1. PHARMACEUTICS- IV (PHT 414 ) Dr. Shahid Jamil PRINCE SATTAM BIN ABDUL AZIZ UNIVERSITY COLLEGE OF PHARMACY 1/15/20161 NASAL DRUG DELIVERY SYSTEM

2. 1/15/2016 2 NASAL DRUG DELIVERY SYSTEM

3. 1/15/2016 3 Inhalation/pulmonary drug delivery system includes  Metered dose inhalers  Dry powder inhalers  Inhalation nasal sprays  Inhalation solutions & suspensions (for nebulizers)

4. 1/15/2016 4 Avoidance of hepatic first-pass metabolism Merits Rapid onset of pharmacological action User-friendly, painless, non-invasive, needle-free administration mode Rate of absorption comparable to IV medication

5. 1/15/2016 5 Lower dose & hence lower side effects Merits... For CNS drugs, better site for rapid onset of action Eg. Inhalation anesthesia, Morphine etc. Useful for both local & systemic drug delivery

6. 1/15/2016 6 Limitations  Pathologic conditions such as cold or allergies may alter significantly the nasal bioavailability  Once administered, rapid removal of the therapeutic agent from the site of absorption is difficult

7. 1/15/2016 7 NASAL ROUTE - medical aspects

8. 1/15/2016 8  The respiratory tract, which includes the nasal mucosa hypopharynx large airways & small airways  provides a relatively large mucosal surface area of approx. 100 m2 (in normal adult) for drug absorption

9. 1/15/2016 9 Cross-sectional view Pathways for nasal absorption Nasal site of drug spray & absorption

10. 1/15/2016 10 Cross-sectional view a – nasal vestibuled – middle turbinate b – palatee – superior turbinate (olfactory mucosa) c – inferior turbinatef – nasopharynx

11. 1/15/2016 11 Site of drug spray & absorption

12. 1/15/2016 12 Pathways for nasal absorption  Absorption through the olfactory neurons - transneuronal absorption. Olfactory epithelium is considered as a portal for substances to enter CNS  Absorption into the cerebrospinal fluid  Absorption through the supporting cells & the surrounding capillary bed - venous drainage

13. 1/15/2016 13 Transneuronal absorption Olfactory nerve – 1 st cranial sensory nerve

14. 1/15/2016 14 Cytochrome P 450 dependent monooxygenases, Lactate dehydrogenase, Oxidoreductase, Hydrolases, Esterase, lactic dehydogenase, malic enzymes, lysosomal proteinases, steroid hydroxylases., etc., Cytochrome P450 dependent mono oxygenases has been reported to catalyse the metabolism of xenobiotics, nasal decongestants, nicotine, cocaine, phenacetin, nitrosamine progesterone etc., Insulin zinc free was hydrolysed slowly by leusine aminopeptidase, PG of E series was inactivated 15 hydroxyprostaglandin dehydrogenase Nasal enzymes

15. 1/15/2016 15 Progesterone and testosterone were metabolized by several steroid hydroxylases in the nasal mucosa of rats Nasal enzymes – contd.,

16. 1/15/2016 16 Nasal secretion of adult : 5.5-6.5 Infants and children: 5-6.7 It becomes alkaline in conditions such as acute rhinitis, acute sinusitis. Lysozyme in the nasal secretion helps as antibacterial and its activity is diminished in alkaline pH Nasal pH

17. 1/15/2016 17 Therapeutic class of drugs for nasal route

18. 1/15/2016 18 Therapeutic class of drugs 1.  2 adrenergic agonists 2. Corticosteroids 3. Antiviral 4. Antibiotics 6. More recently, vaccines 5. Antifungal

19. 1/15/2016 19 Drugs commonly administered through pulmonary route include 1. Terbutaline Sulphate -  2 adrenergic agonist 2. Salbutamol -  2 adrenergic agonist 4. Ipratropium Bromide - anticholinergic 5. Sodium Chromoglycate – mast cell stabilizer 3. Budesonide - corticosteroid

20. 1/15/2016 20 Formulation Development

21. 1/15/2016 21 Formulation Development Dosage form Formulation considerations Factors affecting drug absorption Factors affecting drug absorption Physiological Pharmaceutical

22. 1/15/2016 22 Dosage forms Liquid drop Liquid spray/nebulizers Suspension spray/nebulizers Gel Sustained release Aerosol

23. 1/15/2016 23 Factors affecting drug absorption Drug concentration Vehicle of drug delivery Mucosal contact time pH of the absorption site Size of the drug molecule Relative lipid solubility Degree of drug’s ionization

24. 1/15/2016 24 Physiological effects - Drug metabolism in the respiratory tract & reduction of systemic effect - Mucociliary transport causing increased or decreased drug residence time - Protein binding

25. 1/15/2016 25 Physiological effects.... - Local or systemic effects of propellants, preservatives, or carriers - Local toxic effects of the drug Eg., edema, cell injury, or altered tissue defenses

26. 1/15/2016 26 Pharmaceutical -Physico-chemical properties of a drug candidatePhysico-chemical properties of a drug candidate - Spray pump devices -Methods to enhance drug absorptionMethods to enhance drug absorption

27. 1/15/2016 27 1. Effect of particle size 2. Effect of molecular size 3. Effect of solution pH 5. Effect of drug concentration 4. Effect of drug lipophilicity

28. 1/15/2016 28 1.Effect of particle size (aerodynamic size distribution) - Access to distal airways is a function of particle size - Large particles (> 7 microns) will be lost in the gastrointestinal tract - Intermediate particles (3 to 7 microns) reach the actual site of action - Small particles (< 3 microns) will be lost in exhaled breathe

29. 1/15/2016 29 2. Effect of molecular size - A good systemic bioavailability can be achieved for molecules with a molecular weight of up to 1000 Daltons when no absorption enhancer is used - Higher the molecular size, lower the nasal absorption

30. 1/15/2016 30 2. Effect of molecular size..... Absorption enhancers: Polyacrylic acid Sodium Glycocholate Sodium Deoxycholate Polysorbate 80 etc. - With the assistance of absorption enhancer, a good bioavailability can be extended to a molecular weight of at least 6000 Daltons

31. 1/15/2016 31 3. Effect of solution pH - Nasal absorption is pH dependent - Absorption is lower as the pH increases beyond the dissociation constant - Absorption is higher at a pH lower than the dissociation constant (pKa) of the molecule

32. 1/15/2016 32 4. Effect of drug lipophilicity - Polar (water soluble) drugs tend to remain on the tissues of the upper airway - Lipid soluble drugs are absorbed more rapidly than water soluble drugs - Non-polar (lipid soluble) drugs are more likely to reach distal airways

33. 1/15/2016 33 5. Effect of drug concentration - The absorption follows first-order kinetics - Absorption depends on the initial concentration of the drug

34. 1/15/2016 34 Methods to enhance nasal absorption of drugs Structural modification Formulation design Salt or ester formation

35. 1/15/2016 35 SPRAY PUMP DEVICES - Unidose - Multidose - Bidose

36. 1/15/2016 36 Bidose Unidose

37. 1/15/2016 37 Multidose

38. 1/15/2016 38 Applications Delivery of non-peptide pharmaceuticals Delivery of diagnostic drugs Delivery of peptide-based pharmaceuticals

39. 1/15/2016 39 1. Delivery of non-peptide pharmaceuticals Drugs with extensive pre-systemic metabolism, such as - progesterone - estradiol - propranolol - nitroglycerin - sodium chromoglyate can be rapidly absorbed through the nasal mucosa with a systemic bioavailability of approximately 100%

40. 1/15/2016 40 2. Delivery of peptide-based pharmaceuticals Peptides & proteins have a generally low oral bioavailability because of their physico-chemical instability and susceptibility to hepato- gastrointestinal first-pass elimination Eg. Insulin, Calcitonin, Pituitary hormones etc. Nasal route is proving to be the best route for such biotechnological products

41. 1/15/2016 41 3. Delivery of diagnostic drugs Diagnostic agents such as  Phenolsulfonphthalein – kidney function  Secretin – pancreatic disorders  Pentagastrin – secretory function of gastric acid

42. 1/15/2016 42