Jean-Claude Chaumeil

Rheological study of a thermoreversible morphine gel

AbstractThe rheological behavior of a poloxamer 20% thermoreversible gel with morphine or without was studied. Its behavior was newtonian below the transition temperature and became non newtonian above this temperature. The non newtonian part was best fitted with the Herschel-Bulkley equation in comparison with the Casson equation. The sol-gel transition was associated with a drastic increment of the apparent viscosity and a brutal modification of the Herschel-Bulkley equation parameters. Likewise, the oscillatory parameters (the lag phase, the storage modulus and the loss modulus) revealed the great influence of the temperature on the viscoelastic properties of the sample. Different rheological methods have been described in order to determine the transition temperature usable for the control of preparations. The temperature interval corresponding to the sol-gel transition ranged between 22-25°C for the solution with morphine and between 23-26°C for the solution without. Thereby, the addition of morphine...

Poloxamer 407 as a Thermogelling and Adhesive Polymer for Rectal Administration of Short-Chain Fatty Acids

Objectives: The purpose of the study was to gel a rectal solution of short-chain fatty acids to decrease the loss of active materials in the colonic lumen and thereby optimize their absorption. Methods: Five thermogels were prepared with poloxamer 407 at concentrations ranging from 17% to 20%. Their viscosities were measured at room temperature and 37°C, and their gelling temperatures were determined. The adhesive properties of each gel were assessed in vitro at 37°C. Short-chain fatty acid release was studied using Guyot cells. Results: From the threshold concentration of 17.5%, the solutions, Newtonian at room temperature (50–80 mPa · s), gelled at 37°C. The higher the concentration, the higher the viscosity (1750 to 49,000 mPa · s), the lower the gelling temperature (27.6°C to 23.4°C), and the stronger the work of adhesion (2.2 to 4.5 mJ). Short-chain fatty acid release from the 18% polymer gel was decreased by 60% compared to the rectal solution. Conclusion: The 18% poloxamer 407 concentration provided a solution that was liquid at room temperature, that gelled at 37°C, possessed adhesive properties, and controlled short-chain fatty acid release.

Endotoxemia affects citrulline, arginine and glutamine bioavailability

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

Copper(II)–l-glutamine complexation study in solid state and in aqueous solution

Abstract Among copper transport alterations in humans, Menkes disease is due to a lethal genetic disorder. The current treatment is the administration of physiological Cu(II)– l -histidine complex. However, this therapy is only effective in some cases and when started early in life. In order to distribute copper in all the biological compartments for Menkes disease patients, the administration of other Cu(II) amino acids complexes has been considered. Several ternary Cu(II)–amino acids complexes were detected in human serum playing an important role in the copper pathway, in particular l -histidine–Cu(II)– l -glutamine. Before the biopharmaceutical studies of l -histidine–Cu(II)– l -glutamine complex, a physicochemical characterisation of binary Cu(II)– l -glutamine complex must be conducted. Indeed, the identification of Cu(II)– l -glutamine species has not been clearly determined at physiological pH in the past. In the present work, the stoichiometry, formation constants and distribution of the various Cu(II)– l -glutamine species have been determined by polarography and UV–Vis spectroscopy in a large pH range. [Cu(II)(Gln) 2 ] complex is the major component at physiological pH and its formation constant is equal to 10 12.5 l 2 mol −2 . For the first time, the structure of [Cu(II)(Gln) 2 ] has been determined in the solid state and in solution. Given the small size of the obtained crystals, it has been necessary to use an X-ray synchrotron source to collect the diffraction data. X-ray crystal structure showed a 4-2 distorted octahedral geometry. In the basal plane Cu–O and Cu–N distances ranged from 1.93 to 1.98 A. Two additional oxygen atoms at 2.70 and 2.86 A complete a severely distorted octahedron. EXAFS and EPR results have shown that the structure of [Cu(II)(Gln) 2 ] is preserved at physiological pH in aqueous solution.

Mechanisms and kinetics of citrulline uptake in a model of human intestinal epithelial cells

BACKGROUND & AIMS Citrulline is a major precursor of arginine by de novo synthesis in the kidneys. Oral citrulline supplementation may be beneficial in some clinical conditions. However, citrulline bioavailability depends on its intestinal absorption. Since the mechanism of citrulline transport across the intestine has not been established yet, this study was designed to characterize L-[(14)C]-citrulline uptake by Caco-2 cells. METHODS Caco-2 cells were cultured in a bicameral insert system. Inhibition studies were conducted in the presence of neutral, cationic, acidic and non-metabolized amino acids. We performed control inhibition studies for arginine uptake. RESULTS Citrulline uptake was pH-independent whereas the uptake rate was reduced in the absence of Na(+). Kinetic analysis indicated the involvement of Na(+)-dependent and Na(+)-independent saturable transport components. For competition studies, both the transport components were markedly inhibited by large, small neutral and cationic amino acids. It was also noticed that specific inhibitor of system lBCH inhibited uptake. The inhibition profile of arginine transport was different from that of citrulline transport as arginine uptake was insensitive to BCH. CONCLUSIONS These characteristics suggest that system B(0,+) might be responsible for the Na(+)-dependent uptake of citrulline, whereas Na(+)-independent uptake may include systems L and b(0,+). Our results show that systems involved in citrulline transport are partly different from those involved in arginine transport.

Formulation and evaluation of ATP-containing liposomes including lactosylated ASGPr ligand

An original ligand (Lac-10-Chol) designed to interact with asialoglycoprotein receptors to potentially target hepatocyte was synthesised by grafting a lactose head to a cholesteryl structure, which was then included in liposomes. Preliminary formulation tests led to the selection of conventional formulations based on soybean phosphatidylcholine/cholesterol/DOTAP (± DOPE) (± Lac-10-Chol) that present reproducible absolute entrapment value (1.45 ± 0.10%), with a size of 109 ± 7 nm and a slight positive charge (3.77 ± 1.59 mV). Cell viability (via the MTT test), expressed as the percentage of nontreated cells in HepG2 cells, was very close to the control. Internalization tests evidenced an intracellular penetration of fluorescent liposomes, but no specific ligand effect was demonstrated (P > 0.05). Nevertheless, regarding the adenosine triphosphate (ATP) assay, a slight increase was obtained with liposome loaded with ATP incorporating Lac-10-chol after 24 hours (P < 0.05).

Characterization of the Absorption of Theophylline From Immediate- and Controlled-Release Dosage Forms With a Numerical Approach Using the In Vitro Dissolution-Permeation Process Using Caco-2 Cells

After oral administration, drug absorption rate is recognized to be dependent on two major factors: dissolution and intestinal cells permeability. Caco-2 monolayer cells have been largely used as a permeation study model. In this study, a numerical approach funded on an exponential first-order time relationship was tested to compare immediate- and controlled-release tablets of theophylline using a dissolution-permeation system. The dissolution performance using USP II paddle apparatus was coupled to the permeability studies investigated in Caco-2 cell monolayers. The dissolved samples were taken at different times; their pH and osmolarity were adjusted to render them suitable to Caco-2 permeability studies (osmolarity = 300 mosm, pH = 7.4). The experimental data show that the dissolution fits the exponential first-order relationship rate. The permeability values were in a range of 4.45 10− 6–5.28 10− 6 cm/s, and percentages of absorbed drug dose were dependent on the fraction initially present in the donor compartment, indicating that absorption of theophylline was dissolution rate limited. Plotting experimental absorbed fractions (Fa) against experimental dissolved fractions (Fd) show that permeation is the rate-limiting step in drug absorption process in the extended release form of theophylline. Our results demonstrate a general agreement between observed Fa/Fd relationships and theoretical Fa/Fd relationships obtained with our approach funded on dissolution and permeation behavior. We concluded that the couple dissolution-caco-2 system could be a useful tool to characterize intestinal permeation for a new formulation of a drug compared with the conventional one.

Libération et diffusion à travers une membrane artificielle de la théophylline à partir d’un système matriciel

Resume Le present travail est une approche de la liberation et de la diffusion de la theophylline a travers une membrane artificielle, a partir de systemes matriciels. Il s’agit de comprimes a base d’ethylcellulose et obtenus par compression directe, dits « a liberation prolongee ». Les cinetiques de liberation et de diffusion ont ete etudiees a l’aide d’un simulateur d’absorption. Les milieux donneurs sont i) des milieux de pH 1,2 5 et 6, ii) des milieux identiques additionnes de glucose a 10 % et iii) une solution concentree en acides amines, le milieu receveur est a pH 7,4. L’equation d’Higuchi a ete utilisee pour decrire le mecanisme de liberation de la theophylline dans le milieu donneur. Les vitesses de dissolution sont influencees par la solubilite de la theophylline, leur mecanisme est diffusionnel avec des coefficients de correlations acceptables. La cinetique de passage a travers la membrane artificielle a ete evaluee en calculant les coefficients de diffusion. Elle est principalement influencee par la vitesse de dissolution de la theophylline.