刺激响应聚合物微针在经皮给药中的应用

聚合物微针自身具有良好的机械性能和优异的生物相容性,能以微创的方式刺穿皮肤角质层,实现药物的高效经皮吸收,从而有效治疗各种疾病,如糖尿病、癌症、肥胖以及眼部疾病等.如何调控聚合物微针中负载药物的释放行为,是微针经皮给药需要关注的核心要素.刺激响应释放聚合物微针作为一种新兴的按需给药技术,能根据外界环境条件或自身生理环境...     

Microneedles: One-Plane Bevel-Tipped Fabrication by 3D-Printing Processes

This article presents microneedles analyses where the design parameters studied included length and inner and outer diameter ranges. A mathematical model was also used to generalize outer and inner diameter ratios in the obtained ranges. Following this, the range of inner and outer diameters was completed by mechanical simulations, ranging from 30 μm to 134 μm as the inner diameter range and 208 μm to 250 μm as the outer diameter range. With these ranges, a mathematical model was made using fourth-order polynomial regressions with a correlation of 0.9993, ensuring a safety factor of four in which von Misses forces of the microneedle are around 17.931 MPa; the ANSYS software was used to analyze the mechanical behavior of the microneedles. In addition, the microneedle concept was made by 3D printing using a bio-compatible resin of class 1. The features presented by the microneedle designed in this study make it a promising option for implementation in a transdermal drug-delivery device.     

辅以时滞的pH-敏感介孔膦酸锆对双氯芬酸钠的可控结肠靶向释放

以pH-敏感介孔膦酸锆作为药物载体, 选用治疗时辰节律性疾病(风湿性关节炎)的药物双氯芬酸钠作为药物模型, 利用蘸涂的方法对载药的pH-敏感介孔膦酸锆进行时滞膜的包覆, 建立起一个时滞型和pH-敏感型相结合的口服结肠靶向给药系统. 在系统研究pH-敏感介孔膦酸锆对双氯芬酸钠吸附和释放的基础之上, 通过调控时滞膜的厚度控制释放双氯芬酸钠的时滞时间约为6 h. 该给药系统在人工模拟胃液中3 h内完全不释放双氯芬酸钠, 而在人工模拟肠液中最初的3 h(可以看成发生在小肠)所释放的双氯芬酸钠仅为全部释放量的9%, 在之后的46 h内(可以看成发生在结肠)缓慢释放的双氯芬酸钠则占全部释放量的90%以上. 这样, pH-敏感介孔膦酸锆作为新型药物载体与时滞效应相结合, 通过时滞和pH-敏感双重控制实现了治疗时辰节律性疾病药物在结肠的定位释放.     

羧甲基纤维素钠水凝胶的制备及其生物降解性研究

用羧甲基纤维素钠(CMC—Na)制得了含水量高达98％的水凝胶，考察了防腐剂、交联剂、无机态氮素、有机态氮素、碳水化合物的加入量以及环境中pH值等因素对生物降解性的影响。结果表明：制备条件不同，水凝胶的生物降解性不同；环境中一定量铵根离子的存在有利于水凝胶的生物降解；在pH=5．2的环境中纤维素酶活性最高，降解程度最大。     

羧甲基纤维素钠／羟乙基纤维素复合溶液的性能

羧甲基纤维素钠（ＮａＣＭＣ）和羟乙基纤维素（ＨＥＣ）作为油田用驱油剂，具有抗剪切能力强，原料丰富和对环境污染少等优点，但单独使用效果不理想．前者虽有较好的增粘性，但易受油藏温度、盐度的影响；后者虽有较好的耐温、耐盐性，但其增稠能力较差、用量较大［１，...     

A Rapidly Dissolvable Microneedle Patch with Tip-Accumulated Antigens for Efficient Transdermal Vaccination

Dissolvable microneedles (DMNs) are an attractive alternative for vaccine delivery due to their user-friendly, skin-targeted, and minimally invasive features. However, vaccine waste and inaccurate dosage remain significant issues faced by DMNs, as the skin's elasticity makes it difficult to insert MNs completely. Here, a simple and reliable fabrication method are introduced based on two-casting micromolding with centrifugal drying to create a rapidly DMN patch made of hyaluronic acid. Ovalbumin (OVA), as the model antigens, is concentrated in the tip parts of the DMNs (60% of the needle height) to prevent antigen waste caused by skin elasticity. The time and temperature of the initial centrifugal drying significantly affect antigen distribution within the needle tips, with lower temperature facilitating antigen accumulation. The resulting DMN patch is able to penetrate the skin with enough mechanical strength and quickly release antigens into the skin tissue within 3 min. The in vivo study demonstrates that immunization of OVA with DMNs outperforms conventional vaccination routes, including subcutaneous and intramuscular injections, in eliciting both humoral and cellular immunity. This biocompatible DMN patch offers a promising and effective strategy for efficient and safe vaccination.     

含5-氟尿嘧啶的羧甲基纤维素钠/聚(N-异丙基丙烯酰胺)半互穿网络水凝胶的药物释放性能

以5-氟尿嘧啶(5-FU)为模型药物,对羧甲基纤维素钠/聚(N-异丙基丙烯酰胺)半互穿网络水凝胶(CMC/PNIPA semi-IPN)的药物释放性能进行了研究。结果表明:在37℃、pH=7.4时,药物的释放速率以及释放量都随着凝胶中羧甲基纤维素钠含量的增加而增大。在25℃时,pH对药物释放速率的影响较小;而在37℃时,药物释放速率受pH的影响较大。该凝胶体系用做5-FU的口服释放载体具有较佳的释放性能。     

Self‐Adhesive Microneedles with Interlocking Features for Sustained Ocular Drug Delivery

The interests in sustained ocular drug delivery have grown rapidly in recent years, with hope to replace repeated intravitreal injections. Microneedles (MNs), which are minimally invasive, have been shown to be a feasible vehicle for sustained drug delivery. However, securing an MN patch in the eye remains challenging. In this study, a new design of hydrogel MNs with interlocking features to achieve self‐adhesion is proposed. Upon swelling, the swollen interlocking features help secure the MNs in place. A new molding process is developed to fabricate MNs with interlocking features that can cause issues when demolding using the regular micromolding process. MNs with two different interlocking feature designs are used in this study and are made with polyvinyl alcohol. MNs with the interlocking features show an 80% increase in adhesion strength and a small amount of increase in penetration force, in comparison to MNs without any feature. The experiments are performed using both a sclera‐mimicking phantom and ex vivo eyes harvested from rabbits and are shown to have comparable results. This study demonstrates the feasibility of incorporating interlocking features to MNs to achieve self‐adhesion that can enable sustained drug delivery via MNs.     

Thermosensitive Microneedles Capable of On Demand Insulin Release for Precise Diabetes Treatment

As a novel painless and minimally invasive transdermal drug delivery method, microneedles have solved the challenges of microbial infection and tissue necrosis associated with multiple subcutaneous injections in patients with diabetes. However, traditional soluble microneedles cannot switch drug release on and off according to the patient's needs during long-term use, which is one of the most critical elements of diabetes treatment. Herein, an insoluble thermosensitive microneedle (ITMN) that can control the release of insulin by adjusting the temperature, enabling the precise treatment of diabetes is designed. Thermosensitive microneedles are produced by in situ photopolymerization of the temperature-sensitive compound N-isopropylacrylamide with the hydrophilic monomer N-vinylpyrrolidone, which is encapsulated with insulin and bound to a mini-heating membrane. ITMN are demonstrated to have good mechanical strength and temperature sensitivity, can release significantly different insulin doses at different temperatures, and effectively regulate blood glucose in type I diabetic mice. Therefore, the ITMN provides a possibility for intelligent and convenient on-demand drug delivery for patients with diabetes, and when combined with blood glucose testing devices, it has the potential to form an integrated and precise closed-loop treatment for diabetes, which is of great importance in diabetes management.     

Crosslinked Alginate Films as Rate Controlling Membranes for Transdermal Drug Delivery Application

The present investigation was undertaken to prepare and evaluate the crosslinked sodium alginate (SA) films as rate controlling membranes (RCM) for transdermal drug delivery application. The drug free films of SA were prepared by mercury substrate method and evaluated for thickness uniformity, tensile strength and water vapor permeation (WVP). The films were characterized by scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). Drug diffusion characteristics of the films were studied using diclofenac diethylamine as a model drug. The prepared membranes were thin, flexible and smooth. Tensile strength measurement and DSC analysis suggested that as the crosslink density increases, the tougher membranes were formed. The WVP and drug diffusion were dependent upon the crosslink density and thickness of the films. The permeability was decreased with increasing crosslink density and thickness of the films. The molar mass between the crosslinks and crosslink density were calculated using empirical equations. The primary skin irritation study indicated that the prepared membranes were less irritant and safe for transdermal application.     

光谱法测定复方双氯灭痛注射液含量

本实验对复方双氯灭痛注射液中扑热息痛和双氯灭痛两种主要成分分别采用双波长紫外分光光度法及紫外差示分光光度法进行含量测定。可在不用分离的情况下连续测定两种成分的含量。实验结果:扑热息痛的直线回归方程C=31.34A+0.078,R=0.9999,回收率100.69%,CV%=0.91。双氯灭痛的直线回归方程C=24.94A—0.202,R=0.9997,回收率为100.91%,CV%=0.77。本法具有方法简便,结果准确,重现性好,实用等优点。     

羧甲基纤维素钠/聚(N-异丙基丙烯酰胺)纳米复合水凝胶的制备及结构性能表征

以无机粘土为交联剂制备了具有温度、pH双重敏感特性的羧甲基纤维素钠/聚(N-异丙基丙烯酰胺)/粘土半互穿网络纳米复合水凝胶(CMC/PNIPA/Clay semi-IPN),并通过红外和透射电镜对其结构和形态进行了表征。在酸性(pH=1.2)和20℃条件下,分别研究了温度和不同pH缓冲液对该凝胶溶胀度的影响,测定了复合水凝胶的力学性能。结果表明:水凝胶中的粘土被剥离成单片层,且均匀分散在凝胶网络中,起交联剂的作用,而CMC以线性大分子的形态存在;CMC/PNIPA/Clay具有良好的温度、pH双重敏感特性;凝胶的断裂伸长率>1 000%。     

Diclofenac Solubilization in Microemulsions Based on Mixed Nonionic Surfactants and R (+)-limonene

Diclofenac is a nonsteroidal anti-inflammatory drug that reduces inflammation and pain hormones in the body. Dispersing the drug in water is impossible and its solubility in oils is very limited. In this study, we solubilized sodium diclofenac in nanostructures of the constructed U-type water/sucrose laurate/ethoxylated mono-di-glyceride/oleic phase microemulsions. The mixing ratio (w/w) of sucrose laurate/ethoxylated mono-di-glyceride equals unity. The oleic phase was the pure R (+)-limonene or R (+)-limonene mixed with ethanol at a weight ratio equals unity. The solubilization capacity of the drug in these systems is many times higher than in either oil or water systems. The sodium diclofenac solubilized microemulsions are fully diluted with water without phase separation. The solubilization capacity decreases as the water content increases. The system free of alcohol solubilizes less amounts of drug over all the range of water contents compared to the system containing alcohol. Small angle x-ray scattering was used to evaluate the effect of solubilized sodium diclofenac on the microstructure and diffusion properties of the loaded microemulsions. From the periodicity and correlation length measured by small angle x-ray scattering, we learned that the drug affects the structure of loaded microemulsion droplets probably less spherical than the empty systems. The transition from water-in-oil to a bicontinuous phase occurs at the different water contents compared to the empty (i.e., without drug) microemulsions. The drug remains solubilized at the interface upon further dilution with water and is oriented with its hydrophilic part facing the water, and strongly affects the inversion to oil-in-water droplets.     

CMC/PNIPAAm半互穿网络水凝胶的溶胀动力学研究

以羧甲基纤维素钠(CMC)和N-异丙基丙烯酰胺(NIPAAm)为原料,制备了具有温度和pH敏感性的半互穿网络(CMC／PNIPAAmsemi-IPN)水凝胶,并研究了水凝胶在不同温度和pH值条件下的溶胀行为。结果表明：在弱碱性(pH-7．4)条件下,凝胶的溶胀速率和溶胀度都随着凝胶中CMC含量的增加而增大;而在酸性(pH-1．O)条件下则相反。在弱碱性条件下,水分子在凝胶中的扩散行为都可用non-Fickian扩散来描述,水分子在凝胶中的扩散系数D随着凝胶溶胀速率的增大而增大;在酸性条件下,20℃时凝胶的溶胀过程符合non-Fickian扩散规律,而37℃时凝胶的溶胀过程符合Fickian扩散规律,但水分子的扩散系数D相差不大。     

Development of Biopolymer Based Matrix Type Multiple Unit Systems for Sustained Release of Diclofenac Sodium: In vitro and In vivo Evaluation

The objective of the present study was to investigate the applicability of matrix type chitosan treated alginate multiple unit systems (MUS) for sustained release of diclofenac sodium. The multiple unit systems (MUS) were prepared by the ionotropic gelation method. Spherical MUS with 1.852±0.041–2.173±0.265 mm diameter range and 66.66±3.21 to 78.55±6.49% entrapment efficiency were produced. The addition of chitosan increased the swelling of MUS in acidic conditions and reduced the drug release from MUS. The fluoroscopic study reveals that the MUS retained in gastrointestinal tract (GIT) for more than 12 h and distributed throughout the GIT. The in vivo evaluation in healthy human volunteers of the MUS and that of Voveran SR tablets each containing 100 mg drug revealed that the MUS was bioequivalent to Voveran SR producing a non‐significantly different (p>0.05) AUC. This study demonstrates that the matrix type chitosan treated alginate MUS can be a good alternative to sustained release tablets to deliver diclofenac sodium and expected to be less of an irritant to gastric and intestinal mucosa.     

In Vitro Release of Local Anaesthetic and Anti-Inflammatory Drugs from Crosslinked Collagen Based Device

The drug delivery systems that are the object of this article take the form of a hydrophilic matrix (collagen or crosslinked collagen) containing a drug. These devices can be used as The model active agents, were chosen from the range of local anaesthetics (lidocaine hydrochloride), anti-inflammatory (diclofenac sodium salt) and antioxydant (caffeic acid). Whatever the drug affinity for water, in the first time of the experiments, the release appears to be systematically delayed when the matrix is crosslinked. For lidocaine hydrochloride based systems, as the amount of drug increases in the matrix, the high gap concentration between the matrix and the buffer solution promote the diffusion and a Fickian behavior is observed on the release curves. Depending on the chemical nature of the drug and its solubility, several interactions between the drug and the collagen matrix can be considered. A new drug delivery system containing caffeic acid as the anti-inflammatory and antioxydant molecule could be tested. This new system was able to release 95% of the drug in 5 h and the global release rate depends on the initial drug concentration in the device.     

A Rapid and Sensitive Method for The Determination of Diclofenac Sodium in Plasma By High-Performance Liquid Chromatography

Abstract

A rapid and sensitive high-performance liquid chromatographic method for the determination of diclofenac sodium in plasma has been developed. The method is specific and free of interference from metabolites and common anti-inflammatory agents. The UV detector (215 nm) response was linear over a range of 5-1000 ng/ml. Day-to-day and within-day calibration curves were reproducible. The method was validated by analysis of spiked human plasma samples, partly in a blind fashion. The accuracy and precision of the method are satisfactory over the range of 5-1000 ng/ml. The method was cross-checked with the GC method. Results show a correlation coefficient of 0.983 and a slope of 1.04. The method is suitable for the routine analysis of large numbers of plasma samples usually obtained in bioavailability and pharmacokinetic studies.     

Interaction Between 1-Dodecyl-3-Methylimidazolium Bromide and Sodium Carboxymethylcellulose in Aqueous Solution: Effect of Polymer Concentration

Effect of the concentration of water-soluble polyanion (sodium carboxymethylcellulose, NaCMC) on the interaction between a cationic surfactant (1-dodecyl-3-methylimidazolium bromide, C₁₂mimBr) and NaCMC in aqueous solution has been studied by isothermal titration microcalorimetry (ITC), conductivity, surface tension, and rheological measurements. From the surfactant/polymer interacting enthalpy, it can be deduced that the electrostatic attraction between the cationic surfactant and anionic polyelectrolyte causes an endothermic process, and the C₁₂mimBr monomers binding to the NaCMC chains to form micelle-like aggregates through hydrophobic interaction is an exothermic process. Increasing the NaCMC concentration causes the interaction between C₁₂mimBr and NaCMC to decrease, and the characteristic surfactant concentrations, including the critical aggregation surfactant concentration (CAC), the surfactant concentration to form free micelles (C_m), and the saturation concentration of surfactant on the NaCMC chains (C_S) to increase. Because of the strong electrostatic interaction between C₁₂mimBr and NaCMC, the formation of C₁₂mimBr/NaCMC complexes can lead to precipitation or redissolution depending on solution composition, so the critical precipitation concentration (C_P) and the onset of a redissolution concentration (C_R) has been determined by the electrical conductivity. The rheological results reveal a dramatic increase in solution viscosity around the CAC, attributed to interpolymer cross-linking through the formation of mixed micelles involving the carboxylic acid groups of NaCMC and the surfactant.     

分光光度法快速测定食品中糖精钠含量

基于在硫酸介质中,次甲基蓝与糖精钠反应生成憎水型离子缔合物,且该缔合物可被氯仿定量萃取,提出了分光光度法测定食品中糖精钠含量。在室温下,当0.2 mol.L-1硫酸用量为2.5 mL,0.04 mol.L-1次甲级蓝溶液用量为2 mL时,糖精钠的质量浓度在15 mg.L-1范围内与其吸光度呈线性关系,检出限(3s/k)为0.11 mg.L-1。用此法测定几种食品中糖精钠含量,回收率在100.1%~114.0%之间,相对标准偏差(n=6)均小于5.0%。     

Six-Step Continuous Flow Synthesis of Diclofenac Sodium via Cascade Etherification/Smiles Rearrangement Strategy: Tackling the Issues of Batch Processing

Diclofenac sodium is a widely used nonsteroidal anti-inflammatory drug (NSAID) as over-the-counter (OTC) medication for the treatment of inflammatory diseases. Herein, the development of an intensified six-step continuous flow synthesis of diclofenac sodium from commercially available aniline and chloroacetic acid is described. A challenging and unprecedented etherification/Smiles rearrangement cascade of 2-chloro-N-phenylacetamide and 2,6-dichlorophenol into hydroxyacetyldiphenylamine operated with the precise control of reaction conditions in continuous flow was realized as the key step in this multistep synthetic chemistry. The undesired amide hydrolysis in Smiles rearrangement was addressed and the extra installation of N-chloroacetyl group in current industrial batch mode was avoided. Diclofenac sodium was obtained in 63 % isolated yield with an average yield of above 90 % for each step in a total residence time of 205 min.