Fabrice Pirot

Sustained ex vivo skin antiseptic activity of chlorhexidine in poly(ϵ-caprolactone) nanocapsule encapsulated form and as a digluconate

In this work, the sustained bactericidal activity of chlorhexidine base loaded poly(epsilon-caprolactone), PCL, nanocapsules against Staphylococcus epidermidis inoculated onto porcine ear skin was investigated. Drug loaded nanocapsules were prepared by the interfacial polymer deposition following solvent displacement method, then characterized by photon correlation spectroscopy, electrophoretic measurements, transmission and scanning electron microscopy. Antimicrobial activity of these colloidal carriers was evaluated (i) in vitro against eight strains of bacteria, and (ii) ex vivo against Staphylococcus epidermidis inoculated for 12 h onto porcine ear skin surface treated for 3 min either with 0.6% chlorhexidine base loaded or unloaded nanocapsules suspended in hydrogel, or 1% chlorhexidine digluconate aqueous solution. Chlorhexidine absorption into the stratum corneum (SC) was evaluated by the tape-stripping method. The results showed that chlorhexidine nanocapsules in aqueous suspension having a 200-300 nm size and a positive charge exhibited similar minimum inhibitory concentrations against several bacteria with chlorhexidine digluconate aqueous solution. Ex vivo, there was a significant reduction in the number of colony forming units (CFUs) from 3-min treated skin with chlorhexidine nanocapsule suspension (5 to <1 log(10)) compared to chlorhexidine digluconate solution (5 to 2.02 log(10)) after a 8-h artificial contamination. After a 12-h artificial contamination, both formulations failed to achieve a 5 log(10) reduction. Furthermore, from a 3-min treatment with an identical applied dose and a subsequent 12-h artificial contamination, a residual chlorhexidine concentration in the SC was found to be three-fold higher with chlorhexidine nanocapsule suspension than with chlorhexidine digluconate solution. Interestingly, nanocapsules were shown in porcine skin follicles. Consequently, a topical application of chlorhexidine base-loaded positively charged nanocapsules in an aqueous gel achieved a sustained release of bactericide against Staphylococcus epidermidis for at least 8 h. Enhancement of drug delivery by mediating a more direct and prolonged contact between the carrier and (i) bacteria, (ii) skin surface, and (iii) skin follicles was assumed.

Liposomes and niosomes as potential carriers for dermal delivery of minoxidil

The aim of this work was to formulate minoxidil loaded liposome and niosome formulations to improve skin drug delivery. Multilamellar liposomes were prepared using soy phosphatidylcholine at different purity degrees (Phospholipon® 90, 90% purity, soy lecithin (SL), 75% purity) and cholesterol (Chol), whereas niosomes were made with two different commercial mixtures of alkylpolyglucoside (APG) surfactants (Oramix® NS10, Oramix® CG110), Chol and dicetylphosphate. Minoxidil skin penetration and permeation experiments were performed in vitro using vertical diffusion Franz cells and human skin treated with either drug vesicular systems or propylene glycol–water–ethanol solution (control). Penetration of minoxidil in epidermal and dermal layers was greater with liposomes than with niosomal formulations and the control solution. These differences might be attributed to the smaller size and the greater potential targeting to skin and skin appendages of liposomal carriers, which enhanced globally the skin drug delivery. The greatest skin accumulation was always obtained with non-dialysed vesicular formulations. No permeation of minoxidil through the whole skin thickness was detected in the present study irrespective of the existence of hair follicles. Alcohol-free liposomal formulations would constitute a promising approach for the topical delivery of minoxidil in hair loss treatment.

Characterization of Transport of Chlorhexidine-Loaded Nanocapsules through Hairless and Wistar Rat Skin

Nanocapsules appear a promising approach as a drug system for topical application. However, the transport mechanism of nanocapsule-associated drug through the skin is still being questioned. In the present study, the transport of chlorhexidine-loaded poly(Ε-caprolactone) nanocapsules through full-thickness and stripped hairless rat skin was investigated in static-diffusion cell. The chlorhexidine permeation profiles fitting the Fickian diffusion model showed that the drug encapsulation reduced the percutaneous drug absorption through stripped skin. Possible nanocapsule transport within skin conducts was suggested from the analysis of permeation parameters and confirmed by confocal laser microscopy studies. Furthermore, the chlorhexidine permeation and drug release data were highly correlated, suggesting that the magnitude of percutaneous absorption was controlled by the diffusion across the polymeric carrier. The behavior of nanocapsules at the skin interface was investigated by contact angle and surface tension measurements. The small ‘wetting’ of the nanocapsule on the stratum corneum surface preserved the mechanical integrity of the carrier characterized by a high specific surface at the skin interface. The flexibility of the nanocapsules assured a satisfying bioadhesion to the skin, whereas the rigidity of the carrier limited the molecular ‘spill’ into the skin and controlled the drug delivery to the skin.

Ex vivo study of bevacizumab transport through porcine nasal mucosa

INTRODUCTIONnHereditary hemorrhagic telangiectasia (HHT) is a genetic disorder associated with abnormal angiogenesis and disabling epistaxis, for which bevacizumab is reported to be a new therapeutic option. In the present study, bevacizumab transport in porcine nasal mucosa was investigated to determine antibody bioavailability.nnnMATERIAL AND METHODSnTransmucosal absorption of bevacizumab was examined by using nasal mucosa specimens mounted onto static vertical diffusion cells then treated with bevacizumab solution (25 mg mL(-1), 500 μg) for 2.5h. Bevacizumab concentrations were measured by enzyme-linked immunosorbent assays. Mucosal integrity was examined by histological examination of treated mucosa.nnnRESULTSnTransmucosal transport of bevacizumab followed a Fickian diffusion process (permeability coefficient: [0.63 ± 22]× 10(-6) cm s(-1); and steady-state flux: 56.4 ± 19.6 μg cm(-2)h(-1)). Total recovery of bevacizumab throughout the 2.5h experiment was 83% of the initial dose distributed (i) at the mucosal surface (263 ± 73 μg; ∼53%) and (ii) into (95 ± 14 μg; ∼19%) and through (56 ± 26 μg; ∼11%) the mucosa. There was no evidence of any noticeable histological effects, confirming the harmlessness of nasal bevacizumab delivery.nnnCONCLUSIONnIn the present study, absorption of bevacizumab into nasal mucosa was demonstrated, providing new fundamentals that are mandatory for further clinical trials in HHT patients.

Effects of physical and chemical treatments upon biophysical properties and micro-relief of human skin

The aim of the present study was to determine the attendant effects of physical (tape-stripping) and chemical (three commercial hydrating formulations) treatments upon biophysical and micro-relief properties of human skin. In the first set of experiment, the effects of tape-stripping onto human stratum corneum (SC) biophysical and micro-relief properties were assessed in nine volunteers. Transepidermal water loss (TEWL), skin hydration and micro-relief parameters (including total length of the lines in mm per mm2; total surface in %; roughness of the skin measured in gray level (Ra); maximum profile valley (Rv) depth; maximum profile peak height (Rp); maximum height (Rt), peak density (Pc) and coefficient of anisotropy) were determined by using SkinEvidence® Pro after subsequent tape-stripping of SC. The relevance of roughness determination as gray level by SkinEvidence® Pro was confirmed by using surface roughness standards. In the second set of experiment, the effectiveness of three commercial hydrating formulations onto human SC biophysical parameters and micro-relief properties were assessed in six volunteers. TEWL, hydration and micro-relief parameters were assessed onto pre-treated acetone skin and then treated by three commercial hydrating formulations after 2, 4 and 6xa0h skin exposure. A linear relation between hydration and cutaneous parameters (total length of the lines, Ra and Rp) as function of SC removed was shown. Skin barrier properties evaluated by TEWL measurements, were not modified by topical formulations. However, skin treated by topical formulations showed slightly higher hydration than the one determined in control group, while micro-relief parameters were not modified. In this study was showed that biophysical and micro-relief parameters were closely related in tape-stripping experiment. Efficiency of topical formulations was suggested upon skin hydration but not onto skin micro-relief and barrier function recovering. From both experiments, it appears that different mechanisms relating to skin hydration and potential modification of cutaneous micro-relief were suggested.

Effects of Osmosis on Water-Holding Capacity of Stratum corneum and Skin Hydration

The stratum corneum (SC) is characterized by highly hydrophilic compounds exhibiting osmotic properties. The role of osmosis in iontophoretic transdermal drug delivery has been a subject in numerous studies. However, the effects of osmosis on the water-holding capacity (WHC) of SC and skin hydration need to be clarified. In the present study, the WHC and skin hydration were found to be correlated with osmotic pressure and the SC permeability of osmolytes. The WHC and skin hydration enhancement were related to the increase in SC osmolality. A mathematical model was proposed to predict the WHC and skin hydration from physicochemical parameters of compounds.

Aqueous dispersions of organogel nanoparticles – potential systems for cosmetic and dermo-cosmetic applications

The preparation and physicochemical characterization of organogel nanoparticles dispersed in water have been developed. These systems could be employed as nanocarrier for cosmetic applications or as hydrophobic reservoirs for drug delivery.

Pharmaceutical and safety considerations of tablet crushing in patients undergoing enteral intubation.

Medication in patients undergoing enteral intubation addresses various challenging issues considering safety and treatment efficiency. Ideally, other routes of administration (i.e. intravenous or intramuscular routes) or especially dedicated formulations should be used. However, in absence of liquid dosage form, tablets or pills must be crushed and suspended in a vehicle before administration. The administration of oral dosage forms by enteral tube is usually performed by the nursing staff facing (i) pharmaceutical relevance of crushing, (ii) loss and concomitant aero-contamination of drug substance, (iii) drug-nutriment interactions and (iv) enteral feeding tube clogging. In the present study, different combinations of either open or confined crushing and suspending protocols were compared by taking into account the crushing yield, the stability and granulometry of the solid oral form suspension and finally the extend of aerosol contamination during crushing and suspending. All protocols exhibited comparable crushing efficiency and suspending properties, but significantly higher aerosolisation of tablet particles was observed in both open crushing and suspending protocol. Therefore, both confined crushing and suspending protocol constitutes an efficient, time saving and safe alternative to the absence of available liquid dosage form for intubated patients.

Stratum Corneum: An Ideal Osmometer?

Water and osmolyte homeostasis is an essential biological function. Remarkably devoid of aquaporin (i.e., water channel protein) expression, the stratumcorneumavoids a substantial transepidermal water loss, compulsory for the adaptation to terrestrial life. In spite of its heterogeneity, the stratum corneumexhibits a homogeneous water transport, whereas highly osmotic endogenous materials control its water-holding capacity and skin’s physical properties (e.g., stiffness, firmness, flexibility) under various conditions. However, the contingent interplay between water homeostasis of the stratum corneumand an exogenous osmotic stress has been not reported, although constituting a cornerstone of skin physiology. Here, we show that an osmotic shock reinforces the endogenous stratum corneumosmolality proportionally to the osmotic pressure exerted against it and, therefore, reduces the magnitude of outward water transfer and net evaporation. The strengthening of endogenous osmolality enhanced the water-holding capacity of the stratum corneum with respect to chemical potentials. This property was found for organic osmolytes, but questioned for mineral electrolytes characterized by minimal stratum corneumpermeability. Besides, straightforward experiments performed using a built-in house osmometer, a so-called ‘corneosmometer’, have confirmed water transfer through the stratum corneumsubmitted to a gradient of osmotic pressure. Thus, the ambivalent function of the stratum corneum, which firstly behaves as an ideal osmometer and secondly adapts its own osmolality to an exogenous gradient of osmotic pressure, has been clearly demonstrated. This duality influences the water-holding capacity of the stratum corneum, by regulating the water transfer proportionally to an initial osmotic stress, and, finally, conditions the further capacity of the stratum corneumto facilitate or impede skin hydration.

A quantitative and qualitative method to control chemotherapeutic preparations by Fourier transform infrared-ultraviolet spectrophotometry

Chemotherapy products in hospitals include a reconstitution step of manufactured drugs providing an adapted dosage to each patient. The administration of highly iatrogenic drugs raises the question of patients’ safety and treatment efficiency. In order to reduce administration errors due to faulty preparations, we introduced a new qualitative and quantitative routine control based on Fourier Transform Infrared (FTIR) and UV-Visible spectrophotometry. This automated method enabled fast and specific control for 14 anticancer drugs. A 1.2u2009mL sample was used to assay and identify each preparation in less than 90u2009sec. Over a two-year period, 9370 controlled infusion bags showed a 1.49% nonconformity rate, under 15% tolerance from the theoretical concentration and 96% minimum identification matching factor. This study evaluated the reliability of the control process, as well as its accordance to chemotherapy deliverance requirements. Thus, corrective measures were defined to improve the control process.