Drug Candidate Selection

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Although it may appear to be a simple task to select lead compounds for pharmaceutical product development, based on therapeutic rationale and compound safety and efficacy, the practicalities of this procedure are somewhat more complex. For the most part, therapeutic efficacy is dependent on the ability of a compound to cross biological barriers, travel to the target site, and interact with specific receptors. However, as pointed out and excellently reviewed (3), it is often more appropriate in dermatological therapy to select compounds based on their inability to breach relevant biological barriers. Because the site of action may be the skin surface, the stratum corneum, the viable epidermis, the appendages, the dermis, or the local subcutaneous tissues, the rules of candidate selection will vary. For the purposes of this discussion it will be assumed that the therapeutic rationale for dermal drug delivery has been established and that a series of compounds with appropriate pharmacological activity have been identified. It will also be assumed that each compound within the series possesses equivalent chemical and physical stability. In other words, drug candidate selection need only be based on the ability to deliver the compound to its site of action.

Earlier chapters in this volume have taught that the primary requirement for a compound to penetrate the skin is the ability to leave the delivery system and enter the stratum corneum. Furthermore, this characteristic is dependent on the stratum corneum-vehicle partition coefficient of the compound, for which the octanol-water partition coefficient is often used as a surrogate. Whereas it is immediately apparent that a high value for this parameter will favor delivery into the stratum corneum, it will not favor movement into the more hydrophilic regions of the viable epidermis. Furthermore, the rate of diffusion through the stratum corneum and lower layers of the skin is linked to the molecular volume of the permeant. It is evident that a compound with a high octanol-water partition coefficient and a relatively high molecular volume will possess a high affinity for the stratum corneum (i.e., be substantive to the stratum corneum). This principle is used extensively in the design of sunscreen agents, for which it is not uncommon to add a medium-length or branched-chain alkyl to the UV-absorbing molecule to increase residence time in the skin and reduce systemic uptake.

The use of the skin as a route of delivery into the systemic circulation was neither commercially nor scientifically exploited until the 1950s, when ointments containing agents such as nitroglycerin and salicylates were developed. Angina could be controlled for several hours by applying an ointment containing 2% nitroglycerin (23). Similarly, topical salicylates could be absorbed through the skin into arthritic joints. More recently, nonsteroidal anti-inflammatory agents, such as ibuprofen and ketoprofen, and hormonal steroids, such as estradiol and testosterone, have been developed and marketed in semisolid preparations. A major problem with transdermal semisolid preparations, however, is that of control. Drug concentrations in plasma or duration of action, are not reliably predictable for several reasons, including the amount and area of application and dosage frequency.

The specific advantages of transdermal therapy have been fully discussed elsewhere (24). Briefly, transdermal devices are easy to apply, can remain in place for up to 7 days (depending on the system), and are easily removed following, or during, therapy. The reduced-dosing frequency, and the production of controllable and sustained plasma levels, tend to minimize the risk of undesirable side effects sometimes observed after oral delivery. The avoidance of extensive hepatic first-pass metabolism is a further advantage. The major limitation to transdermal drug delivery is the intrinsic barrier property of the skin. Although marketed patch-type transdermal delivery systems are available for only a limited number of drugs (e.g., scopolamine, nitroglycerin, clonidine, estradiol, fentanyl, testosterone, and nicotine), several other candidates are at various stages of development. Many of the drugs under investigation do not intrinsically possess any significant ability to cross the skin; therefore, ways must be found to improve their transdermal delivery. This could be achieved by the use of prodrugs designed such that they are more rapidly absorbed than the parent compound, yet are metabolized to the active species before receptor site occupancy (25,26). Physical methods, such as iontophoresis (27), electroporation (28), and sonophoresis (29) have proved experimentally useful for increasing the skin permeation of several compounds. Alternatively, the barrier may be modulated using thermodynamic strategies, or chemically modified to reduce diffusive resistance by the use of penetration enhancers, both of which are discussed in Chapter 6. Such developmental strategies will increase the number of candidate drugs for transdermal delivery in the future.

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Cure Your Yeast Infection For Good

Cure Your Yeast Infection For Good

The term vaginitis is one that is applied to any inflammation or infection of the vagina, and there are many different conditions that are categorized together under this ‘broad’ heading, including bacterial vaginosis, trichomoniasis and non-infectious vaginitis.

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