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.     

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.     

Preparation and Characterization of Coacervate Microcapsules for the Delivery of Antimicrobial Oyster Peptides

Oyster peptides-loaded alginate/chitosan/starch microcapsules were prepared using external gelation method and internal emulsion gelation method. The solution of oyster peptides complexes was encapsulated into the microcapsules, which endowed the microcapsules with intestine passive targeting properties. The swelling behavior, encapsulation efficiency, and release behavior of oyster peptides from the microcapsules at different pH values were investigated. The microcapsules exhibited sustained release of the peptides in intestinal medium, and the release rate could be regulated by the pH value: in simulated gastric fluid, the release rate was greatly decreased, and in simulated body fluid and intestinal fluid, the microcapsules exhibited a sustained release in 24 h with different release rates. The microspheres were characterized by Fourier transform infrared. The results suggested that the alginate/chitosan/starch microcapsules could be a suitable copolymeric carrier system for intestinal protein or peptides delivery in the intestine.     

Preparation and characterization of coacervate microcapsules for the delivery of antimicrobial oyster peptides

Oyster peptides-loaded alginate/chitosan/starch microcapsules were prepared using external gelation method and internal emulsion gelation method. The solution of oyster peptides complexes was encapsulated into the microcapsules, which endowed the microcapsules with intestine passive targeting properties. The swelling behavior, encapsulation efficiency, and release behavior of oyster peptides from the microcapsules at different pH values were investigated. The microcapsules exhibited sustained release of the peptides in intestinal medium, and the release rate could be regulated by the pH value: in simulated gastric fluid, the release rate was greatly decreased, and in simulated body fluid and intestinal fluid, the microcapsules exhibited a sustained release in 24 h with different release rates. The microspheres were characterized by Fourier transform infrared. The results suggested that the alginate/chitosan/starch microcapsules could be a suitable copolymeric carrier system for intestinal protein or peptides delivery in the intestine.     

Controlled release of theophylline through semi-interpenetrating network microspheres of chitosan-(dextran-g-acrylamide)

Semi-interpenetrating network microspheres of chitosan-(dextran-g-acrylamide) were prepared by emulsion-crosslinking method using glutaraldehyde (GA) as a crosslinking agent. Graft copolymerization of dextran with acrylamide (Dx-g-AAm) was carried out by aqueous free-radical polymerization using ceric ammonium nitrate (CAN) as initiator. The grafting efficiency was found to be 92%. Theophylline (TH), antiasthmatic drug, was successfully encapsulated into semi-INP microspheres by varying the ratio of Dx-g-AAm and amount of GA. The laser light scattering technique shows that the particles size increased with increasing amount of graft copolymer and decrease with increasing amount of GA. The % encapsulation efficiency was found to vary between 50 and 78. MPs were characterized by FTIR spectroscopy and differential scanning calorimetry (DSC) techniques to confirm the graft copolymer, formation of semi-IPN structure of MPs and molecular distribution of the drug molecules in the polymer matrix. In vitro release studies of TH from these matrices have been investigated at Ph 1.2 and 7.4 media and the slow release were extended up to 18 h at 37°C. The release rates were fitted to an empirical equation to estimate the diffusion exponent n, which indicated that the release from the MPs follows non-Fickian type.     

Preparation and characterization of theophylline loaded chitosan/β-cyclodextrin microspheres

The purpose of this project was to develop sustained release chitosan/β-cyclodextrin microspheres of theophylline (TH) prepared by spray drying method. The effect of several formulation variables on the characteristics of microspheres was studied. The B microspheres had a narrower particle size distribution with the diameter between l and 10 μm. SEM showed spherical microspheres with smooth or slightly wrinkled surfaces. FT-IR spectroscopy revealed that hydrogen bonds were formed between TH and chitosan or β-cyclodextrin. The drug entrapments significantly increased from 13.33 to 35.70% with an increase of the ratio of drug/polymer. The encapsulation efficiencies were from 85.16 to 91.40%. The in vitro release of TH from microspheres was related to the pH of the medium, swelling ability, especially in the ratio of drug/polymer. The B microspheres had a prolonged release pattern with the release rate of 60.20% (pH 6.8) within 8 h.     

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。     

Formulation and in vitro characterization of long-acting PLGA injectable microspheres encapsulating a peptide analog of LHRH

The present study aimed to formulate triptorelin acetate(TA)into poly(D,L-lactic-co-glycolic)acid(PLGA)based injectable sustained-release microspheres(TA-PLGA-MS)by usingdouble emulsion solvent extraction/evaporation(DESE)technique and investigate the effects of various material attributes and process parameters on the quality attributes such as size,shape,surface morphology,encapsulation efficiency(EE)and in vitro release behavior of these microspheres.Variable compositions of the outer water phase,type of the organic solvents,volume ratios of inner water phase to oil phase,PLGA concentrations,and the powers for emulsification in the preparation of the microspheres showed an influence on their quality attributes.An optimal formulation(F-2)obtained from this univariate approach possess an excellent EE value of 63.5%±3.4%and an average volumetric particle size of 35.3±1.8μm.This formulation was further accomplished with different solidification rates assisted by variable incubation temperatures,which exhibited an impact on the shape/surface and inner morphology of the microspheres.The resultant microspheres also displayed different in vitro release patterns.The matrices processed with a high incubation temperature conferred the fastest and the most complete drug release profile over the period of 63 days.Thus,the solidification rate could be identified as one of the critical process parameters that affected the quality of the PLGA based injectable microspheres specifically designed for the prolonged delivery of TA.     

An In Vitro Comparative Evaluation of Pancreatic Enzyme Preparations

Abstract

An in vitro evaluation of various commercial pancreatic enzyme preparations was undertaken to compare three main types of dosage forms, namely uncoated tablets and powder filled capsules, enteric coated tablets and encapsulated enteric coated microspheres. Each product was analyzed for its amylase, lipase and protease contents. All preparations were subjected to a pH-dependent dissolution method to evaluate the release pattern of enzymes. The measured enzyme contents of most preparations were proportionate to their declared values. Acid resistance and dissolution profiles varied among different and similar types of preparations. The enteric coated preparations showed more resistant to acid and displayed rapid rate of enzyme release once the pH threshold was attained. Of the three enteric coated microspheres tested, Creon contained the highest lipase content per capsule, was most resistant to acid and afforded greater release of enzyme activity in pH-dependent dissolution tests.     

Reduction in the initial-burst release by surface crosslinking of PLGA microparticles containing hydrophilic or hydrophobic drugs

Sustained-release approaches are emerging for the delivery of drugs from polymer encapsulation. However, the most persistent problem that remains is the initial burst release of the drug, which can exceed the toxic limits. Dexamethasone, a hydrophobic drug, was encapsulated in poly(lactide-co-glycolide) (PLGA) microparticles using the solvent evaporation method. The drug release profile of these microparticles was studied and the initial burst was reduced by crosslinking of the microparticle surface using ethylene glycol dimethacrylate and tri(ethylene glycol) dimethacrylate. Due to surface crosslinking, an additional diffusional resistance was created, which prevented easy dissolution of the drug into the release medium and brought about a substantial reduction in the initial burst release. Moreover, the time required for reaching a stationary-state release was also observed to be delayed, prolonging the sustained drug delivery. This concept was further tested with a hydrophilic drug, the sodium salt of dexamethasone phosphate, encapsulated in PLGA polymer microparticles and was observed to reduce the burst release as well. For synthesizing the polymer microparticles containing dexamethasone, an o/w microemulsion and solvent evaporation technique was used; whereas, for those containing dexamethasone phosphate, w/o/o/o phase separation/coacervation technique was used. The surface crosslinking was performed by ultraviolet radiation.     

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.     

A pH-sensitive nanocomposite microsphere based on chitosan and montmorillonite with in vitro reduction of the burst release effect

Objective: The aim of this study was to prepare pH-sensitive ofloxacin (OFL)/montmorillonite (MMT)/chitosan (CTS) nanocomposite microspheres that improve the burst release effect of the drug by the solution intercalation technique and emulsification cross-linking techniques. Methods: First, OFL/MMT hybrids were prepared through the solution intercalation technique. Then, OFL/MMT-intercalated OFL/MMT/CTS nanocomposite microspheres were obtained through emulsification cross-linking technology. The intercalated nanocomposite was confirmed by Fourier-transform infrared spectroscopy and X-ray diffraction. Finally, in vitro release of OFL from the microspheres was performed in simulated gastric fluids and simulated intestinal fluids. The effect of MMT content on drug encapsulation efficiency and the drug release of the nanocomposite microspheres were investigated. Results: The results showed that the release rate of OFL from the nanocomposite microspheres at pH 7.4 was higher than that at pH 1.2. Compared with pure CTS microspheres, the incorporation of certain amount of MMT in the nanocomposite microspheres can enhance the drug encapsulation efficiency and reduce the burst release. Conclusion: A sustained release particulate system can be obtained by incorporating MMT into the nanocomposite microspheres and can improve the burst release effect of the drug.     

Preparation,characterization, and in vivo evaluation of insulin-loaded PLA–PEG microspheres for controlled parenteral drug delivery

Aim: The aim of this study was to prepare insulin-loaded poly(lactic acid)–polyethylene glycol microspheres that could control insulin release at least for 1 week and evaluate their in vivo performance in a streptozotocin-induced diabetic rat model. Methods: The microspheres were prepared using a water-in-oil-in-water double emulsion solvent evaporation technique. Different formulation variables influencing the yield, particle size, entrapment efficiency, and in vitro release profiles were investigated. The pharmacokinetic study of optimized formulation was performed with single dose in comparison with multiple dose of Humulin® 30/70 as a reference product in streptozotocin-induced diabetic rats. Results: The optimized formulation of insulin microspheres was nonporous, smooth-surfaced, and spherical in structure under scanning electron microscope with a mean particle size of 3.07 ×μm and entrapment efficiency of 42.74% of the theoretical amount incorporated. The in vitro insulin release profiles was characterized by a bimodal behavior with an initial burst release because of the insulin adsorbed on the microsphere surface, followed by slower and continuous release corresponding to the insulin entrapped in polymer matrix. Conclusions: The optimized formulation and reference were comparable in the extent of absorption. Consequently, these microspheres can be proposed as new controlled parenteral delivery system.     

Optimization studies on floating multiparticulate gastroretentive drug delivery system of famotidine

The objective of this study was to optimize floating microballoons of famotidine by the emulsion solvent diffusion technique using central composite design. Formulations F1-F15 were prepared using three independent variables (pH of medium, drug: Eudragit S100 ratio and ethanol : dichloromethane ratio) and evaluated for dependent variables (shape, percentage buoyancy, and encapsulation). The optimized formulation F9 was fractionated and a polymer combination of (Eudragit S100 : Eudragit L100-55, 9.5:0.5) resulted in microballoons that exhibited zero order release (94.73%) with 84.20% buoyancy at the end of the eighth hour when studied in the mesh-designed modified USP type II apparatus.     

Development of novel interpenetrating network gellan gum-poly(vinyl alcohol) hydrogel microspheres for the controlled release of carvedilol

Novel interpenetrating polymeric network microspheres of gellan gum and poly(vinyl alcohol) were prepared by the emulsion cross-linking method. Carvedilol, an antihypertensive drug, was successfully loaded into these microspheres prepared by changing the experimental variables such as ratio of gellan gum:poly(vinyl alcohol) and extent of cross-linking in order to optimize the process variables on drug encapsulation efficiency, release rates, size, and morphology of the microspheres. Formation of interpenetrating network and the chemical stability of carvedilol after preparing the microspheres was confirmed by Fourier transform infrared spectroscopy. Differential scanning calorimetry and x-ray diffraction studies were made on the drug-loaded microspheres to investigate the crystalline nature of the drug after encapsulation. Results indicated a crystalline dispersion of carvedilol in the polymer matrix. Scanning electron microscopy confirmed the spherical nature and smooth surface morphology of the microspheres produced. Mean particle size of the microspheres as measured by laser light scattering technique ranged between 230 and 346 µm. Carvedilol was successfully encapsulated up to 87% in the polymeric matrices. In vitro release studies were performed in the simulated gastric fluid or simulated intestinal fluid. The release of carvedilol was continued up to 12 h. Dynamic swelling studies were performed in the simulated gastric fluid or simulated intestinal fluid, and diffusion coefficients were calculated by considering the spherical geometry of the matrices. The release data were fitted to an empirical relation to estimate the transport parameters. The mechanical properties of interpenetrating polymeric networks prepared were investigated. Network parameters such as molar mass between cross-links and cross-linking density for interpenetrating polymeric networks were calculated.     

Development of Novel Interpenetrating Network Gellan Gum-Poly(vinyl alcohol) Hydrogel Microspheres for the Controlled Release of Carvedilol

Novel interpenetrating polymeric network microspheres of gellan gum and poly(vinyl alcohol) were prepared by the emulsion cross-linking method. Carvedilol, an antihypertensive drug, was successfully loaded into these microspheres prepared by changing the experimental variables such as ratio of gellan gum:poly(vinyl alcohol) and extent of cross-linking in order to optimize the process variables on drug encapsulation efficiency, release rates, size, and morphology of the microspheres. Formation of interpenetrating network and the chemical stability of carvedilol after preparing the microspheres was confirmed by Fourier transform infrared spectroscopy. Differential scanning calorimetry and x-ray diffraction studies were made on the drug-loaded microspheres to investigate the crystalline nature of the drug after encapsulation. Results indicated a crystalline dispersion of carvedilol in the polymer matrix. Scanning electron microscopy confirmed the spherical nature and smooth surface morphology of the microspheres produced. Mean particle size of the microspheres as measured by laser light scattering technique ranged between 230 and 346 µm. Carvedilol was successfully encapsulated up to 87% in the polymeric matrices. In vitro release studies were performed in the simulated gastric fluid or simulated intestinal fluid. The release of carvedilol was continued up to 12 h. Dynamic swelling studies were performed in the simulated gastric fluid or simulated intestinal fluid, and diffusion coefficients were calculated by considering the spherical geometry of the matrices. The release data were fitted to an empirical relation to estimate the transport parameters. The mechanical properties of interpenetrating polymeric networks prepared were investigated. Network parameters such as molar mass between cross-links and cross-linking density for interpenetrating polymeric networks were calculated.     

pH-Sensitive oral insulin delivery systems using Eudragit microspheres

In this paper, we present in vitro and in vivo release data on pH-sensitive microspheres of Eudragit L100, Eudragit RS100 and their blend systems prepared by double emulsion-solvent evaporation technique for oral delivery of insulin. Of the three systems developed, Eudragit L100 was chosen for preclinical studies. Insulin was encapsulated and in vitro experiments performed on insulin-loaded microspheres in pH 1.2 media did not release insulin during the first 2 h, but maximum insulin was released in pH 7.4 buffer media from 4 to 6 h. The microspheres were characterized by scanning electron microscopy to understand particle size, shape and surface morphology. The size of microspheres ranged between 1 and 40 μm. Circular dichroism spectra indicated the structural integrity of insulin during encapsulation as well as after its release in pH 7.4 buffer media. The in vivo release studies on diabetic-induced rat models exhibited maximum inhibition of up to 86%, suggesting absorption of insulin in the intestine.     

Biodegradable Progesterone Microsphere Delivery System for Osteoporosis Therapy

The purpose of this study was to formulate and characterize a controlled-release biodegradable delivery system of progesterone for the treatment or prevention of osteoporosis. Microspheres of progesterone were formulated using copolymers of poly(glycolic acid-co-dl-lactic acid)(PGLA 50/50 and PGLA 15/85) and poly(L-lactic acid)(L-PLA) of similar molecular weight by the emulsion solvent evaporation technique. The effects of process variables, such as volume fraction, polyvinyl alcohol (PVA) concentration, polymer composition, and stir speed during preparation, on the yield, encapsulation efficiency (EEF), particle size distribution, in vitro release profiles of progesterone, and surface morphology of progesterone microspheres were investigated. Increasing the volume fraction from 9% to 22% increased the EEF without significantly increasing the yield; however, the rate of progesterone release from the microspheres decreased. Increasing the PVA concentration from 1% to 5% had no significant influence on the EEF, but the rate of progesterone release from microspheres increased. Polymer composition had no significant effect on the EEF, but had a significant effect on the particle size distribution, surface morphology, and release rate of progesterone from the microspheres. Stir speed did not have a significant influence on the EEF; however, stir speed influenced particle size distribution and the rate of progesterone release from microspheres of the same sieve-size range. The results suggest that controlled release of progesterone is possible by varying the different process variables, and that PGLA 50/50 provided the slowest release of progesterone. This should provide a means of delivering progesterone for months for the treatment or prevention of osteoporosis in postmenopausal women.     

Biodegradable progesterone microsphere delivery system for osteoporosis therapy

The purpose of this study was to formulate and characterize a controlled-release biodegradable delivery system of progesterone for the treatment or prevention of osteoporosis. Microspheres of progesterone were formulated using copolymers of poly(glycolic acid-co-dl-lactic acid)(PGLA 50/50 and PGLA 15/85) and poly(L-lactic acid)(L-PLA) of similar molecular weight by the emulsion solvent evaporation technique. The effects of process variables, such as volume fraction, polyvinyl alcohol (PVA) concentration, polymer composition, and stir speed during preparation, on the yield, encapsulation efficiency (EEF), particle size distribution, in vitro release profiles of progesterone, and surface morphology of progesterone microspheres were investigated. Increasing the volume fraction from 9% to 22% increased the EEF without significantly increasing the yield; however, the rate of progesterone release from the microspheres decreased. Increasing the PVA concentration from 1% to 5% had no significant influence on the EEF, but the rate of progesterone release from microspheres increased. Polymer composition had no significant effect on the EEF, but had a significant effect on the particle size distribution, surface morphology, and release rate of progesterone from the microspheres. Stir speed did not have a significant influence on the EEF; however, stir speed influenced particle size distribution and the rate of progesterone release from microspheres of the same sieve-size range. The results suggest that controlled release of progesterone is possible by varying the different process variables, and that PGLA 50/50 provided the slowest release of progesterone. This should provide a means of delivering progesterone for months for the treatment or prevention of osteoporosis in postmenopausal women.     

Double-walled microspheres loaded with meglumine antimoniate: preparation,characterization and in vitro release study

Objective: The objective of this study was to fabricate double-walled poly(lactide-co-glycolide) (PLGA) microspheres to increase encapsulation efficiency and avoid rapid release of hydrophilic drugs such as meglumine antimoniate.

Methods: In this study, double-walled and one-layered microspheres of PLGA were prepared using the emulsion solvent evaporation technique to better control the release of a hydrophilic drug, meglumine antimoniate (Glucantime®), which is the first choice treatment of cutaneous leishmaniasis. The effect of hydrophobic coating on microspheres' size, morphology, encapsulation efficiency and drug release characteristics was evaluated. Furthermore, the presence of antimony in meglumine antimoniate made it possible to observe the drug distribution within the microspheres' cross section by means of energy dispersive X-ray spectroscopy.

Results: Drug distribution images confirmed accumulation of the drug within the inner core of double-walled microspheres. In addition, these microspheres encapsulated the drug more efficiently up to 87% and demonstrated reduced initial burst and prolonged release compared to one-layered microspheres. These superiorities make double-walled microspheres an optimum candidate for sustained delivery of hydrophilic drugs.

Conclusion: Double-walled microspheres provide some advantages over traditional microspheres overcoming most of their limitations. Double-walled microspheres were found to be more efficient than their corresponding one-layered microspheres in terms of encapsulation efficiencies and release characteristics.