant pharmaceutical properties (pK_a, stability, solubility, lipophilicity, in vitro permeability, binding protein, xanthine oxidase binding) were also determined. The results obtained showed that derivatives behave as prodrugs of Allop, since they exhibit improved physicochemical and pharmacokinetic properties relative to their precursor. This behavior turns these compounds into active reservoirs of Allop, and reduces its unfavorable characteristics, so 2a–f compounds are excellent candidates for the treatment of Chagas disease. This work is therefore an important contribution leading to the suppression of Chagas disease.     

超高效液相色谱-串联质谱法对鳗鱼及制品中禾草丹残留量的测定

本文建立了用超高效液相色谱-串联质谱法对鳗鱼及制品中禾草丹的检测方法。采用乙腈对样品中的禾草丹进行提取,浓缩后用固相萃取SPE小柱、氧化铝、无水硫酸钠进行净化,最后用超高效液相色谱-质谱联用法进行分离和定性定量分析。方法线性相关系数为0.9966,5-20μg/kg,加标样品的回收率在75%-85%之间,相对标准偏差在8.3%-12.7%,定量检出限可达到0.5μg/kg,该方法具有快速、高效、灵敏度高,符合出口检测限量的要求。     

UPLC-MS/MS测定人血浆中罗红霉素的浓度及在药代动力学中的应用

建立一种快速、准确测定人血浆中罗红霉素浓度的UPLC-MS/MS分析方法。以克拉霉素为内标,0.2mL含药血浆经碱化、乙酸乙酯萃取后进样分析;色谱柱为Acquity UPLC BEH C18（2.1mm×50mm×1.7μm）,流动相组成为乙腈∶0.01%醋酸铵=30∶70,梯度洗脱方式,乙腈比例在4 min内从30%变为70%,流速0.3 mL/min,柱温为35℃,进样量3μL。质谱条件：气动辅助电喷雾离子化（ESI）源;正离子检测（MRM）模式,罗红霉素质荷比为（m/z 837.53→m/z 158.15）和克拉霉素质荷比为（m/z 748.48→m/z 590.30）。罗红霉素在0.05~25.6μg/mL的浓度范围内呈线性,定量下限为0.05μg/mL,基质效应影响小,日内变异系数小于10.3%,日间变异系数小于9.4%,相对回收率在97.5%~106.4%之间。该方法准确、快速、灵敏,可用于微量血浆的罗红霉素药物浓度监测、人体内药代动力学及生物等效性研究。     

粮食中T-2/HT-2毒素胶体金快速定量法研究

以小麦、玉米为原料,采用胶体金快速定量法检测其T-2/H-2毒素含量并探讨胶体金快速定量法的适用性,同时,采用高效液相色谱-串联质谱联用法(LC-MS/MS)验证该方法的准确性.结果 表明,小麦、玉米中T-2/H-2毒素胶体金快速定量法检出限分别为4.3 μg/kg和2.9 μg/kg,定量限分别为10.9μg/kg和...     

织物柔软剂酯基季铵盐生物降解性的研究

制备了单酯基季铵盐、双酯基季铵盐、三酯基季铵盐和混合酯基季铵盐,对其生物降解性能进行了研究。结果表明:单酯基季铵盐、双酯基季铵盐和三酯基季铵盐易生物降解,13天后降解度都在90%以上;水溶性不好的双酯季铵盐、混合酯季铵盐及三酯季铵盐用吐温-85乳化后进行生物降解发现,酯基季铵盐前期降解速度明显增加,但降解度都稍有下降。最后提出了酯基季铵盐的生物降解途径。     

膨胀石墨/TiO2/NiO对原油的吸附及被吸附原油的降解性能研究

将硝酸镍与氨水的反应产物、异丙醇钛盐和水洗并干燥后的可膨胀石墨混合，加热，制备出膨胀石墨／TiO2/NiO复合吸附材料。分别采用SEM、XRD和FT-IR对产物进行了表征，测定了产物对原油的最大吸附量，并对比了吸附在膨胀石墨／TiO2和膨胀石墨／TiO2/NiO中原油的降解程度。结果表明：每克膨胀石墨／TiO2／NiO最多可吸附原油56g；在紫外光（UV）照射下，吸附在膨胀石墨／TiO2和膨胀石墨／TiO2／NiO中的原油均能被降解掉，其中吸附在膨胀石墨／TiO2／NiO中的原油远比吸附在膨胀石墨／TiO2的原油降解得快。     

过氧化物预硫化天然胶乳硫化反应的交联度及其医用胶乳制品热氧降解的研究

使用溶胀指数的测定方法研究叔丁基过氧化物预硫化天然胶乳(PPVL)胶膜硫化交联度,并采用热重分析法(TGA)研究空气状态下胶管试样热氧降解反应过程及其反应动力学.结果显示,过氧化物预硫化天然胶乳反应在70℃温度下硫化3.5h到达正硫点,此时胶膜溶胀指数为5.9.第一步热氧降解反应前,试样出现明显的吸氧增重现象,其最大热氧降解率Cp、最终热氧降解率Cf、反应活化能E和频率因子A均随β的增加而增大,表观活化能E0=107.5kJ/mol.