Nasal bioavailability

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. 

Desmopressin can be administered intravenously, subcutaneously, intranasally, or orally. The half-life of circulating desmopressin is 1.5-2.5 hours. Nasal desmopressin is available as a unit dose spray that delivers 0.1 mL per spray it is also available with a calibrated nasal tube that can be used to deliver a more precise dose. Nasal bioavailability of desmopressin is 3-4%, whereas oral bioavailability is less than 1%. 

Yetkin, G., et al. 1999. The effect of dimethyl-beta-cyclodextrin and sodium taurocholate on the nasal bioavailability of salmon calcitonin in rabbits. STP Pharma Sci 3 249. 

Matsubara, K., et al. 1995. Improvement of nasal bioavailability of luteinizing hormone-releasing hormone agonist, buserelin, by cyclodextrin derivatives in rats. J Pharm Sci 84 1295. 

The implications to nasal bioavailability of these deposition patterns from the different delivery devices is discussed further below (see Section 9.6). 

List the physiological factors affecting nasal bioavailability. 

Describe the formulation factors that may affect nasal bioavailability. 

Figure 11.5 Ovulation induction by leuprorelin in diestrous rats after iv, sc, rectal, nasal, oral, and vaginal routes of administration. (Note nasal absorption may have been underestimated in this study, due to drainage of the test solution. For example, nasal bioavailability has been determined as 18.7% in rats, in a study in which the nasal cavity was closed at the orifice and outlet)...

Suspensions may also be used to deliver nasal formulations, though only rarely, since a number of complicating factors (e.g., particle size and morphology) must be considered. Suspensions offer the advantage of increasing residence time in the nasal cavity, thus possibly augmenting nasal bioavailability. 

Diazepam As mentioned earlier, because of shortcomings of rectal administration, the nasal delivery of diazepam has gained interest. The nasal bioavailability of diazepam in sheep was estimated and further compared with results obtained earlier in humans and rabbits [106] in this study, human and rabbit nasal bioavailability for the first 30min was reported to be 37 and 54%, respectively [113]. Diazepam solubilized in PEG 300 was used for nasal administration via a modified nasal device, a Pfeiffer unit dose (Princeton, NJ). The sheep received the nasal formulations in a fixed standing position such that the head was slightly tilted back. It was found that the serum concentration after administration of a 7-mg solution of diazepam was... 

Butorphanol, an analog of buprenorphine, showed a nasal bioavailability of 70% and also a much lower Tmax after nasal absorption as compared with the sublingual and buccal routes [115]. Lindhardt et al. [106] compared buprenorphine formulated in 30% PEG-300 in sheep with that of the 5% dextrose formulation mentioned earlier. A unit-dose Pfeiffer device was again used to administer the formulation. It was found that nasal bioavailability in sheep was about 70% when buprenorphine was formulated in PEG-300 and approximately 89% when it was formulated with 5% dextrose. The rate of absorption was reported to be very fast, with a Tmax of 10 min the Cmax was found to be 37 and 48ng/mL for PEG-300 and dextrose, respectively. In sheep, the pharmacokinetics of buprenorphine showed a two-compartment model as compared to a three-compartment model in humans. 

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],... 

Ishikawa, F., Katsura, M., Tamai, I., and Tsuji, A. (2001), Improved nasal bioavailability of elcatonin by insoluble powder formulation, Int. J. Pharm., 224,105-114. 

El-Shafy, M. A., Kellaway, I. W., Taylor, G, and Dickinson, P. A. (2000), Improved nasal bioavailability of FITC-dextran (Mw 4300) from mucoadhesive microspheres in rabbits, J. Drug Target., 7, 355-361. 

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. 

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 ... 

In summary, the common concepts, extracted from the described major strategies, for achieving improved nasal peptide and protein delivery are illustrated in Fig. 8. Ultimately, three major barriers (i.e., mucus, enzymatic, and penetration barriers) must be overcome to realize sufficient nasal bioavailability. To that end, additive or synergistic effects, by combining all concepts shown in the figure, may be necessary, which will depend on the ideas, skills, and enthusiastic efforts of formulation scientists. 

Bagger MA, Nielsen HW, Bechgaard E. Nasal bioavailability of peptide T in rabbits absorption enhancement by sodium glycocholate and glycofurol. Eur ] Pharm Sci 2001 14(1) 69-74. Dale O, Sheffels P, Khorasch ED. Bioavailabilities of rectal and oral methadone in healthy subjects. Br ] Clin Pharmacol 2004 58(2) 156-162. 

The pulmonary and nasal bioavailability are important determinants for the potential of an inhaled or nasally... 

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 %. 

Nasal administration of drugs is often difficult because of the poor membrane permea-bihty and less contact time due to the high turnover rate of secretion in the nasal passage, which ultimately reduces the nasal bioavailability of drugs. The exclusive properties of chitosan, i.e., bioadhesiveness and opening of tight intercellular jimctions, have made it... 

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