Predicting the physical state of spray dried composites: salbutamol sulphate/lactose and salbutamol sulphate/polyethylene glycol co-spray dried systems

The effect of spray drying salbutamol sulphate, salbutamol sulphate/lactose and salbutamol sulphate/polyethylene glycol (PEG) solutions was investigated. Co-spray drying salbutamol sulphate with lactose, which is amorphous when spray dried alone, resulted in amorphous composites. Co-spray drying salbutamol sulphate with PEG 4000 and PEG 20,000, which do not form amorphous systems when spray dried alone, resulted in systems of varying crystallinity, the crystallinity depending on the weight ratio of polymer to drug. Examination of the physical properties of these salbutamol sulphate co-spray dried systems and those of bendroflumethiazide/PEG and lactose/PEG composites suggested that the formation and physical stability of amorphous composites prepared by spray drying is dependent on whether the glass transition temperature, Tg, of one of the two components is high enough to result in a Tg of the composite sufficiently high that the Kauzmann temperature of the mix is greater than the temperature of storage. The modified Gordon-Taylor equation proved to be useful in predicting the likelihood that a two-component composite will be amorphous on spray drying. Furthermore, the Gordon-Taylor equation was also useful in predicting the likely physical stability of amorphous two component composites and predicted that even polymers with apparently low Tgs, such as PEGs, may be stabilised in an amorphous composite by a suitable additive having a sufficiently high Tg.     

Preparation and characterisation of controlled release co-spray dried drug-polymer microparticles for inhalation 2: Evaluation of in vitro release profiling methodologies for controlled release respiratory aerosols.

Three in vitro methodologies were evaluated as models for the analysis of drug release from controlled release (CR) microparticulates for inhalation. USP Apparatus 2 (dissolution model), USP Apparatus 4 (flow through model) and a modified Franz cell (diffusion model), were investigated using identical sink volumes and temperatures (1000ml and 37 degrees C). Microparticulates containing DSCG and different percentages of PVA (0%, 30%, 50%, 70% and 90%) were used as model CR formulations. Evaluation of the release profiles of DSCG from the modified PVA formulations, suggested that all data fitted a Weibull distribution model with R(2)0.942. Statistical analysis of the t(d) (time for 63.2% drug release) indicated that all methodologies could distinguish between microparticles that did or did not contain PVA (Students t-test, p<0.05). However, only the diffusion model could differentiate between samples containing different PVA percentages. Similar results were observed when analysing the data using similarity and difference factors. Furthermore, analysis of the release kinetic profiles for all samples suggested the data fitted the Higuchi diffusion model (R(2)0.862 for the diffusion methodology data set). Due to the relatively low water content in the respiratory tract and the lack of differentiation between formulations for USP Apparatus 2 and 4, it is concluded that the diffusion model is more applicable for the evaluation of CR inhalation medicines.     

Simultaneous controlled vitamin release from multiparticulates: theory and experiment

The aim of this study was to simultaneously control the release of multiple vitamins exhibiting very different water-solubility and molecular weights from multiparticulates. Several types of sucrose esters and triglycerides were studied as matrix formers in granules prepared by wet granulation, melt granulation or compression and grinding. The vitamin release kinetics were measured in 0.1N HCl, phosphate buffer pH 6.8 and water in a USP paddle apparatus. An appropriate analytical solution of Fick's second law of diffusion was used to better understand the underlying mass transport phenomena. Importantly, the release rates of nicotinamide, pyridoxine hydrochloride, riboflavin 5'-phosphate, riboflavin, thiamine chloride hydrochloride and thiamine nitrate can simultaneously be controlled from the investigated multiparticulates. Varying the total vitamin content, granule size, type of preparation technique and type of matrix former (Sucrose Stearate S370, Sucrose Stearate S1170, glycerol dibehenate, glycerol dipalmitostearate), desired vitamin release rates can be adjusted. Interestingly, diffusion seems to be the dominant mass transport mechanism in most cases. Thus, appropriate solutions of Fick's law can be used to quantitatively predict the effects of the systems' composition and dimensions on the resulting vitamin release patterns. This knowledge can significantly help facilitating device optimization.     

Coating of multiparticulates for sustained release

Multiparticulates are discrete particles that make up a multiple-unit system. They provide many advantages over single-unit systems because of their small size. Studies have shown that multiparticulates are less dependent on gastric emptying, resulting in less inter- and intra-subject variability in gastrointestinal transit time. They are also better distributed and less likely to cause local irritation. The drug dose in a multiple-unit system is divided over the multiparticulates that make up that system. As such, failure of a few units may not be as consequential as failure of a single-unit system. Multiparticulates may be prepared by several methods. Different methods require different processing conditions and produce multiparticulates of distinct qualities. Some of these methods may be broadly classified as pelletization, granulation, spray drying, and spray congealing. Drug particles may be entrapped within the multiparticulates or layered around them. Subsequently, these multiparticulates may be modified in many ways to achieve the desired drug-release profile. One approach to the modification of drug-release profiles in multiparticulates is to coat them. Reasons for the application of coating onto multiparticulates are to obtain functional coats, provide chemical stability, improve physical characteristics, and enhance patient acceptance. Coats are formed from various polymeric coating materials broadly classified as aqueous polymer dispersions, polymer solutions, molten polymers, and dry powders. Depending on the type of coating material used, functions such as sustained release (SR), targeted release, delayed release, and pulsatile release can be achieved. The focus of this review is on SR coating. The most common method used for the application of coating onto multiparticulates is air suspension coating. Other methods include compression coating, solvent evaporation, coacervation, and interfacial complexation. It is also possible to form coated microparticles by spray drying and spray congealing. A major part of this review is focused on factors affecting the coating of multiparticulates and drug-release characteristics from SR coated multiparticulates. Knowledge of these factors is important in the development of SR coated multiparticulates because control of these factors ensures consistency of drug release between batches of multiparticulates. These factors may be classified into four groups: characteristics of cores, characteristics of SR coats, coating equipment, and coating process conditions.     

硫酸沙丁胺醇脉冲控释片的研制

目的:制备硫酸沙丁胺醇双层包衣脉冲片,考察处方及释放条件对体外释药行为的影响,解析其释放机理.方法:混合粉末直接压片,滚转包衣锅法分别包溶胀层和控释衣层.通过测定释放度研究脉冲片的制剂学特征.结果:双层包衣片以脉冲形式释放,释药时滞随控释衣层厚度增加而延长,释药速度减小;渗透压活性物质和溶胀层可提高快速释放期的释药速率.溶出介质pH值和搅拌速度对释药行为无影响.释药机理包括扩散、溶胀和渗透泵机理.结论:调整控释衣膜厚度和组成可获得理想的脉冲释药行为,满足时辰治疗的要求.本给药系统设计可推广应用于水溶性药物的脉冲给药系统研究.     

Enhancement of griseofulvin release from liquisolid compacts

The potential of hydrophilic aerogel formulations and liquisolid systems to improve the release of poorly soluble drugs was investigated using griseofulvin as model drug. The in vitro release rates of this drug formulated as directly compressed tablets containing crystalline griseofulvin were compared to aerogel tablets with the drug adsorbed onto hydrophilic silica aerogel and to liquisolid compacts containing the drug dissolved or suspended in PEG 300. Furthermore, the commonly used carrier and coating materials in liquisolid systems Avicel® and Aerosil® were replaced by Neusilin®, an amorphous magnesium aluminometasilicate with an extremely high specific surface area of 339 m²/g to improve the liquisolid approach.Both the liquisolid compacts containing the drug dissolved in PEG 300 and the aerogel tablets showed a considerably faster drug release than the directly compressed tablets. With liquisolid compacts containing the drug suspended in PEG 300, the release rate increased with rising fraction of dissolved drug in the liquid portion. It could be shown that Neusilin® with its sevenfold higher liquid adsorption capacity than the commonly used Avicel® and Aerosil® allows the production of liquisolid formulations with lower tablet weights.     

Preparation and characterisation of controlled release co-spray dried drug–polymer microparticles for inhalation 1: Influence of polymer concentration on physical and in vitro characteristics

A series of co-spray dried microparticles containing di-sodium cromoglycate (DSCG) and polyvinyl alcohol (PVA - 0%, 30%, 50%, 70% and 90% w/w, respectively), were prepared as potential controlled release (CR) viscous/gelling vehicles for drug delivery to the respiratory tract. The microparticles were characterised in terms of particle size, crystal structure, density, surface morphology, moisture sorption, surface energy and in vitro aerosolisation efficiency. The co-spray dried particles were amorphous in nature and had spherical geometry. High-resolution atomic force microscopy analysis of the surfaces of the DSCG/PVA suggested no significant differences in roughness between microparticles containing 30-90% w/w PVA (ANOVA, p<0.05), while no specific trend in either size or density was observed with respect to PVA concentration. In comparison, a linear decrease in the relative moisture sorption (R2=0.997) and concurrent increase in total surface free energy (R2=0.870) were observed as PVA concentration was increased. Furthermore a linear increase in the aerosolisation efficiency, measured by inertial impaction, was observed as PVA concentration was increased (R2=0.993). In addition, the increase in aerosolisation efficiency showed good correlation with equilibrium moisture content (R2=0.974) and surface energy measurement (R2=0.905). These relationships can be attributed to the complex interplay of particle forces at the contiguous interfaces in this particulate system.     

曲尼司特的壳聚糖纳米粒的制备和体外释放研究

目的：制备载有曲尼司特的壳聚糖纳米粒,考察它的性质和体外释放。方法：用多聚磷酸钠（TPP—Na）做交联剂,采用离子交联法制备的曲尼司特壳聚糖纳米粒。测定纳米粒的大小和电位,并考察纳米粒溶液的稳定性和纳米粒的体外释放。结果：制备了粒径为285．5nm的米粒,而且多分散指数为0．04,药物的包封率为82.4％。结论：壳聚糖可用作制备曲尼司特纳米粒的载体,制备的载药纳米粒有可能开发成注射剂。     

Preparation of superoxide dismutase loaded chitosan microspheres: characterization and release studies.

Superoxide dismutase (SOD) is the most potent antioxidant enzyme. In this study, SOD was encapsulated in chitosan microspheres to obtain suitable sustained protein delivery. Protein-loaded chitosan microspheres with various formulations were prepared based on complex coacervation process. Due to the inherent characteristic of SOD, high encapsulation efficiency could not be obtained with simple preparation method. The pH of chitosan solution is 3.0; when the chitosan microspheres were prepared with this solution, encapsulation was low. Therefore, several strategies have been tested to increase the encapsulation efficiency and good results have been obtained. 70-80% protein encapsulation efficiency was obtained. The addition of PEG to the protein solution enhanced the encapsulation efficiency also. Mean sizes of microspheres were between 1.38 and 1.94 microm. Factors affecting the release behaviour of SOD from microspheres have been studied. They included pH values of chitosan solution (the pH of chitosan solution is 3.0), addition of PEG to the protein solution and the use of adsorption technique. In general, biphasic release profiles were obtained with these formulations. The protein activity changed between 70 and 100% during the release. In general, the protein activity remained in acceptable limits. The SOD encapsulated chitosan microspheres can be prepared by changing the pH or addition of PEG, allowing the safe incorporation of protein for controlled release.     

Factors influencing drug release from stearic acid based compacts

Fatty acids are potentially suitable carriers for use in the design of drug delivery systems, being biocompatible, biodegradable inexpensive and of low toxicity. The release of the model compound benzoic acid from fatty acid compacts of stearic acid was evaluated using the USP Apparatus 2 dissolution assembly in phosphate buffer pH 7.4. Matrix controlled drug release was expected. Release profiles were approximated by square root of time kinetics. Release rate was independent of stirring speed in the rpm range 50-150, however, at 200 rpm a significant increase in release rate was observed particularly at later times, the amount released versus square root of time plots becoming non-linear. Release was independent of compression pressure in the range 1-7 tons. The particle size of the benzoic acid and stearic acid used had a significant influence on release. The use of particles in the range 250-500 microm gave release rate constants (k, g/cm(2) per min(0.5)) approximately 1.5 greater than those of smaller particle size (63-125 microm). The formation factor (F) tended to increase exponentially with drug loading, the increase being steeper for compacts prepared from the larger particle sizes. At 80% drug loading for large sized systems the matrix appeared to offer little resistance to drug release and F approached one.     

阿司匹林壳聚糖微球的制备及体外释放的研究

本文通过乳化-交联法制备了阿司匹林-壳聚糖载药微球,采用红外技术对其结构进行了分析,确定了阿司匹林包埋在壳聚糖微球中,测得其载药量为15.44%,包封率达到60.4%。pH=3.6时释药曲线较好,接近匀速释放。     

白藜芦醇改性壳聚糖水凝胶的制备及体外释放研究

目的研究聚乙二醇化的壳聚糖对白藜芦醇体外释放的影响及载药水凝胶对氧化应激状态下人视网膜色素上皮细胞的保护作用。方法通过有机合成、化学交联等方法制备聚乙二醇-壳聚糖水凝胶,以白藜芦醇为模型药物,采用透析袋法研究其释放机制,对释放曲线进行拟合分析;建立H2O2诱导的ARPE-19细胞的氧化应激模型,利用试剂盒测定乳酸脱氢酶释放率及丙二酸含量。结果与白藜芦醇对照组相比,载药水凝胶的体外释放度明显提高(前者为24%,后者为82%); H2O2能够增加乳酸脱氢酶释放率和丙二酸含量,应用白藜芦醇后降低了以上效应,呈现剂量依赖性;相较于同浓度白藜芦醇对照组,载药水凝胶的抑制作用更好。结论聚乙二醇-壳聚糖水凝胶可提高白藜芦醇的体外释放率、抗氧化保护作用更明显。     

芹菜素壳聚糖微球的制备及体外释药研究

目的以芹菜素为模型药物、脱乙酰壳聚糖为药物载体,制备芹菜素壳聚糖微球,并测定微球中芹菜素的体外释放度。方法采用复乳-乳化化学交联法制备微球,正交试验优化微球制备的工艺,高效液相色谱法检测芹菜素含量。结果最佳工艺制备4批微球,形态良好,微球圆整,平均载药量为8.54%,平均包封率为69.69%,平均粒径为84.33μm。微球在pH 6.8和pH 7.4的磷酸盐缓冲液中释放36 h。结论所选制备工艺稳定,适用于芹菜素壳聚糖微球的制备,体外药物释放结果显示,微球具有良好的缓释效果。     

In vivo-in vitro correlation of salbutamol release from a controlled release osmotic pump delivery system.

The drug release of salbutamol from a controlled release (osmotic pump) tablet was determined in vitro by four different dissolution apparatuses. From published in vivo data, percent of drug absorbed and percent of drug released in vivo were estimated. The highest correlation was obtained between percentage released in vitro versus percentage released in vivo using polynomial regression.     

Preparation and improvement of release behavior of chitosan microspheres containing insulin

Sophisticated delivery systems, such as nanoparticles, represent a growing area in biomedical research. Nanoparticles (Np) were prepared using a solvent emulsion evaporation method (SEEM) to load zinc(II) phthalocyanine (ZnPc). Np were obtained using poly (d,l latic-co-glycolic acid) (PLGA). ZnPc is a second generation of photoactive agents used in photodynamic therapy.

ZnPc loaded PLGA nanoparticles were prepared by SEEM, characterized and available in cellular culture. The process yield and encapsulation efficiency were 80 and 70%, respectively. The nanoparticles have a mean diameter of 285 nm, a narrow size distribution with polydispersive index of 0.12, smooth surface and spherical shape. ZnPc loaded nanoparticles maintains its photophysical behavior after encapsulation. Photosensitizer release from nanoparticles was sustained with a moderate and burst effect of 15% for 3 days. The photocytotoxicity of ZnPc loaded PLGA Np was evaluated on P388-D1 cells what were incubated with ZnPc loaded Np (5 μM) by 6 h and exposed to red light (675 nm) for 120 s, and light dose of 30 J/cm². After 24 h of incubation, the cellular viability was determined, obtaining 61% of cellular death. All the physical–chemical, photophysical and photobiological measurements performed allow us conclude that ZnPc loaded PLGA nanoparticles is a promising drug delivery system for photodynamic therapy.     

盐酸吉西他滨壳聚糖纳米粒的制备及其体外释药特性研究

目的:优化盐酸吉西他滨壳聚糖纳米粒的制备参数,考察纳米粒体外释药特性。方法:以壳聚糖为辅料,采用离子交联法制备盐酸吉西他滨壳聚糖纳米粒,以包封率、载药量、粒径为参考指标设计试验,确定优化制备参数,以透射电镜观察其表观特征,考察纳米粒体外释药程度。结果:以优化参数制备的盐酸吉西他滨壳聚糖纳米粒包封率为(78.93±1.52)%,载药量为(11.71±0.88)%,纳米粒的平均粒径为(169±24)nm,体外释放试验表明纳米粒中盐酸吉西他滨的释放过程符合Higuchi方程。结论:盐酸吉西他滨可以通过离子交联法制备壳聚糖纳米粒,其粒径、包封率、载药量可控,具有缓释效果。     

普罗布考壳聚糖纳米粒子的制备及体外释放

［摘要］目的：制备负载普罗布考的壳聚糖纳米粒子,观察其一般特性、载药量、包封率和体外释放特性。方法：将疏水性药物普罗布考溶解于二氯甲烷,滴加到壳聚糖醋酸溶液中,形成O/W微乳液,室温下缓慢滴加三聚磷酸钠(TPP)溶液,交联形成负载普罗布考的壳聚糖纳米粒子。观察其一般特性,计算载药量和包封率,并模拟体内条件研究普罗布考壳聚糖纳米粒子的体外释放特性。结果：纳米粒子表面圆整,粒径在50nm左右,包封率可达75%以上,载药量在10%左右。药物突释量大小与TPP浓度、壳聚糖浓度以及壳聚糖的相对分子质量有关,释放时间可持续7d左右。结论：普罗布考壳聚糖纳米粒子制备工艺效果好,具有明显的缓释作用。     

Preparation and characterization of chitosan microspheres for controlled release of synthetic oligopeptide derived from BMP-2

The localized and temporally controlled release of growth factors is key to achieving optimal clinical efficacy. To achieve sustained delivery of a novel bone-induced growth factor, chitosan microspheres loaded with synthetic oligopeptide (S([PO4])KIPKASSVPTELSAISTLYLDDD, P24) were prepared by an emulsion-ionic cross-linking method in the presence of tripolyphosphate, with bovine serum albumin (BSA) as a control. Both microspheres containing oligopeptide or BSA were of spherical shape with size ranging from 10-60 μm. The encapsulation efficiency was usually higher than 80% and the loading capacity was affected by initial protein dosage. From the release experiments, it was found that both proteins were slowly released from the microspheres over 7 days in a PBS solution (pH 7.4), in which the release rate of oligopeptide was much lower than that of BSA. Released oligopeptide was demonstrated to possess biological activity as evidenced by stimulation of rabbit marrow mesenchymal stem cells (MSCs) alkaline phosphatase (ALP) activity in vitro. These results indicate that the TPP-chitosan microspheres loaded with synthetic oligopeptide may possess potential application in bone tissue engineering.     

Preparation and characterization of chitosan microspheres for controlled release of synthetic oligopeptide derived from BMP-2

The localized and temporally controlled release of growth factors is key to achieving optimal clinical efficacy. To achieve sustained delivery of a novel bone-induced growth factor, chitosan microspheres loaded with synthetic oligopeptide (S^[PO4]KIPKASSVPTELSAISTLYLDDD, P24) were prepared by an emulsion-ionic cross-linking method in the presence of tripolyphosphate, with bovine serum albumin (BSA) as a control. Both microspheres containing oligopeptide or BSA were of spherical shape with size ranging from 10–60 µm. The encapsulation efficiency was usually higher than 80% and the loading capacity was affected by initial protein dosage. From the release experiments, it was found that both proteins were slowly released from the microspheres over 7 days in a PBS solution (pH 7.4), in which the release rate of oligopeptide was much lower than that of BSA. Released oligopeptide was demonstrated to possess biological activity as evidenced by stimulation of rabbit marrow mesenchymal stem cells (MSCs) alkaline phosphatase (ALP) activity in vitro. These results indicate that the TPP-chitosan microspheres loaded with synthetic oligopeptide may possess potential application in bone tissue engineering.     

Formulation factors affecting the release of ezetimibe from different liquisolid compacts

Context: Liquisolid technique is one of the methods used to improve the dissolution rate of the poorly water soluble drugs utilizing non volatile liquids.Objectives: Enhancement of the release of ezetimibe from different liquisolid formulations.Materials and Methods: Four liquid vehicles were used to prepare the liquid medications with different drug concentrations. The interaction between the drug and the excipients in liquisolid powders were characterized by DSC, X-ray, FTIR and SEM. Furthermore, the powder characteristics were evaluated by Carr’s Index and powder wetting time determinations, respectively. All prepared formulations were compressed at different pressures to end with the same constant porosity and the tablets were evaluated by different tests and compared with conventional formula. Results and Discussion: No interaction had been detected in all liquisolid formulations as shown in the results of XRD, FTIR, DSC and SEM. In addition to that, all liquisolid compacts had expressed faster dissolution profiles compared with that of conventional formula. Conclusion: The dissolution rate was affected by the drug concentration, solubility of the drug in the liquid vehicle and type of carrier. In addition, the presence of the liquid vehicle has been found to affect the mechanical properties of the liquisolid formulations.