互为内标法测定紫杉醇和多西紫杉醇血浆药物浓度及临床应用

摘 要 目的： 建立高效液相色谱（HPLC）法测定人血浆中紫杉醇、多西紫杉醇浓度为临床个体化给药方案、疗效及不良反应评价提供实验依据。方法: 紫杉醇和多西紫杉醇互为内标,血浆样品采用乙腈提取法,以DikMA Diamonsil C₁₈反相色谱柱分离样品,流动相为乙腈∶水（55∶45）,检测波长为227 nm,流速为1.2 ml·min^-1,柱温为25℃。结果: 紫杉醇和多西紫杉醇血药浓度在0.078～10.0 mg·L^-1范围内线性关系良好;最低定量下限为0.039 mg·L^-1;平均方法回收率分别为99.85%和100.35%;日内、日间相对标准差均低于5%;短期稳定性、长期稳定性和反复冻融稳定性相对标准差均低于10%。紫杉醇临床样本血浆药物浓度监测结果范围为0.18～6.16 mg·L^-1,临床监测结果存在明显个体差异。结论:紫杉醇和多西紫杉醇血浆药物浓度差异明显,进行两药治疗药物监测十分必要。本方法灵敏、准确、便捷、快速,适用于紫杉醇和多西紫杉醇的临床常规治疗药物监测及药动学研究。     

青蒿素及其衍生物纳米制剂在抗肿瘤领域中的研究进展

摘 要青蒿素及其部分衍生物在抗肿瘤方面具有潜在的临床应用价值,但存在水溶性差、半衰期短等缺点,故促使众多学者对其药物制剂进行开发和研究。纳米药物传输系统是一种新型药物递送工具,相比传统的片剂、栓剂、注射剂等,具有稳定性好、靶向释药和联合载药等诸多优点。本文综述了青蒿素类药物的纳米传输载体,包括：纳米粒、脂质体、胶束、纳米微乳和其他纳米载体,概括了青蒿素类药物纳米制剂在肿瘤治疗方面的成果和特点,其中着重介绍青蒿素类药物与转铁蛋白的联合载药递药体系的研究进展。     

疏水改性白及多糖自组装载紫杉醇纳米粒子在大鼠体内药动学研究

目的 建立一种简便、灵敏的测定大鼠尾静脉和灌胃给予胆甾醇琥珀酰基白及多糖载紫杉醇纳米粒子后的血浆药物浓度的HPLC方法,并评价其药动学特征。方法 以酮康唑为内标,采用AgilentTC-C₁₈色谱柱（250 mm×4.6 mm,5 μm）,以甲醇-乙腈-水（45：20：35）为流动相,流速为1.0 ml/min,采用统计矩法计算药动学参数,评价药动学特征。结果 紫杉醇在大鼠血中浓度在0.5~20 μg/ml范围内线性关系良好（r=0.999 7）,准确度和精密度均符合生物样品分析要求。尾静脉注射3种不同取代度的自制纳米粒和紫杉醇注射液后的t_1/2分别为3.86、3.76、3.35和2.62 h;灌胃给予自制紫杉醇纳米粒溶液和紫杉醇混悬液后的t_1/2分别为5.28和3.72 h。结论 该测定方法可用于紫杉醇纳米粒子在大鼠体内的药动学研究,且载紫杉醇自组装纳米粒子在体内的滞留时间比紫杉醇注射液和紫杉醇混悬液有明显延长。     

难溶性药物logP值对纳米脂肪乳载药特性的影响

目的 考察难溶性药物油/水分配系数(log P值)对纳米脂肪乳载药量、体外释药特性、相分布等载药特性的影响。 方法 选取6种难溶性药物:尼莫地平(NIM)、多西紫杉醇(DTX)、姜黄素(CUR)、紫杉醇(PTX)、替尼泊苷(TEN)、水飞蓟宾(SLB),分别考察其log P值与PEG400中溶解度、载药纳米脂肪乳的载药量、粒径、Zeta电位、体外释药特性以及相分布等的关系。 结果 随着log P值的增加,药物在PEG400中的溶解度呈先上升后下降的趋势,在纳米脂肪乳中的载药量增高,体外释放速率减慢,在油相中的分布增加,在乳化剂层的分布减小;药物log P值与载药纳米脂肪乳的粒径及Zeta电位无关。 结论 可综合考虑药物的log P值及PEG400中的溶解度,用以初步判断纳米脂肪乳的载药特性。     

8种胃癌化疗药物与药品不良反应的聚类关系分析

目的：分析胃癌化疗药物不良反应与药品品种间的聚类关系,促进临床安全合理用药。方法：收集109家药品生产企业2010-2014年生产的8种胃癌化疗药物氟尿嘧啶、卡培他滨、表柔比星、顺铂、伊立替康、紫杉醇、奥沙利铂和多西他赛的不良反应报告数据,运用数据挖掘技术对药品不良反应与药品品种间的关系进行聚类分析,使用Clementine 14.1软件进行统计。结果与结论：共收集有效报告10572份,卡培他滨和顺铂,表柔比星和伊立替康,多西他赛和紫杉醇联合用药发生一般药品不良反应的可能性较大。卡培他滨、顺铂、伊立替康和表柔比星联合用药;多西他赛、氟尿嘧啶和紫杉醇联合用药时,出现严重药品不良反应的概率较高。瘙痒、过敏性休克、顺铂、多西他赛在聚类过程中的运算比重较大。     

紫杉醇与多西他赛在ⅠB2期及ⅡA2期宫颈癌新辅助化疗中的疗效比较

目的 探讨紫杉醇与多西他赛在ⅠB2期及ⅡA2期宫颈癌新辅助化疗中的近期疗效及毒副反应。方法 回顾性分析安徽省立医院2014年1月至2016年1月122例宫颈癌患者临床资料，根据化疗方案的不同将患者分为两组：紫杉醇组（62例）采用紫杉醇联合奈达铂化疗；多西他赛组（60例）采用多西他赛联合奈达铂化疗。每3周为1个疗程，共2个疗程，3周后评估局部疗效，随即手术。结果 紫杉醇组和多西他赛组总有效率分别为59.68%（37/62）、53.33%（32/60），差异无统计学意义（P>0.05）。紫杉醇组引起过敏反应、神经毒性发生率高于多西他赛组，骨髓抑制发生率低于多西他赛组，差异均有统计学意义（P均<0.05），而在脱发、肌肉关节疼痛、恶性呕吐等毒副反应方面，两组差异无统计学意义（P>0.05）。紫杉醇组手术切除率为90.32%，多西他赛组手术切除率为95.00%，术后病理检查紫杉醇组淋巴转移9例（15.79%），多西他赛组淋巴转移11例（19.30%），差异均无统计学意义（P均>0.05）。结论 多西他赛联合奈达铂为局部晚期宫颈癌患者提供了有效、低毒副反应的新辅助化疗方案，可为患者赢得手术机会，其疗效与紫杉醇相似，但在过敏反应、神经毒性方面明显低于紫杉醇。     

注射用紫杉醇纳米制剂的研究进展

紫杉醇广泛用于卵巢癌、乳腺癌、肺癌等多种肿瘤的治疗。传统的紫杉醇制剂生物利用度低,临床应用有限。纳米给药系统是现代药物制剂的研究热点,近年来临床上陆续开发了紫杉醇的纳米新剂型。纳米乳、纳米粒、胶束等也正在实验研究之中。本文就紫杉醇纳米制剂的开发和应用进展进行综述。     

聚合物胶束在经皮给药系统中的应用

摘 要 目的：综述聚合物胶束作为药物载体在经皮传递系统中的应用进展。方法: 根据国内外发表的最新文献,对聚合物胶束的制备方法、促进皮肤渗透的机制、释药过程及其在经皮给药系统中的应用进行分析与讨论。结果: 聚合物胶束具有增加难溶性药物的溶解度,促进药物的经皮吸收等作用,作为药物载体在经皮传递系统的应用越来越广泛。结论:聚合物胶束可作为药物载体被广泛用于经皮给药系统的研究中,具有较好的发展前景。     

HPLC测定紫杉醇纳米脂质体凝胶剂在小鼠皮肤中的含量

目的 考察紫杉醇纳米脂质体凝胶剂给药4 h后在小鼠皮肤各层中的含量分布情况。方法 采用胶带粘贴技术剥脱角质层,以HPLC测定紫杉醇在皮肤各层中的含量,比较紫杉醇脂质体凝胶剂以及紫杉醇凝胶剂在皮肤各层中的分布特点。结果 紫杉醇纳米脂质体给药4 h后在角质层和活性皮肤层中的药物含量分别为3.41,5.35 μg·cm^-2,与紫杉醇凝胶剂比较,能显著提高药物在皮肤中的滞留量（P<0.05）。结论 与紫杉醇凝胶剂相比,紫杉醇纳米脂质体能增加药物的皮肤滞留量。     

紫杉醇/低分子肝素-胱胺-维生素E琥珀酸酯胶束的制备及其体外细胞毒性

目的 优化紫杉醇/低分子肝素–胱胺–维生素E琥珀酸酯（PTX/LMWH-cys-TOS）胶束的处方，评价其制剂学特性和体外细胞活性。方法 以载药率和包封率为指标，考察有机溶剂、药物载体比例对胶束载药能力的影响，优化最佳处方。利用冷冻干燥法制备了胶束冻干粉针并考察复溶稳定性，采用透析法研究了胶束在不同浓度的二硫素糖醇溶液中的释放动力学，采用CCK8法研究了胶束在紫杉醇敏感和耐药细胞上的抗肿瘤活性，利用HPLC法测定了紫杉醇在肿瘤细胞内的质量浓度。结果 紫杉醇和LMWH-cys-TOS的最佳比例是1∶3.6，使用乙醇作为有机溶剂。加入冻干保护剂的胶束产品外观良好，复溶后的胶束应该在4 ℃保存，而且要尽快使用；在二硫苏糖醇存在的释放介质中，紫杉醇释放速度随着二硫苏糖醇浓度的增加而增加，二硫苏糖醇的浓度是20 mmol/L时，紫杉醇的36 h的累积释放量高达93%。胶束能提高紫杉醇在耐药细胞HCT-15/Taxol上的毒性和药物在肿瘤细胞内的质量浓度。结论 PTX/LMWH-cys-TOS胶束改善了紫杉醇的溶解度，实现了靶向给药。     

Emerging role of nanocarriers to increase the solubility and bioavailability of curcumin

Introduction: Curcumin is a safe, affordable and natural bioactive molecule of turmeric (Curcuma longa). It has gained considerable attention in recent years for its multiple pharmacological activities. However, its optimum pharmaceutical potential has been limited by its lack of aqueous solubility and poor bioavailability. To mitigate the above limitations, recently various nanostructured water-soluble delivery systems were developed to increase the solubility and bioavailability of curcumin.

Areas covered: Major reasons contributing to the low bioavailability of curcumin appear to be owing to its poor solubility, low absorption, rapid metabolism and rapid systemic elimination. The present review summarizes the strategies using curcumin in various nanocarrier delivery systems to overcome poor solubility and inconsistent bioavailability of curcumin and describes the current status and challenges for the future.

Expert opinion: The development of various drug delivery systems to deliver curcumin will certainly provide a step up towards augmenting the therapeutic activity of curcumin thereby increasing the solubility and bioavailability of curcumin. However, the future of such delivery technology will be highly dependent on the development of safe, non-toxic and non-immunogenic nanocarriers.     

Evaluation of glycosylated docetaxel-encapsulated liposomes prepared by remote loading under solubility gradient

Docetaxel comprises one of the most effective anti-cancer drugs despite of serious side effects. Liposomes encapsulation is practically feasible to deliver the drug. However, due to the significant hydrophobicity, docetaxel will be integrated into the lipid bilayer resulting in poor encapsulation capacity. Here, we evaluated a remote loading strategy using a solubility gradient made between the two solvents for 7-glucosyloxyacetyldocetaxel, which has enhanced water solubility of docetaxel with a coupled glucose moiety. Therefore, 7-glucosyloxyacetyldocetaxel was more effectively encapsulated into liposomes with 71.0% of encapsulation efficiency than docetaxel. While 7-glucosyloxyacetyldocetaxel exhibited 90.9% of tubulin stabilisation activity of docetaxel, 7-glucosyloxyacetyldocetaxel encapsulated in liposomes significantly inhibited the growth of tumour in vivo with side effects less than unencapsulated drug. Collectively, the encapsulation of 7-glucosyloxyacetyldocetaxel into liposomes by remote loading under the solubility gradient is considered to be a promising application to prepare practical drug delivery system.     

纳米立方液晶系统作为抗肿瘤药物载体的研究进展

摘 要对近年来纳米立方液晶系统作为药物载体在抗肿瘤方面的研究进展进行综述。介绍纳米液晶的结构、特点、制备方法和常用材料,及其在肿瘤方面的应用。纳米立方晶具有提高药物溶解度和稳定性的优势,并具有良好的生物相容性,作为新型纳米药物载体广泛受到人们关注。     

Potentials and challenges in self-nanoemulsifying drug delivery systems

Introduction: A significant number of new chemical entities (almost 40%), that are outcome of contemporary drug discovery programs, have a potential therapeutic promise for patient, as they are highly potent but poorly water soluble resulting in reduced oral bioavailability. Self-nanoemulsifying drug delivery systems (SNEDDS) have emerged as a vital strategy to formulate these poorly soluble compounds for bioavailability enhancement.

Areas covered: The review gives an insight about potential of SNEDDS with regards to oral drug delivery. The effect of various key constituents on formulation of SNEDDS and their applications in oral drug delivery is also discussed. Various aspects of formulation, characterization and biopharmaceutical aspects of SNEDDS are also been explored. The choice and selection of excipients for development of SNEDDS is also discussed.

Expert opinion: The ability of SNEDDS to present the drug in single unit dosage form either as soft or hard gelatin capsule with enhanced solubility maintaining the uniformity of dose is unique. With the ease of large-scale production, high drug-loading capacity, improvement in release behavior of poorly water-soluble drugs and improvement of oral bioavailability, SNEDDS have emerged as preferable system for the formulation of drug compounds with bioavailability problems due to poor aqueous solubility.     

壳聚糖衍生物作为siRNA纳米递送系统材料的研究进展

小干扰RNA(small interfering RNA,siRNA)在治疗疾病方面具有高效性、特异性、瞬时性等优良特性,是目前药物研发关注的焦点。但裸露的siRNA稳定性差、细胞摄取率低,难以发挥其基因沉默作用,因此需要一种优质的递送系统将其递送至靶细胞中,使其发挥作用。大部分纳米递送系统因毒性、载药问题不利于siRNA的转运,而壳聚糖衍生物具有较高的水溶性、安全性、稳定性,已受到广泛关注。本文综述了壳聚糖衍生物应用于siRNA纳米递送系统的研究进展,为正在进行纳米递送系统研究的科研工作者提供参考。     

Curcumin-docetaxel co-loaded nanosuspension for enhanced anti-breast cancer activity

ABSTRACT

Purpose: A curcumin-docetaxel co-loaded nanosuspension with increased anti-breast cancer activity was developed. Curcumin is a potential anticancer agent with p-glycoprotein (p-gp) inhibiting activity may be co-administered with docetaxel as a nanosuspension to enhance its anticancer effect by increasing the oral bioavailability and decreasing drug efflux.

Methods: Nanosuspensions of curcumin and docetaxel were prepared by precipitation-homozenisation technique and evaluated for particle size, polydispersity, zeta potential and drug release. The in vitro MTT assay was conducted using MCF-7 for anti-breast cancer activity. The in vivo biodistribution by radiolabeling and tumor inhibition study was conducted in mice.

Results: Homogenous nanosuspensions of 80 ± 20 nm were obtained with increased solubility. The drugs as nanosuspensions showed higher cytotoxicity on MCF-7 cell line compared to their suspensions due to the increased in vitro cellular uptake. Due to this increased solubility, sensitization of tumor cells and inhibition of p-gp the in-vivo results showed greater tumor inhibition rate of up to 70% in MCF-7 treated mice. Histopathological results showed higher apoptotic activity and reduced level of angiogenesis.

Conclusions: The in vitro and in vivo study of the nanosuspensions has shown that Co-administration of Curcumin as a p-gp inhibitor with docetaxel may have the potential to increase the anti-breast cancer efficacy of both drugs.     

基于纳米载药技术的丹参难溶性成分在抗肿瘤治疗中的研究进展

丹参难溶性成分因能对抗多种恶性肿瘤而成为很好的抗肿瘤候选药物,但因其水溶性差、半衰期短、生物利用度低,极大限制了其临床应用。随着纳米技术的持续发展,基于纳米粒、脂质体、聚合物胶束等中药纳米给药系统能够很好地克服这些不足并被开发应用于临床。本文对近年报道的丹参难溶性成分纳米给药系统在抗肿瘤治疗中的研究进展进行综述,以期为今后进一步开发丹参难溶性成分的纳米给药系统提供理论依据。     

Oral formulation strategies to improve solubility of poorly water-soluble drugs

Introduction: In the past two decades, there has been a spiraling increase in the complexity and specificity of drug–receptor targets. It is possible to design drugs for these diverse targets with advances in combinatorial chemistry and high throughput screening. Unfortunately, but not entirely unexpectedly, these advances have been accompanied by an increase in the structural complexity and a decrease in the solubility of the active pharmaceutical ingredient. Therefore, the importance of formulation strategies to improve the solubility of poorly water-soluble drugs is inevitable, thus making it crucial to understand and explore the recent trends.

Areas covered: Drug delivery systems (DDS), such as solid dispersions, soluble complexes, self-emulsifying drug delivery systems (SEDDS), nanocrystals and mesoporous inorganic carriers, are discussed briefly in this review, along with examples of marketed products. This article provides the reader with a concise overview of currently relevant formulation strategies and proposes anticipated future trends.

Expert opinion: Today, the pharmaceutical industry has at its disposal a series of reliable and scalable formulation strategies for poorly soluble drugs. However, due to a lack of understanding of the basic physical chemistry behind these strategies, formulation development is still driven by trial and error.     

Biomedical applications of microneedles in therapeutics: recent advancements and implications in drug delivery

Introduction: The skin, as the largest organ, is a better option for drug delivery in many diseases. However, most transdermal delivery is difficult due to the low permeability of therapeutics across the various skin layers. There have been many innovations in transdermal drug delivery to enhance the therapeutic efficacy of the drugs administered. Microneedles (MN), micron sized needles, are of great interest to scientists as a new therapeutic vehicle through transdermal routes, especially for vaccines, drugs, small molecules, etc.

Areas covered: This review covers new insights into different types of MNs such as solid, hollow, coated and dissolving MNs (SMNs, HMNs, CMNs, and DMNs) for selected biomedical applications in detail. Specific focus has been given to CMNs and DMNs for vaccine and drug delivery applications with recent developments in new MNs covered.

Expert opinion: This review explores the feasibility of innovative MNs used as a drug delivery carrier. Because most of the SMNs and HMNs have many limitations, it is difficult to achieve therapeutic efficacy. Therefore, many scientists are investigating functional modifications of MNs through covalent and non-covalent methods, especially for CMNs and DMNs. The biomedical applications of MNs are growing and new exciting improvements could be achieved, thus resulting in better micro/nano technologies in the near future.