Formulation study of topically applied O/W lotion containing vitamin D3 derivative, focusing on skin permeability of the drug

Abstract

Permeation of 22-oxacalcitriol-1α, 25-dihydroxyvitamin D(3) (OCT) through excited hairless mouse skin was determined after application of OCT as solutions and O/W lotions consisted of different polarities of solvents: medium-chain fatty acid triglyceride (MCT), myristate isopropyl (IPM), 1,3-butylene glycol (1,3-BG), and propylene glycol (PG). OCT concentration in skin was also followed after applying these formulations. A two-layer diffusion model was composed to analyze dermatopharmacokinetic profiles of OCT for each vehicle. In the OCT solutions, skin permeation profile of OCT differed depending on solvent polarity. The O/W lotion with a high MCT content led to a low amount of OCT in skin. On the other hand, the O/W lotion with a high 1,3-BG content led to a high amount of OCT in skin. This dermatopharmacokinetic analysis indicated that addition of MCT to the formulation decreases the skin/vehicle partition coefficient of OCT and increases the diffusion coefficient of OCT in skin. However, the opposite effects on these two parameters were found in the case of 1,3-BG. Thus, skin permeability of OCT differed depending on the solvents used in the formulation. These results indicate that skin permeability of OCT is influenced by the physicochemical properties (i.e. polarity) of OCT, solvent, and skin. Our findings on the solvent effects of the skin permeability of OCT are thus useful for designing topical drug formulation, especially in aiming for bioequivalent dosage formulas.

Dermal and Transdermal Delivery of Active Substances from Semisolid Bases

“…The composition of the semisolid base impacts parameters of the active substance that are important from the point of view of the release, skin and transdermal delivery such as: concentration of dissolved form, thermodynamic activity, skin/base partition coefficient as well as diffusion coefficient in stratum corneum (skin permeability) [2,[15][16][17][18][19] . The values of these parameters should be as high as possible to maximize the rate of release and skin and transdermal delivery [2,[15][16][17][18][19] .…”

“…The solubility of the active substance in the emulsion base may be increased by emulsifiers or solvents that may be easily incorporated into the formulation [16,21,43] . Emulsion bases enable to incorporate both hydrophilic and hydrophobic solvents of active substances [16] . The active substance may be localized in the external phase or in the dispersed phase (depending on its solubility in the oil phase and in the aqueous phase as well as the emulsion type).…”

“…The impact of semi-solid base components on the skin, in particular on the stratum corneum, includes: hydration and incorporation of some semisolid base components into the intercellular cement lipids leading to increased disordering of lamellar and lateral packing of lipids and/or increased solubility of the active substance within the stratum corneum lipids [4,16,18] . These interactions may alter the stratum corneum permeability (influence on skin penetration and permeation rate) or change the value of skin/base partition coefficient (influence on the rate of the skin retention) [16] . The degree of the interaction between the base components and the skin can be assessed by a comparative analysis of the release rate and the skin permeation rate of the active substance [62] .…”

“…The aspects that must be taken into account when deciding which type of the base (emulsion or hydrophilic) should be chosen in a specific case are: physicochemical characteristics of the active substance, solubility of the active substance in the base, concentration of an active substance dissolved form, thermodynamic activity of the active substance in the base, the presence of base components, which can serve as solvents or solubilizers as well as penetration enhancers of the active substance [1,2,16] .…”

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“…The stages of skin permeation once the active substance overcomes the stratum corneum are similar to the in vitro release through the artificial membrane whose properties resemble those of the deeper layers of the skin. These layers are more hydrophilic and permeable than the stratum corneum [9]. The proper selection of semisolid base type the active substance, vehicle and the skin should be considered as a kind of multifactorial system, not separately.…”