**4. Nasal route**

Delivery of protein or peptide via nasal route has been employed in delivering desmopressin, calcitonin, and seasonal influenza vaccine [137, 138]. Advantages of this method include patient convenience and comfort, elimination of needlerelated injuries and infections, and decreased syringe-related medical waste. Some disadvantages of this method include nasal irritation, limitation on the amount of drug that can be delivered, peptidases, and large interpatient variability in absorption. However, highly effective and non-irritating absorption enhancers have been developed to overcome some of the limitations [139]. This route could be important for drugs used in crisis treatment (e.g., pain, sleep induction, panic attack, nausea, heart attack, etc.) due to the rapid absorption of drugs from the nasal cavity to the systemic circulation. In some of these cases, the putative pathway from nose to brain might provide a faster and more specific therapeutic effect [140]. This route is also very important for delivering drugs against respiratory infections since this route provides not only systemic immune response but also local mucosal immune response. The latter should provide a much higher immune response against these diseases. Considering the potential benefits of this route of delivery, we can expect novel nasal products in the near future. Some nasal delivery systems are described below.

#### **4.1 Chitosan**

Chitosan has attracted much attention as a nasal delivery system recently. Chitosan is produced by the deacetylation of chitin found in crustacean shells. The resulting free amino groups allow chitosan to exist in the protonated form (see Section 2.9.2) in the acidic environment. Chitosan glutamate is a pharmaceutically acceptable chitosan salt for nasal drug delivery. It has an average molecular weight of ~250 kDa and a degree of deacetylation > 80% [140]. A nasal morphine product containing chitosan as an absorption enhancer is being investigated. Morphine is a polar drug and is not readily absorbed via the nasal route using simple formulations [141]. However, the addition of chitosan to the nasal formulation leads to a remarkable increase in nasal morphine absorption. As discussed in Section 2.9.2, chitosan improves the transport of polar drugs across the epithelial membrane via the transient opening of the tight junctions in the cell membrane [142–144]. Another mechanism of improving the transport of polar drug across the epithelial membrane by chitosan is via bioadhesion. Finally, chitosan is non-toxic and nonirritant to the nasal membrane [145].

Other cationic polymers, such as poly-L-Arg and aminated gelatin has also been investigated for their application as absorption enhancers. These polymers work in a way similar to chitosan. These polymers improve the absorption of fluorescein-isothiocyanate (FITC)-dextran and insulin with negligible nasal toxicity [146–148].
