Info

Dose interruption

Removing patches

Washing residuals

Delivery efficiency

Relatively low, <60%

Low, <20%

Other than possibly for the insensible perspiration they absorb, transdermal patches tend to operate as thermodynamically static systems, meaning as compositionally fixed systems, from the moment they are applied until their removal. Compositional steadfastness is still the rule, however, and it is this feature that bestows the zero-order delivery attribute on the ordinary transdermal patch. Drug is present within the patches in reservoir amounts irrespective of whether or not the reservoir compartment is easily distinguished for there must be enough drug to sustain delivery over the full course of patch wear.

In some prototypes, for example, the nitroglycerine transdermal systems, huge excesses of drug are placed in the patch to assure that the drug's activity remains essentially level during the patch's wear. Only a small fraction of the drug, well under 50% of the patch's total content, is actually delivered during the prescribed time the patch is to be worn. Part of the inherent stability of the delivery environment of patches results because their main materials of construction are polymers, fabricating laminates and adhesives, all of which tend to be chemically robust. Solubilizing solvents (e.g., ethanol) and skin penetration enhancers (e.g., propylene glycol monolaurate) may also be present and their absorption into the skin may change compositions, but even here the processes are carefully orchestrated to gain a stable delivery environment over the long term.

A transdermal patch is a self-contained system that is applied as it is packaged, with its only manipulation being removal of the release liner to expose and ready its adhesive surface. The size of a patch, meaning its area of contact with the skin, is determined even before it is made. All of this area or only an inner portion of it may actually be involved in drug delivery, but, either way, the area is fixed. Since absorption is proportional to the area, to meet the differing drug requirements of individual patients, patches of different sizes are generally made available. The application site is also a constant of therapy in that a specific site or sites are recommended for use (not always for scientifically supportable reasons, e.g., nitroglycerine patches are worn over the heart!). Users tend to follow such dictates. Beyond this, the manner of application is also highly reproducible. Thus, there is as tight a control over absorption area and application site variables here as can be found in all of therapy. The only variability not customarily controlled for is that associated with the skin's permeability itself, but even here attempts have been made to make the systems operate with high delivery precision by incorporating rate-controlling membranes into them. However, with the possible exception of the antinauseant patch containing scopolamine, the rate-controlling membranes do not actually control the rate of delivery, the stratum corneum does. Regardless, the manner of function of the systems is highly reproduced from one application to the next.

Measures of function of transdermal systems distinguish them among the systems we use topically. Since systemic actions are sought, blood levels of the drug in question must reach and remain within therapeutic bounds. More often than not the requisite blood level is known from a drug's use by other routes of administration. Thus, a clear systemic target level usually exists, and an absolute rate of delivery commensurate with reaching this is a built-in feature of the patch. Bioequivalency of different systems built around a specific drug is easily measured in terms of the blood levels they produce. And if therapy is not going well, one can bring delivery to a reasonably abrupt halt by simply removing a patch.

Topical Delivery—Attributes of Topical Delivery Systems

Despite the fact that often less than 1% and almost never more than 15% of the drug in a dermatological application is systemically absorbed (systemically recoverable), topical delivery nevertheless allows one to achieve drug levels in local tissues far in excess of those that can be achieved by other means of administration. At the same time, systemic toxicities of the drug are rarely encountered with topical administration, with the exceptions occurring when dermatological formulations are used liberally over extensive areas. Because of only small amounts of a drug being ordinarily applied topically, in most instances the amounts absorbed are so limited that one has trouble even measuring them.

As shown in Table 7, we tend to think of topical dosage forms being much the same as transdermal delivery systems, but the functioning of semisolid dermatological products stands in stark contrast with that of transdermal delivery systems. To begin with, most topical applications are left open to the atmosphere. Amounts applied per unit area depend on the individual making the application. Of singular importance with respect to system function, extraordinary physicochemical changes accompany the evaporative concentration of these formulations, possibly including the precipitation of the drug or other substances that were comfortably in solution at the moment of their application. Evaporative concentration can also upset the oil-to-water balance of emulsions, destabilizing them, at times causing them to break or invert. In a matter of hours, if not just minutes, a surface film or dry residue having a totally different delivery faculty than the bulk formulation may be all that is left of the application. Such precipitous changes, if out of control, can bring drug delivery to an abrupt halt.

The amounts of semisolids people apply are highly individualized, and so are the techniques of application. Some patients vigorously rub semisolid formulations into the skin, while others just spread films until they are more or less uniform over the desired area. For many diseases, disease manifestation can be anywhere on the body. Moreover, from individual to individual, it varies in intensity and vastness. Thus, more area may be involved in one case than in another, and the barrier function of the skin may be more or less intact in any instance. The net of this creates a set of imponderables with respect to delivery, efficacy, and safety.

The removal of the dermatological applications is rarely deliberate. Rather, some substance is usually transferred to clothing, etc., some is absorbed, some is evaporated, and some is inadvertently removed by activities such as bathing. Of course, applications can be deliberately washed from the skin if one wishes to terminate the therapy. Partly because of their temporal inhabitancy, local applications tend to be short acting relative to transdermal delivery systems. Other factors here are the finite doses that are actually administered and the oftentimes rapid evaporative concentration of such films to compositions that cease supporting dissolution of the drug and its diffusion to the skin's surface. Such finite doses do not sustain delivery, and thus delivery wanes after several hours irrespective of the wearability of the application and of processes attending its evaporative shrinkage. Since all these attending processes defy quantification, there is precious little existing information to guide one concerning a fitting regimen of application for most topical dosage forms. Rather, dosing regimens evolve historically from collective clinical experience. All in all, topical therapy is an extraordinarily complex operation.

Compositional changes following the application of certain topical systems are unavoidable. Many o/w creams contain as much as 80% to 85% external phase, usually primarily water. Lotions and gels also contain volatile constituents in large proportion. All rapidly evaporate down after their application and, consequently, the drug delivery system is the formed, concentrated film that develops on the skin and not the medium as packaged in the tube, jar, or bottle. Ingredients should be chosen to assure that compositional changes as invariably occur interfere as little as possible with delivery and therapy. In this regard, the rate at which the volatile components evaporate to form the equilibrium film can itself be a factor in bioavailability (80). It has been reported, for instance, that a thinly applied corticosteroid preparation produced greater vasoconstriction than did thicker applications of the same material (81). Though the total amount of drug per unit area was greater with the thick films, responses were less in their case because evaporative concentration of the steroid in the applied medium proceeded more slowly. Even without knowing the mechanistic details, we can conclude from this that less steroid was driven into the skin from the thick applications in the course of the test. It has also been demonstrated that vasoconstriction is more pronounced at low concentrations when steroid is applied in volatile ethanol than when applied in propylene glycol (60). While differences in solvency play their role here, it is also clear that the rapid evaporation of solvents as ethanol drives drug into the skin. Such observations emphasize the importance of distinguishing between the system as packaged and the transitional system following application. Unfortunately, this distinction is not always made, and much topical delivery research aimed at assessing the relative abilities formulations have to deliver drug has been performed by placing extraordinarily thick layers of formulation over the skin. Such thick applications do not even remotely simulate the clinical release situation, especially when it comes to creams and gels. This area of drug delivery is in need of much research.

In summary, the way a topical drug is formulated has a great deal to do with its clinical effectiveness, a nonsurprising conclusion, given what is known about the relationships between bioavailability and formulation for other modes of administration. Yet in the area of topical drug performance, antiquated concepts and approaches to system design linger on. In days when topical bioavailability was little understood and therefore ignored, formulators concentrated on vehicle elegance and stability. Attempts were made to design vehicles compatible with all types of drugs, so-called universal vehicles. Universal vehicles are still discussed in many standard texts. Today's technology and science clearly indicate that the universal vehicle is akin to a unicorn, beautiful but totally mythical. In the real world, each system must be designed around the drug it contains to optimize the clinical potential of the active ingredient. The duration of action will depend on how long the drug remains appreciably in solution within its spread film. These matters

Table 8 Factors for Evaluation of Semisolids

Stability of the active ingredient(s) Stability of the adjuvants Visual appearance Color

Odor (development of pungent odor or loss of fragrance) Viscosity, extrudability

Loss of water and other volatile vehicle components Phase distribution (homogeneity or phase separation, bleeding) Particle size distribution of dispersed phases pH

Texture, feel upon application (stiffness, grittiness, greasiness, tackiness) Particulate contamination

Microbial contamination and sterility (in the unopened container and under conditions of use) Release and bioavailability are carefully examined when a drug delivery system, topical or otherwise, reaches the FDA as an Investigational New Drug Application (IND), New Drug Application (NDA), or Abbreviated New Drug Application (ANDA) (82).

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