Welcome!

1. Welcome! NASAL DRUG DELIVERY SYSTEM Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D Associate Professor Department of Pharmaceutics KLE University, Belgaum – 590010 Karnataka, INDIA [Company Name] Sinhgad College of Pharmacy, Vadgaon, Pune-411041

2. CONTENTS Novel Drug Delivery System Global trends in drug delivery systems Nasal Drug Delivery System Medical aspects Formulation Development Applications Conclusion Sinhgad College of Pharmacy, Vadgaon, Pune-411041

3. NOVEL DRUG DELIVERY SYSTEM - an overview Sinhgad College of Pharmacy, Vadgaon, Pune-411041

4. Novel drug delivery is one of the fastest growing healthcare sectors, with sales of drugs incorporating novel drug delivery systems increasing @ an annual rate of 15% Sinhgad College of Pharmacy, Vadgaon, Pune-411041

5. By 2010, the US drug delivery market alone will be worth $30 billion Sinhgad College of Pharmacy, Vadgaon, Pune-411041

6. There are great opportunities for companies investing in R&D for new, improved drug delivery system, allowing for improved therapeutic absorption and efficacy in patients Sinhgad College of Pharmacy, Vadgaon, Pune-411041

7. Why Novel Drug Delivery system? To optimize drug’s therapeutic effect, convenience and dose To enhance a product’s life-cycle To improve `patient compliance To target drug delivery To control overall healthcare costs To facilitate biological drug delivery Sinhgad College of Pharmacy, Vadgaon, Pune-411041

8. The Novel Drug Delivery industry is comprised of companies seeking to develop Novel alternatives to existing delivery systems Eg. implantable pumps Enhancements to existing systems Eg. sustained release oral dosage forms to reduce dosing frequency  Commercially enabling delivery systems that provide viable alternatives for therapeutics that are not fully developed and marketed because there are limited practical means of administration Eg. polar organics and other poorly absorbed therapeutics Sinhgad College of Pharmacy, Vadgaon, Pune-411041

9. Novel drug delivery companies have existed since the late 1960s, when Alzaand Elan pioneered the oral methods of enhanced drug delivery The introduction of hypodermic devices but especially metered dose inhalers & nasal sprays, promoted the concept and absolute need for specific drug delivery systems for specific diseases Sinhgad College of Pharmacy, Vadgaon, Pune-411041

10. Today there are between 300 & 350 companies worldwide with an interest in drug delivery, operating in a fierce environment where the number of drug launches using proven delivery technology is growing More novel technologies such as pulmonary delivery of insulin or needle-less human growth hormone injections are under development and are yet to be commercialized Sinhgad College of Pharmacy, Vadgaon, Pune-411041

11. Drug Delivery Systems Oral Inject-able Mucosal Topical Trans-dermal Ocular Vaginal/Anal Needle Nasal Active Needle-less Buccal Passive Pulmo-nary Sinhgad College of Pharmacy, Vadgaon, Pune-411041

12. Global drug delivery market by administration mode Nasal 2% Ocular 2% Injectable/Implant 3% Oral 53% Transdermal 8% Inhalation 32% Sinhgad College of Pharmacy, Vadgaon, Pune-411041

13. NASAL DRUG DELIVERY SYSTEM Sinhgad College of Pharmacy, Vadgaon, Pune-411041

14. Inhalation/pulmonary drug delivery system includes  Metered dose inhalers  Dry powder inhalers  Inhalation solutions & suspensions (for nebulizers)  Inhalation nasal sprays Sinhgad College of Pharmacy, Vadgaon, Pune-411041

15. Historically, nasal drug delivery system has received interest since ancient times Therapy through intranasal administration has been an accepted form of treatment in the Ayurvedic system of Indian medicine Sinhgad College of Pharmacy, Vadgaon, Pune-411041

16. Nasal Drug Delivery System & Opportunity Annual market growth Development time vis-a-vis new chemical entity Development cost vis-a-vis new chemical entity Merits Limitations Sinhgad College of Pharmacy, Vadgaon, Pune-411041

17. 30% 11% Annual growth of locally acting products Annual growth of systemically acting products Sinhgad College of Pharmacy, Vadgaon, Pune-411041

18. Drug development time 10 – 14 years New Chemical Entity 2 – 5 years Nasal Drug Delivery Sinhgad College of Pharmacy, Vadgaon, Pune-411041

19. Drug development cost New Chemical Entity $300-600 mio $50 mio Nasal Drug Delivery Sinhgad College of Pharmacy, Vadgaon, Pune-411041

20. Merits Avoidance of hepatic first-pass metabolism Rate of absorption comparable to IV medication Rapid onset of pharmacological action User-friendly, painless, non-invasive, needle-free administration mode Sinhgad College of Pharmacy, Vadgaon, Pune-411041

21. Merits... Lower dose & hence lower side effects Useful for both local & systemic drug delivery For CNS drugs, better site for rapid onset of action Eg. Inhalation anesthesia, Morphine etc. Sinhgad College of Pharmacy, Vadgaon, Pune-411041

22. Limitations Once administered, rapid removal of the therapeutic agent from the site of absorption is difficult  Pathologic conditions such as cold or allergies may alter significantly the nasal bioavailability Sinhgad College of Pharmacy, Vadgaon, Pune-411041

23. NASAL ROUTE - medical aspects Sinhgad College of Pharmacy, Vadgaon, Pune-411041

24. 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 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

25. Cross-sectional view Nasal site of drug spray & absorption Pathways for nasal absorption Sinhgad College of Pharmacy, Vadgaon, Pune-411041

26. Cross-sectional view a – nasal vestibule d – middle turbinate b – palate e – superior turbinate (olfactory mucosa) c – inferior turbinate f – nasopharynx Sinhgad College of Pharmacy, Vadgaon, Pune-411041

27. Site of drug spray & absorption Sinhgad College of Pharmacy, Vadgaon, Pune-411041

28. Pathways for nasal absorption  Absorption through the olfactory neurons - transneuronal absorption. Olfactory epithelium is considered as a portal for substances to enter CNS  Absorption through the supporting cells & the surrounding capillary bed - venous drainage  Absorption into the cerebrospinal fluid Sinhgad College of Pharmacy, Vadgaon, Pune-411041

29. Transneuronal absorption Olfactory nerve – 1st cranial sensory nerve Sinhgad College of Pharmacy, Vadgaon, Pune-411041

30. Venous drainage Sinhgad College of Pharmacy, Vadgaon, Pune-411041

31. Nasal enzymes • Cytochrome P 450 dependent onooxygenases, 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, nocotine, cocaine, phenacetin, nitrosamine progesterone etc., • Insulin zinc free was hydrolysed slowly by leusine aminopeptidase, • PG of E series was inactivated 15 hydroxyprostaglandin dehydrogenase Sinhgad College of Pharmacy, Vadgaon, Pune-411041

32. Nasal enzymes – contd., • Progesterone and testosterone were metabolized by several steroid hydroxylases in the nasal mucosa of rats Sinhgad College of Pharmacy, Vadgaon, Pune-411041

33. Nasal pH • 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 Sinhgad College of Pharmacy, Vadgaon, Pune-411041

34. Therapeutic class of drugs for nasal route Sinhgad College of Pharmacy, Vadgaon, Pune-411041

35. Therapeutic class of drugs 1.2 adrenergic agonists 2.Corticosteroids 3. Antiviral 4. Antibiotics 5. Antifungal 6. More recently, vaccines Sinhgad College of Pharmacy, Vadgaon, Pune-411041

36. Drugs commonly administered through pulmonary route include 1. Terbutaline Sulphate - 2 adrenergic agonist 2. Salbutamol - 2 adrenergic agonist 3. Budesonide - corticosteroid 4. Ipratropium Bromide - anticholinergic 5. Sodium Chromoglycate – mast cell stabilizer Sinhgad College of Pharmacy, Vadgaon, Pune-411041

37. Formulation Development Sinhgad College of Pharmacy, Vadgaon, Pune-411041

38. FormulationDevelopment Dosage form Factors affecting drug absorption Formulation considerations Physiological Pharmaceutical Sinhgad College of Pharmacy, Vadgaon, Pune-411041

39. Dosageforms Liquid drop Liquid spray/nebulizers Aerosol Suspension spray/nebulizers Gel Sustained release Sinhgad College of Pharmacy, Vadgaon, Pune-411041

40. Drug concentration Factors affecting drug absorption Vehicle of drug delivery Mucosal contact time Degree of drug’s ionization pH of the absorption site Size of the drug molecule Relative lipid solubility Sinhgad College of Pharmacy, Vadgaon, Pune-411041

41. Physiological effects - Drug metabolism in the respiratory tract & reduction of systemic effect - Protein binding - Mucociliary transport causing increased or decreased drug residence time Sinhgad College of Pharmacy, Vadgaon, Pune-411041

42. Physiological effects.... - Local toxic effects of the drug Eg., edema, cell injury, or altered tissue defenses - Local or systemic effects of propellants, preservatives, or carriers Sinhgad College of Pharmacy, Vadgaon, Pune-411041

43. Pharmaceutical • Physico-chemical properties of a drug candidate • Methods to enhance drug absorption - Spray pump devices Sinhgad College of Pharmacy, Vadgaon, Pune-411041

44. 1. Effect of particle size 2. Effect of molecular size 3. Effect of solution pH 4. Effect of drug lipophilicity 5. Effect of drug concentration Sinhgad College of Pharmacy, Vadgaon, Pune-411041

45. 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 - Small particles (< 3 microns) will be lost in exhaled breathe - Intermediate particles (3 to 7 microns) reach the actual site of action Sinhgad College of Pharmacy, Vadgaon, Pune-411041

46. 2. Effect of molecular size - Higher the molecular size, lower the nasal absorption - A good systemic bioavailability can be achieved for molecules with a molecular weight of up to 1000 Daltons when no absorption enhancer is used Sinhgad College of Pharmacy, Vadgaon, Pune-411041

47. 2. Effect of molecular size..... - With the assistance of absorption enhancer, a good bioavailability can be extended to a molecular weight of at least 6000 Daltons Absorption enhancers: Polyacrylic acid Sodium Glycocholate Sodium Deoxycholate Polysorbate 80 etc. Sinhgad College of Pharmacy, Vadgaon, Pune-411041

48. 3. Effect of solution pH - Nasal absorption is pH dependent - Absorption is higher at a pH lower than the dissociation constant (pKa) of the molecule - Absorption is lower as the pH increases beyond the dissociation constant Sinhgad College of Pharmacy, Vadgaon, Pune-411041

49. 4. Effect of drug lipophilicity - Polar (water soluble) drugs tend to remain on the tissues of the upper airway - Non-polar (lipid soluble) drugs are more likely to reach distal airways - Lipid soluble drugs are absorbed more rapidly than water soluble drugs Sinhgad College of Pharmacy, Vadgaon, Pune-411041

50. 5. Effect of drug concentration - Absorption depends on the initial concentration of the drug - The absorption follows first-order kinetics Sinhgad College of Pharmacy, Vadgaon, Pune-411041