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.     

Solid lipid microparticles produced by spray congealing: Influence of the atomizer on microparticle characteristics and mathematical modeling of the drug release

The first aim of the work was to evaluate the effect of atomizer design on the properties of solid lipid microparticles produced by spray congealing. Two different air atomizers have been employed: a conventional air pressure nozzle (APN) and a recently developed atomizer (wide pneumatic nozzle, WPN). Milled theophylline and Compritol® 888ATO were used to produce microparticles at drug-to-carrier ratios of 10:90, 20:80, and 30:70 using the two atomizers. The results showed that the application of different nozzles had significant impacts on the morphology, encapsulation efficiency, and drug release behavior of the microparticles. In contrast, the characteristics of the atomizer did not influence the physicochemical properties of the microparticles as differential scanning calorimetry, Hot Stage microscopy, X-ray powder diffraction, and Fourier transform infrared spectroscopy analysis demonstrated. The drug and the lipid carrier presented in their original crystalline forms in both WPN and APN systems. A second objective of this study was to develop a novel mathematical model for describing the dynamic process of drug release from the solid lipid microparticles. For WPN microparticles the model predicted the changes of the drug release behavior with particle size and drug loading, while for APN microparticles the model fitting was not as good as for the WPN systems, confirming the influence of the atomizer on the drug release behavior. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:916–931, 2010     

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.     

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.     

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.     

In vitro characterization of polyorthoester microparticles containing bupivacaine

Laboratory-scale spray-congealing equipment was utilized to fabricate injectable microparticles consisting of polyorthoester and bupivacaine. Operating conditions for the spray-congealing process were optimized to produce microparticles with the desired shape and particle size to yield acceptable syringeability and injectability. Characterizations were performed to determine the chemico-physical properties of polyorthoester before and after microparticle fabrication. Microparticles with different drug loadings and comparable particle sizes were produced, and their in vitro drug-release profiles were determined. The in vitro drug release of microparticles with a high drug loading was markedly faster than those with a low drug loading. This is partially attributed to a more significant initial burst-drug release of the microparticles with a high drug loading. The microparticles have demonstrated the potential to be used for long-acting postsurgery pain management by local injection.     

Bimodal Release of Olanzapine from Lipid Microspheres

Olanzapine was formulated as 10% (w/w) mixture with cutina® to which stearic acid was added, ranging from 10% to 90% (w/w) of the total mass to control the drug release. The molten mixtures were processed by ultrasound-assisted spray-congealing technique, obtaining solid microspheres. The drug is stable under these conditions and only a partial miscibility in the solid state was observed by DSC between the two fatty materials with two separated melting endotherms in the thermograms: this can be due to the presence of two phases inside the solid dispersion. Olanzapine is distributed into the two phases according to its partition coefficient: two phases make the system less suitable to crystallization of the drug; the loading of the drug could reach saturation with difficulty and the rate of the olanzapine release is differentiated, since the drug is released from two different carriers. Dissolution profiles suggest occurrence of a bimodal release, where each portion of the release profile is linear and the slope increases with a higher content of stearic acid in the carrier mixture, that behaves as a release promoter. Tests were also carried out with palmitic and lauric acids for comparison and also for systems in the absence of ultrasound.     

Sodium pantoprazole-loaded enteric microparticles prepared by spray drying: effect of the scale of production and process validation

Pantoprazole is a prodrug used in the treatment of acid related disorders and Helicobacter pylori infections. It is activated inside gastric parietal cells binding irreversibly to the H(+)/K(+)-ATPase. In this way, pantoprazole must be absorbed intact in the intestinal tract, which indicates that enteric drug delivery systems are required for its oral administration. The purpose of this study was to investigate the physical characteristics of enteric pantoprazole-loaded microparticles prepared by spray drying using a blend of Eudragit S100 and HPMC. The microparticles were produced in different spray dryers and operational conditions at laboratory and pilot scales. Microparticles produced with two fluid nozzle atomizer and air pressure of 196 kPa presented satisfactory encapsulation efficiency and gastro-resistance. Microparticles produced with the same atomizer but using 49 kPa of air pressure presented strings in the powder. The microparticles produced in mixed flow presented very high polydispersity and the ones produced with rotating disc atomizer presented drug crystals adsorbed on the particle surfaces. The microparticles produced with two fluid nozzle atomizer and 196 kPa were prepared in three consecutive days for the process validation. The powders showed reproducible diameter, polydispersity, densities, encapsulation efficiency and gastro-resistance profile.     

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.     

New spray congealing atomizer for the microencapsulation of highly concentrated solid and liquid substances

A new pneumatic atomizer for spray congealing, called wide pneumatic nozzle (WPN), was developed. To evaluate its performance, microparticles containing highly concentrated either solid drug (Propafenone hydrochloride, PRF) or liquid nutraceutical (Vitamin E, VE) have been prepared and characterized. The results showed that the spray congealing nozzle enabled the production of spherical and not aggregated microparticles with high yields (95% w/w) and relatively narrow size distributions; moreover, increasing the viscosity of the suspension from 50 to 500 mPa s, the particle size increased. The loading of the drug was high for microspheres (50% for PRF and 30% for VE) and the encapsulation efficiency was good for all formulations. The drug release was easily modified according to the nature of the used excipients, as both lipophilic (carnauba wax, cetearyl and stearyl alcohols) and hydrophilic (PEG 4000) carriers were employed. Moreover the results evidenced that it was possible to encapsulate actives (VE) that are in a liquid form and to enhance their availability. In conclusion the developed spray congealing nozzle was able to nebulize very viscous systems that are usually not processed by conventional apparatus and to produce microspheres with high and uniform drug content.     

脂溶性药物在O/W型微乳中的分配行为

以亮菌甲素和氧氟沙星为模型药物，采用荧光光谱法考察微乳中各组分对药物荧光光谱的影响，以研究脂溶性小分子药物在O/W型微乳中的分配行为。结果显示在分别采用苯甲醇和PEG 400为助表面活性剂的微乳体系中，亮菌甲素主要存在于表面活性剂组成的界面膜中；氧氟沙星在油酸/橄榄油(1∶1)的微乳体系中的主要分布部位为油核，而在Gradamol GTCC为油相的微乳体系中主要存在于界面膜中；在各体系中药物均倾向于增溶在对药物溶解能力最强的组分所处的微环境中，具体的存在位置与该组分的用量有关。由此可见脂溶性药物在O/W型微乳中的存在部位可能取决于各组分对药物的溶解能力。     

Absorption and metabolism of albendazole after intestinal ischemia/reperfusion.

Pathophysiological processes involving inflammatory response may affect absorption and biotransformation of some drugs, modifying their pharmacokinetic behaviour. Ischemia/reperfusion (I/R) injury has been used as a model for inflammatory processes. The aim of this work was to study the effect of intestinal I/R injury on the absorption and metabolism processes of one orally administered drug, albendazole that is anthelmintic drug, it undergoes intestinal bioconversion into albendazole sulfoxide by two enzymatic systems, cytochromes P450 (CYP450) and flavin-containing monooxygenase (FMO). Male Wistar rats were used to study the influence of I/R in the intestinal absorption and metabolism of albendazole, after 60 min of mesenteric occlusion and 30 min of reperfusion. The intestinal studies were performed in microsomal, and everted ring incubations. During in situ studies, the I/R group had faster disappearance of albendazole from the lumen. In addition, albendazole only appeared in blood samples of the I/R group, while albendazole sulfoxide appeared in both samples and was higher in the control group. These findings are supported by significant reductions of albendazole sulfoxide formation in intestinal everted ring assays and in microsomal incubations after the I/R process. Both metabolizing systems, CYP4503A and FMO, were affected by I/R. Our data indicate that I/R injury, considered as an inflammatory model, reduces absorption and metabolism processes of albendazole.     

门诊患儿雾化吸入治疗的规范化管理

目的:探讨雾化吸入治疗在门诊统一管理的必要性和实施方法。方法:通过对门诊雾化室进行基线调查,了解雾化常见疾病、雾化药物的用法用量,从中发现问题,并联合多科室对雾化药物使用进行干预。结果:多科室共同制订雾化治疗模板,嵌入到医院信息系统(HIS),门诊医师开处方时可自动调出相关信息。结论:雾化治疗的统一规范化管理保证了药品使用的安全性和有效性,有利于合理用药的开展。     

Implication of inclusion complexation of glimepiride in cyclodextrin-polymer systems on its dissolution, stability and therapeutic efficacy

The effect of complexation of glimepiride, a poorly water-soluble antidiabetic drug, with β-cyclodextrin and its derivatives (HP-β-CyD and SBE-β-CyD) in presence of different concentrations of water-soluble polymers (HPMC, PVP, PEG 4000 and PEG 6000) on the dissolution rate of the drug has been investigated. The results revealed that the dissolution rate of the drug from these ternary systems is highly dependent on polymer type and concentration. The dissolution rate of the drug from ternary systems containing PEG 4000 or PEG 6000 seems to be generally higher than from systems containing HPMC or PVP. An optimum increase in the dissolution rate of the drug was observed at a polymer concentration of 5% for PEG 4000 or PEG 6000 and at 20% concentration of HPMC or PVP. The dissolution rate of the drug from the ternary system glimepiride–HP-β-CyD–5% PEG 4000 was high compared to the other systems. Tablets containing the drug or its equivalent amount of this ternary system were prepared and subjected to accelerated stability testing at 40 °C/75% R.H. to investigate the effect of storage on the chemical stability as well as therapeutic efficacy of the tablets. The results revealed stability of the tablets and consistent therapeutic efficacy on storage.     

The potential of calcium silicate hydrate as a carrier of ibuprofen

Calcium silicate nanostructured materials are promising drug carriers owing to their excellent biocompatibility, good bioactivity and high drug-loading capacity. In recent years, studies have been carried out on the synthesis of calcium silicate hydrate (CSH) nanostructured materials with desirable sizes and morphologies and their applications in drug delivery, where very interesting results and important insights have been documented. This editorial is not intended to offer a comprehensive review on the research on CSH nanostructured materials as drug carriers; rather, it presents representative examples: i) mesoporous microspheres; ii) ultrathin nanosheets; iii) iron oxide/CSH core/shell nanocomposites; and iv) CSH/block copolymer nanocomposites, and important results obtained in the study of CSH drug delivery systems for ibuprofen (IBU) as a model drug. These results show that the nanostructured CSH materials with specially designed architectures as IBU carriers have ultrahigh drug-loading capacity and sustainable drug release properties; thus, they are promising drug carriers for IBU. In addition, a new drug release kinetics has been found in the nanostructured CSH drug delivery systems. Most recently, new insight has been gained by tracking the behavior of these drug delivery systems on the molecular level using synchrotron-based X-ray spectroscopy.     

Formulation and evaluation of liquisolid compacts of diclofenac sodium

The technique of liquisolid compacts is a promising method towards enhancing the dissolution of poorly soluble drugs. In the present study, the potential of liquisolid systems to improve the dissolution properties of water-insoluble agents was investigated using diclofenac sodium as the model drug. Several formulations of liquisolid compacts having different drug concentration (30% to 50% w/w) and with varying ratios of carrier to coat (i.e., different R values, ranging from 5 to 50) were prepared. Avicel and Aerosil were used as carrier and coat material, respectively, and propylene glycol was used as a nonvolatile liquid to prepare liquid medication. The effect of added liquid on the flowability and compressibility of the final admixture was studied and the effect of drug concentration on the dissolution pattern of diclofenac sodium was investigated. Liquisolid compacts demonstrated significantly higher drug release rates than the pure drug.     

Skin penetration and deposition of carboxyfluorescein and temoporfin from different lipid vesicular systems: In vitro study with finite and infinite dosage application

The aim of the present research is to evaluate the influence of different lipid vesicular systems as well as the effect of application mode on skin penetration and deposition behaviors of carboxyfluorescein (hydrophilic model drug) and temoporfin (lipophilic model drug). All of the lipid vesicular systems, including conventional liposomes, invasomes and ethosomes, were prepared by film hydration method and characterized for particle size distribution, ζ-potential, vesicular shape and surface morphology, in vitro human skin penetration and skin deposition. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) defined that all of lipid vesicles had almost spherical structures with low polydispersity (PDI < 0.2) and nanometric size range (z-average no more than 150 nm). In addition, all lipid vesicular systems exhibited a negative zeta potential. In vitro skin penetration and deposition experiments demonstrated that, in the case of CF with finite dose application (10 μl/cm2) and infinite dose application (160 μl/cm2), lipid vesicular systems, especially ethosomes and invasomes, compared with non-vesicular systems, can significantly improve the delivery of hydrophilic drug such as carboxyfluorescein into skin deep layers or across the skin. While in the case of mTHPC with finite and infinite dose application, most of drug accumulation was observed in the skin superficial layer for both lipid vesicular systems and non-vesicular systems. The results also revealed that the factors influencing the drug skin distribution concern the physicochemical characteristics of the drug, the choice of the vehicle formulation and the application mode applied.     

Investigation and Comparison of Performance of Effervescent and Standard Pneumatic Atomizer Intended for Soluble Aqueous Coating

Effervescent atomizers belong to the group of internal mixing atomizers. The effervescent approach might be a potential alternative to traditional atomization techniques, e.g., for applications where low atomization air consumption is advantageous In this paper, performance of one proposed design of the effervescent atomizer is investigated and compared to that of a standard pneumatic atomizer. The purpose of the comparison is to evaluate the actual potential of the specific effervescent atomizer in pharmaceutical relevant aqueous coating applications. Aqueous solutions of Hypromellose 5 as well as Povidone K-90F were characterized in terms of rheological properties and surface tension. Solutions were atomized by means of a standard Schlick pneumatic atomizer as well as a customized inside-out type effervescent atomizer. Spray droplet size distributions were recorded by a Spraytec instrument. Increased shear viscosity in the range 24–836 mPa.s had a modest effect on spray mean diameters for pneumatic sprays of the Newtonian solutions of Hypromellose 5. In contrast, mean droplet diameters increased by a factor of 3–5 in pneumatic sprays of Povidone K-90F solutions 11–175 mPa.s in viscosity, where non-Newtonian behavior was observed. Further, sprays of all solutions of Povidone K-90F have considerably larger mean droplet size. The effervescent atomizer atomized low viscosity solutions of Povidone K-90F more efficiently than Hypromellose 5 solutions of corresponding shear viscosity. However, atomization of high viscosity Povidone K-90F results in a coarser spray than that of the corresponding Hypromellose 5 solution. Viscosity, visco-elasticity, and surface tension of solutions all seem to affect atomization efficiency. The pneumatic atomizer was not sensitive to changes in airflow above 8.4 kg/h and liquid flow only had a considerable effect at suboptimal air flows. In its current design the effervescent atomizer improved efficiency throughout the investigated range of air flow of 0.18–0.84 kg/h and consistently produced smaller drops at liquid flow of 10 g/min compared to 35 g/min. In spite of the very low level of air consumption, the effervescent atomizer can produce fine sprays. Within its working range, the standard pneumatic atomizer, however, is capable of producing sprays of even smaller mean droplet size. All together this suggests the described effervescent atomizer as an alternative for applications where advantages of reduced atomization air flow outweigh the disadvantages of a less fine spray, e.g., in coating of attrition- prone substrate.