T T

Time

Figure 9.22 Drug penetration-time profile for an idealised drug diffusing through human skin; once steady-state diffusion occurs Qt can be obtained using equation (9.14) where t = (time elapsed - t).

Time

Before steady-state penetration is achieved, the rate builds up over a period of time and a lag phase will be apparent (Fig. 9.22). The lag time, t, does not indicate the point at which steady-state is achieved which, as shown in Fig. 9.22, is obtained by extrapolation. The linear portion of the graph can be described by an equation relating the total amount absorbed at time t, Qt, to ACv, P, 6, t and D. From equation (9.10), as Qt = Jt,

But from Fig. 9.22 it is obvious that the time to be substituted is the time over which steady-state flux has been maintained; namely, t - t. Thus we write

As the lag time, t, has been shown to be equal to à2/6D, the diffusion coefficient D is readily

Figure 9.22 Drug penetration-time profile for an idealised drug diffusing through human skin; once steady-state diffusion occurs Qt can be obtained using equation (9.14) where t = (time elapsed - t).

obtained from data such as those shown in Fig. 9.22. Values of t range from a few minutes to several days, so lag times are of obvious clinical relevance.

9.5.1 Routes of skin penetration

Solute molecules may penetrate the skin not only through the stratum corneum but also by way of the hair follicles or through the sweat ducts, but these offer only a comparatively minor route because they represent such a small fraction of the surface area. Only in the case of molecules that move very slowly through the stratum corneum may absorption by these other routes predominate. Passage through damaged skin is increased over normal skin. Skin with a disrupted epidermal layer will allow up to 80% of hydrocortisone to pass into the dermis, but only 1% is absorbed through intact skin.

The physicochemical factors that control drug penetration include the hydration of the stratum corneum, temperature, pH, drug concentration, and the molecular characteristics of the penetrant and the vehicle. The stratum corneum is a heterogeneous structure containing about 40% protein (keratin, a disul-fide-crosslinked linear polypeptide), about

40% water and 18-20% lipids (principally triglycerides and free fatty acids, cholesterol and phospholipids). Hydration of the stratum corneum is one determinant of the extent of absorption: increased hydration decreases the resistance of the layer, presumably by causing a swelling of the compact structures in the horny layer. Occlusive dressings increase the hydration of the stratum corneum by preventing water loss by perspiration; certain ointment bases are designed to be self-occluding. The use of occlusive films may increase the penetration of corticosteroids by a factor of 100 and of low molecular weight penetrants 2-fold to 5-fold. As temperature varies little in the clinical use of a topical preparation, this parameter will not be discussed here. A pH in excess of 11 will greatly increase skin permeability.

Occluded skin may absorb up to 5-6 times its dry weight of water. In the idealised model of the stratum corneum shown in Fig. 9.23, L represents the lipid-rich interstitial phase and P the proteinaceous phase. If p = PL/PP (the ratio of the partition coefficients of the drug between vehicle and the L and P phases), and Dl and DP are the diffusion coefficients of the drug in these phases, the flux through stratum corneum of average thickness (that is, 40 ^m) is found to reduce to

J = 0.98p D (^g cm-2 h-1) dp when p(DL /DP) is very small. When p(DL /DP) is very large, the flux becomes

J = (2.3 x 10-4)p D (jig cm-2 h-1) dp which emphasises the importance of the partition coefficient and diffusion coefficient of the drug in the absorption process.

9.5.2 Influence of drug

The diffusion coefficient of the drug in the skin will be determined by factors such as molecular size, shape and charge; the partition coefficient will be determined not only by the properties of the drug but also by the vehicle as this represents the donor phase, the skin being the receptor phase. The quantity p can be approximated by experimentally determined oil/water partition coefficients. Thus, substances that have a very low oil solubility will display low rates of penetration.

The major pathway of transport for water-soluble molecules is transcellular, involving passage through cells and cell walls. The pathway for lipid-soluble molecules is presumably the endogenous lipid within the stratum corneum, the bulk of this being intercellular. Increase in the polar character of the penetrant molecule decreases permeability, as seen from the data on steroids in Table 9.9, in which progesterone and hydroxyprogesterone and desoxycortone and cortexolone should be compared. Each pair differs by a hydroxyl group. The lipid/water partition coefficients of

0 0

Post a comment