Permeability-Enhancing Excipients

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 

Guidance for industry. Extended release oral dosage form development, evaluation, and application of in vitro/in vivo correlations, http //www.fda.gov/cder/guidance/ index.htm. 

Guidance for industry. Waiver of in vivo bioavailability and bioequivalence studies for immediate release solid oral dosage forms based on a bioplrannaceutics classification system. CDER/FDA, August 2000. 

Lobenberg R, Amidon GL. Modern bioavailability, bioequivalence and biophannaceutics classification system. New scientific approaches to international regulatory system. Eur J Pharm Biopharm 2000 50 5-12. 

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Oral bioavailability is generally very low, ranging from 1 to 3%. Ongoing studies, however, indicate that oral bioavailability can be increased by the appropriate release of drug and permeability-enhancing excipients [59]. PONs have also been administered via subcutaneous, intradermal, and pulmonary application routes. 

Where an unusual excipient is chosen, or where an established excipient is chosen for a dosage form that results in its administration by a novel route of administration, then additional data will need to form part of the application. In effect, a novel excipient will need to be supported by data similar to those required for a new drug, with full supporting data including composition, function, and safety. Novel excipients include the components of the matrix in prolonged release products, new propellants, and new permeability enhancers. The exception to this need for extensive supporting data would be for a material already approved for food use and administered by the oral route or a material already approved for cosmetic use with a topical route of administration. In all cases the quality of the excipients has to be described adequately and shown to be satisfactory (which will depend on its role). 

Nasal drug absorption can be accomplished by use of prodrugs, chemical modification of the parent molecule, and use of physical methods of increasing permeability. Special excipient used in the nasal preparations comes into contact with the nasal mucosa and may exert some effect to facihtate the drug transport. The mucosal pores are easier to open than those in the epidermis. The following characteristics should be considered in choosing an absorption enhancer ... 

Co-administration of ofloxacin and chitosan in eyedrops increased the bioavailabUity of the antibiotic [290]. Trimethyl chitosan was more effective because of its solubility (plain chitosan precipitates at the pH of the tear fluid). On the other hand, N-carboxymethyl chitosan did not enhance the corneal permeability nevertheless it mediated zero-order ofloxacin absorption, leading to a time-constant effective antibiotic concentration [291]. Also W,0-carboxymethyl chitosan is suitable as an excipient in ophthalmic formulations to improve the retention and the bioavailability of drugs such as pilocarpine, timolol maleate, neomycin sulfate, and ephedrine. Most of the drugs are sensitive to pH, and the composition should have an acidic pH, to enhance stability of the drug. The delivery should be made through an anion exchange resin that adjusts the pH at around 7 [292]. Chitosan solutions do not lend themselves to thermal sterilization. A chitosan suspension, however. 

Solvents used to increase solubility for compounds during screening of permeability across the cell monolayers, together with commonly used excipients for formulations, can also affect the barrier as they contain ingredients which enhance drug absorption [100, 151]. There are different mechanisms by which these compounds can modulate the barrier [4, 149, 150] for example, they may increase the tight junctional pathway inhibiting carrier-mediated transport, or cholesterol... 

While there are limitations associated with the use of an in vitro permeability model for assessing the transport of compounds across the buccal mucosa, it can still be useful in assessing and comparing the permeability of compounds under different conditions, such as pH, temperature, and osmolarity, which provide valuable information on the mechanisms involved in drug transport. Additionally, the preliminary effects of potential chemical penetration enhancers or formulation excipients may be assessed, and these may provide a substantial rationale for subsequently assessing the effect of these agents in man. 

Membrane transporters are excipients that enhance permeability of a drug across the gastrointestinal (GI) epithelium by increasing the flux across the membrane. As illustrated in Figure 3, the enhancement could occur as a result of receptor-mediated... 

The permeability of two peptides, P-gp substrate and non P-gp substrate, across caco-2 cells in the presence or absence of polysorbate 80 and cremophor EL, commonly used surfactants in pharmaceutical formulations, was investigated. The permeability of the P-gp substrate peptide across caco-2 cells was enhanced in the presence of polysorbate 80 and cremophor EL, whereas the non-P-gp substrate peptide was not affected by these surfactants [94]. Another commonly used lipidic excipient that has been shown to inhibit P-gp mediated efflux is D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS) [95]. The insertion of a known CYP3A4 and P-gp inhibitor to the formulation is another approach to elevate bioavailability. 

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. 

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