NASAL DELIVERY OF INSULIN

 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

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

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

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

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

 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

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

 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

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

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

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

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 minutes. 13

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

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

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

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

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

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

 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

Soluble starch (microspheres & powder) EnhancerAnimal model Result -RatsA comparison between microspheres and starch powders (mw and 25000) indicated that the insoluble starch of mw & 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

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

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

 Nose Spray  Nasal Gel  Hydrogel Formulation Formulations 24

 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

 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

 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

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

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

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