Nasal administration systemic bioavailability

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]. 

Numerous papers have reported on the possible utility of nasal administration of a variety of compounds, including peptide and protein drugs. However, only a small number of products are of clinical use for intranasal systemic delivery, as mentioned earlier. Especially, most peptide and protein drugs show insufficient nasal bioavailability, which may be one of the reasons for difficulties in development. To improve the nasal absorption of peptide and protein drugs, several strategies classified as follows have been intensively investigated and discussed during the last two decades ... 

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,... 

As for a formulation using another administration route, Leitner et al. developed a nasal delivery system of hGH [194] based on the thiomer polycarbophil-cysteine (PCP-Cys) in combination with the permeation mediator glutathione (GSH). Microparticles were prepared by dissolving PCP-Cys/GSH/hGH (7.5 1 1.5), PCP/ hGH (8.5 1.5), and mannitol/hGH (8.5 1.5) in demineralized water, followed by lyophilization and micronization. PCP-Cys/GSH/hGH and PCP/hGH microparticles showed a comparable size distribution (80% in the range of 4.8 to 23 pm) and swelled to almost four fold size in phosphate-buffered saline. Both formulations exhibited almost identical sustained drug release prohles. The intranasal administration of the PCP-Cys/GSH/hGH microparticulate formulation resulted in a relative bioavailability of 8.11%, which represents a three fold and a 3.3-fold improvement compared with that of PCP/hGH microparticles and mannitol/hGH powder, respectively. The nasal microparticulate formulation based on PCP-Cys/ GSH/hGH might represent a promising novel tool for the systemic delivery of hGH. 

Following IV suspension or inhalation administration, mometasone furoate was detected in the plasma for up to 8 hours, with a half-life of 4 to 6 hours (Table 33.5) and an oral bioavailability of less than 1%. It is extensively metabolized with less than 10% of the administered dose recovered in the urine unchanged (108). Among the polar metabolites ( 80%) and their conjugates (42%) that were recovered were 6(3-hydroxymometasone furoate and its 21-hydroxy metabolite. In contrast, following intranasal administration, its plasma concentrations were below the limit of quantification, and the systemic bioavailability by this route was estimated to be less than 1 %. The majority of the intranasal dose for mometasone furoate is deposited in the nasal mucosa and swallowed without absorption in the Gl tract until eliminated in the feces (approximately 50-90% of the intranasal dose is recovered in the feces). That portion of the intranasal dose that was absorbed was extensively metabolized. These results indicate that inhaled mometasone furoate has negligible systemic bioavailability and is extensively metabolized, with reduced risk for causing systemic adrenal suppression effects. 

The nasal administration was shown to be an effective administration route for lipophilic active substances like fentanyl. Moreover, the nasal route has also been used for the systemic administration of small peptides like buserelin acetate, nafarelin acetate and desmopressin, aU of them containing ten or less amino acid residues. However, for these molecules the nasal route forms only a poor non-invasive alternative to injection, since the nasal bioavailability of these peptides is less than 3-5 %. 

In recent years, much of the research work in the pharmaceutical sciences was focused on the development of effective vehicle systems, such as micelles, microemulsions, and liposomes, for drugs that are critical with respect to bioavailability. Knowledge of this subject is a prerequisite to developing vehicle systems for special administration routes, such as dermal, transdermal, intravenous, and nasal. 

A slightly different approach is to deliver the active drug in a dry powder carrier system, for example microcrystalline cellulose, hydroxyethyl starch, cross-linked dextran, microcrystalline chitosan, carbomer, pectin, or alginic acid. The polymer absorbs water upon contact with the nasal mucosa and swells to become a viscous gel, often demonstrating bioadhesive properties. Such systems can remain in the nasal cavity for as long as six hours. For example, the bioavailability in rats of the somatostatin analogue, octreotide, was shown to be enhanced by the co-administration of alginic acid and cross-linked dextran as dry powders. 

Although no adverse reactions have been reported with intranasal administration of propranolol, complications may occur, as ocular administration has produced some systemic side effects [118]. The influence of substrate lipophilicity on drug uptake by the nasal route was reported in humans. Alprenolol and metoprolol, 3 blockers with varying degrees of lipophilicity, were used. The findings from these studies demonstrate that the more hydrophilic drugs showed a lower bioavailability. Alprenolol showed rapid uptake into the systemic circulation by the nasal route and also a higher bioavailability [126,127]. 

Hormones, proteins, and small peptides are not suitable for oral administration without complex modifications in the formulation. A variety of approaches for insulin delivery, as a model drug, have been attempted to improve on its bioavailability. Advances have been realized in the delivery of insulin through oral, nasal, rectal, dermatologic, and ocular routes. Proteins can also be delivered transdermally, using a lipid-based, biphasic delivery system in therapeutic quantity. 

The lack of activity after oral administration for most peptides and proteins resulted in the past besides parenteral application into the utilization of nonoral administration pathways, for example, nasal, buccal, rectal, vaginal, percutaneous, ocular, or pulmonary drug delivery [27]. Drug delivery via these administration routes, however, is also frequently accompanied by presystemic degradation processes. Bioavailability of numerous peptides and proteins is, for example, markedly reduced after subcutaneous or intramuscular administration compared to their intravenous administration. The pharma-cokinetically derived apparent absorption rate constant is thus the combination of absorption into the systemic circulation and presystemic degradation at the absorption... 

Absolute bioavailability of a drug is the systemic availability of the drug after extravascular administration of the drug and is measured by comparing the area under the drug concentration-time curve after extravascular administration to that after IV administration, provided the and Vd are independent of the route of administration. Extravascular administration of the drug comprises routes such as oral, rectal, subcutaneous, transdermal, nasal, etc. 

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