球结膜下注射用西罗莫司缓释微球的制备及其体外释药性能

目的使用3-羟基丁酸-co-3-羟基戊酸共聚物制备西罗莫司缓释微球,为预防和治疗角膜移植术后免疫排斥反应奠定基础。方法采用乳化-溶剂挥发法制备微球,正交实验法优化,测得载药量、包封率等指标,结合光镜观察其形态特征,得出最佳制备条件后,模拟眼内前房环境检测其体外释药性能。结果微球制备工艺稳定,重复性好。微球成球率高,形态圆整,表面光滑,载药量为(37.34±1.25)%,包封率为(99.63±0.93)%,能够在体外稳定缓释,500 h累积释药率为71%。结论西罗莫司缓释微球表征良好,载药量、包封率较高,有望发挥稳定释药的临床作用。     

Preparation,statistical optimisation and in vitro characterisation of poly (3-hydroxybutyrate-co-3-hydroxyvalerate)/poly (lactic-co-glycolic acid) blend nanoparticles for prolonged delivery of teriparatide

The purpose of this study was the preparation, optimisation and in vitro characterisation of PHBV and PLGA blend nanoparticles (NPs) for prolonged delivery of Teriparatide. Double emulsion solvent evaporation technique was employed for the fabrication of NPs. The nanoformulation was optimised using the Box–Behnken methodology. The morphological properties of NPs were assessed by both SEM and transmission electron microscopy (TEM). Encapsulation of Teriparatide within the NPs and lacking of chemical bonds between drug and copolymers were proved by XRPD, FTIR and DSC. The structural stability of Teriparatide after processing was confirmed by fluorescence spectrometry. The average size of optimised NPs was 250.0?nm with entrapment efficiency (EE) of 89.5% and drug loading (DL) of 5.0%. Teriparatide release from optimised NPs led to 64.4% release over 30 days and it showed a diffusion-based mechanism. Based on the favourable results, PHBV/PLGA blend NPs could be a promising candidate for designing a controlled release formulation of Teriparatide.     

Application of Artificial Neural Networks in the Design and Optimization of a Nanoparticulate Fingolimod Delivery System Based on Biodegradable Poly(3-Hydroxybutyrate-Co-3-Hydroxyvalerate)

Formulation of a nanoparticulate Fingolimod delivery system based on biodegradable poly(3-hydroxybutyrate-co-3-hydroxyvalerate) was optimized according to artificial neural networks (ANNs). Concentration of poly(3-hydroxybutyrate-co-3-hydroxyvalerate), PVA and amount of Fingolimod is considered as the input value, and the particle size, polydispersity index, loading capacity, and entrapment efficacy as output data in experimental design study. In vitro release study was carried out for best formulation according to statistical analysis. ANNs are employed to generate the best model to determine the relationships between various values. In order to specify the model with the best accuracy and proficiency for the in vitro release, a multilayer percepteron with different training algorithm has been examined. Three training model formulations including Levenberg-Marquardt (LM), gradient descent, and Bayesian regularization were employed for training the ANN models. It is demonstrated that the predictive ability of each training algorithm is in the order of LM > gradient descent > Bayesian regularization. Also, optimum formulation was achieved by LM training function with 15 hidden layers and 20 neurons. The transfer function of the hidden layer for this formulation and the output layer were tansig and purlin, respectively. Also, the optimization process was developed by minimizing the error among the predicted and observed values of training algorithm (about 0.0341).     

Design and evaluation of thermoreversible in situ gelling system of forskolin for the treatment of glaucoma

The contact time of a vehicle on the cornea is of utmost importance for ophthalmic drug delivery. The poor bioavailability and therefore poor therapeutic response exhibited by the conventional ophthalmic solutions due to pre-corneal elimination of a drug may be overcome by the use of the in situ gel forming systems, which upon instillation as drops into the eye, undergo a sol-gel transition in the cul-de-sac. The purpose of this work was to develop an ophthalmic delivery system of the forskolin, based on the concept of temperature activated in situ gelation. Poloxamer 407 (Pluronic F-127) is a block copolymer made of poly (oxy ethylene) and poly (oxy propylene). The sol-gel transition is induced by an increase in temperature; however, it depends on the concentration of the polymer and presence of other additives. The developed formulations were therapeutically efficacious (on albino New Zealand rabbit model); reducing intra ocular pressure (IOP) for 12 hours and showed sol-gel phase transition (gelling) temperature of 22°C and sustained drug release 72%?±?0.056% in vitro behavior over a period of 4?h.     

多肽及蛋白质类药物智能化原位凝胶控释给药系统研究进展

本文综述了国内外近年来多肽及蛋白质类药物智能化原位凝胶控释给药系统的研究进展,主要包括温敏型、pH敏感型、电场驱动型及复合型智能化原位凝胶控释新剂型、新技术研究进展。     

原位凝胶应用于眼部给药系统的研究进展

介绍原位凝胶在眼部给药系统中的研究新方法和新进展,以及原位凝胶的不同胶凝机理,分析胶化过程和眼部应用时的影响因素。原位凝胶滴眼剂可以显著延长药物释放,提高药物生物利用度。原位凝胶滴眼剂作为一种新型眼部药物新剂型,具有良好的应用前景。     

Bioerodible injectable poly(ortho ester) for tetracycline controlled delivery to periodontal pockets: Preliminary trial in humans

The semisolid consistency of poly(ortho esters) (POEs) containing tetracycline free base allows direct injection in the periodontal pocket and shows sustained and almost constant in vitro release in phosphate buffer, pH 7.4 at 37°C, for up to 14 days. Total polymer degradation concomitant with drug release was obtained. Formulations containing 10% or 20% (wt/wt) tetracycline were evaluated in a panel of 12 patients suffering from severe and recurrent periodontitis. In the first trial including 6 patients, single-rooted teeth and molar teeth with furcations were treated immediately after scaling and root planing. Patients tolerated both formulations well, experienced no pain during application, and showed no signs of irritation or discomfort during the observation period. However, retention of the formulation was minimal in this first study. An improved clinical protocol followed in the second study (stopping bleeding after scaling and root planning) prolonged the retention of the formulations in the inflamed periodontal pockets. For up to 11 days, tetracycline concentrations in the gingival crevicular fluid were higher than the minimum inhibitory concentration of tetracycline against most periodontal pathogens.     

Alginate-based sustained release drug delivery systems for tuberculosis

Drug delivery systems have wide biomedical applications owing to their distinct therapeutic advantages, such as controlled release of drugs over prolonged periods, protection against premature drug degradation, reduction in drug toxicity and drug–drug interactions. All these factors are important considerations in the treatment of chronic infectious diseases such as tuberculosis. In tuberculosis, patient non-compliance is a vexing problem which is responsible not only for treatment failure, but also for the emergence of multi-drug resistant cases. Alginate, a natural polymer, has attracted researchers owing to its ease of availability, compatibility with hydrophobic as well as hydrophilic molecules, biodegradability under physiological conditions, lack of toxicity and the ability to confer sustained release potential. It is not therefore surprising that the controlled release phenomenon of this polymer has been documented for a vast array of drugs. In particular, the ability of alginate to co-encapsulate multiple antitubercular drugs and offer a controlled release profile is likely to have a major impact in enhancing patient compliance for better management of tuberculosis.     

A glucose-triggered solubilizable polymer gel matrix for an insulin delivery system

A poly(acrylamidophenylboronic acid-co-acrylamide) (poly(AAPBA-co-AAM) gel was synthesized using diglucosylhxanediamine (DGHDA) as a croslinking agent in order to prepare a glucose-responsive insulin delivery system. The system described here is a water-soluble polymer gel matrix whose erosion rate is glucose-dependent. At physiological pH, in the absence of glucose, anionic tetrahedral complexes between boronic acid moieties of the poly(AAPBA-co-AAM) and glucose moieties of DGHDA were maintained and the release rate of entrapped insulin was low. In the presence of glucose, however, the gel matrix was disrupted by replacement of DGHDA with glucose through competitive binding to boronic acid, resulting in the rapid solubilization of the matrix and a significant increase in the release rate of insulin.     

Bioadhesive film formed from a novel organic-inorganic hybrid gel for transdermal drug delivery system

A novel organic-inorganic hybrid film-forming agent for TDDS was developed by a modified poly(vinyl alcohol) (PVA) gel using γ-(glycidyloxypropyl)trimethoxysilane (GPTMS) as an inorganic-modifying agent, poly(N-vinyl pyrrolidone) (PVP) as a tackifier and glycerol (GLY) as a plasticizer. The prepared gels can be applied to the skin by a coating method and in situ form very thin and transparent films with good performance, comfortable feel and cosmetic attractiveness. The key properties of the bioadhesive films produced from the hybrid gels were investigated and the results showed that the incorporation of appropriate GPTMS (GPTMS/(PVA + GPTMS) in the range of 20-30%) into the PVA matrix not only can significantly enhance mechanical strength and skin adhesion properties of the resultant film, but also can decrease the crystalline regions of PVA and hence facilitate the diffusion of water vapor and drug. Furthermore, the investigations into in vivo skin irritation suggested the films caused non-irritation to skin after topical application for 120 h. In conclusion, the bioadhesive films formed from organic-inorganic hybrid gels possessed very good qualities for application on the skin and may provide a promising formulation for TDDS, especially when the patient acceptability from an aesthetic perspective of the dosage form is a prime consideration.     

The effective combination therapy against human osteosarcoma: doxorubicin plus curcumin co-encapsulated lipid-coated polymeric nanoparticulate drug delivery system

Objective: To overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure incurred from multidrug resistant (MDR) in osteosarcoma (OS), biodegradable lipid-coated polymeric nanoparticles (LPNs) were explored for the loading of doxorubicin (DOX) and curcumin (CUR).

Methods: DOX plus CUR co-encapsulated LPNs (DOX?+?CUR LPNs) of mixed lipid monolayer shell and biodegradable polymer core were prepared. The cytotoxicity effect of DOX?+?CUR LPNs, single drug loaded LPNs, and free drug solutions were evaluated on human OS cell line KHOS cells and mice KHOS cells xenograft in vivo.

Results: DOX?+?CUR LPNs displayed a curative effect on OS cell lines than the free drug counterparts. Also, best anti-OS effects were observed on the animal model compared with other groups tested.

Conclusion: This promising dual drugs co-encapsulated lipid-coated polymeric nanoparticulate drug delivery system enhanced the cell delivery and activity of drugs against human OS cancer cell lines and in cancer bearing mice. This research may offer new options for the treatment of OS.     

Microencapsulation of antibiotic rifampicin in poly(3-hydroxybutyrate-co-3-hydroxyvalerate)

The aim of this study was the preparation of microparticles containing rifampicin using a biodegradable polymer poly(3-hydroxybutyrate-co-3-hydroxyvalerate) for oral administration produced by a bacteria. The poly(3-hydroxybutyrate-co-3-hydroxyvalerate) microparticles with and without rifampicin were prepared by the emulsification and solvent evaporation method, in which chloroform and polyvinyl alcohol are used as the solvent and emulsifier, respectively. Microparticles were obtained within a size range of 20-60 μm by changing the initial poly(3-hydroxybutyrate-co-3-hydroxyvalerate), polyvinyl alcohol and rifampicin concentrations. An encapsulation efficiency value of 14% was obtained. The optimized total yield of 60% of the poly(3-hydroxybutyrate-co-3-hydroxyvalerate)/ rifampicin was obtained. A load of 0.035 mg/1 mg of PHBV was reached. Almost 90% of the drug loaded in the microparticles was released after 24 h. The size, encapsulation efficiency and ribampicin release of the microparticles varied as a function of the initial poly(3-hydroxybutyrate-co-3-hydroxyvalerate), polyvinyl alcohol and rifampicin concentrations. It was demonstrated that the microencapsulated rifampicin, although was not totally available in the medium, exhibited a similar inhibition value as free rifampicin at 24 h of incubation with S. aureus. Cytotoxicity assays demonstrated a reduction of the toxicity when rifampicin was microencapsulated in poly(3-hydroxybutyrate-co-3-hydroxyvalerate) while maintaining its antibacterial activity.     

Study of a pingyangmycin delivery system: Zein/Zein-SAIB in situ gels

Venous malformations (VM) are common vascular abnormality, and their management remains difficult. Pingyangmycin hydrochloride (PYM) is a useful sclerosant to treat venous malformations. This study was aimed to evaluate the effect of a new drug delivery system, PYM-loaded Zein/Zein-sucrose acetate isobutyrate (SAIB) in situ gels, in gelling and extending the local release of PYM. It was demonstrated that in vitro and in vivo release of PYM from the in situ gels could be extended up to 7 and 4 days, respectively. SAIB could significantly cut down the initial burst of PYM from the in situ gels (P<0.05). The possible gel forming and drug release mechanisms were described according to the morphology analysis by atomic force microscopy (AFM), optical microscopy and SEM. The gel forming efficacy and the viscosity of in situ gel solutions were satisfying.     

大蒜素自微乳的制备与质量评价

目的:制备大蒜素(DATS)自微乳制剂,并评价其质量.方法:采用伪三元相图法,以聚氧乙烯氢化蓖麻油RH-40为表面活性剂,无水乙醇为助表面活性剂,油酸为油相,绘制该系统的相图,在此基础上制备DATS自微乳;建立HPLC法测定DATS自微乳中DATS的含量;对自微乳的外观性状、相对密度、黏度、pH值、电导率、形态、粒径及粒度分布、Zeta电位、含量、配伍和稳定性等进行研究.结果:DATS自微乳为无色澄明液体,稳定性良好,相对密度为0.840 g·mL-1,黏度为5.447 mPa·s,遇水形成O/W型微乳,稀释250倍后电镜下观察成圆球形,平均粒径26.4 nm,Zeta电位0.398 mV,pH值5.62,电导率为8.37μs·cm-1,3批制剂的含量分别为31.77,31.45,32.15 mg·mL-1.DATS自微乳与葡萄糖注射液、氯化钠注射液等配伍稳定.结论:DATS自微乳制备工艺简单,性质稳定,质量易控.     

温敏性壳聚糖凝胶的阿霉素药物体外缓释研究

目的 壳聚糖辅以甘油磷酸钠制成温敏性凝胶，将该温敏性凝胶用作阿霉素药物栽体并观察其缓释特性。方法 制备负载阿霉素的温敏性壳聚糖凝胶，建立体外持续流动释放系统，应用紫外分光光度法测定阿霉素的含量，对该栽药凝胶进行体外的缓释实验。结果 制备了负载阿霉素的温敏性壳聚糖凝胶，并得到了其缓释曲线。结论 该温敏性凝胶能够用于负载并释放阿霉素，这为改善阿霉素使用途径提供了实验基础。     

Folate-decorated poly(3-hydroxybutyrate-co-3-hydroxyoctanoate) nanoparticles for targeting delivery: optimization and in vivo antitumor activity

Abstract

Context: Doxorubicin (DOX)-loaded folate-targeted poly(3-hydroxybutyrate-co-3-hydroxyoctanoate) [P(HB-HO)] nanoparticles [DOX/FA-PEG-P(HB-HO) NPs] have potential application in clinical treatments for cervical cancer due to specific affinity of folate and folate receptor in HeLa cells.

Objective: The aim of this study was to develop an optimized formulation for DOX/FA-PEG-P(HB-HO) NPs, and investigate the targeting and efficacies of the nanoparticles.

Materials and methods: DOX/FA-PEG-P(HB-HO) NPs were prepared by W₁/O/W₂ solvent extraction/evaporation method, and an orthogonal experimental design [L₉ (3⁴)] was applied to establish the optimum conditions. The physico–chemical characteristics, microscopic observation and in vivo antitumor study of the nanoparticles were evaluated.

Results: The optimum formulation was obtained with DOX 10% (w/v), FA-PEG-P(HB-HO) 6.5% (w/v), PVA 3%(w/v) and oil phase/internal water phase volume ratio of 3/1. The size distribution, drug loading and encapsulation efficiency of the optimized nanoparticles were 150–350?nm, 29.6?±?2.9% and 83.5?±?5.7%, respectively. In vitro release study demonstrated that 80% of the drug could release from the nanoparticles within 11 days. Furthermore, in vitro microscopic observation and in vivo antitumor study showed that DOX/FA-PEG-P(HB-HO) NPs could inhibit HeLa cells effectively, and the tumor inhibition rate (TIR) in vivo was 76.91%.

Discussion and conclusions: DOX/FA-PEG-P(HB-HO) NPs have been successfully developed and optimized. In vitro drug release study suggested a sustained release profile. Moreover, DOX/FA-PEG-P(HB-HO) NPs could effectively inhibit HeLa cells with satisfying targeting, and reduce side effects and toxicity to normal tissues. DOX/FA-PEG-P(HB-HO) NPs were superior in terms of inhibiting HeLa tumor over non-targeted formulations therapy.     

Novel chronotherapeutic rectal aminophylline delivery system for therapy of asthma

The aim of this study was to develop a new chronotherapeutic pharmaceutical preparation as a sustained-release suppository for prevention and therapeutic use against bronchial asthma in the early morning. Sustained-release hollow-type (SR-HT) suppositories using sodium alginate (Alg-Na), sodium polyacrylate (PANa) or polyacrylate-PANa co-polymer (PA-PANa) as gelling polymers (gel agent) were prepared and pharmaceutical characteristics of these suppositories were investigated. Type A SR-HT suppositories comprised a suppository shell prepared with oleaginous base and containing aminophylline only or aminophylline with Alg-Na or PANa in the cavity (hollow space). Type B SR-HT suppositories comprised a suppository shell prepared with oleaginous base and gel agent (30%), with aminophylline in the hollow space. In drug-release studies, the acrylate polymer-containing suppositories showed linearity of delayed release rate, providing significantly decreased the highest concentration of theophylline in plasma (C_max) and delayed the time required to reach C_max (t_max) and the mean residence time (MRT) after rectal administrated in rabbits. In particular, suppositories containing PA-PANa maintained significantly higher theophylline concentrations than control suppositories at 12 h after rectal administration. Furthermore, histopathological examination indicated that these suppositories using acrylate polymers did not result in rectal lesions. The SR-HT suppository, particularly using PA-PANa as a gel agent, may thus be useful against nocturnal symptoms of asthma. In this study, we confirmed new formulation of sustained-release suppository for chronotherapy of theophylline using oily base material in combination with polymer such as PA-PANa. The hollow-type suppository containing oleaginous base and hydrophilic polymer in the shell could be useful device for rectal administration of various drugs with prolongation of plasma concentration.     

中药靶向制剂研究进展

检索了近5年(1999-2004年)来万方、维普、CNKI、PubMed和ScienceDirect数据库中有关中药靶向制剂研究的文献,井对其进行了综合分析和总结.从微球制剂、复合性乳剂以及脂质体三方面对中药靶向制剂的研究进展作了介绍和展望.指出了中药靶向制剂研究存在的问题与进一步研究的建议.中药靶向制剂的研究切实可行,并且具有其独特的临床意义和优势.