Preparation of controlled release anticancer agents I: 5-fluorouracil-ethyl cellulose microspheres

Abstract

Microspheres of 5-fluorouracil have been prepared, using three grades of ethyl cellulose as wall forming materials, and utilizing a solvent evaporation technique under ambient conditions. An alcoholic solution of 5-fluorouracil and polymer was dispersed in liquid paraffin containing 33.3 per cent n-heptane. The effect of stirring rate, time of stirring, drug loading, and polymer grade on drug release in two different media were evaluated. The drug loaded particles were spherical in shape and had a diameter range of 25-200 mm and were suitable for incorporating into a gel base. Drug release studies in aqueous media, showed that acidic media provide a faster release rate than neutral media. The drug release study from an aqueous gel base preparation at pH 7.0 through a synthetic membrane was found to be promising for formulation of a gel-microsphere product for the treatment of skin lesions.     

5-Fluorouracil in topical liposome gels for anticancer treatment--formulation and evaluation

Liposome gels bearing an antineoplastic agent, 5-fluorouracil, intended for topical application have been prepared and drug release properties in vitro have been evaluated. Different formulations of liposomes were prepared by the film hydration method by varying the lipid phase composition (PL 90H/cholesterol mass ratio) and hydration conditions of dry lipid film (drug/aqueous phase mass ratio). Topical liposome gels were prepared by incorporation of lyophilized liposomes into a structured vehicle (1%, m/m, chitosan gel base). Also, hydrogels containing different concentrations of 5-fluorouracil were prepared and drug release properties were investigated. The rate of drug release from liposome gels was found to be dependent on the bilayer composition and the dry lipid film hydration conditions. Also, liposomes embedded into a structured vehicle of chitosan showed significantly slower release than hydrogels. The drug release obeyed the Higuchi diffusion model, while liposomes acted as reservoir systems for continuous delivery of the encapsulated drug.     

Preparation and Characterization of 5-Fluorouracil-loaded Microparticles as Biodegradable Anticancer Drug Carriers

To provide a device releasing 5-fluorouracil in a controlled manner and injectable into the brain by stereotaxy, biodegradable poly ((±)-lactide-co-glycolide) (PLAGA) microparticles were prepared by an emulsion-extraction process. Although the solubility profile of the drug was not suitable for its encapsulation by the aforementioned method, careful choice of process variables allowed significant drug loading, reaching 30%. Thus, the size of the 5-fluorouracil crystals, the organic phase/aqueous phase ratio, the theoretical drug loading and the microparticle size played a predominant role. The microsphere size was adjusted to 20–40 μm by selecting the appropriate PLAGA and polyvinylalcohol concentrations, and the stirring rate of the initial emulsion. It was shown that the microparticle structure depended directly on the experimental conditions governing the precipitation rate of the coating material: two types of microparticles, I and II, were characterized. The morphology of the particles influenced the 5-fluorouracil-release patterns, as did other process parameters, such as the 5-fluorouracil crystal size and the PLAGA concentration. It was possible to sustain the 5-fluorouracil release over 18 days.     

蛇床子素温敏型原位凝胶的研制及含量测定

目的：蛇床子素温敏型凝胶剂的研制,并建立其含量测定方法。方法建立用HPLC法测定制剂的含量及体外释药量。采用搅拌子法测定相变温度并测定其动态黏度,从而确定处方。用转篮法进行处方的体外释放实验。结果确定蛇床子素温敏型凝胶的最佳基质配比是质量分数为25%的泊洛沙姆407和质量分数为10%的泊洛沙姆188的组合。结论该制剂制备工艺简单,进入体内形成凝胶并且24 h累计释放药物约83%。含量测定方法操作简便、快速准确。     

Studies on microencapsulation of 5-fluorouracil with poly(ortho ester) polymers

Microencapsulation of 5-fluorouracil was successfully accomplished with poly(ortho ester) polymers by the emulsification-solvent evaporation method. While actual drug loading increased with increasing drug load (5-15% w/w), the entrapment efficiency remained essentially unaffected, under a given set of experimental conditions. Incorporation of sorbitan sesquioleate enhanced entrapment efficiency, decreased the volume-surface mean diameter of the poly(ortho ester) microspheres and provided controlled release of 5-fluorouracil. The volume of the aqueous phase was more important than the concentration of polyvinyl alcohol in it. The entrapment efficiency improved from 13 to 33% when the volume of the aqueous phase was increased from 20 to 80 ml. The volume of organic phase (methylene chloride) and the concentration of polymer in it played an important role. The use of smaller volumes of more concentrated polymer solution enhanced actual drug loading, entrapment efficiency and produced larger microspheres. The release studies conducted in 0.01 M phosphate buffer at 37+/-1.0 degrees C demonstrated that the release of 5-FU from the microspheres prepared with sorbitan sequioleate was nearly independent of the initial drug load with a mean zero-order rate constant of 0.0063% per hour. The data suggested that drug release was largely a diffusional process with contributions from dissolution and polymer degradation.     

Studies on microencapsulation of 5-fluorouracil with poly(ortho ester) polymers

Microencapsulation of 5-fluorouracil was successfully accomplished with poly(ortho ester) polymers by the emulsification-solvent evaporation method. While actual drug loading increased with increasing drug load (5-15% w/w), the entrapment efficiency remained essentially unaffected, under a given set of experimental conditions. Incorporation of sorbitan sesquioleate enhanced entrapment efficiency, decreased the volume-surface mean diameter of the poly(ortho ester) microspheres and provided controlled release of 5-fluorouracil. T he volume of the aqueous phase was more important than the concentration of polyvinyl alcohol in it. The entrapment efficiency improved from 13 to 33 %when the volume of the aqueous phase was increased from 20 to 80 ml. The volume of organic phase (methylene chloride) and the concentration of polymer in it played an important role. The use of smaller volumes of more concentrated polymer solution enhanced actual drug loading, entrapment efficiency and produced larger microspheres. The release studies conducted in 0.01M phosphate buffer at 37 +/- 1.0°C demonstrated that the release of 5-FU from the microspheres prepared with sorbitan sequioleate was nearly independent of the initial drug load with a mean zero-order rate constant of 0.0063% per hour. The data suggested that drug release was largely a diffusional process with contributions from dissolution and polymer degradation.     

5-Fluorouracil-loaded chitosan coated polylactic acid microspheres as biodegradable drug carriers for cerebral tumours

The development of injectable microspheres for anticancer drug delivery into the brain is a major challenge. The possibility of entrapping 5-fluorouracil (5-FU) in chitosan coated monodisperse biodegradable microspheres with a mean diameter of 10-25um was demonstrated. An emulsion of 5-FU (in water) and polylactic acid (PLA) dissolved in acetone-dichloromethane mixture was poured into an aqueous solution of chitosan (or poly-vinyl alcohol) with stirring using a high-speed homogenizer, for the formation of microspheres. 5-FU recovery in microspheres ranged from 44-66% depending on the polymer and emulsification systems used for the preparation. Scanning electron microscopy revealed that the chitosan coated microspheres had less surface micropores compared to PVA based preparations. The drug release behaviour from microspheres suspended in phosphate buffered saline exhibited a biphasic pattern. The amount of drug release was much higher initially (25%),followed by a constant slow release profile for a 30 days period of study. This chitosan coated PLA/PLGA microsphere formulation may have potential for the targeted delivery of 5-FU to treat cerebral tumours.     

5-Fluorouracil-loaded chitosan coated polylactic acid microspheres as biodegradable drug carriers for cerebral tumours

The development of injectable microspheres for anticancer drug delivery into the brain is a major challenge. The possibility of entrapping 5-fluorouracil (5-FU) in chitosan coated monodisperse biodegradable microspheres with a mean diameter of 10-25 um was demonstrated. An emulsion of 5-FU (in water) and polylactic acid (PLA) dissolved in acetone-dichloromethane mixture was poured into an aqueous solution of chitosan (or poly-vinyl alcohol) with stirring using a high-speed homogenizer, for the formation of microspheres. 5-FU recovery in microspheres ranged from 44-66% depending on the polymer and emulsification systems used for the preparation. Scanning electron microscopy revealed that the chitosan coated microspheres had less surface micropores compared to PVA based preparations. The drug release behaviour from microspheres suspended in phosphate buffered saline exhibited a biphasic pattern. The amount of drug release was much higher initially (approximately 25%), followed by a constant slow release profile for a 30 days period of study. This chitosan coated PLA/PLGA microsphere formulation may have potential for the targeted delivery of 5-FU to treat cerebral tumours.     

Drug Release From Hydrocolloid Embeddings with High or Low Susceptibility to Hydrodynamic Stress

Purpose. The subject of the study was the influence of hydrodynamic stress on the drug release from direct compressed hydrocolloid embeddings. Additionally a correlation between the release kinetics and different polymer characterising parameters was attempted. Methods. The drug release was fitted to an expanded Korsmeyer equation to describe the release kinetics. The influence of the stirring rate of the paddle in the USP paddle apparatus on the Mean Dissolution Time (MDT) was expressed as quotient of the MDT's at the stirring rate of 200 and 100 min^–1. Results. If the drug release followed the square root of time kinetics, nearly no effect of the agitation speed on the release rate was observed. To achieve this diffusion controlled drug release the developing gel layer had to be hydrated very well and resistant against erosion (viscosity of at least 4000 mPa · s of the 2% polymer solution and a small expansion of the swelling gel especially at the beginning of the release). The erosion controlled zero order release was generally much affected by the hydrodynamic stress except for some hydrocolloids with incomplete swelling. Thus, it was possible to define a new release mechanism, the polymer particle erosion. The drug release was controlled by the attrition of partially swollen polymer particles and not by the polymer dissolution or drug diffusion. Conclusions. Polymer particle erosion or diffusion control should be the release controlling mechanisms for negligible influence of hydrodynamic stress.     

Sustained release of 5-fluorouracil from polymeric nanoparticles

The use of biodegradable nanoparticles loaded with 5-fluorouracil was investigated as a potential means to sustain the release of this drug. Nanoparticles prepared from four biodegradable polymers were loaded with 5-fluorouracil using three loading concentrations of drug and three different concentrations of added polymer. Washing particles using a centrifugation/re-suspension with ultrasound protocol was found to dislodge the majority of drug, resulting in an over-estimation of incorporation efficiency and low levels of strongly entrapped drug. Increasing the initial 5-fluorouracil concentration before polymer/monomer addition increased the drug loading in both washed and unwashed particles. Increasing the amount of polymer used to make nanoparticles did not increase loadings, but did produce increased amounts of unusable polymer waste. Drug release from nanoparticles was evaluated using a Franz cell diffusion apparatus, which showed an initial burst effect followed by a slower release phase over 24 h. Indeed, nanoparticles prepared from poly(lactide-co-glycolide) released 66% of their 5-fluorouracil payload over this period. It was concluded that 5-fluorouracil-loaded nanoparticles could be readily included into a hydrogel-based delivery system to provide sustained drug release for trans-epithelial drug-delivery applications.     

On the mechanism of drug release from oil suspensions in vitro using local anesthetics as model drug compounds

The objective of this study was to gain insight into factors influencing the drug release kinetics from oil suspensions. The in vitro drug release from suspensions was investigated at pH 7.4 using the local anesthetics, bupivacaine and ropivacaine, as model drug compounds. Two dialysis membrane-based in vitro release models differing with respect to stirring of the donor compartment were employed to study the release characteristics of oil suspensions comprising the free base or the corresponding drug hydrochloride salt. In the rotating dialysis cell model identical release profiles from aqueous and oil suspensions of the base form were obtained for both ropivacaine and bupivacaine. From the steady state fluxes, drug concentrations in the aqueous donor compartment were found to be in agreement with drug solubilities at pH 7.4. Also relatively fast transformation of a sesame oil suspension of the oil insoluble ropivacaine hydrochloride salt into an aqueous suspension of ropivacaine base was observed. Collectively, these observations indicate a lability of the oil film surrounding the solid particles eventually caused by rotation of the donor cell. In the Float A Lyzer^® model, which operates at much less intensive stirring, significantly slower release rates from aqueous and oil suspensions of ropivacaine base were obtained. In the latter model, ropivacaine was released faster from oil suspensions containing the hydrochloride salt than from the corresponding oil suspensions of the free base form. These findings suggest that the oil film surrounding the particles also is instable in the absence of significant shear forces.     

阳离子聚合物Eudragit RL对电解质的敏感性及其对不同药物释放的影响

研究聚合物Eudragit RL在电解质溶液中的膨胀行为,以及介质组成及聚合物膨胀度对硝苯地平、氯苯那敏(扑尔敏)和吲哚美辛从聚合物骨架中释放的影响。用转篮法及浆板法测定微球和药膜的释放度。结果表明Eudragit RL的膨胀度随电解质浓度增加而下降,且受电解质种类的影响显著。硝苯地平和氯苯那敏从聚合物骨架中的释放速率与聚合物膨胀行为间呈良好正相关,但吲哚美辛从聚合物中的释放速率受聚合物膨胀和离子对药物的置换两种因素同时控制。提示Eudragit RL骨架中药物的释放方式受介质组成和药物种类的影响。     

可注射5-氟尿嘧啶缓释凝胶体外释放及其大鼠体内药动学研究

目的:制备可注射5-氟尿嘧啶(FU)缓释凝胶,并研究其体外释药及体内药动学特征。方法:以pH/温度双重敏感生物可降解嵌段共聚物OSM1-PCLA-PEG-PCLA-OSM1为载体材料,采用物理混合法制备5-FU缓释凝胶。考察载药量和共聚物浓度对其体外释药情况的影响。采用高效液相色谱法分别测定大鼠皮下注射5-FU水溶液(参比制剂)及缓释凝胶(受试制剂)后不同时间点的血药浓度,绘制药-时曲线,计算药动学参数。结果:5-FU在载药量为0.5%,共聚物浓度为15%、20%、25%的缓释凝胶中第9天时平均累积释放百分率为89.66%、87.59%、80.85%;载药量为0.2%、0.5%、1%,共聚物浓度为25%的缓释凝胶中第9天时平均累积释放百分率为75.30%、80.85%、86.90%;参比制剂与受试制剂在大鼠体内tmax分别为0.25、0.50h,Cmax分别为72.7、31.1μg·mL-1,AUC(0～)t分别为44.5、342.4mg·h·mL-1,MRT分别为0.57、27.2h。结论:5-FU缓释凝胶中5-FU体外释放呈现Higuchi动力学特征,表现为以扩散控制型为主的释药模式;释药初期,载药量对释药速率影响较大;释药后期,共聚物浓度对释药速率影响较大。皮下注射给药后,与水溶液相比,缓释凝胶可持续释药3d,具有良好的缓释作用。     

Development of novel combined time and pH-dependent based drug delivery systems for targeting 5-fluorouracil to the colon

The present work is aimed to develop new oral drug delivery systems of 5-fluorouracil for the treatment of colorectal cancer by using hydrophilic swellable polymer hydroxy propyl methyl cellulose (HPMC) and pH responsive soluble polymer Eudragit L100 (ED) as coating materials. Core tablets containing 50mg of 5-fluorouracil were prepared by direct compression. The core tablets compression coated with different ratios (9:1, 8:2, 7:3, 6:4 and 5:5) of HPMC and ED with a coat weight of 300 and 400mg. All the formulations were evaluated for the hardness, friability, drug content uniformity and in vitro drug release studies in media of different pH 1.2, 7.4 and 6.8. The formulations released 0 to 7% of the drug in physiological environment of stomach and small intestine depending upon proportion of HPMC and ED used in the coat. Among the different ratios used for coating with HPMC:ED combination, ratio 9:1 gave the best release profile with the coat weight of 300mg (1.34% in the initial 5h and 87% in 24 h). Further increase in the coat weight to 400mg with different ratios of 9:1, 8:2, 7:3, 6:4 and 5:5 led to drug release of 0%, 0%, 0%, 3.47% and 6.25%, respectively in the initial 5 h and 73.52%, 87.03%, 92.18%, 96.33% and 97.61%, respectively, in 24 h. Thus, based on the results of in vitro drug release studies, the ratio 7:3 with a coat weight of 400mg was found to be suitable for targeting 5-fluorouracil to the colon without being released in physiological environment of stomach and small intestine. The formulation showed no change in physical appearance, drug content or in vitro release pattern after storage at 40° C / 75% RH for 3 months. The release of 5-fluorouracil from developed formulation was directly proportional to amount of ED used in the coat. The DSC and FTIR studies indicated no possibility of interaction between 5-fluorouracil and excipients.     

A comparative in vitro assessment of the drug release performance of pH-responsive polymers for ileo-colonic delivery

The aim of this study was to investigate the in vitro dissolution characteristics of pH-responsive polymers in a variety of simulated fluids. Prednisolone tablets were fabricated and coated with the following polymer systems: Eudragit S (organic solution), Eudragit S (aqueous dispersion), Eudragit FS (aqueous dispersion) and Eudragit P4135 (organic solution). Dissolution tests were conducted using a pH change method whereby tablets were transferred from acid to buffer. Three different buffer media were investigated: two compendial phosphate buffers (pH range 6.8-7.4) and a physiological buffer solution (Hanks buffer) with very similar ionic composition to intestinal fluid (pH 7.4). There was considerable drug release from tablets coated with Eudragit P4135 in acid, prompting discontinuation of further investigations of this polymer. Eudragit S (organic solution), Eudragit S (aqueous dispersion) and Eudragit FS on the other hand prevented drug release in acid, though subsequent drug release in the buffer media was found to be influenced by the duration of tablet exposure to acid. At pH 7.4 drug release rate from the polymer coated tablets was similar in the two compendial media, however in the physiological buffer, they were found to differ in the following order: Eudragit S (aqueous dispersion)>Eudragit FS>Eudragit S (organic solution). The results indicate that the tablets coated with the newer Eudragit FS polymer would be more appropriate for drug delivery to the ileo-colonic region in comparison to the more established Eudragit S. More importantly, however, dissolution in the physiological buffer was found to be markedly slower for all the coated tablets than in the two compendial buffers, a result akin to reported slower dissolution of enteric coated tablets in vivo. There is therefore the need to adequately simulate the ionic composition of the intestinal fluid in the dissolution media.     

Photoregulation of drug release in azo-dextran nanogels

A simple photoresponsive azo-dextran polymer has been investigated for its ability to act as a nanogel drug carrier. Self aggregation of the azo-dextran polymer leads to the formation of nanogels, AD (5 and 10) in aqueous media, which were characterized by TEM and DLS. When examined under UV light (365 nm), the unloaded nanogels, which were observed to be in the range of 120-290 nm, show dependence on the degree of crosslinking, pH and ionic concentration of the dispersed media. Nanogels, AD (5 and 10), have been loaded with a model fluorophore, rhodamine B and a drug, aspirin, by freeze drying an aqueous dispersion of the nanogels in the presence of the substrate dissolved in water or PBS buffer. The release pattern of the encapsulated bio-active molecules from these nanogels was regulated by (trans-cis) photoisomerization of the azobenzene moiety present in the crosslinker. A comparison of the release behavior of the loaded (rhodamine, aspirin) AD (5 and 10) nanogels reveal that the rate of release of the encapsulated active molecules from the nanogels was slower when the azo moiety was in E-configuration as compared to that the azo in the Z-configuration. The in vitro release behavior of drug from these polymeric micellar systems is revelative of the potential of the nanogels for targeted drug delivery in nanomedicine.     

Floating microspheres of cimetidine: formulation, characterization and in vitro evaluation

The present study involves preparation and evaluation of floating microspheres with cimetidine as model drug for prolongation of gastric residence time. The microspheres were prepared by the solvent evaporation method using polymers hydroxypropylmethyl cellulose and ethyl cellulose. The shape and surface morphology of prepared microspheres were characterized by optical and scanning electron microscopy, respectively. In vitro drug release studies were performed and drug release kinetics was evaluated using the linear regression method. Effects of the stirring rate during preparation, polymer concentration, solvent composition and dissolution medium on the size of microspheres and drug release were also observed. The prepared microspheres exhibited prolonged drug release (approximately 8 h) and remained buoyant for > 10 h. The mean particle size increased and the drug release rate decreased at higher polymer concentration. No significant effect of the stirring rate during preparation on drug release was observed. In vitro studies demonstrated diffusion-controlled drug release from the microspheres.     

5-氟尿嘧啶-聚α,β(2-羟乙基)-DL-天冬酰胺的合成及体内释放的研究

以5-氟尿嘧啶为模型药物,将药物以共价键的形式键合于生物降解型高分子材料聚-α,β(2-羟乙基)-DL-天冬酰胺上制成高分子载体药物,药物接入率达37.1%(w/w)。用红外和差热分析法对载体药物进行了表征。以纯种大白兔为实验动物,把载体药物制成混悬型和棒状型两种剂型,进行药物体内释放实验。结果表明:以棒状型药物给药在一定程度上可以降低释药初期的“爆释”现象,为进一步临床应用提供了重要依据。     

5-氟尿嘧啶结肠定位释药微丸的研制及释药特性

采用流化床喷雾包衣法,研制了2种5-氟尿嘧啶结肠定位释药微丸.以羟丙甲纤维素为溶胀层,乙基纤维素水分散体为控制层,制备时间依赖型包衣微丸;另以肠溶型丙烯酸树脂Eudragit S100为包衣材料,制备pH依赖型微丸.测定了2种微丸在模拟胃肠道各区段pH环境下的释放度.结果表明,时间依赖型包衣微丸体外持续、缓慢释放;pH依赖型包衣微丸在模拟胃和小肠中上部pH的介质中基本不释药,在模拟回盲部区段pH介质中脉冲释药,即后者在体外显示出较好的结肠定位释药特性.     

Dimensional changes, gel layer evolution and drug release studies in hydrophilic matrices loaded with drugs of different solubility

The objective of this investigation was to explore the effects of drug solubility on the evolution of matrix dimensions and gel layer's during drug release and investigate the relationship between these effects and the mechanism and the rate of drug release. Two hydrophilic swellable polymers Polyox (POL) and cross-linked Carbopol (CARB) were employed as carriers. Caffeine (CAF) and theophylline (THE), two drugs having similar chemical structure but different aqueous solubility, were used as model drugs. Both drug and polymer characteristics were found to influence the dimensional changes of matrices and the development of the gel layer formed around the glassy core. The dimensional expansion in CAF matrices was always more pronounced than the THE matrices. Also the CARB matrices demonstrated greater maximum expansion and lower drug release than the POL matrices, due to a smaller degree of erosion of CARB. The dimensions of CARB/CAF matrices, unlike all the other matrices studied, exhibited a biphasic increase at early times, which was attributed to the cross-linked structure of CARB and the high solubility of CAF. With both polymers, a thinner gel layer was developed in the matrices containing the less soluble THE compared to the CAF matrices. The thickness of the gel layer increased continuously with time in the CAF matrices whereas it increased initially and after reaching a maximum started to decrease in THE matrices. All formulations except those of CARB/THE exhibited burst release, which depended on drug and polymer characteristics. The gel layer thickness and erosion rate appeared to determine the rate of drug release from the CARB and POL formulations. The results clearly indicate that for these matrices gel thickness and fluctuation of gel thickness affect the release rate/h of drug proportionally. Analysis of the release kinetics indicated that CAF was released mainly through diffusion whereas, THE was released mainly through matrix erosion.