Nanoparticulate delivery system of a tyrphostin for the treatment of restenosis.

Restenosis, the principal complication of percutaneous transluminal coronary angioplasty is responsible for the 35-40% long-term failure rate following coronary revascularization. The neointimal formation, a morphological substrate of restenosis, is dependent on smooth muscle cells (SMC) proliferation and migration. Signal transduction through the platelet-derived growth factor (PDGF)/PDGF receptors system is involved in the process of post-angioplasty restenosis. The unsuccessful attempts to control restenosis by systemic pharmacological interventions have prompted many researchers to look for more promising therapeutic approaches such as local drug delivery. Tyrphostins are low molecular weight inhibitors of protein tyrosine kinases. We assessed the release kinetics and in vivo effects of nanoparticles containing PDGF-Receptor beta (PDGFRbeta) tyrphostin inhibitor, AG-1295. AG-1295-loaded poly(DL-lactide) (PLA) nanoparticles were prepared by spontaneous emulsification/solvent displacement technique. In vitro release rate and the impact of drug/polymer ratio on the nanoparticle size were determined. The degree of tyrosine phosphorylation was assessed by Western blot with phosphotyrosine-specific antibody in rat SMC extracts. Several bands characteristic of PDGF BB-stimulated SMC disappeared or weakened following tyrphostin treatment. Local intraluminal delivery of AG-1295-loaded PLA nanoparticles to the injured rat carotid artery had no effect on proliferative activity in medial and neointimal compartments of angioplastisized arteries, indicating a primary antimigration effect of AG-1295 on medial SMC.     

Hydrotropic agents for study of in vitro paclitaxel release from polymeric micelles.

A new experimental method for in vitro release studies of poorly soluble drugs from polymeric micelle systems was developed using a hydrotropic agent, sodium salicylate. It is difficult to maintain a good sink condition for poorly water-soluble drugs, such as paclitaxel (PTX), because of their low aqueous solubility. In this study, a good sink condition for PTX was achieved by using aqueous sodium salicylate solution which solubilized more than 10 times the total amount of PTX incorporated in polymeric micelles. Sodium salicylate at 1 M concentration increased the aqueous PTX solubility by 100 times without destroying the micellar structure of poly(ethylene glycol)-block-poly(phenylalanine) (PEG-b-PPhe) copolymer. PTX was continuously released from PEG-b-PPhe micelles in the hydrotropic release medium. The hydrotropic solution presents a simple method for studying in vitro release behavior of poorly soluble drugs from polymeric micelles in aqueous media.     

Cervical cancer treatment with a locally insertable controlled release delivery system.

Local delivery of cancer chemotherapeutics enables sustained drug levels at the site of action thereby reducing systemic side effects. A novel insertable polymeric drug delivery system for cervical cancer treatment is presented. Cisplatin, the first line of therapy employed for cervical cancers, was incorporated in a poly(ethylene-co-vinyl acetate) (EVAc) device that is similar to those currently used for vaginal contraceptive delivery. Cisplatin crystals were uniformly dispersed in the polymeric system without undergoing significant dissolution in the polymer matrix. Cisplatin dissolution from the devices was biphasic, consistent with a matrix-type controlled-release system with an initial rapid release phase followed by a slower, near linear release phase. Depending on the drug loading in the polymeric devices, the near-linear release phase varied in rate according to both empirical, linear curve-fitting (0.38+/-0.15 microg/day to 46.9+/-10.0 microg/day) and mechanistic, diffusion analysis based upon diffusion through a porous structure (D(app) from 1.3+/-0.5 x 10(-9) cm2/s to 5.8+/-0.3 x 10(-12) cm2/s). The devices were tested for in vitro activity and found to be effective against both HPV positive and HPV negative cervical cancer cell lines. Preliminary studies indicate that this delivery system would be a good candidate for investigation as a choice of treatment in cervical cancers.     

Influence of silicone elastomer solubility and diffusivity on the in vitro release of drugs from intravaginal rings.

The in vitro release characteristics of eight low-molecular-weight drugs (clindamycin, 17beta-estradiol, 17beta-estradiol-3-acetate, 17beta-estradiol diacetate, metronidazole, norethisterone, norethisterone acetate and oxybutynin) from silicone matrix-type intravaginal rings of various drug loadings have been evaluated under sink conditions. Through modelling of the release data using the Higuchi equation, and determination of the silicone solubility of the drugs, the apparent silicone elastomer diffusion coefficients of the drugs have been calculated. Furthermore, in an attempt to develop a quantitative model for predicting release rates of new drug substances from these vaginal ring devices, it has been observed that linear relationships exist between the log of the silicone solubility of the drug (mg x ml(-1)) and the reciprocal of its melting point (K(-1)) (y=3.558x-9.620, R=0.77), and also between the log of the diffusion coefficient (cm(2) s(-1)) and the molecular weight of the drug molecule (g x mol(-1)) (y=-0.0068x-4.0738, R=0.95). Given that the silicone solubility and silicone diffusion coefficient are the major parameters influencing the permeation of drugs through silicone elastomers, it is now possible to predict through use of the appropriate mathematical equations both matrix-type and reservoir-type intravaginal ring release rates simply from a knowledge of drug melting temperature and molecular weight.     

New drug delivery system for water-soluble drugs using silicone and its usefulness for local treatment: application of GCV-silicone to GCV/HSV-tk gene therapy for brain tumor.

Controlled release of a water-soluble low-molecular-weight drug from silicone and its usefulness as a local therapeutic drug were studied. For application to ganciclovir/helpes simplex virus thymidine kinase (GCV/HSV-tk) suicide gene therapy for brain tumor, two kinds of GCV-containing silicone formulations were prepared for evaluation. In vitro, GCV release from matrix-type formulation consisting of a single matrix was characterized by Fickian diffusion, while covered-rod-type formulation, in which the side surface of the outer layer was covered with 100% silicone, exhibited a near-zero-order release pattern. In an in vivo study using a rat 9L glioblastoma model, administration of GCV-silicone formulation into brain tumor yielded sustained intracerebral GCV concentration for 4 days after administration, with excellent antitumor effect equal to or better than that of daily intraperitoneal administration of aqueous solution of GCV, at a dose less than 1/100 of the total dose of solution for intraperitoneal administration. Furthermore, GCV was undetectable in blood, suggesting that decrease in systemic adverse reactions can be expected with intracerebral administration of GCV-silicone formulation.     

Microstructure and release characteristics of the minipellet, a collagen-based drug delivery system for controlled release of protein drugs.

We have developed the minipellet, a matrix-type system for the sustained delivery of protein drugs using collagen as a biodegradable drug carrier. In this study, we analyzed the microstructure and release profile of the minipellet containing human serum albumin (HSA) as a model drug.The findings suggest that the minipellet has a structure in which collagen fibers are strongly oriented in the direction of extrusion from the nozzle in the molding process of the minipellet, and that HSA exists as fine particulate clusters which are homogeneously distributed among the collagen fibers in the minipellet. During release, the HSA clusters dissolve and HSA is retained within the collagen matrix as a solution.The results of release experiments indicate that HSA release from the minipellet is mainly controlled by diffusion in the collagen matrix, and that sustained release is achieved by the dense structure of the collagen matrix which is formed in the manufacture process. In addition, more detailed study suggests that the minipellet has unique directional release behavior caused by its microstructure.     

Calcium silicate based microspheres of repaglinide for gastroretentive floating drug delivery: preparation and in vitro characterization.

Gastroretentive dosage forms have potential for use as controlled-release drug delivery systems. Multiple unit systems avoid the 'all-or-none' gastric emptying nature of single-unit systems. A controlled release system designed to increase its residence time in the stomach without contact with the mucosa was achieved through the preparation of floating microspheres by the emulsion solvent diffusion technique consisting of (i) calcium silicate (FLR) as porous carrier; (ii) repaglinide, an oral hypoglycemic agent; and (iii) Eudragit S as polymer. The effect of various formulation and process variables on the internal and external particle morphology, micromeritic properties, in vitro floating behavior, physical state of the incorporated drug, drug loading and in vitro drug release were studied. The microparticles were found to be regular in shape and highly porous. The release rate was determined in simulated gastro-intestinal fluids at 37 degrees C. The formulation demonstrated favorable in vitro floating and release characteristics. The drug encapsulation efficiency was high. Incorporation of FLR in the microspheres proved to be an effective method to achieve the desired release behavior and buoyancy. The designed system, combining excellent buoyant ability and suitable drug release pattern, could possibly be advantageous in terms of increased bioavailability of repaglinide.     

药物控释载体材料的性质

学术背景：将药物或其他的活性物质与适当的载体按一定的形式制成的药物控释制剂己成为药学领域的重要发展方向，然而不同性质的药物载体材料具有不同的药物释放行为，为了获得令人满意的释药速率，新型药物载体材料的研究成为近年来的研究重点。目的：介绍几种用作药物载体的材料，分析材料的性质及其在药物控释中的应用。检索策略：由该论文作者应用计算机检索中国期刊全文数据库1998—01／2007—06的相关文献，检索词：“高分子水凝胶，聚乳酸，壳聚糖，丝素蛋白，药物控释，药物载体”，限定文章语言种类为中文。纳入标准：①不同类型药物载体材料的制备及性能：②不同类型药物载体材料的药物控释性研究。排除标准：较陈旧的文献。文献评价：共检索到86篇相关文章，28篇符合标准，其中10篇为综述，其余为临床或基础实验研究。资料综合：①目前用作药物载体的材料主要包括高分子凝胶、聚乳酸（PLA），乳酸-羟基乙酸（PLGA）、壳聚糖及其衍生物、丝素蛋白等。②智能高分子水凝胶对温度、酸度、压力、光等引起的刺激，能及时地作出溶胀和收缩应答的智能效应，这种特殊的环境敏感性使它被广泛地应用于药物缓释体系。③聚乳酸和聚乳酸-羟基乙酸是一种生物可降解高分子材料，具有生物相容性、生物可降解性、降解产物无毒等优点，用作药物控释载体材料时，可通过调节聚乳酸的降解速率改变释放速率，提高药效。④壳聚糖具有很好的吸附性、成膜性和通透性，较低相对分子质量的水溶性壳聚糖更易在体内降解，不易积聚，以壳聚糖为载体材料制备纳米粒、微球等给药系统是近年来的研究热点。⑤天然高分子材料丝素蛋白无毒、无刺激，具有良好的物理、化学、生物学性能，与人体有较好的组织相?     

两种普朗尼克材料联合聚氰基丙烯酸正丁酯载紫杉醇的控药释放能力

背景：包含普朗尼克P123的载紫杉醇聚合物胶束能够有效的延长药物体内循环时间,并且能够改变紫杉醇的作用靶位.但是,这种紫杉醇聚合物胶束在溶液中的稳定性以及载药能力仍有待提高. 目的：观察载紫杉醇聚氰基丙烯酸正丁酯-普朗尼克P123/F68胶束的药剂学特性和体外抗肿瘤能力.方法：采用薄膜水化法,以聚氰基丙烯酸正丁酯为交联剂,普朗尼克P123/F68为载体材料,制备载疏水性药物-紫杉醇纳米胶束.应用透射电镜观察胶束形态;电位粒度分析仪测定胶束电位和粒径;高效液相色谱分析方法测定胶束载药量和包封率;荧光探针法测定胶束临界胶束浓度;体外试验考察胶束的释药情况、稳定性以及抗肿瘤情况. 结果与结论：实验制备的载药胶束为圆形,粒径和电位分别在100 nm和-10 mV左右,包封率和载药量为（93.3±2.15）%和（1.82±0.04）%,临界胶束浓度为0.067 g/L.药物体外释放试验和稳定性试验显示,该载药胶束具有一定的缓释功能和抗稀释能力.MTT试验结果表明,与游离药物相比,载药胶束具有更强的杀伤乳腺癌细胞MCF-7的能力.可见,载紫杉醇聚氰基丙烯酸正丁酯-普朗尼克P123/F68胶束具有明显的控制药物释放的能力和良好的稳定性,抗肿瘤能力强.     

Micelles of methoxy poly(ethylene oxide)-b-poly(epsilon-caprolactone) as vehicles for the solubilization and controlled delivery of cyclosporine A.

The commercial formulation of Cyclosporine A (CsA) for intravenous administration contains Cremophor EL, a low molecular weight surfactant known to be toxic. In this study, micelles of methoxy poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PEO-b-PCL) were investigated as alternative vehicles for the solubilization and delivery of CsA. PEO-b-PCL block copolymers having identical PEO chain lengths and PCL molecular weights of 5000, 13,000, or 24,000 g mol(-)(1) were synthesized and assembled into polymeric micelles using a co-solvent evaporation method. PEO-b-PCL micelles were then compared to Cremophor EL micelles for their functional properties in drug delivery including micellar size, thermodynamic stability, core viscosity, CsA encapsulation, and in vitro CsA release. Among different PCL block lengths, optimum solubilization was achieved by utilizing polymeric micelles having a PCL block of 13,000 g mol(-)(1). CsA reached an aqueous solubility of 1.3 mg/mL in the presence of PEO-b-PCL micelles. This concentration is comparable to injectable CsA levels in its Cremophor EL formulation (0.5-2.5 mg/mL). In contrast to the Cremophor EL formulation, the in vitro rate of CsA release was significantly sustained by the polymeric micellar carrier. Within 12 h, only 5.8% of CsA was released from polymeric micelles while Cremophor EL micelles released 77% of their drug content. Accordingly, viscosity of the PEO-b-PCL micellar core was found to be significantly higher than Cremophor EL micelles. The results points to a potential for PEO-b-PCL micelles as nanoscopic drug carriers for efficient solubilization and controlled delivery of CsA.     

Lipophilic drug loaded nanospheres prepared by nanoprecipitation: effect of formulation variables on size, drug recovery and release kinetics.

The nanoprecipitation method of nanosphere preparation offers several important advantages, such as readily adjustable and reproducible carrier size in the nanometer range and use of ingredients with low toxic potential, especially important for intravascular delivery. The applicability of the method to encapsulation of strongly lipophilic drugs has not been adequately addressed to date. In this study we applied nanoprecipitation to prepare PLA nanospheres loaded with a lipophilic tyrphostin compound, AG-1295, a potent antirestenotic agent. The effect of several formulation variables on the nanosphere basic properties (carrier size, drug release rate and drug recovery yield) was investigated. The nanosphere size was shown to be readily controlled by modifying the PLA and PLA non-solvent amounts in the organic phase. Carrier size and organic solvents' elimination rate are the main determinants of the drug release rate. The stability and drug recovery yield in the formulation depend on the drug to polymer ratio. Nanoprecipitation protocol modifications were suggested to produce nanospheres combining ultrasmall size (<100 nm) with high drug recovery yield, and to reduce the surfactant amount in the formulation.     

Nonlinear mixed-effects model for the dissolution assays of drugs.

Sustained or controlled release delivery systems can achieve predictable and reproducible drug release rates. With the aim of optimizing the bioavailability of conventional drugs with minimum side effects, new drug delivery systems continue to attract much attention. This research has been addressed to investigate in vitro metoclopramide release behavior from inert polymeric matrix tablets. Model-dependent and model-independent approaches are commonly used to investigate the release process and a fitted model results for each experimental condition. The aim of this work was to study the release characterization of the whole batch, therefore, we have developed a population model, taking into account the differences between tablets, experimental conditions, heterogeneity, and autocorrelation of residuals. The study of dissolution profiles was carried out using a mixed-effect model, which has provided a satisfactory tool for this kind of data.     

Drug release characteristics of unimolecular polymeric micelles.

Biodegradable, unimolecular polymeric micelles possess several features that are attractive for drug delivery applications: Thermodynamic stability, ability to encapsulate and solubilize a hydrophobic guest molecule, biodegradability, as well as size and surface characteristics that prevent rapid clearance by the RES. Here we investigate the potential of these unimolecular polymeric micelles to release a drug for an extended time. Lidocaine was used as a model drug for in vitro studies using a horizontal diffusion cell and cellulose membrane that prevented polymer transport from the source to the receiver compartment. The transport of free lidocaine from source to receiver under sink conditions was zero-order and complete within 8 h. The transport of lidocaine initially encapsulated in polymer was zero-order for the first 14 h, and 96% of the lidocaine was detected within 24 h.     

Programmable delivery of hydrophilic drug using dually responsive hydrogel cages.

Micro-capsules normally encapsulate therapeutic agents only inside their cavities. In this paper, we report on the synthesis of dually responsive poly(N-isopropylacrylamide) (PNiPAM)-co-acrylic acid (AA) hydrogel cages sub-micrometer in size and the use of these cages as drug carriers. The cavity structure of the cages can enhance volume phase transition compared to solid gel particles, thus favoring drug loading and release. TEM images and FT-IR spectra confirmed that the model drug isoniazid (INH) is located in two regions: within the shell and inside the cavity of the cages. The drugs residing in the shell can form hydrogen bonds with the cage matrix, while the drugs in the cavity are interaction free with the carrier. This difference from the residency of drugs exploited to a structure induced drug release which was programmable controlled by external pH and temperature. In vitro drug release studies showed that in a neutral medium (pH=7.4), major drugs were preserved within the shell, while in an acidic medium (pH=1.2), nearly all of the drugs were released due to the dissociation of hydrogen bonds.     

Assemblage of novel release modules for the development of adaptable drug delivery systems.

The aim of this paper was to study the applicability of the release module assemblage technology for an adaptable control of drug delivery rate and site. The elementary release module was a swellable matrix having one base convex and the other concave, named Dome Matrix. The swelling and release behavior of the release module was studied. The presence of the convex and concave bases in the swellable matrix slightly changed the overall drug delivery kinetics exhibited by a flat base cylindrical matrix having the same weight and composition. The swelling and drug release of the individual bases of the matrix was also studied to investigate the effect of the surface shape. The concave, convex and flat bases exhibited different swelling and release kinetics. The convex base released drug at faster rate than the concave base, whereas the flat base was intermediate. The release mechanisms of convex and concave bases were significantly different. The Dome Matrix module was selected for assembling several modules in a delivery system obtained by a guided insertion of the convex base into the concave base or by concave/concave base sticking. The module assemblage shows different drug release behavior depending on the geometry of assembled systems.     

Efficiency of nanoparticles as a carrier system for antiviral agents in human immunodeficiency virus-infected human monocytes/macrophages in vitro.

Polyhexylcyanoacrylate nanoparticles loaded with either the human immunodeficiency virus (HIV) protease inhibitor saquinavir (Ro 31-8959) or the nucleoside analog zalcitabine (2',3'-dideoxycytidine) were prepared by emulsion polymerization and tested for antiviral activity in primary human monocytes/macrophages in vitro. Both nanoparticulate formulations led to a dose-dependent reduction of HIV type 1 antigen production. While nanoparticle-bound zalcitabine showed no superiority to an aqueous solution of the drug, a significantly higher efficacy was observed with saquinavir-loaded nanoparticles. In acutely infected cells, an aqueous solution of saquinavir showed little antiviral activity at concentrations below 10 nM, whereas the nanoparticulate formulation exhibited a good antiviral effect at a concentration of 1 nM and a still-significant antigen reduction at 0.1 nM (50% inhibitory concentrations = 4.23 nM for the free drug and 0.39 nM for the nanoparticle-bound drug). At a concentration of 100 nM, saquinavir was completely inactive in chronically HIV-infected macrophages, but when bound to nanoparticles it caused a 35% decrease in antigen production. Using nanoparticles as a drug carrier system could improve the delivery of antiviral agents to the mononuclear phagocyte system in vivo, overcoming pharmacokinetic problems and enhancing the activities of drugs for the treatment of HIV infection and AIDS.     

Lipid microparticles as a parenteral controlled release device for peptides.

To investigate the potential of physiological lipids as an alternative to synthetic polymeric materials such as poly(lactide-co-glycolide), peptide-containing glyceryl tripalmitate microparticles were prepared. A modified solvent evaporation method and a melt dispersion technique without the use of organic solvent were employed. Thymocartin (TP-4), an immunomodulating tetrapeptide and insulin were chosen as model peptides and incorporated as a solid or dissolved in 100 microl aqueous solution. The resulting microparticles were characterized with respect to particle size and morphology, biocompatibility, drug content (encapsulation efficiency) and in vitro release behavior. Electron spectroscopy for chemical analysis was used to investigate the adsorption of the model peptides to the lipid matrix material. The modified solvent evaporation as well as the melt dispersion method were suitable for the preparation of microparticles in the size range of 20-150 microm with an acceptable yield. The biocompatibility of the glyceryl tripalmitate microparticles after implantation into NMRI-mice was comparable to poly(lactide-co-glycolide) microparticles. The encapsulation efficiency for both model peptides was high (>80%) even at high theoretical loadings when the peptide was incorporated as a solution with the melt dispersion technique. The in vitro release behavior was substantially influenced by the physicochemical properties of the model peptides used in this study.     

Development of a multifunctional matrix drug delivery system surrounded by an impermeable cylinder.

A multifunctional drug delivery system based on hydroxypropyl methylcellulose (HPMC)-matrices (tablets) placed within an impermeable polymeric cylinder (open at both ends) was developed. Depending on the configuration of the device, extended release, floating or pulsatile drug delivery systems could be obtained. The release behaviour of the different devices was investigated as a function of HPMC viscosity grade, HPMC content, type of drug (chlorpheniramine maleate or ibuprofen), matrix weight, position of the matrix within the polymeric cylinder, addition of various fillers (lactose, dibasic calcium phosphate or microcrystalline cellulose) and agitation rate of the release medium. The drug release increased with a reduced HPMC viscosity grade, higher aqueous drug solubility, decreased HPMC content and increased surface area of the matrix. The release was fairly independent of the agitation rate, the position of the tablet within the polymeric cylinder and the length of the cylinder. With the pulsatile device, the lag time prior to the drug release could be controlled through the erosion rate of the matrix (matrix weight and composition).     

Design of long-acting formulation of protein drugs with a double-layer structure and its application to rhG-CSF.

In order to design a sustained-release formulation of protein drugs characterized by excellent long-acting properties without an initial burst, a new double-layer minipellet (DL-MP) in which the lateral side of a matrix-type sustained-release formulation 'minipellet' using collagen as a carrier was coated with collagen was designed, and its performance was evaluated. In a DL-MP using bovine serum albumin (BSA) as a model drug, the initial burst observed with a single-layer minipellet (SL-MP) was effectively inhibited in an in vitro release test, and the addition of additives such as chondroitin sulfate (CS) permitted control of release rate. This formulation of recombinant human granulocyte colony-stimulating factor (rhG-CSF) was then prepared, and its characteristics were determined in normal rats. It was found that blood rhG-CSF concentration was maintained for about 1 week after administration of a DL-MP with additional CS, with persistent increase in white cell count. The results of this study indicated that DL-MP was useful as a long-acting formulation of rhG-CSF characterized by excellent long acting properties without an initial burst.     

Molecular design of biodegradable polymeric micelles for temperature-responsive drug release.

We designed thermo-responsive and biodegradable polymeric micelles for an ideal drug delivery system whose target sites are where external stimuli selectively release drugs from the polymeric micelles. The thermo-responsive micelles formed from block copolymers that were composed both of a hydrophobic block and a thermo-responsive block. Poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) showing a lower critical solution temperature (LCST) around 40 degrees C was synthesized for the thermo-responsive block, while biodegradable poly(D,L-lactide), poly(epsilon-caprolactone), or poly(D,L-lactide-co-epsilon-caprolactone) was used for the hydrophobic block. By changing both the block lengths of the poly(D,L-lactide)-containing block copolymers, physical parameters such as micelle diameter and critical micelle concentration were varied. On the other hand, the choice of the hydrophobic block was revealed to be critical in relation to both on the thermo-responsive release of the incorporated anti-cancer drug, doxorubicin, and the temperature-dependent change of the hydrophobicity of the micelles' inner core. One polymeric micelle composition successfully exhibited rapid and thermo-responsive drug release while possessing a biodegradable character.