Theoretical and Experimental Vibrational Study of Miconazole and Its Dimers with Organic Acids: Application to the IR Characterization of Its Inclusion Complexes with Cyclodextrins

in International Journal of Pharmaceutics (2008), 350(1-2), 155-165

The geometry, frequency and intensity of the vibrational bands of miconazole were derived from the density functional theory (DFT) calculations with the hybrid functional B3LYP and the 6-31G(d) basis set ... [more ▼]

The geometry, frequency and intensity of the vibrational bands of miconazole were derived from the density functional theory (DFT) calculations with the hybrid functional B3LYP and the 6-31G(d) basis set. Starting from the fully AM1 optimized geometries of miconazole/betaCD/acids complexes, the miconazole/acid dimers were reoptimized at the B3LYP/6-31G(d) level. Three acids were studied: maleic, fumaric and l-tartaric acids. To begin with the vibrational spectral data obtained from solid phase in mid FT-IR spectrum of miconazole and its dimers are assigned based on the results of the normal modes calculations. All the observed spectra and the calculated ones are found to be in good agreement. In a second step, theoretical results allowed the assignment of FT-IR spectrum for the miconazole/HPgammaCD inclusion complex produced by supercritical carbon dioxide treatment and confirmed the inclusion of miconazole. The experimental spectra for the miconazole/HPgammaCD/acids complexes prepared by supercritical carbon dioxide processing were also assigned using theoretical results. The results confirmed the presence of a genuine inclusion complex and also the interaction between miconazole and the acid. [less ▲]

Contribution of cyclodextrins in the development of different pharmaceutical formulations of a new matrix metalloproteinase inhibitor

in Journal of Inclusion Phenomena and Macrocyclic Chemistry (2007, April), 57(1-4), 303-308

Ro 28-2653 is a new synthetic inhibitor of matrix metalloproteinases. The ability of these enzymes to degrade various components of the extracellular matrix seems to play a major role in tumors ... [more ▼]

Ro 28-2653 is a new synthetic inhibitor of matrix metalloproteinases. The ability of these enzymes to degrade various components of the extracellular matrix seems to play a major role in tumors progression and is potentially effective against bronchial remodeling in asthma and BPCO. Ro 28-2653 is very poorly soluble in water. This low solubility estimated at about 0.56 mu g/ml in water at 25 degrees C gives rise to difficulties in pharmaceutical formulation of oral, injectable or nebulizable solutions. The purpose of our study is to prepare and to characterize inclusion complexes between Ro 28-2653 and cyclodextrins and to investigate the biopharmaceutical repercussion of the inclusion of the active substance. The complex formation was investigated by phase solubility studies. H-1-NMR spectroscopy and molecular modeling studies were carried out to elucidate the structure of the inclusion complex between Ro 28-2653 and cyclodextrin. Oral, intravenous and nebulizable solutions of Ro 28-2653 were developed with cyclodextrin. The in vivo studies were performed on healthy sheep for the pharmacokinetic evaluation of the oral and intravenous formulations while the nebulization of the complex solution was studied by using an asthma model in mouse. [less ▲]

Contribution of cyclodextrins in the developement of different pharmaceutical formulations of a nex matrix metalloproteinase inhibitor

in Journal of Inclusion Phenomena and Molecular Recognition in Chemistry (2007)

Ro 28-2653 is a new synthetic inhibitor of matrix metalloproteinases. The ability of these enzymes to degrade various components of the extracellular matrix seems to play a major role in tumors ... [more ▼]

Ro 28-2653 is a new synthetic inhibitor of matrix metalloproteinases. The ability of these enzymes to degrade various components of the extracellular matrix seems to play a major role in tumors progression and is potentially effective against bronchial remodeling in asthma and BPCO. Ro 28-2653 is very poorly soluble in water. This low solubility estimated at about 0.56 lg/ml in water at 25 C gives rise to difficulties in pharmaceutical formulation of oral, injectable or nebulizable solutions. The purpose of our study is to prepare and to characterize inclusion complexes between Ro 28-2653 and cyclodextrins and to investigate the biopharmaceutical repercussion of the inclusion of the active substance.The complex formation was investigated by phase solubility studies. 1H-NMR spectroscopy and molecular modeling studies were carried out to elucidate the structure of the inclusion complex between Ro 28-2653 and cyclodextrin. Oral, intravenous and nebulizable solutions of Ro 28-2653 were developed with cyclodextrin. The in vivo studies were performed on healthy sheep for the pharmacokinetic evaluation of the oral and intravenous formulations while the nebulization of the complex solution was studied by using an asthma model in mouse. [less ▲]

Inclusion of miconazole into cyclodextrins by means of supercritical carbon dioxide: effect of acidic ternary compound and molecular modelling study

Poster (2005, September)

Pharmacokinetic study of a new syntheyic MMP inhibitor (Ro 28-2653) after IV and oral administration of solutions containing hydroxypropyl-b-cyclodextrin

Poster (2005, June)

In vitro release of salbutamol acetonide from solid lipid nanoparticles

in Proceedings of 1st Pharmaceutical Sciences Fair and Exhibition (2005)

The Effect of Cyclodextrins on the Aqueous Solubility of a New Mmp Inhibitor: Phase Solubility, 1 H-Nmr Spectroscopy and Molecular Modeling Studies, Preparation and Stability Study of Nebulizable Solutions

in Journal of Pharmacy & Pharmaceutical Sciences : A Publication of the Canadian Society for Pharmaceutical Sciences (2005), 8(2), 164-175

PURPOSE: Ro 28-2653 (RO) is a synthetic inhibitor of matrix metalloproteinases (MMPs), which is potentially effective against bronchial remodeling. Given that this molecule has very poor aqueous ... [more ▼]

PURPOSE: Ro 28-2653 (RO) is a synthetic inhibitor of matrix metalloproteinases (MMPs), which is potentially effective against bronchial remodeling. Given that this molecule has very poor aqueous solubility, different cyclodextrins (CDs) have been tested to increase its solubility. The aim of this study was to prepare and to characterize inclusion complexes between RO and CDs, in order to develop nebulizable solutions. METHODS: The complex formation was investigated by phase solubility studies. (1)H-NMR spectroscopy and molecular modeling studies were carried out to elucidate the structure of the inclusion complex between RO and dimethyl-beta-CD (DIMEB). Nebulizable solutions of RO were developed with CDs and a stability study was performed over 9 months. RESULTS: The phase solubility studies showed that beta-CD and its derivatives form a 1:2 complex with RO, whereas gamma-CD includes RO with a 1:1 stoichiometry and a weak stability constant. T-ROESY spectra showed that DIMEB is able to complex two RO substituents (nitrophenyl and biphenyl groups) with preferential orientations, while molecular modeling demonstrated that the configurations observed with (1)H-NMR are energetically favorable, especially owing to H-bond formation between RO and DIMEB. Two CDs were selected to develop nebulizable solutions of RO and the stability study demonstrated that RO degradation in solution is strongly dependent on the concentration of the 1:2 inclusion complex. CONCLUSIONS: CDs are able to include RO and to improve its aqueous solubility. The beta-CD derivatives can be used to formulate nebulizable solutions of RO, the stability of which depends on the concentration of the 1:2 complex. [less ▲]

Effect of methylated-b-cyclodextrin on the skin and influence on cyproterone acetate percutaneous absorption

Poster (2004, May)

Solid lipid Nanoparticles for administration by inhalation : Optimisation of manufacturing parameters

Conference (2004)

Comparison of two methods currently used to determine the interaction between cyclodextrins and drugs: phase solubility diagrams and NMR spectroscopy

in Journal of Drug Delivery Science and Technology (2004), 14(1, JAN-FEB), 87-91

Two methods usually used in the literature to determine stability constant values (Kc) of cyclodextrin complexes were compared: the phase solubility diagram and NMR spectroscopy. Two model drugs were used ... [more ▼]

Two methods usually used in the literature to determine stability constant values (Kc) of cyclodextrin complexes were compared: the phase solubility diagram and NMR spectroscopy. Two model drugs were used to determine limitations of both techniques: betamethasone and miconazole, with three cyclodextrins: beta-cyclodextrine (betaCD), dimethylated-betaCD (Dimeb) and trimethylated-betaCD (Trimeb). This study shows that both techniques can give the same Kc value if they are used in exactly the same conditions with well defined cyclodextrins. As a matter of fact, if the degree of substitution of cyclodextrin is not well defined (as it is often the case with Dimeb), results are biased. This study also shows that when interactions between both molecules are weak (< 1000 M-1), stability constants can not be determined by NMR due to low chemical shift variations. The limitations of the phase solubility diagram method are an oversimplification of the solubility data which can lead to large errors in the calculation of the stability constant values. Moreover, this method is time and material consuming. [less ▲]