Tamoxifen in topical liposomes: development, characterization and in-vitro evaluation

Abstract

Purpose: Tamoxifen, an anti-estrogen compound, has recently been figured as a useful agent in the treatment of certain skin specific disorders. This recent found application has generated an interest in its topical formulation in order to avoid the side effects associated with oral administration, while parenteral administration is restricted due to its limited aqueous solubility. Liposomal carriers, well known for their potential in topical drug delivery, have been chosen to help transport tamoxifen molecules in the skin layers. These vesicles are also expected to provide lipid enriched hydrating conditions to help retain the drug molecules within the dermal layers, at or near to the site of action. With this objective, tamoxifen loaded liposomal systems have been prepared and their topical performance has been compared with non-liposomal systems containing tamoxifen.

Method: Multilamellar liposomes of tamoxifen were prepared by thin film hydration method. Various formulation ( viz. lipid composition, drug-lipid ratio, amount and type of surface charge imparting agent etc.) and process parameters (hydration temperature, hydration time etc.) were studied to obtain liposomes with desired attributes. Prepared liposomes were characterized for morphological and micromeritic attributes, employing Malvern mastersizer and optical microscopy. Stability of the liposomes in terms of their drug holding capacity was assessed for a period of 5 weeks, on storage under defined conditions. Liposomal formulations of tamoxifen were evaluated for in-vitro skin permeation, using mice skin. The results thus obtained were compared with that of aqueous solution and Carbopol gel, containing tamoxifen in equal amounts.

Results: Optimized process and formulation parameters resulted in multilameller, homogenous population of liposomes in the size range of 1 to 13 mm (mean vesicle diameter 5.3 microm), exhibiting normal size distribution. Maximum loading of tamoxifen was noted to be 57.5% (38.3 mu g of drug per mg of lipids), for liposomes composed of hydrogenated phosphatidylcholine and cholesterol, employing 66.6 microg drug per mg of lipids during preparation. Incorporation of dicetylphosphate or stearylamine as charge imparting agent did not influence the vesicular entrapment of TAM in a favorable manner. Amongst different storage conditions, the liposomes stored at 2 to 8 degrees C were found to be most stable, with only 5% drug loss over the storage period of 5 weeks. Significantly higher skin permeation of tamoxifen from liposomal formulations (flux values 63.67 microg/cm2/h and 59.87 microg/cm2/h for liposomal suspension and liposomal gel) has been achieved, as compared to solution (21.65 microg/cm2/h) and Carbopol gel (24.55 microg/cm2/h) containing tamoxifen. Higher magnitude of tamoxifen retention in the skin layers was noted with liposomal formulations vis-à-vis non-liposomal formulations of the drug.

Conclusion: Tamoxifen molecules could be successfully entrapped in the liposomes with reasonable drug-loading and desired vesicle specific characters. Higher rate of drug transfer across the skin with liposomal formulations of tamoxifen, suggests that the drug in its lipo-solubilised state might have found facilitated entry into the tough barrier consisting of stratum corneum. The phospholipid enriched amphiphillic nature of the vesicles can be held responsible for modifying the properties of the keratinised layer. Integration of phospholipid molecules with the skin lipids might have served further, to help retain the drug molecules within the skin, thus leading to prolonged presence of drug molecules at the receptor site. These findings have been seen to support the improved and localized drug action in the skin, thus providing a better option to deal with skin-cited problems.