Penetration enhancement fatty acids

Many other papers have described the use of DSC in the predication of penetration eidiancement using the following penetration enhancers oleic acid/propylene glycol [20], straight chain fatty acids, monosaturated and polyunsaturated fatty acids [21], carvone [22], menthol [23], 5-aminolevulinic acid [24], and phospholipids [25]. 

For a good therapeutic effect the choice of the active substance and the choice of the vehicle are important. Physical and chemical factors play an important role. The solubility of the active substance in the vehicle and the concentration, the size of the molecule of the active substance, the partition between vehicle and skin, the particle size (in case of suspensions) and the nature of the vehicle (aqueous or lipid) determine the penetration speed and depth. Hydrocortisone, for example, is more lipid soluble in the ester form (hydrocortisone acetate). The latter will penetrate into the skin faster and more complete. Hydrocarbons, such as soft and liquid paraffin, release lipophilic active substances only very slowly and substances formulated in these bases will penetrate only in limited amounts into the skin. Fatty oils (vegetable oils, triglycerides) are able to pass into the upper layers of the skin. Penetration enhancers (salicylic acid, dimethyl sulfoxide, propylene glycol, urea) increase the penetration of active substances into the skin. 

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-... 

A possible source of groundwater contamination, which has up to now almost been neglected, is associated with the introduction of surfactants into soils as pesticide additives (Table 6.7.3). Non-ionic surfactants composed of alcohols and fatty acids are most widely recommended as adjuvants to facilitate and enhance the absorbing, emulsifying, dispersing, wetting and penetrating properties of pesticides. Other pesticide adjuvants are silicone-based surfactants,... 

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. 

Penetration enhancers have different mechanisms of action depending on their physicochemical properties. Some examples of penetration enhancers and their mechanisms are bile salts (micellization and solubilization of epithelial lipids), fatty acids such as oleic acid (perturbation of intracellular lipids) [25,26], azone (l-dodecylazacycloheptan-2-one) (increasing fluidity of intercellular lipids), and surfactants such as sodium lauryl sulfate (expansion of intracellular spaces). The complete list of enhancers and their mechanism of actions are discussed in detail in Chapter 10. 

A wide variety of long-chain fatty acids increase transdermal delivery the most popular is oleic acid. It is relevant that many penetration enhancers contain saturated or unsaturated hydrocarbon chains and some structure-activity relationships have been drawn from the extensive studies of Aungst et al. [22,23] who employed a range of fatty acids and alcohols, sulfoxides, surfactants, and amides as enhancers for naloxone. From these experiments, it appears that saturated alkyl chain lengths of around Cio to C12 attached to a polar head... 

Aungst, B.J., N.J. Rogers, and E. Shefter. 1986. Enhancement of naloxone penetration through human skin in vitro using fatty acids, fatty alcohols, surfactants, sulfoxides and amides. Int J Pharm 33 2256. 

Aungst, B.J. 1989. Structure-effects studies of fatty acid isomers as skin penetration enhancers and skin irritants. Pharm Res 6 244. 

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. 

J. Engblom, S. Engstrom, and K. Fontell, The effect of the skin penetration enhancer Azone on fatty acid-sodium soap-water mixtures, J. Control. Rel. 33 299— 305 (1995). 

Penetration enhancers are substances that can increase the absorption of a co-administered dmg, and include surfactants, bile salts, chelating agents, and fatty acids. Penetration enhancers are widely used in dmg delivery to potentiate absorption across various types of epithelia, including the epithelium of the gastrointestinal tract. However, a major limiting factor in the general acceptance of absorption enhancers for improving oral dmg absorption is the non-specific nature of their effects. 

Penetration enhancers act by increasing the permeability of the corneal cell membrane and/or loosening the tight junctions between the epithelial cells, which primarily restrict the entry of molecules via the paracellular pathway. Classes of penetration enhancers include surfactants, bile salts, calcium chelators, preservatives, fatty acids, and some glycosides such a saponin. 

The fatty acids have received extensive interest as potential penetration enhancers [129]. Over the years, in addition to studies investigating the potential... 

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. 

The stratum corneum basically contains a mixture of cholesterol, free fatty acids, and ceramides, placed in multilayers. They mediate both the epidermal permeability barrier and the transdermal delivery of both lipophilic and hydrophilic molecules. Studies have shown that each of the three key lipid classes is required for normal barrier function (32). These reports also show the potential of certain inhibitors of lipid synthesis to enhance the trans-dermal delivery of drugs like lido-caine or caffeine. Thus, the modulation of stratum corneum lipids is an important determinant of the barrier permeability to both hydrophobic and hydrophilic compounds transport and drug penetration. It has been reported that an inverse correlation exists between solute penetration and stratum corneum lipid content (33). 

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. 

Some fatty acids, especially unsaturated fatty acids, are well-known skin penetration enhancers. It is also known that many fatty acids possess antimicrobial activity. The topical activity of the anti-viral drug acyclovir is hampered by its inadequate permeability through the skin barrier. Some reports have shown that fatty acid extract of cod liver oil as well as the extract in the form of an ointment show effective antiviral properties against herpes simplex virus (HSV-1) (37). 

Movement of penetrants across the mucous membranes is by diffusion. At steady state, the amount of a substance crossing the tissue per unit of time is constant and the permeability coefficients are not influenced by the concentration of the solutions or the direction of nonelectrolyte transfer. As in the epidermis of the skin, the pathways of permeation through the epithelial barriers are intercellular rather than intracellular. The permeability can be enhanced by the use surfactants such as sodium lauryl sulfate (a cationic surfactant). An unsaturated fatty acid, oleic acid, in a propylene glycol vehicle can act as a penetration enhancer for diffusion of propranolol through the porcine buccal mucosa in vitro. Delivery of biopharmaceuticals across mucosal surfaces may offer several advantages over injection techniqnes, which include the following ... 

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