Kinetics of drug release from polylactic acid—hydrocortisone microcapsules

Abstract

Polylactic acid microcapsules of similar particle size distribution containing various drug loadings of hydrocortisone were prepared. The microcapsules, which contained randomly dispensed drug particles, showed a dissolution pattern which consists of a fast first-stage and a slow second-stage drug release. Our studies showed that the kinetics of drug release from the microcapsules can be adequately described by a spherical matrix model based on a flux mechanism involving the diffusion of dissolved drug at the penetrating front of the dissolution medium. Drug loading played an important role in the control of drug release rate. An empirical relationship between drug loading and drug diffusi-bility through the polymeric matrix was developed and showed that the rate of drug release increased exponentially with the increase in drug loading. The microcapsules were further shown to exhibit increased rate of drug release in dissolution medium containing either cetylpyridium chloride or aerosol OT. The effect of the surfactants was attributed to surface tension lowering and improved wetting of the microcapsule particles.     

Effect of surface active agents on drug release from polylactic acid-hydrocortisone microcapsules

Polylactic acid microcapsules containing randomly distributed hydrocortisone particles were prepared. The rate of release of hydrocortisone from the microcapsules in pH 7.4 phosphate buffer was found to be largely increased by the presence of polysorbate 80, cetylpyridinium chloride, or aerosol OT in the dissolution medium. The surfactant effect was attributed to the ability of the surface active agent to improve solvent penetration into the microcapsules by lowering the surface tension at the solid-liquid interface. The effect of the cationic surfactant, cetylpyridinium chloride on the rate of drug release is similar in magnitude to that of the nonionic surfactant, polysorbate 80. In these systems, the rate of drug release from the microcapsules was found to be linearly related to the surface tension of the dissolution medium in the range of 40-60 dyn/cm (x 10(-3) N/m). In the same surface tension range, the effect of aerosol OT on rate increase was found to be much less than those of the cationic and nonionic surfactants. This suggests that the anionic surfactant is not well adsorbed at the interface due to the negative charge characteristics of the surface of the polylactic acid microcapsules. However, at nearly the critical micelle concentration of aerosol OT, where the corresponding surface tension is much lower than those of the cationic and nonionic surfactants, the microcapsules exhibited the highest rate of drug release.     

Preparation and in vitro evaluation of polylactic acid-mitomycin C microcapsules

Abstract

An emulsion method was developed for the incorporation of water-soluble mitomycin C into polylactic acid biodegradable microcapsules. With an average particle size of about 95 μm, microcapsules with a desired loading of from 3.65 to 13.80 per cent were prepared. These microcapsules, which contained both crystalline and finely dispersed drug particles, showed a dose-dependent drug release pattern with microcapsules of higher drug loading having a faster release rate than those of lower drug loading. Effective sterilization of the microcapsules for parenteral use was achieved by ⁶⁰Co γ-ray irradiation, which did not affect the microcapsule structure, release rate or drug stability. Mitomycin C showed dose-dependent antiproliferative activity against the growth of the K562 human erythroleukaemia cells. The microencapsulated dosage form of mitomycin C was found to enhance the drug's activity through sustained drug release. In experiments where drug concentrations in the cell medium were reduced according to the drug's biological half-life, the microcapsule systems showed a distinct advantage over the non-capsulated dose for the kinetic inhibition of K562 cell growth.     

Control release of prostaglandin E2 from polylactic acid microcapsules, microparticles and modified microparticles

Low molecular weight polylactic acid (PLA) microparticles containing prostaglandin E2 were prepared. An average particle size of 30 micron was obtained by grinding at low temperature. These particles were further treated by heating to modify the shape and the release pattern. Microscopic studies showed that the modified particles had a smoother surface than the non-modified particles. The drug was also incorporated into PLA microcapsules using the solvent evaporation process, but the incorporation efficiency was lower. We studied the release profiles of modified particles prepared using different molecular weight PLA. The release rate depended on the molecular weight with lower molecular weights having a greater release rate. In addition, the release studies showed different matrix forms made from the same molecular weight PLA had different release patterns. For example, the microcapsules released the drug very slowly whereas the modified particles exhibited a moderate release rate. It was also noted that the matrix release model could describe the release patterns of microcapsules and modified particles very well. However, the release patterns of non-modified microparticles did not follow this model.     

Preparation and physical evaluation of microcapsules of hydrophilic drug-cyclodextrin complexes.

An emulsion-solvent evaporation method for preparation of microcapsules containing water-soluble 2-hydroxypropyl-beta-cyclodextrin complex of a lipophilic water-insoluble drug, hydrocortisone, is described. The release of the drug from the microcapsules was determined in simulated gastric fluid. The drug release rate from the microcapsules could be controlled by addition of a plasticizer and it was sustained over extended time. Addition of solubilizing compounds to the dissolution medium did not affect the drug release rate.     

Effect of excipients on tablet properties and dissolution behavior of theophylline-tableted microcapsules under different compression forces

Theophylline ethylcellulose microcapsules were tableted by compression with or without excipients [lactose or hydroxypropyl cellulose (HPC-H)]. Tablets without excipients had a crushing strength that was independent of the applied compression force and the particle size of the microcapsules used, but tablet thickness decreased with an increase in the particle size of the microcapsules. The dissolution characteristics of theophylline from tableted microcapsules without excipients were almost independent of the applied compression force, but showed a sustained-release behavior. However, the thickness, crushing strength, and dissolution properties of tablets containing excipients were found to be affected by the type of excipient. Tableted microcapsules containing lactose showed an increase in tablet crushing strength that correlated with an increase in the applied compression pressure, but the tablet thickness did not change. In contrast, tableted microcapsules containing HPC-H showed a decrease in tablet thickness with an increase in the applied compression pressure, but the tablet crushing strength was initially reduced and then increased with an increase in the compression force. There was a rapid release rate for theophylline from tableted microcapsules containing lactose; a zero-order release rate for theophylline was found in tableted microcapsules containing HPC-H. The insoluble compacted matrix formation, disintegration of tablet, rupture of microcapsules, and gel matrix formation may be responsible for the release behavior of theophylline-tableted microcapsules with or without excipients. The reduced surface area and porosity resulted in a prolongation of the release from tableted microcapsules compared with untableted microcapsules.     

Preparation and release studies of alkannin-containing microcapsules

Microcapsules containing the pharmaceutical substance alkannin were prepared by the solvent evaporation method to enhance alkannin stability (reduce photo-oxidation, polymerization), to decrease its hydrophobicity and to control its release rate. The effect of various parameters, such as the type of polymeric matrix, the type of surfactant used for microcapsules preparation and the addition of Pistacia lentiscus resin in the core, on the characteristics of the produced microcapsules and the release rate of alkannin were investigated experimentally. Among the polymers tested for matrix, ethylcellulose of viscosity 46cp was the most successful, while ethylcellulose 10cp gave microcapsules with good morphological characteristics but high release rate. Beeswax resulted in flocculation and P. lentiscus resin with or without colophony as the matrix resulted in compact particles with no pores and much slower release, but did not allow alkannin to release easily from the matrix. Sodium dodecyl sulfate resulted in microcapsules with desirable morphological and physicochemical characteristics, while acacia and tragacanth gums were not indicated as surfactants in alkannin microencapsulation since they gave a high release rate and a great extent of particle size, respectively. The incorporation of Pistacia lentiscus resin in the capsule core increased loading and microencapsulation efficiency. Ethylcellulose of 46cp viscosity with sodium dodecyl sulfate as surfactant had the best characteristics studied for alkannin microencapsulation. Finally, the dissolution rate of alkannin from microcapsules was studied in a simulated intestinal and gastric environment and an external environment. Alkannin-containing microcapsules with improved properties can be used internally and externally as a new drug-delivery system.     

Microencapsulation using poly(DL-lactic acid). III: Effect of polymer molecular weight on the release kinetics

Poly(DL-lactic acid) [DL-PLA] microcapsules containing phenobarbitone (PB) were prepared using a w/o emulsion-evaporation method. DL-PLA of three different molecular weights, 20,200, 13,300 and 5,200 were used to prepare microcapsules of nominal core: polymer (C:P) ratios of 1 : 2, 1 : 2.5, 1 : 3 and 1 : 4. The release of PB was investigated in aqueous buffer of pH 2, pH 7 and pH 9 at 37 degrees C and found to follow a square root of time dependent release mechanism. The first order and zero order release mechanisms were disproved by the lower correlation coefficient of the release data as compared to that of the t1/2 mechanism. These microcapsules showed an initial burst phase release followed by a lag phase, during which time little PB was released. This lag time was affected by the polymer molecular weight and pH of the buffer. The polymer matrix was hydrated during the lag phase and a steady state release occurred. The steady state release rate per unit specific surface area (Kh2/SSA) was found to increase exponentially with the increase in core loading of the microcapsules. However the extent of normalized release rate reduced linearly with the increase in polymer molecular weight at any particular core loading (e.g. 20 per cent or 30 per cent). Increases in the normalized steady state release rate with an increase in buffer pH could be correlated to PB solubility in the dissolution medium. PB release from these microcapsules was diffusion controlled. However, swelling and erosion also contributed to the release process.     

Preparation and release studies of alkannin-containing microcapsules

Microcapsules containing the pharmaceutical substance alkannin were prepared by the solvent evaporation method to enhance alkannin stability (reduce photo-oxidation, polymerization), to decrease its hydrophobicity and to control its release rate. The effect of various parameters, such as the type of polymeric matrix, the type of surfactant used for microcapsules preparation and the addition of Pistacia lentiscus resin in the core, on the characteristics of the produced microcapsules and the release rate of alkannin were investigated experimentally. Among the polymers tested for matrix, ethylcellulose of viscosity 46cp was the most successful, while ethylcellulose 10cp gave microcapsules with good morphological characteristics but high release rate. Beeswax resulted in flocculation and P. lentiscus resin with or without colophony as the matrix resulted in compact particles with no pores and much slower release, but did not allow alkannin to release easily from the matrix. Sodium dodecyl sulfate resulted in microcapsules with desirable morphological and physicochemical characteristics, while acacia and tragacanth gums were not indicated as surfactants in alkannin microencapsulation since they gave a high release rate and a great extent of particle size, respectively. The incorporation of Pistacia lentiscus resin in the capsule core increased loading and microencapsulation efficiency. Ethylcellulose of 46cp viscosity with sodium dodecyl sulfate as surfactant had the best characteristics studied for alkannin microencapsulation. Finally, the dissolution rate of alkannin from microcapsules was studied in a simulated intestinal and gastric environment and an external environment. Alkannin-containing microcapsules with improved properties can be used internally and externally as a new drug-delivery system.     

Evaluation of the sustained release properties of Eudragit RS, RL and S (acrylic resins) microcapsules containing ketoprofen in beagle dogs

Eudragit RS, RS-RL, RL and S microcapsules containing ketoprofen were prepared by the solvent evaporation process in oil phase. The sustained release effect of these microcapsules and Oruvail, the representative commercial product of ketoprofen, was evaluated by the pH shift dissolution method and in beagle dogs, respectively. The dissolution patterns of ketoprofen from Eudragit RS, RS-RL and RL microcapsules were independent of the pH of the dissolution medium, and its dissolution rate increased with increasing content of ketoprofen in microcapsules. But the dissolution pattern of ketoprofen from Eudragit S microcapsules and Oruvail was found to depend on the pH of the dissolution medium. The rank order of the dissolution rate of ketoprofen from Eudragit RS, RS-RL and RL microcapsules containing 30 and 40 per cent (w/w) ketoprofen was sufficiently clear as to enable prediction of the relative bioavailability of ketoprofen from these microcapsules. In vivo evaluation using beagle dogs, sustained release effects of Eudragit RL and Eudragit S microcapsules containing 30 per cent (w/w) ketoprofen and Eudragit RS-RL microcapsules containing 40 per cent (w/w) ketoprofen were almost the same as or slightly superior to that of Oruvail.     

Effect of ethylene-vinyl acetate concentration on ethylcellulose-walled microcapsules: preparation and release kinetics of theophylline microcapsules

The effect of concentration of ethylene-vinyl acetate (EVA) copolymer, used as a coacervation-inducing agent, on the preparation of ethylcellulose microcapsules was studied with theophylline as the core material. The influence of EVA concentration on the micromeritic properties of the microcapsules and their drug release behaviour were investigated. Particle size distribution of the microcapsules obtained was dependent on the amount of EVA copolymer. As the EVA concentration increased the quantity of larger particles was reduced and that of the smaller particles was increased. Thus EVA might be used as a protective colloid to prevent aggregation of the microcapsules. The porosity of the microcapsules decreased with respect to EVA concentration, but the wall thickness of the microcapsules showed a corresponding increase. Zero-order release kinetics, from the resulting microcapsules in the initial dissolution phase was obtained. The apparent zero-order release rate in the initial steady-state decreased with the increase of EVA concentration, but T50 increased. The higher concentration of EVA causing a thick, compact wall lead to an effective prolongation of drug release.     

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 water-soluble. 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 T20 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.     

油中干燥法制备甘氨酸茶碱钠微囊及其释药特性的研究

采用油中干燥法，以ＥｕｄｒａｇｉｔＲＳ１００和Ｅｕｄｒａｇｉｔ ＲＬ１００为囊材制备水溶性药物甘氨酸茶碱钠微囊。实验结果表明，所得微囊能延缓药物的释放，且以ＥｕｄｒａｇｉｔＲＳ１００为囊材制得到的微囊缓释性能较优。     

Modulation of rifampicin release from spray-dried microspheres using combinations of poly-(DL-lactide).

Microspheres containing 20% w/w rifampicin (RIF) with smooth morphology have been readily prepared from combinations of low, R104 (Mw, 2000) and moderate, R202H (Mw, 9000), molecular weight poly(D,L-lactide) (PDLLA) as a means to modulate drug release from either polymer when used alone. These have been characterized with respect to their drug loading, granulometry, in vitro drug release and thermal behaviour. Particle size distributions were Gaussian, whereby mean microsphere diameter was found to increase from 2.11 to 2.98 microns as the proportion of more viscous R202H increased, whilst > 95% of particles were < 10 microns, irrespective of the polymer blend used. Use of a reduced inlet temperature for spray-drying gave uncharacteristically high production yields in the range of 55.8-80.7% for the process. Encapsulation efficiencies were quantitative with the weight proportion of drug co-dissolved (p < 0.05), yielding microspheres of high and predictable RIF loading. In vitro drug release revealed a dramatic shift in release profile between 40 and 60% R104. Closer examination in this range showed the predicted pattern of increased release rate as the fraction of more hydrophilic R104 increased. However, disproportionate differences were evident between 44 and 48% R104. From the apparent temperature dependent drug release, the criticality of matrix composition was attributed to the coincidence of matrix softening with the dissolution medium temperature and consequent hydration, which, at a finite composition, resulted in a controlled auto-hydration mechanism. Dramatic dependence of release rate with dissolution methodology was accountable to the fact that drug release was considerably quicker where microspheres remained suspended and individualized with the USP paddle method as opposed to aggregated with the shaking bath methodology. In conclusion, the utility of blending racemic PDLLA to modulate drug release and the convenience of spray-drying as a technique to produce microspheres of predictable character have been demonstrated. The temperature-dependent release exhibited may have application in the site-specific delivery of drugs where local increased biochemical activity promotes drug release in response to an increased pharmacological need.     

Modulation of rifampicin release from spray-dried microspheres using combinations of poly-(DL-lactide)

Microspheres containing 20% w/w rifampicin (RIF) with smooth morphology have been readily prepared from combinations of low, R104 (Mw, 2000) and moderate, R202H (Mw, 9000), molecular weight poly(D,L-lactide) (PDLLA) as a means to modulate drug release from either polymer when used alone. These have been characterized with respect to their drug loading, granulometry, in vitro drug release and thermal behaviour. Particle size distributions were Gaussian, whereby mean microsphere diameter was found to increase from 2.11 to 2.98mum as the proportion of more viscous R202H increased, whilst &gt;95% of particles were &lt;10mum, irrespective of the polymer blend used. Use of a reduced inlet temperature for spray-drying gave uncharacteristically high production yields in the range of 55.8-80.7% for the process. Encapsulation efficiencies were quantitative with the weight proportion of drug co-dissolved (p &lt; 0.05), yielding microspheres of high and predictable RIF loading. In vitro drug release revealed a dramatic shift in release profile between 40 and 60% R104. Closer examination in this range showed the predicted pattern of increased release rate as the fraction of more hydrophilic R104 increased. However, disproportionate differences were evident between 44 and 48% R104. From the apparent temperature dependent drug release, the criticality of matrix composition was attributed to the coincidence of matrix softening with the dissolution medium temperature and consequent hydration, which, at a finite composition, resulted in a controlled auto-hydration mechanism. Dramatic dependence of release rate with dissolution methodology was accountable to the fact that drug release was considerably quicker where microspheres remained suspended and individualized with the USP paddle method as opposed to aggregated with the shaking bath methodology. In conclusion, the utility of blending racemic PDLLA to modulate drug release and the convenience of spray-drying as a technique to produce microspheres of predictable character have been demonstrated. The temperature-dependent release exhibited may have application in the site-specific delivery of drugs where local increased biochemical activity promotes drug release in response to an increased pharmacological need.     

Preparation and evaluation of celecoxib-loaded microcapsules with self-microemulsifying core

The purpose of this study was to prepare alginate microcapsules with a self-microemulsifying system (SMES) containing celecoxib in the core. An Inotech IE-50 R encapsulator equipped with a concentric nozzle was used to prepare the microcapsules. The encapsulated SMES was shown to increase celecoxib solubility over that of the pure drug more than 400-fold. Microcapsules prepared with a high SMES:celecoxib ratio exhibited distinct core vesicles containing liquid SMES. By modifying the SMES and including an additional chitosan coating, drug loading in the range from 12–40% could be achieved with the degree of encapsulation ranging from 60–82%. Alginate microcapsules loaded with SMES and celecoxib showed increased dissolution rate of celecoxib over that of alginate microcapsules loaded with celecoxib or of the celecoxib alone. Compared to the previous report, drug loading capacity was significantly improved, enabling the formulation of dosage forms which are of suitable size for peroral application.     

Papaverine hydrochloride release from ethyl cellulose-walled microcapsules

The mechanism of papaverine hydrochloride release from ethyl cellulose-walled microcapsules in both simulated gastric and intestinal fluid is discussed. The microcapsules were prepared by coacervation using different core: wall ratios. The rupture of the thin-walled microcapsules after release in simulated gastric fluid was shown and attributed to the internal osmotic pressure, supporting a mechanism for drug dissolution. The internal osmotic pressure produced only a few small holes in the thin-walled microcapsules after release in simulated intestinal fluid. No rupture of the thick-walled microcapsules after release in either medium was shown. Therefore these release data fitted diffusion-type kinetics. It is suggested that the internal osmotic pressure developed after penetration of the medium is affected by the ratio between the core dissolution rate and the drug diffusion rate through the wall.     

喷雾干燥法制备吡哌酸缓释微囊

用喷雾干燥法制备吡哌酸缓释微囊,以乙基纤维素作囊材,硬脂酸作阻滞剂,制备的微囊能明显延缓药物的释放。药物释放速率随其含量增加而增加,释药的表观扩散系数随微囊粒径降低而降低。家兔体内药物动力学研究结果表明,与片剂相比,吡哌酸微囊口服后,血药浓度维持时间较长。     

正交实验设计优化岩白菜素微囊的制备工艺

目的优化岩白菜素微囊的制备工艺,并对制备的岩白菜素微囊进行质量评价。方法以明胶为囊材,单凝聚法制备岩白菜素微囊,通过正交实验设计优化其制备工艺,并对包封率、载药量、平均粒径、体外溶出率进行研究。结果明胶制备岩白菜素微囊的最佳工艺条件为:明胶质量分数为6%,囊心囊材质量比为1∶2,搅拌速度为750r·min^-1。此最佳工艺制备的岩白菜素微囊包封率为75.90%,载药量为23.09%,体外溶出度测定30min为28.6%,12h累计释放达到90%以上。结论以最佳工艺条件制备岩白菜素微囊工艺稳定,包封率高,同时体外释放实验表明,该微囊具有较好的缓释作用。     

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.