Transdermal therapeutic development

Walters, K.A. (1989). Penetration enhancers and their use in transdermal therapeutic systems. In Transdermal Drug Delivery — Development Issues and Research Initiatives, J. Hadgraft and R.H. Guy, eds. Marcel Dekker, New York, 197-246. 

J. Shaw, Development of Transdermal Therapeutic Systems, Drug Dev. Ind. Pharm. 9, 579 (1983). 

Transdermal administration can avoid first-pass metabolism as well as provide a large surface area for continuous-controlled administration of drugs with short biological half-lives and narrow therapeutical indices. The route has been used for nitroglycerin ointments, and transdermal therapeutical systems (patches) have been developed for scopolamine, nitroglycerin, clonidine, estradiol, and nicotine. 

Membrane-controlled Transdermal Drug Administration Drug administration through the intact skin, transdermal therapy, was realized at the end of the 20th century with the development of transdermal therapeutic systems [22, 59]. Various polymers are necessary for this. 

In the pharmaceutical field, development of transdermal therapeutic systems (TTS) is booming, and thus skin has become a matter of interest because of its potency as the route of systemic administration. However, skin is essentially a barrier against... 

As pharmaceutical scientists gain experience and tackle the primary challenges of developing stable parenteral formulations of proteins, the horizons continue to expand and novel delivery systems and alternative routes of administration are being sought. The interest in protein drug delivery is reflected by the wealth of literature that covers this topic [150-154]. Typically, protein therapeutics are prepared as sterile products for parenteral administration, but in the past several years, there has been increased interest in pulmonary, oral, transdermal, and controlled-release injectable formulations and many advances have been made. Some of the more promising recent developments are summarized in this section. 

Virtually all therapeutic proteins must enter the blood in order to promote a therapeutic effect. Such products must usually be administered parenterally. However, research continues on the development of non-parenteral routes which may prove more convenient, less costly and obtain improved patient compliance. Alternative potential delivery routes include transdermal, nasal, oral and bucal approaches, although most progress to date has been recorded with pulmonary-based delivery systems (Chapter 4). An inhaled insulin product ( Exubera , Chapters 4 and 11) was approved in 2006 for the treatment of type I and II diabetes. 

Atropine-, hyoscine- and hyoscyamine-based drugs are developed on a large scale and they also have a variety of clinical purposes. Atropinol, for example, is based on atropine. This drug contains atropine sulphate. Another example is Buscopan, based on hyoscine. Hyoscyamine is used in transdermal plasters. Bella sanol also contains hyoscyamine. The therapeutic use is similar to that of atropine. At least 50 different products from these alkaloids have been developed and introduced on the pharmaceutical market. 

Buprenorphine, the other option for transdermal application on account of its potency, is more difficult to apply dermally in therapeutic doses (Roy et al., 1994 Grond et al., 2000). A surrogate parameter for skin penetration, provided the other prerequisites are fulfilled (Fig. 7), is the melting point of the active substance. With buprenorphine base this is 209°C and about 260°C for buprenorphine hydrochloride, compared with, for example, 83°C for fentanyl base and 150°C for fentanyl dihydrogen citrate. The DDS developer LTS devised a technical solution for reliable transdermal buprenorphine administration in the form of a matrix patch (Fig. 9). 

The use of therapeutic proteins is growing rapidly and it has been suggested that this class of drugs may soon represent a significant fraction of the pharmaceutical market [45]. There is an urgent need for the development of delivery systems for proteins because, so far, the use of therapeutic proteins is limited to their low oral and transdermal bioavailability. 

This very powerful analgesic had been limited to parenteral use during and after surgery. Accurate dose titration is necessary because of the drug s very narrow therapeutic window (1-2 ng mL ). The potential of fentanyl, however, to significantly improve the treatment of acute post-operative pain and chronic cancer pain provoked the development of the now-approved Duragesic transdermal system. This reservoir system can be used for up to 3 days and is available in four doses (10, 20, 30 and 40 cm2 delivering, respectively, 25, 50, 75 and 100 pg hr 1). 

As discussed in Chapter 1 (Section 1.1) certain drugs (including peptides, proteins and nucleic acid therapeutics) are unsuitable for oral delivery and must be given intravenously. Research has recently been directed towards the development of alternatives to the parenteral route, such as the transdermal, nasal and other routes thus far discussed in this book, for the systemic delivery of such drugs. 

One of the key pieces to development of a successful drug product is the ability to deliver the drug to the site of action with minimal discomfort or inconvenience to the patient. For small molecule therapeutics, there is a wide range of options available for drug administration. Delivery via injection (IV, IM, and SC), oral, nasal, ocular, transmucosal (buccal, vaginal, and rectal), and transdermal routes is possible with small molecule drugs. However, the size of proteins and the complexity of their structures severely limit the routes of administration available to proteins. 

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