Preparation of double-encapsulated microcapsules for mitigating drug loss and extending release

The double-encapsulated microcapsules were prepared by the non-solvent addition, phase-separation method to form core material and, encapsulated with the O/W emulsion non-solvent addition method to increase drug loading and regulate drug release rate. The drug used was theophylline, which is watersoluble. Dichloromethane and n-hexane were used as the solvent and non-solvent, respectively. This study investigated how various core material and microcapsule EC/TH ratios affect the drug loss, particle size, surface morphology and release rate. The drug loss of the double-encapsulated microcapsules was 12.8% less than that of microcapsules prepared by the O/W emulsion non-solvent addition method alone. The particle size of these double-encapsulated microcapsules decreased as the concentration of EC polymer was increased in the second encapsulation process. The roughness of their surface was also in proportion to the concentration of polymer solution used in the second encapsulation process. The dissolution study showed that the T 20 of the double-encapsulated microcapsules ranged from 2-35.4 h, while that of the O/W emulsion non-solvent addition method microcapsules was from 2.7-7.7 h. The greater the level of EC in the polymer solution, the slower the release rate of the drug from the microcapsules when the EC was not over the critical amount.     

Studies on the Properties of Ethylcellulose Microcapsules Prepared by Emulsion Non-Solvent Addition Method in the Presence of Non-Solvent in Polymer Solution

Abstract

Ethylcellulose microcapsules containing theophylline were prepared by the O/W emulsion non-solvent addition method. Toluene-cyclohexane was chosen as a solvent-non-solvent pair. The effect of the non-solvent added to the polymer solution on the properties of microcapsules was investigated. The results indicated that the size distribution and drug content of microcapsules were slightly affected by the amount of non-solvent in polymer solution. However, the internal conformation of microcapsules was directly related to the amount of non-solvent added to the polymer solution. The greater the non-solvent to solvent ratio in polymer solution the larger the percentage of microcapsules having a hollow conformation. Dissolution studies showed that the release rate of theophylline from microcapsules increased with increasing amount of non-solvent added to the polymer solution, but the release pattern of microcapsules was not obviously changed.     

Polyacrylate resin (Eudragit retard) microcapsules as a controlled release drug delivery system-improved non-solvent addition phase separation process

Eudragit retard microcapsules were prepared using an improved non-solvent addition phase separation process with tetrahydrofuran as the solvent. The evolution of microcapsule wall formation was studied by direct methodology. Eudragit coacervation was effected by progressive uptake of tetrahydrofuran by the non-solvent cyclohexane in the presence of a protective colloid, polyisobutylene (PIB). The core materials had a higher affinity for the acrylic that the PIB phase, thus ensuring encapsulation. Microcapsule batch reproducibility depended mainly on the variation in particle size distribution of the recrystallized core material. All batches gave apparent first-order release profiles, confirmed by regression procedures. The release rate was decreased by raising the wall/core ratio, holding constant concentration of either the wall polymer or the core material. Increase in the non-solvent addition rate elevated the release rate, probably due to structural changes in the microcapsule wall. The velocity fell, however, with decrease in particle size of the core material, contrary to expectations. PIB concentration increase elevated the release rate by enhancing wall porosity, shown by scanning electron microscopy.     

Microencapsulation using poly(DL-lactic acid) I: Effect of preparative variables on the microcapsule characteristics and release kinetics

Abstract

Poly(DL-lactic acid) (DL-PLA, molecular weight 20 500) microcapsules containing phenobarbitone (PB) as a reference core were prepared using a water/oil (W/O) emulsion system. Surface morphology, particle size and ‘encapsulation efficiency’ of the microcapsules prepared using different preparative variables have been investigated. Buffer pH 9 was used as a dissolution medium to determine the affect of preparative variables on the release rate from these microcapsules.

With an increase in temperature of evaporation the microcapsule surface became increasingly irregular and porous, due to deposition of phenobarbitone crystals near the vicinity of the microcapsule surface leading to rapid release of the core. The normalized release rate was found to increase exponentially with an increase in the temperature of evaporation. Microcapsule morphology was also severely affected due to differences in polymer concentration in the disperse phase solvent. With the increase in polymer concentration, the microcapsule surface was found to be increasingly irregular and non-continuous, due to rapid precipitation of the polymer. Increased polymer concentrations also increased mean microcapsule diameter. The release rate increased with the increase in polymer concentration due to surface defects and did not exhibit a straight line correlation. When core loading was very high (e.g. C:P, 2:1 and 1:1), crystals of phenobarbitone appeared at the surface and these caused a very rapid burst effect. However, microcapsules containing a lower phenobarbitone content were found to follow t^1/2 dependent release. The encapsulation efficiency was not seriously affected due to variations in temperature of preparation and polymer concentration. However, with the decrease in initial core loading the encapsulation efficiency of microcapsules was found to be reduced.     

Polyacrylate resin (Eudragit Retard) microcapsules as a controlled release drug delivery system improved non-solvent addition phase separation process

Abstract

Eudragit retard microcapsules were prepared using an improved non-solvent addition phase separation process with tetrahydrofuran as the solvent. The evolution of microcapsule wall formation was studied by direct methodology. Eudragit coacervation was effected by progressive uptake of tetrahydrofuran by the non-solvent cyclohexane in the presence of a protective colloid, polyisobu tylene (PIB). The core materials had a higher affinity for the acrylic that the PIB phase, thus ensuring encapsulation. Microcapsule batch reproducibility depended mainly on the variation in particle size distribution of the recrystallized core material. All batches gave apparent first-order release profiles, confirmed by regression procedures. The release rate was decreased by raising the wall/core ratio, holding constant concentration of either the wall polymer or the core material. Increase in the non-solvent addition rate elevated the release rate, probably due to structural changes in the microcapsule wall. The velocity fell, however, with decrease in particle size of the core material, contrary to expectations. PIB concentration increase elevated the release rate by enhancing wall porosity, shown by scanning electron microscopy.     

Preparation and in vitro dissolution of isoniazid from ethylcellulose microcapsules

Microcapsules of isoniazid were prepared by phase separation coacervation process induced by non-solvent addition and using ethylcellulose (EC) as coating polymer. When polyisobutylene (PIB)--a protective colloid was present at sufficient concentration, film coated drug particles were formed. At 0-6% PIB concentration, the microcapsules were aggregated. Increase of colloid concentration produced microcapsules of less aggregation and higher drug content because coating became progressively thinner. PIB concentration also controlled the particle size and the release rate of drug from microcapsules. Wall thickness and EC loss were calculated from drug content. Microcapsules coated with EC were prepared with 7-9% PIB. Scanning Electron Microscopy was used to study the nature of aggregation and coating behaviour. The in vitro dissolution study confirmed the first order release pattern and also the Higuchi Matrix model.     

Microencapsulation of acetaminophen into poly(L-lactide) by three different emulsion solvent-evaporation methods

Poly(L-lactide) (PLLA) microcapsules containing acetaminophen (APAP) were prepared by three emulsion solvent-evaporation methods including an O/W-emulsion method, an O/W-emulsion co-solvent method and a W/O/W-multiple-emulsion method. The average size and morphology of the microcapsules varied substantially among these three preparation methods. Various alcohol and alkane co-solvents were found to exert significant impact on the O/W-emulsion co-solvent method and a more lipophilic co-solvent such as heptane appeared to enhance drug encapsulation with an efficiency nearly double of the O/W-emulsion method. When a small amount of water was added as the internal aqueous phase in the W/O/W-multiple-emulsion method, the encapsulation efficiency was found nearly triple of that for the O/W-emulsion method. While having a higher encapsulation efficiency, the microcapsules prepared by the W/O/W-multiple-emulsion method had as good controlled release behaviour as those prepared by the O/W-emulsion method. The release kinetics of microcapsules prepared by the O/W-emulsion method and the O/W-emulsion co-solvent (alcohol) method fitted the Higuchi model well in corroboration with the uniform distribution of APAP in PLLA matrix, i.e. the monolithic type microcapsules. However, the release kinetics of microcapsules prepared by the O/W-emulsion co-solvent (alkane) method and the W/O/W-multiple-emulsion method fitted the first-order model better, indicating the reservoir type microcapsules.     

Microencapsulation of acetaminophen into poly(L-lactide) by three different emulsion solvent-evaporation methods

Poly(L-lactide) (PLLA) microcapsules containing acetaminophen (APAP) were prepared by three emulsion solvent-evaporation methods including an O/W-emulsion method, an O/W-emulsion co-solvent method and a W/O/W-multiple-emulsion method. The average size and morphology of the microcapsules varied substantially among these three preparation methods. Various alcohol and alkane co-solvents were found to exert significant impact on the O/W-emulsion co-solvent method and a more lipophilic co-solvent such as heptane appeared to enhance drug encapsulation with an efficiency nearly double of the O/W-emulsion method. When a small amount of water was added as the internal aqueous phase in the W/O/W-multiple-emulsion method, the encapsulation efficiency was found nearly triple of that for the O/W-emulsion method. While having a higher encapsulation efficiency, the microcapsules prepared by the W/O/W-multiple-emulsion method had as good controlled release behaviour as those prepared by the O/W-emulsion method. The release kinetics of microcapsules prepared by the O/W-emulsion method and the O/W-emulsion co-solvent (alcohol) method fitted the Higuchi model well in corroboration with the uniform distribution of APAP in PLLA matrix, i.e. the monolithic type microcapsules. However, the release kinetics of microcapsules prepared by the O/W-emulsion co-solvent (alkane) method and the W/O/W-multiple-emulsion method fitted the first-order model better, indicating the reservoir type microcapsules.     

Microencapsulation using poly(DL-lactic acid). I: Effect of preparative variables on the microcapsule characteristics and release kinetics

Poly(DL-lactic acid) (DL-PLA, molecular weight 20,500) microcapsules containing phenobarbitone (PB) as a reference core were prepared using a water/oil (W/O) emulsion system. Surface morphology, particle size and 'encapsulation efficiency' of the microcapsules prepared using different preparative variables have been investigated. Buffer pH 9 was used as a dissolution medium to determine the affect of preparative variables on the release rate from these microcapsules. With an increase in temperature of evaporation the microcapsule surface became increasingly irregular and porous, due to deposition of phenobarbitone crystals near the vicinity of the microcapsule surface leading to rapid release of the core. The normalized release rate was found to increase exponentially with an increase in the temperature of evaporation. Microcapsule morphology was also severely affected due to differences in polymer concentration in the disperse phase solvent. With the increase in polymer concentration, the microcapsule surface was found to be increasingly irregular and non-continuous, due to rapid precipitation of the polymer. Increased polymer concentrations also increased mean microcapsule diameter. The release rate increased with the increase in polymer concentration due to surface defects and did not exhibit a straight line correlation. When core loading was very high (e.g. C:P, 2:1 and 1:1), crystals of phenobarbitone appeared at the surface and these caused a very rapid burst effect. However, microcapsules containing a lower phenobarbitone content were found to follow t1/2 dependent release. The encapsulation efficiency was not seriously affected due to variations in temperature of preparation and polymer concentration. However, with the decrease in initial core loading the encapsulation efficiency of microcapsules was found to be reduced.     

Microencapsulation of peptides and proteins

Microcapsules were prepared by using a double-emulsion technique. A new production method called 'induced phase separation method' was applied to encapsulate peptides and proteins. To find the optimal adjuvants a matrix was set up combining the appropriate organic solvents and the suitable surfactants. The polymer was chosen with regard to the required release period. The aqueous drug solution was intensively mixed with the organic polymer solution. An aqueous surfactant solution was slowly added to the O/W emulsion. The obtained W/O/W emulsion is stirred under partial vacuum conditions until the organic solvent was removed. After removing the solvent from the W/O/W emulsion the microcapsules were washed and lyophilized. The morphology of the microparticles (spheres, sponges, capsules, surplus polymer) was checked by microscopy, particle size distributions were measured by laser diffraction.     

Micromeritics and release behaviours of cellulose acetate butyrate microspheres containing theophylline prepared by emulsion solvent evaporation and emulsion non-solvent addition method

The present research work compares the effect of microsphere preparation technique on micromeritics and release behaviors of theophylline microspheres. Microspheres were prepared by oil-in oil (O₁/O₂) emulsion solvent evaporation method (ESE) using different ratios of anhydrous theophylline to cellulose acetate butyrate (CAB). Cyclohexane was used as non-solvent to modify the ESE technique (MESE method) and the effect of non-solvent volume on properties of microspheres was investigated. The obtained microspheres were analyzed in terms of drug content, particle size and encapsulation efficiency. The morphology of microsphere was studied using scanning electron microscope. The solid state of microspheres, theophylline and CAB were investigated using X-ray, FT-IR and DSC. The drug content of microspheres prepared by MESE method was significantly lower (15.54% ± 0.46) than microspheres prepared by ESE method (41.08 ± 0.40%). The results showed that as the amount of cyclohexane was increased from 2 mL to 6 mL the drug content of microspheres was increased from 15.54% to 28.71%. Higher encapsulation efficiencies were obtained for microspheres prepared by ESE method (95.87%) in comparison with MESE method (64.71%). Mean particle size of microsphere prepared by ESE method was not remarkably affected by drug to polymer ratio, whereas in MSES method when the volume of cyclohexane was increased the mean particle size of microsphere was significantly decreased. The ratio of drug to polymer significantly changed the rate of drug release from microspheres and the highest drug release was obtained for the microsphere with high drug to polymer ratio. The amount of cyclohexane did not significantly change the drug release. Although, x-ray showed a small change in crystallinity of theophylline in microspheres, DSC results proved that theophylline in microspheres is in amorphous state. No major chemical interaction between the drug and polymer was reported during the encapsulation process.     

丙氨瑞林微球制备工艺优化和体外释放研究

目的:制备包封率高、可持续释药35 d的丙氨瑞林微球.方法:以生物可降解聚合物聚乳酸-聚羟基乙酸(PLGA)为载体,采用W/O/W复乳溶剂挥发法制备缓释丙氨瑞林微球,以包封率为观察指标,用正交设计L9(34)对微球制备工艺进行优化.在pH=7.0的磷酸盐缓冲溶液中考察微球的体外释放.结果:经优化工艺制备的丙氨瑞林微球包封率为(93.2±1.6)％,90％的微球粒径分布范围为55～65 μm.在选择的释放条件下,至35 d时,药物累积释放92.3％,突释为9.7％.结论:该制备工艺简单、稳定.优化条件下制备的丙氨瑞林微球包封率高、粒径适宜、突释少.     

Microencapsulation using poly(DL-lactic acid). II: Effect of polymer molecular weight on the microcapsule properties

Poly(DL-lactic acid) (DL-DPA) of three different molecular weights, 20,500; 13,300 and 5200, was used to prepare microcapsules containing differing contents of phenobarbitone (PB), as a reference core. A water/oil (W/O) emulsion evaporation method was used. The effect of polymer molecular weight on the particle size, 'encapsulation efficiency', morphology, density, thermal behaviour and swelling property has been reported. A general trend towards lowering the mean microcapsule size, both by volume and population, was observed with respect to lower polymer molecular weight. The gross morphology of the microsapsule surface, encapsulation efficiency and density were unaffected by variations in polymer molecular weight. Differential scanning calorimetric analysis of the microcapsules showed a lowering of glass transition temperature after microencapsulation. The melting endotherm for phenobarbitone also indicated the presence of crystalline drug in the microcapsule matrix. These microcapsules were found to swell in the aqueous environment and the mean size increased linearly with time. However, the rate of swelling was higher with low molecular weight polymer and also depended on core loading.     

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.     

Preparation and characterization of quercetin-loaded polymethyl methacrylate microcapsules using a polyol-in-oil-in-polyol emulsion solvent evaporation method

Flavonoids and related compounds exhibit a wide range of useful pharmacological properties but present challenges related to their stability and solubility in commonly available solvents. In this study, polymethyl methacrylate (PMMA) microcapsules were prepared using a novel polyol-in-oil-in-polyol (P/O/P) emulsion solvent evaporation method as a means of stabilizing the flavonoids, using quercetin as a model flavonoid drug. The morphology of the microcapsules was evaluated using a scanning electron microscope, revealing a spherical shape with a smooth surface. The cross-section image of the PMMA microcapsules prepared with an amphiphilic polymer in the inner polyol phase showed that the microcapsule was filled with several submicron microspheres. The mean diameter varied from 1.03+/-0.12 microm to 2.39+/-0.42 microm, and the encapsulation efficiency ranged from 12.7% to 26.9%. When free quercetin was stored at 42 degrees C, the residual quercetin content gradually decreased to 18% over 28 days as a result of oxidation. However, when encapsulated in PMMA microcapsules with an amphiphilic polymer in the inner polyol phase, the residual quercetin content decreased to just 82%. In-vitro release studies indicated a sustained release pattern throughout the 36-h study. The release kinetics of the microcapsules with an amphiphilic polymer followed a diffusion-controlled mechanism and the microcapsule without amphiphilic polymer followed an anomalous diffusion behaviour. This study suggests that the novel P/O/P emulsion solvent evaporation method can be applied to the encapsulation of flavonoids.     

Bupivacaine-loaded biodegradable poly(lactic-co-glycolic) acid microspheres I. Optimization of the drug incorporation into the polymer matrix and modelling of drug release

Bupivacaine has been encapsulated by solvent evaporation method based on O/W emulsion, using poly(DL-lactic-co-glycolic) acid (PLGA) 50:50. The particle size can be controlled by changing stirring rate and polymer concentration. The encapsulation efficiency was affected by polymer concentration and burst effect of bupivacaine released from particles was affected by drug/polymer mass ratio. Orthogonal design was used to optimize the formulation according to drug content, encapsulation efficiency and burst effect. The dissolution profile and release model were evaluated with two different bupivacaine microspheres (bupi-MS) groups including low drug loading (6.41%) and high drug loading (28.92%). It was observed that drug release was affected by drug loading especially the amount of drug crystal attached on surface of bupi-MS. The drug release profile of low drug loaded bupi-MS agreed with Higuchi equation and that of high drug loaded bupi-MS agreed with first order equation.     

Development and characterization of different low methoxy pectin microcapsules by an emulsion-interface reaction technique

In the controlled release area, biodegradable microcapsules are one of the most useful devices to deliver materials in an effective, prolonged and safe manner. A new charged film microcapsular carrier system, using three different pectins, is described. The study utilized pectin microcapsules prepared by two encapsulation mechanisms of interfacial reaction explored through interaction of charged droplet-oil-anionic surfactant-calcium or oil-cationic surfactant with negatively charged pectin. A method for drug encapsulation was developed based on the type of pectin, surfactants and emulsification technique. Both types of surfactant, anionic sodium dodecyl sulphate (SDS) and cationic benzalkonium chloride (BzACl) promoted polymer film formation on the oil droplet surfaces, probably through cross-linking and electrostatic interaction, respectively. Microcapsules consisting of pectin as shell and hydrophobic oil as core were characterized. The resulting microcapsules were relatively small particles (d< 3 microm), had high total particle number, specific surface area and drug encapsulation efficiency. They also demonstrated good stability with minimum particle aggregation. Correlation between physicochemical and drug release kinetic parameters were investigated with regard to the effect of pectin macromolecular structure and nature of surfactant used as a counterion in the manufacturing of microcapsules. The release rate of the encapsulated material (prednisolone) in three microcapsules can be controlled by manipulating the conformational flexibility of pectins in the presence of different counterions. As a result, biodegradable pectin microcapsules offer a novel approach for developing sustained release drug delivery systems that have potential for colonic drug delivery.     

PLGA微球的制备及其用于脉冲给药的初步研究

目的：制备聚乳酸-羟基乙酸共聚物（PLGA）微球,并考察其用于脉冲式释药系统的可行性。方法：以牛血清白蛋白（BSA）为模型药物,用S/O/W（Solid-in-oil-in-water）法和S/O/O（Solid-in-oil-in-oil）法制备PLGA（75：25）和PLGA（50：50）微球,比较2种方法制备的微球的表面形态、包封率及载药量等,并考察2种微球的体外释放行为。结果：S/O/W法和S/O/O法制备的微球均圆整、无粘连、形态良好,但S/O/W法制备的微球表面较为平整,而S/O/O法表面均匀分布有较大的凹陷。S/O/W法制备的PLGA（75：25）和PLGA（50：50）微球包封率分别为（60.15±5.95）%、（49.50±3.69）%,载药量分别为（2.56±0.25）%、（2.10±0.16）%,10h内药物释放均为10%左右,而后随着聚合物的降解药物的释放量突然增加;S/O/O法所制微球包封率分别为（84.36±1.11）%、（77.94±1.42）%,载药量分别为（3.58±0.05）%、（3.31±0.06）%,24h内药物释放均可达50%左右,而后呈现较为平稳的释放行为。S/O/O法制备的微球包封率及载药量均较S/O/W法高;S/O/W法制备的PLGA微球药物释放呈现一定的脉冲行为,其中PLGA（75：25）微球体外释放行为受微球粒径的影响较大。结论：S/O/W法制备的PLGA微球具有一定的脉冲式释药效果,微球的粒径最好控制在120μm以下。     

Taste masking of diclofenac sodium using microencapsulation.

This study addresses how to mask the undesirable taste of diclofenac sodium (DS) without interfering with an adequate rate of drug release. DS microcapsules were successfully prepared using a system of ethylcellulose (EC)-toluene-petroleum ether. The system was optimized by the construction of the phase diagram and determination of the amount of EC precipitated under different solvent:non-solvent ratios to determine the most appropriate conditions for preparing good microcapsules. Microcrystalline cellulose (Avicel) and lactose were mixed with DS powder and converted into spherical cores by the wet agglomeration technique which facilitated coacervation and formation of thin and uniform microcapsule walls. Diethylphthalate (DEP) and Polyethyleneglycol 600 (PEG) in different concentrations (20 or 40% w/w) were used as plasticizers to impart better elasticity to the microcapsules. The microcapsules were evaluated for DS released against crushed commercial DS enteric coated tablet (Voltaren). The prepared microcapsules were taste evaluated by a taste panel of 10 volunteers. The results revealed that the optimum solvent:non-solvent ratio required for microcapsule formation was 1:2. Microcapsules containing PEG 20% or DEP 40% showed a faster rate of DS release compared to that obtained from other microcapsules and crushed commercial enteric coated tablets (Voltaren). The palatability and the taste of DS were significantly improved by microencapsulation. The extent of taste masking was influenced by the microcapsule core:wall ratio, the presence of additives within the core, the type and concentration of plasticizer and initial core size.     

Microencapsulation of insulin using a W/O/W double emulsion followed by complex coacervation to provide protection in the gastrointestinal tract

Abstract

Microcapsules containing insulin were prepared using a combination of a W/O/W double emulsion and complex coacervation between WPI (used as a hydrophilic emulsifier) and CMC or SA with further spray drying of the microcapsules in order to provide protection in the gastrointestinal tract. The microcapsules prepared exhibited high encapsulation efficiency and showed the typical structure of a double emulsion. After spray drying of these microcapsules, the integrity of the W/O/W double emulsion was maintained and the biological residual activity remained high when using the combination of 180?°C inlet air temperature and 70?°C outlet air temperature. The microcapsules exhibited low solubility at pH 2 and high solubility at pH 7 so they might protect insulin at acid pH values in the stomach and release it at intestinal pH values. The microcapsules developed in this study seem to be a promising oral delivery vehicle for insulin or other therapeutic proteins.