Azone absorption enhancers

Nevertheless, there are reports on enhancement of ocular drug absorption by bile salts [33], surfactants [200], and chelators [149], Newton et al. [35] demonstrated that Azone, an enhancer widely tested in transdermal drug delivery [201], increased the ocular absorption of cyclosporine, an immunosuppressant, by a factor of 3, thereby prolonging the survival of a corneal allograft. In 1986, Lee et al. [34] reported that 10 pg/mL cytochalasin B, an agent capable of condensing the actin microfilaments, increased the aqueous humor and iris-ciliary body concentrations of topically applied inulin (5 kDa) by about 70% and 700%, respectively, in the albino rabbit. 

Kurosaki Y, TakatoriT, KitayamaM, Nakayama T, Kimura T (1988b) Application of propranolol to the keratinized oral mucosa Avoidance of first-pass elimination and the use of 1 -dodecylazacycloheptan-2-one (Azone) as an absorption enhancer of bioadhesive film-dosage form. J Pharmacobiodyn 11 824—832... 

K. Sugibayashi, K. Hosaya, Y. Moromoto, and W. Higuchi, Effect of the absorption enhancer azone on the transport of 5 fluorouracil across hairless rat skin, J. Pharm. Pharmacol. 37 578-580 (1985). 

Azone (l-Dodecylazacycloheptan-2-one) and related compounds have been studied as transdermal penetration and oral absorption enhancers. Although some efficacy has been shown, an emulsifying agent appears to be necessary for azone to penetrate the intestinal mucosal membrane in order to promote drug absorption. One study reported the absence of gross morphological damage after exposure of mucosa to azone but additional information on the effect of azone on overall mucosa structure is not avalable. 

The combined effect of (3-CyD with absorption enhancers such as sodium glycocholate or Azone on the nasal absorption of human fibroblast interferon- 3 in powder form in rabbits has been described. HP- 3-CyD was useful as a biocompatible solubilizer for lipophilic absorption enhancers involved in the nasal preparations of peptides.When insuUn was admiifistered nasally to rats, simultaneous use of an oily penetration enhancer, HPE-101, (l-[2-(decylthio)-ethyl]azacyclopentane-2-one) or oleic acid solubilized in HP-(3-CyD showed a marked increase in serum immuno-reactive insulin levels and marked hypoglycemic (Figure 40.11). The potentiation of the enhancing effect of HPE-101 by HP-(3-CyD can be explained by the facilitated transfer of HPE-101 into the nasal mucosa. Studies on the release of membrane proteins and scanifing electron microscopic observations of rat nasal mucosa indicated that the local mucosal damage due to the combination with HP- 3-CyD may not be serious obstacles to their safe use. 

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. 

Kurosaki Y, Hisaichi S, Nakayama T, Kimura T (1989a) Enhancing effect of l-dodecylazacycloheptan-2-one (Azone) on the absorption of salicylic acid from keratinized oral mucosa and the duration of enhancement in vivo. Int J Pharm 51 47-54... 

Other Toxicity Concerns. Additional toxicity concerns include interference with normal metabolism and function of mucosal cells, for example, water absorption by these cells [80]. The unconjugated bile acids are known to block amino acid metabolism [81] and glucose transport [82]. There is a possibility of biotransformation of these enhancers to toxic or carcinogenic substances by hepatic monooxygenases [83]. Absorption of permeation enhancers into the systemic circulation can also cause toxicity, for example, azone [84] and hexamethylene lauramide [85] which are absorbed... 

Azone (laurocapram) is used extensively as a transdermal permeation enhancer, and has also found use in buccal drug delivery. It is a lipophilic surfactant in nature (Figure 10.4). Permeation of salicylic acid was enhanced by the pre-application of an Azone emulsion in vivo in a keratinized hamster cheek pouch model [35]. Octreotide and some hydrophobic compounds absorption have also been improved by the use of Azone [36], Azone was shown to interact with the lipid domains and alter the molecular moment on the surface of the bilayers [37], In skin it has been proposed that Azone was able to form ion pairs with anionic drugs to promote their permeation [38],... 

Nicolazzo et al. [52] considered the use of the lipophilic skin penetration enhancers, octisalate and padimate (both used in sunscreens), in comparison to Azone on the buccal absorption of various drugs in vitro. They were found to have limited effect in enhancing the permeation of triamcinolone acetonide (although some increase in tissue uptake was proposed in some cases) relative to Azone, while reducing the penetration of estradiol and caffeine. One interesting report is that of the effect of capsaicin from capsicum, a commonly used food ingredient, which has been reported to enhance the permeability of sulfathiazole in human volunteers [53] presumably by a direct irritation effect on the mucosa. This raised an interesting issue of the effect of diet on oral mucosal permeability. 

Wiechers, J.W. 1989. Absorption, distribution, metabolism, and excretion of the cutaneous penetration enhancer azone. PhD thesis, University of Groningen. 

A second and potentially more potent enhancer of percutaneous absorption that has received much attention in recent years is Azone. Compressional investigation of monolayers consisting of Azone and DPPC have revealed much regarding its possible mechanism of action as an enhancer. The effect of Azone on the LC/LE phase transition of DPPC is very much greater than that of OA (the transition being abolished completely on incorporation of 30% Azone),... 

On the other hand, SEPA (2-n-nonyl-l,3-dioxolane) has been shown to be a more versatile penetration enhancer in terms of its ease of formulation, chemical stability and its ability to enhance the skin penetration of a wide variety of compounds of varying physicochemical characteristics. Permeants that have been evaluated include indomethacin, ibuprofen, minoxidil, acyclovir, caffeine, econazole, papaverine, progesterone and estradiol. The degree of skin penetration enhancement using SEPA is dependent on the physicochemical characteristics of the permeant. For example, following application of indomethacin in a simple ethanol-propylene glycol vehicle to human skin in vitro, cumulative absorption over 24 h amounted to 0.7 percent of the applied dose. The addition of 2 percent SEPA to the vehicle increased the 24 h absorption value to 23 percent of the applied dose (Marty et al. 1989). Furthermore, in comparative studies between SEPA and Azone, SEPA was shown to be a more effective human skin permeation enhancer for indomethacin (Figure 14.6, Marty et al. 1989). 

Baker, E. J., and J. Hadgraft. 1995. In vitro percutaneous absorption of arildone, a highly lipophilic drug, and the apparent no-effect of the penetration enhancer Azone in excised human skin. Pharm. Res. 

Pure Azone is poorly absorbed in hiunans, and the small amount of azone absorbed is cleared rapidly by the kidneys (Wiechers et al., 1987). Azone is usually used in combination with a solvent (Table 12.5). An extensive review covering the entire in vivo and clinical studies with azone as a percutaneous penetration enhancer has been published (Hadgraft et al., 1993). The percutaneous absorption of 2 3 -dideox-yinosine in rats was higher when the skin was pretreated with azone (Mukherji et al., 1994). Enhanced percutaneous absorption of methotrexate was shown using azone in combination with PG (Chatteijee etal., 1997). The disposition and metabolic profile of azone was also reported in vivo in animals and humans (Wiechers et al., 1990). 

Table 12.5 Summary of In Vitro Percutaneous Absorption of Drugs Using Azone as a Penetration Enhancer...

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