Jean-Paul Marty

Release mechanisms in gelforming sustained release preparations

Abstract A system consisting of quinidine sulfate, excipient and gum (in various concentrations) was tested in tablet form. The insensitivity of this system to (a) the nature of the excipient and (b) the pH of the dissolution liquid is noted. The release mechanism is established as being limited by the rate of water penetration and back diffusion of the dissolved substance, whereas gelation rates and actual dissolution rate of the drug are not rate determining.

Positively and negatively charged submicron emulsions for enhanced topical delivery of antifungal drugs.

Charged submicron emulsions are a priori interesting candidates for the delivery of drugs in and/or through the skin. In the present study, it was possible by using stearylamine or deoxycholic acid (DCA) to incorporate either econazole or miconazole nitrate, respectively, in positively and negatively charged submicron emulsions. The investigation of the relationship between the physicochemical properties of the vehicles, especially the charge of the emulsion and skin permeation, was conducted ex vivo during percutaneous absorption experiments using hairless female rat skin. In addition, drug quantification was carried out using two different analytical techniques (HPLC and radioactivity measurements) in order to examine if the drug analysis approach might affect the results. The results clearly indicate that the surface-modified droplets have a significant influence on the diffusion through the skin. Furthermore, the method of preparation of the formulation and subsequently the analytical method of drug concentration measurement are able to influence the results of percutaneous experiment.

In vivo Evaluation of the Stratum corneum Barrier Function in Blacks, Caucasians and Asians with Two Noninvasive Methods

This study compared in man the in vivo barrier function of stratum corneum in three racial groups: black, Caucasian and Asian, by two noninvasive technics. They were transepidermal water loss (TEWL) determination measured with an evaporimeter and laser Doppler velocimetry (LDV) to measure the lag time before the vasodilation induced by application of methyl nicotinate (10 microliters of 0.5% solution in ethanol/propylene glycol 95/5 v/v). Both methods were performed simultaneously on each forearm of 7 black, 8 caucasian and 6 Asian subjects before and after removal of the stratum corneum by stripping. TEWL measurements were higher (p < 0.01) in Asians and Blacks compared to Caucasians. Stripping (8 or 12 strips) increased TEWL in all groups; TEWL increase percentage was higher (p < 0.05) in Asians compared to Caucasians. Vasodilatation lag times assessed by LDV showed that skin permeability was more important in Asians (p < 0.01) and in Caucasians (p < 0.05) than in blacks. Lag times decreased with stripping. After 8 or 12 strips, the order of sensitivity was: Asian > Caucasian > black. Our study showed that, with both noninvasive methods, removal of the stratum corneum increased permeability, with racial differences.

Quantitative HPLC analysis of sunscreens and caffeine during in vitro percutaneous penetration studies

This report describes rapid analytical HPLC for the quantification of five UV filters (octyl methoxycinnamate, benzophenone-3, benzophenone-4, octyl triazone and octocrylene) and of caffeine in various skin layers (stratum corneum, dermis, epidermis and receptor fluid) and in cosmetic preparations. The predominant purpose of the study was to establish standard operating procedures for rapid analysis of the compounds in various skin samples. Particular attention was paid to the preparation of biological samples whose natural constitution could interfere with the quantitative analysis. Our methods used the isocratic chromatographic mode in an RP-HPLC with UV detection and did not involve centrifugation or evaporation. Our results were validated in terms of specificity, linearity, precision, accuracy and limits of detection and quantification. The first results, obtained after in vitro experiments, are presented in this report.

Oil–water–oil multiple emulsions for prolonged delivery of hydrocortisone after topical application: comparison with simple emulsions

Abstract Multiple emulsions show a high potential for prolonged delivery of drugs. In multiple emulsions, the entrapped substance can be transfered from the internal phase to the external phase through the middle phase, i.e. the membrane phase. These systems could be used for prolonged delivery of drugs. The present study was aimed to assess the suitability of oil–water–oil emulsions as prolonged release topical formulations of hydrocortisone. In order to avoid any influence of the composition of the formulation and to study only the effect of the emulsion type, a multiple emulsion as well as a simple emulsion were prepared with exactly the same composition. The percutaneous absorption of hydrocortisone from these two emulsion types was studied. At a finite dose, the percentage of hydrocortisone absorbed from the simple emulsion was 1.5-fold greater than that observed from the multiple emulsion, and the drug was kept longer in the epidermis and dermis from this galenic form. It was concluded that the multiple oil–water–oil emulsion systems may be used for obtaining a prolonged topical release of hydrocortisone.

Transdermal delivery of glucose through hairless rat skin in vitro: effect of multiple and simple emulsions

Abstract Three types of oil–water emulsions (W/O/W, O/W and W/O emulsions) were obtained and evaluated on hairless rat skin biopsies, using Franz diffusion cells. Natural emulsifiers (soybean phospholipids) were used to formulate stable multiple and simple emulsions. The qualitative and quantitative composition of the three emulsions was the same. In order to compare the emulsions that have been prepared with this new utilization of soybean phospholipids as emulsifier for vesicular systems and to achieve the importance of application conditions on the diffusion of glucose, a finite dose in open-cap and an infinite dose with occlusion were evaluated. After 24 h of diffusion, the maximum flux (0.69±0.21 μ g/cm 2 /h) for a finite dose was obtained with simple O/W emulsion, with a rank order of emulsions identical when compared to an infinite dose application: O/W>W/O/W>W/O.

In vivo noninvasive evaluation of hairless rat skin after high-voltage pulse exposure

Short high-voltage pulses have recently been shown to dramatically increase and expedite transdermal drug transport via a mechanism hypothesized to involve electroporation. This study addresses tolerance issues of the method in vivo in hairless rat. Chromametry, transepidermal water loss (TEWL), laser Doppler flowmetry (LDF) and corneometry were jointly used for noninvasive sensing of skin biophysical parameters. Slight increases in skin redness, TEWL and LDF values followed the application of electric pulses. The changes in skin capacitance were nonsignificant. The magnitude of the alterations depended on the electrical features of the pulses. When compared to iontophoresis, high-voltage pulses did not induce stronger alterations of skin functions. This report provides the first in vivo demonstration of the safety of the high-voltage pulses proposed for transdermal delivery.

Influence of three synthetic membranes on the release of caffeine from concentrated W/O emulsions.

We measured the release rate characteristics of caffeine from concentrated emulsions using three different sources of synthetic membranes. The formulations tested included, on the one hand, two stable cosmetic concentrated W/O emulsions (90% w/w) - one with a non ionic surfactant and one with a silicone surfactant - and on the other hand, a commercially available hydroalcoholic gel. All formulations contained 5% caffeine. In vitro diffusion measurements (24 h) were performed with static diffusion Franz cells. A silicone membrane could not allow us to differentiate the two concentrated emulsions (CE), but the two other membranes, not rate limiting, showed difference in the release profile of caffeine from the two CE. Results with the cellulose and polysulfone membrane showed that in vitro release of caffeine is influenced by the nature of the emulsifier in the concentrated emulsion, the non ionic surfactant being more efficient than the silicone surfactant. The polysulfone membrane was the only one that allows statistical differentiation of the three products. For further studies the polysulfone membrane will be use to make screening on concentrated emulsions.

Physical model for release of drug from gelforming sustained release preparations

Certain sustained release preparations contain a substance which, when exposed to an aqueous medium, forms a gel. Liquid will continue to penetrate the gel layer with time (θ) and the release of drug is both a function of liquid penetration rates (α) and diffusion of drug through the gelled layer (with a permeation coefficient of II). The thickness of the layer will be a function of time, because as liquid penetrates, more gel is formed. Development of this model leads to a third-power equation for the amount of drug released (m) as a function of time: m = aθ3 + bθ2 + cθ; the coefficients a, b and c contain an integral: ƒ10 exp[(−π/α)(1/u)du which is evaluated graphically and found equal to 0.93 exp[−2.6π/α]. The data by Bamba et al. (1979) were used to demonstrate that the fit of experimental data to the third-power equation is a good as or superior to conventional plotting techniques.

Vehicle influence on in vitro release of glucose: w/o, w/o/w and o/w systems compared

Abstract The in vitro release and percutaneous absorption of glucose as a hydrophilic model drug from oil/water (o/w), water/oil/ water (w/o/w) and water/oil (w/o) emulsions has been studied. All the emulsions were prepared with exactly the same composition in order to avoid any influence of the formulation. The glucose release studied with a cellulose membrane was nonlinear and fastest in case of the o w emulsion. In contrast, the release from w o emulsion was linear and the slowest. Release from w/o/w emulsion was non-linear and intermediate in rate. The release with a silicone membrane was linear from three emulsions studied and presented the same rank order. The rate of release for o/w, w/o/w and w/o emulsions was found to be 0.10, 0.036 and 0.014 μg/cm2/h respectively. The in vitro percutaneous absorption data of glucose indicate the same rank order as that observed with synthetic membranes. However, when compared with the release across the silicone membrane the differences between the emulsions increased considerably and only the w o emulsion reached a steady-state rate of absorption during the 30 h test period. The w/o/w emulsion showed some tendency toward steady state during the first 3–12 h and the flex was found to be 1.7 times greater than that from w/o emulsion. The total uptake of glucose in whole skin was found to be in following order: o w > w/o/w > w/o; this in good agreement with the results of the studies of absorption. Differences between o/w and w/o/w emulsions could be attributed to differences in the effective glucose concentration of their external aqueous phase. Differences between w/o/w and w/o emulsions could be attributed to the stratum corneum/vehicle partition coefficient.