1. NASAL DRUG DELIVERY SYSTEM Welcome! [Company Name]
Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D
Associate Professor
Department of Pharmaceutics
KLE University, Belgaum –
Karnataka, INDIA
[Company Name]
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

2. CONTENTS Novel Drug Delivery System
Global trends in drug delivery systems
Nasal Drug Delivery System
Medical aspects
Formulation Development
Applications
Conclusion
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

3. NOVEL DRUG DELIVERY SYSTEM
- an overview
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

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

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

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
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Sinhgad College of Pharmacy, Vadgaon, Pune

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
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

8.  Enhancements to existing systems
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
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

9. Novel drug delivery companies have existed since the late 1960s, when Alza and 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
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

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
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

11. Drug Delivery Systems Oral Inject-able Mucosal Topical Trans-dermal
Ocular
Vaginal/Anal
Needle
Nasal
Active
Needle-less
Buccal
Passive
Pulmo-nary
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

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

13. NASAL DRUG DELIVERY SYSTEM
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

14. Inhalation/pulmonary drug delivery system includes
 Metered dose inhalers
 Dry powder inhalers
 Inhalation solutions & suspensions (for nebulizers)
 Inhalation nasal sprays
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

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
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

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
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Sinhgad College of Pharmacy, Vadgaon, Pune

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

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

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

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
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Sinhgad College of Pharmacy, Vadgaon, Pune

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.
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

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
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Sinhgad College of Pharmacy, Vadgaon, Pune

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

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
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Sinhgad College of Pharmacy, Vadgaon, Pune

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

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

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

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
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Sinhgad College of Pharmacy, Vadgaon, Pune

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

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

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
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Sinhgad College of Pharmacy, Vadgaon, Pune

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

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
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Sinhgad College of Pharmacy, Vadgaon, Pune

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

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

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
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

37. Formulation Development 03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

38. Factors affecting drug absorption Formulation considerations
Formulation Development
Dosage form
Factors affecting drug absorption
Formulation considerations
Physiological
Pharmaceutical
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

39. Liquid spray/nebulizers Suspension spray/nebulizers
Dosage forms
Liquid drop
Liquid spray/nebulizers
Aerosol
Suspension spray/nebulizers
Gel
Sustained release
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

40. Factors affecting drug absorption
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
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

41. Physiological effects
- Drug metabolism in the respiratory tract & reduction of systemic effect
- Protein binding
- Mucociliary transport causing increased or decreased drug residence time
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

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
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

43. Physico-chemical properties of a drug candidate
Pharmaceutical
Physico-chemical properties of a drug candidate
Methods to enhance drug absorption
- Spray pump devices
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

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
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

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
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

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
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

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.
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

48. 3. Effect of solution pH dissociation constant (pKa) of the molecule
- 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
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

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
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

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

51. Methods to enhance nasal absorption of drugs
Structural modification
Salt or ester formation
Formulation design
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Sinhgad College of Pharmacy, Vadgaon, Pune

52. SPRAY PUMP DEVICES - Unidose - Bidose - Multidose 03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

53. Bidose
Unidose
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Sinhgad College of Pharmacy, Vadgaon, Pune

54. Multidose
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Sinhgad College of Pharmacy, Vadgaon, Pune

55. LEADING PUMP SUPPLIERS
Pfeiffer, Germany
Valois, France
Becton Dickinson, France
Nemo, Spain
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

56. Applications Delivery of non-peptide pharmaceuticals
Delivery of peptide-based pharmaceuticals
Delivery of diagnostic drugs
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

57. 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%
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

58. 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
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

59. 3. Delivery of diagnostic drugs
Diagnostic agents such as
 Phenolsulfonphthalein – kidney function
 Secretin – pancreatic disorders
 Pentagastrin – secretory function of gastric acid
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

60. CONCLUSION
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

61. 11% for locally acting drugs 30% for systemically acting drugs
Nasal route is a part of drug delivery strategy that is emerging to be a fastest growing drug delivery system with an annual growth of
11% for locally acting drugs
&
30% for systemically acting drugs
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

62. Nasal drug delivery offers such benefits as
Rapid onset of action with lower dose & minimal side effects
Has an advantage of site-specific delivery with improved therapeutic effects
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune

63. Attractive for delicate molecules allowing systemic administration without significant degradation
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Sinhgad College of Pharmacy, Vadgaon, Pune

64. Nasal drug delivery system offers flexibility for multiple formulations ranging from nasal drop to suspension spray
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Sinhgad College of Pharmacy, Vadgaon, Pune

65. Recent activities indicate a bright prospect for site-specific delivery of biotechnological products such as Insulin & other hormones
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Sinhgad College of Pharmacy, Vadgaon, Pune

66. THANK YOU Cell No: 00919742431000; E-mail: bknanjwade@yahoo.co.in
03/10/2009
Sinhgad College of Pharmacy, Vadgaon, Pune