Intranasal delivery enhancement

Parenteral calcitonin (32 aa) formulations are used to regulate calcemia. Intranasal delivery of calcitonin, a potentially convenient alternative, produces low bioavailability and is not useful as such. Permeation enhancers, including mixed micelle formulations composed of either... 

STDHF has also been shown to enhance intranasal delivery of insulin. The bioavailability of insulin (51 aa) formulated as a nasal drop or spray containing STDHF was 16% to 47% in healthy volunteers [22].The... 

Zaki NM, Mortada ND, Awad GAS, AbdElHady SS (2006) Rapid-onset intranasal delivery of metoclopramide hydrochoride part II safety of various absorption enhancers and phamacokmetic evaluation. Int J Pham 327 97-103... 

Iontophoresis techniques (i.e., the use of electric current to facilitate transdermal delivery) have also been advocated as a way to enhance transdermal opioid delivery to the systemic circulation.11 By varying the amount of electric current, iontophoresis may ultimately allow the patient to control the rate of transdermal administration of the opioid.10,76,78 Finally, certain opioids such as fentanyl can be administered systemically via lozenges or a lollipop that dissolves in the mouth (transmucosal delivery), or via nasal spray (intranasal administration).21,54 It will be interesting to see if these newer methods of administration will gain widespread acceptance in the future. 

Kagatani et al. [90] studied the effect of acylcamitines as drug absorption enhancers for the nasal delivery of azetirelin in a rat model. A buffered azetirelin sample solution was administered intranasally, as described previously [47], The nasal and oral absorptions of azetirelin were then compared. The Fabs after nasal absorption was found to be 17.1%, which was 21 times greater than the 0.8% after oral administration. As reported above, a pilot study of oral azetirelin showed a bioavailability of about 2%. A bioavailability of about 20% was seen in the case of nasally administered TRH in humans as well as rats. The authors predicted that since azetirelin is an analog of TRH, its pharmacokinetic properties after nasal delivery in humans could also be about 20% [90,91]. 

Virosomes are liposomes containing viral fusion proteins that allow efficient entering into cells fusion with endosome membranes. Viral fusion proteins become activated in the low pH environment in the endosome to release its contents into the cytosol. Hepatitis A and influenza vaccines constructed on virosomes elicited fewer local adverse reactions than did their classic counterparts and displayed enhanced immunogenicity. Virosome-formulated influenza vaccine has also been shown to be safe and immunogenic when administered by the intranasal route. Other studies have suggested that immunopotentiating reconstituted influenza virosomes can be a suitable delivery system for synthetic... 

Sulfobutylether P-cyclodextrin can form noncovalent complexes with many types of compounds including small organic molecules, peptides, and proteins. It can also enhance their solubility and stability in water. The first application of sulfobutylether P-cyclodextrin was in injectable preparations it can also be used in oral solid and liquid dosage forms, and ophthalmic, inhalation, and intranasal formulations. Sulfobutylether P-cyclodextrin can function as an osmotic agent and/or a solubilizer for controlled-release delivery, and has antimicrobial preservative properties when present at sufficient concentrations. 

Alternative means that help overcome these nasal barriers are currently in development. Absorption enhancers such as phospholipids and surfactants are constantly used, but care must be taken in relation to their concentration. Drug delivery systems, including liposomes, cyclodextrins, and micro- and nanoparticles are being investigated to increase the bioavailability of drugs delivered intranasally [2]. 

Intranasal Insulin. Insulin administered nasally has considerable potential for the treatment of both type 1 and type 2 diabetes. Using enhancers or novel delivery systems such as adequate bioadhesive microspheres, it is believed that the low bioavailability of simple formulations of insulin can be greatly improved [33]. 

Baudner, B.C., Giuliani, M.M., Verhoef, J.C., Rappuoli, R., Junginger, H.E., and Giudice, G.D. 2003. The concomitant use of the LTK63 mucosal adjuvant and of chitosan-based delivery system enhances the immunogenicity and efficacy of intranasally administered vaccines. Vaccine. 21 3837-3844. 

Nasal insulin delivery has been studied in several animal models, in vitro (Bechgaard et al, 1992 Maitani et al, 1992 Carstens et al, 1993) and in vivo using a plethora of different t es of promoters (Table IV). Intranasal insulin is better absorbed when administered as a spray than as drops (Pontiroli et al, 1987), and lyophilized insulin in an aerosol is more efficient than spray of an insulin solution (Nagai et al, 1984). As would be expected, large interspecies differences in the nasal absorption appear to exist, and enhancers differ substantially in efficacy and safety between species (Merkus et al, 1993). It is therefore extremely difficult to extrapolate absorption results obtained fi"om a particular animal study to humans. 

A great number of clinical studies of nasal insulin administration have been performed during the last 15 years (Table V Gizurarson and Bechgaard, 1991b). Negligible effect on blood glucose was observed without addition of enhancer, and the effect differed in type I and type II diabetics compared to normal subjects (Moses et al, 1983). Pharmacokinetics of intranasal insulin are close to those of intravenous insulin, as delivery to... 

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