Philippe Arnaud

Microencapsulation of lipophilic drugs in chitosan-coated alginate microspheres

Chitosan-coated alginate microspheres containing a lipophilic marker dissolved in an edible oil, were prepared by emulsification/internal gelation and the potential use as an oral controlled release system investigated. Microsphere formation involved dispersing a lipophilic marker dissolved in soybean oil into an alginate solution containing insoluble calcium carbonate microcrystals. The dispersion was then emulsified in silicone oil to form an O/W/O multiple phase emulsion. Addition of an oil soluble acid released calcium from carbonate complex for gelation of the alginate. Chitosan was then applied as a membrane coat to increase the mechanical strength and stabilize the microspheres in simulated intestinal media. Parameters studied included encapsulation yield, alginate concentration, chitosan molecular weight and membrane formation time. Mean diameters ranging from 500 to 800 micron and encapsulation yields ranging from 60 to 80% were obtained. Minimal marker release was observed under simulated gastric conditions, and rapid release was triggered by transfer into simulated intestinal fluid. Higher overall levels of release were obtained with uncoated microspheres, possibly due to binding of marker to the chitosan membrane coat. However the slower rate of release from coated microspheres was felt better suited as a delivery vehicle for oil soluble drugs.

In vitro and in vivo evaluation of carbamazepine-PEG 6000 solid dispersions

The present work extended previous physico-chemical investigations on the effects of solid dispersion on the solubility, the dissolution rate and the pharmacokinetic profile of carbamazepine. Solubility studies showed a linear increase in carbamazepine solubility with the increase of PEG 6000 concentration. There is no marked difference between physical mixtures and solid dispersions for the enhancement of carbamazepine solubility by PEG 6000. Less than 60% of pure carbamazepine was dissolved in 90 min. Physical mixtures (carbamazepine phase III) and solid dispersions (carbamazepine phase II) dissolution rates were higher in comparison of the parent drug. The dissolution of carbamazepine phase III was more pronounced than that evoked by the phase II. The dissolution profiles indicated that the percentage of the drug dissolved was dependent on the proportion of PEG 6000. In solid dispersions there was a remarkable enhancement in the dissolution rates of the drug in the vicinity of the eutectic composition as compared with those of corresponding physical mixtures. Hence, the optimum value for the solid dispersion was 80.5+/-1.7% of carbamazepine having dissolved within the first 10 min compared to 40+/-1% for the corresponding physical mixtures of the same composition. Statistical analysis of pharmacokinetic parameters confirmed that the carbamazepine:PEG 6000 binary systems displayed higher bioavailability of the drug than the pure carbamazepine. The area under the curve (AUC) values highlighted the evidence that only slight differences in the bioavailability of the drug occur between physical mixtures and solid dispersions prepared at the 80:20 and 50:50 drug:carrier compositions. However, the mean normalized plasma concentrations showed that standard error deviations are rather wide intervals for pure drug and physical mixtures in comparison to solid dispersions. One additional interesting point to consider is the disappearance of the multiple peaks on the individual kinetic curves of the 50:50 solid dispersion composition. Furthermore, our investigations have highlighted the interest of solid dispersions prepared at <<near>>-eutectic composition as our preliminary data show that the plasma concentration (C(5h)) of the drug for the 15:85 dispersed sample containing 150 mg of carbamazepine is not significantly different from that obtained for the 50:50 dispersed sample containing 300 mg of the drug.

Endotoxemia affects citrulline, arginine and glutamine bioavailability

Eur J Clin Invest 2012; 42 (3): 282–289

Transport of cephalosporins across artificial membranes and rabbit ileum

The aim of this study is to determine transepithelial transport of aminocephalosporins (cephalexin, cefaclor and cefadroxil) with in vitro models using artificial and biological membranes. The three antibiotics have higher partition coefficient (Kp) at pH 5 than at pH 6 and cephalexin passes through the lipid barrier faster than cefadroxil and cefaclor. With a cephalexin concentration of 1 mM, the diffusion rate constant (Kd) through the artificial intestinal barrier was 0.563 ± 0.001 and 0.426 ± 0.031 ( × 10−3 cm/min) at pH 5 and 6, respectively. The transepithelial passage of the three aminocephalosporins through rabbit ileum tissues is measured in an Ussing chamber. The mean transepithelial mucosal to serosal fluxes (Φm-s) were 52.54 ± 6.45 nmol/h/cm2 and 27.51 ± 2.43 nmol/h/cm2 for cephalexin and cefadroxil, respectively. No effect on intensity short-circuit (Isc) and conductance (G) of the tissue were observed with cephalexin. In Grass cell diffusion with pH ranged from 6 to 7.4, showed a maximal cephalexin transport at pH 6. The concentration dependence of cephalexin absorption and transport was examined over a concentration range of 0.1–5 mM. The cephalexin transport involves Michaelis-Menten kinetics. Moreover, D-glucose does not affect the cephalexin (CFX) flux across the ileal tissue.

Characteristics of cephalexin transport across isolated rabbit ileum

Abstract The purpose of this study was to examine the total transepithelial (transcellular, paracellular and carrier-mediated) transport of cephalexin (CFX) across isolated rabbit ileum. This epithelium was mounted in Grass diffusion cells to separate the mucosal and serosal compartments. The tissue was immersed on each side into a Ringers solution or a PBS buffer solution at 37°C and oxygenated (O 2 /CO 2 in 95/5, v/v). The concentration dependence of CFX transport was examined over a concentration range of 0.1–5 mM and showed a Michaelis–Menten kinetics. The inhibition of CFX transport was 97±1% at 4°C and 30 and 61% with metabolic inhibitors such as sodium azide (1 mM) and 2.4 dinitrophenol (0.1 mM) respectively. The CFX transepithelial flux was greater at pH 6 (11.42±2.24) than at pH 7–7.4 (5.0±1.03) in nmol/h per cm 2 . Without a pH gradient at pH 7.4 this effect was inhibited by FCCP and nigericin. At pH 7.4, amiloride did not affect CFX transport but ouabaine significantly affected the CFX flux with an inhibition of 90%. No paracellular diffusion was observed in the presence of d -glucose (25 mM). The mucosal to serosal flux of 0.1 mM of CFX was significantly inhibited by 1 mM of gly-pro. Similarly, cephradine (2 mM) inhibited 0.2 mM of CFX by 23% and amoxicilline (5 mM) reduced the transport by 56%. l -phenylalanine did not affect the transport of 0.5 mM of CFX. The transport of CFX through rabbit ileum followed Michaelis–Menten kinetics at lower concentrations, was pH-dependent, energy-dependent, Na + -independent and occurred across the intestinal mucosa through a transcellular route via dipeptide carrier system(s).

Reduction of Hepatotoxicity Induced by Doxorubicin

Doxorubicin (DOX) has been used in the treatment of variety of cancers but its administration is limited by a dosedependent toxicity. Its cytotoxic effects on malignant cells have shown an increase in the risk of cardiotoxicity, hepatoxicity, renal insufisance. Antioxydants have been explored for both their cancer preventive properties and chemodulatory of DOX toxicity. Resveratrol (RSV) is a polyphenolic constituent of several dietary mainly of grapes and wine origin recently its anticancer potential has been extensively explored, revealing its anti-proliferative effect on different cancer cell lines, both in vitro and in vivo. RSV is also known to have modulatory effects on cell apoptosis, migration and growth via various signaling pathways. Though, RSV possesses great medicinal value, its applications as a therapeutic drug is limited. Problems like low oral bioavailability and poor aqueous solubility make RSV an unreliable candidate for therapeutic purposes. Additionally, the rapid gastrointestinal digestion of RSV is also a major barrier for its clinical translation. Hence, to overcome these disadvantages RSV-based nanodelivery systems have been considered in recent times. Nanodelivery systems of RSV have shown promising results in its uptake by the epithelial system as well as enhanced delivery to the target site. Herein we have tried to bring new new insights into the molecular mechanisms of DOX toxicity with respect to DNA damage, free radicals and whether RSV can be a playmaker as chemodulatory of DOx.

Gastro-intestinal diffusion tablet: Influence of polyoxyethyleneglycol 400

Abstract The influence of the incorporation of PEG 400 in a cellulose acetate film to control the release of indomethacin or aminophylline was studied. The aminophylline tablets coated with 20% of PEG 400 and 10 or 20% of diethylphthalate were resistant in purified water if the membrane amount was higher than 13 mg per tablet. The dissolution rate of indomethacin was very low, 1.3–6.0%. Without PEG in the membrane the dissolution rate of aminophylline tablets was slow (6% in 18 h). The increase of the membrane weight (28–41 mg) resulted in a decrease of the dissolution rate with 10 and 20% of diethylphthalate. There was a correlation between the T 20% and the coating amount for aminophylline. The solubility of the drug had a large influence on its dissolution rate. With indomethacin which is poorly soluble, it was difficult to obtain efficient dissolution with a GDS system using PEG 400.