Penetration enhancers solubility effects

Oral dosage forms may contain various other additives to increase the solubility and hence oral bioavailability of the drag, such as co-solvents, buffers and surfactants. Newer technologies may also incorporate additives such as enzyme inhibitors, to prevent premature degradation of enzymatically labile drags. For example, the inclusion of trypsin inhibitors, such as soyabean trypsin inhibitor and aprotinin, have been shown to be effective in enhancing the effect of insulin in rats. Penetration enhancers may also be included to facilitate the uptake of poorly absorbed moieies. These are discussed below in Section 6.7.4. 

Penetration into the skin can be enhanced by penetration enhancers. These excipients diffuse into the stratum comeum and interact with components of this layer. The barrier function of the skin decreases. The effect of penetration enhancers is based on two mechanisms. The penetration enhancer can change the stracture of the stratum comeum or the solubility of the active substance in the skin. Penetration enhancers should not damage the underlying skin layers and should not be toxic or allergenic. Moreover, the effect must be reversible. Because of the different properties and mechanisms of action of penetration enhancers it is difficult to predict which enhancer will be most effective for the penetration of a specific active substance. Substances such as dimethyl sulfoxide (DMSO), salicylic acid, urea, propylene glycol, ethanol, isopropyl alcohol and many acids can act as penetration enhancers. 

Zinc oxide gives an alkaline reaction in water which leads to chemical incompatibilities in cutaneous preparations. One of the best known is the interaction with salicylic acid which is turned into salicylate. The keratolytic or penetration enhancing effect of salicylic acid is based on the acid function. Salicylate does not have these effects. The incompatibility may be prevented by replacing zinc oxide by titanium dioxide. Titanium dioxide is in comparison to zinc oxide only soluble in very strong acids. Therefore no interaction is expected. 

For a good therapeutic effect the choice of the active substance and the choice of the vehicle are important. Physical and chemical factors play an important role. The solubility of the active substance in the vehicle and the concentration, the size of the molecule of the active substance, the partition between vehicle and skin, the particle size (in case of suspensions) and the nature of the vehicle (aqueous or lipid) determine the penetration speed and depth. Hydrocortisone, for example, is more lipid soluble in the ester form (hydrocortisone acetate). The latter will penetrate into the skin faster and more complete. Hydrocarbons, such as soft and liquid paraffin, release lipophilic active substances only very slowly and substances formulated in these bases will penetrate only in limited amounts into the skin. Fatty oils (vegetable oils, triglycerides) are able to pass into the upper layers of the skin. Penetration enhancers (salicylic acid, dimethyl sulfoxide, propylene glycol, urea) increase the penetration of active substances into the skin. 

The performance of soluble oils is made possible not only by their high specific heat and thermal conductivity but by their low viscosity, which permits good penetration into the very fine clearances around the cutting zone. Consequently, these fluids are used mainly where cooling is the primary requirement. Lubricating properties can be improved by polar additives, which are agents that enhance the oiliness or anti-friction characteristics. Further improvements can be effected by EP (extreme-pressure) additives, which are usually compounds of sulfur or chlorine. 

PFE is based on the adjustment of known extraction conditions of traditional solvent extraction to higher temperatures and pressures. The main reasons for enhanced extraction performance at elevated temperature and pressure are (i) solubility and mass transfer effects and (ii) disruption of surface equilibria [487]. In PFE, a certain minimum pressure is required to maintain the extraction solvent in the liquid state at a temperature above the atmospheric boiling point. High pressure elevates the boiling point of the solvent and also enhances penetration of the solvent into the sample matrix. This accelerates the desorption of analytes from the sample surface and their dissolution into the solvent. The final result is improved extraction efficiency along with short extraction time and low solvent requirements. While pressures well above the values required to keep the extraction solvent from boiling should be used, no influence on the ASE extraction efficiency is noticeable by variations from 100 to 300 bar [122]. 

Increasing the concentration increases the penetration, but not to the same degree. Solubility of the corticosteroid in the vehicle is an other determinant of absorption and efficacy. So different formulations of the same corticosteroid can end up in a different efficacy classification. Efficacy can be further augmented by using the corticosteroid under occlusion. Occlusion with plastic enhances penetration and also absorption. However, with increased absorption also the risk of systemic side-effects increases. Systemic absorption will suppress the pituitary-adrenal axis and may cause Cushing s syndrome and a plethora of other adverse events (see Chapter 24, Section Il.b). Even small amounts absorbed may already cause growth retardation in children. 

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