Supersaturation as a Galenic Concept for Improving the Cutaneous Bioavailability of Drugs in Topical Therapy

Abstract

The essential force that allows an epicutaneously applied drug to penetrate the skin is mediated by diffusion. The physicochemical properties of the skin tissue at the site of application and the concentration gradient of the dissolved drug between the vehicle and the stratum corneum are decisive here. One way to specifically improve these diffusion conditions is to use supersaturation. This uses the physical principle of the difference between the solubility curve and precipitation curve (Ostwald-Miers range). During the conversion of the application vehicle into the segregation vehicle, supersaturation of the dissolved drug substance in a solvent is achieved by evaporation, e.g., of a solubilizer. In principle, the change in solubility can also be achieved by heating and then cooling a solution. This principle has already been realized in a formulation of a fixed combination of calcipotriol and betamethasone dipropionate, two lipophilic drugs susceptible to hydrolysis, and is available on the market as a spray foam.

Topical drug delivery strategies for enhancing drug effectiveness by skin barriers, drug delivery systems and individualized dosing

“…The formula based on Fick’s first law of diffusion indicates that the maximum flux of a drug is proportional to the difference in skin concentration and inversely proportional to the thickness of the stratum corneum. Fick’s second law of diffusion suggests that the relationship between diffusion distance and the duration until an isopore (an area of the same drug concentration) is reached is not linear, but increases disproportionately with increasing diffusion distance ( Wohlrab and Eichner, 2023 ). However, the efficacy of some drugs decreases significantly with increasing drug concentration ( Hemmati et al, 2011 ), indicating that in addition, there are other important factors that similarly influence drug penetration and absorption.…”

Galenic concept of supersaturation may improve the cutaneous absorption of calcipotriol plus betamethasone dipropionate aerosol foam compared with other topical formulations

“…2 Skin absorption depends on several attributes, including the magnitude of the concentration gradient of the dissolved API between the vehicle and stratum corneum. 3 This attribute can be improved using the galenic concept of supersaturation, in which the concentration of a solution is increased beyond its saturation point by increases in pressure and/or temperature. 3 The supersaturation concept was used to develop CAL/BD aerosol foam (Enstilar®), a solution of CAL/BD 0.005%/0.064% in a base of white petrolatum, polyoxypropylene stearyl ether, mineral oil, all-rac-alphatocopherol, and butylhydroxytoluene in a pressurized spray can.…”

“…3 This attribute can be improved using the galenic concept of supersaturation, in which the concentration of a solution is increased beyond its saturation point by increases in pressure and/or temperature. 3 The supersaturation concept was used to develop CAL/BD aerosol foam (Enstilar®), a solution of CAL/BD 0.005%/0.064% in a base of white petrolatum, polyoxypropylene stearyl ether, mineral oil, all-rac-alphatocopherol, and butylhydroxytoluene in a pressurized spray can. 2 The aerosol propellants dimethyl ether and butane evaporate after application, leaving a nonexpanding foam that gradually collapses to form a stable supersaturated film of CAL/BD on the skin.…”