In the present study, we describe the development of betaxolol hydrochloride and montmorillonite with ion exchange in a single formulation to create a novel micro-interactive dual-functioning sustained-release delivery system (MIDFDS) for the treatment of glaucoma. Betaxolol hydrochloride molecule was loaded onto the montmorillonite by ion exchange and MIDFDS formation was confirmed by XPS data. MIDFDS showed similar physicochemical properties to those of Betoptic, such as particle size, pH, osmotic pressure, and rheological properties. Nevertheless, the microdialysis and intraocular pressure test revealed better in vivo performance of MIDFDS, such as pharmacokinetics and pharmacodynamics. With regards to wettability, MIDFDS had a larger contact angle (54.66 ± 5.35°) than Betoptic (36.68 ± 1.77°), enabling the MIDFDS (2.93 s) to spread slower on the cornea than Betoptic (2.50 s). Moderate spreading behavior and oppositely charged electrostatic micro-interactions had a comprehensive influence on micro-interactions with the tear film residue, resulting in a longer precorneal retention time. Furthermore, MIDFDS had a significant sustained-release effect, with complete release near the cornea. The dual-functioning sustained-release carrier together with prolonged pre-corneal retention time (80 min) provided sufficiently high drug concentrations in the aqueous humor to achieve a more stable and long-term IOP reduction for 10 h. In addition, cytotoxicity and hemolysis tests showed that MIDFDS had better biocompatibility than Betoptic. The dual-functioning microspheres presented in this study provide the possibility for improved compliance due to low cytotoxicity and hemolysis, which suggests promising clinical implications.

The research on the pharmacodynamic substance basis of traditional Chinese medicine(TCM) is a key scientific issue for the inheritance and development of TCM. At present, a large number of remarkable achievements have been made in the field of chemical components in Chinese medicine, however, another important aspect, namely the physical structure and mode of action of the multi-component assembly of TCM, has not been clearly understood and deeply studied. From the bottleneck of restricting material ba-sic research, we objectively analyzed the common cause of the existing problems. Based on the new discoveries and advances of active substances from TCM emerging in recent years, we extracted and summarized the concept of structural Chinese medicine, elaborated the basic ideas, main features and research modes, hoping to provide theoretical and practical references for the study on the pharmacodynamic substance basis and other research fields of TCM.

目的:将阳离子型药物盐酸倍他洛尔(BH),与具有离子交换性能的蒙脱石及聚丙烯酸树脂联合使用制备新型盐酸倍他洛尔/蒙脱石聚丙烯酸树脂微球(Mt-BH-MP)新型眼用微纳米混悬剂,考察其刺激性及眼前端滞留能力.方法:采用油包油乳化-溶剂挥发法制备微球,以BH水溶液和市售贝特舒为对照,分别采用永生化人角膜上皮细胞(iHCECs)构筑角膜前滞留的细胞模型和荧光示踪法评价Mt-BH-MP在细胞模型及兔眼眼袁的滞留能力;以MTT法、兔眼眨眼实验及角膜荧光损失来共同评价该新型给药系统的刺激性.结果:iHCECs细胞模型角膜前滞留实验结果表明,Mt-BH-MP的眼部滞留能力明显优于贝特舒组和BH水溶液组;Mt-BH-MP兔眼在体角膜前荧光可维持(46±1)min,亦明显长于BH水溶液和贝特舒滴眼液组(P＜0.05),上述二项实验结果一致.MTT实验结果显示,iHCECs与各制剂接触2h后,细胞存活率大小顺序为:空白微球＞Mt-BH-MP＞ BH水溶液＞贝特舒;兔眼眨眼刺激性及荧光角膜损伤实验结果表明,Mt-BH-MP给药后并无明显异物感及角膜机械损伤.结论:制备的新型微球眼部递药系统具有良好的眼部滞留能力且刺激性相对较小,具有良好的眼部递药应用前景.

以Compritol? 888 ATO(山嵛酸甘油酯)为骨架材料制备双氯芬酸钠缓释片并对其体外释放进行评价,得到与市售产品Voltaren-SR体外释放一致的自制片.通过差示扫描量热(DSC)、傅里叶红外变换光谱(FT-IR)和粉末X线衍射(PXRD)等手段探究Compritol? 888 ATO与双氯芬酸钠的二元体系,采用热熔挤出联合粉末直压的工艺制备双氯芬酸钠缓释片并测定体外释放.结果发现:Compritol? 888 ATO与双氯芬酸钠二元体系表现为偏晶行为,且偏晶体系的形成对药物释放影响不大,Compritol? 888 ATO用量越多,药物释放越慢.结论:Compritol? 888 ATO的疏水性对药物释放起着更为显著的作用,骨架材料的用量与药物释放速率呈负相关性.

Multidrug resistance (MDR) due to P-glycoprotein (P-gp) overexpression is a major obstacle to successful leukemia chemotherapy. The combination of anticancer chemotherapy with a chemosensitizer of P-gp inhibitor is promising to overcome MDR, generate synergistic effects, and maximize the treatment effect. Herein, we co-encapsulated a chemotherapeutic drug of mitoxantrone (MTO) and a P-gp inhibitor of β-elemene (βE) in solid lipid nanoparticles (MTO/βE-SLNs) for reversing MDR in leukemia. The MTO/βE-SLNs with about 120 nm particle size possessed good colloidal stability and sustained release behavior. For the cellular uptake study, doxorubicin (DOX) was used as a fluorescence probe to construct SLNs. The results revealed that MTO/βE-SLNs could be effectively internalized by both K562/DOX and K562 cells through the pathway of caveolate-mediated endocytosis. Under the optimized combination ratio of MTO and βE, the in vitro cytotoxicity study indicated that MTO/βE-SLNs showed a better antitumor efficacy in both K562/DOX and K562 cells than other MTO formulations. The enhanced cytotoxicity of MTO/βE-SLNs was due to the increased cellular uptake and blockage of intracellular ATP production and P-gp efflux by βE. More importantly, the in vivo studies revealed that MTO/βE-SLNs could significantly prolong the circulation time and increase plasma half-life of both MTO and βE, accumulate into tumor and exhibit a much higher anti-leukemia effect with MDR than other MTO formulations. These findings suggest MTO/βE-SLNs as a potential combined therapeutic strategy for overcoming MDR in leukemia.

Herein, lactoferrin (Lf)/phenylboronic acid (PBA)-functionalized hyaluronic acid nanogels crosslinked with disulfide-bond crosslinker was developed as a reduction-sensitive dual-targeting glioma therapeutic platform for doxorubicin hydrochloride (DOX) delivery (Lf-DOX/PBNG). Spherical Lf-DOX/PBNG with optimized physicochemical properties was obtained, and it could rapidly release the encapsulated DOX under high glutathione concentration. Moreover, enhanced cytotoxicity, superior cellular uptake efficiency, and significantly improved brain permeability of Lf-DOX/PBNG were observed in cytological studies compared with those of DOX solution, DOX-loaded PBA functionalized nanogels (DOX/PBNG), and Lf modified DOX-loaded nanogels (Lf-DOX/NG). The pharmacokinetic study exhibited that the area under the curve of DOX/PBNG, Lf-DOX/NG, and Lf-DOX/PBNG increased by 8.12, 4.20 and 4.32 times compared with that of DOX solution, respectively. The brain accumulation of Lf-DOX/PBNG was verified in biodistribution study to be 12.37 and 4.67 times of DOX solution and DOX/PBNG, respectively. These findings suggest that Lf-DOX/PBNG is an excellent candidate for achieving effective glioma targeting.

植入型给药系统是缓控释给药系统的重要分支之一,适用于长期给药和靶向给药,具有载药量高、体积较小、作用时间长、副作用小、生物利用度高等特点,同时还可以大大提高长期慢性病患者的依从性,因此愈来愈被行业所重视.随着品种类型、给药途径及生产技术不断发展,植入型给药系统目前已被应用于生殖健康、肿瘤治疗、疼痛治疗、眼部治疗等众多领域.对近几年国内外植入剂的种类及临床研究和应用进展进行综述,为该剂型后续深入研究提供参考.

Physiological reflexes and anatomical barriers render traditional eye drop delivery inefficient. We previously reported that drug-loaded nanoparticles and microspheres prepared from montmorillonite and Eudragit polymers exhibited good sustained-release and lowered intraocular pressure. Here, we compared the performance of optimized formulations to select the most suitable formulation for glaucoma therapy. We found that the microspheres had much higher encapsulation efficiency and drug loading than nanoparticles. Moreover, cytocompatibility experiments demonstrated that nanoparticles showed more severe cytotoxicity than microspheres, probably due to their smaller particles, enhanced cell uptake, and intracellular solubility. Interestingly, the pre-corneal retention time of nanoparticles reflected a clear advantage over microspheres, while the duration of the pharmacological effect of nanoparticles was not as good as that of microspheres: compared with the nanoparticle depressurization duration of only 8 h, the microspheres continuously depressurized for 12 h. The slower release of the microspheres and its micro-interaction mechanism with the discontinuous mucin layer of the tear film led to the inconsistency between duration of pharmacodynamics and fluorescence ocular retention time. In summary, the lower cytotoxicity and longer pharmacological effect of microspheres indicate their potential advantages for glaucoma applications.

A major obstacle to the clinical use of curcumin (CUR) is its reduced bioavailability because of the drug's hydrophobic nature, low intestinal absorption, and rapid metabolism. In this study, a novel oral drug delivery system was constructed for improving the stability and enhancing mucoadhesion of CUR in the gastrointestinal (GI) tract. First, CUR was encapsulated in the bovine serum albumin nanoparticles (CUR-BSA-NPs). Then, N-acetyl cysteine (NAC)-modified CUR-BSA-NPs (CUR-NBSA-NPs) were obtained. The average particle size and zeta potential of CUR-NBSA-NPs were 251.6 nm and -30.66 mV, respectively; encapsulation efficiency and drug loading were 85.79 and 10.9%, respectively. CUR-NBSA-NPs exhibited a sustained release property and prominently enhanced stability in simulated GI conditions. Additionally, enhanced mucoadhesion of CUR-NBSA-NPs was also observed. An MTT study showed that the CUR-NBSA-NPs were safe for oral administration. Overall, NAC-modified BSA-NPs may potentially serve as an oral vehicle for improving CUR stability in the GI tract and enhancing mucoadhesion.

目的 建立微透析技术的体外回收率测定方法,并考察体外回收率的影响因素,并进一步将微透析技术应用到蒙脱石镶嵌盐酸倍他洛尔微球(Mt-BH-MPs)混悬液在兔眼房水的药动学评价.方法 采用浓度差法对各影响因素在体外回收率的高低进行评价,同时利用反向透析法对2.8 mg/mL Mt-BH-MPs混悬液在眼部给药后进行房水取样,以高效液相色谱法测定其药物浓度.结果 正、反向透析法测定的回收率在同一流速下基本一致(RSD均小于2％),且探针回收率随流速增加呈下降趋势;正、反向透析法所得的回收率在同一浓度下均很接近(56.22％,55.06％);Mt-BH-MPs混悬液的生物利用度最高,其AUC(2326.77±29.29)(μg?min)/mL分别是BH水溶液组的3.12倍与贝特舒组的1.27倍,Cmax(8.56±0.26)μg/mL明显高于贝特舒组(7.48±0.18)μg/mL和BH水溶液组(7.05±0.16)μg/mL,Tmax是BH水溶液组的4倍,与贝特舒组一致,持续释药时间是BH水溶液组的2倍.结论 连续取样微透析技术用于该新型离子交换微球混悬液的眼部药动学研究方法可行,相较于BH水溶液和贝特舒,Mt-BH-MPs混悬液缓慢释放药物,提高了药物在眼部的生物利用度.

Multifunctional nanomedicines with active targeting and stimuli-responsive drug release function utilizing pathophysiological features of the disease are regarded as an effective strategy for treatment of rheumatoid arthritis (RA). Under the inflammatory environment of RA, activated macrophages revealed increased expression of folate receptor and elevated intracellular reactive oxygen species (ROS) level. In this study, we successfully conjugated folate to polyethylene glycol 100 monostearate as film-forming material and further prepared methotrexate (MTX) and catalase (CAT) co-encapsulated liposomes, herein, shortened to FOL-MTX&CAT-L, that could actively target to activated macrophages. Thereafter, elevated intracellular hydrogen peroxide, the main source of ROS, diffused into liposomes and encapsulated CAT catalyzed the decomposition of hydrogen peroxide into oxygen and water. Continuous oxygen-generation inside liposomes would eventually disorganize its structure and release the encapsulated MTX. We characterized the in vitro drug release, cellular uptake and cytotoxicity studies as well as in vivo pharmacokinetics, biodistribution, therapeutic efficacy and safety studies of FOL-MTX&CAT-L. In vitro results revealed that FOL-MTX&CAT-L possessed sufficient ROS-sensitive drug release, displayed an improved cellular uptake through folate-mediated endocytosis and exhibited a higher cytotoxic effect on activated RAW264.7 cells. Moreover, in vivo results showed prolonged blood circulation time of PEGylated liposomes, enhanced accumulation of MTX in inflamed joints of collagen-induced arthritis (CIA) mice, reinforced therapeutic efficacy and minimal toxicity toward major organs. These results imply that FOL-MTX&CAT-L may be used as an effective nanomedicine system for RA treatment.

药品安全、有效、稳定与顺应性是药剂研发与生产中遵循的准则,数以万计的制剂品种为防病治病发挥了极其重大的作用.为了改进治疗效果、降低成本和绿色制造等目的,缓控释制剂、透皮制剂、干粉吸入制剂、脂质体及微球制剂等应运而生.无论普通制剂或新型制剂,其研发与生产都是一项复杂的系统工程,包含对多种技术的应用,隐含关键的技术参数,药品质量常常据此跃上新台阶,在竞争中脱颖而出或难以超越,成为具有很长市场生命周期的品牌,许多改良型新药则是对现有药品技术创新或改革的代表性成果.

为提高吲哚美辛的溶出度,采用热熔挤出法制备吲哚美辛-烟酰胺共晶.以温度和转速为变量考察最佳制备条件,联合热重分析(TGA)、含量测定和有关物质测定评价制备中的热稳定性,通过差示扫描量热法(DSC)、傅里叶红外变换光谱法(FTIR)和粉末X射线衍射法(PXRD)进行物相分析,并评价共晶的溶解度和溶出度优势.结果 表明:热熔挤出法在115℃下能成功制备吲哚美辛-烟酰胺共晶,在热熔挤出过程中存在低共熔现象,该共晶明显提高了吲哚美辛在各介质中的溶解度、溶出速率和溶出度.通过热熔挤出法制备难溶性药物共晶能明显改善其溶解性,为难溶性药物的开发和共晶技术的发展提供新的思路.

Combination therapy is a common clinical practice in the management of malignancies. Synergistic therapeutic outcomes are achieved only when tumor cells are exposed to drugs in an optimal ratio and sequence; therefore, carriers coencapsulating multiple drugs are widely pursued for their coordinated delivery. However, it is challenging to coload drugs with different physicochemical properties in a single carrier with specific ratios. It is not even beneficial to load them in one carrier if they need to be released at different times. We propose to load drugs into chemically compatible carriers separately, equalize different carriers by a simple, rapid, and versatile camouflage technique based on natural polyphenol tannic acid (TA), and administer them in desirable ratios and sequences. To demonstrate this potential, different nanoparticles (NPs) with different charges and material basis, such as polymeric (carboxyl-terminated or amine-terminated cationic polystyrene NPs or poly(lactic- co-glycolic acid (PLGA) NPs), inorganic (mesoporous silica NPs (MSNs)), and liposomal NPs, are camouflaged with TA layers and further modified with folate-conjugated polyethylene glycol to aid in the delivery to tumors. The camouflaged NPs show similar physicochemical properties and interactions with KB cells despite the difference in core platforms, and their mixtures interact with common cell targets in a ratiometric manner. In KB-tumor-bearing mice, the camouflaged PLGA NPs and MSNs show near-perfect colocalization in tumors. These results support that TA helps equalize different NPs with high versatility and enables their ratiometric delivery to common targets. This approach can relieve technical challenges in ratiometric codelivery or sequential delivery of therapeutic agents with distinct physicochemical properties.

A micelle system based on hyaluronic acid (HA)-octadecylamine (OA) conjugate (HOA) functionalized with N-acetylcysteine (NAC) was constructed to yield NAC modified HOA conjugate (NHOA) for improving oral paclitaxel (PTX) delivery (PTX-NHOA). The average size of spherical PTX-NHOA micelles was 162.7 nm with a zeta potential of -27.6 mv. The encapsulation efficiency (EE) and drug loading (DL) of PTX-NHOA micelles were 92.64% and 6.96%, respectively. Additionally, NHOA micelles exihibited significantly higher cellular uptake in comparison with HOA micelles by caveolin-mediated and clathrin-mediated endocytosis. Higher permeation ability of NHOA micelles (2.75-fold and 1.32-fold, respectively) through cell monolayers of Caco-2/HT29 cells than that of Taxol and HOA micelles were also observed. The intestinal biodistribution result showed that NAC-modified micelles could enhance its adhesion to the intestinal surface and permeate deeply within the intestinal villi. The NHOA micelles were better absorbed in the duodenum, followed by the jejunum and the ileum. In vivo pharmacokinetic studies showed that AUC(0-t) value of PTX-NHOA micelles was about 5.92-fold and 2.47-fold higher compared to that of Taxol and PTX-HOA micelles, respectively. In a word, NHOA micelles is a promising drug delivery system in improving the oral absorption of insoluble drugs. (C) 2019 Elsevier B.V. All rights reserved.

Melittin (Mel), one of the host defense peptides derived from the venom of honeybees, demonstrates substantial anticancer properties, which is attributed to augmenting reactive oxygen species (ROS) generation. However, little has been reported on its pro-oxidation capacity in cancer oxidation therapy. In this study, an ROS amplifying nanodevice was fabricated through direct complexation of two natural pro-oxidants, Mel and condensed epigallocatechin gallate (pEGCG). The obtained nanocomplex (NC) was further covered with phenylboronic acid derivatized hyaluronic acid (pHA) through the ROS-responsive boronate ester coordination bond to produce pHA-NC. Upon undergoing receptor-mediated endocytosis into cancer cells, the inner cores of pHA-NC will be partially uncovered once pHA corona is degraded by hyaluronidase and will then escape from the lysosome by virtue of cytolytic Mel. The elevated ROS level in the tumor cytoplasm can disrupt the boronate ester bond to facilitate drug release. Both Mel and pEGCG could synergistically amplify oxidative stress and prolong ROS retention in cancer cells, leading to enhanced anticancer efficacy. This ROS cascade amplifier based on selective coordination bond and inherent pro-oxidation properties of natural ingredients could detect and elevate intracellular ROS signals, potentiating to move the tumor away from its homeostasis and make the tumor vulnerable. Compared to previously reported chemosynthetic pro-oxidants, the ROS self-sufficient system, fully composed of natural medicine, from this study provides a new insight in developing cancer oxidation therapy.

Alginate sodium derives from brown seaweed, which is a kind of anionic linear polysaccha-rides composed of different proportions of (1-4)-linked β-D-mannuronate and (1-4)-linked α-L-guluronate residues. Alginate sodium has attracted much attention and been widely used in biomedical fields to date including cell engineering, 3D bioprinting, drug release control and surgical dressing due to its extensive availability, biocompatibility and biodegradation. The review presents the latest researches and suggests per-spectives for future studies of alginate sodium in biomedical fields.

儿童偏好甜味,药物的苦味常常导致患儿服药顺应性降低,苦味药物的掩味是儿童口服制剂研发过程中面临的一大难题.简介苦味产生机制,传统和新型掩味方法和技术,各制药公司提出的掩味专利以及掩味效果的评价方法等,为掩味制剂的进一步开发提供参考.

The aim of this study was to evaluate the potential of polyelectrolyte complex nanoparticles (PENPs) based on hyaluronic acid/chitosan hydrochloride (HA/HCS) for co-loading mitoxantrone (MTO) and verapamil (VRP) to overcome multidrug resistance in breast tumors. PENPs co-loaded with MTO and VRP (MTO-VRP-PENPs) were affected by the method of preparation, molecular weight of HA, mass ratios and initial concentrations of HA/HCS, pH, and drug quantities. Optimized MTO-VRP-PENPs were ~209 nm in size with a zeta potential of approximately -24 mV. Encapsulation efficiencies (%) of MTO and VRP were 98.33%±0.27% and 44.21%±8.62%, respectively. MTO and VRP were successfully encapsulated in PENPs in a molecular or amorphous state. MTO-VRP-PENPs showed significant cytotoxicity in MCF-7/ADR cells in contrast to MTO-loaded PENPs (MTO-PENPs). The reversal index of MTO-VRP-PENPs was 13.25 and 10.33 times greater than that of the free MTO and MTO-PENPs, respectively. In conclusion, MTO-VRP-PENPs may serve as a promising carrier to overcome tumor drug resistance.