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.     

Control of Drug Release Rate by Use of Mixtures of Polycaprolactone and Cellulose Acetate Butyrate Polymers

Chlorpromazine microspheres were prepared by an emulsion solvent evaporation technique using polycaprolactone and cellulose acetate butyrate as the matrix. The fluidity of the polymer solution was easily adjusted by use of mixtures of two polymers and thus provided a practical means to control the microsphere size. The In Vitro release pattern was easily changed by changing the ratios of these two polymers. An increase in polycaprolactone content of the polymer microsphere matrix brought about an increase in the release rate. Drug loading had no predictable effect on the dissolution rate, but smaller microspheres gave more rapid drug release due to the greater surface area.     

Evaluation and Optimization of Preparative Variables for Controlled-Release Floatable Microspheres Prepared by Poor Solvent Addition Method

The aim of this study was to evaluate and optimize preparative parameters for floatable theophylline microspheres prepared by the emulsion–solvent evaporation method. A three-factor three-level Box–Behnken design was employed using amount of poor solvent, temperature-increase rate and drug loading as independent factors, and percentage floating at 3 h and time required for 50% drug release as dependent variables. Simultaneous optimization of the parameters for maximum buoyancy and desirable drug release was conducted using a partitioned artificial neural network. A microsphere using 27.6% of drug loading, 0.29°C/min of temperature-increase rate, and 1.7 mL of poor solvent was identified for maximizing buoyancy and sustaining drug release.     

Evaluation and optimization of preparative variables for controlled-release floatable microspheres prepared by poor solvent addition method

The aim of this study was to evaluate and optimize preparative parameters for floatable theophylline microspheres prepared by the emulsion-solvent evaporation method. A three-factor three-level Box-Behnken design was employed using amount of poor solvent, temperature-increase rate and drug loading as independent factors, and percentage floating at 3 h and time required for 50% drug release as dependent variables. Simultaneous optimization of the parameters for maximum buoyancy and desirable drug release was conducted using a partitioned artificial neural network. A microsphere using 27.6% of drug loading, 0.29 degrees C/min of temperature-increase rate, and 1.7 mL of poor solvent was identified for maximizing buoyancy and sustaining drug release.     

Control of Drug Release Rate by Use of Mixtures of Polycaprolactone and Cellulose Acetate Butyrate Polymers

Abstract

Chlorpromazine microspheres were prepared by an emulsion solvent evaporation technique using polycaprolactone and cellulose acetate butyrate as the matrix. The fluidity of the polymer solution was easily adjusted by use of mixtures of two polymers and thus provided a practical means to control the microsphere size. The In Vitro release pattern was easily changed by changing the ratios of these two polymers. An increase in polycaprolactone content of the polymer microsphere matrix brought about an increase in the release rate. Drug loading had no predictable effect on the dissolution rate, but smaller microspheres gave more rapid drug release due to the greater surface area.     

Antibacterial activity of ciprofloxacin-loaded zein microsphere films

Our aim was to produce an antibiotic-emitting coating composed of zein microspheres for the prevention of bacterial infection on implanted devices. Ciprofloxacin-loaded zein microspheres were prepared using a phase separation procedure, with particle sizes between 0.5 and 2 µm. Drug encapsulation and drug loading varied with the amount of both zein and ciprofloxacin, and the highest encapsulation efficiency was 8.27% (2 mg/ml ciprofloxacin and 20 mg/ml zein; n = 3). A ciprofloxacin-loaded zein microsphere film (CF-MS film) was generated via solvent evaporation. Continuous drug release from a trypsin-degraded microsphere film was observed for up to 28 days. The liberation of ciprofloxacin from the trypsin-degraded film and the biodegradation of the microsphere film were highly correlated. Proliferation assay of the growth of human umbilical vein endothelial cells (HUVECs) by the MTT method showed that the microsphere film had no toxicity when compared with cells grown on Corning culture plates alone and plates with a zein film alone. Quantification of bacteria adhesion showed that adhesion on the microsphere film is significantly suppressed. In addition, according to the results of bacterial growth tests, ciprofloxacin-loaded microsphere films maintained antibacterial activity for more than 6 days. In contrast, a control medium containing a zein film allowed constant bacterial growth. These results indicate that CF-MS films might be useful as antibacterial films on implanted devices.     

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.     

pH-Dependent Cellulosic Microspheres Containing Cefuroxime Axetil: Stability and In Vitro Release Behavior

Cefuroxime axetil (CA) was encapsulated in pH-dependent cellulosic microspheres with the final aim of masking taste while assuring its release into the intestinal cavity. The polymers selected were: CAT (cellulose acetate trimellitate) and two types of hydroxypropylmethylcellulose phthalate, HPMCP-55 and HPMCP-50. The CA-loaded CAT and HPMCP-55 microspheres were obtained by a solvent extraction procedure, whereas the encapsulation of CA into HPMCP-50 microspheres was only achieved by a solvent evaporation technique. All the formulations displayed pH-dependent release profiles, releasing their total content in 30 min when exposed to an aqueous medium of pH 6.0. Analysis of the encapsulated molecule by HPLC revealed that a problem of compatibility arises between CA and CAT, leading to the formulation of a high amount of CA impurities. By contrast, a minimum amount of impurities was detected upon encapsulation of CA within HPMCP, this amount being lower for HPMCP-55 than for HPMCP-50. Finally, the taste-masking test carried out for the formulation made of HPMCP-55 evidenced the efficacy of the polymer coating in preventing the release of CA in an acidic medium and thus masking its taste.     

可生物降解聚乳酸载青风藤总碱微球的制备工艺

探索青风藤总生物碱微球(CSA-MS)的制备方法并优化制备工艺.采用乳化-溶剂挥发法制备CSA-MS,紫外分光光度法测定MS的包封率和栽药量,扫描电镜观察MS的形貌,粒径测定仪测MS粒径分布情况,并测试药物的体外释放情况.结果显示,MS外观圆整,平均粒径为(21.5±1.22)μm.正交实验优化了MS的制备工艺,其优化...     

Emulsion Spray-Drying for the Preparation of Albumin-Loaded PLGA Microspheres

The purpose of this work was to study the encapsulation of bovine serum albumin (BSA) in polylactide-co-glycolide (PLGA) microspheres using an emulsion/spray-drying method. Albumin was dissolved in an aqueous phase (w) in the presence of surfactant and emulsified in an organic phase containing the polymer (o). To stabilize the emulsion, different types of surfactant (Pluronic® F68, Pluronic F127, sodium oleate, dioctylsulfosuccinate) were added to the aqueous phase. The w/o emulsion was spray-dried to obtain BSA-loaded PLGA microspheres. The effect of type of surfactant on microsphere characteristics was evaluated. The microspheres were characterized for their morphology by scanning electron microscopy (SEM) and granulometric analysis; drug content determination and in vitro dissolution tests were performed. Results showed that the emulsion/spray-drying method is suitable for obtaining small microparticles (2-5 μm) characterized by high drug payloads (70%-80% encapsulation efficiency). The type of surfactant affects the microsphere shape and BSA release behavior.     

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.     

5-Fluorouracil encapsulated HA/PLGA composite microspheres for cancer therapy

5-Fluorouracil (5FU) was successfully entrapped within poly(lactide-co-glycolide) (PLGA) and hydroyapatite (HA) composite microspheres using the emulsification/solvent extraction technique. The effects of HA to PLGA ratio, solvent ratio as well as polymer inherent viscosity (IV) on encapsulation efficiency were investigated. The degradation and drug release rates of the microspheres were studied for 5?weeks in vitro in phosphate buffered solution of pH 7.4 at 37?°C. The drug release profile followed a biphasic pattern with a small initial burst followed by a zero-order release for up to 35?days. The initial burst release decreased with increasing HA content. The potential of HA in limiting the initial burst release makes the incorporation of HA into PLGA microspheres advantageous since it reduces the risk of drug overdose from high initial bursts. The linear sustained drug release profile over the course of 5?weeks makes these 5-FU-loaded HA/PLGA composite microparticles a promising delivery system for the controlled release of chemotherapy drugs in the treatment of cancer.     

Evaluation of Tableted Microspheres of Dipyridamole

Microspheres of dipyridamole were prepared by solvent evaporation methods. The effect of additives Avicel PH 101, and beta cyclodextrin on the release rate of tableted microspheres were studied. Incorporating Avicel or beta cyclodextrin increased the dipyridamole release rates in tableted microspheres. Beta cyclodextrin was found to be a good additive for microsphere tablets to increase the drug release rates without causing disintegration.     

Preparation of Gelatin: Phenytoin Sodium Microsphers: An IN VITRO and IN VIVO Evaluation

In this study phenytoin sodium microspheres were formulated with biodegradable acid-treated gelatin. The microspheres were subjected to in vitro and in vivo testing. The percent drug retained in the microspheres, as well as its release from the microspheres, was tested. In vitro data revealed a decrease in percent druq retained in the microspheres with an increase in addition of glutaraldehyde to the microsphere formulations. The statistically most consistent drug release was observed from formulations containing 10 g of gelatin and 2 g of phenytoin sodium. From this formulation the slowest release was observed when 5 ml of glutaraldehyde were added to the various formulations, whereas the fastest release was observed when no glutaraldehyde was added. In vivo studies consisted of administering phenytoin sodium in microsphere form and an aqueous solution v i a various routes of administration and determining phenytoin plasma concentration vs. time profiles in female Sprague Dawley Rats. Computer fitting of the in vivo data and subsequent statistical testing enabled comparison of the effect of microsphere formation and the effect of microsphere dose on selected pharmacokinetic parameters.     

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。     

Rapid Production of Cell‐Laden Microspheres Using a Flexible Microfluidic Encapsulation Platform

This study establishes a novel microfluidic platform for rapid encapsulation of cells at high densities in photocrosslinkable microspherical hydrogels including poly(ethylene glycol)‐diacrylate, poly(ethylene glycol)‐fibrinogen, and gelatin methacrylate. Cell‐laden hydrogel microspheres are advantageous for many applications from drug screening to regenerative medicine. Employing microfluidic systems is considered the most efficient method for scale‐up production of uniform microspheres. However, existing platforms have been constrained by traditional microfabrication techniques for device fabrication, restricting microsphere diameter to below 200 µm and making iterative design changes time‐consuming and costly. Using a new molding technique, the microfluidic device employs a modified T‐junction design with readily adjustable channel sizes, enabling production of highly uniform microspheres with cell densities (10–60 million cells mL^?1) and a wide range of diameters (300–1100 µm), which are critical for realizing downstream applications, through rapid photocrosslinking (≈1 s per microsphere). Multiple cell types are encapsulated at rates of up to 1 million cells per min, are evenly distributed throughout the microspheres, and maintain high viability and appropriate cellular activities in long‐term culture. This microfluidic encapsulation platform is a valuable and readily adoptable tool for numerous applications, including supporting injectable cell therapy, bioreactor‐based cell expansion and differentiation, and high throughput tissue sphere‐based drug testing assays.     

Formulation and in vitro evaluation of prolonged release floating microspheres of atenolol using multicompartment dissolution apparatus

The aim of the present work was to prepare floating microspheres of atenolol as prolonged release multiparticulate system and evaluate it using novel multi-compartment dissolution apparatus. Atenolol loaded floating microspheres were prepared by emulsion solvent evaporation method using 3² full factorial design. Formulations F1 to F9 were prepared using two independent variables (polymer ratio and % polyvinyl alcohol) and evaluated for dependent variables (particle size, percentage drug entrapment efficiency and percentage buoyancy). The formulation(F8) with particle size of 329?±?2.69 µm, percentage entrapment efficiency of 61.33% and percentage buoyancy of 96.33% for 12?h was the of optimized formulation (F8). The results of factorial design revealed that the independent variables significantly affected the particle size, percentage drug entrapment efficiency and percentage buoyancy of the microspheres. In vitro drug release study revealed zero order release from F8 (98.33% in 12?h). SEM revealed the hollow cavity and smooth surface of the hollow microspheres.     

Colorectal cancer targeted Irinotecan-Assam Bora rice starch based microspheres: a mechanistic,pharmacokinetic and biochemical investigation

The purpose of this investigation was to evaluate the colon-targeted Irinotecan Hydrochloride (ITC-HCl) loaded microspheres by pharmacokinetic and biochemical studies. The microspheres were prepared by double emulsion solvent evaporation method with natural polymer Assam Bora rice starch. The microspheres were characterized for their micromeritics properties, incorporation efficiency, in vitro and in vivo drug release studies. The release study confirmed the insignificant release of ITC-HCl in physiological condition of stomach and small intestine and major drug release in the caecal content. In vivo release study of the optimized microsphere was compared with immediate release (IR) ITC-HCl. ITC-HCl was distributed predominantly in the upper GI tract from the IR, whereas ITC-HCl was distributed primarily to the lower part of GI tract from the microspheres formulation. Enhanced levels of liver enzymes were found in animals given IR ITC-HCl as well as augmented levels of serum albumin, creatinine, leucocytopenia and thrombocytopenia was also observed. In summary, Assam Bora rice starch microspheres exhibit slow and extended release of ITC-HCl over longer periods of time with reduced systemic side-effects.     

Ondansetron-loaded chitosan microspheres for nasal antiemetic drug delivery: an alternative approach to oral and parenteral routes

Background: The aim of this study was to develop chitosan microspheres for nasal delivery of ondansetron hydrochloride (OND). Method: Microspheres were prepared with spray-drying method using glutaraldehyde as the crosslinking agent. Microspheres were characterized in terms of morphology, particle size, zeta potential, production yield, drug content, encapsulation efficiency, and in vitro drug release. Results: All microspheres were spherical in shape with smooth surface and positively charged. Microspheres had also high encapsulation efficiency and the suitable particle size for nasal administration. In vitro studies indicated that all crosslinked microspheres had a significant burst effect, and sustained drug release pattern was observed until 24 hours following burst drug release. Nasal absorption of OND from crosslinked chitosan microspheres was evaluated in rats, and pharmacokinetic parameters of OND calculated from nasal microsphere administration were compared with those of both nasal and parenteral administration of aqueous solutions of OND. In vivo data also supported that OND-loaded microspheres were also able to attain a sustained plasma profile and significantly larger area under the curve values with respect to nasal aqueous solution of OND. Conclusion: Based on in vitro and in vivo data, it could be concluded that crosslinked chitosan microspheres are considered as a nasal delivery system of OND.     

Sustained release microspheres of diclofenac sodium using PEGylated rosin derivatives

The PEGylated derivatives of rosin-PD-1 and PD-2 synthesized and characterized earlier (Nande et al., 2006) were investigated as potential materials for sustained release microsphere prepared by emulsion solvent evaporation method using diclofenac sodium (DCS) as model drug. All the microspheres exhibited smooth surfaces intercepted by pores; their sizes (d(90)) ranged between 11-24 microm. The entrapment efficiency (< 80%) of the microspheres increased proportionally with derivative concentration. Presence of solvent like isopropyl alcohol or dichloromethane rendered the microspheres with large sizes but with reduced drug entrapment. Microspheres with small size were obtained at an optimum viscosity of liquid paraffin; any change lead to increase in the particle size. Magnesium stearate was found to be most suitable detackifier in the present system. The drug release was directly related to the particle size--small sized microspheres released drug at a faster rate. The dissolution data complied with Higuchi equation while the mechanism of drug release was Fickian diffusion (n approximately 0.5). Controlled inhibition of edema, as tested by hind paw edema method, was observed for 10 h when the microspheres were administered intraperitoneally. The present study found the derivatives as promising materials for preparing microspheres for sustained delivery of DCS.