NasalDrugDeliverySystem

1. NASAL
Welcome!
DRUG DELIVERY
SYSTEM
Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D
Associate Professor
[Company Name]
Department of Pharmaceutics
KLE University, Belgaum – 590010
Karnataka, INDIA
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 1

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-411041 2

3. NOVEL DRUG DELIVERY
SYSTEM
- an overview
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 3

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%
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 4

5. By 2010, the US drug
delivery market alone will
be worth $30 billion
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 5

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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 6

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-411041 7

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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 8

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-411041 9

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-411041 10

11. Drug Delivery Systems
Inject- Trans- Vaginal/
Oral Mucosal Topical Ocular
able dermal Anal
Needle Nasal Active
Needle-
Buccal Passive
less
Pulmo-
nary
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 11

12. Global drug delivery market by administration mode
Nasal 2%
Ocular 2%
Injectable/ Oral 53%
Implant 3%
Transdermal
8%
Inhalation
32%
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 12

13. AS AL
N ST EM
SY
RY
EL IVE
D
R UG
D
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 13

14. Inhalation/pulmonary drug delivery system includes
² Metered dose inhalers
² Dry powder inhalers
² Inhalation solutions & suspensions (for nebulizers)
² Inhalation nasal sprays
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 14

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-411041 15

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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 16

17. 30%
11%
Annual growth of Annual growth of
locally acting systemically acting
products products
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 17

18. Drug development time
10 – 14 years New Chemical
Entity
2 – 5 years Nasal Drug Delivery
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 18

19. Drug development cost
$300-600 mio New Chemical
Entity
$50 mio
Nasal Drug Delivery
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 19

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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 20

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-411041 21

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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 22

23. U TE
R O
ts
S AL sp ec
N A la
di ca
e
-m
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 23

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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 24

25. Cross-sectional view
Nasal site of drug spray & absorption
Pathways for nasal absorption
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 25

26. Cross-sectional view
a – nasal vestibule d – middle turbinate
b – palate e – superior turbinate (olfactory mucosa)
c – inferior turbinate f – nasopharynx
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 26

27. Site of drug
spray &
absorption
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 27

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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 28

29. Transneuronal absorption
Olfactory nerve – 1st cranial sensory nerve
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 29

30. Venous drainage
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 30

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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 31

32. Nasal enzymes – contd.,
•Progesterone and testosterone were
metabolized by several steroid
hydroxylases in the nasal mucosa of rats
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 32

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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 33

34. of
ss te
la u
c
ic l ro
ut sa
pe na
ra or
e f
Th gs
d ru
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 34

35. Therapeutic class of drugs
1. β2 adrenergic agonists
2. Corticosteroids
3. Antiviral
4. Antibiotics
5. Antifungal
6. More recently, vaccines
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 35

36. Drugs commonly administered through pulmonary
route include
1. Terbutaline Sulphate - β2 adrenergic agonist
2. Salbutamol - β2 adrenergic agonist
3. Budesonide - corticosteroid
4. Ipratropium Bromide - anticholinergic
5. Sodium Chromoglycate – mast cell stabilizer
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 36

37. Formulation
Development
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 37

38. Formulation Development
Dosage form
Factors affecting drug
absorption
Formulation considerations
Physiological
Pharmaceutical
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 38

39. Dosage forms
Liquid drop
Liquid spray/nebulizers
Aerosol
Suspension spray/nebulizers
Gel
Sustained release
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 39

40. Drug concentration
Factors affecting
Vehicle of drug delivery
drug absorption
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-411041 40

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-411041 41

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-411041 42

43. 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-411041 43

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-411041 44

45. 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
- 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-411041 45

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-411041 46

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-411041 47

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
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 48

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-411041 49

50. 5. Effect of drug concentration
- Absorption depends on the initial concentration of
the drug
- The absorption follows first-order kinetics
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 50

51. Methods to enhance nasal absorption of drugs
Structural modification
Salt or ester formation
Formulation design
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 51

52. SPRAY PUMP DEVICES
- Unidose
- Bidose
- Multidose
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 52

53. Bidose
Unidose
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 53

54. Multidose
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 54

55. LEADING PUMP SUPPLIERS
Pfeiffer, Germany
Valois, France
Becton Dickinson, France
Nemo, Spain
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 55

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-411041 56

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-411041 57

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-411041 58

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-411041 59

60. IO N
LU S
O N C
C
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 60

61. 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-411041 61

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-411041 62

63. Attractive for delicate molecules
allowing systemic administration
without significant degradation
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 63

64. Nasal drug delivery system offers
flexibility for multiple formulations
ranging from nasal drop to
suspension spray
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 64

65. Recent activities indicate a bright
prospect for site-specific delivery of
biotechnological products such as
Insulin & other hormones
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 65

66. Cell No: 00919742431000; E-mail: bknanjwade@yahoo.co.in
03/10/2009 Sinhgad College of Pharmacy, Vadgaon, Pune-411041 66