Abstract: This contribution focused on the solubility improvement of the poorly water-soluble steroid hormone progesterone which, in its natural state, presents a reduced oral bioavailability. In the first part of this study, two simple, reproducible methods that were candidates for use in the preparation of inclusion complexes with cyclodextrins were investigated. Solubility capacities of the progesterone complex with hydroxypropyl-beta-CD (HPbeta-CD), hydoxypropyl-gamma-CD (HPgamma-CD), permethyl-beta-CD (PMbeta-CD), and sulfobutylether-beta-CD (SBEbeta-CD), prepared by the freeze-drying and precipitation methods, were evaluated by Higuchi phase solubility studies. The results showed that HPbeta-CD and PMbeta-CD were the most efficient among the four cyclodextrins for the solubilization of progesterone, with the highest apparent stability constants. Therefore, dissolution studies were conducted on these latest progesterone/cyclodextrin complexes and physical mixtures. Two additional natural cyclodextrins, beta-CD and gamma-CD, were taken as references. Hence, the influence of more highly soluble derivatives of beta-CD (HPbeta-CD, PMbeta-CD) on the progesterone dissolution rate, in comparison to pristine beta-CD, alongside an increase in the cavity width for gamma-CD versus beta-CD, were investigated. The dissolution kinetics of progesterone dissolved from HPbeta-CD, PMbeta-CD, and gamma-CD revealed higher constant rates in comparison to beta-CD. Therefore, the aim of the second part of this study was to investigate the possibility of improving the dissolution rate of progesterone/beta-CD binary systems upon formation of ternary complexes with the hydrophilic polymer, PEG 6000, as beta-CD had the smallest progesterone solubility and dissolution capacity among the four cyclodextrins studied (beta-CD, HPbeta-CD, HPgamma-CD and PMbeta-CD). The results indicated that dissolution constant rates were considerably enhanced for the 5% and 10% progesterone/beta-CD complexes in PEG 6000. The interaction of progesterone with the cyclodextrins of interest on the form of the binary physical mixtures, complexes, or ternary complexes were investigated by differential scanning calorimetry (DSC) and Fourier transformed-infrared spectroscopy (FT-IR). The results proved that progesterone was diffused into the cyclodextrin cavity, replacing the water molecules and, in case of ternary systems, that the progesterone beta-cyclodextrin was well dispersed into PEG, thus improving progesterone bioavailability for subsequent oral delivery in the same way as derivatized cyclodextrins. The present work proves that ternary complexes are promising systems for drug encapsulation.

Abstract: Several aspects of the manufacture of nanospheres containing metronidazole were studied. Nanospheres made of amphiphilic beta-cyclodextrin containing metronidazole were prepared by adding an acetone solution of amphiphilic cyclodextrin to an aqueous solution of metronidazole with or without Pluronic PE/F68 as the surfactant. An optimized formulation with high encapsulation efficiencies and with an appropriate particle size for intravenous administration, was developed. The entrapment of metronidazole was strongly dependent of the method of preparation and drug concentrations. These nanospheres prepared by nanocrystallization are promising carriers for metronidazole in the treatment of hepatic abscess.

Abstract: PURPOSE: Microparticles of diameter < 5 microm were synthesized by interfacial cross-linking of 7.5% (w/v) beta-cyclodextrins (beta-CD) with 4.5% (w/v) terephtaloyle chloride in 1 M NaOH, in order to provide stable vector for drug encapsulation suitable for administration at the alveolar scale. METHODS: Batches were prepared varying different parameters such as amount of monomer (beta-CD) (5-30% w/v), NaOH concentration (0.5-4 M), reaction time (15-240 min), agitation rate (8000-24000 rpm), amount of cross-linking agent (terephtaloyle chloride: 1.25-10% w/v), surfactant percentage (2.5-10% of Span 85), studying the influence of the freeze-drying step. Microparticles were controlled with respect to their size by a laser diffraction technique, pH of the colloidal suspension, IR spectroscopy, Differential Scanning Calorimetry. After optimization of the microparticles size, complexation with amikacin sulfate was investigated comparing encapsulation efficiency and yield at each step of the preparation (solubilization, emulsification, cross-linking, freeze-drying), contact time and influence of the amount of amikacin. RESULTS: An optimized method was obtained with 1 M NaOH, 4.5% (w/v) cross-linking agent and 5% (w/v) surfactant agent, a 30 min reaction time, a 24000 rpm agitation rate, conducting to microparticles whose size is inferior to 5 microm. Amikacin sulfate encapsulation in polycondensed beta-cyclodextrin showed that better incorporation was obtained during the solubilization step or just before freeze-drying. CONCLUSIONS: Amikacin encapsulation in 5 microm diameter microparticles of beta-CD is achievable for pulmonary drug delivery.

Abstract: The aim of this study was to determine if the use of both enzyme and surfactant in the dissolution medium changes the in vitro drug release from cross-linked hard gelatin capsules containing a water-insoluble drug. Hard gelatin capsules were cross-linked by a controlled exposure to formaldehyde resulting in different stressed capsules and carbamazepine (CBZ) was chosen as a drug model. In vitro dissolution studies were conducted using simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) with enzymes. Sodium lauryl sulfate (SLS) was added in the dissolution medium at a concentration of 2% m/v both in SGF and SIF with pepsin and pancreatin, respectively. The percentage of CBZ dissolved was reduced by increasing the degree of gelatin cross-linking. For unstressed hard gelatin capsules, 36% of the CBZ was released after 1 h, lowering to 5% for highly stressed hard gelatin capsules in the SGF. A similar effect was observed with SIF. In the case of moderately stressed hard gelatin capsules, addition of enzyme in the dissolution medium enhanced the percentage of CBZ dissolved. The dissolution level increased from 12% to 39% in SGF with pepsin for hard gelatin capsules cross-linked with 1500 ppm formaldehyde. On the contrary, the use of enzyme in the dissolution medium did not increase the dissolution of CBZ from highly stressed hard gelatin capsules. Surprisingly, the addition of SLS in the medium did not allow the release of the CBZ both in SGF and in SIF. The results of this study demonstrate that the use of enzyme in the dissolution medium is justified for moderately cross-linked hard gelatin capsules. However, the action of a surfactant added in the medium containing enzyme remains unclear.