With an increasing number of poor water-soluble active substances (AS) the need for developing optimal delivery systems for improving solubility is increasing. Among the most successful approaches are lipid delivery systems, including oleogels, semi-solid lipid systems consisting of oleogelator and oil. Since they have not yet been used as oral delivery systems, we wanted to develop an oleogel, which would be suitable for oral application. It would incorporate water-soluble amlodipine (AML) and lipid soluble atorvastatin (ATV), which are already used in combination. By incorporating it in an oleogel, we want to improve the solubility of ATV and achieve a prolonged release of both AS. For oleogel formation, an indirect oleogelation approach was used, where the hydrophilic oleogelator was first dissolved in water. In selecting the most suitable oleogelator, we looked for one which would be suitable for oral administration, and at the same time be water-soluble in order to be able to incorporate AML in the dissolution phase. Hydroxypropylmethylcellulose (HPMC) was selected. The water was then removed by the lyophilization process. The resulting HPMC cake was crushed, and then the liquid oil was incorporated into it. When choosing an oil phase, we looked for one in which ATV would be soluble, suitable for oral administration and would at the same time contribute to the appropriate viscosity of the oleogel. In the first phase we selected two, olive oil and Capmul MCM EP. With both we prepared oleogels with different concentrations of aqueous HPMC solutions (1 %, 2 % and 3 % (w/w)) and then rheologically evaluated them. We were searching for the optimum HPMC concentration and studying what kind of effect different types of oil and additions of a surfactant had on the viscosity of oleogels. Based on rheological tests and the solubility of ATV, we decided to prepare oleogels with Capmul MCM EP and 2 % (w/w) of HPMC aqueous solution. Prepared oleogels were evaluated by an in vitro release test according to USP 2. The release tests were carried out for two different formulations of oleogels with AS (with addition of Tween 20 (2,7% (m/m) and without) and for both pure AS in acidic (pH 1.2) and in a basic medium (pH 6.8). By incorporating a lipid soluble ATV into the oleogel formulation, we increased the extent of the released AS, while the prolonged release of both AS was achieved. With the addition of a surfactant to the oleogel formulation we were unable to improve the release of AS, so we tried to add it to the release medium itself. To the acid medium we added 0.25 and to the base medium 0.5 % (w/w) of sodium dodecyl sulfate. By adding a surfactant to the acidic medium, we managed to improve the ATV release, while the release of AML was diminished. In the basic medium with the addition of a surfactant, only the release of pure AML was improved, while the releases of AML and ATV from oleogel formulations, were diminished. Both formulations of oleogels were also evaluated using the in vitro lipolysis method. Decomposition of lipid formulations was in the beginning very slow. The degradation of oleogels without the addition of a surfactant was a bit faster. Likewise, both AS from the formulations without added PAS were released to a greater extent. In both formulations, more AML was released compared to ATV.
In the master's thesis, we succeeded to prove that HPMC oleogels could be suitable lipid delivery systems in the future for the simultaneous delivery of different AS in one prolonged-release pharmaceutical form. It has also been shown that the incorporation of a lipid soluble AS into oleogel improves its solubility and consequently a greater proportion of the released AS was achieved.
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