Permeability penetration enhancers

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. 

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. 

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]. 

Figure 8 (A) In vitro permeability of candidate drug molecules in the presence of synergistic combinations of penetration enhancers (SCOPE) formulations. Open circles indicate passive skin permeability and closed circles indicate skin permeability in the presence of SCOPE formulations as a function of the molecular weight of the solute. (B) In vivo delivery of leuprolide acetate, a synthetic analogue of LHRH in hairless rat model, y-axis shows blood plasma concentration of leuprolide acetate as a function of time for control formulation (open circles) and SCOPE formulation (closed circles). Abbreviation-. LHRH, luteinizing hormone-releasing hormone.

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. 

Penetration enhancers have been used to facilitate the absorption of higher molecular weight molecules. The mode of action of the surfactant enhancers is often attributed to membrane damage [37]. However, studies in epithelial cell monolayers suggest that some surfactant-based absorption enhancers act primarily by increasing the permeability of tight junctions [38]. Nevertheless, except for the chelators and nonsurfactants, which exert their... 

This approach consists of transiently increasing the permeability characteristics of the cornea by appropriate substances, known as penetration enhancers or absorption promoters. It bears a strict analogy to techniques aimed at facilitating drug penetration through the skin and other epithelia such as the buccal, nasal, intestinal, or rectal. 

Action on the membrane components Numerous studies have shown that the passive transcellular transport of hydrophilic compounds, including macromolecules such as peptides, can be enhanced by interaction of the penetration enhancers with both the phospholipid bilayer and the integrated proteins, thereby making the membrane more fluid and thus more permeable to both lipophilic and hydrophilic compounds. 

In order to increase the number of drugs which can be administered transdermally, the barrier function of the skin must be reduced. The kinetic model can be used to assess the role of a penetration enhancer as a function of the physicochemical properties of the drug. In its simplest form a penetration enhancer may be considered to act in one of two ways. Firstly it may increase the permeability of the skin and, secondly, it may additionally modify the partitioning characteristics at the stratum corneum-viable tissue interface. For illustration, two enhancers have been arbitrarily chosen, the first PE1 increases the permeability by a factor of 10, i.e. k- is increased ten fold. The second, PE2, increases k- by a factor of 10 and decreases kg by a similar amount. Thus PE2 additionally reduces the partition coefficient by a factor of 10. The relative effects can be seen by considering two model drug... 

Penetration enhancers have been investigated for most mucosal and epithelial routes (see Sections 6.7.4, 8.5.3 and 9.7.1 for further details). The major challenge that remains is to find enhancers that will reversibly increase membrane permeability without causing toxicity during long-term use. Various surfactants and protease inhibitors have been reported to increase the pulmonary absorption of peptides and proteins on an experimental basis but their clinical use is not established and the current general consensus seems to be against their inclusion in pulmonary formulations. 

Although, as described above, the vagina is permeable to many peptides and proteins, in most cases the bioavailability is insufficient for systemic therapy and is also highly variable. Penetration enhancers may be used to promote peptide absorption across the vaginal epithelium. However, less extensive investigations on the use of penetration enhancers for the vaginal route have been carried out in comparison to other routes, such as intranasal and transdermal (see Sections 9.7.1 and 8.6.1). 

Penetration Enhancers The transport process across the corneal tissue is the rate-limiting step in ocular drug absorption. Increasing the permeability of the corneal epithelium by penetration enhancers is likely to enhance the drug transport across the corneal tissues and therefore improve ocular bioavailability of the drug. 

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. 

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