The characteristics of betamethasone-loaded chitosan microparticles by spray-drying method

Betamethasone (BTM)-loaded microparticles prepared by a spray drying method using chitosan (CTS) as raw material, type-A gelatin and ethylene oxide-propylene oxide block copolymer (Pluronic F68) as modifiers. The BTM-loaded in varied chitosan/Pluronic F68/gelatin microparticle formulations was investigated. By properly choosing excipient type and concentration a high degree of control was achieved over the physical properties of the BTM-loaded microparticles. Microparticle characteristics (zeta potential, tap density, particle size and yield), loading efficiencies, microparticle morphology and in-vitro release properties were examined. Surface morphological characteristics and surface charges of prepared microparticles were observed by using scanning electron microscopy (SEM) and microelectrophoresis. A SEM micrograph shows that the particle sizes of the varied chitosan composed microparticles ranged from 1.1-4.7 microm and the external surfaces appear smooth. The BTM-loaded microparticles entrapped in the chitosan/Pluronic F68/gelatin microparticles with trapping efficiencies up to 93%, collected yield rate 44%, and mean particle size varied between 1-3 microm, positive surface charge (20-40 mv), and tap densities (0.04-0.40 g/cm3) were obtained. The collected BTM yield and size of particle was increased with increasing BTM-loaded amount but both zeta potential and tap density of the particles decreased with increasing BTM-loaded amount. The in vitro release of BTM showed a dose-dependent burst followed by a slower release phase that was proportional to the drug concentration in the concentration range between 5-30%w/w. The in vitro drug release from the chitosan/Pluronic F68/gelatin 1/0.1/0.4 microspheres had a prolong release pattern. These formulation factors were correlated to particulate characteristics for optimizing BTM microspheres in pulmonary delivery.     

Surface modification of poly (l-lactic acid) microspheres for site-specific delivery of ketoprofen for chronic inflammatory disease

The purpose of this research was to investigate the potential of surface modified Poly (l-lactic acid) (PLA) microspheres as a carrier for site-specific delivery of anti-inflammatory drug, ketoprofen, for the treatment of rheumatoid arthritis. Microspheres were prepared by solvent evaporation method using 20% w/w PLA in methylene chloride and 100 mL of a 2.5% poly vinyl alcohol (PVA) solution. Formulations were optimized for several processing parameters like drug to polymer ratio, stirring rate and volume of preparation medium etc. The surface of PLA microspheres was modified with gelatin to impart fibronectin recognition. The microspheres were characterized by surface morphology, size distribution, encapsulation efficiency, and by in vitro drug release studies. The prepared microspheres were light yellow, discrete, and spherical. Formulation with optimum drug to polymer ratio exhibited smallest vesicle size (43.02), high drug encapsulation efficiency (81.11) and better process yield (83.45). The release of drug was extended up to 24 h with Higuchi pattern of drug release. The in vivo results showed that the gelatin modified formulation reduced paw edema at greater extent than pure drug and PLA microspheres and it could be a promising carrier system for controlled and site-specific delivery of ketoprofen with possible clinical applications.     

尼莫地平明胶微球的制备及其性质研究

目的研究尼莫地平明胶微球的制备工艺,并考察其体外释药特性。方法以天然的可生物降解的明胶为载体,液体石蜡为油相,Span80为乳化剂,采用正交设计优化空白明胶微球的制备工艺,用乳化法制备尼莫地平明胶微球。结果优选所制尼莫地平明胶微球形态圆整,大小均匀,表面光滑,载药量为13.48%。体外释药结果表明,一级动力学方程能较好地对其进行拟合。结论制备工艺稳定可行,所得尼莫地平明胶微球具有良好的缓释效果。     

Sustained release chitosan microspheres prepared by novel spray drying methods.

Modified spray drying methods, especially a novel w/o/w emulsion-spray drying method, were developed to prepare chitosan microspheres with a sustained drug release pattern. Release of the model drugs cimetidine and famotidine, from the microspheres prepared by the emulsion-spray drying methods, was greatly retarded with release lasting for several hours, compared with drug loaded microspheres prepared by conventional-spray drying or emulsion methods where drug release was almost instant. The slow release of drug was partly due to the poor wetting ability of the microspheres which floated on the surface of the dissolution medium. The addition of a wetting agent increased the release rate significantly. The coating of the microspheres with gelatin decreased the rate of release of drug in the presence of wetting agents.     

Development and in vitro evaluations of gelatin A microspheres of ketorolac tromethamine for intranasal administration

Gelatin A microspheres (MS) of ketorolac tromethamine (KT) for intranasal systemic delivery were developed with the aim to avoid gastro-intestinal complications, to improve patient compliance, to use as an alternative therapy to conventional dosage forms, to achieve controlled blood level profiles, and to obtain improved therapeutic efficacy in the treatment of postoperative pain and migraine. Gelatin A microspheres were prepared using the emulsification-crosslinking technique. The drug was dispersed in polymer gelatin and formulated into a w/o emulsion with liquid paraffin, using glutaraldehyde as a crosslinking agent. The formulation variables were drug loading and the concentrations of polymer (gelatin), co-polymer (chitosan) and the crosslinking agent. All the prepared microspheres were evaluated for physical characteristics, such as particle size, incorporation efficiency, swelling ability, in vitro bioadhesion on rabbit small intestine and in vitro drug release characteristics in pH 6.6 phosphate buffer. All the microspheres showed good bioadhesive properties. Gelatin A and chitosan concentrations, percentage of the crosslinking agent and also the drug loading affected significantly the rate and extent of drug release. The data indicated that the KT release followed Higuchi's matrix model.     

Development of gelatin microspheres loaded with diclofenac sodium for intra-articular administration

We have previously reported on the targeting of diclofenac sodium in joint inflammation using gelatin magnetic microspheres. To overcome complications in the administration of magnetic microspheres and achieve higher targeting efficiency, the present work focuses on the formulation of gelatin microspheres for intra-articular administration. Drug-loaded microspheres were prepared by the emulsification/cross-linking method, characterized by drug loading, size distribution, scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC), X-ray diffraction (XRD), gas chromatography, and in vitro release studies. The targeting efficiency of microspheres was studied in vivo in rabbits. The microspheres showed drug loading of 9.8, 18.3, and 26.7% w/w with an average size range of 37–46 µm, depending upon the drug–polymer ratio. They were spherical in nature and free from surface drug as evidenced by the SEM photographs. FT-IR, DSC, and XRD revealed the absence of drug–polymer interaction and amorphous nature of entrapped drug. Gas chromatography confirms the absences of residual glutaraldehyde. The formulated microspheres could prolong the drug release up to 30 days in vitro. About 81.2 and 43.7% of administered drug in the microspheres were recovered from the target joint after 1 and 7 days of postintra-articular injection, respectively, revealing good targeting efficiency.     

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.     

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.     

糖类交联明胶微球的制备及其释药特性研究

目的:以生物相容性的糖作交联剂制备明胶药物载体并研究其释药特性。方法:用葡萄糖、葡聚糖、氧化葡萄糖、氧化葡聚糖作交联剂制备明胶盘和微球,测定其溶胀动力学,分别以阿司匹林和牛血清白蛋白为药物模型,紫外分光光度法测定药物包裹率、载药率,并检测明胶微球在模拟体内条件下药物的释放速率。结果:葡萄糖、氧化葡萄糖、葡聚糖、氧化葡聚糖作交联剂制备的凝胶溶胀率分别为204%、246%、166%、233%;4种阿司匹林和牛血清白蛋白明胶微球平均载药率分别为8.73%和4.05%,平均包封率分别为62.55%和31.40%;2h药物释放百分率依次为30%、14%、76%、73%和97.2%、86.6%、60.8%、50.1%。结论:上述4种糖均可以取代化学交联剂制备明胶微球;天然糖交联微球缓释效果优于氧化糖。     

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.     

Targeted delivery of diclofenac sodium via gelatin magnetic microspheres formulated for intra-arterial administration

In the present work, we have attempted to deliver diclofenac sodium to a target site by intra-arterial injection of gelatin magnetic microspheres and subsequent localization using an external magnet. Drug-loaded magnetic microspheres were prepared by emulsification/cross-linking method, characterized by drug loading, magnetite content, size distribution, optical microscopy, scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) analysis, differential scanning calorimetry (DSC), X-ray diffraction (XRD), absence of glutaraldehyde by gas chromatography, and in vitro release studies. The targeting efficiency and the therapeutic efficacy of microspheres were studied in vivo in rabbits. The microspheres showed drug loading of 9.1, 18.7, 24.9% w/w, magnetite content of 27.8–28.9% w/w with an average size range of 25–30.6 μm, depending upon the drug–polymer ratio. They were spherical in nature as evidenced by optical microscopy and SEM. FT-IR, DSC, and XRD studies revealed the absence of drug–polymer interaction. Gas chromatography confirmed the absence of residual glutaraldehyde. The microspheres were able to prolong the drug release over 24–30 days and the application of sonication during in vitro release study has slightly increased the release rate. After intra-arterial administration of microspheres, 77.7% of injected dose was recovered at the target site which revealed good targeting efficiency. The microspheres effectively reduced joint swelling, but lesser extent than the oral diclofenac sodium in high dose, in antigen induced arthritic rabbits without producing gastric ulceration which was observed in rabbits treated with oral diclofenac sodium.     

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.     

Preparation and characterization of oxybenzone-loaded gelatin microspheres for enhancement of sunscreening efficacy

The objective of our present study was to prepare and evaluate gelatin microspheres of oxybenzone to enhance its sunscreening efficacy. The gelatin microspheres of oxybenzone were prepared by emulsion method. Process parameters were analyzed to optimize the formulation. The in vitro drug release study was performed in pH 7.4 using cellulose acetate membrane. Microspheres prepared using oxybenzone:gelatin ratio of 1:6 showed slowest drug release and those prepared with oxybenzone:gelatin ratio of 1:2 showed fastest drug release. The gelatin microspheres of oxybenzone were incorporated in aloe vera gel. Sun exposure method using sodium nitroprusside solution was used for in vitro sunscreen efficacy testing. The formulation C₅ containing oxybenzone-bearing gelatin microspheres in aloe vera gel showed best sunscreen efficacy. The formulations were evaluated for skin irritation test in human volunteers, sun protection factor, and minimum erythema dose in albino rats. These studies revealed that the incorporation of sunscreening agent-loaded microspheres into aloe vera gel greatly increased the efficacy of sunscreen formulation more than four times.     

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.     

Development,characterization and solubility enhancement of comparative dissolution study of second generation of solid dispersions and microspheres for poorly water soluble drug

The poor dissolution characteristics of water-insoluble drugs are a major challenge for pharmaceutical scientists. Reduction of the particle size/increase in the surface area of the drug is a widely used and relatively simple method for increasing dissolution rates. The objective of this study was to improve solubility, release and comparability of dissolution of a poorly soluble drug using two different types of formulations (solid dispersions and microspheres). Hydrochlorothiazide was used as a model drug. The solid dispersions and microspheres were prepared by solvent evaporation method using ethyl cellulose, hydroxypropyl methylcellulose in different drug-to-carrier ratios (1:1, 1:2 w:w). The prepared formulations were evaluated for interaction study by Fourier transform infrared spectroscopy, differential scanning calorimetry, percentage of practical yield, drug loading, surface morphology by scanning electron microscopy, optical microscopy and in-vitro release studies. The results showed no interaction between the drug and polymer, amorphous state of solid dispersions and microspheres, percentage yield of 42.53% to 78.10%, drug content of 99.60 % to 99.64%, good spherical appearance in formulation VI and significant increase in the dissolution rate.     

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 poly(DL-lactide-co-glycolide) microspheres encapsulating all-trans retinoic acid

Poly(DL-lactide-co-glycolide) (PLGA) microspheres containing all-trans retinoic acid (atRA) were prepared by o/w solvent evaporation method and various preparation parameters, such as poly(vinyl alcohol) (PVA) concentration in aqueous solution, PVA MW, drug weight, solvent, polymer MW, and polymer weight, on the characteristics of microspheres and drug release were investigated. PVA concentration in water phase was a critical factor in making microspheres consistently with smooth surface and round shape. In our study, at least 2% (w/v) of PVA in aqueous solution was necessary for making microspheres with round shape. The particle size of microspheres ranged 10-100 microm. AtRA was slowly released from PLGA microspheres over 30 days. Sterilization of microspheres by ethylene oxide (EO) gas at 37 degrees C did not significantly affect the characteristics of drug release or its morphology. Cell growth inhibition of atRA was affected by preparation process of microspheres rather than the EO-gas sterilization process. These results indicate that PLGA microspheres containing atRA are acceptable for controlled release devices for use in the treatment of brain tumor.     

Poly(hydroxybutyrate-hydroxyvalerate) microspheres containing progesterone: preparation, morphology and release properties.

The biodegradable polyesters, poly(hydroxybutyrate) (PHB) and poly(hydroxybutyrate-hydroxyvalerate) (PHBV) were investigated for use as sustained delivery carriers of a model drug, progesterone. Spherical microspheres containing the drug were prepared by an emulsion solvent-evaporation method with gelatin as an emulsifier. Methylene chloride as the polymer solvent yielded smoother microspheres than chloroform. The surface texture was also dependent upon the temperature of the preparation and polymer used. Surface crystals were observed when the drug loading was increased beyond 5 per cent w/w. Thermograms of the microspheres did not show an endotherm corresponding to the melting of the drug because the drug dissolved in the melted polymer while heating. The amount of residual solvent in the microspheres (gas chromatographic assay) ranged from 3.4 to 58.4 ppm and was dependent on the processing temperature, concentration of the polymer in the solvent and the polymer composition. In vitro release of the drug was slowest from microspheres made from copolymer containing 9 per cent hydroxyvalerate. A less porous microsphere matrix was formed by this copolymer.     

Carboplatin-loaded PLGA microspheres for intracerebral injection: formulation and characterization.

The purpose of this study is to prepare and characterize injectable carboplatin-loaded poly(D,L,-lactic-co-glycolic) acid copolymer (PLGA) microspheres for the intracerebral treatment of malignant glioma. The microspheres were prepared by an acetone/mineral oil emulsion and solvent evaporation method. Preparation variables were optimized and the following processing conditions resulted in the highest drug loading and best yields of the microspheres compared with those prepared with the other variables: the PLGA concentration was 8% (w/w) in the internal phase; the emulsifier (Span 80) concentration was 8% (w/w) in the external phase; the ratio of the internal phase: the external phase was 1:8; the stirring speed was 1500 rpm; the emulsion time was 15 min; the solvent evaporation time was 3.75 hr. Microspheres so prepared were analysed for size distribution, drug loading, in vitro release and morphological characteristics. The drug release in phosphate buffer solution started with a 10-day slow release period, followed by a fast near zero order release period from 12 to 22 days. The carboplatin release in brain homogenate was slower than in phosphate buffer solution. The morphological changes of the microspheres during the in vitro degradation correlated with the drug relase profile. In conclusion, the carboplatin-loaded PLGA microspheres were specifically prepared to meet the specification as an injectable and biodegradable brain implant.     

Carboplatin-loaded PLGA microspheres for intracerebral injection: formulation and characterization

The purpose of this study is to prepare and characterize injectable carboplatinloaded poly(D,L-lactic-co-glycolic) acid copolymer (PLGA) microspheres for the intracerebral treatment of malignant glioma. The microspheres were prepared by an acetone/mineral oil emulsion and solvent evaporation method. Preparation variables were optimized and the following processing conditions resulted in the highest drug loading and best yields of the microspheres compared with those prepared with the other variables: the PLGA concentration was 8%(w/w) in the internal phase; the emulsifier (Span 80) concentration was 8%(w/w) in the external phase; the ratio of the internal phase: the external phase was 1:8; the stirring speed was 1500 rpm; the emulsion time was 15 min; the solvent evaporation time was 3.75 hr. Microspheres so prepared were analysed for size distribution, drug loading, in vitro release and morphological characteristics. The drug release in phosphate buffer solution started with a 10- day slow release period, followed by a fast near zero order release period from 12 to 22 days. The carboplatin release in brain homogenate was slower than in phosphate buffer solution. The morphological changes of the microspheres during the in vitro degradation correlated with the drug relase profile. In conclusion, the carboplatin-loaded PLGA microspheres were specifically prepared to meet the specification as an injectable and biodegradable brain implant.