Transdermal delivery rate

Ointments, creams, and plasters are used for transdermal drug delivery. In the latter case, sustained release is accomplished by diffusion from a reservoir through a microporous membrane and into the skin [26,48,49]. Iontophoresis and electroporation has been reported to successfully promote transdermal delivery rates [50-52]. 

Figure 3 Transdermal delivery rate (mean S.D.) of PG across hairless mouse skin In vitro from device (a) (PG alone).

Dissolution testing has become an important component of the assessment of the quality of solid oral dosage forms and oral suspensions. The basic procedures for these oral dosage forms have been extended to transdermal delivery systems as well. The release rate for modified-release oral dosage forms adds a level of sophistication to the concept of dissolution testing, setting acceptance criteria at multiple time points. 

Transdermal delivery is suitable for small, generally lipophilic, potent molecules that require low input rates to achieve effective plasma concentrations. There may be a slow rate of increase of concentration if the drug forms a depot in the skin. Depot formation will also result in a slow decrease in concentration when the system is removed from the skin. These disadvantages can be overcome by the use of iontophoresis, by which the molecules are actively carried across the skin by a small electrical current. This provides a faster and more controllable transfer of drug. Intramuscular/Subcutaneous... 

Dosages and routes of administration For acute (postoperative) pain and for anesthesia, fentanyl is given by the intravenous route. For pre-medication in anesthesia and for break-through pain the compound can also been given as an oral-transmucosal formulation (Ashburn and Streisand, 1994). A transdermal patch has been developed for chronic pain treatment (Jeal and Benfield, 1997 O Siordin, 1998). The intravenous doses for premedication are 50-100 pg, oral-transmucosal systems contain 200-400 pg and patch formulations have a delivery rate of 25-100 pg/h. 

Iontophoresis techniques (i.e., the use of electric current to facilitate transdermal delivery) have also been advocated as a way to enhance transdermal opioid delivery to the systemic circulation.11 By varying the amount of electric current, iontophoresis may ultimately allow the patient to control the rate of transdermal administration of the opioid.10,76,78 Finally, certain opioids such as fentanyl can be administered systemically via lozenges or a lollipop that dissolves in the mouth (transmucosal delivery), or via nasal spray (intranasal administration).21,54 It will be interesting to see if these newer methods of administration will gain widespread acceptance in the future. 

A good example of a transdermal prodrug is an alkyl ester prodrug of naltrexone designed to improve lipophilicity of the parent compound and increase its delivery rate across the skin. The mean naltrexone flux from the prodrug-saturated solutions exceeded the flux of naltrexone base by approximately two- to seven-fold. 

Transdermal delivery is a noninvasive intravenous infusion of drug to maintain efficacious drug levels in the body for predictable and extended duration of activity. Diffusion-controlled transdermal systems are designed to deliver the therapeutic agent at a controlled rate from the device to and through the skin into the systemic circulation. This route of administration avoids unwanted presystemic metabolism (first-pass effect) in the GI tract and the liver. Patient satisfaction has been realized through decreased... 

The majority of controlled drug delivery systems now being marketed or under development are based on diffusion of the drug through a semipermeable membrane to achieve the requisite release rate. Diffusion control is particularly important to transdermal delivery, where biodegradation and dissolution are not viable mechanisms of controlling the release rate. Provided the process is Fickian, the rate of diffusion through the semipermeable polymer is determined by... 

Even if the drag is sufficiently potent, it must yet satisfy other criteria to be considered a viable candidate for transdermal delivery. First, its physicochemical properties must allow it to be absorbed percutaneously. This means that its molecular weight should be reasonable (see above), and that it should have adequate solubility in both lipophilic and aqueous environments since, to reach the dermal microcirculation and gain access to the systemic circulation, the molecule must cross the stratum comeum (a lipoidal barrier) and then transfer through the much-more-aqueous-in-nature viable epidermis and upper dermis. Absence of either oil or water solubility will preclude permeation at a useful rate. 

These testosterone systems illustrate two different approaches to solve the problem of inadequate percutaneous absorption rate. In the former case, the patch must be applied to the body s most permeable skin site, the scrotum (which has been shown to be at least five times more permeable than ary other site). In the latter, the difficulty is resolved by creating a transdermal formulation which includes excipients to reduce barrier function. Neither solution is ideal scrotal application is clearly not preferred from a patient compliance standpoint on the other hand, permeation enhancers, by their very nature, tend to be irritating (and the more effective they are, the greater the irritation they provoke). This general problem, which presently limits the application of transdermal delivery, is now discussed in more detail. 

Consider a drug candidate for transdermal delivery. The effective steady-state concentration of the drug is Css (mg cm-3) and its systemic clearance is Cl (cm3 hr ). It follows that the required transdermal input rate (R mg hr1) is ... 

Using appropriate examples, describe the importance of rate-control in transdermal delivery. 

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