Nasal drug delivery concentration

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]. 

As excipients, CDs have been widely used to cover the bitter taste of drugs, to increase their dissolution rates, to reduce irritation reactions and in low concentrations to suppress the haemolysis induced by some drugs [180]. Great effort has been made to develop CD-based drug formulations with different administrative routes, including parenteral, oral, pulmonary, nasal [181], transdermal, rectal [182] and ophthalmic [183] drug delivery [184]. 

Among the cyclodextrins, the use of DMpCD was shown to have the highest effect on the transnasal bioavailability of insulin in rats. Several studies reported on their concentration-dependent effect. Besides for peptides, the methylated p-cyclodextrins have shown to be useful in nasal delivery of lipophilic drugs. The toxicological profile of dimethyl p-cyclo-dextrins and of randomly methylated p-cyclodextrins appeared excellent. Attention should be paid, if possible, onbioavailability differences between animal and human models. 

The nasal route of delivery is not applicable to all drugs. Polar drugs and some macromolecules are not absorbed in sufficient concentration because of poor membrane permeability, rapid clearance, and enzymatic degradation into the nasal cavity. 

Intemasal delivery of peptide and protein drugs is severely restricted by pre-systemic elimination due to enz5miatic degradation or mucociliary clearance and by the limited extent of mucosal membrane permeability. a-CyD has been shown to remove some fatty acids from nasal mucosa and to enhance the nasal absorption of leuprolide acetate in rats and dogs. The utility of chemically modified CyDs as absorption enhancers for peptide drugs in rats has been demonstrated. For example, DM-P-CyD was shown to be a potent enhancer of insulin absorption in rats, and a minimal effective concentration of DM-(3-CyD for absorption enhancement exerted only a mild effect on the in vitro ciliary movement.The scope of interaction of insulin with CyDs is limited, because CyDs can only partially include the hydrophobic amino acid residues in peptides with small stability constants. Under in vivo conditions, these complexes will readily dissociate into separate components, and hence the displacement by membrane lipids may further destabilize the complexes. The direct interaction of peptides with CyDs is therefore of minor importance in the enhancement of nasal absorption. Of the hydrophilic CyDs tested, DM- 3-CyD had the most prominent inhibitory effect on the enzymatic degradation of both BLA and insulin in rat nasal tissue homogenates. Because of the limited interaction between peptides and CyDs,... 

The delivery of freeze-dried preparations can be performed by different routes oral, nasal, anal, pulmonary, transdermal and parenteral. Of these routes, some do not require any treatment of the drug before it is administered, e.g. in the form of powders or tablets or in inhaling devices. For parenteral administration, however, whether by injection or infusion, the freeze-dried cake must be returned to a liquid state, a process referred to as reconstitution . The main vehicle will normally consist of water for injection or a solution, the concentration of which will establish isotonicity. The time required for the complete dissolution of the cake may in some cases be critical and should therefore be known. 

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