Overview of milling techniques for improving the solubility of poorly water-soluble drugs

Milling involves the application of mechanical energy to physically break down coarse particles to finer ones and is regarded as a“topedown”approach in the production of fine particles.Fine drug particulates are especially desired in formulations designed for parenteral,respiratory and transdermal use.Most drugs after crystallization may have to be comminuted and this physical transformation is required to various extents,often to enhance processability or solubility especially for drugs with limited aqueous solubility.The mechanisms by which milling enhances drug dissolution and solubility include alterations in the size,specific surface area and shape of the drug particles as well as millinginduced amorphization and/or structural disordering of the drug crystal(mechanochemical activation).Technology advancements in milling now enable the production of drug micro-and nano-particles on a commercial scale with relative ease.This review will provide a background on milling followed by the introduction of common milling techniques employed for the micronization and nanonization of drugs.Salient information contained in the cited examples are further extracted and summarized for ease of reference by researchers keen on employing these techniques for drug solubility and bioavailability enhancement.

Evaluation of Albuminated Curcumin as Soluble Drug Form to Control Growth of Cancer Cells <i>in Vitro</i>

Curcumin (Curc) is well known for its anticancer activity, but its poor solubility in aqueous medium is a major concern for little therapeutic outcome. Therefore, the effort to improve its bioavailability is a major research interest. The current study aimed at conjugation of Curc to serum albumin (Alb) to increase aqueous solubility of the former without affecting its drug action on cancer cell lines and primary cells in culture. Conditions for preparation of albumin-curcumin (Alb-Curc) conjugate were standardized to obtain pure and stable drug. The product was obtained in sufficient quantity to test its effect on cells in culture at different doses. Briefly, the conjugate was prepared by mixing Curc dissolved in DMSO with the Alb dissolved in phosphate buffered saline;conjugate was purified by gel filtration chromatography and was analyzed using UV-Vis spectroscopy for characteristic peaks of both molecules. The conjugate was added to culture medium to identify the effect of conjugate on cell cycling and apoptosis. Albuminated curcumin that showed 100-fold higher solubility than free Curc was stable and inhibitory to proliferation, induced cell cycle arrest and apoptosis. The conjugate showed apoptotic effects on endothelial cells indicating its anti angiogenic property. Primary fibroblast growth was also inhibited but at the higher dose. The in vitro results suggest that Alb-Curc which is free of insoluble native drug may find application in cancer therapy after appropriate in vivo evaluations.

搭载雷帕霉素纳米晶的透明质酸微针贴片的制备及性质初步探究

目的可降解载药微针可以持续、安全、无痛地实现局部药物缓释,而微针载药系统用于心血管领域可最大程度发挥药物的局部抗凝,抑制内膜增生,减小药物全身给药带来的毒副作用。为此本文制备了一款搭载雷帕霉素纳米晶的透明质酸(hyaluronic acid,HA)微针贴片,并对该贴片进行初步理化性质评价、体外模拟释药性能评估以及刺入大隐静脉性能的分析评价。方法首先以150万分子量的透明质酸为基材掺杂的雷帕霉素水相纳米晶混悬液(rapamycin nanoparticles,RAP-NPs)形成药物均匀分散的水凝胶;然后通过聚二甲基硅氧烷微针模板(polydimethylsiloxane,PDMS)制备可溶于水的雷帕霉素水相纳米晶混悬液的透明质酸微针贴片(hyaluronic acid-rapamycin-microneedle,HA-RAP-MN);最后对这种载药微针进行初步理化性质评价和体外模拟释药性能分析评价。结果RAP-NPs水相混悬液可与HA水凝胶形成混匀的混合物,使药物能够均匀分散在微针中并持续释放药物,解决了难溶性药物分子无法在HA水凝胶中均匀分散的技术瓶颈。药物模拟释放实验表明雷帕霉素可在8h内释放70%以上,达到缓释效果。免疫荧光结果表明雷帕霉素均匀分布于静脉中膜及内膜。结论可溶于水的雷帕霉素水相纳米晶混悬液的透明质酸微针贴片在局部降低冠状动脉旁路移植术后内膜增生方面具有可预期的应用潜力。

甲基对苯醌的理化性质及类药性预测研究

目的:测定甲基对苯醌的平衡溶解度以及油水分配系数,并分析其对不同肿瘤细胞的细胞毒活性。方法:采用摇瓶法-HPLC法测定甲基对苯醌在不同pH溶液中的平衡溶解度和油水分配系数。色谱条件:采用Ecosil-C18色谱柱(4.6 mm×250 mm,5μm),流动相为乙腈-0.1%甲酸水溶液(70:30),流速1.0 mL/min,检测波长250 nm,柱温30℃,进样量10μL。利用SwissADME和pkCSM预测药物的类药性,采用MTT法分析甲基对苯醌对HT29、CT26、Caco-2、Hela、HepG25株细胞的细胞毒活性。结果:甲基对苯醌在pH为1.2、2.0、5.0、6.7、7.0、7.4的溶液中,12 h的平衡溶解度分别为7.65、8.05、9.31、8.43、9.33、7.93 mg/mL,油水分配系数分别为0.78、0.80、0.83、0.82、0.77、0.82,SwissADME预测的溶解度和油水分配系数均与实验结果一致。同时预测结果发现,甲基对苯醌具有较好的类药性以及较弱的血脑屏障透过性。甲基对苯醌对5株细胞的IC50依次为7.98、3.21、8.96、7.96、6.31μmol/L。结论:测定甲基对苯醌平衡溶解度和油水分配系数的摇瓶法-HPLC法简单可行,且在pH 5.0~7.0的溶液条件下能够适当增强甲基对苯醌的溶解度,同时药物的ADME/T在线预测软件具有一定的可靠性,甲基对苯醌对HT29、CT26等多株细胞具有显著的抑制作用。

口溶膜类新药的开发与评价探讨

膜剂系指原料药物与适宜的成膜材料经加工制成的膜状制剂,口溶膜系指在口腔可迅速溶化的膜剂。口溶膜具有剂量准确、携带方便、可提高特定适应证人群患者依从性等特点。本文结合注册法规要求及近年来国内外口溶膜药物的开发和审评审批情况,对口溶膜新药的开发立项、处方工艺、质量研究和控制等方面的评价进行了探讨。研究建议企业在立项开发时应全面评估,合理选择申报策略和路径。处方工艺开发时,根据剂型特点关注影响产品质量的关键因素,并有针对性地进行质量研究和控制。希望通过本文能够指导现阶段口溶膜类新药产品的开发和评价,助力有临床需求的、高质量的口溶膜类新药的获批上市。

药物晶型研究中溶解度的高效测定

药物晶型研究是药学研究领域的一个重要分支,很多药物晶型研究实验设计需要大量的溶解度数据支撑。如何快速、高效获得大量的药物溶解度数据的同时又保证数据的准确性,已成为晶型研究的一个棘手问题。本文结合动态溶剂法和静态平衡法,提出一种采用高效液相色谱高效、快速地测定药物溶解度的方法,克服了这两种测定方法的缺点,并讨论了测试过程中的注意事项,提出了一些建设性的建议,供药物晶型研究人员参考。

溴己新注射剂临床配伍用药研究

目的考察导致溴己新注射剂临床输液药液混浊原因,为保障该注射剂质量和临床安全使用提供参考。方法结合溴己新溶解度分析实验,开展代表性的临床配伍实验研究,关注非治疗性药物的配伍情况。结果药液p H环境高度影响溴己新的溶解度,结合复方氯化钠注射液和复方电解制注射液的验证性临床配伍实验,溴己新注射剂临床配伍用药的环境p H偏碱性时易出现药液变混浊的不良状况。结论溴己新注射液配伍后浑浊现象的关键影响因素为p H而非输液溶媒,提示非治疗性药物的临床配伍问题应予以重视。

ROS-responsive drug delivery systems for biomedical applications

In the field of biomedicine, stimuli-responsive drug delivery systems(DDSs) have become increasingly popular due to their site-specific release ability in response to a certain physiological stimulus, which may result in both enhanced treatment outcome and reduced side effects. Reactive oxygen species(ROS) are the unavoidable consequence of cell oxidative metabolism. ROS play a crucial part in regulating biological and physiological processes,whereas excessive intracellular ROS usually lead to the oxidation stress which has implications in several typical diseases such as cancer, inflammation and atherosclerosis. Therefore,ROS-responsive DDSs have elicited widespread popularity for their promising applications in a series of biomedical research because the payload is only released in targeted cells or tissues that overproduce ROS. According to the design of ROS-responsive DDSs, the main release mechanisms of therapeutic agents can be ascribed to ROS-induced carrier solubility change, ROS-induced carrier cleavage or ROS-induced prodrug linker cleavage. This review summarized the latest development and novel design of ROS-responsive DDSs and discussed their design concepts and the applications in the biomedical field.

Pharmaceutical particle technologies: An approach to improve drug solubility, dissolution and bioavailability

Pharmaceutical particle technology is employed to improve poor aqueous solubility of drug compounds that limits in vivo bioavailability owing to their low dissolution rate in the gastrointestinal fluids following oral administration.The particle technology involves several approaches from the conventional size reduction processes to the newer,novel particle technologies that modify the solubility properties of the drugs and produce solid,powdered form of the drugs that are readily soluble in water and can be easily formulated into various dosage forms.This review highlights the solid particle technologies available for improving solubility,dissolution and bioavailability of drugs with poor aqueous solubility.

Preparation and evaluation of alpha-mangostin solid self-emulsifying drug delivery system

Alpha-mangostin(AMG),a natural xanthone extracted from Garcinia mangostana Linn,has a variety of pharmacological therapeutic effects such as antioxidant activity,antibacterial activity,anticancer,and anti-inflammatory[1].However,it has poor aqueous-solubility and dissolution,which results in low bioavailability.Solid self-emulsifying drug delivery system(solid-SEDDS),an effective pharmaceutical strategy,offers the potential for enhancing the oral bioavailability of poorly water-soluble drugs[2].Therefore,solid-SEDDS is of interest as a potential method for enhancing the solubility and dissolution of AMG.

Enhanced drug loading efficiency of contact lenses via salt-induced modulation

Low drug loading efficiency is one of the main obstacles hindering the application of contact lenses(CLs) as the carrier for extended ocular drug delivery. Here in this study, a simple and effective drug loading method based on salt induced modulation was proposed and demonstrated with mechanism elucidation. First of all, using poly(2-hydroxyethyl methacrylate)(p-HEMA) as the contact lens material, betaxolol hydrochloride, Diclofenac Sodium and Betaxolol Base as the model drugs with different solubility, influence of salt concentration,salt type(sodium salts of sulfate, chloride, and sulfocyanate) and drug properties in the loading solution on drug loading efficiency was investigated. Mechanism of enhanced drug loading in contact lens was further explored via studying the influence of salt on the absorption isotherm, drug solubility and water content of CLs. Applicability of this method to other CLs materials was also investigated. It was demonstrated that adjusting the ionic strength of loading solutions resulted in significant increase of drug loading in CLs. Type and concentration of the salts and solubility of the drug were the main factors influencing enhancement ratio of drug loading. The mechanism for improved drug loading was related to the reduced drug solubility in loading solutions and the reduced bound water content in contact lenses. Modulation of drug loading by adjusting ionic strength was also applicable to other CLs and the light transmittance was not affected. This method was more suitable for salt-form drugs with high solubility. In summary, adjusting ionic strength of loading solution is an economical and effective way to improve drug loading in CLs, and this simple method may also find application in other hydrogel based drug delivery systems.

Hot melt extrusion: An application for enhancing drug solubility

Low aqueous solubility of API is a problem of drug product development.There are several methods to enhance drug solubility.Although drugs can increase solubility using many chemical and physical modifications,the few methods are able to enhance drug solubility for industrial scale[1].Hot-melt extrusion is one reliable process for enhancing drug solubility in a large scale production.It has been recognized as a one step process with several advantages.It can not only increase solubility of drug,but can also be used as a process to prepare controlled release dosage forms.Using a biodegradable polymer with hot-melt extrusion,the drug release of up to 1–6 months can be achieved[2].

盐酸溴己新注射剂临床配伍的应用性研究

目的考察导致盐酸溴己新注射剂临床输液时药液混浊的原因。方法研究溴己新溶解度曲线,尝试开展数据拟合的模型分析,并开展代表性的临床配伍试验进行验证。结果溴己新的溶解性与pH环境高度相关,结合验证性的临床配伍试验,确认盐酸溴己新注射剂临床配伍用药的环境pH偏碱性时易出现药液变混浊的不良状况。结论不科学的临床配伍用药是导致盐酸溴己新药液变混浊的主要原因,其中溶解度是重要指标参数,而pH是关键影响因素。

手性介孔二氧化硅纳米粒的合成及在载药递药中的应用

背景:近些年来,手性介孔二氧化硅纳米粒逐渐成为了一种热门的药物载体,其是凭借哪些性能具有独特递送药物优势呢?目的:探讨手性介孔二氧化硅纳米粒在药物递送系统中发挥优势作用的关键因素。方法:从手性介孔二氧化硅纳米粒的合成、成型机制、手性性质、载药释药性能及生物安全性研究等方面入手,利用PubMed和中国知网数据库检索1990-2022年的有关文献,根据纳入与排除标准对所有文章进行初筛后,保留相关性较高的49篇文章进行综述。结果与结论:除了模板是合成手性介孔二氧化硅纳米粒的重要条件外,表面活性剂及反应温度、酸碱度、搅拌速度、表面活性剂链长、阴阳离子等因素对合成材料的结构也有所影响。在作为药物载体的应用中,手性介孔二氧化硅纳米粒的扭曲孔道使其在载药和递药方面更具优势,如手性介孔二氧化硅纳米粒的高孔隙网络结构特性可以增加药物的负载量。一般情况下,手性介孔二氧化硅纳米粒的比表面积和孔容越大,载药量越高。手性介孔二氧化硅纳米粒的孔径对药物的晶体结构有抑制作用,可有效改变药物晶型为无定形,从而显著提高药物的生物利用度。如何根据药物应用需求精确设计具有手性形貌或手性结构亦或分子级手性的手性介孔二氧化硅纳米粒是实现该种载体应用价值的关键问题,有待更多的研究。

PIVAS难溶性药物氯诺昔康成品输液配制质量监测与改进

目的:考察静脉用药集中调配中心(pharmacy intravenous admixture services, PIVAS)难溶性药物注射用氯诺昔康成品输液的配制质量,优化输液调配流程,以保障静脉输液安全。方法:收集某三甲医院PIVAS、临床病房(区)难溶性药物氯诺昔康成品输液样品,采用高效液相色谱法测定氯诺昔康药物含量,依据含量监测结果进行原因分析、输液调配流程优化等质量改进措施。结果:氯诺昔康输液合格率PIVAS集中调配明显高于临床病房(区)自行调配;质量改进后,PIVAS配制的氯诺昔康成品输液合格率由92.0%提高至100.0%(P<0.05),且输液质量的均一性明显提升。结论:对PIVAS难溶性药物成品输液进行配制质量监测与改进,能有效提高难溶性药物成品输液配制质量,确保静脉输液安全有效。

聚合物微针体系用于眼部药物递送的进展

聚合物微针是目前最有潜力的透皮给药技术,具有精准、快速、可溶解、可降解等特点,已被广泛用于递送疫苗、麻醉类、止痛类等大分子药物。聚合物微针能够有效地穿过眼表屏障,使药物顺利靶向递送至患病处。因此,综述了聚合物微针在眼科领域的应用的进展,通过对目前的聚合物微针的制备、器件类型和设计原则、生物安全方面的研究,总结了该领域的最新进展,然后,分析了聚合物微针在眼部疾病中的具体应用及其在眼部疾病中的工作特点,包括眼压、感染、眼部皱纹等。在提出了目前面对的关键挑战的同时,对聚合物微针在眼部药物递送的前景进行了展望,促进了聚合物微针治疗眼部疾病的发展。

硫酸新霉素可溶性粉中非法添加4种苯并咪唑类和3种大环内酯类抗寄生虫药物HPLC-PDA检测方法的建立

建立了硫酸新霉素可溶性粉中非法添加7种抗寄生虫药物的HPLC-PDA检测方法。采用十八烷基键合硅胶为填充剂;以水-乙腈为流动相,梯度洗脱,流速1.0 mL/min;二极管阵列检测器,波长为245 nm。通过液相色谱保留时间、峰纯度检查和光谱相似度检查对非法添加物进行确证。结果表明,该色谱条件下,7种抗寄生虫药物间分离度良好,在3~80μg/mL浓度范围内线性关系良好(R2>0.9998),回收率在103.9%~105.8%之间,RSD≤2.5%,4种苯并咪唑类和3种大环内酯类的检测限分别为0.05 g/kg和0.3 g/kg。该方法操作简便、快速、灵敏度高,可用于硫酸新霉素可溶性粉中非法添加抗寄生虫药物的测定。

搭载右旋布洛芬缓释型微针的制备及性能测试

载药缓释型微针可以无痛、有效地释放疫苗激素类药物。以交联透明质酸为基材,分别使用预载药和后载药的方法制备右旋布洛芬缓释型微针,研究载药缓释型微针的最佳制备工艺。对这2种载药方法制备的微针阵列进行了力学性能测试,同时通过体外透皮扩散实验评价了微针的释药性能。实验结果表明,预载药法更适合制备载药缓释型微针,微针阵列的成型较好,并且具有足够的力学性能刺破皮肤。体外透皮扩散实验显示,预载药法制备的右旋布洛芬缓释型微针的释药性能更加优异。微针在6 h时释放了约42%的药物,最终,累计释放了约95%的药物。实验结果证明了载药缓释型微针的有效性,为疫苗、激素类药物的临床应用提供了新的研究方向。

Fundamental aspects of solid dispersion technology for poorly soluble drugs

The solid dispersion has become an established solubilization technology for poorly water soluble drugs.Since a solid dispersion is basically a drug-polymer two-component system,the drug-polymer interaction is the determining factor in its design and performance.In this review,we summarize our current understanding of solid dispersions both in the solid state and in dissolution,emphasizing the fundamental aspects of this important technology.

不同载体材料卡维地洛固体分散体性质研究

本文以卡维地洛为模型药物,研究第三代载体材料在难溶性药物固体分散体技术中的应用。本文分别以共聚维酮、丙烯酸树脂、醋酸羟丙甲纤维素琥珀酸酯、邻苯二甲酸羟丙甲纤维素酯为载体材料,以溶剂法制备固体分散体。通过X射线衍射以及差示扫描量热检测对其进行表征,结果显示卡维地洛吸热峰消失,表明药物以无定型态载于介质中。卡维地洛原料药和物理混合物60分钟溶出度未超过10%,卡维地洛固体分散体的溶出速度显著提高,其中以丙烯酸树脂为载体的处方效果最佳,其溶出度接近80%。第三代载体材料能显著提高卡维地洛的溶解度,为固体分散体技术解决药物难溶性问题提供了新思路,为其工业化生产的应用提供参考。