1. Oral insulin delivery: Existing barriers and current counter-strategies 1 S.Nikhil PE/2017/315

2. Prevalence of diabetes globally Introduction of Insulin Disadvantages of SC Injections Benefit of oral Insulin Reasons for oral Insulin Challenges in oral insulin delivery 2 Flow of presentation

3. Prevalence of Diabetes globally 3

4. ACTIONS OF INSULIN 4 Introduction of Insulin

5. Disadvantages of the SC route >2 Injections needed to reduced long-term complications hyperglycaemia Patient non compliance Repeated injections results in lipoatrophy & lipohypertrophy Insulin given by SC directly go to circulation cause hyperinsulinemia 5

6. 1. Patient compliance2. Convenient3. Painless4. Easy for self-medication5. Avoid weight gain6. Reduces danger of hypoglycemic incidents, immune responses7. Cost effective Benefits of an oral insulin delivery 6

7. Why oral insulin Physiological reasons Oral insulin better replicates the normal physiological insulin pathway leads to better glucose homeostasis Abs > liver > systemic circulation liver is sensitive to insulin, and within few minutes, glucose production by the liver is blocked by a portal insulin concentration oral insulin plays a role in protection of b-cells of the pancreas from autoimmune destruction. Pharmaceutical reasons 7

8. ` x 8 c 1.weight gain 2.Hyperinsulinemia

9. The mucous layer Intestinal epithelium Tight junctions Luminal pH: Enzymatic degradation Challenges in oral delivery of insulin Physical barriers Biochemical barrier 9

10. 10

11. 11 Barrier Strategies introducedExamples of agents used and/or contributing factor Major findings Mucus layer Mucoadhesive systems PLGA, thiomers Mucus penetration systems Chitosan, alginate, polyacrylic acid The strategy increases the residence time of the delivery system at the absorption site Hydrophilic polymer coating such as (PEG), Virus-mimicking strategy (highly charged surface) Mucoadhesive polymers provide an intimate contact with the mucosa at the drug uptake site Increased the residence time of the delivery system at the absorption site Efficient mucus permeation requires:highly densely charged surface, Hydrophilic shell and slightly negative surface charge Intestinal epithelial cells and the transcellular route Carrier-mediated transcellular Absorption Cell penetrating peptides (CPPs) Absorption enhancers Transferrin, immunoglobulins biotin, lectins, folate, vitamin B12 Penetratin, oligoarginine, transportan EDTA, surfactants, fatty acids, ZOT Due to their large molecular weight, conjugation of proteins to receptor- recognisable ligands will have the potential to improve cellular internalisation Perturbing cell membrane, endocytosis or even channel formation could be a possible mechanism of their action Perturb the cell membrane

12. BarrierStrategies introduced Examples of agents used and/or contributing factorMajor findings Tight junction and paracellular Route Absorption enhancers Selectively open tight junctions Particulate carrier systems Lipid suspension, liposomes, submicroemulsion, nanospheres, SLN, HDV-I, SNEDDS Selectively open tight junctions They circumvent the harsh gastric conditions without affecting the bioactivity of macromolecules like insulin M cells of Peyer’s patches play a unique role in the uptake of small particles Luminal pHColon-targeting and enteric coatingCODES, capsulin, ORMD-0801Low level of luminal and brush border proteases Enzymatic degradationProtease inhibitorsNa-glycocholate, soya bean trypsin inhibitor, aprotinin, bacitracin, camostat mesilate, chicken and duck ovomucoids Concerns about long-term use and protein malabsorption 12

13. Clinical-stage technologies for oral peptide delivery 13

14. 14

15. PROTEIN ORAL DELIVERY TECHNOLOGY POD™ Enteric coated capsule have oily suspension of peptide Absorption enhancer; soy bean trypsin inhibitor Enzyme inhibitor EDTA or biles alt Oramed`s oral delivery offers platform for protection of proteins and enhance absorption reach blood circulation via portal vein establishing physiological protein gradient when compared to other delivery system 15

16. ELIGEN TECHNOLOGY This technology uses SNAC (sodium N-[8-(2-hydroxybenzoyl)amino] caprylate or salcaprozatesodium) 5-CNAC (N-(5-chlorosalicyloyl)-8-aminocaprylic acid), 4-CNAB (4-[(4-chloro-2-hydroxy- benzoyl)amino]butanoic acid) SNAD (N-(10-[2-hydroxybenzoyl]-amino)decanoic acid) as absorption enhancers SNAC achieved generally recognised as safe (GRAS) status 16

17. Robotic pill to replace injection Might replace insulin shots Balloon, needle and drug, are assembled in a cellulose capsule shell coated with a pH-sensitive polymer that is designed to dissolve at a pH >6.5. Capsule goes duodenum, and the pH rises above 6.5, the outer shell dissolves, triggering the chemical reaction inside the balloon. The balloon then inflates and delivers the needle with the drug. Once the needle is delivered, all that is left is a deflated polymer, having the consistency of a bell pepper skin or tomato skin, which the patient passes out 17 RANI AUTO PILL

18. 18

19. conclusion Relative bioavailability is still low Even with the most advanced state-of-the-art technologies, limiting their application. Most advanced technologies still suffer considerable food effects drug-drug interactions – an issue which, if addressed, could significantly improve on the currently available technologies. 19

20. References Gedawy, A., et al. “Oral insulin delivery: existing barriers and current counter ‐ strategies”. Journal of Pharmacy and Pharmacology, (2018). 70(2), 197-213. Matteucci, E., et al. “Insulin administration: present strategies and future directions for a noninvasive (possibly more physiological) delivery”. Drug design, development and therapy, (2015). 9, 3109. Hassani, L. et al. “Oral peptide delivery: technology landscape and current status. On Drug Delivery”, (2015). 59, 12- 17. Aronoff, S. L., et al. “Glucose metabolism and regulation: beyond insulin and glucagon”. Diabetes Spectrum, (2004). 17(3), 183-190. Hirlekar, R. S. “Oral Insulin Delivery: Novel Strategies. Asian Journal of Pharmaceutics (AJP)”. Asian J Pharm, (2017). 11(03). 20