Nasal mucosa barrier

Opioids are easily absorbed subcutaneously and intramuscularly, as well as from the gastrointestinal tract, nasal mucosa (e.g., when heroin is used as snuff), and lung (e.g., when opium is smoked). About 90% of the excretion of morphine occurs during the first 24 hours, but traces are detectable in urine for more than 48 hours. Heroin (diacetyhnorphine) is hydrolyzed to monoacetylmorphine, which is then hydrolyzed to morphine. Morphine and monoacetylmorphine are responsible for the pharmacologic effects of heroin. Heroin produces effects more rapidly than morphine because it is more lipid soluble and therefore crosses the blood-brain barrier faster. In the urine, heroin is detected as free morphine and morphine glucuronide (Gutstein and Akil 2001 Jaffe et al. 2004). 

This refers to the transport across the epithelial cells, which can occur by passive diffusion, carrier-mediated transport, and/or endocytic processes (e.g., transcytosis). Traditionally, the transcellular route of nasal mucosa has been simply viewed as primarily crossing the lipoidal barrier, in which the absorption of a drug is determined by the magnitude of its partition coefficient and molecular size. However, several investigators have reported the lack of linear correlation between penetrant lipophilicity and permeability [9], which implies that cell membranes of nasal epithelium cannot be regarded as a simple lipoidal barrier. Recently, compounds whose transport could not be fully explained by passive simple diffusion have been investigated to test if they could be utilized as specific substrates for various transporters which have been identified in the... 

Because most proteins are susceptible to protease degradation and denaturation in biologic fluids, most biopharmaceuticals must be administered by intravenous, intramuscular, or subcutaneous injection (see Table 5.5). High concentrations of proteases are found in the gastrointestinal tract, nasal mucosa, bronchioles, and alveoli, which severely limit the bioavailability of protein pharmaceuticals after oral, intranasal, and inhalation administration. Diffusional barriers to the passage of relatively large macromolecules preclude transdermal and mucosal administration of protein pharmaceuticals. Research is under way to develop methods that will protect protein drugs from proteolysis and improve transmembrane diffusion. 

Another hypothesis is that environmental chemicals gain access to the central nervous system via the olfactory and limbic pathways. The absence of a blood-brain barrier in the olfactory system could permit direct access of environmental chemicals through the nasal mucosa to the olfactory bulb. The olfactory and limbic systems are anatomically linked and participate directly and indirectly in the regulation of cognitive, endocrine, and immune functions. In this hypothesis, chemical exposure could induce lasting changes in limbic and neuronal activity and alter a broad spectrum of behavioral and physiological functions. 

Upon intranasal administration, a drug is not as susceptible to dilution and first-pass effects as in oral delivery.46 47 The nasal route may also be an effective means of delivering drugs to the brain 46 Barriers to nasal delivery include the enzymes of the nasal mucosa, the epithelial barrier, the mucus layer, and limited absorption time resulting from mucociliary clearance.48... 

In an investigation of the ability of different molecular substances to elicit ocular anaphylaxis when applied topically to the eye, Kahn et al. (1990) concluded that only substances having a molecular weight less than 3500 penetrate the conjunctival barrier. Therefore, systemic delivery via the ocular route seems to rely on overflow of the instilled dmg to the nasal cavity. Thus, the nasal mucosa contributed about 4 times more than the conjunctival mucosa to the systemic absorption of ocularly applied insulin (Yamamoto et al, 1989). Topically applied insulin administered chronically without surfactant seems to be nontoxic to the external human eye (Bartlett etal, 1994a). 

Mucociliary clearance, with a half-life of 10 20 min in humans, is one of the major physical barriers for the nasal absorption of insulin. This rapid clearance substantially limits the residence time of insulin at the nasal mucosa, and it is probably the major contributory factor in the loss of insulin from potential absorption and the resulting low bioavailability (Vora and Owens, 1991). The pH of5.5-6.5 in the mucous layer of the nasal cavity further contributes to reduce the absorption of insulin, which possesses limited solubility in this pH range. 

Proteolysis. Proteolysis is the cleavage of amide bonds that comprise the backbone of proteins and peptides. The reaction can occur spontaneously in aqueous medium under acidic, neutral, or basic conditions. This process is accelerated by proteases, ubiquitous enzymes that catalyze peptide-bond hydrolysis at rates much higher than occur spontaneously. In humans, these enzymes only recognize sequences of L-amino acids but not d-amino acids. They are found in barrier tissues (nasal membranes, stomach and intestinal linings, vaginal and respiratory mucosa, ocular epithelium), blood, all internal solid organs, connective tissue, and fat. The same protease may be present in multiple sites in the body. 

Whole-body autoradiography of male Sprague-Dawley rats given intravenous injections (2.7 mg/kg bw) of 7V-nitroso[ C]diethanolamine showed an even distribution in most tissues except for tissue-bound radioactivity that was localized in the liver and the nasal olfactory mucosa. A lower level of labelling in the central nervous system probably indicated that 7V-nitrosodiethanolamine penetrated the blood-brain barrier poorly, while higher labelling in the kidney and urinary bladder may reflect elimination of 7V-nitroso[ C]diethanolamine in urine (Lofbeig Tjalve, 1985). 

The nonperoral mucosal delivery routes such as buccal, nasal, and vaginal sites offer barriers to drug molecules similar to that of the peroral route. Drugs delivered via these routes have to be small (<300 Da), lipophilic in nature, and with low dosage regimen requirements. The different approaches used to deliver drugs across these mucosae include the use of enzyme inhibitors, penetration enhancers, bioadhesive patches, prodrugs, liposomes, and solubility modifiers.96,106,130... 

The human buccal mucosae of the oral cavity, i.e., the buccal and the sublingual epithelia, offer a robust and easily accessible area for systemic delivery and the advantage of low enzymatic activity (Lee et al., 1987 Yamamoto et al, 1990). Unfortunately, the multilayered buccal barrier is relatively thick and dense, and proteinaceous substances are not readily absorbed via this route. Thus, permeability of insulin via this route has been calculated to be 12 orders of magnitude less than via the nasal route (Harris and Robinson, 1990). 

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