Excipients permeation enhancers

At present, despite the advantages offered by the buccal delivery route, such as the bypass of intestinal and hepatic first-pass metabolism for systemic delivery, very few pharmaceutical products employ this route of administration. The reasons that contribute to this situation include (1) high costs associated with development, (2) lack of standardized tests to identify drug candidates suitability for this route, (3) the limited understanding of the impact of metabolism and/or transporters found in the oral cavity mucosa on buccal delivery, and (4) the relatively small number of reports describing the usefulness and safety of excipients/permeation enhancers in humans [82, 83], Therefore, the... 

Permeation enhancement by excipients has generated some interest, but there is still much research that needs to be done to elucidate the mechanism of these excipients. PEG-400 (and many other excipients such as polyethylene glycol, poloxamers, polysorbates, and vitamin E) is known to inhibit p-glycoprotein, which may increase the bioavailability of the API, which was a substrate for this efflux pump. On the other hand, it has been demonstrated that PEG-400 can accelerate small intestinal transit, and thereby reduce the bioavailability of some drugs (e.g., ranitidine) (5). 

Receptor-mediated transporters are excipients that serve as substrates to exploit specific receptors present on cell membranes. Examples of various receptors that have been explored for permeation enhancement include bile acids (45), vitamin Bi2 (46), amino acids (47), and folic acid (48). Most of the work in receptor-mediated transporters is conducted via the use of prodrugs. For example, a prodrug of acyclovir conjugated to bile acids was seen to have higher permeability as compared to the original drug, because of receptor-mediated transport of the prodrug via bile acid transporters (49). 

Permeation-enhancing excipients have added a significant promise to the concept of oral delivery of macromolecules. Physical complexes of macromolecules and... 

Strategies to overcome the absorption barrier focus on the other hand on low molecular mass permeation enhancers (Chapter 5) such as medium chain fatty acids, which can still be regarded as a kind of gold standard. As low molecular mass permeation enhancers are per se rapidly uptaken from the gastrointestinal mucosa, however, the macromolecular drug is to a considerable high extent left alone behind in the gastrointestinal tract. In addition, local and systemic toxic side effects of low molecular mass permeation enhancers cannot be excluded. In contrast, polymeric permeation enhancers (Chapter 6) are simply too big to be absorbed from the GI tract. Consequently, systemic toxic side effects can be excluded. More recently various excipients could be identified as potent efflux pump inhibitors which can be subdivided into low molecular mass efflux pump inhibitors and polymeric efflux pump inhibitors (Chapter 7). Certain polymeric... 

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. 

Dosage Forms Lipid Excipients Table 3 Lipid permeation enhancers... 

Because of its potential damage to the membrane, permeation enhancers elicit great safety concern, especially in chronic therapy. Some of these include (l)potential tissue irritation and damage, (2) effect of the enhancer on structural integrity of the mucosal membrane, (3 Reversibility of membrane perturbation, (4) long-term effect of continued exposure to the enhancer, and (5)potential to also enhance absorption of any potential harmful substances that are also present in the intestine. All these issues may have significant toxicity ramifications. Therefore, the FDA has not approved any permeation enhancer, although use of some common excipients that are reported to enhance absorption may be acceptable (Table 18.8). 

In the design of TDDS, the skin permeability often needs to be enhanced by various approaches including the use of skin permeation enhancers to reduce the barrier property of the skin. In the absence of permeation enhancers, systemic delivery of most drugs through the skin is limited, primarily because of the barrier function of the stratum corneum. Certain enhancers including some terpenes have a tendency to form eutectics when mixed with certain chemical entities. Terpenes are a group of chiral skin penetration enhancers that are derived from plant essential oils and are widely used as pharmaceutical excipients with various drugs. Terpenes are... 

Uses Excipient, amphiphilic oil, permeation enhancer, coemulslfierforphamtaceu-tlcals, creams, ointments, gels, and lotions Trade Names Labrafac PC... 

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