Guy Couarraze

Controlled release of vancomycin from Poloxamer 407 gels

The purpose of this study was to investigate Poloxamer 407 25% (w/w) formulations aimed at prolonging the residence time of vancomycin, a time-dependent antibiotic, in a body site with a high infectious risk. Reversible thermal gelation of the formulations permitted their local injection in liquid form and in situ gelation as they warmed to body temperature. Neither the rheological properties of the Poloxamer matrices nor the antibacterial activity of vancomycin was altered by their combination. In vitro, the dispersed form exhibited prolonged release, with a lower diffusion coefficient of vancomycin compared to the solubilized form (4.7x10(-8) vs 2. 1x10(-7) cm(2) s(-1)131 mg l(-1) for the solubilized form), followed by lower but effective antibacterial levels for at least 8 days. Controlled-release profiles, good preservation of vancomycin activity, good tolerability in rats, and ease of administration suggest that Poloxamer 407 may be useful as a vancomycin delivery vehicle for local prophylaxis of infections, especially in prosthetic surgery.

Release of mifepristone from biodegradable matrices: experimental and theoretical evaluations.

Diffusion of mifepristone in poly [(D,L) lactide-co-glycolide)] films was studied by release experiments. Five 50/50 copolymers of increasing molecular weights were used. The degradation effects were shown by gel permeation chromatography (GPC). Release kinetics show the effect of copolymer molecular weights on diffusion and degradation properties of loaded films. A new theoretical model for drug release from a biodegradable matrix was proposed with two assumptions: correlation of the diffusion coefficient with the polymer molecular weight and existence of a first order degradation kinetic. Higuchis equation is verified at early time and the diffusion coefficient in the non-degraded polymer can be measured. The degradation constant is determined at long time and is compared with the results of GPC.

Percutaneous absorption of sunscreens from liquid crystalline phases.

The purpose of the present study was to investigate the effects of two nonionic surfactants with liquid crystalline structures on the cutaneous availability of two sunscreens. Three liquid crystalline structures were investigated: lamellar, hexagonal and cubic. The diffusion of sunscreens within the liquid crystals was determined by measuring transport kinetics into an unloaded surfactant medium from a similar system loaded with the sunscreens. The diffusion coefficients were the greatest in the cubic systems for benzophenone-4 (a hydrosoluble sunscreen) and in lamellar systems for octyl methoxycinnamate (a liposoluble sunscreen). So the diffusion in this surfactant systems was strongly dependent on the structure of the liquid crystal and on the physicochemical properties of the solute. The transcutaneous fluxes were determined using a Franz-type diffusion cell. The liquid crystalline vehicles modified the transcutaneous fluxes of benzophenone-4 but did not change those of octyl methoxycinnamate. The solute diffusion within the vehicle was not the rate-determining step for transcutaneous permeation for either sunscreen. The diffusion of benzopenone-4 within the stratum corneum and that of octyl methoxycinnamate within the dermis could be the rate-determining steps for their transcutaneous permeation. These two steps could be affected differently by nonionic surfactant vehicles.

Formulation study of a transdermal delivery system of primaquine

Abstract A potential transdermal application of an anti-malarial drug, primaquine, was investigated. In-vitro percutaneous absorption through hairless rat skin using either the salt or free base form of this drug was studied. Investigations were performed in order to choose an adequate vehicle for transdermal delivery of the free base form. The vehicles studied were Mygliol ® 840 (M), Labrafac Hydrophile ® (LH), Transcutol ® (T), propylene glycol (PG), oleic acid (OA) and a mixture LH/T 50:50. Finally, transdermal release of primaquine from different matrix transdermal therapeutic systems (TTS) was compared. In this optimization we studied the influence of polymer type (Eudragit ® RL 100 or ethyl cellulose), adhesive layer and drug concentration in the polymeric matrix on the release profiles. Primaquine free base was found to be very suitable for transdermal delivery. Mygliol ® 840 showed the best enhancement factor of the percutaneous flux of primaquine. The optimized TTS, which was an ethyl cellulose-based formulation with Mygliol ® 840 as vehicle, showed a percutaneous flux of 180 μg cm −2 h −1 .

Microencapsulation of nitrofurantoin in poly(ϵ-caprolactone): tableting and in vitro release studies

Abstract Nitrofurantoin, an antibacterial agent, has been incorporated into poly(ϵ-caprolactone) microspheres using the solvent evaporation process. Microscopy studies showed that increasing the drug content in the microspheres produced rod-like crystals at the microparticle surface. For all the drug contents investigated, nitrofurantoin formed crystalline domains dispersed in the polymer matrix. When the microspheres were tableted, the cohesion of the compact augmented with increasing the nitrofurantoin content and/or with reducing the mean microsphere diameter. The in vitro release rate of nitrofurantoin from the microspheres could be modified according to the size distribution and the drug loading of the microparticles. Tableting them produced a much slower release rate. Based on the non-linear search procedure, most of the microsphere samples studied exhibited a release profile obeying the Higuchi equation. However, in some cases where the payload was equal to or above 20% (w/w), the early and the middle stage of release followed a first-order kinetic pattern. This deviation from the Higuchi model was believed to be due to the heterogeneity of individuals forming the samples analyzed.

Structural parameters involved in the permeation of propranolol HCl by iontophoresis and enhancers

The purpose of this work was to study the effect of iontophoretic transport of Propranolol hydrochloride on the lipidic organization of the stratum corneum pretreated under passive or iontophoretic conditions by two model penetration enhancers, sodium lauryl sulfate and hexadecyl trimethylammonium bromide. Characterization of human stratum corneum was performed by X-ray diffraction, attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy and differential scanning calorimetry (DSC). The structural properties were compared with the iontophoretic permeability of propranolol hydrochloride on human stratum corneum. The iontophoretic fluxes of propranolol hydrochloride were effectively increased by two-fold in stratum corneum pretreated with sodium lauryl sulfate. In contrast, they were halved in stratum corneum pretreated with hexadecyl trimethylammonium bromide. These results could be related to changes in the electrical and structural properties of the stratum corneum after incorporation of these enhancers.

Investigation of PDMS gels and solutions by small angle scattering

Abstract Measurements of swollen end-linked PDMS gels by means of small angle X-ray and neutron scattering are reported. Hexane and octane were used as solvents. The usual excess scattering associated with frozen-in elastic constraints in observed in the small Q region of the spectra. Contrast variation shows the gels to be chemically homogeneous. In the extended Q range explored, the observed structure factor of the gels is satisfactorily described by a two-term expression, the first of which is of Ornstein-Zernike (lorentzian) form, as in polymer solutions, the second being a squared lorentzian. While the scattering amplitudes associated with these two components decrease in a similar way when the gel is deswollen, the respective correlation lengths are distinct, and exhibit different behaviour.

Mechanisms Involved in lontophoretic Transport of Angiotensin

AbstractPurpose. The feasibility of using iontophoresis to enhance the permeation rate of a model peptide was investigated in vitro using hairless mouse skin. Methods. Angiotensin 2 (AT 2) was employed as a permeant probe, using optimum iontophoresis conditions. A number of physicochemical parameters (donor ionic strength; valence of competitive ions; pH of donor solution) were studied with the aim of exploring the mechanisms involved in the iontophoretic transport through the skin: electrokinetic transport or convective transport. For this purpose, the magnitude of the convective solvent flow was also evaluated by the permeation of (3H) H2O. The interest of pulsed currents for peptide delivery was also investigated and the effect of current density and frequency was studied. Results. AT 2 transport was found to be enhanced 20-fold in comparison to passive permeation and was found to be proportional to the current density with direct currents as with pulsed currents. Conclusions. Although the flux enhancement of ions during iontophoresis is due principally to the electrical potential gradient, secondary effects such as convective solvent flow contribute also to flux enhancement of peptide delivery. This effect is dependent of physicochemical conditions of formulation.

Interpretation and prediction of plasma levels of primaquine following transdermal delivery in Swiss mice

A therapeutic transdermal system based on ethyl cellulose polymer and matrix diffusion-controlled release of an antimalarial, primaquine (PQ), was investigated with respect to the in vitro percutaneous penetration and in vivo skin absorption profile of the drug. In order to correlate in vitro and in vivo data, pharmacokinetic modelling was performed. Thus, the diffusion of the drug through the polymeric device and its pharmacokinetics parameters were both considered. Franz-type diffusion cells were used for in vitro determinations. In vivo experiments were performed with Swiss mice. Drug plasma profiles following transdermal treatment showed constant primaquine plasma levels, indicating controlled and systemic delivery of the drug over a period of 40 h.

Preservation of skin permeability during in vitro iontophoretic experiments

Abstract In vitro methodology was developed to investigate the iontophoretic transport of ionic compounds across hairless mouse skin. Improvement of iontophoretic delivery was evaluated by measuring the transport of an ionic model molecule of morphine hydrochloride (MHCl). By using Ag/AgCl electrodes and a simple permeation cell design, it was possible to obtain steady fluxes of MHCl, modulation of the delivery of MHCl with direct current intensity, and stability of pH without the use of buffered solution. Under these simple conditions, an increase in the applied current (from 0.085 to 0.28 mA/cm 2 ) produced an increase in the observed iontophoresis efficiency. By using a new permeation cell, allowing the use of two disc electrodes, placed on the same side of the skin, it was observed that the electrode localization and geometry of the receptor compartment have an effect on the MHC1 fluxes, however, the use of this cell design did not lead to stabilization of the iontophoresis efficiency. The use of pulsed current (1 kHz, on/off ratio 1:1, from 0.085 to 0.56 mA/cm 2 ) was then investigated. Lower MHCl fluxes were observed compared to the results obtained with constant current, however, an increase in the applied current produced a linear increase in fluxes, leading to stability of iontophoresis efficiency. A parallel study using tritiated water showed that after the application of a 0.28 mA/cm 2 direct current for 5 h, the passive water flux did not return to the initial passive value. With the pulsed current (0.28 mA/cm 2 ), passive fluxes were the same before and after application of the current for 5 h. This result suggests that the pulsed currents lead to an improvement of the skin state agreement.