Introduction: Vitamin D3 (VD3) or cholecalciferol is a steroid hormone produced in the skin when exposed to ultraviolet light or can be obtained from dietary sources. Vitamin D3 and its analogues can influence keratinocyte differentiation and are therefore used in treatment of several skin disorders including psoriasis. VD3 is extremely hydrophobic (log P=9) and unstable in aqueous solution that make this drug challenging to formulate. An ABA-triblock copolymer composed of hydrophobic B-block oligomers of desaminotyrosyl tyrosine ester and diacid and hydrophilic PEG A-blocks has been developed at the Rutgers N J Center for Biomaterials. This copolymer can undergo self-assembly in an aqueous environment to form polymeric micelles known as TyroSpheres, that are capable encapsulating hydrophobic substances. The purpose of this study was to investigate the potential ability of TyroSpheres as a formulation carrier for topical delivery of VD3 improving both its skin delivery as well as its stability. Methods: VD3 was loaded in TyroSpheres at various drug to polymer ratios. The nanosphere formulations were characterized for drug loading, binding efficiency, particle size, drug release and stability. Solubility of VD3 in presence of different concentrations of Tween 80 was measured and compared with TyroSphere nano dispersion. The release of VD3 from TyroSpheres and diffusion through stratum corneum was evaluated using Franz diffusion cells. The photo stability of VD3-TyroSpheres at 15% initial drug loading was also tested and compared with VD3 solution in methanol. Results and Discussion: TyroSpheres provided substantial enhancement in the solubility of VD3 in phosphate buffer saline (PBS) pH=7.4. The average particle size of VD3-TyroSpheres was 68-77 nm (PDI＜0.2). TyroSpheres were capable of encapsulating cholecalciferol up to 30 % loading efficiency (Figure 1) and producing an aqueous formulation with maximum VD3 content of 3.5 mg/ml. High flexibility and extreme hydrophobicity of VD3 allowed for hydrophobic interactions with the core of TyroSphere, which resulted in high loading efficiencies. VD3 release from Tyrospheres into stratum comeum occurred in a sustained manner and fitted the Higuchi square root model (Figure 2.a). Rate of drug release was independent of drug loading. Moreover, encapsulation of VD3 in TyroSpheres was observed to significantly enhance its stability in aqueous medium and also reduce the rate of photo-degradation (Figure 2b). Figure 1. Vitamin D3 (VD3) loading and binding efficiency in TyroSphere. Data is presented as mean ± SD. Figure 2. Cumulative release of Vitamin D3 (VD3) from TyroSpheres and diffusion through stratum corneum (SC) at two different drug to polymer ratio loadings, 4% (bule) and 15% (red). Figure 3. Degradation profile of vitamin D3 (VD3) in methanol (red) and in TyroSpheres (blue) when exposed to UV light. Conclusions: Using TyroSpheres as carriers for VD3 we were able to develop aqueous-based formulations of cholecalciferol with high drug loading. These formulations delivered adequate amounts of active into the skin in vitro. In addition, TyroSpheres were able to shield the active against hydrolysis and photodegradation in the formulation.
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