Absorption enhancers nasal

Hamman et al. [281,282] tested five trimethyl chitosans with different degrees of quaternization as nasal delivery systems the degree of quaternization had a major role in the absorption enhancement of this polymer across the nasal epithelia in a neutral environment. 

Agu RU, Vu Dang H, Jorissen M, Willems T, Kinget R, Verbeke N (2002) Nasal absorption enhancement strategies for therapeutic peptides an in vitro study using cultured human nasal epithelium. Int J Pharm 237 179-191. 

Tengamnuay P, Sahamethapat A, Sailasuta A, Mitra AK (2000) Chitosans as nasal absorption enhancers of peptides comparison between free amine chitosans and soluble salts. Int J Pharm 197 53-67. 

Merkus FWHM, Marttin E, Romeijn SG, Verhoef J (1996) In situ perfusion is an unrealistic approach to assess the effects of absorption enhancers on nasal epithelium. Eur J Pharm Biopharm 42 159. 

Wang J, Sakai S, Deguchi Y, Bi D, Tabata Y, Morimoto K (2002) Aminated gelatin as a nasal absorption enhancer for peptide drugs evaluation of absorption enhancing effect and nasal mucosa perturbation in rats. J Pharm Pharmacol 54 181— 188. 

Keywords Nasal absorption Air-interfaced culture Absorption enhancer Liquid-covered culture Mucociliary clearance Nasal epithelial cell mono-layer Paracellular absorption Tight junction Transcelluar absorption Drug transport... 

S. S. Davis and L. Ilium. Absorption enhancers for nasal drug delivery. Clin Pharmacokinet 42 1107-1128 (2003). 

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. 

Oechslein, C.R., Fricker, G., and Kissel, T., Nasal delivery of octreotide Absorption enhancement by particulate carrier systems, 7 t. J. Pharm., 139 25-32 (1996). 

Ahsan, E., ]. ]. Arnold, E. Meezan, and D. ]. Pillion. Sucrose cocoate, a component of cosmetic preparations, enhances nasal and ocular peptide absorption. Int J Pharm 2003 251(1-2) 195-203. 

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

Marttin, E., Verhoef, J. C., and Merkus, F. W. H. M. 1998. Ef cacy, safety and mechanism of cyclodextrins as absorption enhancers in nasal delivery of peptide and protein dtdgsug Target. 6 17-36. 

Watanabe, Y., et al. 2000. Absorption enhancement of a protein drug by nitric oxide donor Effect on nasal absorption of human granulocyte colony-stimulating factor. J Drug Target 8 185. 

The total surface area of the nasal cavity is about 150 cm2, with the area available for absorption enhanced by the convolutions of the turbinates and the presence of microvilli on the surface of the ciliated and unciliated cells of the respiratory epithelium. The arterial supply of the nose is particularly rich in the respiratory epithelium where the Kiesselbach s plexus lies, an area that is rich in numerous capillary loops. The nasal blood flow has been shown to be sensitive to the action of a variety of inhaled compounds, both locally or systemically acting. Clonidine has been shown to decrease the blood flow whereas histamine and phenylephrine have been shown to induce the converse effect. Such direct changes to blood flow are important in determining the rate and extent of drug absorption from the nasal cavity. 

In chronic administration to the nasal cavity, or in the treatment of conditions where normal resistance to injury is impaired, concerns about biocompatibility are pertinent. This is particularly important if the use of absorption enhancers is being considered. 

Direct toxic effects such as irritation, inflammation, or increased permeability will bring about symptoms such as the sneeze reflex, nasal discomfort, and hypersecretion with the possibility of underlying pathological changes such as squamous metaplasia, cilia erosion, plasma exudation, epithelial necrosis, inflammatory remodeling, or neutrophil accumulation. Indirect adverse effects can also occur and any alteration to normal nasal homeostasis should be avoided. For example, a reduction in mucociliary clearance can cause rhinitis, sinusitis, and an increased susceptibility to airway infections, and consequently ciliary movement should not be altered by any nasal medication. In the context of absorption enhancers, the rate and extent of recovery of normal nasal epithelial function after nasal administration is a prime consideration. 

Another type of absorption enhancer, which has been shown to have a better safety profile, is cyclodextrin (CD) [39]. CDs have been shown to form inclusion complexes with lipophilic drugs, thereby improving their aqueous solubility and stability. A powdered insulin formulation containing dimethyl-(3-cyclodextrin improved the absolute bioavailability of insulin by 13% in rabbits compared to a control liquid formulation (1%) of insulin with dimethyl-(3-cyclodextrin [40]. Recently, hydroxypropyl (3-cyclodextrin has been shown to be more effective for enhancing the nasal absorption of acyclovir than a range of other absorption enhancers in vivo [41]. 

Merkus, F.W.H.M., et al. 1993. Absorption enhancers in nasal drug delivery—Efficacy and safety. J Control Release 24 201. 

Schipper, N.G.M., et al. 1993. Nasal insulin delivery with dimethyl- 3-cyclodextrin as an absorption enhancer in rabbits-powder more effective than liquid formulations. Pharm Res 10 682. 

The impact of the mucus layer of the nasal cavity on peptide drug absorption is poorly understood, but in the absence of absorption enhancers it could play a significant role in limiting drug absorption. Several agents that enhance nasal peptide drug absorption have demonstrable effects on the mucus layer (described below). 

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. 

Calcitonin is a peptide hormone produced in the thyroid gland that serves to lower serum calcium and phosphate levels by inhibiting bone resorption. Calcitonin has been used in the treatment of a variety of diseases, such as primary hyperparathyroidism, Paget s disease, and postmenopausal osteoporosis [99,100]. Salmon calcitonin has a longer half-life than human calcitonin. Salmon calcitonin, 3.6 kDa, is available as a nasal formulation that contains only benzalkonium chloride as a preservative, without an absorption enhancer, and as a parenteral product for injection. The direct effect of benzalkonium chloride on the nasal mucosa is under... 

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