Penetration enhancement ethanol

As recently reviewed by Gupta and Garge (2002), there are some materials known to penetrate the skin readily and appear to be capable of acting as penetration enhancers for certain selected drugs. These enhancers sometimes work more effectively in the presence of solvents such as ethanol or propylene glycol. A well-known example is the use of the insect repelent DEET (N,N diethyl-m-toluamide) as an enhancer for corticosteroids or the use of isopropyl myristate and propylene glycol for diclofenac sodium. Indeed, cyclodextrins have also been employed as penetration enhancers for hydrocortisone although how this system functions is not easy to visualize (see later section on cyclodextrins). 

Morimoto, EL, et al. 2002. In vitro skin permeation of morphine hydrochloride during the finite application of penetration-enhancing system containing water, ethanol and 1-menthol. Biol Pharm Bull 25 134. 

Vaddi, H.K., et al. 2003. Oxide terpenes as human skin penetration enhancers of haloperidol from ethanol and propylene glycol and their modes of action on stratum corneum. Biol Pharm Bull 26 220. 

Figure 16 CH2 asymmetric stretching frequencies, VajCH2 (originating from the SC lipids), as a function of SC weight removed, following treatment with ethanol alone (O) or 5% (v/v) [ H] oleic acid in ethanol ( ). Mean SD, n = 7 or 8. (From Ref. 153. Reprinted from Journal of Controlled Release, 37, Naik et al. Mechanism of oleic acid-induced skin penetration enhancement in vivo in humans, pp. 299-306,1995, with kind permission from Elsevier Science, NL, Sara Burgerhartstraat 25, 1055 KV, Amsterdam, The Netherlands.)...

Transdermal delivery is a case in point. The skin, particularly the stratum corneum presents a formidable barrier to diffusion. Materials used to enhance its permeability have ranged from simple solvents such as ethanol or propylene glycol to aromatic chemicals such as terpenoids. Such penetration enhancers appear to work by disrupting the lipid domains in the stratum... 

Ethanol and aqueous ethanol solutions of various concentrations (see Sections 8 and 17) are widely used in pharmaceutical formulations and cosmetics see Table 1. Although ethanol is primarily used as a solvent, it is also employed in solutions as an antimicrobial preservative. Topical ethanol solutions are also used as penetration enhancers " and as disinfectants. Ethanol has also been used in transdermal preparations in combination with Labrasol as a 7)... 

Verma DD, Fahr A. Synergistic penetration enhancement of ethanol and phospholipids on the topical delivery of cyclosporin A. Controlled Release 2004 97(1) 55-66. 

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]. 

Morimoto Y, WadaY, Seki T, and Sugihayashi K In Vitro Skin Permeation of Morphine Hydrochloride During the Finite Application of Penetration-Enhancing System Containing Water, Ethanol and 1-menthol. Biol Pharm Bull 2002 25 134-136. 

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). 

Perfusion of skin with transdermal-penetration-enhancing agents such as ethanol, DMSO-ds and propylene glycol was studied by in vitro P NMR [39]. Epidermal strips from abdominal pig skin were placed in a 10 mm O.D. NMR tube modified for continuous perfusion with buffered salt solution and a serial spectra were recorded on a Broker AMX500 spectrometer. Signal intensities for phosphomono- and di-esters PME and PDE, phosphocreatine PCr, inorganic phosphate Pi and nucleotide triphosphorate, >3-NTP were followed in time. Additional spectra were recorded when the perfusion medium contained dexamethasone. The dexamethasone perfusion resulted in a dose-dependent decrease in PCr and NTP levels and had an effect on PME metabolism. 

Manabe, E. Sugibayashi, K. Morimoto, Y. Analysis of skin penetration enhancing effect of drugs by ethanol-water mixed systems with hyrodynamic pore theory. Int. J. Pharm. 1996, 129, 211-217. 

DSC may also be used to determine the properties of lipid delivery systems, to facilitate penetration into the skin. Ethosomes are composed of phospholipids, ethanol and water to facilitate transdermal delivery because ethanol is a well known penetration enhancer. DSC curves comparing ethosomes and liposomes without ethanol showed transitions at -15.2 °C and 6.3 °C, respectively. This suggests that the ethosomes could be in a more fluid state. Further investigation showed that the increased fluidity may be attributed to the particle size and the fact that the phospholipid is solubilized in the ethosomal system. Even small amounts of ethanol are capable of disrupting the lipid bilayers and increasing fluidity... 

Penetration into the skin can be enhanced by penetration enhancers. These excipients diffuse into the stratum comeum and interact with components of this layer. The barrier function of the skin decreases. The effect of penetration enhancers is based on two mechanisms. The penetration enhancer can change the stracture of the stratum comeum or the solubility of the active substance in the skin. Penetration enhancers should not damage the underlying skin layers and should not be toxic or allergenic. Moreover, the effect must be reversible. Because of the different properties and mechanisms of action of penetration enhancers it is difficult to predict which enhancer will be most effective for the penetration of a specific active substance. Substances such as dimethyl sulfoxide (DMSO), salicylic acid, urea, propylene glycol, ethanol, isopropyl alcohol and many acids can act as penetration enhancers. 

Skin penetration of benzoic acid was significantly enhanced by all three volatile oils. In combination with ethanol and propylene glycol the amount of benzoic acid was increased, but the permeability coefficients were decreased. In conclusion, cinnamon oil, eugenia oil, and galangal oil might be used as percutaneous penetration enhancers for benzoic acid. 

Vesicle systems, described as ethosomes composed of phospholipid, ethanol, and water, have been shown to enhance the transdermal delivery of minoxidil and testosterone when compared to more traditional formulations (Fig. The quantities of drug penetrating... 

Consequently, eliminating aU or part of the stratum corneum drastically enhances the absorption of physical and chemical agents that could not have penetrated an intact protective stratum corneum. The ability of a product to penetrate the skin also depends on how it interacts with the corneocytes and the intercellular matrix. At the same molecular weight, a proteolytic product will penetrate the skin more readily than a product that is not proteolytic. The more liposoluble a molecule is, the greater its partition between the vehicle and the skin barrier and as a result its ability to penetrate is improved. Another factor to be taken into account is how solvents interact ethanol diffuses better in the stratum corneum when it is mixed with oil rather than water. How well hydrated the stratum corneum is also plays an essential role in the skin s absorption capacity. When the stratum corneum is hydrated, products can be absorbed up to 10 times more efficiently. Hydration swells... 

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