Absorption enhancers mucosa

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... 

Wang J, Sakai S, Deguchi Y, Bi D, Tabata Y, Morimoto K (2002) Aminated gelatin as a nasal absorption enhancer for peptide drugs evaluation of absorption enhancing effect and nasal mucosa perturbation in rats. J Pharm Pharmacol 54 181— 188. 

Ilium et al. [49] evaluated chitosan solutions as delivery platforms for nasal administration of insulin to rats and sheep. They reported a concentration-dependent absorption-enhancing effect with minimal histological changes of the nasal mucosa in all concentrations applied. 

In the past two decades, many studies have tested adjuvants that act by either permeabilizing the rectal mucosa or inhibiting drug degradation. Oral and rectal routes of drug administration are unsuitable for adequate absorption of various compounds with a peptide or protein structure and of several hydrophilic antibiotics. The use of absorption enhancers, e.g., salicylates, enamines, surfactants, and straight-chain fatty acids, has gained wide interest... 

An important issue that has been recognized recently concerns the potential adverse effect of absorption enhancers on the rectal mucosa, as shown in rats after a single application [61,62], Safety evaluation of the applicability of absorption enhancers is imperative. In clinical application, medium-chain fatty acids such as sodium caprate are used only for suppositories containing antibiotics [36],... 

Van Hoogdalem, E.J., et al. 1990. Topical effects of absorption enhancing agents on the rectal mucosa of rats in vivo. J Pharm Sci 79 866. 

In this chapter, we especially focus on the strategies for enhancement of rectal absorption of various drugs including peptides and proteins from rectal mucosa using pharmaceutically useful excipients, cyclodextrins (CyDs), and the other absorption enhancers. 

The factors that hinder the absorption of peptides through the intestinal epithelium, namely high molecular weight, charge, and hydrophilicity also affect their absorption through the oral mucosa. Combinations of mucoadhesive systems, absorption enhancers, and enzyme inhibitors have enabled better absorption. 

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... 

Calcitonin is a peptide hormone produced in the thyroid gland that serves to lower serum calcium and phosphate levels by inhibiting bone resorption. Calcitonin has been used in the treatment of a variety of diseases, such as primary hyperparathyroidism, Paget s disease, and postmenopausal osteoporosis [99,100]. Salmon calcitonin has a longer half-life than human calcitonin. Salmon calcitonin, 3.6 kDa, is available as a nasal formulation that contains only benzalkonium chloride as a preservative, without an absorption enhancer, and as a parenteral product for injection. The direct effect of benzalkonium chloride on the nasal mucosa is under... 

The second reason to consider the intracellular enzymes is because of the absorption mechanisms by which macromolecules may cross the intestinal mucosa. There are two possible mechanisms for relatively small macromolecules such as therapeutic peptides and oligonucleotides, they may be able to pass via the paracellular route between the cells, particularly if some absorption enhancers are present. For example, Tsutsumi et al. (2008) have shown in vitro that in the presence of chenodeoxycholate as an absorption enhancer modified oligonucleotides with molecular weights of nearly 3,700 and 7,400 Da could cross rat intestine via the paracellular route. In the case of the paracellular route the macromolecules will not be exposed to the intracellular enzymes and thus they will not be subject to intracellular hydrolysis. However, macromolecules, especially larger ones, will cross the epithelium via the transcellular mechanism of endocytosis. In this case they will be taken into the lysosomes that contain a formidable array of digestive enzymes (see later in Section 1.5.2). 

Since the concentrations of insulin to be administered in the sheep model would have been large, the insulin-loaded chitosan nanoparticles were not investigated in that model. However, the pharmacodynamics and pharmacokinetics of various insulin-chitosan preparations were compared with postloaded insulin-chitosan nanoparticles. It was found that chitosan solution and chitosan powder formulations were far better, with the chitosan powder formulation showing a bioavailability of 17% as against 1.3 and 3.6% for the chitosan nanoparticles and chitosan solution [72], The effects of the concentration and osmolarity of chitosan and the presence of absorption enhancers in the chitosan solution on the permeation of insulin across the rabbit nasal mucosa in vitro and in vivo were investigated, and the same... 

Midazolam, Triazolam, and Flurazepam The feasibility of intranasal administration of midazolam, flurazepam, and triazolam has been studied and compared with oral absorption in dogs. There was a 3.4-fold increase in the Cmax after nasal administration, from 5.5-8.7ng/mL to 17.4-30.0 ng/mL. The mean tm showed comparable values for both routes. The Tnmx obtained after nasal administration of midazolam was found to be 15 min, as compared with the 15-45 min observed for oral dosing, while the Cmax after nasal administration was 6.5-20.3 ng/mL, as compared with 3.0-8.6ng/mL observed for the oral route. Like midazolam and triazolam, flurazepam also showed a shorter half-life, 15 min, as compared with 15 15 min with oral administration. The Cmax for oral administration was 0.14-0.59 ng/mL after nasal administration it was in the range of 2.6-11.1 ng/mL, a 16.4-fold increase. Since the gastrointestinal tract at bedtime is likely to be in the fed state, causing a twofold decrease in the absorption of midazolam and triazolam, the nasal route may be a better option for the treatment of amnesia, since these drugs cross the nasal mucosa effectively without the use of an absorption enhancer, as shown in these studies [108],... 

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. 

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. 

To increase the residence time in the nasal mucosa, a bioadhesive formulation may be one of the most reasonable approaches. In fact, microspheres containing bioadhesive polymers such as starch, albumin, and Sephadex with a particle size of 40-60 pm have been found to be cleared from the nasal cavity much more slowly than solutions. Starch microspheres improved the nasal absorption of insulin, with synergistic effects of some absorption enhancers in sheep. In another paper, dry powder containing starch and Carbopol 974P showed significantly higher bioavailability after nasal administration than the formulation without Carbopol. ° Chitosan, already mentioned above, also has a bioadhesive property and is found to be useful as a potent absorption enhancer for nasal peptide delivery. Other bioadhesive polymer systems,... 

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