Sheep nasal

F. Y. Chung and M. D. Donovan. Nasal pre-systemic metabolism of peptide drugs Substance P metabolism in the sheep nasal cavity. Int J Pharm 128 229-237 (1996). 

Soane, R. J., Hinchcliffe, M., Davis, S. S, Ilium, L. (2001]. Clearance characteristics of chitosan based formulations in the sheep nasal cavity. Int. 1. Pharm.. 217,183-191. 

K. Kojima, L.J. Bonassar, A.K. Roy, H. Mizuno, J. Cortiella, C.A. Vacanti, A composite tissue-engineered trachea using sheep nasal chondrocyte and epithelial cells, FASEB J. 17 (8) (May 2003) 823-828. 

JP Longenecker, AC Moses, JS Flier, RD Silver, MC Carey, EJ Dubovi. (1987). Effects of sodium taurodihydrofusidate on nasal absorption of insulin in sheep. J Pharm Sci 76 351-355. 

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... 

Excised nasal mucosae obtained from various animal species are tools frequently used to study nasal transport and metabolism ([53], Chap. 4). Maintaining the viability of the excised nasal tissues during the experimental period is crucial. Most studies were performed with epithelia excised from rabbits, bovine, sheep, and dogs tissues [54-57], This excised nasal tissue model has been shown to be well suited for studies on nasal permeation and metabolism of drugs. However, species differences in the activity of various enzymes found in human versus these animal nasal mucosae have become an important issue. 

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. 

Nasal tissue from animals can be mounted in Ussing chambers, permitting experiments similar to those performed in cell cultures to be performed in intact tissues. The nasal tissues of rabbits, dog, sheep, and cattle have been used and such experiments provide the reassurance that the ex vivo system is representative of the nasal mucosa in vivo. The limitations of this technique are the requirement for the use of fresh tissue, the limited duration of tissue viability, and interspecies variation in tissue permeability and metabolic capacity. 

Chitosan is a cationic polysaccharide produced from the deacetylation of chitin, a component of crab and shrimp shells [7,57,58], Chitin is composed of units of 2-deoxy-2-(acetylamino) glucose joined by glycosidic bonds that form a linear polymer. Ilium et al. [7,57,58] demonstrated the ability of chitosan to increase the bioavailability of insulin and other small peptides and polar macromolecules in different animal models. In both the sheep and rat models, the addition of chitosan at concentrations of 0.2%-0.5% to nasal formulations of insulin resulted in significant increases in plasma insulin and reductions in blood glucose. Reversibility studies indicated that the effect of chitosan on the nasal absorption of insulin... 

Dogs, sheep, and monkeys can be kept conscious during nasal delivery to mimic the human [51]. Sheep, because of their large nostrils and docile nature, serve as excellent models for studies of this kind. 

Chitosan is a linear cationic polysaccharide made up of copolymers of glucosamine and A-acetylglucosaminc. It is commercially obtained by alkaline deacetylation of chitin [53, 68] and has been used for the nasal delivery of a number of drugs. The usefulness of chitosan in the enhancement of nasal absorption was reported first by Ilium [69]. Later, Ilium and his group also published experimental results indicating that solution formulations with 0.5% chitosan promoted the absorption of nasally administered insulin in rat and sheep [70]. 

Since the concentrations of insulin to be administered in the sheep model would have been large, the insulin-loaded chitosan nanoparticles were not investigated in that model. However, the pharmacodynamics and pharmacokinetics of various insulin-chitosan preparations were compared with postloaded insulin-chitosan nanoparticles. It was found that chitosan solution and chitosan powder formulations were far better, with the chitosan powder formulation showing a bioavailability of 17% as against 1.3 and 3.6% for the chitosan nanoparticles and chitosan solution [72], The effects of the concentration and osmolarity of chitosan and the presence of absorption enhancers in the chitosan solution on the permeation of insulin across the rabbit nasal mucosa in vitro and in vivo were investigated, and the same... 

FIGURE 17 Morphine plasma concentration after nasal administration of morphine formulations in sheep Mor Sol, morphine solution Mor Chi Sol, morphine solution containing chitosan Mor Chi PWD, morphine chitosan powder Mor SMS LPC, starch microspheres with lysophosphatidylcholine and morphine as a freeze-dried powder. (Reproduced from ref. 105 with permission of the American Society for Pharmacology and Experimental Therapeutics.)... 

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. 

The nasal absorption of insulin after administration in chitosan powder was the most effective formulation for nasal delivery of insulin in sheep compared to chitosan nanoparticles and chitosan solution [11], Similarly, chitosan powder formulations have been shown to enable an efficient nasal absorption of goserelin in a sheep model where bioavailabilities of 20-40% were obtained depending on the nature of the formulation [9],... 

There has been a report on chitosan utility in improving the intranasal absorption of high-molecular-weight (>10-kDa) therapeutic protein. Chitosan glutamate powder blend or granules with recombinant hGH have been evaluated for intranasal administration in sheep. Relative to subcutaneous injection the nasal formulations produced bioavailabilities of 14 and 15%, respectively [77],... 

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],... 

Ilium, L., Faraj, N., Davis, S., Johansen, B., and O Hagan, D. (1990), Investigation of the nasal absorption of biosynthetic human growth hormone in sheep Use of a bioadhesive microsphere delivery system, Int. J. Pharm., 63,207-211. 

Critchley, H., Davis, S. S., Farraj, N. F., and Ilium, L. (1994), Nasal absorption of desmopressin in rats and sheep. Effect of a bioadhesive microsphere delivery system, / Pharm. Pharmacol., 46, 651-656. 

Hyaluronic acid ester In sheep Increased nasal absorption 128... 

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