Beatrice Albertini

Preparation and characterisation of ibuprofen-poloxamer 188 granules obtained by melt granulation

The aim of this study was to prepare, by melt granulation, granules containing ibuprofen as a poorly water soluble model drug in order to improve its dissolution rate and its availability; lactose as a diluent and poloxamer 188 (Lutrol F68), as a new meltable hydrophilic binder, were used. The granules were prepared in a laboratory-scale high-shear mixer, using a jacket temperature of 50 degrees C and an impeller speed of 500 rpm. The particle size analysis shows that the main fraction was between 200 and 500 microm, while the determination of drug content indicated that ibuprofen was quite uniformly distributed in all the fractions. Scanning Electron Microscopy (SEM), image and fractal analysis revealed that the granules did not have a perfect spherical shape and a rugged surface (D(s)=2.6475). The in vitro dissolution tests showed an increase in the dissolution rate of granules compared to pure drug and physical mixture. The characterisation of the samples, performed by Differential Scanning Calorimetry (DSC) and X-ray powder diffraction (XRD), suggests that the improvement of dissolution rate could be correlated to the formation of a eutectic mixture between the drug and the binder. Stability studies indicated that the granule properties do not change, at least after 1 year of storage at 25 degrees C. In conclusion, the results of this work suggest that the melt granulation technique is an easy and fast method to improve the dissolution rate of ibuprofen, using poloxamer 188 as a new hydrophilic meltable binder.

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 100-355mum 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.

Development of microparticulate systems for intestinal delivery of Lactobacillus acidophilus and Bifidobacterium lactis.

In the present study intestinal delivery systems resistant to gastric juice, loaded with the probiotic bacteria Lactobacillus acidophilus LA14 and Bifidobacterium lactis BI07, were produced by the polyelectrolyte complexation. First, beads were prepared by the traditional extrusion method and nine formulations were developed using alginate as main carrier and the biopolymer, xanthan gum (XG), as hydrophilic retardant polymer or the cellulose derivative, cellulose acetate phthalate (CAP), as gastro-resistant polymer. The results showed that the incorporation of the 0.5% (w/v) of XG or the 1% (w/v) of CAP within the 3% (w/v) of alginate solution increased the survival of the probiotic bacteria in acid conditions from 63% of the freeze-dried bacteria up to 76%. Subsequently, these formula was used to prepare smaller microcapsules by means of an atomization device. Despite of the high viscosity of the biomass suspension, the spraying system produced spherical and non-aggregated microcapsules able to survive in harsh condition better than beads: the survival of the probiotic bacteria after acid incubation was 91%. The performance of the microcapsules in simulated gastric fluid (SGF) containing pepsin and in gut medium (GM) containing bile salts was excellent (viability>95%). Furthermore, the viability of probiotic bacteria was maintained after an incubation of 24h in GM. Finally, stability tests performed at 5 degrees C highlighted a bacterial viability of about 82% and 70% after 6 and 9 months, respectively.

Controlled release of verapamil hydrochloride from waxy microparticles prepared by spray congealing

In this work, the potential of waxes for preparing with the ultrasonic spray congealing technique microparticles for controlling the in vitro release of verapamil HCl was investigated. The first part of the study encompassed the optimisation of the formulation to achieve an efficient drug incorporation together with a satisfactory in vitro drug release rate. In particular, microcrystalline wax, stearyl alcohol and mixtures of the two were used. Also a surfactant (soya lecithin) was added to the formulations. After the particle size analysis, the characterisation of the microparticles involved the study of the solid state of drug and carriers in the systems (DSC, HSM and XRD) and the morphological and chemical analyses of the microparticle surface (SEM and XPS). Finally, the drug release mechanism from these devices was evaluated using the statistical moment analysis. The results of this study show that by selecting the type and the amount of the carriers, microparticles with a spherical shape and a good encapsulation efficiency were observed. These particles showed a zero-order release for 8 h, without modifying the solid state properties of the drug. Therefore, waxy microparticles prepared by the ultrasonic spray congealing technique are promising solvent-free devices for controlling the release of verapamil HCl.

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.

Melt granulation of pharmaceutical powders: a comparison of high-shear mixer and fluidised bed processes.

The main aim of this research was to compare in situ melt granulation process in high-shear mixers and fluidised bed equipments with particular attention to the final properties of granules. In addition, the study evaluated the suitability of melt granulation in fluidised bed for improving the dissolution rate of drugs. Agglomerates having identical composition (10%, w/w, of ibuprofen or ketoprofen, 20%, w/w, of PEG 6000 and 70%, w/w, of lactose monohydrate) were produced using both equipments and their morphology, particle size, flowability, friability, drug loading, dissolution behaviors at pH 1.2 and 7.4 and physicochemical properties (DSC and XRD analysis) have been evaluated and compared. The results showed that melt granulation can be successfully performed in both granulators. The utilization of a different equipment had strong impact on the particle size distribution of the granules and on their morphology, while the effect on others physical properties was little, as all the granules possess low friability and excellent flowability. Moreover both the solid state characteristics of the products and the dissolution behaviors of ibuprofen and ketoprofen granules were found to be practically independent of the equipment and all granules showed a significant increase of the drug dissolution rate in acidic conditions. In conclusion in situ melt granulation in fluidised beds could be considered a suitable alternative to the melt granulation in high-shear mixers.

Ultrasound-compacted and spray-congealed indomethacin/polyethyleneglycol systems

The product obtained by ultrasound (US)-assisted compaction was compared with a solid dispersion for systems containing polyethyleneglycols (PEGs) of different molecular weights and indomethacin (IMC), at the weight ratio 9:1, obtained by traditional melting and followed by a new US-assisted spray-congealing technique. US-discharge during compaction affects crystallinity of both IMC and PEG: pure IMC changes to an amorphous form and, when in mixture with PEG, partially dissolves in the excipient: this causes an increase of the dissolution rate of the drug. Differential scanning calorimetry (DSC) thermograms do not reveal any endothermic peak associated with the melting of the drug, while X-ray diffractograms show a loss of crystallinity of both IMC and PEG in the US-compacted granules. The extent of a back-crystallisation, which reduces the dissolution rate, as a function of the ageing of the material, depends on the type of the selected PEG. When a molten IMC/PEG mixture was transformed into microspheres by an US-assisted spray-congealing technique, the behaviour at dissolution almost recalls that of US-compacted granulates and some differences are briefly discussed.

Evaluation of spray congealing as technique for the preparation of highly loaded solid lipid microparticles containing the sunscreen agent, avobenzone

Solid lipid microparticles (SLMs) loaded with high amounts of the sunscreen agent, butyl methoxydibenzoylmethane (avobenzone) were prepared in order to reduce its photoinstability. The microparticles were produced, using carnauba wax as lipidic material and phosphatidylcholine as the surfactant, by the classical melt dispersion method or the spray congealing technique with pneumatic atomizer. The sunscreen agent loading was 40.1-48.5% (w/w), with no significant differences between the production methods. However, release studies indicated that spray congealing enabled a more efficient modulation of avobenzone release from the SLMs (26% of encapsulated avobenzone released after 2 h as compared to 60% for melt dispersion). The photoprotective efficacy of the SLMs was evaluated after their introduction in a model cream. A statistically significant decrease of the light-induced degradation of avobenzone was obtained by the SLMs prepared by the melt dispersion procedure (the extent of degradation was 38.6 +/- 3.6% for nonencapsulated avobenzone and 32.1 +/- 4.3% for the microparticle-entrapped sunscreen). On the other hand, the SLMs produced by spray congealing achieved a more marked reduction in avobenzone photodecomposition to 15.4 +/- 4.1%. Therefore, the spray congealing technique was superior to the classical melt dispersion method for rapid and solvent free production of SLMs with a high avobenzone loading capacity.

Evaluation of solid lipid microparticles produced by spray congealing for topical application of econazole nitrate.

OBJECTIVES The aims of this study were to evaluate the suitability of the spray congealing technique to produce solid lipid microparticles (SLMs) for topical administration and to study the skin permeation of a drug from SLMs compared with solid lipid nanoparticles (SLNs). METHODS Econazole nitrate was used as model drug and Precirol ATO 5 as the lipidic carrier. SLMs and SLNs were both prepared at 5:1, 10:1 and 12.5:1 lipid:drug weight ratios and characterised in terms of particle size, morphology, encapsulation efficiency and chemical analysis of the particle surface. SLMs and SLNs were also incorporated into HPMC K 100M hydrogels for ex-vivo drug permeation tests using porcine epidermis. KEY FINDINGS SLMs had particle sizes of 18-45 microm, while SLNs showed a mean diameter of 130-270 nm. The encapsulation efficiency was 80-100%. Permeation profiles of econazole nitrate were influenced by both particle size (significant difference until 9 h) and the amount of lipid. CONCLUSIONS The results confirm the usefulness of SLNs as carriers for topical administration and suggest the potential of SLMs for the delivery of drugs to the skin.

Poloxamer 407 microspheres for orotransmucosal drug delivery. Part I: Formulation, manufacturing and characterization

The two-part article aimed to investigate poloxamer 407-based microspheres as a novel platform for enhancing and controlling the delivery of atenolol across the oromucosal tissue. In the Part I of the work, atenolol-loaded poloxamers 407 microparticles were prepared by the solvent free spray congealing technology. This approach was feasible upon the high viscosity of the systems allowing for high loaded (20% w/w) non-aggregated microspheres. Several formulations were studied and the results demonstrated that the drug release patterns, solubility data, mucoadhesion to buccal tissue and gelling properties in saliva could be modified by adding different amount of an amphiphilic polymer-lipid excipient (Gelucire(®) 50/13) to poloxamer 407. Particularly, microspheres based only on poloxamer 407 exhibited very high solubility, mucoadhesive strength and gelling behaviour. To assess their potential as matrix for buccal application, the gelling property and the drug release from tablets obtained from direct compression of the microparticles were further evaluated. The microspheres were then characterized by differential scanning calorimetry, X-ray powder diffraction and Fourier transform-infrared spectra analysis. No solid state modifications and chemical interactions were detectable in the microspheres after manufacturing and during storage, suggesting their stability and use as orotransmucosal delivery systems.