Biomedical subjects

Géraldine Piel

Publications and source records attributed to Géraldine Piel.

8 recordsLinked to original sources

PubMed2006

Solid lipid microparticles as a sustained release system for pulmonary drug delivery.

The controlled release of drugs for pulmonary delivery is a research field which has been so far rather unexploited but is currently becoming increasingly attractive. The introduction part of this research article first details the potential advantages of solid lipid microparticles (SLMs) as drug carrier compared to liposomes and polymeric microspheres. The aim of this work is to use SLMs to impart a sustained release profile to a model drug, salbutamol acetonide (SA). SA was synthesized from salbutamol in order to increase the lipophilicity of this molecule and thereby to increase its incorporation efficiency into SLMs. SA-loaded SLMs were then produced by a hot emulsion technique followed by high-shear homogenisation and the manufacturing parameters were optimized using the experimental design methodology in order to reach a suitable particle size for pulmonary administration. Scanning electron micrographs showed that SLMs are spherical, have a smooth surface and that SA crystallizes outside of the particles when the drug loading is higher than 20%. This was confirmed by X-ray diffraction. SA in vitro release study from SLMs showed that the release rate increased with SA loading but remained in every case lower than the dissolution rate of pure SA.

Administration, Inhalation↗

PubMed2006

Pharmacokinetic study of a new synthetic MMP inhibitor (Ro 28-2653) after IV and oral administration of cyclodextrin solutions.

Ro 28-2653 (5-biphenyl-4-yl-5-[4-(4-nitro-phenyl)-piperazin-1-yl]-pyrimidine-2,4,6-trione) is a new synthetic inhibitor of matrix metalloproteinases (MMPs) with a high selectivity towards MMP2, MMP9 and membrane type 1-MMP. It has been shown that cyclodextrins (CDs) are able to form inclusion complexes with Ro 28-2653 and to increase its aqueous solubility. The aim of this study is to demonstrate that an increase in Ro 28-2653 solubility, via ternary complex formation, can lead to an increase in the oral bioavailability of this drug. This study shows that a synergistic effect exists between hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and l-lysine. The use of this multicomponent system enabled the preparation of oral and intravenous solutions of Ro 28-2653. In vivo evaluation of the oral solution of the inclusion complex of Ro 28-2653 in comparison with a suspension of the same uncomplexed drug showed a significant (p<0.05) increase in absolute bioavailability. The area under curve (AUC) and the peak serum concentration (Cmax) were approximately 10 times higher than those obtained with the suspension, while the time (Tmax) to reach Cmax was reduced. Moreover, in vivo administration of Ro 28-2653 solutions highlighted some information about the pharmacokinetic behavior of Ro 28-2653: a long biologic half-life (about 15.5h) and a small overall volume of distribution (8l).

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed2006

Betamethasone-in-cyclodextrin-in-liposome: the effect of cyclodextrins on encapsulation efficiency and release kinetics.

Lipophilic drugs have limited solubility in phospholipid systems, hence maximum entrapment levels in liposomes are known to be low. "Drugs-in-cyclodextrin-in-liposome" systems were previously proposed to overcome this drawback but studies were limited to betaCD and HPbetaCD. In some cases, other cyclodextrins may be more interesting than betaCD or HPbetaCD, such as methylated cyclodextrins. However, these cyclodextrins are known to extract lipid components from the lipid membrane, which may destabilize liposomes. We tested the influence of several cyclodextrins (betaCD, gammaCD, Dimeb, Trimeb, Crysmeb, Rameb, HPbetaCD and HPgammaCD) on the aqueous solubility of betamethasone by phase solubility diagrams and on the encapsulation efficiency in liposomes. The release kinetics of betamethasone was studied using Franz diffusion cells. We showed that release kinetics are directly correlated with encapsulation efficiency, which is closely related to betamethasone concentration in cyclodextrin complex solution. No liposome destruction was observed, even with the testing of methylated cyclodextrins at the highest concentration (40 mM). This can be explained by the fact that these cyclodextrins have a higher affinity for betamethasone than for cholesterol. This was proved by the comparison of phase solubility diagrams of both betamethasone and cholesterol.

Amines↗

PubMed2005

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.

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.

Cyclodextrins↗

PubMed2005

Cyclodextrin-mediated drug release from liposomes dispersed within a bioadhesive gel.

PURPOSE: The aim of the present study was to design a new mucosal drug delivery system composed of liposomes dispersed within a bioadhesive hydrogel containing methyl-beta-cyclodextrin (Me(beta)CD) for controlled drug release. METHODS: A hydrophilic model molecule, inulin, was encapsulated within positively charged and PEG-ylated liposomes and its release was measured in the presence of Me(beta)CD after vesicle dispersion within the bioadhesive Carbopol 974P gel. Freeze-fracture electron microscopy (FFEM) was used to follow liposome morphological changes when dispersed within the hydrogel. Liposome-Me(beta)CD interactions were investigated by turbidity monitoring during continuous addition of Me(beta)CD to liposomes and by FFEM. RESULTS: Inulin diffusion within the gel was influenced by Carbopol 974P concentration since no gel erosion occurred. When dispersed within the gel, positively charged liposomes displayed a higher stability than PEG-ylated vesicles. In the presence of Me(beta)CD, higher amounts of free inulin were released from liposomes, especially in Carbopol-free system. Me(beta)CD appeared to diffuse towards lipid vesicles and permeabilized their bilayer allowing inulin leakage. Indeed, freeze-fracture experiments and liposome turbidity monitoring have shown that Me(beta)CD behaved as a detergent behavior, resulting in lipid vesicle solubilization. CONCLUSION: is able to mediate, within a bioadhesive hydrogel, the release of a liposome-encapsulated molecule allowing further application of this delivery system for mucosal administration.

Acrylic Resins↗

PubMed2005

Solid lipid microparticles: formulation, preparation, characterisation, drug release and applications.

This review details the properties of solid lipid microparticles (SLMs): a promising drug carrier system that has been until now rather unexploited. First, the advantages of SLMs compared with other drug carrier systems are listed. Then an overview of SLM manufacturing compounds and techniques is presented. A detailed discussion of the characteristics of SLMs follows, and includes the determination of particle size distribution, the determination of SLM morphology, the solid-state analysis, the determination of SLM drug loading and the factors influencing it. The in vitro drug release studies that have been carried out so far and the parameters affecting them are also described. Some preliminary in vivo aspects (in vivo drug release studies, biocompatibility studies and in vivo fate) are also considered.

Animals↗

PubMed2004

Effect of acidic ternary compounds on the formation of miconazole/cyclodextrin inclusion complexes by means of supercritical carbon dioxide.

PURPOSE: The aim of the study is to evaluate the effect of different acidic compounds on the inclusion of miconazole (MICO) in several cyclodextrins (CDs) using supercritical carbon dioxide (SCCO(2) ) processing. METHODS: Physical mixtures were processed by SCCO(2) at 30 MPa, 125 degrees C during 60 minutes in a static mode to produce inclusion complexes. The inclusion complexes were characterized by differential solubility, Fourier transform infrared spectroscopy (FT-IR) and dissolution test. RESULTS: The best inclusion yields were achieved with the combination of MICO base and HPgammaCD with or without acids. Maleic and fumaric acids influenced the MICO inclusion differently in function of their conformation. During the process, a miconazole salt was observed with maleic acid and characterized by thermal analysis and mass spectrometry. The kinetics inclusion followed a saturation-type shape curve. FT-IR confirmed the presence of genuine inclusion complexes. The complexes MICO base/HPgammaCD/(L-tartaric acid) enhanced the dissolution rates of MICO more than the corresponding physical mixtures did. Lastly, the stability study revealed that the complexes were stable. CONCLUSIONS: The formation of stable complexes between MICO and CDs is possible using SCCO(2). Moreover an acidic ternary compound is able to modify the formation of the complex. The inclusion complexes, which show better dissolution profiles than those with the corresponding physical mixtures, could lead to an increase of the oral bioavailability of MICO.

Carbon Dioxide↗

PubMed2004

Development and validation of a high-performance liquid chromatographic method for the determination of cyproterone acetate in human skin.

In the framework of a preliminary study on the transdermal penetration of cyproterone acetate (CPA), a simple and rapid procedure involving an extraction step coupled to a HPLC-UV determination has been developed for the separation and quantification of CPA in the two main skin layers-epidermis and dermis-after local application. The separation of epidermis and dermis layers was carefully carried out by means of a sharp spatula after skin immersion in heated water at 65 degrees C. The two skin layers were then treated separately according to the same process: (1) sample homogenization by vibration after freezing with liquid nitrogen in a Mikro-Dismembrator; (2) CPA extraction with methanol after addition of the internal standard (betamethasone dipropionate); (3) centrifugation; (4) evaporation of a supernatant aliquot; (5) dissolution of the dry residue in methanol and addition of water; (6) centrifugation; (7) injection of a supernatant aliquot into the HPLC system. The separation was achieved on octadecylsilica stationary phase using a mobile phase consisting in a mixture of acetonitrile and water (40:60 (v/v)). The method was then validated using a new approach based on accuracy profiles over a CPA concentration range from 33 to 667 ng/ml for each skin layer. Finally, the method was successfully applied to the determination of CPA to several skin samples after topical application of different gel formulations containing CPA.

Chromatography, High Pressure Liquid↗