1. NASAL DELIVERY OF INSULIN

2.  Insulin is a peptide hormone composed of 51 amino acids & has molecular weight of 5808 Da  It is produced in the islets of Langerhans in the pancreas  Type I Diabetes Mellitus- External Insulin Type II Diabetes Mellitus- Insulin resistant INTRODUCTION 2

3. What are delivery systems?  Conventional Delivery Insulin syringes  Painless Delivery Oral Delivery Pulmonary Delivery Intranasal Delivery Transdermal Delivery Ocular Delivery Rectal Delivery Transmucosal Delivery 3

4. Why nasal Delivery?  High permeability of nasal mucous membrane  Fairly wide absorption area  Porous and thin endothelial basement membrane of the nasal epithelium  Transfer of drug into blood is faster  Avoids hepatic first pass effect  Rapid action and low risk of overdose 4

5. Challenges for nasal delivery?  Nasal bioavailability of insulin is low due to it’s hydrophilic structure  Mucociliary clearance  Enzymatic barriers and irritation of the nasal mucosa  presence of pathological conditions 5

6. About nasal route  Consists of three functional areas, namely the vestibular, respiratory and olfactory.  In respiratory area drugs are absorbed to greatest interest.  Particles larger than 10 μ m are accumulated in the respiratory area via respiration, those smaller than 5 μ m are inhaled and reach the lungs, and those smaller than 0.5 μ m are exhaled.  Nasal epithelia are covered with a new mucus layer approx. every 10 min. 6

7.  Adhere to the mucus in the nasal cavity or are dissolved in the mucus and pushed to the nasopharynx to be thrown into to the gastrointestinal channel.  The clearance of the mucus and the components is called mucocilliary clearance.  The passage of drugs via the nasal mucosa is achieved in three ways, which are paracellular, transcellular and transcytotic. 7

8. (1) Paracellular route (1a) intercellular spaces, (1b) tight junctions, (2) transcellular route (2a) passive diffusion, (2b) active transport, (3) transcytosis 8

9.  Low bioavailability of HMW drugs like insulin is enhanced by various approaches- Modification of chemical structure of HMW molecules. Applied with enzyme inhibitors. Inclusion of absorption enhancers. Development of novel formulations including drug carrier systems. 9

10. Various approaches for delivery Insulin Nasal Delivery Microspheres Nanoparticles Powders Permeation enhancer 10

11.  Degradable starch  Crosslinked starch & Dextran  Hyaluronic Acid Ester  Aminated gelatin 1. Microspheres 11

12. Degradable starch EnhancerAnimal model Result LFCSheepWhile the relative bioavailability of insulin from microspheres was10.7%, addition of enhancer to the formulation, bioavailability of insulin was increased to 31.5%. 12

13. Crosslinked starch & Dextran EnhancerAnimal model Result EpichlorohydrinRatsThe effect on the glucose level of insulin from starch and dextran microspheres was rapid and maximum decrease in plasma glucose level was achieved in 30- 40 minutes. 13

14. Hyaluronic Acid Ester EnhancerAnimal modelResult -SheepAverage relative bioavailability of insulin from microspheres was calculated as 11% when compared with insulin administered by subcutaneous route. 14

15. Aminated Gelatin EnhancerAnimal modelResult -RatsAminated gelatin microspheres have significantly increased the nasal absorption of insulin when administered in dry formulation but no significant hypoglycemic effect was observed when given as a suspension. 15

16.  Crosslinked starch  Chitosan  Cross linked Chitosan  Thiolated Chitosan 2. Nanoparticles 16

17. Chitosan EnhancerAnimal model Result NACRatsNasal administration of chitosan- NAC nanoparticles increased the insulin absorption compare to unmodified chitosan nanoparticles and control insulin solution. 17

18. Crosslinked chitosan EnhancerAnimal model Result -RatsMicrospheres containing chitosan and ascorbyl palmitate caused a 67% reduction of blood glucose compared to intravenous route and absolute bioavailability of insulin was found as 44%. 18

19. Thiolated Chitosan EnhancerAnimal modelResult -RatsInsulin-loaded thiolated chitosan microspheres let to more than 1.5-fold higher bioavailability and more than 7-fold higher pharmacological efficacy than unmodified chitosan microspheres. 19

20.  Soluble starch  Starch- Carbopol® 974P and maltodextrin - Carbopol® 974P  Amioca® starch and Carbopol® 974P  Anionic resin (SPS), nonionic resins (PAE, SDBC) and cationic resin (CA) 3. Powders 20

21. Soluble starch (microspheres & powder) EnhancerAnimal model Result -RatsA comparison between microspheres and starch powders (mw 11000 and 25000) indicated that the insoluble starch of mw 25000 & the microspheres reduced the plasma glucose level to the same extent. Besides water soluble starch powder (mw11000) did not change the plasma glucose level. 21

22. Starch- Carbopol® 974P and maltodextrin - Carbopol® 974P EnhancerAnimal model Result -RabbitsThe nasal bioavailability achieved with the application of Starch-Carbopol® 974P powder was significantly higher than that of the maltodextrin-Carbopol® 974P mixtures. 22

23. Amioca® starch and Carbopol® 974P EnhancerAnimal modelResult -RabbitsFollowing nasal single-dose application of a physical mixture of Amioca® starch and Carbopol® 974P (9/1) the bioavailability of insulin has been found to be more than 10%. 23

24.  Nose Spray  Nasal Gel  Hydrogel Formulation Formulations 24

25.  Useful for Alzheimer's Disease.  Insulin abnormalities contribute to the pathophysiology of AD  Intranasal insulin provides rapid delivery of insulin to the CNS without adversely affecting blood insulin or glucose levels. Nose Spray 25

26.  Combination of carbopol and hydroxypropyl methylcellulose as gelling agent  The in vivo efficacy was assessed by measuring the blood glucose levels and serum insulin levels at specified time intervals in rats and humans  Promoted the prolonged contact between the drug and the absorptive sites as well as facilitated direct absorption of medicament Nasal Gel 26

27.  characteristics of mucoadhesion and the ability to facilitate transport of insulin were achieved through the employment of trimethylated chitosan.  Combination with glycerophosphate and polyethylene glycol provide a barrier to the continuous clearance mechanism of the cilia.  Prolonging the residence at mucosal surfaces Hydrogel Formulation 27

28. Factors affecting pharmacokinetics & bioavailability of intranasal administrations  Physiological factors Speed of mucous flow Change in physiological state Atmospheric conditions in nasal cavity  Dosage form factors Physicochemical properties of active drug Concn. of active drug Physicochemical properties of excipients Density, viscosity, and pH Toxicity of dosage form 28

29.  Yie W. Chien, “Novel Delivery Systems,” Second Edition, Revised And Expanded, Marcel Dekker Series, Page No. 229-267.  Yıldız Ozsoy, Sevgi Gungor and Erdal Cevher; Nasal Delivery of High Molecular Weight Drugs. Molecules, 2009,14, 3759-3763.  Jaleh Varshosaz, Insulin Delivery Systems for Controlling Diabetes. Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2007, 1, 25-40 Reference 29

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