Nasopulmonary Drug Delivery System (NPDDS)

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

  1. The
    absorption enhancers used to improve nasal drug  delivery system may have histological
    toxicity
    which is  not yet
    clearly established

  2. Absorption
    surface area is less when compared to GIT.

  3. Once
    the drug administered cannot be removed.

  4. Nasal
    irritation.

  5. 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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