(493g) Membrane Assisted Production of Sphingosine-1-Phosphate Loaded Solid Lipid Nanoparticles

Sphingosine-1-phosphate (S1P) is a signaling sphingolipid. Sphingolipids at large form a class of lipids characterized by a particular aliphatic aminoalcohol which is sphingosine. Sphingosine can be released from ceramides, a process catalyzed by the enzyme ceramidase. Phosphorylation of sphingosine is catalyzed by sphingosine kinase, an enzyme ubiquitously found in the cytosol and endoplasmatic reticulum of various types of cells. S1P is a potent messenger molecule. It operates both intra- and intercellularly, thus forming a major agent of signal transduction in various tissues. S1P is of importance in the entire human body, it might be particularly relevant in the skin. It modulates the proliferation of skin cells. This in particular applies to keratinocytes. Apart from cell growth and differentiation S1P also is responsible for chemotaxis and angiogenesis. While S1P suppresses epidermal proliferation as the glucocorticoids do it differs from them in so far as proliferation of dermal fibroblasts is not reduced. In fact, S1P even activates fibroblast-derived extracellular matrix protein production. Due to the hyperproliferative action against epidermal cells S1P has been considered as an active pharmaceutical ingredient for hyperproliferative skin diseases, in particular psoriasis vulgaris and acne vulgaris.

Although S1P is active at very low concentrations, bioavailability of the compound in human skin is a concern. Therefore a topical formulation based on specific drug carriers has been considered inevitable.

Solid lipid nanoparticles (SLN) were introduced at the beginning of the 1990s, as an alternative to solid nanoparticles, emulsions and liposomes in cosmetic and pharmaceutical preparations. We investigated a membrane process for the preparation of S1P loaded SLN using ceramic membranes. The lipid phase was pressed, at a temperature above the melting point of the lipid, through the membrane pores allowing the formation of small droplets. The aqueous phase circulated inside the membrane module, and swept away the droplets forming at the pore outlets. SLN were formed by the following cooling of the preparation to room temperature. The influence of the ingredients of the topical formulation and of process parameters (aqueous phase and lipid phase temperatures, aqueous phase crossflow velocity and lipid phase pressure, membrane pore size) on the lipid flux and on the SLN size was investigated. It was shown that the membrane system allows the preparation of SLN with a mean SLN size between 200 and 360 nm. The advantages of this process are its facility of use, the control of the SLN size by an appropriate choice of process parameters, and its scaling-up abilities.