Cellulose acetate microspheres prepared by o/w emulsification and solvent evaporation method

The study is concerned with the development of cellulose acetate microspheres by the o/w emulsification and solvent evaporation method in the presence of polyvinyl alcohol as an emulsifying agent. The influence of process parameters such as solvent mixture (acetone + dichloromethane) composition, concentration of the emulsifying agent and speed of stirring has been examined. The microspheres have been analysed for their size, drug loading capacity and release kinetics. Spherical and smooth surfaced microspheres with encapsulation efficiencies ranging between 73-98% were obtained. Use of acetone in the oil phase drastically reduced the particle size. Slow drug release from microspheres occurred up to ~8h and the release was found to be non-Fickian. An optimization procedure was employed to investigate and identify the key parameters affecting the properties of the microspheres. A 3 3 randomized full factorial design was used in the analyses of the data. A linear model with interactive terms was generated using a multiple linear regression approach. The statistical analysis confirms the significant effect of solvent composition and concentration of emulsifying agent on the drug release characteristics.     

Release kinetic studies of aspirin microcapsules from ethyl cellulose, cellulose acetate phthalate and their mixtures by emulsion solvent evaporation method

The present study was oriented towards microencapsulation of aspirin and the study of its release kinetics. The desired encapsulation was achieved by emulsion solvent evaporation method using ethyl cellulose (EC), cellulose acetate phthalate (CAP) and their mixture (1:1) of polymeric constituents. Characterization of the formulations was performed by size, shape, drug loading efficiency and in-vitro drug release analysis. The in-vitro release profiles from different polymeric microcapsules were applied on different kinetic models. The prepared microcapsules were found free flowing and almost spherical in shape with particle sizes ranging from 300–700μm, having a loading efficiency of 75–85%. The best fit model with the highest correlation coefficient was observed in Higuchi model, indicating diffusion controlled principle. The n value obtained from Korsemeyer-Peppas model varied between 0.5–0.7, confirming that the mechanism of drug release was diffusion controlled. Comparative studies revealed that the release of aspirin from EC microcapsules was slower as compared to that of CAP and their binary mixture.     

Influence of nanofiber alignment on the release of a water-soluble drug from cellulose acetate nanofibers

Cellulose acetate nanofibers with different degrees of alignment (randomly aligned (RA), partially aligned (PA), and highly aligned (HA)) were produced using an electrospinning technique. The different degrees of alignment were obtained by adjusting the rotation speed of the collector. Alpha-arbutin (3% w/w) employed as a model water-soluble compound was incorporated into the nanofibers during the fabrication process. The drug release characteristics were investigated using the nanofiber mats with the same size and weight. The prepared nanofibers with different degrees of alignment showed similar physical characteristics, including the fiber diameter, drug loading efficiency and capacity, and molecular form of the drug in the fibers. Interestingly, alpha-arbutin was released from HA nanofibers at a significantly faster rate than the PA and RA nanofibers. Eighty percent of the drug was released into the medium in 1.7, 4.2, and 9.4 min for HA, PA, and RA nanofibers, respectively. The orientation of nanofibers played a crucial role in governing the drug release, probably by creating network meshes with different degrees of entanglement, affecting the diffusion of drug to the external medium. Consequently, this approach can be used as a simple means of achieving immediate-release or fast-acting characteristics of cellulose-based formulations containing a water-soluble drug.     

Effect of the dispersion of Eudragit S100 powder on the properties of cellulose acetate butyrate microspheres containing theophylline made by the emulsion-solvent evaporation method

The dispersion/incorporation of Eudragit S100 powder as a filler in cellulose acetate butyrate (CAB-551-0.01) microsphere containing theophylline was investigated as a means of controlling drug release. Microspheres of CAB-551-0.01 of different polymer solution concentrations/viscosities were prepared (preparations Z(0), Z(A), Z(B) and Z(C)) and evaluated and compared to microspheres of a constant concentration of CAB-551-0.01 containing different amounts of Eudragit S100 powder as a filler (preparations X(A), X(B) and X(C)). The organic solvent acetonitrile used was capable of dissolving the matrix former CAB-551-0.01 only but not Eudragit S100 powder in the emulsion-solvent evaporation method. The CAB-551-0.01 concentration in Z(A), Z(B) and Z(C) was equal to the total polymer concentration (CAB-551-0.01 and Eudragit S100 powder) in X(A), X(B) and X(C), respectively. Scanning electron microscopy (SEM) was used to identify microspheres shape and morphology. In vitro dissolution studies were carried out on the microspheres at 37 degrees C (+/-0.5 degrees C) at two successive different pH media (1.2 +/- 0.2 for 2 h and 6.5 +/- 0.2 for 10 h). Z preparations exhibited low rates of drug release in the acidic and the slightly neutral media. On the other hand, X preparations showed an initial rapid release in the acidic medium followed by a decrease in the release rate at the early stage of dissolution in the slightly neutral pH which could be due to some relaxation and gelation of Eudragit S100 powder to form a gel network before it dissolves completely allowing the remained drug to be released.     

Viscosity of polymer solution phase and other factors controlling the dissolution of theophylline microspheres prepared by the emulsion solvent evaporation method

The objectives of this investigation are to evaluate the effect of the viscosity of polymer solution phase on microsphere properties, especially the drug release characteristics since no studies on this formulation variable have been reported. Also, since it is known that polymer molecular weight affects both the viscosity of the polymer solution and the release properties of microspheres, the interaction of these factors was studied. Microspheres with 33% theoretical drug loading of anhydrous theophylline core material were prepared by the emulsion solvent evaporation method. Two cellulose acetate butyrate polymers, (CAB381-2, CAB381-20), chemically similar but having different molecular weights, were used to prepare different polymer solutions having different apparent viscosities in acetone. A Brookfield viscometer was used to evaluate the viscosities of polymer solutions. Dissolution rates of microspheres prepared from the polymer solutions were inversely related to the initial polymer solution viscosities for both CAB381-2 and CAB381-20. The times for the release of 30 and 50% of the drug from the microspheres have a linear relationship with initial polymer solution viscosity. Initial release was significantly decreased with increasing polymer solution viscosity. Unlike CAB381-2 microspheres which follow Higuchi spherical matrix release kinetics, microspheres prepared from the higher molecular weight polymer (CAB381-20) showed extended release dissolution profiles with near zero order kinetics. It is evident that both the polymer solution viscosity and the molecular weight have an effect on the drug release from microspheres. These results suggest that release rates of matrix microspheres could be predictably optimized by adjusting the viscosity of polymer solutions.     

Synthesis and release studies of shikonin-containing microcapsules prepared by the solvent evaporation method

Microcapsules, containing the pharmaceutical substance shikonin, were prepared by the solvent evaporation method in order to enhance shikonin stability (reduce photo-oxidation, polymerization), decrease its hydrophobicity and control its release rate. The effect of various parameters, such as type of polymer, type and concentration of surfactant, solvent volume and mastic gum (Pistacia lentiscus resin) content/concentration as core additive, on the characteristics of the produced microcapsules and the release rate of shikonin, were experimentally investigated. Among the polymers tested for matrix, ethylcellulose (EC) of viscosity 10 cp was the most successful; EC 100 cp and mastic gum result in larger/compact particles with no pores and much slower release. Sodium dodecyl sulphate (SDS) results in microcapsules with desirable morphological and physicochemical characteristics, while polyethylene glycol (PEG) and polyvinyl alcohol (PVA) are not indicated as surfactants in shikonin microencapsulation. Decreasing the solvent volume (dichloromethane) results in increased mean particle size and, thus, in slower release rate of shikonin, while the incorporation of mastic gum in the capsule core results in better control of shikonin release. Finally, the combination of EC 10 cp as matrix, mastic gum as core additive, low dichloromethane (DCM) volume and low SDS concentration results in microcapsules with the best characteristics in terms of efficiency, loading, release and particle size distribution.     

Particle size and loading efficiency of poly(D,L-lactic-coglycolic acid) multiphase microspheres containing water soluble substances prepared by the hydrous and anhydrous solvent evaporation methods

PLGA multiphase microspheres were prepared by the multiple emulsion solvent evaporation method using acetonitrile as the polymer solvent and mineral oil as the evaporation medium. The preparation process was further developed in the present study to reduce the particle size and to increase the loading capacity of brilliant blue, bovine serum albumin (BSA) and tumour necrosis factor-alpha (TNF-alpha) which were used as water soluble model drug substances. Sorbitan sesqui-oleate (SO-15EX), present at the 1% w/w level in the evaporation medium, prevented agglomeration of the microspheres containing a solid-in-oil (S/O) suspension as the core phase. This S/O suspension core provided significantly higher loading efficiency of the proteins to the W/O emulsion core. The W/O emulsion system resulted in agglomeration of the protein-loaded microspheres and the loading efficiency decreased significantly. When brilliant blue was included as the model compound, the loading efficiencies were not influenced by the core type. Heavy mineral oil was employed to stabilize the dispersed unhardened microspheres rather than light mineral oil that was reported previously. This anhydrous emulsion system employing the S/O suspension core and containing a dispersion of TNF-alpha enabled the encapsulation of this protein without loss of activity. It was concluded that the anhydrous emulsion system is asuitable approach toprepare multiple microspheres as an alternative to the W/O emulsion system, especially when solvent sensitive proteins are incorporated into the microspheres.     

Diclofenac sodium loaded-cellulose acetate butyrate: Effect of processing variables on microparticles properties,drug release kinetics and ulcerogenic activity

The aim of this study was to develop and characterize diclofenac sodium loaded-cellulose acetate butyrate microparticles in order to obtain a controlled-release system. The influence of the type of polymer, the volume and composition of the internal phase, drug loading, surfactant concentration and additive added on microparticles characteristics (particle size, encapsulation efficiency, surface morphology and in vitro release profiles) was studied to optimize the microparticles system. The resultant microparticles were evaluated for the recovery, average particle size, drug loading and incorporation efficiency. The microparticles exhibited good flowing nature and compressibility index when compared to pure drug. Dissolution rate of diclofenac sodium in phosphate buffer (pH 6.8) increased with increases in initial drug loading, surfactant concentration and addition of alcohol as co-solvent but decreased with increases in the concentration of additives such as Gantrez® AN or Eudragit S100 in the internal phase. The dissolution data showed a Higuchi diffusion pattern for most of the formulations. About 56–81% reduction in ulcerogenic activity was observed with microparticles containing Eudragit S100 17–25%, based on total polymer concentration, when compared with pure diclofenac sodium.     

In vitro and in vivo release of poly(DL-lactic acid) microspheres containing neurotensin analogue prepared by novel oil-in-water solvent evaporation method.

Poly(DL-lactic acid) (PLA) microspheres containing a neurotensin analogue [NA; H(CH3)-Arg-Lys-Pro-Trp-tert-Leu-Leu-OEt.3HCl] were prepared by a novel oil-in-water (o/w) solvent evaporation method, and the release behaviors were evaluated in vitro. About 20% of the loaded NA was released initially, and the subsequent release lasted for a month from microspheres prepared with PLA of molecular weight 2000 (PLA 2000). A smaller initial release from PLA 4000 and PLA 6000 microspheres was found, but a lag time of 2-3 weeks during which the drug was not released was observed with PLA 4000 and PLA 6000 microspheres. The addition of relatively hydrophilic monoglycerides decreased the lag time, and a fairly constant release of NA was achieved. The pharmacokinetic behavior of NA from PLA 2000 microspheres was studied in rats. The release of the drug after a subcutaneous injection exhibited pseudo-zero-order kinetics for 1 month. The initial release of the drug from the microspheres was reflected in a sharp increase of the plasma levels of the de-ester form of NA [H(CH3)-Arg-Lys-Pro-Trp-tert-Leu-Leu-OH], and the subsequent steady-state levels agreed well with the predicted levels obtained from analysis of constant-infusion kinetics.     

Polylactic acid microspheres containing quinidine base and quinidine sulphate prepared by the solvent evaporation method. III. Morphology of the microspheres during dissolution studies

Poly(dl-lactide) (PLA) microspheres containing quinidine or quinidine sulphate were prepared by the emulsification-solvent evaporation technique. The in vitro release profile of quinidine or quinidine sulphate from the microspheres was characterized by three phases: a lag time, a rapid release phase (burst), and a slow release phase. Drug release was studied as a function of the ionic strength of the dissolution medium, to demonstrate the importance of the water imbition into the microspheres which induced the drug release. The lag time increased with increasing ionic strength. The microspheres stayed intact during the dissolution study as shown by scanning electron microscopy (SEM). Disintegration of microspheres which was initially observed was an artifact introduced during the SEM procedure. The high vacuum applied either during the coating of the microspheres with gold-palladium or during the actual observation in the scanning electron microscope caused the microspheres to collapse or rupture.     

壳聚糖/海藻酸钠自组装微球的制备及释药性能

目的利用壳聚糖(CS)聚阳离子及海藻酸钠(ALG)聚阴离子电解质的性质,在药物微球表面自组装形成多层包覆结构的壳聚糖载药微球,并研究组装层数、温度及盐离子浓度对自组装微球释药性能的影响。方法采用乳化交联法制备CS载四环素(TC)的药物微球,并在其表面交替自组装ALG及CS。利用IR测试技术及电极电位法进行表征。结果CS交联微球未破坏CS及TC的结构,CS与ALG以静电作用相结合。CS交联微球的载药量为40.2%,自组装六层的微球载药量为32%。组装后,药物释放时间延长,初期暴释现象得到极大改善,释药速率随组装层数的增加而下降,温度较高时组装完整,盐离子浓度存在较佳点。结论温度为60℃、盐离子浓度为0.5 mol.L-1、组装层数为四层的微球释药性能较佳。     

In vitro and in vivo evaluation of PLAGA (50/50) microspheres containing 5-fluorouracil prepared by a solvent evaporation method

Poly (DL-lactide-co-glycolide) PLAGA (50/50) microspheres containing an antineoplastic drug, 5-fluorouracil (5-FU) were prepared by a solvent evaporation process in order to passively target liver carcinomas. The microspheres were spherical with diameters 2–5 μm and encapsulated more than 70% (w/w) of the 5-FU. In vitro release patterns of 5-FU from microspheres were determined for various systems. It was found that drug release depended upon the amount of entrapped drug, the polymer molecular weight and pH of the dissolution medium. The in vitro release mechanism was diffusion controlled and followed a square-root of time relationship. In vivo distribution of ^99mTc labeled microspheres after intravenous injection into mice was characterized by an initially high uptake by organs of the mononuclear phagocyte system (MPS). Following i.v. administration of fluorescein-labeled PLAGA microspheres, accumulation was into the MPS, mainly the Kupffer cells cytoplasm and near the liver sinusoids.     

Effect of viscosity and concentration of wall former, emulsifier and pore-inducer on the properties of amoxicillin microcapsules prepared by emulsion solvent evaporation

This study reports the laboratory optimization for the preparation of sustained release amoxicillin (AMX) ethylcellulose microcapsules by an emulsion solvent evaporation process by adjusting the viscosity and concentration of ethylcellulose, ratio of amoxicillin to ethylcellulose, and concentration of emulsifier and pore inducer. When ethylcellulose with a viscosity of 45 mPa.s was used, almost no material stuck to the inside wall of the beaker and uniform microcapsules were prepared. The average diameter of microcapsules increased and yield and release rate decreased as the concentration of ethylcellulose increased from 1% to 8%. The release of amoxicillin from microcapsules was influenced by the ratio of the weight of drug to that of ethylcellulose and ratios of 2:1 and 4:1 were most suited for optimum amoxicillin release. The average diameter of microcapsules decreased and the release rate increased as the concentration of the emulsifier increased from 1.5% to 6.0%, however, the size distribution became significantly wider with the increase in the concentration of sorbitan monooleate. Addition of small amounts of a water-soluble agent sucrose improved the release of active ingredient from the microcapsule matrix without influencing the morphology and particulate properties of the microcapsules.