KULDEEP SAINI MASTER OF PHARMACY ( DEPARTMENT OF PHARMACEUTICAL SCIENCES, KUMAUN UNIVERSITY ) " NASAL TO BRAIN AND MECHANISM OF DRUG ABSORPTION"

1. Nasal to Brain
DRUGDELIVERYSYSTEM
N2B
KULDEEPSAINI
M.PHARMA, 3RD SEM.
Department of pharmaceutical sciences, Kumaun
university (Nainital) 1

2. CONTENT
INTRODUCTION
ANATOMY AND PHYSIOLOGY OF NASAL
CAVITY
MECHANISM OF DRUG ABSORPTION
FACTORS AFFECTING NASAL DRUG
ABSORPTION
CONCULSION
2

3. oNeurological disorder are the most common cause of disability. And
2nd most common cause of death over all world, representing 16.8%
of overall world.
oThus, there is need such drug delivery system (DDS) which delivery of
a drug for treatment of brain disease, the drug which main site of
action is brain and it much be localise selectively and effectively to
the brain.
INTRODUCTION
3

4. oNose to Brain drug delivery system is new developing approach to
deliver drug to the brain.
oNose to Brain approach is a great area of interest for direct transport
pathway of drugs in nose to brain through olfactory and trigeminal
nerve cells through nose they can bypassing the BBB and enter
directly in to brain.
NOSE TO BRAIN
DDS
4

5. oDirect nose to brain drug delivery system is a practical, safe, non-
invasive and convenient form of formulation strategy and could be
viewed as an excellent alternative approach to conventional dosage
forms.
oThis strategy is useful to treat variety of CNS disorders like- Migraine,
Parkinson’s, Brain tumour, Schizophrenia and Alzheimer’s disease.
5

6. Parameters Intranasal Orally Parental Transdermal
Avoid BBB Yes No No No
Hepatic first pass
metabolism
No Yes No No
Targeted deliver Yes No Yes Yes
Administration pain No No Yes No
Rapid onset action Yes No Yes Yes
Drug degradation No Maximum No Minimum
Comparison between
intranasal, orally, parental
and transdermal drug
delivery systems
6

7. oDeliver of therapeutic medicament into brain are most difficult and
challenging, mainly due to the unpassable nature of BBB.
oTherapeutic drug (agents) in opposite should reach the brain by way
of BBB and BCSFB which restrain the entry all large molecules of drug
and more than 98% of small molecules drug .
oNasal mucosa is observe as possible administration route to obtain
quickly and high quantity of drug absorption.
WHY ? NOSE TO
BRAIN
7

8. oNose is composite multiskilled organ along with the oral cavity.
oThe nasal cavity involve exterior opening for respiratory organ give a
route for the entry of the air before it reaches the lower part of the
airway.
oNasal cavity in physiological feature such as humidity and temperature
regulation of the clean inhaled air and olfaction.
oIt is provide defensive and supportive activity.
 ANATOMY AND
PHYSIOLOGY OF NASAL
CAVITY
8

9. oIt’s overall surface area is 150-200 cm sq. and the total volume are
range between 13-25 mL appropriately
oStructural point of view, nasal septum are divided into two
symmetrical cavity also known as Nostrils.
oEach nostril are contain 3 different regions.
A. Vestibule region
B. Olfactory region
C. Respiratory region
9

10. oThe nasal cavity vestibule, lie prone from opening of nasal cavity to
the anterior part of the nasal cavity.
oA first blockade barrier for the airborne particle.
oIt’s barrier contain low vascularization made up of stratified
squamous and keratinized epithelial cells include nasal hairs which
manage the filtering out the air and external particle.
oThe nasal vestibule with the important region known as the nasal
valve which resistance50% of the nasal airflow and manage 80% of
respiratory tract.
A. VESTIBULE REGION
10

11. oThe olfactory region is important part of nasal due to the pathway for
the direct delivery of therapeutic agents to the brain and the CSF.
oFrom structural point of view, the olfactory region contain less than
10% of surface area of nasal cavity and it is situated in the roof of the
nasal cavity.
oIt has large vascularization and large absorption area compare to
vestibule region.
B. OLFACTORY REGION
11

12. oThe respiratory region also known as Conchae and it is occupy the
biggest part of the nasal cavity approx. 130 cm2.
oIt is distribute in different part such as superiors, middle, and inferior
turbinate which are estimate from the lateral wall.
oThese unique structure are manage and oversee humidification and
temperature of inhaled air and its regulation.
C. RESPIRATORY REGION
12
12

13. oThe nasal respiratory epithelium contain of pseudo-stratified
epithelial cells, goblets cells, basal cells and mucous and serous gland.
o These epithelial cells are enclose on their surface with microvilli and
the major part is known as Cilia.
oMicrovilli are necessary to enhance the surface area of the respiratory
region for drug absorption and transportation.
oThe nasal respiratory region find the important region for delivery of
the therapeutic agent.
13

14.  STRUCTURE OF 3 REGION OF
NOSTRIL
14

15. oThe first step of the drugs absorption is that the drug in nasal cavity
must pass through the mucus layer and epithelial membrane before
reaching the blood stream or pass directly to the CNS.
oThe main protein of the mucus is mucin, it has the capability to bind
the solutes.
oThe transport of drug molecules from nasal cavity to parenchyma of
the brain take place through both olfactory and trigeminal nerve
pathway.
 MECHANISM OF
DRUG ABSORPTION
15

16. oNumbers of drug absorption mechanism were
confirmed ultimately but this process take place via
two mechanism-
a.- Para-cellular mechanism
b.- Trans-cellular mechanism
a. Para-cellular mechanism:-
oIt’s passive and slow aqueous route of deliver a drug molecules
between intra-cellular tight junction or the open split space of the
epithelial cells of the nasal cavity.
oIt is also known as extracellular route.
16

17. o In nose to brain delivery of a drug, the para-cellular
mechanism involve two extracellular route, first
across the olfactory neuron and second across the
trigeminal nerve.
oAfter these two mechanism , therapeutic agent reach in to the
olfactory bulb or trigeminal region and then therapeutic agent is
enter in to other brain region by simple diffusion, facilitated diffusion
by arterial pulsation driven perivascular pump.
oPara-cellular mechanism is show inverse log-log correlation between
intranasal absorption and molecular weight of hydrophilic drug
compound.
17

18. b. Trans-cellular mechanism:-
oIt’s mechanism contain a lipoidal route in which drug molecules
transport through it by receptor mediated endocytosis.
oIt is also known as intracellular mechanism and it’s mainly for the
delivery of small and large lipophilic drug molecules.
18

19. PHYSIOCHEMICA
L FACTOR
BIOLOGICAL
FACTOR
FORMULATION
FACTOR
o pH
o OSMOLARITY
o VISCOSITY
o NASAL BLOOD
FLOW
o ENZYMATIC
ACTIVITY
o MUCOCILIARY
CLEARANCE
o PARTICLE SHAPE
o MOLECULAR
WEIGHT
o POLYMORPHISM
o CHEMICAL FORM
o SOLUBILITY AND
DISSOLUTION RATE 19

20. A). PARTICLE SHAPE:- The shape of particle has an important role to
play in the absorption of a drug in nasal cavity and here cyclic shape of
drug show better absorption compare to the linear shape of a drug
particle.
B). PARTICLE SIZE:- It has been denoted that the drug required the
particle size for the nose to brain targeting should between 5-10 µm,
because if the particle size is greater than 10µm, then the particle can
be settle in to the nasal cavity. And another side, if particle size is less
than 5µm it can directly enter in to the lungs.
1. PHYSIOCHEMICAL
FACTOR
20

21. C). MOLECULAR WEIGHT:- Molecular weight has been
a linear inverse correlation with absorption of drug.
The molecular weight up to 300 Dalton of the drug is
optimum for the nose to brain delivery.
D). POLYMORPHISM:- Polymorphism nature of the drug known to affect
the dissolution rate and also the solubility of the drug which affect the
absorption of a drug through biological membrane of nasal cavity.
E). LIPOPHILICITY:- Lipophilicity is a most important factor that control
the transport on nasal administration. Lipophilicity has been linear
proportional correlation with permeation of the drug through nasal
membrane.
21

22. G). SOLUBILITY AND DISSOLUTION RATE:- Solubility and dissolution
rate of a drug are key factor for find out the absorption of drug from
dosage form such as powder and suspension.
 After administration of drug particle settle in the nasal cavity required
to be dissolved prior to absorption.
 The nasal cavity has small in size, so the volume of drug solution for
administration should be small and low.
F). DISSOCIATION CONSTANT (pKa):- Dissociation
constant is based on degree of ionisation and degree of
un-ionisation. The nasal cavity absorption is mainly
based on the pKa of the drug and it pH of the
absorption site. The nasal cavity absorption of weak
electrolytes based on their degree of ionisation and the
un-ionised drug occur highest absorption
22

23. A). NASAL BLOOD FLOW:- Nasal mucosa is provide the high vasculature
and large surface area for better drug absorption.
The blood flow is mainly affect the systemic nasal absorption of drugs
which increase the drug permeation through the membrane reaching to
the circulation.
Drug absorption is occur by the diffusion, the better blood flow is
necessary to maintain the concentration gradient from the site of
absorption to blood.
2. BIOLOGICAL FACTOR
23

24. B). ENZYMATIC ACTIVITY:- The drug is main
metabolised in lumen of the nasal cavity due to
presence of cytochrome P450 based Monooxygenase,
lactose dehydrogenase, oxidoreductase, hydrolase,
acid phosphatase and esterase. And the proteolytic
enzyme such as amino-peptidase and protease are
main barrier for protein and peptide drugs like insulin,
Desmopressin and calcitonin.
C). MUCOCILIARY CLEARANCE (MCC):- Mucociliary clearance is a
upper respiratory tract function which prevent the noxious substance
such as allergens, bacteria, viruses, toxin, etc. from reaching the lower
airways.
When these type substance trapped and dissolve in the mucus lining
or layer of nasal cavity, Mucociliary clearance take towards the
nasopharynx for discharge. 24

25. A). FORMULATION pH :- The pH of both formulation and surface of
nasal cavity can affect the drugs permeation. The nasal formulation pH
should be adjusted within 4.5 to 6.5 for avoid the nasal irritation.
B).OSMOLARITY:- The osmolarity of nasal formulation should within
285-310 mOsmol/l for intranasal delivery for avoiding the nasal mucosa
irritation, absolutely tonic effect.
Nasal drug absorption are also affect by tonicity of formulation
because hypertonic solution can shrinkage of epithelial cell and also
stop ciliary activity.
 FORMULATION
FACTOR
25

26. The viscosity, contact time and permeation are linear proportional to
each other because increase the viscosity then increase the contact
time and permeation of drug.
But the viscosity of nasal formulation should not too much high
because it can affect the normal function of nasal cavity such as
mucociliary clearance, ciliary etc. and also change the permeability of
drug.
C).VISCOSITY:- The viscosity of nasal formulation are
important factor which ensured the contact time
between the drug formulation and nasal mucosa.
26

27. • In past few years, Many advanced and efficacious techniques have come
out for brain targeting drug delivery. Nose to brain drug delivery system
has come out as a great strategy one of them, which direct deliver the
drug through olfactory and trigeminal pathway to the brain. And it’s
decrease the systemic exposure, systemic side effect and non-invasive in
nature.
• Although, many factors work in together which affect the drug delivery.
And these factors are physiological factor of nasal cavity, physiochemical
factor of drugs and pharmaceutical challenges with respect to brain
targeting drug delivery.
CONCLUSION
27

28. 28