DELIVERY OF PROTEINS: ROUTES OF ADMINISTRATION AND ABSORPTION ENHANCEMENT

1. DELIVERY OF PROTEINS: ROUTES OF ADMINISTRATIONAND ABSORPTION ENHANCEMENT Saeb Aliwaini

2. Parenteral Route of Administration • Intravenous (IV) • Intramuscular (IM) • Sub-cutaneous (SC) • Intraperitoneally (IP) • Intraosseous (IO) Saeb Aliwaini

3. Lymphatic System • One way system: to the heart • Return of collected excess tissue fluid • Return of leaked protein • “Lymph” is this fluid • Edema results if system blocked or surgically removed Saeb Aliwaini

4. Lymph capillaries • Have one way minivalves allowing excess fluid to enter but not leave • Picks up bacteria and viruses as well as proteins, electrolytes and fluid (lymph nodes destroy most pathogens) Saeb Aliwaini

5. Saeb Aliwaini

6. The Oral Route of Administration Preferable way but; • protein degradation (ii) poor permeability Saeb Aliwaini

7. protein degradation • Pepsins cleave peptide bonds between two hydrophobic amino acids at acidic ph. Other endopeptidases ( trypsin, chymo-trypsin, and elastase) are active in the GI tract at neutral pH values Exopeptidases(carboxypeptidaseA and B) Saeb Aliwaini

8. Permeability • High molecular weight molecules do not readily penetrate -The oral route of administration for therapeutic proteins is not the best choice till now. Saeb Aliwaini

9. Exceptions • Oral vaccines: only a (small) fraction of the antigen (protein) has to reach lymphocytes and antigen presenting accessory cells located in Peyer’s patches. The B-lymphocyte population includes cells that produce secretory IgA antibodies Saeb Aliwaini

10. Peyer’s patches microfold (M) cells little lysosomal degradation capacity Goblet cell density is reduced over Peyer’s patches. This facilitates access to the M cell To improve antigen delivery via the Peyer’s patches and to enhance the immune response by using microspheres, liposomes or modified live vectors, such as attenuated bacteria and viruses have been used. Saeb Aliwaini

11. Saeb Aliwaini

12. Alternative Routes of Administration The nose, lungs, rectum, oral cavity, and skin have been selected as potential sites of application. Nasal, buccal, rectal, and transdermal routes needs absorption enhancing technology -The bioavailability in rats of intratracheally administered protein solutions with a wide range of molecular weights. -In humans the drug should be inhaled instead of intratracheallyadminstered The first pulmonary insulin formulation was approved by FDA in January 2006 Saeb Aliwaini

13. Uptake of insulin is faster than after a regular SC insulin injection (peak 5–60 minutes versus 60–180 minutes). • The fraction of insulin that is absorbed from the lung is estimated to be around 20% • These figures demonstrate that insulin absorp-tion via the lung may be a promising route; but the fraction absorbed is small. Saeb Aliwaini

14. We still look to develop a system that temporarily decreases the absorption barrier resistance with minimum and acceptable safety concerns • Suggestions : - Absorption Enhancing Effects Saeb Aliwaini

15. Mechanism of Absorption Enhancement: Permeation enhancers in general act by following ways : 1. Increasing the fluidity of the cell membrane 2. Extracting inter and intracellular lipids 3. Disrupting lipid structure e.g., solubilization by formation of micelles to create aqueous channels 4. Altering cellular proteins 5. Increasing the thermodynamic activity of the drug 6. Overcoming enzymatic barriers, particularly for peptide and protein drugs 7. Altering surface mucin rheology Saeb Aliwaini

16. Saeb Aliwaini

17. Sodium glycodeoxycholate acts in the intercellular lipid domain at lower concentrations (2 mM), apparently reducing the amount of polar lipids, whereas disorganizing cell membrane lipids at higher concentrations Generally, they act reversibly without producing major damage to the mucosa. Bile salts used in permeation enhancement studies include the trihydroxy salts sodium cholate, sodium glycocholate, and sodium taurocholate and the dihydroxy salt sodium deoxycholate, sodium glycodeoxycholate, and sodium taurodeoxycholate. Saeb Aliwaini

18. Major issues now being addressed are reproducibility, effect of pathological conditions on absorption and safety aspects of chronic use. Interestingly, absorption enhancing effects were shown to be species dependent. Pronounced differences in effect were observed between rats, rabbits, and humans. Saeb Aliwaini

19. Iontophoresis Iontophoresisa transdermal electrical current is induced by positioning two electrodes on different places on the skin Saeb Aliwaini

20. Saeb Aliwaini