PLGA/TPGS Nanoparticles for Controlled Release of Paclitaxel: Effects of the Emulsifier and Drug Loading Ratio

PURPOSE: We successfully manufactured nanoparticles of biodegradable polymers for controlled release of paclitaxel. TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate) could be a novel material to make nanoparticles of high drug encapsulation efficiency (EE) and desired physicochemical and pharmaceutical properties of the drug loaded nanoparticles. Among various controlling parameters in the process, the present work is to elucidate the effects of the surfactant stabilizer and the drug loading ratio. METHODS: Paclitaxel loaded PLGA nanoparticles were formulated at various drug-loading ratios by a modified single emulsion solvent extraction/evaporation technique. TPGS was introduced either as the emulsifier or as a matrix material component by using different technique. Polyvinyl alcohol (PVA) was also used for a comparison. The nanoparticles of various recipes were characterized by various state-of-the-art instrument technology for their properties. RESULTS: The EE and the in vitro release behavior were found significantly influenced by the drug loading ratio and the surfactant stabilizer encountered. TPGS involved nanoparticles can have high EE and other favorable properties. CONCLUSIONS: TPGS could be a novel and effective emulsifier, which can result in high EE and desired properties of paclitaxel-loaded polymeric nanoparticles.     

Small Angle X-Ray Scattering Data Analysis and Theoretical Modelling for the Size and Shape Characterization of Drug Delivery Systems Based on Vitamin E TPGS Micelles

We developed a simple two-dimensional/two-components theoretical model that describes the structure and functionality of a VitE-TPGS system of micelles assuming a hydrophobic inner core and an outer hydrated hydrophilic shell. We then conceptually applied the developed methodology to a simple system of VitE-TPGS micelles unloaded and loaded with an active pharmaceutical ingredient, eltrombopag, to verify if the model could reliably monitor the size change of the micelle upon loading. The fit of laboratory Small Angle X-Ray Scattering data against such model allows us to extract absolute values of the micelles size under a spherical shape hypothesis as well as the distribution within the system between components and level of hydration. The intensity scale of the SAXS experimental data needs to be normalized to a reference standard (pure water) to get absolute scattered intensities. The mathematical model which has been developed under a general hypothesis of ellipsoidal micelles, is applied to our experimental data under the simplified spherical assumption, which suitably fits our experimental data.     

Novel Mixed Polymeric Micelles for Enhancing Delivery of Anticancer Drug and Overcoming Multidrug Resistance in Tumor Cell Lines Simultaneously

Purpose  

To evaluate novel mixed polymeric micelles based on monomethoxy poly(ethylene glycol)-poly(D,L-lactic acid) (mPEG-PLA) and Pluronic L61 for delivery of paclitaxel (PTX) to circumvent unfavorable effects resulting from Cremophore EL in Cremophore EL-based PTX formulation and overcoming multidrug resistance (MDR) in tumor cells at the same time.     

Development of Nanoparticles for Drug Delivery to Brain Tumor: The Effect of Surface Materials on Penetration Into Brain Tissue

Surface-modified poly(d,l-lactic-co-glycolic acid) PLGA nanoparticles (NPs) were fabricated via nanoprecipitation for obtaining therapeutic concentration of paclitaxel (PTX) in brain tumor. The cellular uptake and cytotoxicity of NPs were evaluated on C6 glioma cells in vitro, and BALB/c mice were used to study the brain penetration and biodistribution upon intravenous administration. Results showed that by finely tuning nanoprecipitation parameters, PLGA NPs coated with surfactants with a size around 150 nm could provide a sustained release of PTX for >2 weeks. Surface coatings could increase cellular uptake efficiency when compared with noncoated NPs, and d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) showed the most significant enhancement. The in vivo evaluation of TPGS-PLGA NPs showed amplified accumulation (>800% after 96 h) of PTX in the brain tissue when compared with bare NPs and Taxol^®. Therefore, PLGA-NPs with PLGA-TPGS coating demonstrate a promising approach to efficiently transport PTX across blood-brain barrier in a safer manner, with the advantages of easy formulation, lower production cost, and higher encapsulation efficiency.     

探讨引入JCI标准理念提升药品检验机构留样管理质量

目的:引入美国医疗机构评审联合委员会国际部(JCI)标准理念,促进药品检验机构改进留样管理.方法:借鉴JCI标准理念,从管理制度和操作规程、工作目标与计划、人员管理与培训、留样出入库和库存管理、留样管理信息化和质控工作以及留样库房安全管理等方面,探讨加强药品检验机构留样管理的方法.结果 与结论:药品检验机构引入JCI标...     

Transferrin-Modified Vitamin-E/Lipid Based Polymeric Micelles for Improved Tumor Targeting and Anticancer Effect of Curcumin

Purpose

Transferrin receptor (TfR) is up-regulated in various malignant tumors not only to meet the iron requirement, but also to increase the cell survival via participation in various cellular signaling pathways. Here we explored transferrin as ligand for Poly(ethylene Glycol) (PEG)-ylated vitamin-E/lipid (PE) core micelles (VPM).

Methods

Transferrin modified polymer was synthesized and drug loaded micelles were evaluated in 2D Hela and HepG2 cancer cells for cellular uptake and cytotoxicity and in 3D Hela spheroids for growth inhibition, uptake and penetration studies.

Results

Targeted (Tf-VPM) and non-targeted (VPM) micelles showed mean hydrodynamic diameter of 114.2?±?0.64 nm and 117.4?±?0.72 nm and zeta potential was ?22.8?±?0.62 and ?14.8?±?1.74 mV, respectively. Cellular uptake study indicated that the Tf-CVPM were taken up by cancer cells (Hela and HepG2) with higher efficiency. Enhanced cytotoxicity was demonstrated for Tf-VPM compared to CVPM. Marked spheroid growth inhibition following treatment with Tf-CVPM was observed compared to the treatment with non-targeted CVPM.

Conclusions

The developed transferrin-modified micelles have improved ability to solubilize the loaded drugs and could actively target solid tumors by its interaction with over-expressed transferrin receptors. Therefore, the nano-micelles could be further explored for its potential utilization in cancer therapy.

     

Multicompartimental Nanoparticles for Co-Encapsulation and Multimodal Drug Delivery to Tumor Cells and Neovasculature

Purpose

The purpose of this work was the development of a multicompartimental nanocarrier for the simultaneous encapsulation of paclitaxel (PTX) and genistein (GEN), associating antiangiogenic and cytotoxic properties in order to potentiate antitumoral activity.

Method

Polymeric nanocapsules containing PTX were obtained by interfacial deposition of preformed polymer and coated with a phospholipid bilayer entrapping GEN. Physical-chemical and morphological characteristics were characterized, including size and size distribution, drug entrapment efficiency and drug release profile. In vivo studies were performed in EAT bearing Swiss mice.

Results

Entrapment efficiency for both drugs in the nanoparticles was approximately 98%. Average particle diameter was 150 nm with a monomodal distribution. In vitro assays showed distinct temporal drug release profiles for each drug. The dose of 0.2 mg/kg/day of PTX resulted in 11% tumor inhibition, however the association of 12 mg/kg/day of GEN promoted 44% tumor inhibition and a 58% decrease in VEGF levels.

Conclusions

Nanoparticles containing GEN and PTX with a temporal pattern of drug release indicated that the combined effect of cytotoxic and antiangiogenic drugs present in the formulation contributed to the overall enhanced antitumor activity of the nanomedicine.     

Factors Contributing to Retention of Not-in-Treatment Drug Users in an HIV/AIDS Outreach Prevention Project

SUMMARY

Studies have attempted to identify the characteristics of substance-abusing clients that are related to premature termination from alcohol and drug treatment. Few studies, however, have looked at predictors of loss to follow-up among drug users participating in HIV/AIDS prevention projects. This paper develops and tests models of program retention employing data from approximately 250 not-in-treatment drug users enrolled in an outreach based HIV risk reduction program. Logistic regression was used to fit a model which included measures of: (1) demographic characteristics including: age and ethnicity; (2) social environmental factors including: living situation and type of network connection; (3) risk behaviors including: composite scores for drug use in the past 30 days and history of Sexually Transmitted Diseases (STDs); and (4) program factors including: outreach workers' knowledge of clients and number of intervention sessions received. Findings suggest that social environmental and program factors are most predictive of client retention in the program. Implications for ways in which to monitor retention of out-of-treatment drug users participating in AIDS prevention programs are addressed.     

PK/PD参数与抗菌药物的优化用药

反映时间依赖性抗菌药物的PK/PD参数为t>MIC,反映浓度依赖性抗菌药物的PK/PD参数为cmax/MIC或AUC/MIC。时间依赖性与浓度依赖性抗菌药物都与抗菌药物后效应(PAE)和半衰期(t1/2)密切相关。运用PK/PD参数优化抗菌药物的合理用药,叙述了时间依赖性和浓度依赖性抗菌药物及其运用PK/PD参数优化用药的注意点。     

PDCA循环在提高肿瘤科住院病房用药咨询成效中的应用

目的探讨提高肿瘤科住院病房用药咨询效果的办法。方法应用PDCA循环管理办法对我院肿瘤科病房用药咨询情况进行现状调查,查找问题,分析原因,制定对策并实施干预。结果实施PDCA循环后,肿瘤科住院病房医师咨询人次提升了571.43%,咨询采纳率由14.29%升至77.5%;患者咨询人次提升了136.67%,咨询采纳率由50%升至85.91%,差异有统计学意义(χ2=9.26,P<0.01;χ2=71.82,P<0.01),护士咨询人次提升了233.33%,咨询采纳率由66.67%升至80%,差异无统计学意义(χ2=0.09,P>0.1)。则PDCA实施后,医师、患者的用药咨询次数和采纳率均显著上升,护士采纳率没有明显进步,但咨询人次显著提高。结论应用PDCA循环管理办法能有效地提高药学服务质量。     

盐酸丁螺环酮透皮促渗剂选择及其透皮机制的研究

目的研究透皮促渗剂对盐酸丁螺环酮体外经皮渗透的影响以及盐酸丁螺环酮的透皮机制。方法采用改良Franz扩散池,比较不同促渗剂种类、浓度、配比对盐酸丁螺环酮的促渗效果,同时通过改变扩散池的介质pH及皮肤的状态,研究药物的透皮机制。结果采用3%氮酮为透皮促渗剂时药物透过量最大。盐酸丁螺环酮随着分子型浓度的升高透过量也随之增加,皮肤去除角质层后,药物的透过量显著大于完整皮肤,而完整皮肤的贮库效应大于去角质皮肤。结论药物透皮以3%氮酮为透皮促进剂促渗效果最佳。盐酸丁螺环酮主要是以分子型透过皮肤,药物的透皮屏障与贮库效应发生的主要部位是皮肤的角质层。     

Redesign of a Required Undergraduate Pharmacy Management Course to Improve Student Engagement and Concept Retention

Objective. To change the structure of a required pharmacy management course to make it more interactive and engaging for students.Design. The course is a required component of undergraduate curriculum and is completed over 2 semesters during the students’ third year. Changes included requiring students to lead classroom discussions and complete a business plan in groups.Assessment. A questionnaire centering on methods of delivery, course content, and outcomes was distributed in 2 academic years, with 74.7% of students responding. Even though the redesigned course required more time, there was strong support for the course among students because they realized the content contributed to their learning. Conclusion. A major course redesign is a big commitment by faculty members, but if done through consultations with former and current students, it can be rewarding for all involved. Students overwhelmingly embraced the changes to the course as they realized the restructuring and the resulting increase in workload were necessary to raise the relevance of the course to their future professional practice.     

基于前药构建混合胶束实现紫杉醇/阿霉素共递送

为了达到靶向递送,实现肿瘤的联合治疗,制备两亲性紫杉醇-聚乙二醇前药以及小分子阿霉素前药,两者共同构成混合胶束实现共递送.合成还原敏感性的聚乙二醇-紫杉醇前体药物(mPEG-SS-PTX)和靶向性叶酸修饰的聚乙二醇-紫杉醇前体药物(FA-PEG-SS-PTX).同时合成pH敏感阿霉素-乌头酸酐(CAD)小分子前药,采用...     

维A酸维生素C棕榈酸酯泡囊的体外释放、经皮渗透和皮肤贮留研究

目的研究维生素C棕榈酸酯泡囊作为维A酸载体时,主药的体外释放、经皮渗透和皮肤贮留情况。方法采用Franz扩散池测定维A酸从载体中的释放速度,扩散池与供给池之间为纤维素膜（截留分子量8000～14000）,扩散池面积为2.92cm^2。体外透皮试验用小鼠、大鼠或兔子背部皮肤替代半透膜。在体外透皮试验完结后,取下皮肤,剪碎匀浆,用50%异丙醇-生理盐水提取,提取液处理后用HPLC测定药物浓度。结果结果表明维A酸释放速率和累积经皮渗透量大于市售乳膏,同时具有较高的皮肤贮留量。结论维生素C棕榈酸酯泡囊作为维A酸载体有助于增加局部药物浓度。     

Educational and Organizational Interventions to Improve the Usefulness of Clinical Pharmacological Advice for Personalized Drug Dosing Based on Therapeutic Drug Monitoring

This study was aimed at increasing the clinical usefulness of clinical pharmacological advice (CPA) for personalized drug dosing based on therapeutic drug monitoring (TDM). Educational and organizational interventions focused on improving the knowledge of clinical pharmacology among hospital healthcare workers and reducing the incidence of errors throughout the process were planned. After a pre‐interventional period of risk assessment, different list forms of the types of error occurring in the various phases of the process (Phase 1, request for CPA and blood sampling for TDM; Phase 2, sample delivery to and check in at the CPU; Phase 3, TDM execution and CPA production) were created. In the interventional period, the errors were collected daily and educational programmes were carried out. The pre‐intervention error rate was 19.5%, and resulted significantly higher for the requests coming from the medical wards compared with those from the surgical wards or the ICUs (26.0% versus 10.5% versus 13.7%, p < 0.001). The educational programme trained 303 nurses and 145 physicians. Afterwards, the error percentage progressively dropped (15.5% in the 2nd trimester; 12.3% in the 3rd one; 10.5% in the 4th one). The adopted strategy resulted in significant improvements which may be useful both to improve quality of patient care and to reduce waste in healthcare costs.     

The Role of the Drug/Excipient Particle Size Ratio in the Percolation Model for Tablets

Purpose. In previous papers, a linear relationship between drug particle size and drug percolation threshold was found in inert matrix tablets. The main objectives of the present work are: to study the influence of the excipient particle size on the drug percolation threshold and to investigate if the change in the drug percolation threshold is due either to the absolute or to the relative drug particle size. Methods. Matrix tablets have been prepared using KC1 (7 different particle size fractions) as a drug model and Eudragit^® RS-PM (4 granulommetric fractions) as matrix forming material. In vitro release assays were carried out on the 66 lots of tablets. The drug percolation thresholds were estimated following the method of Bonny and Leuenberger. Results. The particle size of the excipient has shown an opposite effect to the drug size on the drug percolation threshold. Nevertheless, the influence of drug and excipient sizes on the drug percolation threshold are of the same magnitude. Conclusions. The drug percolation threshold depends linearly on the relative drug particle size. This finding is in agreement with percolation theory and can facilitate the use of the percolation threshold as a preformulation parameter to improve the pharmaceutical dosage forms design.     

Validation of Human MDR1-MDCK and BCRP-MDCK Cell Lines to Improve the Prediction of Brain Penetration

It is of great challenge to predict human brain penetration for substrates of multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), 2 major efflux transporters at blood-brain barrier. Thus, a physiologically based pharmacokinetic (PBPK) model with the incorporation of in vitro MDR1 and BCRP transporter function data and transporter protein expression levels has been developed. As such, it is crucial to generate MDR1 and BCRP substrate data with a high fidelity. In this study, 2 widely used human MDR1 cell lines from Borst and National Institutes of Health laboratories were evaluated using rodent brain penetration data, and the study suggested that the MDR1 expressed in Madin-Darby canine kidney (MDCK) cell line from National Institutes of Health laboratory predicted brain penetration better, particularly for compounds with a high passive permeability. In addition, human BCRP-MDCK cell line with 1 μM PSC833, a specific MDR1 inhibitor, demonstrated the ability to identify BCRP substrates without the confounding of endogenous canine Mdr1. Comparison of human BCRP and mouse Bcrp transporter functions revealed that the functional differences of BCRP between the 2 species is minimal. The incorporation of both the validated MDR1 and BCRP assays into our brain PBPK model has significantly improved the prediction for the brain penetration of MDR1 and BCRP substrates across species.     

A Treatment Package to Improve Primary Care Services for Relatives of People with Alcohol and Drug Problems

The present paper reports the results of an intervention study with baseline and post treatment measures that was conducted to test the feasibility and impact of a structured treatment package. The latter was used by professionals in the primary care setting working with relatives of people with alcohol and drug problems. The package consisting of a brief psycho-social intervention and information leaflets was tested by a) measuring the impact of the intervention on relatives' stress and coping and b) assessing the feasibility of training General Practitioners, Practice Nurses and Health Visitors to use the package as well as the impact of using the package upon their attitudes and confidence towards working with this group. Both relatives' coping and symptoms and the primary care professionals attitudes and confidence towards working with this group were measured twice, once before and again after the intervention. It was found that following the intervention relatives showed a significant decrease in physical and psychological symptoms and a reduction in engaged and tolerant forms of coping. In addition a significant improvement was found in the confidence and attitudes of the group of professionals who tested the intervention when compared to those who did not. It is concluded that given a coherent package and ongoing support, primary care professionals can be recruited and trained to work with relatives of alcohol and drug users in their health care setting. This work results in positive outcomes for these relatives.