Penetration enhancers toxicity

Irritation is veiy subjective and may differ widely from treatment to control subjects. Most irritation occurs as a result of penetration enhancers. Evaluation of toxicity and irritation should be concerned with mucosal tissue irritation, the extent of damage to the mucosal cells, and the rate of recovery. 

Sasaki H, Kojima M, Nakamura J, Shibasaki J. Acute toxicity and skin irritation of pyr-rolidone derivatives as transdermal penetration enhancers. Chem Pharm Bull 1990 38 2308-2310. 

Wong, O., et al. 1989. Unsaturated cyclic ureas as new non-toxic biodegradable transdermal penetration enhancers. II. Evaluation study. Int J Pharm 52 191. 

Furthermore, addition of a penetration enhancer to the vehicle of an ophthalmic solution has been used to reduce the size of the drop instilled. Since this reduction in drop size results in a decreased washout and systemic drug loss, this would result in a decreased potential for systemic toxicity, at the same time improving the ocular absorption of poorly absorbed drugs [109], Therefore, improved ocular bioavailability and therapeutic response could be obtained. 

Chetoni, P., et al. 2003. Ocular toxicity of some corneal penetration enhancers evaluated by electrophysiology measurements on isolated rabbit corneas. Toxicol In Vitro 17 197. 

Penetration enhancers have been investigated for most mucosal and epithelial routes (see Sections 6.7.4, 8.5.3 and 9.7.1 for further details). The major challenge that remains is to find enhancers that will reversibly increase membrane permeability without causing toxicity during long-term use. Various surfactants and protease inhibitors have been reported to increase the pulmonary absorption of peptides and proteins on an experimental basis but their clinical use is not established and the current general consensus seems to be against their inclusion in pulmonary formulations. 

Finally, it should be noted that during the last decade both weakly crosslinked poly(acrylic acid) derivatives and chitosan derivatives were described as safe penetration enhancers for hydrophilic compounds especially as they can trigger mechanisms of tight junction opening of mucosal tissues and did not show acute toxicity. Poly(acrylic acid) derivatives were shown to have excellent mucoadhesive properties and can inhibit the activity of gut enzymes, such as trypsin, chymo-trypsin, and carboxypepsidases. Chitosan salts and Ni-trimethylchitosan chloride revealed to be potential absorption enhancers for nasal absorption of calcitonin and insulin and for the intestinal absorption of buserilin.f ... 

Cytotoxicity Issues. As with renal toxicity, the various derivatives show dramatically different hemolytic behaviors. The dimethyl derivative shows substantial hemolysis more than even the parent p-CD. This is well illustrated in Fig. 10 where the percentage of cells imdergoing hemolysis is shown as a function of CD concentration. Hemolysis started at concentrations below 0.1% for the DM-p-CD. Four to five times higher concentrations of p-CD are required to give the same hemolysis. This behavior is in agreement with the demonstration of DM-p-CD as a penetration enhancer in skin " and nasal tissue. ... 

The chemical composition of liposomes is an important parameter for their transdcrmal penetration. The most common phospholipid used for tlie preparation of topically applied liposomes is egg or soy derived phosphatidylcholine in mixtures with cholesterol. Phosholipids are very-attractive molecules for skin treatment as they combine penetration enhancement with skin hydration properties due to their tendency to bond water molecules. Their low toxicity makes them even more suitable for topical formulations. 

An approach published in 2001 based on research out of the Klibanov laboratory at MIT is to use ethanol [5]. Ethanol, isopropanol, and other alcohols have long been used successfully as penetration enhancers for medical applications. Ethanol is one of the first molecules to have been used as a transdermal enhancer, because its effects are so easily and well characterized and its systemic and local toxicities are understood. It is currently contained in commercial delivery systems for estradiol [17] and other bioactive molecules. Ethanol and isopropanol have been used in a variety of studies based on their effects on drug transport. More applications can be found in the patent literature [18]. 

Kenneth A. Walters, PhD, is director of An-eX Analytical Services Ltd and an honorary lecturer in pharmaceutical chemistry at the Welsh School of Pharmacy. His research interests are biological membrane penetration enhancement and retardation, particularly with respect to skin. He has experience at Fisons Pharmaceuticals, Eastman Pharmaceuticals (a division of Eastman Kodak Company) and Controlled Therapeutics Ltd. (Scotland). Dr. Walters has published many articles and reviews and has co-edited two volumes on skin penetration enhancement and dermal toxicity. He is a charter member of the American Association of Pharmaceutical Scientists and also a member of the Society of Investigative Dermatology, the Controlled Release Society, the Society of Toxicology and the Society of Cosmetic Scientists. 

In Vivo Efficacy and Dermal Toxicity of Terpenes Used as Penetration Enhancers... 

Azone (l-dodecylazacycloheptan-2-one, laurocapram), along with its derivatives are probably the most widely investigated penetration enhancers and are effective at low concentrations for both lipophilic and hydrophilic drugs but suffer from toxicity problems. Azone is a hybrid of a cychc amide with an alkyl sulfoxide, and its chemical structure has a long alkyl chain and a lactam group (Wilhams and Barry,... 

The flux enhancement and the toxicity of azone and its derivatives with the hydrocarbon chain lengths from C2 to C16 were investigated. The in vitro cytotoxicity as well as the flux increased from C2 to C8, then remained constant from C8 to C14, and subsequently decreased with increasing alkyl chain length. This shows that, with these compounds, a parallehsm exists betweai skin cell toxicity and penetration-enhancing capacity (Ponec etal., 1989). The in vitro percutaneous absorption enhancement of different drugs with Azone is presented in Table 12.5. 

Sasaki, H., Kojima, M., Nakamura, J., and Shibasaki, J. (1990a). Acute toxicity and skin irritation of pyrrolidone derivatives as transdermal penetration enhancer, Chem. Pharm. Bull, 38 2308-2310. 

Williams, A.C. and Barry, B.W., Chemical penetration enhancement, in Dermal Absorption and Toxicity Msessment (M.S. Roberts and K.A. Walters, eds.). New York Dekker, pp. 297-312, 1998. 

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