Intranasal Drug administration Alleviation of local symptoms The nasal mucosa appears to be permeable to drugs more than the GI mucosa Local metabolism is low No first pass metabolism

Anatomy and histology Nasal septum divides the nasal cavity into two cavities. Each part consists of three regions 1. Vestibule 2. Olfactory region 3.Respiratory region: three nasal turbinates: the superior, the middle and inferoir.

Propranolol absorption Peptides and Proteins Absorption enhancers: toxicity Factors that influence nasal abs Enzymatic activity: proteases and amino peptidases are present Complexation: immunoglobulins Formulation pH: Osmolarity: to avoid shrinkage of cells Pathological condition

Nasal Mucosa to Deliver Insulin Improving patient compliance compared with parenteral routes “Large” absorptive surface area and the high vascularity of the nasal mucosa Avoiding hepato-gastrointestinal first-pass metabolism Similar plasma pharmacokinetics (PK) profile to intravenous injection Mimicing pulsatile secretion pattern of insulin Mucociliary clearance – cilia & mucus Insoluble particles removed before being absorbed Gases/solution penetrate further into respiratory tract

Structure of nasal mucosa Mucociliary clearance – cilia & mucus Insoluble particles removed before being absorbed Gases/solution penetrate further into respiratory tract

Barriers to intranasal insulin absorption Removal of deposited insulin by mucociliary clearance: t1/2 of clearance is only 15-30min: decreases time available for drugs to be systemically absorbed Size of particles suitable for nasal delivery: particle aerodynamic diameter: 1-10µm Difficulty of penetrating mucus layer and epithelial membrane Mucus layer: Drugs may interact with mucus glycoproteins Epithelial membrane: Lipophilic compounds via transcellular route Hydrophilic compounds (MW< 1000 daltons): via paracellular route Enzymatic degradation: Nasal cavity is still a significant barrier although it avoids first pass metabolism Systems to Improve Absorption Absorption enhancers or promoters: most frequently used approach Modification of the structure of insulin

System modification Absorption enhancers or promoters most frequently used approach Modification of the structure of insulin

Requirements of enhancer Rapid-acting Transient & reversible modulation Not absorbed systemically Predictable & reproducible degree of absorption enhancement Safe for chronic nasal administration Open tight junction, disrupt membrane

Nasal absorption promoting system

Systemic insulin absorption after intranasal administration to humans

Problems with enhancers LPC = lysophosphatidylcholine DDPC = didecanoyl-L-alpha-phosphatidylcholineBile salts damage nasal epithelim   ciliatoxicity Surfactants low potency -> high dosses -> high cost IgA production -> inactivate insulin chronic rhinitis, loss of sense of smell Chelating agents did not significantly alter rate of nasal clearance Fatty acids metabolic disregulation damage mucosa Enzyme inhibitors insufficient factor to increase bioavailability

Modification of structure Lys(B28)Pro(B29) insulin analogues Powder formulation with cyclodextrin Chemical modification with fatty acids Enhance lipophilicity Pharmacological availability decreased

Use of Bioadhesives Chitosan Enhance via paracellular route due to interaction of negatively charged epithellial cells resulting in structural changes in tight junction associated protein Increase membrane permeability Bioavailability abt 15% relative to subcutaneous; 7% relative to intravenous No adverse effect in nasal cilia beat frequency Non-damaging to biomembranes Reversible reduction in mucociliary transport rate (MTR)

Successful Phase I Study Of Intranasal Insulin In Human Volunteers Stage of development Bentley Pharmaceuticals (BNT) 02 Feb 2004 Phase I clinical trial using proprietary intranasal insulin formulation in human volunteers http://www.biospace.com/ccis/news_story.cfm?StoryID=15018420&full=1 Successful Phase I Study Of Intranasal Insulin In Human Volunteers End

Formulation types in current research Spray Drop Powder