Preparation and characterization of cross-linked guar gum microspheres: optimization using factorial design

In the present work cross-linked guar gum microspheres were prepared for colon specific delivery of ornidazole. Development and optimization of guar gum microspheres for colonic drug delivery was carried out using a 2(4) factorial design based on four independent variables. Microspheres were prepared by emulsification method using glutaraldehyde as cross-linking agent. Morphology and surface characteristics of the formulations were determined by scanning electron microscopy. Particle size of the guar gum microspheres was determined by particle size analyzer. In vitro drug-release studies were performed in conditions simulating stomach-to-colon transit in the presence and absence of rat cecal contents. Only a small fraction of drug was released at acidic pH; however, the release of drug was found to be higher in the presence of rat cecal contents, indicating the susceptibility of guar gum matrix to colonic enzymes released from rat cecal contents. The significance of differences was evaluated by analysis of variance (ANOVA). Differences were considered statistically significant at p<0.05.     

Colon specific chitosan microspheres for chronotherapy of chronic stable angina

In the present work, chitosan microspheres with a mean diameter between 6.32 μm and 9.44 μm, were produced by emulsion cross-linking of chitosan, and tested for chronotherapy of chronic stable angina. Aiming at developing a suitable colon specific strategy, diltiazem hydrochloride (DTZ) was encapsulated in the microspheres, following Eudragit S-100 coating by solvent evaporation technique, exploiting the advantages of microbiological properties of chitosan and pH dependent solubility of Eudragit S-100. Different microsphere formulations were prepared varying the ratio DTZ:chitosan (1:2 to 1:10), stirring speed (1000-2000 rpm), and the concentration of emulsifier Span 80 (0.5-1.5% (w/v)). The effect of these variables on the particle size and encapsulation parameters (production yield (PY), loading capacity (LC), encapsulation efficiency (EE)) was evaluated to develop an optimized formulation. In vitro release study of non-coated chitosan microspheres in simulated gastrointestinal (GI) fluid exhibited a burst release pattern in the first hour, whereas Eudragit S-100 coating allowed producing systems of controlled release diffusion fitting to the Higuchi model, and thus suitable for colon-specific drug delivery. DSC analysis indicated that DTZ was dispersed within the microspheres matrix. Scanning electron microscopy revealed that the microspheres were spherical and had a smooth surface. Chitosan biodegradability was proven by the enhanced release rate of DTZ in presence of rat caecal contents.     

An in vitro and in vivo investigation into the suitability of bacterially triggered delivery system for colon targeting

The colon specific drug delivery systems based on polysaccharides; locust bean gum and chitosan in the ratio of 2 : 3, 3 : 2 and 4 : 1 were evaluated using in vitro and in vivo methods. The in vitro studies in pH 6.8 phosphate buffer containing 2% w/v rat caecal contents showed that the cumulative percentage release of mesalazine after 26 h were 31.25+/-0.56, 46.25+/-0.96, 97.5+/-0.26 (mean+/-S.D.), respectively. The in vivo studies conducted in nine healthy male human volunteers for the various formulations revealed that, the drug release was initiated only after 5 h (i.e.) transit time of small intestine and the bioavailability (AUC(0-->t*)) of the drug was found to be 85.24+/-0.10, 196.08+/-0.12, 498.62+/-0.10 microg x h/ml 26 (mean+/-S.D.), respectively. These studies on the polysaccharides demonstrated that the combination of locust bean gum and chitosan as a coating material proved capable of protecting the core tablet containing mesalazine during the condition mimicking mouth to colon transit. In particular, the formulation containing locust bean gum and chitosan in the ratio of 4 : 1 held a better dissolution profile, higher bioavailability and hence a potential carrier for drug targeting to colon.     

Colon targeted delivery systems of metronidazole based on osmotic technology: development and evaluation

Colon targeted delivery systems of metronidazole (MTZ) based on osmotic technology were developed. The developed systems consisted of osmotic core (drug, osmotic agent and wicking agent), coated with semipermeable membrane (SPM) containing guar gum as pore former, coated core were then further coated with enteric coating to protect the system from acidic environment of stomach. The effect of various formulation variables namely the level of wicking agent (sodium lauryl sulphate), osmotic agent in the osmotic core, the level of pore former (guar gum) in SPM, and the thickness of SPM, were studied on physical parameters and drug release characteristics of developed formulations. MTZ release was inversely proportional to SPM thickness, but directly related to the level of pore former, wicking agent and osmotic agent. On the other hand burst strength of the exhausted shells was decreased with the increase in level of pore former in the membrane but increased with the increase in the thickness of SPM. The drug release from the developed formulations was independent of pH, and agitation intensity, but dependent on the osmotic pressure of the release media. The thickness of enteric coating could prevent formation of delivery pores before contact with simulated colonic fluid, but had no effect on drug release. Result of SEM studies showed the formation of in-situ delivery pores in the membrane from where the drug release occurred, and the number of pores formed were directly related to the initial level of pore former (guar gum) in SPM. The manufacturing procedure was found to be reproducible and formulations were found to be stable during 3 months of accelerated stability studies.     

Pharmacokinetic analysis of multi PEG–theophylline conjugates

In the attempt of prolonging the effect of drugs, a new branched, high-molecular weight multimeric poly(ethylene glycol) (MultiPEG), synthesized with a simple assembling procedure that devised the introduction of functional groups with divergent and selective reactivity, was employed as drug carrier. In particular, the attention was focused on the study of theophylline (THEO) and THEO-MultiPEG conjugates pharmacokinetic after oral administration in rabbit. Pharmacokinetic behavior was studied according to an ad hoc developed mathematical model accounting for THEO-MultiPEG in vivo absorption and decomposition into drug (THEO) and carrier (MultiPEG). The branched high-molecular weight MultiPEG proved to be a reliable drug delivery system able to prolong theophylline staying in the blood after oral administration of a THEO-MultiPEG solution. The analysis of experimental data by means of the developed mathematical model revealed that the prolongation of THEO effect was essentially due to the low THEO-MultiPEG permeability in comparison to that of pure THEO.     

聚L-谷氨酸担载胰岛素口服微球的制备与评价

以聚L-谷氨酸为载体材料, 采用无水乳液法制备了口服胰岛素微球, 微球直径在5~20 μm, 载药质量分数为5%~9%. 载药微球具有良好的pH敏感释放行为, 在胃模拟液中2 h释放量约为5%, 在肠道模拟液中2 h释放90%以上. 考察聚合物分子量、溶液浓度、理论投药量及混合材料对微球释放行为的影响.     

Development of extended release coevaporates and coprecipitates of promethazine HCl with acrylic polymers: formulation considerations

The present investigation studied a novel extended release system of promethazine hydrochloride (PHC) with acrylic polymers Eudragit RLPO and Eudragit RS100 in different weight ratios (1 : 1 and 1 : 5) using coevaporation and coprecipitation techniques. Solid dispersions were characterized by Fourier-transformed infrared spectroscopy (FT-IR), Differential scanning calorimetry (DSC), Powder X-ray diffractometry (PXRD), Nuclear magnetic resonance (NMR), Scanning electron microscopy (SEM) as well as solubility and in vitro dissolution studies in 0.1 n HCl (pH 1.2), double distilled water and phosphate buffer (pH 7.4). Adsorption test from drug solution to solid polymers were also performed. Selected solid dispersion system was subjected to direct compression and compressed tablets were evaluated for in vitro dissolution studies. The progressive disappearance of drug peaks in thermotropic profiles of coevaporates were related to increasing amount of polymers while SEM studies suggested homogenous dispersion of drug in polymer. Eudragit RLPO had a greater adsorptive capacity than Eudragit RS100 and thus its coevaporates in 1 : 5 ratio exhibited higher dissolution rate with 91.90% drug release for 12 h. Among different formulations, tablets prepared by Eudragit RLPO coevaporates (1 : 5) displayed extended release of drug for 12 h with 90.87% release followed by zero order kinetics (r(2)=0.9808).     

Formulation and optimization of orally disintegrating tablets of sumatriptan succinate

The aims of the present research were to mask the intensely bitter taste of sumatriptan succinate and to formulate orally disintegrating tablets (ODTs) of the taste masked drug. Taste masking was performed by coating sumatriptan succinate with Eudragit EPO using spray drying technique. The resultant microspheres were evaluated for thermal analysis, yield, particle size, entrapment efficiency and in vitro taste masking. The tablets were formulated by mixing the taste masked microspheres with different types and concentrations of superdisintegrants and compressed using direct compression method followed by sublimation technique. The prepared tablets were evaluated for weight variation, thickness, hardness, friability, drug content, water content, in vitro disintegration time and in vitro drug release. All the tablet formulations disintegrated in vitro within 37-410 s. The optimized formulation containing 5% Kollidon CL-SF released more than 90% of the drug within 15 min and the release was comparable to that of commercial product (Suminat?). In human volunteers, the optimized formulation was found to have a pleasant taste and mouth feel and disintegrated in the oral cavity within 41 s. The optimized formulation was found to be stable and bioequivalent with Suminat?.     

Formulation and Evaluation of 5-FU Loaded Eudragit Microspheres: Effect of Various Eudragit on Micromeretic Properties of Microspheres

The aim of the present study was to prepare and evaluate microspheres of Eudragit (RS, RL and RSPO) containing an anticancer drug 5-FU. Microspheres were prepared by O/O solvent evaporation method using a acetone/liquid paraffin system. Magnesium stearate was used as the droplet stabilizer and n-hexane was added to harden the microspheres. The prepared microspheres were characterized for their micromeretic properties and entrapment efficiency; as well by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), thin layer chromatography (TLC) and scanning electron microscopy (SEM) revealed the crystalline nature of drug in a final state. The in vitro release studies were performed in a Phosphate Buffer Solution (PBS) pH 7.4. The best fit release kinetics was achieved with a Higuchi plot. The yields of preparation and entrapment efficiencies were very high with a larger particle size for all the formulations. Mean particle size, entrapment efficiency and production yield were highly influenced by the type of polymer and polymer concentration. It is concluded from the present investigation that various Eudragit are promising controlled release carriers for 5-FU.     

Synthesis and characterization of a pH responsive and mucoadhesive drug delivery system for the controlled release application of anti-cancerous drug

In this work a novel pH sensitive composite, polyacrylamide grafted succinyl chitosan intercalated bentonite (AAm-g-NB/SC) was prepared as a drug carrier system for the controlled delivery of paclitaxel. Characterization of the drug delivery system was carried out using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), thermal analysis etc. The equilibrium swelling behaviour of the composite was studied and the result showed a maximum at pH 7.4. The in vitro drug release study of paclitaxel indicated that about 15.6% of drug release was found to be occurred at pH 1.2 within 16 h, whereas about 82.5% of drug release was occurred at the intestinal pH condition of 7.4. In vitro biocompatibility study was performed and the result showed good biocompatibility of the composite in the concentration range 6.25–100 µg/mL. The cytotoxicity assay was carried out in cancerous cell line of Human colorectal Adenocarcinoma. Mucous glycoprotein assay study showed that the drug delivery system having good apparent adhering property towards mucin. The investigation indicated that paclitaxel, an anticancer drug can be successfully entrapped in the AAm-g-NB/SC composite for the controlled and targeted delivery for colorectal cancer therapy.     

接枝微球CPVA-g-PSSS的制备及其对5-氟尿嘧啶载药及体外结肠定位释药特性研究

在具有生物相容性的交联聚乙烯醇(CPVA)微球表面,采用铈盐-羟基氧化还原引发体系,实施了对苯乙烯磺酸钠(SSS)的表面引发接枝聚合,制得了接枝有聚阴离子的接枝微球CPVA-g-PSSS,采用红外光谱(FTIR)、扫描电子显微镜(SEM)及zeta电位测定等法,对接枝微球的化学结构及物理化学特性进行了表征.在此基础上重点考察分析了接枝微球CPVA-g-PSSS对5-氟尿嘧啶(5-FU)的吸附(载药)性能与吸附机理,考察探索了载药微球在不同pH介质中的释放行为.实验结果表明,羟基-铈盐氧化还原引发体系可有效地引发SSS在CPVA微球的表面接枝聚合,在适宜的反应条件下,可制得PSSS接枝度为16.1 g/100g的接枝微球CPVA-g-PSSS.在酸性介质中,受强静电相互作用的驱动,接枝微球CPVA-g-PSSS对5-FU分子表现出很强的吸附能力,吸附容量达105 mg/g,可实现有效载药.载药微球的释药行为具有强烈的pH依赖性,在pH=1的介质中,基本不释药;而在pH=7.4的介质中,则发生突释,表现出良好的结肠定位释放行为.     

Core–Shell Hollow Microspheres of Magnetic Iron Oxide@Amorphous Calcium Phosphate: Synthesis Using Adenosine 5′‐Triphosphate and Application in pH‐Responsive Drug Delivery

Drug nanocarriers with magnetic targeting and pH‐responsive drug‐release behavior are promising for applications in controlled drug delivery. Magnetic iron oxides show excellent magnetism, but their application in drug delivery is limited by low drug‐loading capacity and poor control over drug release. Herein, core–shell hollow microspheres of magnetic iron oxide@amorphous calcium phosphate (MIO@ACP) were prepared and investigated as magnetic, pH‐responsive drug nanocarriers. Hollow microspheres of magnetic iron oxide (HMIOs) were prepared by etching solid MIO microspheres in hydrochloric acid/ethanol solution. After loading a drug into the HMIOs, the drug‐loaded HMIOs were coated with a protective layer of ACP by using adenosine 5′‐triphosphate (ATP) disodium salt (Na₂ATP) as stabilizer, and drug‐loaded core–shell hollow microspheres of MIO@ACP (HMIOs/drug/ACP) were obtained. The as‐prepared HMIOs/drug/ACP drug‐delivery system exhibits superparamagnetism and pH‐responsive drug‐release behavior. In a medium with pH 7.4, drug release was slow, but it was significantly accelerated at pH 4.5 due to dissolution of the ACP shell. Docetaxel‐loaded core–shell hollow microspheres of MIO@ACP exhibited high anticancer activity.     

Preparation of cross-linked guar gum nanospheres containing tamoxifen citrate by single step emulsion in situ polymer cross-linking method

In the present work, guar gum nanospheres containing tamoxifen citrate (TC) were prepared and characterized for using it as a carrier for targeted drug delivery. Tamoxifen is a non steroidal drug used in the treatment of breast cancer. The compound administered to patients is the citrate salt of the trans isomer, tamoxifen citrate. Single step emulsion in situ polymer crosslinking technique was employed to prepare polymer coated drug nanoparticles. Model polymer used in this study was guar gum, which is commonly used for colon specific drug delivery in the pharmaceutical industry. During preparation four-different drug loading solvents were tried and dichloromethane provided the best drug loading result. Briefly, 5 mg drug was dissolved in dichloromethane and emulsified with an aqueous solution of guar gum using span 80 as emulsifier. Cross-linking was made by the use of cross linker glutaraldehyde during the process. A core shell type particles were observed. Drug load was confirmed by FT-IR and quantitated by HPLC. Nanoparticles were further characterized for particle size and morphology. Particle size between 200 and 300 nm were obtained. Influence of process variables on the size of nanoparticles were studied. It was observed that the concentration of polymer and stabilizer determined the size of nanoparticles.     

A new drug delivery system using plasma-irradiated pharmaceutical aids. VIII. Delayed-release of theophylline from double-compressed tablet composed of eudragit as wall material.

The rapid release from a double-compressed tablet containing theophylline as a core drug with the pH-dependent water-soluble polymers, Eudragit L100, S100 or L100-55 used as a wall material was suppressed by argon plasma-irradiation due to an effect of inter-segmental cross-link reactions on the decrease in the surface polymer solubility of outer layer. In addition, the rapid theophylline release from the double-compressed tablet of Eudragit L100-55 with a lower glass transition temperature (Tg) has converted into the delayed-release system under a set of plasma operational conditions due to an additional effect of plasma heat flux on softening of Eudragit L100-55 surface resulting in the formation of the film-like surface with a particle-particle interlinking of the outer layer.     

Novel Carboxymethyl Chitosan Microspheres for Controlled Delivery of Chelerythrine

Novel carboxymethyl chitosan (O-CMCS) microspheres containing an anti-tumor drug chelerythrine (CHE) have been successfully prepared by an emulsion crosslinking method using glutaraldehyde. The optimized microsphere formulation was characterized for particle size, shape, morphology, crystallinity and in vitro drug release. Results for mean particle size, drug loading content, entrapment efficiency and in vitro drug release of chelerythrine loaded microspheres were found to be 12.18 μm, 4.08%, 54.78% and 35.30% at pH 7.4 in 20 h, respectively. The optimized microspheres had an imperfect crystalline lattice and a spherical, rough morphology and the CHE release from O-CMCS microspheres followed the Higuchi matrix model. All these results suggested that O-CMCS microspheres are a promising carrier system for controlled drug delivery.     

Preparation of Crosslinked Chitosan/Silk Fibroin Blend Films for Drug Delivery System

Crosslinked chitosan/silk fibroin blend films were prepared by a solution casting technique using glutaraldehyde as crosslinking agent. Drug release characteristics of the blend films with various blend compositions were investigated. Theophylline, diclofenac sodium, amoxicillin trihydrate, and salicylic acid were used as model drugs. The release studies were performed at 37 °C in buffer solutions at pH 2.0, 5.5, and 7.2. It was found that the blend films with 80% chitosan content showed the maximum amount of model drug release at pH 2.0 for all the drugs studied here. This result corresponded to the swelling ability of the blend films. From a swelling study, the maximum degrees of swelling of the drug‐loaded blend films were obtained at this pH and blend composition. The amount of drugs released from the films with 80% chitosan content, from the highest to the lowest values, occurred in the following sequence: salicylic acid > theophylline > diclofenac sodium > amoxicillin.

Comparison of the amounts of drug released from chitosan and the blend film with 80% chitosan content at pH 2.0: (filled) chitosan film, and (blank) blend film with 80% chitosan content (SAL = salicylic acid, THEO = theophylline, DFS = diclofenac sodium, AMX = amoxicillin).     

大豆蛋白基茶碱控释片的制备及稳定性研究

以茶碱为模型药物,大豆蛋白和海藻酸钠作为骨架材料,采用混合压片法制备了不同比例的药物片剂。采用紫外比色法测定释放效果,考察了大豆蛋白与海藻酸钠不同比例以及不同pH释放介质和高湿度对茶碱片稳定性的影响。结果表明:大豆蛋白和海藻酸钠作为骨架材料的片剂释药时间都达到了8h以上,在pH6.8PBS中的释药率相对pH1.2盐酸溶液要快,具有良好的定向控释特性。随着湿度的增加,茶碱释放率略有下降,具有较好的湿度稳定性。通过适度调节大豆蛋白和海藻酸钠的比例可实现不同控释效果。实验结果表明大豆蛋白和海藻酸钠共混物是一种良好的天然药物缓控释骨架材料,其释放过程符合一级动力学特征,是药物扩散和骨架溶蚀二者共同作用的结果。     

In vitro and in vivo characterization of huperzine a loaded microspheres made from end-group uncapped poly(d,l-lactide acid) and poly(d,l-lactide-co-glycolide acid)

The purpose of this work was to develop biodegradable microspheres for long term delivery of a potent acetyl cholinesterase inhibitor, huperzine A (Hup-A), which is of interest in the palliative treatment of Alzheimer's disease. Microspheres were successfully prepared with specifically end-group uncapped poly(d,l-lactide acid) and poly(d,l-lactide-co-glycolide acid) using a simple o/w solvent evaporation method. The morphology, particle size and size distribution, drug loading capacity, drug entrapment efficiency (EE) and in vitro drug release were studied in detail. It was found that the terminal group and the inherent viscosity (IV) of the polymers played key role in the drug encapsulation: higher EE was achieved with end-group uncapped and low IV polymers. In vitro drug release from microspheres made from the selected three kinds of polymers revealed sustained release of Hup-A without significant burst release. Preliminary pharmacokinetic study following subcutaneous injection of Hup-A loaded microspheres illustrated the sustained release of the drug over 6-8 weeks at clinically relevant doses in vivo. The studies demonstrated the feasibility of long term delivery of Hup-A using biodegradable microspheres.     

Synthesis and characterization of folic acid‐modified carboxymethyl chitosan‐ursolic acid targeted nano‐drug carrier for the delivery of ursolic acid and 10‐hydroxycamptothecin

Carboxymethyl chitosan (CMCS), as a water‐soluble, biocompatible, and biodegradable polymer, is an excellent carrier for a sustained drug delivery system. In this study, a amphiphilic carboxymethyl chitosan‐ursolic acid nano‐drug carrier modified by folic acid (FPCU) were prepared, and then the nano‐drug carrier wrapped another anticancer drug 10‐hydroxycamptothecin were self‐assembled into nanoparticles (FPCU/HCPT NPs). The FPCU/HCPT NPs had a suitable size, high drug loading efficiency of ursolic acid (6.4%) and 10‐hydroxycamptothecin (14.1%). The drug release study in vitro indicated that the nanoparticles have obviously sustained effect and pH sensitive behaviors, the drug release amount was higher at pH 5.5 than at pH 7.4. in vitro and in vivo study showed that the nanoparticles displayed a high antitumor efficiency to tumor cells compared with free drug. The nano delivery system as a carrier for ursolic acid (UA) and 10‐hydroxycamptothecin (HCPT) has good application prospects in cancer treatment.     

凝胶压井液用阴离子改性胍胶的制备及其流变性能

以环氧氯丙烷和NaHSO_3为原料,Na_2SO_3为引发剂,乙二胺四乙酸二钠(EDTA-2Na)为络合增效剂,经酸催化开环反应合成了磺酸型两性表面活性剂中间体3-氯-2-羟基丙磺酸钠,然后在弱酸性条件下与胍胶通过醚化反应制备了磺酸基羟丙基胍胶,其结构经IR表征。通过正交实验确定了合成配方和条件的最优结果,研究了反应温度、pH、改性胍胶浓度对成胶后凝胶的表观粘度影响,并测试了最佳条件下制备的凝胶和对应稀溶液的流变性能。结果表明:氧氯化锆可有效交联改性胍胶,在pH为6、温度为70℃、改性胍胶浓度为0.6%的条件下制备的凝胶具有剪切变稀性质以及较好的粘弹性。