Nasopulmonary Drug Delivery System
CONTENTS
— Introduction
— Advantages
And Disadvantages
— Anatomy
& Physiology of Nasal Cavity
— Mechanism
of Drug Absorption
— Formulation
Approaches
— Evaluation
Test
— Marketed
Preparations
— Patented
Preparations
— Recent
Advances
— Conclusions
Session
Objectives
By the end of this session, students will be able to:
• Defend need for nasopulmonary DDS
• Express advantages and disadvantages of NPDDS
• Explain antomy and physiology of nasal cavity
• Explain mechanisms of absorption
• Enlist the factors affecting nasal absorption
• Discuss factors influencing nasal absorption
NASAL DRUG DELIVERY
INTRODUCTION:
— In
ancient times the Indian Ayurvedic system of medicines used nasal route for administration of drug and the
process is called as “Nasya”
— Intranasal
drug delivery is now recognized to be a useful and reliable alternative to oral
and parenteral routes. Undoubtedly, the intranasal administration of medicines
for the symptomatic relief and prevention or treatment of topical nasal
conditions has been widely used for a long period of time.
— However,
recently, the nasal mucosa has seriously emerged as a therapeutically viable
route for the systemic drug delivery.
— ´Nasal
drug delivery has received a significant attention in recent years as a convenient and reliable route, not
only for local but also for the systemic
administration of drugs
— ´The
nasal cavity is an easily accessible route which is generally well tolerated
— ´It
offers lower doses, more rapid attainment of therapeutic blood levels, quicker onset of pharmacological
activity fewer side effects, high total
blood flow per cm3
— In
general, among the primary targets for intranasal administration are
pharmacologically active compounds with poor stability in gastrointestinal
fluids, poor intestinal absorption and/or extensive hepatic first-pass
elimination, such as peptides, proteins and polar drugs.
— The
nasal delivery seems to be a favorable way to circumvent the obstacles for
blood-brain barrier (BBB) allowing the direct drug delivery in the biophase of
central nervous system (CNS)-active compounds.
— It
has also been considered to the administration of vaccines.
ADVANTAGES
— Hepatic
first pass metabolism avoided.
— Rapid
drug absorption and quick onset of action via vascularized mucosa.
— Bioavailability
of larger drug molecules can be improved by means of absorption enhancer.
— BA
for smaller drug molecules is good.
— Convenient
for long term therapy, compared to parenteral medication.
— Drugs
possessing poor stability G.I.T fluids given by nasal route.
— Easy
and convenient, self-administration
— Easily
administered to unconscious patients.
DISADVANTAGES
• Pathologic
conditions such as cold or allergies may alter significantly the nasal bioavailability.
• The
histological toxicity of absorption enhancers used in nasal drug delivery
system is not yet clearly established.
• Relatively
inconvenient to patients when compared to oral delivery systems since there is
a possibility of nasal irritation.
• Nasal
cavity provides smaller absorption surface area when compared to GIT.
ANATOMY & PHYSIOLOGY OF NASAL CAVITY
lThe lining is ciliated, highly vascular and rich
in mucus gland.
lNasal secretions are secreted by goblet cells,
nasal glands and transudate from plasma.
lIt contains sodium, potassium, calcium,
albumin, enzymes like
leucine,CYP450,Transaminase,etc.
The nasal cavity
consists three main regions:
1)
Nasal
vestibule
2)
Respiratory
region
Major drug absorption.
15-20 % of the respiratory cells covered by layer of long cilia
size 2-4 μm.
3) Olfactory region
Small area in the roof of the nasal cavity of about 10 cm2
Drug is exposed to neurons thus facilitate it across the
cerebro- spinal fluid.
• Normal
pH of the nasal secretions in adult à 5.5-6.5.
• Infants
and young children à 5.0- 6.7.
• Nasal
cavity is covered with a mucous membrane.Mucus secretion is composed of 95%-
water,2%-mucin,1%-salts,1%-of other proteins
Such as albumin,lysozyme and lactoferrin and 1%-lipids.
ANATOMY OF
NASAL CAVITY
It is divided in to two halves by nasal septum.
It contains 3 regions
a) Nasal vestibule
b) Olfactory
region
c) Respiratory region
Nasal cavity is covered with mucous membrane which contains goblet cells and secrets mucous
Nose brain
pathway
Ø The
olfactory mucosa (smelling area in nose) is
in direct contact with the brain and CSF.
Ø Medications
absorbed across the olfactory mucosa directly enter the brain.
Ø This area is termed the nose brain pathway and offers a rapid, direct route for drug delivery to the brain.
LIMITATIONS
of NPDDS
- The
absorption enhancers used to improve nasal drug delivery system may have histological
toxicity which is not yet
clearly established
- Absorption
surface area is less when compared to GIT.
- Once
the drug administered cannot be removed.
- Nasal
irritation.
- There
is a risk of local side effects and irreversible damage of the cilia on
the nasal mucosa
MECHANISM OF DRUG ABSORPTION
• Paracellular
(intercellular) Slow and passive absorption of peptides and proteins
associated with intercellular spaces and tight junctions.
• Transcellular:
Transport of lipophilic drugs passive diffusion/active transport.
• Transcytotic: Particle is taken into a vesicle and transferred to the cell.
THEORIES OF
MUCOADHESION
|
Theory |
Mechanism of bioadhesion |
Comments |
|
Electronic theory |
Attractive electrostatic forces between glycoprotein mucin network and the
bioadhesive material |
Electron transfer occurs between the two forming a double layer of electric charge at the
interface |
|
Adsorption theory |
Surface forces resulting in chemical bonding |
Strong primary forces: covalent bonds. Weak secondary forces: ionic bonds, hydrogen bonds and van der Waal’s forces |
|
Wetting theory |
Ability of bioadhesive polymers to spread and develop intimate contact with the
mucus membranes |
Spreading coefficients of polymers must be positive Contact angle between polymer and
cells must be near to zero |
|
Diffusion theory |
Physical entanglement of mucin strands and the flexible polymer chains Interpenetration
of mucin strands into the porous
structure of the polymer substrate |
For maximum diffusion and best bioadhesive strength: solubility parameters (δ) of
the bioadhesive polymer and the
mucus glycoproteins must be similar |
|
Fracture theory |
Analyses the maximum tensile stress developed during detachment of the BDDS from the mucosal surfaces |
Does not require physical entanglement of bioadhesive polymer chains and mucin
strands, hence appropriate to study
the bioadhesion of hard polymers,
which lack flexible chains |
Factors
affecting nasal absorption
1. Molecular weight:-
The nasal absorption of drugs decreases as the molecular weight increases.
Martin reported a sharp decline in drug absorption having
molecular weight greater than 1000 daltons.
2. Lipophilicity:-
Absorption of drug through nasal route is dependent on the
lipophilicity of drugs.
E.g. Alprenolol and Propranolol which are lipophilic, has
greater absorption than that of hydrophilic Metoprolol.
3. pH of solution:-
pH should be opbarriers timum for maximum absorption.
Nonionised lipophilic form crosses the nasal epithelial via
transcellular route and hydrophilic ionized form passes through the aqueous
paracellular route.
E.g. Decanoic acid shows maximum absorption at pH 4.5.
Beyond this it decreases as solution becomes more acidic or basic.
Nasal absorption is pH dependent .Nasal pH in nasal
secretion of adult: 5.5-6.5.In 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.
4. Drug
concentration:-
The absorption of drug through nasal route is increased as
concentration is increased.
E.g. 1-tyrosine shows increased absorption at high concentration
in rate.
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