1. 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

2. 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.

3. 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

4. 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

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

6. 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

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

8. 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

9. Nasal absorption promoting system

10. Systemic insulin absorption after intranasal administration to humans

11. 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

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

13. 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)

14. 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
Successful Phase I Study Of Intranasal Insulin In Human Volunteers
End

15. Formulation types in current research
Spray
Drop
Powder