Modeling Specific Heat Transient Anomalies during Permeation of Liposomes by Water-Soluble Substances
✍ Scribed by A. Raudino; F. Castelli
- Book ID
- 102579571
- Publisher
- Elsevier Science
- Year
- 1998
- Tongue
- English
- Weight
- 175 KB
- Volume
- 200
- Category
- Article
- ISSN
- 0021-9797
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✦ Synopsis
the external and internal aqueous regions of the vesicle con-We propose a calorimetric method based on a time-dependent tain the same amount of drug. Therefore, the specific heat extension of the van't Hoff model of a depressing of the freezing pattern for a lipid multilayer undergoing a diffusional flux temperature to investigate the slow permeation kinetics of a drug of foreign substances comes out from the convolution of through the bilayers of a lipid vesicle. In particular we investigated different peaks, the position and intensity of which depend the transfer of a drug from water to void unilamellar or multilaon the local time-varying concentration of the additive. mellar vesicles, performing the experiments at temperatures above The phenomenon has been measured by differential scanand below the main transition (melting) of the hydrocarbon chains ning calorimetry and can be modelled by a time-dependent of the lipids. The results show a transient splitting of the peak diffusion equation which allows for the immobilization of associated to the main transition that disappears when the permeation kinetics reaches a steady-state condition. The phenomenon the diffusing specie within the membrane. The diffusional has been described by a model based on the experimental findings. model has to be coupled to a simple picture for the concentra-᭧ 1998 Academic Press tion-dependent specific heat variation of van't Hoff type Key Words: kinetics of membrane transfer; liposomes; diflunisal; in order to relate the transient calorimetric peak with the differential scanning calorimetry.
concentration of the additive within the lipid membrane. This relationship will be developed theoretically in section IV, and the predictions of the model will be compared with
I. INTRODUCTION
the calorimetric results in the last section.
Sparingly soluble substances (e.g. drugs) dissolved in an
II. MATERIALS AND METHODS
aqueous medium and in contact with multilamellar lipid vesicles slowly penetrate through the bilayers into the vesicle A. Materials interior. Whether the drug has a greater solubility in the lipid core than in water, the specific heat jump, associated to Diflunisal (DFN) and dipalmitoylphosphatidylcholine the melting of the lipid chains and measured by differential (DPPC) were obtained from Fluka Chemical Co. The lipid scanning calorimetry (DSC), is generally shifted toward solution was examined by bidirectional TLC. The lipid conlower temperatures, according to a van't Hoff type picture centration was determined by phosphorous analysis (4). for ideal mixtures (1) (see Fig. ), where the magnitude of the shift is proportional to the amount of drug transferred B. Liposomes Preparation from water to the lipid membrane. Obviously, the effect of DPPC multilamellar liposomes were obtained following an impurity on the melting temperature of a lipid bilayer is the usual method of preparation (vortexing the lipidic film a more complex process than that depicted by the van't Hoff in presence of Tris buffer (50 mM, pH 7.4) at a temperature model (2).
above the transition temperature of the phospholipid and However, we are not interested in the fine molecular desuccessively leaving the liposomes for 1 h at 60ЊC). Unilatails about the origin of the temperature shift, rather we mellar vesicles were prepared by extrusion through polycarexploit its change as a tool to follow the concentration of bonate membranes (pore diameter: 100 nm) by a Liposofast an impurity slowly penetrating the lipid bilayer (3). During basic (Avenstin) apparatus the multilamellar liposomes prethe bilayer permeation, the drug is unevenly distributed, the viously obtained. bilayers in contact with the external solution are richer in drug than the internal ones, and a homogeneous distribution C. Differential Scanning Calorimetry across the membrane is reached after a long time when both DSC was performed by a Mettler TA 3000 system