1. Novel delivery systems for treating Type 1 diabetes Nasal Systems Han Yi Chua Gek Huey

2. Outline • Rationale • System description • Evidence for efficacy • Stage of development

3. Rationale • 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

4. Nasal cavity anatomy Increased absorption area turbinates Epithelia monolayer High permeability & rapid absorption

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 • Difficulty of penetrating mucus layer and epithelial membrane • Enzymatic degradation

7. Removal of deposited insulin by mucociliary clearance • Mucociliary mechanism 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

8. Penetration of 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

9. Enzymatic degradation • Nasal cavity is still a significant barrier although intranasal route avoids first pass metabolism

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

11. Formulation types in current research • Spray • Drop • Powder

12. 1922 1931 1932 1935/6 • Major[123,124] • Uses glycols • Normal rabbits, dogs and diabetic patients • Marked decreases in blood glucose conc. • high dosage: 100IU nasal • Poor reproducibility of hypoglycaemic control Woodyatt[23] Fail to generate positive results Horwitz[121] Failed to demonstrate insulin absorption thru nasal route • Collens[122] • Uses saponin (natural glycoside surfactant) • 100IU nasal  10IU subcutaneous injection • Causes nasal congestion & • symptoms of rhinitis Evidence of efficacy (I)

13. 1958 • Hankiss[125] • Nasal tampons (increased contact time) • Healthy volunteers and diabetic patients • 53% that of subcutaneous injection • No absorption promoter used • Unstable & variable • Efficacy calculated 60 mins after administration (subcutaneous injection had not reached nadir) Evidence of efficacy (II)

14. Bile salts SGC SDC STDHF 1977 1983 1987 1988 1989 1994 Laureth-9 Surfactants LPC DDPC LPG Fatty acids Evidence of efficacy (III)

15. Bioadhesive Carbopol Starch microshperes Chitosan 1985 1988 1996 • Chitosan • Rel. Bioavailability (subcutaneous)= 15% • Rel. Bioavailability (intravenous) = 7% • Starch microspheres: • 30% to intravenous dose • Abs bioavailability = 4.5% • Starch microshperes with LPC: • Abs. bioavailability = 13% • Rel. bioavailability (intravenous)= 32% Evidence of efficacy (IV)

16. 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

17. Nasal absorption promoting system

18. Systemic insulin absorption after intranasal administration to humans

19. Problems with enhancers

20. Modification of structure • Lys(B28)Pro(B29) insulin analogues [Merkus, 1996] • Powder formulation with cyclodextrin • Chemical modification with fatty acids [Asada, 1992] • Enhance lipophilicity • Pharmacological availability decreased

21. 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

23. Bioadhesive • Interacts with mucosal layer Back

24. 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 • Does not cause change in saccharin clearance times • No adverse effect in nasal cilia beat frequency • Non-damaging to biomembranes • Reversible reduction in nucociliary transport rate (MTR) Back

25. Bile Salts • Amphiphilic molecules • Possess distinct non-polar and polar regions • critical micellar concentration • Arrest cilia beat frequency • Damage nasal mucosa Back

26. Surfactants • Lower surface and interfacial tension of water • Promote association into micelles • Modify properties of biological membranes • Alter their permeability and transport characteristics Back

27. Fatty acids • Organic compounds which are principal component of most lipids and consist mainly of straight chains of an even number of carbon atoms Back