Absorption enhancers damaging effects

One of the major questions in relation to absorption enhancers such as surfactants or sustained release products is their safety. Whether damage to lung tissue is caused by the different excipients is not yet clear. The results obtained so far are not very promising for substances like surfactants [39]. What the effects of repetitive administration of insoluble or slowly (bio)degrading particles might be, remains to be estabhshed. 

Therefore, the enhancement of transport is not accompanied by damage to the cells, which is superior to the absorption-enhancing effects of other small molecules, which lead to irreversible changes in the cell membrane and damage to the cell. Thus, much attention has been paid to chitosan as a polymeric substance that enhances GI absorption. 

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. 

They are believed to enhance the transbuccal permeation by a mechanism that is similar to that of bile salts, namely, extraction of lipids, protein denaturation, inactivation of enzymes, and swelling of tissues [39], Sodium dodecyl sulfate is reported to have a significant absorption enhancing effect but may also produce damage to the mucosa [13]. The effect of sodium... 

Many papers have been published on the use and efficacy of absorption enhancers for nasal peptide and protein delivery. The enhancing effect of bile salt seemed dependent on its lipophilicity The bioavailability of gentamicin increased with increasing lipophilicity of trihydroxy bile salts (cholate > glycocholate > taur-ocholate), and the enhancement of nasal insulin bioavailability followed the rank order of deoxycholate, chenodeoxycholate, and cholate. However, most studies reported severe damage of bile salts to the mucosa. Deoxycholate had the most ciliotoxic effect, whereas taurocholate had the least ciliotoxic effect. In the case of dihydrofusidates, a dose-dependent increase in bioavailability was reported for peptides such as insulin. 

Sodium salicylate and 5-methoxysalicylate increased the absorption of insulin. Sodium glycocholate was more effective than sodium taurocholate but less effective than sodium-deoxycholate and PE-9-laurylether in enhancing rectal insulin absorption in rabbits. The role of disodium EDTA in the enhancement of rectal drug absorption, along with the damaging effects on the rectal mucosa, has been described for several drugs. ... 

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. 

In Fig. 3, a standard experimental system in rats is shown. Drug solutions of 3-20 mL are continuously circulated through the nasal cavity of anesthesized rats, whereas the drug concentration in the solution is periodically determined by standard analytical procedures. The obtained disappearance kinetics can be used for predicting the in vivo rate of drug absorption. The method is also applicable to the assessment of the damaging effects of absorption enhancers on the nasal mucosa. 

A challenging issue in nasal delivery is related to the safety aspects of excipients, especially absorption enhancers, in the formulation. For most kinds of enhancers, a direct relationship exists between absorptionenhancing ability and local toxic effect. However, the efficacy of some kinds of absorption enhancers may not be necessarily related to their damaging effects on the nasal epithelium. Thus the establishment of a benefit-to-risk ratio for nasal absorption enhancers is of major importance. 

The combined effect of (3-CyD with absorption enhancers such as sodium glycocholate or Azone on the nasal absorption of human fibroblast interferon- 3 in powder form in rabbits has been described. HP- 3-CyD was useful as a biocompatible solubilizer for lipophilic absorption enhancers involved in the nasal preparations of peptides.When insuUn was admiifistered nasally to rats, simultaneous use of an oily penetration enhancer, HPE-101, (l-[2-(decylthio)-ethyl]azacyclopentane-2-one) or oleic acid solubilized in HP-(3-CyD showed a marked increase in serum immuno-reactive insulin levels and marked hypoglycemic (Figure 40.11). The potentiation of the enhancing effect of HPE-101 by HP-(3-CyD can be explained by the facilitated transfer of HPE-101 into the nasal mucosa. Studies on the release of membrane proteins and scanifing electron microscopic observations of rat nasal mucosa indicated that the local mucosal damage due to the combination with HP- 3-CyD may not be serious obstacles to their safe use. 

A systematic study in rats, in which the absorption-enhancing effects of a number of surfactants were compared, was reported by Hirai et al (1981a,b). The promoting effect of several nonionic surfactants was paralleled by their ability to lyse red blood cells and to release protein from the nasal mucosa of rats. Bile salts, however, were found to be less lytic and damaging to the rat nasal mucosa than nonionic ether-type surfactants. Generally, a positive correlation was observed between the damaging effect on the biomembrane and the absorption-promoting effect of the surfactants. 

Gill, I. J., Fisher, A. N., Hinchcliffe, M., Whetstone, J., Farraj, N., Ponti, R. D., and Dluin, L., 1994, Cyclodextrins as protection agents against enhancer damage in nasal delivery systems II. Effect on in vivo absorption ofinsulin and histopathology of nasal membrane, Eur. J. Pharm. Set 1 237-248. 

In some water supply areas, problems are experienced with the corrosion of old cast-iron water mains, such that iron (red-water) discolouration can become an aesthetic problem with iron concentrations exceeding several parts per million (mg/1). In such cases, the loose iron corrosion deposits can settle within a lead pipe and absorb lead it is likely that this absorption enhances lead dissolution from the lead corrosion deposit as the equilibrium concentration for the dissolved lead is given less opportunity to be realised. Any disturbance of the loose deposits, such as the scouring effect of high flow, can cause elevated concentrations of lead in the drinking water. As an approximation, lead concentrations can double as a consequence of the interaction with loose iron deposits. Particulate lead may also arise from the physical sheer of pieces of the lead corrosion deposit from within the lead pipe, as a consequence of physical damage (as can occur in partial lead pipe replacement). Vibration from heavy road traffic might also cause pieces of the lead corrosion deposit to sheer. There is some evidence (Cardew, 2009) that the lead... 

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