Description and preliminary evaluation of a new ultrasonic atomizer for spray-congealing processes.

A new atomizer that operates with ultrasonic energy is described. This apparatus is intended to obtain microparticulate drug delivery systems through spray-congealing or spray-drying technologies. In this work, some experimental results are reported on model systems submitted to spray-congealing. The formulations under examination contained theophylline and fenbufen as model drugs and stearic acid, carnauba wax, Cutina HR(R) and Compritol 888 ATO(R) as low melting excipients. Non-aggregate and spherical-shaped microparticles were obtained with all the materials tested; moreover, they had smooth surface and good flowability. The particle sizes depend on the amount of drug present and in each case the maximum size value of the distribution frequency was found to be 375 mu. In vitro release of the drug depends on its solubility and on the excipient lipophilicity. The results suggest that the ultrasound-assisted atomizer could be proposed as a possible alternative to traditional atomizers used for spray-congealing in the pharmaceutical field.     

Polymer–lipid based mucoadhesive microspheres prepared by spray-congealing for the vaginal delivery of econazole nitrate

This research aimed to evaluate a new approach for the preparation of mucoadhesive microparticles and to design an innovative vaginal delivery systems for econazole nitrate (ECN) able to enhance the drug antifungal activity.Seven different formulations were prepared by spray-congealing: a lipid–hydrophilic matrix (Gelucire^® 53/10) was used as carrier and several mucoadhesive polymers such as chitosan, sodium carboxymethylcellulose and poloxamers (Lutrol^® F68 and F127) were added. All microparticles were characterized and compared for morphology, particle size, drug loading and solubility in simulated vaginal fluid, bioadhesion to mucosal tissue, dissolution behaviour and for their physicochemical properties. The antifungal activity of the microparticles against a strain of Candida albicans ATCC 10231 was also investigated.Non-aggregated microspheres with high yields (>90%, w/w) and with prevalent size in the range 100–355 μm were obtained. Both poloxamers significantly (p < 0.01) improved the solubility and in vitro bioavailability of the low solubility drug and the mucoadhesive strength. Poloxamers/Gelucire^®-based microparticles exhibited an inhibition effect on the C. albicans growth, suggesting their use as an effective treatment for vaginal candidiasis, with potential for reduced administration frequency.In conclusion the results demonstrated that spray-congealing technology can be considered a novel and solvent-free approach for the production of mucoadhesive microparticles for the vaginal delivery of ECN.     

Floating microparticles based on low density foam powder

The aim of this study was to develop a novel multiparticulate gastroretentive drug delivery system and to demonstrate its performance in vitro. Floating microparticles consisting of (i) polypropylene foam powder; (ii) verapamil HCl as model drug; and (iii) Eudragit RS, ethylcellulose (EC) or polymethyl methacrylate (PMMA) as polymers were prepared with an O/W solvent evaporation method. The effect of various formulation and processing parameters on the internal and external particle morphology, drug loading, in vitro floating behavior, in vitro drug release kinetics, particle size distribution and physical state of the incorporated drug was studied. The microparticles were irregular in shape and highly porous. The drug encapsulation efficiency was high and almost independent of the theoretical loading. Encapsulation efficiencies close to 100% could be achieved by varying either the ratio 'amount of ingredients: volume of the organic phase' or the relative amount of polymer. In all cases, good in vitro floating behavior was observed. The release rate increased with increasing drug loading and with decreasing polymer amounts. The type of polymer significantly affected the drug release rate, which increased in the following rank order: PMMA相似文献   

Spray congealed lipid microparticles with high protein loading: preparation and solid state characterisation

The spray-congealing technique, a solvent-free drug encapsulation process, was successfully employed to obtain lipid-based particulate systems with high (10-20% w/w) protein loading. Bovine serum albumin (BSA) was utilised as model protein and three low melting lipids (glyceryl palmitostearate, trimirystin and tristearin) were employed as carriers. BSA-loaded lipid microparticles were characterised in terms of particle size, morphology and drug loading. The results showed that the microparticles exhibited a spherical shape, mean diameter in the range 150-300 μm and an encapsulation efficiency higher than 90%. Possible changes in the protein structure as a result of the manufacturing process was then investigated for the first time using UV spectrophotometry in fourth derivative mode and FT-Raman spectroscopy. The results suggested that the structural integrity of the protein was maintained within the particles. Thermal analysis indicated that the effect of protein on the thermal properties of the carriers could be detected. Spray-congealing could thus be considered a suitable technique to produce highly BSA-loaded microparticles preserving the structure of the protein.     

Multiple unit gastroretentive drug delivery systems: a new preparation method for low density microparticles

The aim of this study was to develop a new preparation method for low density foam-based, floating microparticles and to demonstrate the systems' performance in vitro. Major advantages of the novel preparation technique include: (i) short processing times, (ii) no exposure of the ingredients to high temperatures, (iii) the possibility to avoid toxic organic solvents, and (iv) high encapsulation efficiencies close to 100%. Floating microparticles consisting of polypropylene foam powder, model drug [chlorpheniramine maleate (CPM), diltiazem HCl, theophylline or verapamil HCl] and polymer [Eudragit RS or polymethyl methacrylate (PMMA)] were prepared by soaking the microporous foam carrier with an organic solution of drug and polymer and subsequent drying. The effects of various formulation and processing parameters on the resulting in vitro floating behaviour, internal and external particle morphology, drug loading, in vitro drug release and physical state of the incorporated drug were studied. Good in vitro floating behaviour was observed in most cases and a broad variety of drug release patterns could be achieved by varying the drug loading and type of polymer. Interestingly, PMMA-based microparticles showed incomplete drug release with verapamil HCl. This restriction could be overcome by forming the free base of the drug prior to microparticle preparation. In contrast to the salt, the free base acted as a plasticizer for PMMA, resulting in sufficiently high diffusion coefficients and, consequently, complete drug release. The low density microparticles were compressed into rapidly disintegrating tablets in order to provide an administrable oral dosage form.     

Layered lipid microcapsules for mesalazine delayed-release in children

The goal was to make available a delayed-release dosage form of mesalazine to be dispersed in water to facilitate swallowing in adults and children. Mesalazine microparticles containing carnauba wax were prepared by spray-congealing technique. A second step of spray-congealing of carnauba microparticles dispersed in liquefied stearic acid gave rise to mesalazine lipid microcapsules in which several carnauba microparticles remained embedded as cores in a reservoir structure. In order to favor their water dispersion, the lipid microcapsules were dry coated by tumbling them with different ratios of mannitol/lecithin microparticles prepared by spray-drying. Release rate measurements showed a delayed-release behavior, in particular a pH-dependence with less than 10% of drug released in acidic medium and complete release in phosphate buffer pH 7.4 in 4-5h. The layering with hydrophilic excipient microparticles allowed manufacturing of a pH-dependent dosage form suitable for extemporaneous oral use in adults and children.     

眼镜蛇毒细胞毒素缓释微球制备及体外性质研究

目的研究眼镜蛇毒细胞毒素(Cytotoxin,CTX)聚乳酸/羟基乙酸缓释微球的制备方法,考察其一般性质、体外释药特性及生物学活性。方法采用色谱方法纯化眼镜蛇CTX,MTT方法检测细胞毒活性,复乳-溶剂挥发法制备载药微球,考察微球表面形态、粒径、包封率、载药率、体外释药行为及释放眼镜蛇CTX细胞毒活性。结果纯化眼镜蛇CTX具有明显的细胞毒作用,对肝癌HepG2细胞12,24 h的IC50分别为1.43,1.12μg/mL,对L02肝细胞12,24 h的IC50分别为1.37,1.01μg/mL。微球表面光滑圆整,粒径2.1~7.8μm,包封率和载药率分别为(74.10±9.92)%和(0.72±0.09)%,30 d药物累积释放84.3%,释放眼镜蛇CTX保持较好的生物学活性。结论采用复乳-溶剂挥发法可制备具有较高包封率,良好缓释效果,保持完整生物学活性的眼镜蛇CTX缓释微球。     

Biodegradable microparticulate system of captopril

Albumin microparticles have found many applications in diagnosis and treatment in recent years and more than 100 diagnostic agents and drugs have been incorporated into albumin microparticles. In the present study, bovine serum albumin (BSA) based microparticles bearing captopril were prepared by an emulsification-heat stabilization technique. Four batches of microparticles with varying ratio of drug and polymer were prepared. The prepared microparticles were studied for drug loading, particle size distribution, in vitro release characteristics, in vivo tissue distribution study and stability studies. The microparticles had mean diameter between 2 and 11 microm of which more than 70% were below 5 microm and incorporation efficiency of 41-63% was obtained. In vitro release profile for formulations containing captopril-loaded albumin microparticles with heat stabilizing technique shows slow controlled release up to 24 h. The in vivo result of drug-loaded microparticles showed preferential drug targeting to liver followed by lungs, kidneys and spleen. Stability studies showed that maximum drug content and closest in vitro release to initial data were found in the formulation stored at 4 degrees C. In the present study, captopril-loaded BSA microparticles were prepared and targeted to various organs to a satisfactory level and were found to be stable at 4 degrees C.     

Diclofenac sodium loaded-cellulose acetate butyrate: effect of processing variables on microparticles properties, drug release kinetics and ulcerogenic activity

The aim of this study was to develop and characterize diclofenac sodium loaded-cellulose acetate butyrate microparticles in order to obtain a controlled-release system. The influence of the type of polymer, the volume and composition of the internal phase, drug loading, surfactant concentration and additive added on microparticles characteristics (particle size, encapsulation efficiency, surface morphology and in vitro release profiles) was studied to optimize the microparticles system. The resultant microparticles were evaluated for the recovery, average particle size, drug loading and incorporation efficiency. The microparticles exhibited good flowing nature and compressibility index when compared to pure drug. Dissolution rate of diclofenac sodium in phosphate buffer (pH 6.8) increased with increases in initial drug loading, surfactant concentration and addition of alcohol as co-solvent but decreased with increases in the concentration of additives such as Gantrez AN or Eudragit S100 in the internal phase. The dissolution data showed a Higuchi diffusion pattern for most of the formulations. About 56-81% reduction in ulcerogenic activity was observed with microparticles containing Eudragit S100 17-25%, based on total polymer concentration, when compared with pure diclofenac sodium.     

Optimizing formulation factors in preparing chitosan microparticles by spray-drying method

The chitosan only, chitosan/Pluronic F68, chitosan/gelatin, chitosan/Pluronic F68/gelatin microparticles and betamethasone-loaded chitosan/Pluronic F68/gelatin microparticles were successfully prepared by a spray-drying method. Microparticle characteristics (yield rate, zeta potential, particle size and tap density), loading efficiencies, microparticle morphology and in-vitro release properties were investigated. By properly choosing excipient type, concentration and varying the spray-drying parameters, a high degree of control was achieved over the physical properties of the dry chitosan powders. SEM micrograph shows that the particle sizes of the varied chitosan composed microparticles ranged from 2.12-5.67 microm and the external surfaces appear smooth. Using betamethasone as model drug, the spray-drying is a promising way to produce good spherical and smooth surface microparticles with a narrow particle size range for controlled delivery of betamethasone. The positively charged betamethasone-loaded microparticles entrapped in the chitosan/Pluronic F68/gelatin microparticles with trapping efficiencies up to 94.5%, yield rate 42.5% and mean particle size 5.64 microm varied between 4.32-6.20 microm and tap densities 0.128 g/cm(3). The pH of particle was increased with increasing betamethasone-loaded amount, but both zeta potential and tap density of the particles decreased with increasing betamethasone-loaded amount. The betamethasone release rates from chitosan/Pluronic F68/gelatin microparticles were influenced by the drug/polymer ratio in the manner that an increase in the release% and burst release% was observed when the drug loading was decreased. The in vitro release of betamethasone showed a dose-dependent burst followed by a slower release phase that was proportional to the drug concentration in the concentration range between 14-44%w/w.     

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.     

Characterization of carbamazepine-Gelucire 50/13 microparticles prepared by a spray-congealing process using ultrasounds

In this work, the utilization of a spray-congealing technique using a new ultrasonic atomizer to prepare enhanced-release, solvent-free microspheres of carbamazepine (CBZ)-Gelucire 50/13 in different drug-to-polymer ratios was considered. Scanning electron microscopy analysis showed that it was possible to obtain spherically shaped and nonaggregated microparticles; the prevalent particle size was in the range 150-250 microm and the microspheres had a good encapsulation efficiency (> 90% in the prevalent size fraction). The in vitro dissolution tests displayed a significant increase of the CBZ dissolution rate from microspheres compared with pure drug and to drug-Gelucire 50/13 physical mixture. Differential scanning calorimetry, hot stage microscopy, X-ray powder diffractometry, and diffuse reflectance Fourier transform infrared spectroscopy demonstrated phase stability of the original polymorph of CBZ in all the systems; moreover, no interactions between the drug and Gelucire 50/13 were found. The results of this study suggested that the spray-congealing technique using the ultrasonic atomizer could be considered as a new and interesting method to enhance the dissolution rate of a poorly water-soluble drug as CBZ.     

Studies on the in vitro release characteristics of ibuprofenloaded polystyrene microparticles

Ibuprofen-loaded polystyrene microparticles were prepared by the emulsionsolvent evaporation process from an aqueous system. The effects of different parameters on the drug content and on the release of the drug from the microparticles were investigated. The drug content, in all the formulations, was less than the theoretical drug loading. The lower drug content was due to drug partitioning to the external aqueous phase during formulation. Statistical analysis revealed that the variation in the concentrations of the emulsion stabilizer and the organic disperse phase volume did not significantly alter the release of the drug. Although an increase in drug loading increased drug release from the microparticles, a biphasic linear relationship was observed between the time required for 50% drug release and the drug loading. The effect of size of the microparticles on drug release was more important for the low drug-loaded microparticles than that for the high drug-loaded microparticles. Such release behaviour from the microparticles was explained on the basis of the morphological structure of the microparticles.     

Studies on the in vitro release characteristics of ibuprofen-loaded polystyrene microparticles

Ibuprofen-loaded polystyrene microparticles were prepared by the emulsion-solvent evaporation process from an aqueous system. The effects of different parameters on the drug content and on the release of the drug from the microparticles were investigated. The drug content, in all the formulations, was less than the theoretical drug loading. The lower drug content was due to drug partitioning to the external aqueous phase during formulation. Statistical analysis revealed that the variation in the concentrations of the emulsion stabilizer and the organic disperse phase volume did not significantly alter the release of the drug. Although an increase in drug loading increased drug release from the microparticles, a biphasic linear relationship was observed between the time required for 50% drug release and the drug loading. The effect of size of the microparticles on drug release was more important for the low drug-loaded microparticles than that for the high drug-loaded microparticles. Such release behaviour from the microparticles was explained on the basis of the morphological structure of the microparticles.     

Microparticles prepared by grinding of polymeric films

Microparticles were prepared by a film grinding method, whereby thin drug-containing ethylcellulose films were cryogenically ground into microparticles. The particle size and shape of the microparticles could be controlled by the thickness of the films and by the milling time. The encapsulation efficiency as well as the in vitro drug release depended on the physical state of the drug in the ethylcellulose matrix (dispersed vs dissolved). Increased drug loadings and decreased particle size and film thickness increased the drug release. Microparticles prepared from cast films were more dense and had a slower drug release compared to microparticles prepared from sprayed films or from films prepared from an aqueous colloidal ethylcellulose dispersion, Aquacoat ECD. Lamination of the drug-containing film with a drug-free polymer layer on both sides resulted in a reduced drug release. Hydrophilic plasticizers acted as pore-formers and accelerated drug release, while lipophilic plasticizers reduced the drug release. The solubility of the drug in the organic polymer solution was one of the main parameters to achieve high encapsulation efficiencies and extended drug release, while dispersed drug was released much faster. The drug release from microparticles prepared by film grinding was faster than from microparticles prepared by the solvent evaporation method. The faster release was attributed to the fractured surface of the ground particles. Grinding of microparticles, which were prepared by the solvent evaporation, also resulted in a faster release.     

Preparation, characterization and in vitro cytotoxicity of indomethacin-loaded PLLA/PLGA microparticles using supercritical CO(2) technique.

In this work, indomethacin-loaded poly(l-lactic acid)/poly(lactide-co-glycolide) (IDMC-PLLA/PLGA) microparticles were prepared using solution-enhanced dispersion by supercritical fluids (SEDS) technique in an effort to obtain alternative IDMC formulation for drug delivery system. Surface morphology, particle size and particle size distribution, drug encapsulation efficiency, drug release kinetics, in vitro cytotoxicity and the cellular uptake of drug-loaded microparticles were investigated. The drug-loaded microparticles exhibited sphere-like shape and small particle size with narrow particle size distribution. IDMC was amorphously dispersed within the PLLA/PLGA matrix after the SEDS process. In vitro release studies revealed that the drug-loaded microparticles substantially enhanced the dissolution rate of IDMC compared to the free IDMC, and demonstrated a biphasic drug release profile. In vitro cytotoxicity assays indicated that drug-loaded microparticles possessed longer sustained inhibition activity on proliferation of the non-small-cell lung cancer A549 cell lines than did free IDMC. Fluorescence microscopy and transmission electron microscopy identified the phagocytosis of drug-loaded microparticles into the A549 cells and characteristic morphology of cell apoptosis such as the nuclear aberrations, condensation of chromatin, and swelling damage in mitochondria. These results collectively suggested that IDMC-PLLA/PLGA microparticles prepared using SEDS would have potentials in anti-tumor applications as a controlled drug release dosage form without harmful organic solvent residue.     

Preparation,In Vitro Characterization,and In Vivo Pharmacokinetic Evaluation of Respirable Porous Microparticles Containing Rifampicin

This study aimed to prepare and evaluate rifampicin microparticles for the lung delivery of rifampicin as respirable powder. The microparticles were prepared using chitosan by the spray-drying method and evaluated for aerodynamic properties and pulmonary drug absorption. To control the drug release, tripoly-phosphate in different concentrations 0.6, 0.9, 1.2, and 1.5 was employed to get a sustained drug release profile. The microparticles were evaluated for drug loading, % entrapment efficiency, tapped density, morphological characteristics, and in vitro drug release studies. Aerosol properties were determined using the Andersen cascade impactor. Porous microparticles with particle sizes (d_0.5) less than 10 μm were obtained. The entrapment of rifampicin in microparticles was up to 72%. In vitro drug release suggested that the crosslinked microparticles showed sustained release for more than 12 hrs. The drug release rate was found to be decreased as the TPP concentration was increased. The microparticles showed a fine particle fraction in the range of 55–63% with mass median aerodynamic diameter (MMAD) values below 3 μm. The in vivo pulmonary absorption of the chitosan microparticles suggested a sustained drug release profile up to 72 hrs with an elimination rate of 0.010 per hr. The studies revealed that the spray-dried porous microparticles have suitable properties to be used as respirable powder in rifampicin delivery to the lungs.     

Preparation and characterization of D, L-PLA loaded 17-β-Estradiol valerate by emulsion/evaporation methods

PLA microparticles containing 17-β-estradiol valerate were prepared by an emulsion/evaporation method in order to sustain drug release. This system was characterized concerning particle size, particle morphology and the influence of formulation and processing parameters on drug encapsulation and in vitro drug release. The biodegradation of the microparticles was observed by tissue histological analysis. Scanning electron microscopy and particle size analysis showed that the microparticles were spherical, presenting non-aggregated homogeneous surface and had diameters in the range of 718-880 nm (inert micro-particles) and 3-4 μm (drug loaded microparticles). The encapsulation efficiency was ～80%. Hormone released from microparticles was sustained. An in vivo degradation experiment confirmed that microparticles are biodegradable. The preparation method was shown to be suitable, since the morphological characteristics and efficiency yield were satisfactory. Thus, the method of developed microparticles seems to be a promising system for sustained release of 17-β-estradiol.     

Thermal and fractal analysis of diclofenac/Gelucire 50/13 microparticles obtained by ultrasound-assisted atomization

The study describes the application of a spray-congealing technique, using a new ultrasound-assisted atomizer to prepare microparticles of diclofenac/Gelucire 50/13, with the aim to obtain a formulation of enhanced-release, at 10% w/w drug-to-excipient ratio, without any employ of solvent. Scanning electron microscopy showed that it was possible to obtain almost spherically shaped and non-aggregated microparticles; with good encapsulation efficiency (90% in most size fraction) and with a prevalent particle size in the range 150-350 mum. Image analysis results by SEM and the high fractal dimension value suggested that most particles have actually an ellipsoidal shape and a rather rough contour. Hot stage microscopy, differential scanning calorimetry, and X-ray powder diffractometry analysis were carried out to evaluate the nature of the solid state and the thermal behavior of the microparticles thus prepared. The in vitro tests displayed a significant increase of the diclofenac dissolution rate from ultrasound microparticles, compared with pure drug and with drug/Gelucire 50/13 physical mixtures.     

Accelerated fenofibrate release from spray-dried microparticles based on polymer blends

Fenofibrate-loaded microparticles based on PVP/Eudragit E or HPMC/Eudragit E blends were prepared by spray-drying. The composition of the systems (in particular the polymer/polymer blend ratio and the drug loading) was varied and the resulting key properties were determined (including drug release measurements in 0.1 M HCl, X-ray diffraction studies, solubility measurements and particle size analysis). For reasons of comparison, also the respective physical drug/polymer/polymer mixtures, microparticles based on binary drug/PVP and drug/HPMC blends, the fenofibrate powder as received and a commercially available drug product were investigated. Importantly, highly supersaturated fenofibrate solutions were created upon exposure of the different types of microparticles to the release medium, in contrast to any reference formulation. Also, the presence of co-dissolved Eudragit E led to a significant increase in fenofibrate solubility. At 10 % drug loading, all microparticles were amorphous and drug release stable during one month open storage. However, at 30 % loading, HPMC containing microparticles showed storage instability, due to drug re-crystallization.