Nasal administration

Keywords Chitosan Nanoparticles Microspheres Chemically modified chitosans Polyelectrolyte complexes Oral and nasal administration Nerve, cartilage and bone regeneration Wound dressing... 

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]. 

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... 

Nasal Administration. A route that has gained increasing popularity of late for pharmaceutical administration in humans is the intranasal route. The reasons for this popularity are the ease of use (and, therefore, ready patient acceptance and high compliance rate), the high degree and rate of absorption of many substances (reportedly for most substances up to 1000 molecular weight McMartin et al., 1987), and the avoidance of the highly acid environment in the stomach and first-pass metabolism in the liver (particularly important for some of the newer peptide moieties) (Attman and Dittmer, 1971). The only special safety concerns are the potential for irritation of the mucous membrane and the rapid distribution of administered materials to the CNS. 

Other routes of administration sometimes used in monkey safety assessment studies are intravaginal dosing, topical application, inhalation, and nasal administration. 

The extent of drug absorption following nasal administration depends to a reasonable extent on the ease with which a drug molecule crosses the nasal epithelium without degradation or rapid clearance by the mucociliary clearance system. The effects of these two elimination components are more pronounced for proteins and peptides. The nasal administration of drugs, especially proteins and peptides, as well as other molecules has been studied with excised tissues harvested from rabbit, cow, sheep, and pig species (Table 5.2). A... 

An evaluation of the various studies reported in the literature for preclinical assessment of drugs for nasal administrations indicated the usefulness of in situ, ex vivo, and in vivo approaches. Evidence from the literature also indicates that the choice of a particular model or animal species by different... 

Figure 5.2 Literature data on fraction of drugs absorbed (in percent) after human nasal administration versus apparent permeability (Tapp) data from Ussing chamber studies on porcine nasal mucosa (Reprinted with permission from Elsevier B.V.).

Gavini E, Rassu G, Sanna V, Cossu M, Giunchedi P (2005) Mucoadhesive microspheres for nasal administration of an antiemetic drug, metoclopramide in-vitro/ex-vivo studies. J Pharm Pharmacol 57 287-294. 

Since the uptake of particles in nasal epithelial tissue is known to be mostly mediated by M cells, nasal administration has been investigated as a noninva-sive delivery of vaccines [37], However, since the uptake of naked DNA by endocytocis is limited, use of either nanoparticles as mucosal delivery systems [37] or hypotonic shock [38] is reported for the efficient transfection of gene and vaccine into the nasal epithelium. It was also reported that polypeptides and polypeptide-coated nanospheres (diameter about 500 nm) are transported through endocytic process in rat M cells [39],... 

E. Gavini, A. B. Heqqe, G. Rassu, V. Sanna, C. Testa, G. Pirisino, J. Karlsen, and P. Giunchedi. Nasal administration of carbamazepine using chitosan microspheres in vitro/in vivo studies. Int J Pharm 307 9-15 (2006). 

Nicotine nasal spray is marketed as a pharmacy-only medication in the UK, and is available only by prescription in the USA. The nasal spray was designed to deliver doses of nicotine to the smoker more rapidly than other NRT products. The device is a multidose bottle with a pump that delivers 0.5 mg of nicotine per 50-pL squirt. Each dose consists of two squirts, one to each nostril. Nicotine from the nasal spray is absorbed into the blood more rapidly than from the gum (Schneider et al. 1996). Venous plasma concentrations after a single 1-mg dose range between 5 and 12 ng mL Time to peak plasma concentration (7j ax) with nasal administration is around 11-13 min for 1-mg doses. This rise time is slower than for cigarette delivery (Henningfield et al. 1993), but faster than for the other NRT products. 

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. 

Nakamura et al. [54] deseribe a mieropartieulate dosage form of budesonide, consisting of novel bioadhesive and pH-dependent graft copolymers of polymethacrylic acid and polyethylene glycol, resulting in elevated and constant plasma levels of budesonide for 8 hr after nasal administration in rabbits. 

The most common side-effects to nasal administration of fluticasone are local reactions, including irritation of the nose and throat and epistaxis. Steroids may cause a raised intraocular pressure or glaucoma. Hypersensitivity reactions, including occurrence of bronchospasms, have been reported. 

N-a cetyl-cam os i ne or the decarboxylated form carcinine. In fact N-acetyl-camosine has been proposed as a prodrug to treat cataracts in the eye lens, as the acetyl group is readily removed intracellularly (Barbizhayev et ah, 2004) (see section on cataracts for more details). An alternative way to evade serum camosinase activity would be to introduce carnosine via nasal administration (Hipkiss, 2005). This route may be particularly appropriate for raising carnosine levels in the brain as the olfactory lobe is normally enriched in the dipeptide. 

Nasal administration of butorphanol decreases the onset of action to 15 minutes and decreases the first-pass effect of the drug, which increases bioavailability. Generally the patient sprays a set dose of 1 mg per hour for 2 hours. Tlie duration of action is 4 to 5 hours. The convenience of such administration is a major... 

Pharmacokinetics Minimal absorption after PO, inhalation, or nasal administration. Absorbed portion excreted in urine or by biliary system. Half-life 80-90 min,... 

Poorly absorbed after oral or nasal administration. Metabolism Unknown. Half-life Oral 1.5-2.5 hr. Intranasal 3.3-3.5 hr. IV 0.4-4 hr. 

Calcitonin has proved useful as ancillary treatment in a large number of patients. Calcitonin by itself seldom restores serum calcium to normal, and refractoriness frequently develops. However, its lack of toxicity permits frequent administration at high doses (200 MRC units or more). An effect on serum calcium is observed within 4-6 hours and lasts for 6-10 hours. Calcimar (salmon calcitonin) is available for parenteral and nasal administration. 

For nebulizer and other aqueous aerosol products that use suspension systems, excipients are used to influence particle physical and chemical stability (e.g., microcrystalline cellulose for nasal sprays). The suitability of the physicochemical properties of these critical excipients should be thoroughly investigated and documented (12). Far more excipients have been included in formulations designed for nasal administration (Table 4). 

Pharmacokinetic properties Butorphanol (Vachharajani et al., 1997) is rapidly inactivated by first pass metabolism in the gut. Intramuscular and nasal administration induces a peak effect between 0.5-1 hr and a duration of action of about 3 h, corresponding to the plasma half-life time of the compound. Butorphanol has a plasma protein binding of about 80%, metabolic inactivation includes hydroxylation,... 

Vachharajani, N.N., Shyu, W.C., Greene, D.S., Barbhaiya, R.H. The pharmacokinetics of butorphanol and its metabolites at steady state following nasal administration in humans, Biopharm. Drug Dispos. 1997, 18, 191-202. 

Developments in the administration of insulin through the skin, the mouth, the nose, and the lung have been reviewed (183). Methods of absorption other than subcutaneous, such as nasal insulin, buccal insulin, rectal insulin, and insulin in enteric-coated capsules, are still experimental. A problem in nasal administration is still how to get a daily reproducible dose (184). The frequency of hypoglycemia is comparable to the frequency with subcutaneous insulin (185). Nasal irritation, sometimes with congestion, and dyspnea (186) can occur. Pulmonary insulin, delivered by aerosol inhalation, is another experimental method. No lung obstruction was reported, but the uptake varied considerably (187). 

Insulin is rapidly absorbed after nasal administration, but even with absorption enhancers its systemic availability is low and its metabolic effect very short (183). 

Li HL, Shi FD, Bai XF Nasal tolerance to experimental autoimmune myasthenia gravis Tolerance reversal by nasal administration of minute amount of IFN-"y. Clin Immunopathol 1998 87 15-22. 

Tian, J., Atkinson, M., Clare-Salzler, M., Herschenfeld, A., Forsthuber, T., Lehmann, P. et al. (1996) Nasal administration of glutamic decarboxylase peptides induces Th2 responses and prevents murine insulin-dependent diabetes. J. Exp. Med., 183, 1561-1567. 

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