Development of Biodegradable Drug Delivery System to Treat Addiction

Opiate addiction is a serious problem that has now spread worldwide to all levels of society. Buprenorphine has been used for several years for the treatment of opiate addiction. The objective of this project was to develop sustained-release biodegradable microcapsules for the parenteral delivery of buprenorphine. Biodegradable microcapsules of buprenorphine/poly(lactide-co-glycolide) were prepared using two main procedures based on an in-water drying process in a complex emulsion system. These procedures differ in the way the organic solvent was eliminated: evaporation or extraction. The effect of drug loading and the effect of partial saturation of the aqueous phase with the core material during the in-water solvent evaporation were also studied. The efficiency of encapsulation increased from 11% to 34% when the drug loading was decreased from 20% to 5%. There was no significant change in the efficiency of encapsulation when the aqueous phase was partially saturated with buprenorphine. In changing the solvent removal process from evaporation to extraction, no significant change in the efficiency of encapsulation was observed. The microcapsules prepared by the solvent evaporation were smooth and spherical. However, the microcapsules prepared by the extraction of the organic solvent lost their surface smoothness and became slightly irregular and porous compared with the other batches. The average particle size of the microcapsules was between 14 and 49 μm. The cumulative drug release was between 2% and 4% within the first 24 hr. A sustained drug release continued over 45 days.     

Peculiar effect of polyethylene glycol in comparison with triethyl citrate or diethyl phthalate on properties of ethyl cellulose microcapsules containing propranolol hydrochloride in process of emulsion-solvent evaporation

Plasticizers play a crucial role in various process of microencapsulation. In this study, the effect of incorporation of plasticizer in process of emulsion solvent evaporation was investigated on properties of ethyl cellulose (EC) microcapsules containing propranolol hydrochloride. The effect of plasticizer type and concentration were investigated on characteristics of microcapsules prepared from different viscosity grades of EC. Product yield, encapsulation efficiency, mean particle size, shape, surface characteristics, solid state of drug, and drug release profiles were evaluated. Product yield and encapsulation efficiency were not dependent on plasticizer type and concentration. However, encapsulation efficiency decreased with increase in EC viscosity grade in the most of the cases. The mean particle size was in the range of 724–797?μm and was not dependent on plasticizer type. Microcapsules formed in the presence of PEG had a very smooth surface with few pores. XRD and DSC studies revealed a reduction of drug crystallinity after microencapsulation especially in presence of PEG. The results showed that the presence of TEC and DEP with different concentrations had no marked effect on drug release from microcapsules containing different viscosity grades of EC. This was not the case when PEG was used, and despite its water solubility it reduced the drug release rate noticeably. The reduction in the drug release in the presence of PEG was concentration-dependent. The use of PEG as a plasticizer in process of emulsion solvent evaporation highly improved the EC microcapsule structure and retarded the drug release rate and therefore is recommended.     

Preparation of embolic NEMs loading capecitabine

The nanoparticles-embedded microcapsules (NEMs) with smooth surface, good sphericity, excellent dispersivity and uniform particle size distribution were prepared by emulsification combined with electrospraying to extend the sustained release performance of the embolic microcapsules loading capecitabine (CAP). The sodium alginate and chitosan with good biocompatibility were used as the materials and CAP as a small-molecule model drug. The drug loading, encapsulation efficiency and drug release of CAP in the NEMs were investigated. The results showed that the drug-loading and encapsulation efficiency both increased with the increment of chitosan and CAP concentration. The maximum values of drug loading and encapsulation efficiency were 1.97 and 18.01 % respectively when initial CAP concentration was 5.0 g/L and chitosan molecular weight 100 kDa. The cumulative release rate of CAP released from the NEMs was lower than 30 % in 0.5 h, which indicated that there was no obvious initial burst release behavior. In the subsequent 240 h, the release results confirmed that the NEMs had better sustained release properties compared to pure microcapsules, and it might be a new anticancer drug delivery system in the future studies.     

Preparation and Evaluation of Methotrexate-Loaded Biodegradable Polyanhydride Microspheres

Methotrexate-loaded biodegradable polyanhydride microspheres were prepared by modified hot-melt technique and aqueous solvent evaporation technique. The effect of particle size, drug loading and microencapsulation technique on the in vitro drug release was studied. The in vitro release of methotrexate was evaluated using an automated flow-through cell system. The release profile consisted of burst release and sustained release phases. The burst release from the microspheres prepared by the modified technique was lower than that from the aqueous solvent evaporation technique. In addition, the microspheres with lower loadings released smaller amounts during the burst release phase. For a given loading and processing technique, the amount released by burst decreased with an increase in particle size. The microspheres prepared by the modified hot-melt technique with 10% loading and 177-250 μm size fraction gave desirable prolonged release. This formulation was tested in vivo in rats by subcutaneous implantation. The peak serum level of methotrexate was reached between 15-18 hours compared to that between 0-3 hours observed following the administration of an equivalent dose of methotrexate solution. No microspheres were found at the site of implantation at 48 hours post-implantation.     

Preparation Methods of Biodegradable Microspheres on Bovine Serum Albumin Loading Efficiency and Release Profiles

The solvent evaporation and multiple phase methods for preparing poly-(d, l) lactide microspheres of bovine serum albumin (BSA) were compared. The effects of poly (vinyl alcohol) concentration and external aqueous phase temperature on the loading efficient of BSA microspheres prepared by multiple phase emulsion method were evaluated as well. The BSA loading efficient of microspheres by multiple phase emulsion method was much higher than that by solvent evaporation method. The high aqueous solubility of BSA contributes to the low loading efficieny in the solvent evaporation method, suggesting that this method is inappropriate for proteins with high water solubility. The loading efficieny of microspheres, whcih were prepared by multiple phase emulsion method, increased with PVA concentration but decreased with external aqueous phase temperature. The burst phenomenon of release profiles of microspheres was influenced by poly (vinyl alcohol) concentrations and the external aqueous phase temperature. Considering the duration sustained release, 0.5% w/v of poly (vinyl alcohol) is most appropriate among the concentrations tested for preparing BSA microspheres by multiple phase emulsion method.     

Preparation Methods of Biodegradable Microspheres on Bovine Serum Albumin Loading Efficiency and Release Profiles

The solvent evaporation and multiple phase methods for preparing poly-(d, l) lactide microspheres of bovine serum albumin (BSA) were compared. The effects of poly (vinyl alcohol) concentration and external aqueous phase temperature on the loading efficient of BSA microspheres prepared by multiple phase emulsion method were evaluated as well. The BSA loading efficient of microspheres by multiple phase emulsion method was much higher than that by solvent evaporation method. The high aqueous solubility of BSA contributes to the low loading efficieny in the solvent evaporation method, suggesting that this method is inappropriate for proteins with high water solubility. The loading efficieny of microspheres, whcih were prepared by multiple phase emulsion method, increased with PVA concentration but decreased with external aqueous phase temperature. The burst phenomenon of release profiles of microspheres was influenced by poly (vinyl alcohol) concentrations and the external aqueous phase temperature. Considering the duration sustained release, 0.5% w/v of poly (vinyl alcohol) is most appropriate among the concentrations tested for preparing BSA microspheres by multiple phase emulsion method.     

Preparation and characterization of heparin-loaded polymeric microparticles

Microparticles containing heparin were prepared by a water-in-oil-in-water emulsification and evaporation process with pure or blends of biodegradable (poly-epsilon-caprolactone and poly(D,L-lactic-co-glycolic acid)) and of positively-charged non-biodegradable (Eudragit RS and RL) polymers. The influence of polymers and some excipients (gelatin A and B, NaCl) on the particle size, the morphology, the heparin encapsulation rate as well as the in vitro drug release was investigated. The diameter of the microparticles prepared with the various polymers ranged from 80 to 130 microns and was found to increase significantly with the addition of gelatin A into the internal aqueous phase. Microparticles prepared with Eudragit RS and RL exhibited higher drug entrapment efficiency (49 and 80% respectively) but lower drug release within 24 h (17 and 3.5% respectively) than those prepared with PCL and PLAGA. The use of blends of two polymers in the organic phase was found to modify the drug entrapment as well as the heparin release kinetics compared with microparticles prepared with a single polymer. In addition, microparticles prepared with gelatin A showed higher entrapment efficiency, but a significant initial burst effect was observed during the heparin release. The in vitro biological activity of heparin released from the formulations affording a suitable drug release has been tested by measuring the anti-Xa activity by a colorimetric assay with a chromogenic substrate. The results confirmed that heparin remained unaltered after the entrapment process.     

Ibuprofen Microcapsules: the Effect of Production Variables on Microcapsule Properties

Ibuprofen was microencapsulated with ethylcellulose using the solvent evaporation method. The effect of production variables on the properties of the microcapsules and drug release from them is described. Results show that size distribution, drug loading and the amount of free drug on the surface of the microcapsules is affected by production variables. The release of drug from the microcapsules was observed to be strongly influenced by parameters affecting the presence of uncoated drug on the microcapsule surface.     

BSA-PLGA微球的优化制备及特性

目的:优化BSA-PLGA微球制备工艺,并对其包封率、形态、体外释放药物及微球包裹前后BSA的稳定性进行评价。方法:以PLGA为载体,采用复乳溶剂挥发法制备BSA-PLGA微球。Micro BCA法测定微球的包封率和载药量,扫描电子显微镜观察微球的形态,激光粒度仪测定粒度及分布,聚丙烯酰胺凝胶电泳(SDS-PAGE)研究微球包裹前后BSA分子结构的完整性,同时考察体外释药性能。结果:根据优化工艺制备的微球外观圆整,平均粒径(2275.8±256.9)nm,包封率(82.59±2.92)%,载药量(13.76±0.49)×10-2%,包裹前后BSA结构稳定,体外释放28天以上,释放曲线符合Higuchi方程。结论:本研究获得了较优化的BSA-PLGA微球制备工艺,所制备的微球具有较高的包封率和明显的缓释效果。     

Poly(lactide-co-glycolide)-methoxy-poly(ethylene glycol) nanoparticles: drug loading and release properties

In this work, the drug loading and in vitro release properties of PLGA-mPEG nanoparticles were studied. Three methyl-xanthine derivatives differing significantly in aqueous solubility, i.e., caffeine, theophylline, and theobromine, were employed as model drugs. Two different PLGA-mPEG copolymer compositions, namely PLGA(40)mPEG(5) and PLGA(136)mPEG(5), were included in the study. The nanoparticles were prepared by a double emulsion technique. The drug release properties of the nanoparticles in phosphate buffered saline (PBS) and in human plasma were determined. An increase of the drug proportion in the feed led to increased drug loading. The composition of the PLGA-mPEG copolymer (PLGA/mPEG molar ratio) did not appear to affect drug loading and encapsulation. Caffeine exhibited higher loading in the nanoparticles than theobromine and this exhibited a little higher loading than theophylline. Solid-state solubility of the drug in PLGA-mPEG did not affect drug loading. Drug loading and encapsulation in the PLGA-mPEG nanoparticles appeared to be governed by the partition coefficient of the drug between the organic phase and the external aqueous phase employed in nanoparticle preparation. Relatively low loading and encapsulation values were obtained, suggesting that the physical entrapment of drugs in PLGA-mPEG nanoparticles could only be an option in the development of formulations of potent drugs. Only the release of the least water-soluble theobromine was efficiently sustained by its entrapment in the nanoparticles, indicating that the physical entrapment of drugs provides the means for the development of controlled-release PLGA-mPEG nanoparticulate formulations only in the case of drugs with low aqueous solubility.     

Design and characterization of enteric-coated controlled release mucoadhesive microcapsules of Rabeprazole sodium

The objectives of present work was to design and characterize the rabeprazole sodium loaded microcapsules prepared by solvent evaporation technique using ethyl cellulose (EC) based various mucoadhesive polymer, followed by a triple coating with Eudragit L100. The Box-behnken design (BBD) was applied for optimization of formulations containing EC, HPMCK100M and Eudragit L100 as factors for selected responses like entrapment efficiency, mucoadhesive property and drug release in 24 h. The prepared microcapsules were characterized for particle size, drug content, swelling index, mucoadhesive strength, and in vivo antiulcer activity. FT-IR studies revealed that there was no drug-polymer interaction. SEM studies revealed that microcapsules were non-aggregated, spherical shape and smooth appearance. In vitro drug release data from microcapsules was fitted to different kinetic models to explain release profiles. The correlation coefficient value (r²) indicated that the drug release followed Higuchi model. Analysis of variance (ANOVA) showed significant difference in the release of drug from all formulations at p < 0.05 level. Accelerated stability study of optimized formulation (F4) upto 6 months showed there was no change in drug content and release characteristics during storage. In vivo antiulcer activity showed that the optimized microcapsules were able to protect rat stomach against ulcer formation vis-à-vis aqueous solution of the drug showed only negligible and minimum effect.     

Gelatin nanoparticles produced by a simple W/O emulsion as delivery system for methotrexate

Biodegradable hydrophilic gelatin nanoparticles, containing different initial amounts of methotrexate (MTX), were prepared using a simple solvent evaporation technique based on a single water-in-oil emulsion and stabilized by the use of glutaraldehyde as cross-linking agent. The effects of several parameters on particle size, drug encapsulation efficiency and drug release were investigated. Size and shape of the nanoparticles were examined by scanning electron microscopy. The release of MTX was monitored in vitro and the mechanism of release was studied. Particles with a mean diameter of 100–200 nm were produced, which were able to release MTX following a diffusion-controlled mechanism of release. It was observed that the initial amount of MTX used for sample loading did not have any effect on the pattern of release, while it affected the amount of drug entrapped into the nanoparticles and also both the release rate and the total amount of drug released.     

Preparation of PLGA nanoparticles using TPGS in the spontaneous emulsification solvent diffusion method

D-alpha-tocopheryl poly (ethylene glycol) 1000 succinate (TPGS) is a widely used form of vitamin E that has been used as a solubilizer, an emulsifier and as a vehicle for drug delivery formulations. In this study, poly lactide-co-glycolide (PLGA) nanoparticles were prepared by spontaneous emulsification solvent diffusion (SESD) method. TPGS as an emulsifier and further as a matrix material blended with PLGA was used to enhance the encapsulation efficiency and improve the drug release profile of nanoparticles. Rifampicin and estradiol valerate were used as model drugs with different water solubility. The effect of formulation parameters such as drug/polymer ratio, oil phase combination, volume and surfactant content was evaluated. The surface morphology and size of the nanoparticles were studied by scanning electron microscopy (SEM) and laser light scattering. Drug encapsulation efficiency and in vitro drug release profiles of nanoparticles were determined using high performance liquid chromatography (HPLC). The nanoparticles prepared in this study were spherical with size range of 150–250?nm. It was shown that TPGS was a good emulsifier for producing nanoparticles of hydrophobic drugs and improving the encapsulation efficiency and drug loading and drug release profile of nanoparticles. However, the drug loading efficiency of rifampicin, a slightly water-soluble molecule, was significantly lower than that of estradiol valerate, a water insoluble molecule.     

Preparation and Characterization of Heparin-Loaded Polymeric Microparticles

ABSTRACT

Microparticles containing heparin were prepared by a water-in-oil-in-water emulsification and evaporation process with pure or blends of biodegradable (poly-?-caprolactone and poly(d,l-lactic-co-glycolic acid)) and of positively-charged non-biodegradable (Eudragit® RS and RL) polymers. The influence of polymers and some excipients (gelatin A and B, NaCl) on the particle size, the morphology, the heparin encapsulation rate as well as the in vitro drug release was investigated. The diameter of the microparticles prepared with the various polymers ranged from 80 to 130 µm and was found to increase significantly with the addition of gelatin A into the internal aqueous phase. Microparticles prepared with Eudragit RS and RL exhibited higher drug entrapment efficiency (49 and 80% respectively), but lower drug release within 24 h (17 and 3.5% respectively) than those prepared with PCL and PLAGA. The use of blends of two polymers in the organic phase was found to modify the drug entrapment as well as the heparin release kinetics compared with microparticles prepared with a single polymer. In addition, microparticles prepared with gelatin A showed higher entrapment efficiency, but a significant initial burst effect was observed during the heparin release. The in vitro biological activity of heparin released from the formulations affording a suitable drug release has been tested by measuring the anti-Xa activity by a colorimetric assay with a chromogenic substrate. The results confirmed that heparin remained unaltered after the entrapment process.     

D-Optimal Designing and Optimization of Long Acting Microsphere-Based Injectable Formulation of Aripiprazole

This work was aimed to design and optimize a long acting microsphere-based injectable formulation of aripiprazole by using D-optimal experimental design methodology. Microspheres were prepared by solvent evaporation method using PLGA and cholesterol as release rate retardant materials. The microspheres were characterized for their encapsulation efficiency, particle size, surface morphology, residual solvent content, and drug release behavior. Contour plots were plotted to study the encapsulation and release behaviour of the drug from the microspheres. Desirability technique was used for the optimization of microsphere formulation composition. By using an optimum blend of drug and cholesterol in the microsphere formulation it was possible to attain a consistent drug release for a period of 14 days. The results have confirmed that the D-optimal experimental design technique can be successfully employed for designing the long acting microsphere dosage form.     

Engineering of poly(ε-caprolactone) microcarriers to modulate protein encapsulation capability and release kinetic

Drug delivery applications using biodegradable polymeric microspheres are becoming an important means of delivering therapeutic agents. The aim of this work was to modulate the microporosity of poly(ε-caprolactone) (PCL) microcarriers to control protein loading capability and release profile. PCL microparticles loaded with BSA (bovine serum albumin) have been de novo synthesized with double emulsion solvent evaporation technique transferred and adapted for different polymer concentrations (1.7 and 3% w/v) and stabilizer present in the inner aqueous phase (0.05, 0.5 and 1% w/v). SEM (scanning electron microscope) and CLSM (confocal laser scanning microscope) analysis map the drug distribution in homogeneously distributed cavities inside the microspheres with dimensions that can be modulated by varying double emulsion process parameters. The inner structure of BSA-loaded microspheres is greatly affected by the surfactant concentration in the internal aqueous phase, while a slight influence of polymer concentration in the oil phase was observed. The surfactant concentration mainly determines microspheres morphology, as well as drug release kinetics, as confirmed by our in-vitro BSA release study. Moreover, the entrapped protein remained unaltered during the protein encapsulation process, retaining its bio-activity and structure, as shown through a dedicated gel chromatographic analytical method.     

D-optimal designing and optimization of long acting microsphere-based injectable formulation of aripiprazole

This work was aimed to design and optimize a long acting microsphere-based injectable formulation of aripiprazole by using D-optimal experimental design methodology. Microspheres were prepared by solvent evaporation method using PLGA and cholesterol as release rate retardant materials. The microspheres were characterized for their encapsulation efficiency, particle size, surface morphology, residual solvent content, and drug release behavior. Contour plots were plotted to study the encapsulation and release behaviour of the drug from the microspheres. Desirability technique was used for the optimization of microsphere formulation composition. By using an optimum blend of drug and cholesterol in the microsphere formulation it was possible to attain a consistent drug release for a period of 14 days. The results have confirmed that the D-optimal experimental design technique can be successfully employed for designing the long acting microsphere dosage form.     

Biodegradable nanoparticles for improved kidney bioavailability of rhein: preparation,characterization, plasma,and kidney pharmacokinetics

The aim of this work is to develop biodegradable nanoparticles for improved kidney bioavailability of rhein (RH). RH-loaded nanoparticles were prepared using an emulsification solvent evaporation method and fully characterized by several techniques. Kidney pharmacokinetics was assessed by implanting a microdialysis probe in rat's kidney cortex. Blood samples were simultaneously collected (via femoral artery) for assessing plasma pharmacokinetics. Optimized nanoparticles were small, with a mean particle size of 132.6?±?5.95?nm, and homogeneously dispersed. The charge on the particles was nearly zero, the encapsulation efficiency was 62.71?±?3.02%, and the drug loading was 1.56?±?0.15%. In vitro release of RH from the nanoparticles showed an initial burst release followed by a sustained release. Plasma and kidney pharmacokinetics showed that encapsulation of RH into nanoparticles significantly increased its kidney bioavailability (AUC_kidney/AUC_plasma?=?0.586?±?0.072), clearly indicating that nanoparticles are a promising strategy for kidney drug delivery.     

毒死蜱/脲醛树脂微胶囊的制备工艺优化及缓释动力学

随着人们健康与环保意识的不断加强,农药施用量大、效率低、高残留等问题日益受到人们的重视,对农药进行微胶囊化,有助于有效解决当前农药使用过程中所面临的问题。采用脲醛树脂作为壁材,以十二烷基硫酸钠为乳化剂,采用原位聚合法制备毒死蜱/脲醛树脂微胶囊。研究了乳化剂种类和用量、pH值、酸化时间对微胶囊粒径及其分布的影响,并进一步探讨微胶囊的载药量、包封率及释放动力学。结果表明,采用3%(质量分数)的十二烷基硫酸钠为乳化剂,在酸化时间为90min、酸化终点pH值为2.5、搅拌速度为1 200r/min、芯壁比为1∶3、固化温度为60℃时,所制备的毒死蜱/脲醛树脂微胶囊的粒径分布窄,平均粒径约为113μm,载药量达53%以上,包封率达62%以上。毒死蜱/脲醛树脂微胶囊的缓释性能及动力学研究结果显示,所制备的毒死蜱/脲醛树脂微胶囊的缓释效果明显,10天内能释放90%的药物,释放过程遵循Fick扩散机理。可见,制备的毒死蜱/脲醛树脂微胶囊具有较高的载药量、较好的包封率以及缓释性能,可进一步开发为新型的农药制剂,并为开发缓释农药新剂型提供理论支持与实践参考。     

Development of core-shell microcapsules by a novel supercritical CO2 process

5-fluorouracil-SiO₂-poly(L-lactide) (5-Fu-SiO₂-PLLA) microcapsules were prepared in a novel process of solution-enhanced dispersion by supercritical CO₂ (SEDS). The SiO₂ nanoparticles were loaded with 5-Fu by adsorption at the first place, then the 5-Fu-SiO₂ nanoparticles were coated with PLLA by a modified SEDS process. The resulted microcapsules were characterized by scanning electron microscope (SEM), laser diffraction particle size analyzer, Fourier transform infrared spectrometer (FTIR) and thermogravimeter-differential scanning calorimeter (TG-DSC). The drug load, encapsulation efficiency and drug release profiles were also determined. The resulted microcapsules exhibited a rather spherical shape, smooth surface, and a narrow particle size distribution with a mean particle size of 536 nm. The drug load and encapsulation efficiency of the samples were 0.18% and 80.53%, respectively, 25.05% of 5-Fu was released in the first half hour, then drug released in a sustained process, which was much slower than that of without coated by PLLA. The results indicated that the modified SEDS process could be used to produce drug-polymer microcapsules with a core-shell structure, high encapsulation efficiency and sustained drug release effect.