Polysialic acid and pluronic F127 mixed polymeric micelles of docetaxel as new approach for enhanced antitumor efficacy

In our previous study, polysialic acid-octadecyl dimethyl betaine (PSA-BS18) was synthesized and modified to liposomal EPI. Preliminary experiments revealed that the PSA-BS18 was a potential material for targeting tumor site with superior curative effects. In this study, PSA-BS18 and Pluronic F127 (F127) mixed polymeric micelles encapsulated docetaxel (DTX) (FP/DTX) were prepared by a self-assembly method. The FP/DTX was found to have a diameter of 34.83?±?0.50?nm with a narrow polydispersity, the entrapment efficiency was 99.12?±?1.17%, and the drug loading efficiency of 1.40?±?0.01%. The storage and dilution stability of FP/DTX was fine. In vitro release studies demonstrated that FP/DTX had delayed the drug release from the micelles. In vitro cytotoxicity assay on B16 cells presented that FP/DTX led to a stronger cytotoxic activity in comparison to F127 micelles based DTX (F127/DTX) and Tween80-based DTX (Taxotere^®). The in vivo imaging study showed that the accumulation of FP/DTX at tumor sites was more than F127/DTX. The in vivo antitumor activity of FP/DTX against B16 tumor xenograft model showed a significant higher inhibition and a lower toxicity compared with F127/DTX and Taxotere^®. Taken together, the results obtained above showed that PSA-BS18 and F127 mixed polymeric micelles may be a promising strategy for antitumor delivery of DTX.     

In Vivo Skin Permeation of Sodium Naproxen Formulated in Pluronic F-127 Gels: Effect of Azone® and Transcutol®

The objective of this study was to determine the penetration of sodium naproxen, formulated in Pluronic F-127 (PF-127) gels containing Azone® and Transcutol® as penetration enhancers, through human skin in vivo. It was found that the combination of Azone® and Transcutol® in PF-127 gels enhanced sodium naproxen penetration, with enhancement ratios of up to two fold compared with the formulation containing only Transcutol®. These results were confirmed by TEWL and ATR-FTIR spectroscopy, suggesting a synergic action for Azone® and Transcutol®. Because of the thermo-reversible behavior of Pluronic gels, the influence of the components added to the gel formulations on viscosity, as a function of temperature, was also studied.     

PAA/PVA互穿网络水凝胶膜的制备和药物输送研究

采用自由基溶液聚合和连续的互穿网络技术,以氧化还原引发体系为引发剂、化学交联聚丙烯酸(PAA)和聚乙烯醇(PVA)制备了一系列PAA/PVA水凝胶膜.ATR-FTIR光谱表明,网络组成之间形成了新的相互作用的氢键,DSC分析表示网络组成具有良好的热力学相容性.膜在各种介质中的溶胀性质表明:因PAA的亲水性强于PVA,溶胀比随PAA的增多而提高.以阳离子化合物结晶紫为模板药物考察了在不同的pH缓冲溶液中的释放行为,结果表明,药物的释放能力可以通过改变体系的pH值加以调控.     

Controlled Release Camptothecin Tablets based on Pluronic and Poly(acrylic acid) Copolymer. Effect of Fabrication Technique on Drug Stability,Tablet Structure,and Release Mode

ABSTRACT

Poly(ethylene oxide)-b-poly(propylene oxide)-b-(polyethylene oxide)-g-poly(acrylic acid), a graft-comb copolymer of Pluronic® 127 and poly(acrylic acid) (Pluronic-PAA), was explored as an excipient for tablet dosage form of camptothecin (CPT). The tablets were prepared by either direct compression of the drug-polymer physical blend, suspension in ethanol followed by evaporation, or compression after kneading and characterized with respect to their physical structures, drug stability, and release behavior. Porosity and water uptake rate were strongly dependent on the fabrication procedure, ranking in the order: direct compression of physical blend > compression after suspension/evaporation in ethanol > compression after kneading. Tablets prepared by compression of physical blends swelled in water with a rapid surface gel layer formation that impeded swelling and disintegration of the tablets core. These tablets were able to sustain the CPT release for a period of time longer than those observed with the tablets made by either suspension/evaporation or kneading, which disintegrated within a few minutes. Despite the tablet disintegration, the CPT release was impeded for at least 6 hr, which was attributed to the ability of the Pluronic-PAA copolymers to form micellar aggregates at the hydrated surface of the particles. Physical mixing did not alter the fraction of CPT being in the pharmaceutically active lactone form, whilst the preparation of the tablets by the other two methods caused a significant reduction in the lactone form content. Tablets prepared from the physical blends demonstrated CPT release rates increasing with the pH due to the PAA ionization leading to the increase in the rate and extent of the tablet swelling. The results obtained demonstrate the potential of the Pluronic-PAA copolymers for the oral administration of chemotherapeutic agents.     

Evaluation of the percutaneous absorption of chlorpromazine from PLO gels across porcine ear and human abdominal skin

Objective: The overall objective of this work is to determine the percutaneous absorption of chlorpromazine hydrochloride from pluronic lecithin organogels (PLO gels) and verify the suitability of topically applied chlorpromazine hydrochloride PLO gels for use in hospice patients for relieving symptoms such as vomiting and nausea during the end stages of life.

Methods: PLO gels of chlorpromazine hydrochloride were prepared using isopropyl palmitate (IPP) or ricinoleic acid (RA) as oil phase. In vitro percutaneous absorption of chlorpromazine hydrochloride was assessed through porcine ear and human abdominal skin. Further, the theoretical steady state plasma concentration (C_ss) of chlorpromazine was calculated from the flux values.

Results: The pH, viscosity, and stability of both PLO gels prepared with IPP and RA were comparable. The thixotropic property of RA PLO gel was found to be better than that of IPP PLO gel. The permeation of chlorpromazine hydrochloride was higher from RA PLO gel than from IPP PLO gel and pure drug solution. Theoretical C_ss of chlorpromazine from pure drug solution, IPP PLO gel and RA PLO gel were found to be 1.05, 1.20, and 1.50?ng/ml, respectively. PLO gels only marginally increased the flux and theoretical C_ss of chlorpromazine.

Conclusion: From this study, it is clearly evident that PLO gels fail to achieve required systemic levels of chlorpromazine following topical application. Chlorpromazine PLO gel may not be effective in treating nausea and vomiting for hospice patients with swallowing difficulties.     

水滑石作为药物载体--萘普生的插层和缓释

水滑石(LDHs)是由带正电荷类水镁石层和层间的可交换阴离子组成的阴离子型粘土化合物,由于它的生物适应性,能够以它为主体,以药物为客体,插层组装成超分子结构复合物.抗炎药萘普生采用共沉淀法一步插层进入LDHs,用X射线衍射、红外光谱及热分析方法表征了超分子结构,表明层间距离扩大了,即萘普生已经插层组装成功,并且以单层、垂直作用在层间.萘普生柱撑水滑石的药物释放度在模拟肠液(pH7.4的缓冲液)条件下测定,结果表明萘普生柱撑水滑石释放速度降低,具有缓释作用,说明药物--无机混合物材料能够用作有效的药物传输系统.     

Development of a novel soft hydrogel for the transdermal delivery of testosterone

A soft hydrogel formulation for the transdermal delivery of testosterone (TS) was developed, and the effect of various skin-permeation enhancers was studied in vitro and in vivo. Testosterone was incorporated into a polyvinyl alcohol (PVA)-based soft hydrogel with polyisobutylene (PIB) and various skin-permeation enhancers (dodecylamine, HPE101, oleic acid, or lauric acid). In vitro rat-skin permeation of TS from the soft hydrogel was investigated using Keshary-Chien diffusion cells for 24 hr at 37°C. In vivo plasma-concentration profiles of TS after applying the soft hydrogel on the dorsal skin of rat were determined using a commercial radioimmunoassay kit. The formulated soft hydrogel formed a thin film on the skin within 2 to 3 min after application and remained in a dried-film state for at least 24 hr. Addition of PIB into the hydrogel to increase the adhesion resulted in a negligible reduction in the skin-permeation rate of TS. However, rat-skin permeation of TS increased with the addition of permeation enhancers both in vitro and in vivo. Dodecylamine at the concentration of 3% was the most effective among tested. Plasma concentration of TS significantly increased for at least 24 hr with the addition of dodecylamine. These results suggest the feasibility of the development of a soft hydrogel formulation for the transdermal delivery of TS.     

阳离子光敏抗菌型水凝胶的制备及性能表征

利用蒙脱土(MMT)分别吸附3种阳离子光敏剂(meso-四(1-甲基吡啶嗡-4-基)卟吩对甲苯磺酸盐(TMPyP)、meso-四(N-甲基-4-吡啶)卟吩四氯化锌(Zn-TMPyP)、亚甲基蓝(MB)),然后均匀分散在聚乙烯醇-苯乙烯基吡啶盐缩合物(PVA-SbQ)的水溶液中,通过紫外光交联法制备出相应的光敏MMT/PS水凝胶。借助透射电子显微镜(TEM)对MMT和MMT/PS形貌结构进行分析,利用扫描电子显微镜(SEM)、热重分析仪(TGA)对3种光敏水凝胶的内部形貌、热学性能进行分析,研究其溶胀性能及对金黄色葡萄球菌的抗菌效果。结果表明:3种光敏MMT/PS水凝胶均具有良好的溶胀性能。抗菌结果显示,三者对金黄色葡萄球菌均具有一定的杀灭效果,其中负载Zn-TMPyP的水凝胶在光照条件下对金黄色葡萄球菌的杀菌率达到98.49%。     

双氯灭痛壳聚糖水凝胶微球的制备及其性能研究

在Span80与植物油形成的反相胶束体系中,通过戊二醛交联制备出壳聚糖水凝胶微球(CHM)。采用红外光谱和透射电镜等方法对CHM结构及粒子形态进行了研究。同时对CHM的溶胀度及其对模型药物双氯灭痛的体外释放行为进行了考察。结果表明,CHM具有较好的控制药物释放的作用。交联程度对微球粒径、溶胀度及药物释放性能影响较大。     

Preparation and evaluation of mucin-gelatin mucoadhesive microspheres for rectal delivery of ceftriaxone sodium

Soluble mucin (S-mucin) processed from the small intestines (ileal region) of freshly slaughtered pigs via homogenization, dialysis, centrifugation and lyophilization and its admixtures with type A gelatin were dispersed in an aqueous medium and used to formulate ceftriaxone sodium-loaded mucoadhesive microspheres by the emulsification cross-linking method using arachis oil as the continuous phase. The release profile of ceftriaxone sodium from the microspheres was evaluated in both simulated gastric fluid (SGF) without pepsin (pH 1.2) and simulated intestinal fluid (SIF) without pancreatin (pH 7.4). The microspheres were further evaluated as possible novel delivery system for rectal delivery of ceftriaxone sodium in rats. Release of ceftriaxone sodium from the microspheres in both release media was found to occur predominantly by diffusion following non-Fickian transport mechanism and was higher and more rapid in SIF than in SGF. The results obtained from this study may indicate that ceftriaxone sodium could be successfully delivered rectally when embedded in microspheres formulated with either type A gelatin alone or its admixtures with porcine mucin; hence providing a therapeutically viable alternative route for the delivery of this acid-labile third generation cephalosporin.     

锌酞菁接枝温敏水凝胶的制备及光活性

将具有较高光催化活性的反应型锌酞菁负载到温敏聚合物——聚(N-异丙基丙烯酰胺)水凝胶载体上,制得一种新型的温敏高分子催化剂。研究了酞菁接枝水凝胶的温敏性能,发现其对温度有明显的依赖性和响应性。通过对α-萘酚进行光催化氧化实验,发现其在可见光照射下具有较高的光催化活性,气质分析得到其氧化产物主要是邻苯二甲酸。另外,循环实验表明该催化剂具有较好的稳定性,可重复使用。     

Development of novel pH-sensitive nanoparticles loaded hydrogel for transdermal drug delivery

Objective: Difference of pH that exists between the skin surface and blood circulation can be exploited for transdermal delivery of drug molecules by loading drug into pH-sensitive polymer. Eudragit S100 (ES100), a pH-sensitive polymer having dissolution profile above pH 7.4, is used in oral, ocular, vaginal and topical delivery of drug molecules. However, pH-sensitive potential of this polymer has not been explored for transdermal delivery. The aim of this research work was to exploit the pH-sensitive potential of ES100 as a nanocarrier for transdermal delivery of model drug, that is, Piroxicam.

Methods: Simple nanoprecipitation technique was employed to prepare the nanoparticles and response surface quadratic model was applied to get an optimized formulation. The prepared nanoparticles were characterized and loaded into Carbopol 934 based hydrogel. In vitro release, ex vivo permeation and accelerated stability studies were carried out on the prepared formulation.

Results: Particles with an average size of 25–40?nm were obtained with an encapsulation efficiency of 88%. Release studies revealed that nanoparticles remained stable at acidic pH while sustained release with no initial burst effect was observed at pH 7.4 from the hydrogel. Permeation of these nanocarriers from hydrogel matrix showed significant permeation of Piroxicam through mice skin.

Conclusion: It can be concluded that ES100 based pH-sensitive nanoparticles have potential to be delivered through transdermal route.     

Preparation and characterization of magnetic alginate-chitosan hydrogel beads loaded matrine

The aim of this study was to use alginate-chitosan (Alg-CS) hydrogel beads for developing an oral water-soluble drug delivery system, occupying pH-sensitive property and superparamagnetic. Matrine as a model drug was loaded in Alg-CS hydrogel beads to study the release character of the delivery system. The amount of matrine released from the beads was relatively low in pH 2.5 over 8?h (34.90%), but nearly all of the initial drug content was released in simulated intestinal fluid (SIF, pH 6.8) within 8?h. The results demonstrated that Alg-CS hydrogel beads possess unique pH-dependent swelling behaviors. In addition, the magnetic beads were characterized by Fourier transform infrared spectroscopy, scanning electron microscope, X-ray diffractometry and vibrating-sample magnetometry. Magnetometer measurements data suggested that Alg-CS beads also had superparamagnetic property as well as fast magnetic response. It can be expected that the beads can deliver and release encapsulated anticancer agent at the tumor by the weak magnetic field, and hence could be potential candidates as an orally administered drug delivery system.     

A novel vehicle for local protein delivery to the inner ear: injectable and biodegradable thermosensitive hydrogel loaded with PLGA nanoparticles

Delivery of biomacromolecular drugs into the inner ear is challenging, mainly because of their inherent instability as well as physiological and anatomical barriers. Therefore, protein-friendly, hydrogel-based delivery systems following local administration are being developed for inner ear therapy. Herein, biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) containing interferon α-2?b (IFN α-2?b) were loaded in chitosan/glycerophosphate (CS/GP)-based thermosensitive hydrogel for IFN delivery by intratympanic injection. The injectable hydrogel possessed a physiological pH and formed semi-solid gel at 37?°C, with good swelling and deswelling properties. The CS/GP hydrogel could slowly degrade as visualized by scanning electron microscopy (SEM). The presence of NPs in CS/GP gel largely influenced in vitro drug release. In the guinea pig cochlea, a 1.5- to 3-fold increase in the drug exposure time of NPs-CS/GP was found than those of the solution, NPs and IFN-loaded hydrogel. Most importantly, a prolonged residence time was attained without obvious histological changes in the inner ear. This biodegradable, injectable, and thermosensitive NPs-CS/GP system may allow longer delivery of protein drugs to the inner ear, thus may be a potential novel vehicle for inner ear therapy.     

聚天冬氨酸/聚醚共聚酰胺互穿网络水凝胶复合膜的制备及其性能研究

以聚琥珀酰亚胺(PSI)为改性剂,己二胺(HDA)为交联剂,通过原位交联及水解,制备了聚天冬氨酸/聚醚共聚酰胺(PAsp/PEBA)互穿网络水凝胶复合膜(PAsp/PEBA复合膜)。探讨了PAsp/PEBA复合膜的组成对膜吸水性能、水含量及其在膜中存在状态的影响;采用衰减全反射-红外光谱、扫描电镜及热重等手段对膜进行了表征。结果表明:PAsp组分的引入不但能有效调控PAsp/PEBA复合膜的含水率及其存在状态,而且能同时提高PEBA的力学性能,当PSI用量为15%(PSI占PEBA的质量分数),己二胺用量为3%时,复合膜的综合性能最优,吸水率可达32.01%,结合水含量为3.19%;拉伸强度和断裂伸长率分别比纯PEBA膜提高了21.80%和43.42%;SEM表明,当PSI用量为20%时,复合膜出现相分离。     

溶胶法原位复合聚乙烯醇/羟基磷灰石水凝胶的结构与性能研究

研究了制备聚乙烯醇(PVA)/羟基磷灰石(HA)复合水凝胶的溶胶法原位复合技术,将无机纳米粉体的溶胶-凝胶合成反应引入高分子基体。对该法制备的复合水凝胶的相结构、微观形貌和拉伸强度进行了分析,并与物理共混法复合水凝胶加以比较。结果表明,溶胶法原位复合可以在富水基体中制备晶相的HA粉体,且粉体粒径小于200nm,分散良好,复合材料的力学性能也有进一步改善。     

pH敏感水凝胶微球的制备及二甲酸钾缓释和抗菌性能分析

二甲酸钾(KDF)为抗生素的新型替代品,但在牲畜饲养中还未大量普及。采用水热法自制P型分子筛(Zeolite P),负载KDF分散在羧甲基纤维素(CMC)溶液中,与FeCl₃交联,利用凝聚法制备壳聚糖-羧甲基纤维素-P型分子筛-二甲酸钾pH敏感水凝胶抗菌微球。通过FT-IR,TGA和SEM分析可知,壳聚糖(CS)和CMC通过离子键形成结构稳定的聚电解质复合物,Zeolite P镶嵌缠绕在CMC基质中。溶胀差异性表明水凝胶微球具有高pH敏感性,可以适用不同pH条件下的持续给药。缓释动力学研究表明:抗菌微球对KDF具有一定的缓释作用,且遵循一级动力学释放模型和Higuchi模型。体外抗菌实验发现,抗菌液浓度为24 mg/mL和48 mg/mL时对大肠杆菌和金黄色葡萄球菌有显著的抗菌性,可以有效地抑制细菌的生长。     

纳米掺锶羟基磷灰石/聚乙烯醇/明胶复合水凝胶的制备及矿化性能研究

采用化学沉淀法制备纳米纳米掺锶羟基磷灰石(Sr-HAP)粉体,通过物理法工艺加入聚乙烯醇(PVA)和明胶溶液,经反复冷冻-解冻制备纳米掺锶羟基磷灰石/聚乙烯醇/明胶(Sr-HAP/PVA/明胶)复合水凝胶。利用红外光谱、X射线衍射、扫描电镜对产物的结构进行分析,采用模拟体液法对复合凝胶产物的再矿化行为进行分析。结果表明:实验所制备的复合水凝胶组成均一,凝胶内部Sr-HAP分散良好、分布均匀,且含有大量网状结构,符合理想组织工程支架材料高孔隙率的要求。产物在模拟体液中浸泡15d后,经扫描电镜分析发现凝胶表面有沉积物生成,X射线衍射检测表面沉积物含有类似HAP的物质,说明复合凝胶具有诱导性,有望作为软骨或组织修复材料进一步研究。     

A comparative study of chitosan and poloxamer based thermosensitive hydrogel for the delivery of PEGylated melphalan conjugates

Abstract

Objective: Although the melphalan (ML) used extensively for the management of breast cancer, its clinical application is limited due to significant hemolytic activity. In the present work, a comparative analysis of two distinct in situ-based thermogelling polymers of PEGylated ML was performed.

Methods: Briefly, the PEGylated conjugate of the melphalan (MLPEG 5000) for local and sustained drug release action is loaded into two different thermogelling polymeric systems, namely chitosan- and poloxamer-based systems. The synthesized conjugate was loaded to a chitosan (MLP 5000) and poloxamer-based (MPX-CG) thermogelling injectable hydrogels. These thermogelling hydrogels were evaluated for in vitro hydrolysis, in vitro hemolytic activity. and in vitro anticancer activity.

Results: The lower percent cumulative hydrolysis was witness for both the hydrogels. MPX-CG and MLP 5000 hydrogels as predicted had shown lower percent cumulative hydrolysis of 3.31?±?0.1 and 1.67?±?0.1 after 6?h. The percentage hemolysis of MPX-CG and MLP 5000 even at a concentration of 32?µg/ml was found to be 39.23?±?1.24% and 34.23?±?2.24%, observed at 1?h, respectively. Both the hydrogels showed similar anticancer pattern, the MPX-CG hydrogel showed low cell viability of 8.4?±?1.1% at a concentration of 150?µM and the MLP-5000 hydrogel showed slight higher cell viability (13.12?±?5.4%) as compared with MPX-CG hydrogel.

Conclusion: Hence, from the present study it can be well understood that both the chitosan- and the poloxamer-based thermogelling hydrogel proves to be an effective drug delivery systems for the delivery of the PEGylated conjugates.     

Preparation and characterization of silk fibroin hydrogel as injectable implants for sustained release of Risperidone

The principal objective of the present study is to achieve a depot formulation of Risperidone by gelation of silk fibroin (SF). For this purpose, hydrochloric acid (HCl)/acetone-based and methanol-based hydrogels were prepared with different drug/polymer ratios (1:3, 1:6, and 1:15). For all the drug-loaded methanol-based hydrogels, gel transition of SF solutions occurred immediately and the gelation time was 1?min, while the gelation time of HCL/acetone-based hydrogels was around 360?min. According to the results obtined from Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD) spectra, solvent systems and Risperidone could induce β-sheet structure, but HCL/acetone system had the lowest effect on induction of β-sheets. The crystallinity was increased by increasing the amount of Risperidone, and drug to polymer ratio of 1:3 possessed the highest crystallinity. Thermogravimetric analysis (TGA) indicated that increasing the amount of drug in formulation increased the stability of hydrogels, and methanol-based hydrogel with a ratio of 1:3 had the most stable structure. The release rate of Risperidone from methanol-based hydrogel at ratio of 1:3 was lower than that for HCl/acetone-based one, and it decreased by increasing the amount of Risperidone. The release of Risperidone from methanol hydrogel at ratios 1:3 and 1:6 continued up to 25?d which is acceptable for depot form of Risperidone and shows that the extended release of Risperidone was achieved successfully. In conclusion, SF hydrogel with the ability to respond to the environmental stimuli is an excellent candidate for injectable implants for extended release of Risperidone.