Comparison of the lymphatic transport of a lipophilic drug from vehicles containing alpha-tocopherol and/or triglycerides in rats.

The applicability of alpha-tocopherol as a lymphotropic carrier for a highly lipophilic drug has been evaluated. Transport to the intestinal lymph of the highly lipophilic model drug, Lu28-179, in rats after administration to the stomach in an alpha-tocopherol emulsion was compared with lymphatic transport after administration of a sesame oil emulsion and an alpha-tocopherol/sesame oil emulsion. Lymphatic transport of the triglycerides and of alpha-tocopherol was determined. A conscious rat model was used, and the mesenteric lymph was collected. There was no significant difference between the cumulative masses of triglyceride from the two emulsions containing triglyceride 24 h after administration. Administration of an alpha-tocopherol emulsion seemed to induce mobilization of endogenous triglyceride. The lymphatic transport of alpha-tocopherol was less than 1 mg 24 h after administration of both emulsions containing alpha-tocopherol. The absorption of Lu28-179 from the alpha-tocopherol emulsion was very low, with a lymphatic recovery of 0.05%. When administered in an alpha-tocopherol/sesame oil emulsion, the recovery of Lu28-179 increased sevenfold to 0.35%. However, after administration of Lu28-179 in a sesame oil emulsion, the lymphatic recovery increased a further 13-fold to 4.5%. In conclusion, the study showed that alpha-tocopherol did not promote lymphatic absorption of Lu28-179 and thus was not a good lymphotropic carrier, as compared with sesame oil. Alpha-tocopherol in combination with sesame oil was not a good lymphotropic carrier either. The non-absorbed alpha-tocopherol fraction in the intestine might be able to prevent the absorption of Lu28-179.

A dynamic in vitro lipolysis model. II: Evaluation of the model.

A lipolysis model was characterised and evaluated by investigating the composition of the aqueous phase and the concentration of probucol and danazol in the aqueous phase. Effects of bile salt levels at 5, 10, 20, and 30 mM were investigated. Samples were taken at 0%, 50%, 75% and 95% hydrolysis of the triglycerides, and the aqueous phases were isolated by ultra-centrifugation, whereby the concentrations of bile salts, fatty acids, mono-, di-, triglycerides, and drug substances were measured. At high Ca(2+)-concentrations, bile salts were believed to precipitate with Ca(2+). The concentration of lipolytic products (fatty acids + monoglycerides) was dependent on the bile salt concentration. The ratio between lipolytic product and bile salts was 1.55+/-0.09 (S.D.). This ratio is equivalent to mixed bile salt micelles and vesicles in equilibrium. The aqueous solubility of probucol and danazol was increased in the presence of bile salts. The concentration of danazol in the aqueous phase was dependent on the solubilisation capacity of the aqueous phase. In the case of probucol, the concentration in the aqueous phase was dependent on the partition of probucol between the aqueous phase and the remaining triglyceride phase. This difference between danazol and probucol was attributed to the effect of different lipophilicity.

A dynamic in vitro lipolysis model. I. Controlling the rate of lipolysis by continuous addition of calcium.

Lipolysis by pancreatic lipase was investigated with the aim to establish an in vitro lipolysis model, which can be used to investigate the dissolution of poorly soluble lipophilic drug substances at controlled hydrolysis rates. The effects of three experimental parameters -- the concentrations of bile salts and Ca(2+) and the lipase activity -- were investigated. The effect on the rate of hydrolysis of emulsified soybean oil was investigated in experiments in a pH-stat at pH 6.5 and 37 degrees C. The free fatty acids produced by the hydrolysis were titrated at pH 6.5. It was shown that all three investigated parameters influence the initial rate of hydrolysis, whereas only the lipase activity and the concentration of Ca(2+) affect the subsequent stages. It was also shown that the rate of lipolysis can be controlled by the rate of adding Ca(2+). Thus, it is possible to design an in vitro model using readily available and inexpensive materials in which the hydrolysis rate can be controlled by the continuous addition of Ca(2+).