Effect of Process Variables on Particle Size of Gelatin Microspheres Containing Lactic Acid

Gelatin microspheres containing lactic acid were prepared by a polymerization technique using glutaraldehyde as the cross‐linking agent. Because particle size distribution of microspheres is a vital factor in the characterization of microspheres, the present study was carried out to evaluate the effect of process variables on the microspheres size distribution. It was found that concentration of a gelatin solution is the most important parameter that influences the particle size of microspheres. By using different concentrations of gelatin solution, microspheres with different size ranges were prepared. Both the stirring rate of the system and the volume ratio of aqueous and oil phases exerted a great influence on microsphere‐size distribution, whereas, cross‐linking time and cross‐linker concentration only affected the yield. Lower‐phase volume ratios resulted in small uniform microspheres with smooth surfaces and a narrow size range. The effect of emulsifier concentration (span 80), below 1% (w/w, with respect to the weight of the oil phase), on particle size was appreciable. However, at higher concentrations, little effect was observed.     

Cytotoxicity of 5-fluorouracil entrapped in gelatin microspheres

Gelatin microspheres were prepared by water/oil emulsion polymerization and by cross-linking with glutaraldehyde. For the microsphere preparation procedure, two different gelatin (5 or 10% w/v) and three different glutaraldehyde (5, 0.5 or 0.1% v/v) concentrations were used. The influence of preparation compositions on microsphere recovery, particle size and morphology, swelling and degradation, 5-fluorouracil loading and release, and cytotoxicity were investigated. The concentrations of gelatin and glutaraldehyde influenced the size and surface properties of microspheres. The decrease in gelatin concentration and the increase in glutaraldehyde concentration resulted in the formation of smaller (140.82-71.47 microm for gelatin microspheres with a 5% gelatin content; 297.67-97.44 microm for gelatin microspheres with a 10% gelatin content) microspheres with smoother surface properties. Swelling values were decreased as the amount of glutaraldehyde was increased. In particular, for microspheres with a high glutaraldehyde content (5% v/v), only about 15% were degraded in 12 days, whereas for those with 0.5% (v/v) glutaraldehyde, almost 97% degradation occurred in the same period. The most rapid 5-fluorouracil release was observed from uncross-linked microspheres (about 88% in 4 h), whereas a particular slower release (about 36% in 4 h) profile was obtained for the highly cross-linked ones. Cytotoxicity tests of free and entrapped 5-fluorouracil were carried out with MCF-7 breast cancer cell line. Free 5-fluorouracil produced an immediate effect, whereas entrapped 5-fluorouracil showed a prolonged cytotoxic effect.     

Preparation of magnetic gelatin microspheres for the targeting of drugs

Magnetically responsive gelatin microspheres for the targeting of drugs have been prepared using a water-in-oil emulsion technique with chemical cross-linking of the protein. The manufacturing variables affecting microsphere size, size distribution and surface characteristics have been examined as well as the magnetic responsivenessin vitro. Sesame oil was utilized for non-aqueous phase and magnetic gelatin microspheres of different size from 1.89 to 14.88 μm in mean diameter could be obtained with variation of HLB values of non-ionic surfactants. The content of magnetite which uniformly distributed throughout the microspheres was 26.7% (w/w). It was possible to control the localization of magnetic gelatin microspheres at specific sites within capillary models by using external magnetic field of under 5K gauss.     

Preparation of gelatin microspheres containing lactic acid--effect of cross-linking on drug release

In this study, gelatin microspheres containing lactic acid were prepared by the polymerization technique using glutaraldehyde as the cross-linking agent. Dried microspheres were loaded by immersing them in an aqueous solution of lactic acid. In order to prepare microspheres with an appropriate drug release profile, the effect of time of cross-linking and the amount of cross-linking agent on the swelling properties of microspheres and their release profile were investigated. The microencapsulation efficiency, microspheres appearance, particle size, swelling ratio and drug release profile were also studied. Microspheres prepared with a larger amount of cross-linking agent, or after longer cross-linking time, showed a reduced swelling ratio in aqueous media. In vitro release pattern of lactic acid from gelatin microspheres showed a biphasic profile and the release rates were reduced upon increasing the amount of cross-liking agent and prolonging the cross-linking time.     

Chitosan hydrochloride based microspheres of albendazole for colonic drug delivery

Microspheres of chitosan hydrochloride (CH) were prepared in order to deliver albendazole specifically into the colon. Microspheres were prepared by an emulsion method using different ratios of drug and CH (1:1 to 1:5), agitation speeds (500 to 1500 rpm) and concentrations of glutaraldehyde in toluene as the cross-linking agent (0.25 to 1.0% w/v). The effect of polymer concentration, stirring rate and concentration of cross-linking agent on the particle size and drug loading was studied. With an increase in CH concentration, the average particle size was increased. Increased agitation speed reduced the size of the microspheres but higher agitation speed resulted in irregularly shaped microspheres. Increasing the concentration of cross-linking agent produced more regularly shaped microspheres of smaller size. The drug loading was highest at a drug: CH ratio of 1:3, stirring speed 1000 rpm and 0.75% w/v concentration of cross-linking agent. The effect of CH concentration on in vitro drug release from the microspheres was evaluated in simulated g.i.t fluids. A comparative in vitro drug release study of the optimized formulation was carried out in simulated colonic fluid, with and without 2% rat caecal content. The drug release in 24 h was 48.9% in colonic fluid without rat caecal content, and 76.5% in colonic fluid with rat caecal contents.     

正交试验优选姜黄素明胶微球的处方工艺

目的:优选姜黄素明胶微球的最佳处方工艺。方法:以明胶浓度、油水比例、乳化时间为考察因素,以载药量、包封率、微球粒径为评价指标,以明胶为载体,采用正交试验优选乳化交联法制备姜黄素明胶微球的处方工艺。结果:优选的处方工艺要求油水比为1:5,明胶浓度为25%,乳化时间为30min。结论:该处方工艺稳定、可行,重现性好,可为姜黄素明胶微球的后续研究提供理论依据。     

Preparation and characterization of ibuprofen microspheres

Ibuprofen was microencapsulated with Eudragit RS using an o/w emulsion solvent evaporation technique. The effects of three formulation variables including the drug:polymer ratio, emulsifier (polyvinyl alcohol) concentration and organic solvent (chloroform) volume on the entrapment efficiency and microspheres size distribution were examined. The drug release rate from prepared microspheres and the release kinetics were also studied. The results demonstrated that microspheres with good range of particle size can be prepared, depending on the formulation components. The drug:polymer ratio had a considerable effect on the entrapment efficiency. However, particle size distribution of microspheres was more dependent on the volume of chloroform and polyvinyl alcohol concentration rather than the drug:polymer ratio. The drug release pattern showed a burst effect for all prepared microspheres due to the presence of uncovered drug crystals on the surface. It was shown that the release profiles of all formulations showed good correlation with the Higuchi model of release.     

Preparation and characterization of ibuprofen microspheres

Ibuprofen was microencapsulated with Eudragit RS using an o/w emulsion solvent evaporation technique. The effects of three formulation variables including the drug:polymer ratio, emulsifier (polyvinyl alcohol) concentration and organic solvent (chloroform) volume on the entrapment efficiency and microspheres size distribution were examined. The drug release rate from prepared microspheres and the release kinetics were also studied. The results demonstrated that microspheres with good range of particle size can be prepared, depending on the formulation components. The drug:polymer ratio had a considerable effect on the entrapment efficiency. However, particle size distribution of microspheres was more dependent on the volume of chloroform and polyvinyl alcohol concentration rather than the drug:polymer ratio. The drug release pattern showed a burst effect for all prepared microspheres due to the presence of uncovered drug crystals on the surface. It was shown that the release profiles of all formulations showed good correlation with the Higuchi model of release.     

Gelatin microspheres crosslinked with D,L-glyceraldehyde as a potential drug delivery system: preparation, characterisation, in vitro and in vivo studies

To overcome the restriction in using crosslinked gelatin in the pharmaceutical field, D,L-glyceraldehyde (GAL), a non-toxic crosslinking agent, was proposed. Gelatin microspheres crosslinked with different concentrations of GAL (0.5, 1 or 2%, w/v) and for different time periods (1 or 24 h) were prepared. The effect of the preparation variables was evaluated analysing the extent of crosslinking, the morphological aspect, the particle size and the swelling behaviour. To evaluate the pharmaceutical properties, an antihypertensive drug, clonidine hydrochloride, was chosen as drug model and loaded into the microspheres. Either the increase of the crosslinker concentration or of the crosslinking time period decreased both the swelling and the in vitro drug release processes of the microspheres. After the subcutaneous injection, the loaded microspheres crosslinked with the lowest GAL concentration (0.5%, w/v) or for the shortest time period (1 h) showed a reduction of systolic blood pressure (SBP) similar to that recorded with a clonidine hydrochloride solution having the same drug concentration. Instead, the microspheres crosslinked for 24 h with concentrations of GAL higher than 0.5% (w/v) produced a more gradual and sustained SBP reduction and the antihypertensive effect was maintained until 52-72 h. The biocompatibility studies showed that the microspheres crosslinked with GAL are well tolerated in vivo. These results suggest the potential application of gelatin microspheres crosslinked with GAL as a suitable drug delivery system for the subcutaneous administration.     

Biodegradable bromocryptine mesylate microspheres prepared by a solvent evaporation technique. I: Evaluation of formulation variables on microspheres characteristics for brain delivery

The aim of this study was to formulate biodegradable microspheres containing an anti-parkinsonian agent, bromocryptine mesylate, for brain delivery. The effect of formulation parameters (e.g. polymer, emulsifying agent type and concentration) on the characteristics of the microspheres produced, the efficiency of drug encapsulation, the particle size distribution and in vitro drug release rates from the bromocryptine mesylate microspheres were investigated using a 3(2) factorial design. Bromocryptine mesylate was encapsulated into biodegradable polymers using the following three different polymers; poly(L-lactide), poly(D,L-lactide) and poly(D,L-lactide-co-glycolide). The SEM photomicrographs showed that the morphology of the microspheres greatly depended on the polymer and emulsifying agent. The results indicate that, regardless of the polymer type, increase in emulsifying agent concentration from 0.25-0.75% w/v markedly decreases the particle size of the microspheres. Determination of particle size revealed that the use of 0.75% w/v of emulsifying agent concentration and a polymer solution concentration of 10% w/v resulted in optimum particle size. In order to prepare biodegradable microspheres with high drug content and small particle size, selection of polymer concentration as well as emulsifying agent concentration is critical. Polymer type has a less pronounced effect on the percentage encapsulation efficiency and particle size of microspheres than on the t(50%). The microspheres prepared by all three polymers, at a polymer concentration of 10% w/v and an emulsifying agent concentration of 0.75% w/v with NaCMC:SO (4:1, w/v) mixture was as the optimum formulation.     

Biodegradable bromocryptine mesylate microspheres prepared by a solvent evaporation technique. I: Evaluation of formulation variables on microspheres characteristics for brain delivery

The aim of this study was to formulate biodegradable microspheres containing an anti-parkinsonian agent, bromocryptine mesylate, for brain delivery. The effect of formulation parameters (e.g. polymer, emulsifying agent type and concentration) on the characteristics of the microspheres produced, the efficiency of drug encapsulation, the particle size distribution and in vitro drug release rates from the bromocryptine mesylate microspheres were investigated using a 3 2 factorial design. Bromocryptine mesylate was encapsulated into biodegradable polymers using the following three different polymers; poly(L-lactide), poly(D,L-lactide) and poly(D,L-lactide-co-glycolide). The SEM photomicrographs showed that the morphology of the microspheres greatly depended on the polymer and emulsifying agent. The results indicate that, regardless of the polymer type, increase in emulsifying agent concentration from 0.25-0.75% w/v markedly decreases the particle size of the microspheres. Determination of particle size revealed that the use of 0.75% w/v of emulsifying agent concentration and a polymer solution concentration of 10% w/v resulted in optimum particle size. In order to prepare biodegradable microspheres with high drug content and small particle size, selection of polymer concentration as well as emulsifying agent concentration is critical. Polymer type has a less pronounced effect on the percentage encapsulation efficiency and particle size of microspheres than on the t 50% . The microspheres prepared by all three polymers, at a polymer concentration of 10% w/v and an emulsifying agent concentration of 0.75% w/v with NaCMC:SO (4:1, w/v) mixture was as the optimum formulation.     

Positively charged gelatin microspheres as gastric mucoadhesive drug delivery system for eradication of H. pylori

Gastric mucoadhesive drug delivery systems are very promising for eradication of Helicobacter pylori (H. pylori), a spiral bacterium that resides in the gastric mucus layer and at the mucus- epithelial cell interface. New positively charged biodegradable microspheres were prepared using aminated gelatin by surfactantfree emulsification in olive oil, followed by a cross-linking reaction with glutaraldehyde. The amino group contents of the modified gelatin and the microspheres were determined using a 2,4,6-trinitrobenzenesulfonic acid method. With the increase of glutaraldehyde concentration, the amino group content of the microspheres decreased accordingly. The influence of glutaraldehyde concentration, cross-linking reaction time, drug-loading patterns, and type of release media on the in vitro release characteristics of amoxicillin from the microspheres was investigated. Amoxicillin release rate from the modified gelatin microspheres was significantly reduced compared with that from gelatin microspheres. Furthermore, the release was decreased with the increase of glutaraldehyde concentration and/or cross-linking time. On the other hand, a faster release was observed in a lower pH release medium and/or using a lower pH solution for amoxicillin loading. The gastric mucoadhesive properties of the microspheres were evaluated using RITC-labeled microspheres in an isolated rat stomach. The gastric mucoadhesion of the modified gelatin microspheres was markedly improved compared with that of gelatin microspheres. The modified gelatin microsphere proves to be a possible candidate delivery system for the effective eradication of H. pylori.     

Encapsulation of vitamin C in tripolyphosphate cross-linked chitosan microspheres by spray drying

This paper describes vitamin C-encapsulated chitosan microspheres cross-linked with tripolyphosphate (TPP) using a new process prepared by spray drying intended for oral delivery of vitamin C. Thus, prepared microspheres were evaluated by loading efficiency, particles size analysis, scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), zeta potential and in vitro release studies. The microspheres so prepared had a good sphericity and shape but varied with the volume of cross-linking agent solution added. They were positively charged. The mean particle size ranged from 6.1-9.0 microm. The size, shape, encapsulation efficiency, zeta potential and release rate were influenced by the volume of cross-linking agent. With the increasing amount of cross-linking agent, both the particle size and release rate were increased. Encapsulation efficiency decreased from 45.05-58.30% with the increasing amount of TPP solution from 10-30 ml. FTIR spectroscopy study showed that the vitamin C was found to be stable after encapsulation. XRD studies revealed that vitamin C is dispersed at the molecular level in the TPP-chitosan matrix. Well-defined change in the surface morphology was observed with the varying volume of TPP. The sphericity of chitosan microspheres was lost at higher volume of cross-linking agent. The release of vitamin C from these microspheres was sustained and affected by the volume of cross-linking agent added. The release of vitamin C from TPP-chitosan microspheres followed Fick's law of diffusion.     

Positively Charged Gelatin Microspheres as Gastric Mucoadhesive Drug Delivery System for Eradication of H. pylori

Gastric mucoadhesive drug delivery systems are very promising for eradication of Helicobacter pylori (H. pylori), a spiral bacterium that resides in the gastric mucus layer and at the mucus- epithelial cell interface. New positively charged biodegradable microspheres were prepared using aminated gelatin by surfactantfree emulsification in olive oil, followed by a cross-linking reaction with glutaraldehyde. The amino group contents of the modified gelatin and the microspheres were determined using a 2,4,6-trinitrobenzenesulfonic acid method. With the increase of glutaraldehyde concentration, the amino group content of the microspheres decreased accordingly. The influence of glutaraldehyde concentration, cross-linking reaction time, drug-loading patterns, and type of release media on the in vitro release characteristics of amoxicillin from the microspheres was investigated. Amoxicillin release rate from the modified gelatin microspheres was significantly reduced compared with that from gelatin microspheres. Furthermore, the release was decreased with the increase of glutaraldehyde concentration and/or cross-linking time. On the other hand, a faster release was observed in a lower pH release medium and/or using a lower pH solution for amoxicillin loading. The gastric mucoadhesive properties of the microspheres were evaluated using RITC-labeled microspheres in an isolated rat stomach. The gastric mucoadhesion of the modified gelatin microspheres was markedly improved compared with that of gelatin microspheres. The modified gelatin microsphere proves to be a possible candidate delivery system for the effective eradication of H. pylori.     

Encapsulation of vitamin C in tripolyphosphate cross-linked chitosan microspheres by spray drying

This paper describes vitamin C-encapsulated chitosan microspheres cross-linked with tripolyphosphate (TPP) using a new process prepared by spray drying intended for oral delivery of vitamin C. Thus, prepared microspheres were evaluated by loading efficiency, particles size analysis, scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), zeta potential and in vitro release studies. The microspheres so prepared had a good sphericity and shape but varied with the volume of cross-linking agent solution added. They were positively charged. The mean particle size ranged from 6.1–9.0?µm. The size, shape, encapsulation efficiency, zeta potential and release rate were influenced by the volume of cross-linking agent. With the increasing amount of cross-linking agent, both the particle size and release rate were increased. Encapsulation efficiency decreased from 45.05–58.30% with the increasing amount of TPP solution from 10–30?ml. FTIR spectroscopy study showed that the vitamin C was found to be stable after encapsulation. XRD studies revealed that vitamin C is dispersed at the molecular level in the TPP-chitosan matrix. Well-defined change in the surface morphology was observed with the varying volume of TPP. The sphericity of chitosan microspheres was lost at higher volume of cross-linking agent. The release of vitamin C from these microspheres was sustained and affected by the volume of cross-linking agent added. The release of vitamin C from TPP-chitosan microspheres followed Fick's law of diffusion.     

Effect of formulation variables on cis-platin loaded chitosan microsphere properties

Chitosan microspheres containing cis-platin were prepared using a w/o emulsion system. Variables important for microsphere properties were investigated: these include; chitosan, cis-platin and glutaraldehyde concentrations, the types of chitosan and oil, the cross-linking process and stirring rate. Chitosan and glutaraldehyde concentrations, the types of oil and chitosan have a significant effect on cis-platin entrapment in chitosan microspheres. In general, incorporation efficiency was high and ranged from 28-99%. The type and concentration of chitosan affected cis-platin release from microspheres. The type of oil was also important for release properties. Cis-platin release from microspheres is characterized by an initial burst effect.     

Effect of formulation variables on cis-platin loaded chitosan microsphere properties

Chitosan microspheres containing cis-platin were prepared using a w/o emulsion system. Variables important for microsphere properties were investigated: these include; chitosan, cis-platin and glutaraldehyde concentrations, the types of chitosan and oil, the cross-linking process and stirring rate. Chitosan and glutaraldehyde concentrations, the types of oil and chitosan have a significant effect on cis-platin entrapment in chitosan microspheres. In general, incorporation efficiency was high and ranged from 28-99%. The type and concentration of chitosan affected cis-platin release from microspheres. The type of oil was also important for release properties. Cis-platin release from microspheres is characterized by an initial burst effect.     

Ultrasonically controlled release and targeted delivery of diclofenac sodium via gelatin magnetic microspheres

In the present work, an attempt was made to target diclofenac sodium to its site of action through magnetic gelatin microspheres. The gelatin magnetic microspheres loaded with 8.9% w/w of diclofenac sodium and 28.7% w/w of magnetite were formulated by emulsification/cross-linking with glutaraldehyde. The formulated microspheres were characterized by particle size distribution, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffraction and in vitro release studies. The in vivo distribution and targetability of gelatin magnetic microspheres after i.v. administration were studied in rabbits. The formulated microspheres were below 5 microm and spherical in nature as evidenced by the SEM photographs. DSC and X-ray diffraction studies revealed the absence of drug-polymer interaction. Encapsulated diclofenac sodium was released slowly more than 18 days. Application of sonication, as external stimuli to enhance drug release, during release study, has slightly increased the release rate. The formulated microspheres were injected intravenously after keeping a suitable magnet near the target area. The quantity of drug available at the target and non-target area was determined by HPLC. About 5.5% of injected dose localized near the target organ. Majority of injected dose was recovered from lungs, spleen and liver indicating localization of microspheres in these organs. Further studies are required to improve the targeting efficiency of gelatin microspheres by modifying surface properties to overcome phagocytosis and by selecting suitable particle size to avoid the entrapment of microspheres in non-target organs.     

Formulation factors in preparing BTM-chitosan microspheres by spray drying method

Chitosan (CTS) microspheres were prepared by a spray drying method using type-A gelatin and ethylene oxide-propylene oxide block copolymer as modifiers. Surface morphological characteristics and surface charges of prepared microspheres were investigated by using scanning electron microscopy (SEM) and microelectrophoresis. The particle shape, size and surface morphology of microspheres were significantly affected by the concentration of gelatin. Betamethasone disodium phosphate (BTM)-loaded microspheres demonstrated good drug stability (less 1% hydrolysis product), high entrapped efficiency (95%) and positive surface charge (37.5 mV). The in vitro drug release from the microspheres was related to gelatin content. Microspheres containing gelatin/CTS 0.4 approximately 0.6(w/w) had a prolong release pattern for 12 h. These formulation factors were correlated to particulate characteristics for optimizing BTM microspheres in pulmonary delivery.     

莲心总碱-阿霉素明胶微球的制备研究

目的制备莲心总碱-阿霉素明胶微球。方法采用乳化交联法制备莲心总碱-阿霉素明胶微球,用均匀设计对其制备工艺进行优化。结果莲心总碱-阿霉素明胶微球的最优制备条件为：明胶浓度：22.5%,明胶与药物质量比为1∶20,油水相体积比为1∶17.5,搅拌速度：900 r.min-1,25%戊二醛溶液用量：50μL/0.6 g明胶,Span-80用量：2%。按优化工艺参数制得的载药微球呈圆球形,表面光滑,总载药量为：2.56%,包封率为：66.44%,90%的微球分布在10-100μm。结论采用优化工艺条件制备的莲心总碱-阿霉素明胶微球,载药量较大,包封率较高,粒径分布相对集中,形态较好。