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acting as a solvent for the drug significantly affects permeation.

Thermodynamic activity in topical products

The concept of thermodynamic activity is considered in more detail in chapter 3. The thermodynamic activity of the drug is obviously the ultimate determinant of biological activity. If the solubility of the drug in the base is increased by addition of propylene glycol then its partition coefficient, P, towards the skin is reduced. On the other hand, increasing the amount which can be incorporated in the base is an advantage and the concentration (Cv) gradient is increased. It is apparent that there will be an optimum amount of solubiliser. The optimum occurs at the level of additive which just solubilises the medicament. Addition of excess results in desaturation of the system, and therefore a decrease in thermodynamic activity. As the total amount of drug in the vehicle is increased from 0.5 to 1.0mgg 1 (Fig. 9.25b) more propylene glycol has to be added to cause a decrease in CvP. From Fig. 9.25(b) one could postulate that threefold dilution of a formulation containing 1.0 mg g 1 and 60% solubiliser with a base with no solubiliser would cause the thermodynamic activity to increase. The vehicle affects penetration only when the release of drug is rate-limiting.

In situations where all of the activity gradient is in the applied phase, skin properties play no part. In these cases drug concentration in the vehicle, the diffusion coefficient of the drug in the system and the solubility of the drug are the significant factors. Where these factors are not important, the only significant factor involving the vehicle is the thermo-dynamic activity of the drug contained in it. Using the simplest model, for a solution of concentration C applied to an area A of the skin, the steady-state rate of penetration, dQ/dt, is given by release in terms of the thermodynamic activity, a, of the agent in the vehicle:

where y is the activity coefficient of the agent in the skin barrier phase. Ointments containing finely ground particles of drug where the thermodynamic activity is equal to that of solid drug will have the same rate of penetration, provided that the passage of the drug in the barrier phase is rate-limiting.

Solutes 'held firmly' in the vehicle exhibit low activity coefficients (low escaping tendencies) and thus low rates of penetration. Differences occur in the activity of phenols in mineral oil and polypropylene glycol bases. The latter are bland, the former corrosive. Polyether-phenol complex formation decreases the thermodynamic activity of the phenols, which are therefore less toxic.

Drug release from complex vehicles

In more complex vehicles the activity a is impossible to determine and other approaches must be adopted. For example, in emulsions the relative affinity of drug for the external and internal phases of the emulsion is an important factor. A drug dissolved in an internal aqueous phase of a w/o emulsion must be able to diffuse through the oily layer to reach the skin. Three cases can be considered: solution, suspension and emulsion systems.

Solutions

Release from solutions is most readily understood and quantified by equations of the form dQ dt

d being the thickness of the barrier phase. An equivalent form of this equation expresses where C0 is the initial medicament concentration in solution, D is the diffusion coefficient, and t is the time after application of the vehicle. As D is inversely proportional to the viscosity of the vehicle, one would expect that drug release would be slower from a viscous vehicle. There is evidence for this in section 9.11, where the rheological characteristics of rectal formulations are seen to be correlated with bioavailability.

Suspensions

If a drug in suspension is to have any action it must have a degree of solubility in the base used. An aged suspension of a drug will therefore have a saturated solution of the drug present in the continuous phase. Release of medicament in these conditions is given by dQ _

Ccp\1/2 2t

phases, the effective diffusion coefficient, De, is given by

If 0 2 » and D2 > D1 (likely if phase 2 is water), then

For a system containing 20% water (0 2 = 0.20) the equation simplifies even further to

where Cs is the total solubility of the drug in the vehicle and C0 is the concentration in the vehicle. This equation applies only when Cs < C0. Only material in solution penetrates the stratum corneum and the depleted layer in the vehicle is replenished only by solution of particles and diffusion of the drug molecules to the depleted layer.

Emulsions

For emulsion-type vehicles equations similar to those used to describe germicidal behaviour in two-phase systems can be applied. If D1 and D2 are the diffusion coefficients of the medicament in the continuous and disperse phases respectively, 01 and 02 are the volume fractions of these two phases, and P is the partition coefficient of the drug between the

The importance of P is seen in this equation. The value of De obtained here can be used in equations (9.18) and (9.19) above to obtain an approximation of effects.

9.5.4 Dilution of topical steroid preparations

Inappropriate dilution of carefully formulated creams and ointments may result in changes in stability and the effectiveness. The biophar-maceutical considerations will be apparent from the discussion in this chapter. An example would be clobetasol propionate formulated in a base containing the optimum amount of propylene glycol. The solubilities of the steroid as a function of propylene glycol concentration are shown in Fig. 9.26. A 1 in 2

Drug in solution

30 40 50 60 Per cent propylene glycol

Figure 9.26 A diagram showing the solubility of clobetasol propionate as a function of propylene glycol concentration. The dilution line shows that if a 0.05% cream containing 60% propylene glycol is diluted with a base not containing the glycol, the drug will be precipitated.

Drug in solution

Dilution line

(0.05% cream containing 60% propylene glycol)

30 40 50 60 Per cent propylene glycol

Figure 9.26 A diagram showing the solubility of clobetasol propionate as a function of propylene glycol concentration. The dilution line shows that if a 0.05% cream containing 60% propylene glycol is diluted with a base not containing the glycol, the drug will be precipitated.

dilution of a 0.05% cream, with a vehicle containing water and no propylene glycol will precipitate a large proportion of the steroid. The same principles apply to steroids presented in a fatty acid propylene glycol base.

9.5.5 Transdermal medication: patches and devices

The ease with which some drugs can pass through the skin barrier into the circulating blood means that the transdermal route of medication is a possible alternative to the oral route. Theoretically there are several advantages: 12

• For drugs that are normally taken orally, administration through the skin can eliminate the vagaries which influence gastrointestinal absorption, such as pH changes and variations in food intake and intestinal transit time.

• A drug may be introduced into the systemic circulation without initially entering the portal circulation and passing through the liver.

• Constant and continuous administration of drugs may be achieved by a simple application to the skin surface.

• Continuous administration of drugs percu-taneously at a controlled rate should permit elimination of pulse entry into the systemic circulation, an effect which is often associated with side-effects.

• Absorption of medication can be rapidly terminated whenever therapy must be interrupted.

Matrix

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