Oral absorption enhancement

Absorption can be enhanced via several mechanisms. These include increased membrane fluidity, chelation of the calcium ions that serve to maintain the dimension of the intercellular space, solubilization of the mucosal membrane, enhancement in water flux, and reduction of the viscosity of the mucus layer adhering to the epithelial cells. A discussion of various types of pentration enhancers and their mechanism (s) of action is given in Chapter 8 (Section 8.7.1). Table 6.4 summarises the oral absorption enhancers that have been tested for oral dmg delivery. 

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. 

As already outlined above, P-glycoprotein is constitutively expressed in several organs, such as kidney, liver, intestine, and also at the blood-brain barrier. P-gp substrates therefore show poor oral absorption, enhanced renal and biliary excretion, and usually do not enter the brain [28]. This spurred the development of medium- and high-throughput systems addressing the P-gp substrate properties of compounds of interest. These systems mostly rely on transport studies through a monolayer of P-gp expressing Caco-2 [29] or MDCK cells [30]. In parallel, in silico methods have also... 

The uses of carrier-mediated bile acid for drug delivery purposes can be divided in three groups liver- and gallbladder-directed delivery, oral absorption enhancement, and lowering serum cholesterol. Oral absorption enhancement can be directed to either the liver or gallbladder or systemic delivery. 

Figure 11.9. Oral absorption enhancement of cyclosporine A in the rat model using quaternary ammonium cetyl poly(ethylenimine) nanomedicines. Mean cyclosporine A blood levels in rats following oral dosing (10 mg kg ) of cyclosporine A suspension in water (open circles) or cyclosporine A and quaternary ammonium cetyl poly(ethylenimine) in a polymer, drug weight ratio of 5 1,+ = statistically significant difference (p < 0.05).

Different micelle formulations based upon the amphiphilic polymer poly(ethylenimine), PEI, loaded with cyclosporine A and formed into tablets were tested for comparative drug absorption against CsA-in-water and CsA-microemulsion in a rat model by Le and colleagues [34]. Various PEI-CsA nanoparticles were examined, which differed based on linear or branched formations of the polymer. They determined that polymer hydrophobicity was the primary determinant to enhance CsA encapsulation and oral CsA absorption (bioavailabihty), and not polymer molecular weight or polymer branching. Polymers need at least 10% of their monomers to exhibit hydrophobicity in order to encapsulate sufficient drug and enable oral absorption enhancement. In this study, only the most hydrophobic PEI-CsA nanoparticles produced significantly enhanced CsA absorption compared to CsA-in-water, but none were superior to CsA-ME. 

Another new development has been the application of oral absorption promoters. These materials are designed to enhance the oral bioavailability of many compounds and improve variable absorption. However, many of these compounds are hydrophobic in nature and cause difficulty during tableting itself. The challenge for formulators is to arrive at clever solutions to the process problems while retaining material performance. 

Ethanol has long been employed as a solvent in pharmaceuticals. Since it also acts as a preservative and flavoring agent, it is second only to water in its use in liquid preparations. It has also been suggested that it may enhance the oral absorption of some active ingredients [71],... 

Naesens, L., Clercq, E. de, Van den Mooter, G., Kinget, R., Augustijns, P., Inhibition of intestinal metabolism of the antiviral ester prodrug bis(POC)-PMPA by nature-identical fruit extracts as a strategy to enhance its oral absorption an in vitro study, Pharm. Res. 1999, 16, 1035-1040. 

In spite of its limitations, the ACAT model combined with modeling of saturable processes has become a powerful tool in the study of oral absorption and pharmacokinetics. To our knowledge, it is the only tool that can translate in vitro data from early drug discovery experiments all the way to plasma concentration profiles and nonlinear dose-relationship predictions. As more experimental data become available, we believe that the model will become more comprehensive and its predictive capabilities will be further enhanced. 

Based on the observation that pefloxacin (iV-methylnorfloxacin) exhibits enhanced in vivo activity upon oral administration (although it is less active in vitro) relative to norfloxacin, the same promoiety was investigated as an approach to blocking the secondary amine group, which seems to be associated with reduced oral absorption. Indeed, compound (78) was shown to produce about 5-fold higher serum levels of norfloxacin, after oral administration to mice than did the parent drug, itself. 

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... 

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... 

Thanou M, Verhoef JC, Junginger HE (2001) Oral drug absorption enhancement by chitosan and its derivatives. Adv Drug Del Rev 52 117-126... 

Crowley, P. J. Martini, L. G. Enhancing oral absorption in animals. Curr Opin Drug Discov Dev 2004, 4, 73-80. 

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