Fatty acids permeation enhancers

Permeation enhancers are used to improve absorption through the gastric mucosa. Eor example, oral dehvery of insulin (mol wt = 6000) has been reported from a water-in-oH- emulsion containing lecithin, nonesterified fatty acids, cholesterol [57-88-5], and the protease inhibitor aprotinin [9087-70-1] (23). 

Ganem-Quintanar A, Quintanar-Guerrero D, Falson-Rieg F, Buri P (1998) Ex vivo oral mucosal permeation of lidocaine hydrochloride with sucrose fatty acid esters as absorption enhancers. Int J Pharm 173 203-210... 

Both interferon-a and - 3 have been shown to be absorbed across the rectal mucosa when given with the fatty acid linolenic acid as mixed micelles. In the absence of a permeation enhancer, rectally administered interferons (165 aa) do not achieve detectable levels in blood nor lymph. With 0.56% linolenic acid, a significant degree of lymphatic absorption of interferon-a and -P was detected [20]. The rectally absorbed interferon first distributes into the lymphatics, and interferon concentration is much higher in lymph than... 

Other fatty acids as absorption enhancers have been reported. Ogiso et al. [112] demonstrated that lauric acid (C12) produced the largest increase in permeation rate, penetration coefficient, and partition coefficient of propranolol. Onuki et al. [113] reported that docosa-hexaenoic acid (DHA) has a strong insulin permeability enhancement effect and little toxicity, compared to oleic acid and eicosapentaenoic acid (EPA) using a water-in-oil-in-water (W/O/W) multiple emulsion with no or little mucosal damage. 

Fatty acid esters would be predicted to have little irritation or toxic effects. Ex vivo permeability studies conducted in porcine buccal mucosa showed significant permeation enhancement of an enkephalin from liquid crystalline phases of glycerine monooleate [32]. These were reported to enhance peptide absorption by a cotransport mechanism. Diethylene glycol monoethyl ether was reported to enhance the permeation of essential oil components of Salvia desoleana through porcine buccal mucosa from a topical microemulsion gel formulation [33]. Some sucrose fatty acid esters, namely, sucrose laurate, sucrose oleate, sucrose palmitate, and sucrose stearate, were investigated on the permeation of lidocaine hydrochloride [34], with 1.5% w/v sucrose laurate showing a 22-fold increase in the enhancement ratio. 

CHg [CH2]16 CO OCH2 CHOH CH2OH Glyceryl monooleate FIGURE 10.3 Some fatty acid and fatty acid esters used as permeation enhancers. 

In the case of fatty acids, optimal penetration enhancement has been achieved with a chain length of approximately 9-12. In all cases correlation between the effect and chain-length was parabolic [102-106], Most probably this is due to a balance between the ability of the fatty acid to partition into the SC, which requires a certain degree of lipophilicity, and the ability to change the lipid organization in such a way that increased permeation is achieved when the penetration enhancer itself is in a fluid phase at physiological temperature. For example, long-chain unsaturated fatty acids are not able to create a fluid phase in the SC lipid domains, unless a eutectic mixture is formed with the SC lipids or unless the fatty acid is still dissolved in the solvent, in which it has been applied to the skin surface. 

C. K. Lee, T. Uchida, N. S. Kim, and S. Goto, Skin permeation enhancement of tegafur by ethanol/panasate 800 or ethanol/water binary vehicle and combined effect of fatty acids and fatty alcohols, J. Pharm. Sci. 82 1155-1159 (1993). 

In vitro skin permeation studies in a hydrodynamically well-calibrated skin permeation cell (Figure 4) demonstrated that simple pharmaceutical excipients, like capric acid (a saturated straight-chain fatty acid), can substantially enhance the trandermal permeation rate of progesterone. The time lag is significantly re-... 

It is interesting to note that the enhancement of skin permeation of drugs by fatty acid is dependent upon the alkyl chain length (Figure 6). In addition, the esterification of the carboxylic acid group reduces the effectiveness of fatty acids in skin permeation enhancement. The type of enhancer used and its concentration in the adhesive coating also play an important role in the extent of skin permeation (Figure 7). 

Figure 5. Enhancement in the skin permeation profiles of progesterone by various concentrations of capric acid, a saturated fatty acid, released from the adhesive coating layer.

Figure 6. Dependency of the enhancement factor for the skin permeation of progesterone on the alkyl chain length of saturated fatty acids with maximum enhancement at n=6, and the effect of esterification on skin permeation enhancement.

As the surface concentration of enhancer in the adhesive coating increased, the mechanism of skin permeation enhancement showed some changes as reflected in the relative contribution of fatty matrix and protein gel pathways (Table VII ). The behavior for azone and oleic acid at high concentration was observed to be identical to that at low concentration (compare the data in... 

Low molecular mass permeation enhancers include numerous classes of compounds with diverse chemical properties including detergents, surfactants, N-acetylated x-amino acids, N-acetylated non-a-amino acids, fatty acids, medium-chain mono- and diglycerides, acyl carnitine, alkanoyl cholines, Ca2 + chelating agents, zonula occludens toxins and NO donors. 

Longer chain fatty acids are also effective as intestinal permeation enhancers. Morishita et al. (1998), for instance, could significantly increase the in situ colonic absorption of insulin in rats utilizing emulsions (w/o/w) containing oleic, linoleic or linolenic acid. 

Strategies to eliminate the problem of degradation by nucleases are based on chemical modification such as phosphorothioates (Kurreck et al. 2002) or meth-oxyethyl phosphorothioates (Agrawal et al. 1995). Furthermore, the co-administration of permeation enhancers such as medium chain fatty acid turned out to be a promising strategy to increase the gastrointestinal uptake (Raoofet al. 2002). 

Strategies to overcome the absorption barrier focus on the other hand on low molecular mass permeation enhancers (Chapter 5) such as medium chain fatty acids, which can still be regarded as a kind of gold standard. As low molecular mass permeation enhancers are per se rapidly uptaken from the gastrointestinal mucosa, however, the macromolecular drug is to a considerable high extent left alone behind in the gastrointestinal tract. In addition, local and systemic toxic side effects of low molecular mass permeation enhancers cannot be excluded. In contrast, polymeric permeation enhancers (Chapter 6) are simply too big to be absorbed from the GI tract. Consequently, systemic toxic side effects can be excluded. More recently various excipients could be identified as potent efflux pump inhibitors which can be subdivided into low molecular mass efflux pump inhibitors and polymeric efflux pump inhibitors (Chapter 7). Certain polymeric... 

Transcellular transport Sorption promoters can be used to enhance the transcellular transport in the intestine, including bile salts and fatty acid esters. They tend to fluidize the lipid bilayer and enhance drug permeation across the membrane. 

Aungst, B. J. Fatty acids as skin permeation enhancers. In Percutaneous Penetration Enhancers. E. W. Smith and H. I. Maibach, eds. CRC Press Boca Raton, 1995 pp. m-1%1. 

Some fatty acids, especially unsaturated fatty acids, are well-known skin penetration enhancers. The addition of PC to dermal dosage forms has been reported to increase percutaneous absorption. Lipid disperse systems (LDSs) containing polar lipids, such as PC and glycosylceramide, are also useful for increasing the percutaneous permeation of drug through rat abdominal skin in both in vitro and in vivo systems. 

Stott PW, Williams AC, Barry BW. Mechanistic study into the enhanced transdermal permeation of a model beta-blocker, propranolol, by fatty acids A melting point depression effect. Int J Pharm 2001 219(1-2) 161-176. 

Morimoto K, Haruta T, Tojima H, Takeuchi Y. Enhancing mechanisms of saturated fatty acids on the permeations of indomethacin and 6-carboxyfluorescein through rat skins. Drug Dev Ind Pharm 1995 21(17) 1999-2012. 

Aungst BJ, Blake JA, Hussain MA. Contributions of drug solubilization, partitioning, barrier disruption, and solvent permeation to the enhancement of skin permeation of various compounds with fatty acids and amines. Pharm Res 1990 7(7) 712-718. 

Shin SC, Shin EY, Chow CW. Enhancing effects of fatty acids on piroxicam permeation through rat skins. Drug Dev Ind Pharm 2000 26(5) 563-566. 

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