Bioavailability peptides, nasal

Hussain A, Faraj J, Aramaki Y, Truelove JE (1985) Hydrolysis of leucine enkephalin in the nasal cavity of the rat- a possible factor in the low bioavailability of nasally administered peptides. Biochem Biophys Res Communl33 923-928. 

The nose is equipped with a unique cellular architecture to perform several functions, including filtration of inspired particles, humidification of inspired air, olfaction, and some immunological functions [18,19], The nose is not specifically designed for nutrient or peptide drug absorption. However, the large absorptive capacity of the nasal epithelium has now been fully appreciated because of the extremely high bioavailability of nasally applied peptide drugs observed under certain experimental conditions (described below). 

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,... 

Penetration enhancers are often used to improve peptide bioavailability in nasal formulations. A variety of different enhancers have been tried, and they work by one or several combined mechanisms. Some act by increasing the membrane fluidity and reducing the viscosity of the mucus layer, thereby increasing membrane permeability. Others act by transient loosening of the tight junctions between epithelial cells. The types of penetration enhancers discussed in the research literature include the following. 

The nasal tissue is highly vascularized and provides efficient systemic absorption. Compared with oral or subcutaneous administration, nasal administration enhances bioavailability and improves safety and efficacy. Chitosan enhances the absorption of proteins and peptide drugs across nasal and intestinal epithelia. Gogev et al. demonstrated that the soluble formulation of glycol chitosan has potential usefulness as an intranasal adjuvant for recombinant viral vector vaccines in cattle [276]. 

A number of other peptide molecules are currently being explored for delivery via inhalation (6). Very recently, a much smaller peptide (leuprolide, about 9 amino acid residues) has been delivered by metered dose inhaler (MDI) in a characterized fashion to humans (7). This work revealed that about 50% of a dose deposited in the lung could be bioavailable. This value is much greater than those reported for nasal bioavailabilities of this and similar molecules (8). These results, and ours in the rat lung (9), imply that inhalation administration of some peptide and polypeptide molecules is perfectly feasible. 

Nasal Administration. The nasal mucosa is relative permeable to small molecular weight compounds. The most notorious example is cocaine. Cocaine that is snorted is both rapidly and extensively absorbed. Small peptides have also been successfully administered nasally, although the bioavailability is low. However, where the availability is not critical, nasal administration of peptides has been successful. The best example is... 

The upper respiratory tract, like the nasal cavity, consists of epithelium with columnar structure (30-40 pm thick) that is relatively impermeable to large molecules (Figure 13.4). On the other hand, the deep lung consists of alveolar (air sac) epithelium that is only 0.1 to 0.2 pm thick and substantially more permeable to peptides and proteins. When insuhn (51 aa) and growth hormone (192 aa) are instilled into the deep lung, about 10% to 15% of these therapeutic agents are bioavailable. Because the alveoli surface is large, an estimated... 

Chitosan is a cationic polysaccharide produced from the deacetylation of chitin, a component of crab and shrimp shells [7,57,58], Chitin is composed of units of 2-deoxy-2-(acetylamino) glucose joined by glycosidic bonds that form a linear polymer. Ilium et al. [7,57,58] demonstrated the ability of chitosan to increase the bioavailability of insulin and other small peptides and polar macromolecules in different animal models. In both the sheep and rat models, the addition of chitosan at concentrations of 0.2%-0.5% to nasal formulations of insulin resulted in significant increases in plasma insulin and reductions in blood glucose. Reversibility studies indicated that the effect of chitosan on the nasal absorption of insulin... 

Since its discovery, isolation, and purification in the early twentieth century, insulin has been administered to diabetic patients exclusively by injection until the recent introduction of inhaled insulin. Insulin possesses certain physiochemical properties that contribute to its limited absorption from the gastrointestinal tract, and requires subcutaneous injection to achieve clinically relevant bioavailability. With a molecular size of 5.7 kDa, insulin is a moderately sized polypeptide composed of two distinct peptide chains designated the A chain (21 amino acid residues) and the B chain (30 amino acid residues) and joined by two disulfide bonds. Like all polypeptides, insulin is a charged molecule that cannot easily penetrate the phospholipid membrane of the epithelial cells that line the nasal cavity. Furthermore, insulin monomers self-associate into hexameric units with a molecular mass greater than 30 kDa, which can further limit its passive absorption. Despite these constraints, successful delivery of insulin via the nasal route has been reported in humans and animals when an absorption enhancer was added to the formulation. 

Drug delivery via the nasal route offers a number of advantages, the most important of which is the possibility of needle-free treatment. It also means that—in addition to the newly developed peptide- and protein-based drugs—this method is also suitable for a wide variety and perhaps most of the drugs that are currently in use. However, it is not only convenience that sets nasal drug delivery apart This method also provides a rapid onset of action and high bioavailability. 

Chitosan microspheres were shown to enhance nasal bioavailability of several peptide drugs such as insulin and goserelin. A simple chitosan-insulin powder formulation provided about 20% of absolute insulin bioavailability in sheep [96], Improved bioavailability (of 44%, in rats) was obtained when insulin was loaded into chitosan microspheres prepared with ascorbyl palmitate as cross-linking agent [91]. Chitosan microspheres have also been shown to improve nasal goserelin absorption providing about 40% bioavailability relative to goserelin intravenous application [9],... 

Krauland et al. [93] prepared the microparticles with thiolated chitosan (chitosan-TBA chitosan-4-thiobutylamidine conjugate) intended for nasal peptide delivery. During the preparation process microparticles were stabilized by the formation of inter- and intramolecular cross-linking via disulfide bonds. Chitosan-TBA microparticles were characterized by improved swelling ability and displayed 3.5-fold higher insulin bioavailability compared to unmodified chitosan microparticles. 

Dry powder formulations for nasal delivery of peptides and proteins have been investigated for the first time by Nagai and others [38], Since then, much research work has been done on dry powders containing bioadhesive polymers for nasal drug administration. The bioavailability and duration of action of drugs administered by the nasal route are increased by the use of the principle of mucoadhesion and dry powder formulations. Research work on dry powder formulation containing bioadhesive polymers is summarized in Table 1. 

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. 

In the past years, much research has concentrated on the use of cyclodextrins to enhance bioavailability of peptides and proteins especially because of their mild and reversible effect on the nasal mucociliary clearance. ... 

Among the cyclodextrins, the use of DMpCD was shown to have the highest effect on the transnasal bioavailability of insulin in rats. Several studies reported on their concentration-dependent effect. Besides for peptides, the methylated p-cyclodextrins have shown to be useful in nasal delivery of lipophilic drugs. The toxicological profile of dimethyl p-cyclo-dextrins and of randomly methylated p-cyclodextrins appeared excellent. Attention should be paid, if possible, onbioavailability differences between animal and human models. 

Although many drugs are absorbed rapidly and quantitatively following nasal administration, peptides have generally shown low bioavailabilities. Hussain et al. examined the nasal bioavailability of leucine enkephalin. The low bioavailability of this penta-peptide was attributed to hydrolysis in the nasal cavity, with dipeptides causing significant inhibition of the hydrolysis. They concluded that polar compounds, such as peptides, can cross the nasal mucosa, and that administration of low concentrations results in extensive hydrolysis in the nasal mucosa and that hydrolysis of leucine enkephalin can be reduced by concomitant administration of peptidase labile peptides. 

If the presence of a pharmacologic activity for a peptide is the only criterion for its use in therapy, then nasal administration may be employed, even though bioavailability is not 100%. However, when bioavailability, as determined by plasma level profiles, is considered, the nasal route for peptide administration is not optimal unless enhancers are employed. Enhancers may cause irritation and reduced membrane integrity. Other drawbacks of nasal delivery include the small... 

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