Penetration enhancement

The reasons, therefore, for the excellent barrier properties of the skin are the tortuous route and that a penetrant has to cross sequentially a large number of rigid bilayers. The role of the lipids in topical delivery, how they control water transfer through the skin, and how biophysical techniques have been used to examine them have been reviewed [18-20]. 

To improve topical therapy, it is advantageous to use formulation additives (penetration enhancers) that will reversibly and safely modulate the barrier properties of the skin. Fick s first law of diffusion shows that two potential mechanisms are possible. The two constants that could be altered significantly are the diffusion coefficient in the stratum corneum and the concentration in the outer regions of the stratum corneum. Thus, one of mechanisms of action of an enhancer is for it to insert itself into the bilayer structures and disrupt the packing of the adjacent lipids, thereby, reducing the microviscosity. The diffusion coefficient of the permeant will increase This effect has been observed using ESR and fluorescence spectroscopy [16,17]. 

Inspection of equation (4.6) shows how the effect of an enhancer on the diffusional barrier may be quantified. If an experiment is conducted such 

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Cyclic sulfoxides, lactones, lactams, and other heterocycles as transdermal penetration enhancers 99CLY107. 

W. S. Halliday and D. K. Clapper. Purified paraffins as lubricants, rate of penetration enhancers, and spotting fluid additives for water-based drilling fluids. Patent US 5837655, 1998. 

In addition, data obtained from infrared, thermal, and fluorescence spectroscopic studies of the outermost layer of skin, stratum corneum (SC), and its components imply enhancer-improved permeation of solutes through the SC is associated with alterations involving the hydrocarbon chains of the SC lipid components. Data obtained from electron microscopy and x-ray diffraction reveals that the disordering of the lamellar packing is also an important mechanism for increased permeation of drugs induced by penetration enhancers (for a recent review, see Ref. 206). 

When diabetic rabbits (24) were treated with 50 IU of bovine insulin imbibed at 50 mg/g poly (acrylic acid) (Figure 14) no reduction in serum glucose over that achieved by the dry blend control could be detected. Pretreatment of the animals with oral doses of either a penetration enhancer, sodium taurocholate, or a protease inhibitor, aproteinin, failed to improve the insulin activity. One possible explanation for this unexpected lack of activity might be that the diseased animals exhibit impaired ileal absorption of fluids (25). 

Pharmaceutical Skin Penetration Enhancement, edited by Kenneth A. Walters and Jonathan Hadgraft... 

Penetration enhancers are low molecular weight compounds that can increase the absorption of poorly absorbed hydrophilic drugs such as peptides and proteins from the nasal, buccal, oral, rectal, and vaginal routes of administration [186], Chelators, bile salts, surfactants, and fatty acids are some examples of penetration enhancers that have been widely tested [186], The precise mechanisms by which these enhancers increase drug penetration are largely unknown. Bile salts, for instance, have been shown to increase the transport of lipophilic cholesterol [187] as well as the pore size of the epithelium [188], indicating enhancement in both transcellular and paracellular transport. Bile salts are known to break down mucus [189], form micelles [190], extract membrane proteins [191], and chelate ions [192], While breakdown of mucus, formation of micelles, and lipid extraction may have contributed predominantly to the bile salt-induced enhancement of transcellular transport, chelation of ions possibly accounts for their effect on the paracellular pathway. In addition to their lack of specificity in enhancing mem-... 

Although the ocular absorption of peptide as well as nonpeptide drugs is poor [96,196-198], the ocular route is by far the least studied for the usefulness of penetration enhancers. This is in part due to the perceived sensitivity of ocular tissues to irritation and the fear of corneal and conjunctival damage caused by the enhancers. Whereas the rat nasal epithelium may tolerate up to 5% sodium glycocholate [199], ocular administration of sodium glycocholate at a concentration of 2% and beyond induces reddening of the eye and tear production in rabbits (Kompella and Lee, unpublished observation). 

DD Tang-Liu, JB Richman, RJ Weinkam, H Takruri. (1994). Effects of four penetration enhancers on comeal permeability of chugs in vitro. J Pharm Sci 83 85-90. 

VHL Lee, A Yamamoto, U Kompella. (1991). Mucosal penetration enhancers for facilitation of peptide and protein drug absorption. CRC Crit Rev Drug Carrier Sys 8 91-192. 

Kompella, U.B. and Lee, V.H.L. 2001. Delivery systems for penetration enhancement of peptide and protein drugs design considerations. Advanced Drug Delivery Reviews 46, 211-245. 

Under normal conditions, the transcellular route is not considered as the preferred way of dermal invasion, the reason being the very low permeability through the corneocytes and the obligation to partition several times from the more hydrophilic corneocytes into the lipid intercellular layers in the stratum corneum and vice versa. The transcellular pathway can gain in importance when a penetration enhancer is used, for example, urea, which increases the permeability of the corneocytes by altering the keratin structure. 

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. 

The buccal mucosa does serve as an alternative route for administering compounds systematically however, to ensure particular compounds are candidates for delivery across this biological tissue, preclinical screening is essential. While in vivo human permeability studies are ideal, due to their costs and associated issues, it is necessary to perform such screening in vitro. Assessment of compound permeability across porcine buccal mucosa has been widely used and can provide the preclinical biopharmaceutical scientist with much information relating to permeability, routes of transport, and effects of various chemical penetration enhancers. 

Coutel-Egros A, Maitani Y, Veillard M, Machida Y, Nagai T (1992) Combined effects of pH, cosolvent and penetration enhancers on the in vitro buccal absorption of propranolol through excised hamster cheek pouch. Int J Pharm 84 117-128... 

Gandhi R, Robinson J (1992) Mechanisms of penetration enhancement for trans-buccal delivery of salicylic acid. Int J Pharm 85 129-140... 

Nicolazzo JA, Reed BL, Finnin BC (2004b) Modification of buccal drug delivery following pretreatment with skin penetration enhancers. J Pharm Sci 93 ... 

Sandri G, Poggi P, Bonferoni MC, Rossi S, Ferrari F, and Caramella C (2006) Histological evaluation of buccal penetration enhancement properties of chitosan and trimethyl chitosan. J. Pharm. Pharmacol. 58 1327-1336. 

Sandri G, Rossi S, Ferrari F, Bonferoni MC, Zerrouk N, Caramella C (2004) Mucoadhesive and penetration enhancement properties of three different grades of hyaluronic acid using porcine buccal and vaginal tissue, Caco-2 cell lines and rat jejunum. J Pharm Pharmacol 56 1083-1090. 

Williams AC, Barry BW (2004) Penetration enhancers. Adv Drug Deliv Rev 56 603-618. 

Little is known on the metabolic fate of l-methylpyrrolidin-2-one (5.60), an industrial solvent also useful as a solubilizing agent and a penetration enhancer in topical formulations. A preliminary investigation of the disposition and metabolism of labeled l-methylpyrrolidin-2-one in the rat showed that the compound is excreted mainly in urine [171]. Three urinary metabolites were detected, the major of which (ca. 15% of the dose) was 4-(methylami-no)but-2-enoic acid (5.61). This unsaturated product may likely have been formed by H20 elimination from a hydroxylated metabolite. 

The permeability of the colonic epithelimn may not be suffieient for aehieving a transport rate required for therapeutic activity. This hurdle may be overeome, at least in part, by using the penetration enhancers listed below [36]. 

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