DEPARTMENT OF PHARMACEUTICS, UNIVERSITY COLLEGE OF
PHARMACEUTICAL SCIENCES, KAKATIYA UNIVERSITY, WARANGAL. BY V.
SANDEEP KUMAR M.PHARMACY II ASEMESTER 2010
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Clinical testing of IN Morphine gluconate compared with
traditional IM and oral products
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CONTENTS INTRODUCTION ANATOMY AND PHYSIOLOGY OF NASAL CAVITY
BARRIERS TO NASAL ABSORPTION FACTORS INFLUENCING NASAL DRUG
ABSORPTION STRATEGIES TO INCREASE NASAL DRUG ABSORPTION NOSE TO
BRAIN DELIVERY INTRANASAL DELIVERY OF VACCINES INTRANASAL DELIVERY
OF PEPTIDE AND PROTEINE DRUGS ANIMAL MODELS FOR NASAL ABSORPTION
STUDIES THERAPEUTIC AREAS SUTIABLE FOR INTRANASAL DELIVERY
CONCLUSION REFERENCES
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Avoidance of hepatic first-pass metabolism Non-invasive,
Painless, needle-free administration mode Rate of absorption
comparable to IV medication Self-medication is possible through
this route Easily accessible (even easier to access than IM or IV
sites) Avoids degradation of drug in gastrointestinal tract
resulting from acidic or enzymatic degradation Results in rapid
absorption and onset of effect
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Results in higher bioavailability thus uses lower dose &
hence lower side effects Useful for both local & systemic drug
delivery Drugs that are orally not absorbed can be delivered to the
systemic circulation by nasal drug delivery Offers lower risk of
overdose Direct transport into systemic circulation and CNS is
possible.
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Adversely affected by pathological conditions(cold or allergies
may alter significantly the nasal bioavailability) Normal defence
mechanisms like mucocillary clearance and ciliary beating affects
the permeability of drug Enzymatic barrier to permeability of drugs
Volume that can be delivered into nasal cavity is restricted to
25200 l Interspecies variability is observed in this route
Irritation of nasal mucosa by drugs Absorption enhancers cause
irritation.
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Major functions of the nasal cavity are breathing and
olfaction. Nasal vasculature is richly supplied with blood to
fulfill the basic functions such as heating and humidification,
mucociliary clearance and immunological functions. Relatively large
surface area (~150 cm 2 ) because of the presence of ~400
microvilli per cell. It is divided by middle (or nasal) septum into
two symmetrical halves, each one opening at the face through
nostrils and extending posterior to the nasopharynx. NASAL CAVITY
:ANATOMY, PHYSIOLOGY
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Cross-sectional View a nasal vestibuled middle turbinate b
palatee superior turbinate c inferior turbinatef nasopharynx
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Nasal secretions Nasal secretion contains sodium, potassium,
calcium, mucus glycoproteins, albumins, immunoglobulins IgA, IgG,
lysozymes, cytochrome P450 dependent monooxygenases, lactate
dehydrogenase, oxidoreductases, hydrolases like steroid hydrolases
Nasal pH It varies between 5.56.5 in adults and 5.07.0 in infants.
Nasal epithelium is covered with a thin mucus layer (5 m thick) and
organized in two distinct layers: an external, viscous and
dense(gel), and an internal, fluid and serous(watery). Nasal mucus
layer consists of 95% of water, 2.5-3% of mucin, and 2% of
electrolytes, proteins, lipids, enzymes, antibodies, sloughed
epithelial cells and bacterial products
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MUCOCILIARY CLEARANCE(MCC)
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Lipophilic drugs are generally well absorbed with the
pharmacokinetic profiles identical to those obtained after an I.V
injection and bioavailabilities approaching 100%. Ex: fentanyl
where the T max for both i.v and nasal administration is 7 min or
less and the bioavailability was near to 80%. Nasal permeability of
polar drugs especially large mol.wt polar drugs such as peptides
and proteins is low. Polar drugs with mol.wt below 1000 Da will
generally pass the membrane using paracellular route. Nasal mucosal
lining Enzymes present in nasal cavity Mucociliary clearance
(MCC)
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Tight junctions can open and close to a certain degree, when
needed. Proteins through endocytotic transport process but only in
low amounts. Clearance of the administered formulation from the
nasal cavity due to the mucociliary clearance mechanism. Especially
for drugs that are not easily absorbed and formulations that are
not mucoadhesive. Aldehyde dehydrogenase, glutathione transferase,
epoxide hydrolases, cytochrome P-450-dependent monooxygenases,
carboxyl esterases ex: nasal decongestants, alcohols, nicotine and
cocaine. Aminopeptidases, exopeptidases, endopeptidases are
involved in in pre systemic degradation of peptides and
proteins
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Transport Of Drugs Across Nasal Epithelium A- Transcellular
passive diffusion, B- Paracellular passive diffusion, C-Carrier
mediated, D- Transcytosis, E- Effluxt ransport
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NASAL PHYSIOLOGICAL FACTORS Blood flow and neuronal regulation
Huang et al showed that phenylephrine, a vasoconstrictor agent,
inhibited the absorption of acetylsalicylic acid in nasal cavity.
Kao et al. stated that nasal absorption of dopamine was relatively
slow and incomplete probably due to its own vasoconstrictor effect.
Nasal secretions Viscosity of nasal secretion Diurnal variation pH
of nasal cavity Mucociliary clearance (MCC) The clearance of a drug
product from the nasal cavity is influenced by the site of
deposition.
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Polar drugs are the most affected by MCC. Inter-individual
variability observed in MCC. Enzymatic degradation Transporters and
efflux systems Physicochemical properties of drugs Molecular weight
Lipophilicity pKa Lipophilic drugs well absorbed through
transcellular mechanisms with nasal bioavailability near to 100%(
lower than 1 kDa). Absorption of lipophilic drugs bigger than 1 kDa
is significantly reduced.
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Rate of permeation of polar drugs is highly sensitive to mol.wt
if it is higher than 300 Da. For some small polar molecules only a
10% bioavailability is suggested. The value may go down to 1% for
large molecules such as proteins. Huang, C.H. et al. studied
absorption of benzoic acid at pH 7.19 (99.9% of the drug existed in
ionized form) it was found that >10% of drug was absorbed.
Solubility Drugs poorly soluble in water and/or requiring high
doses may constitute a problem as allowable volume of drug solution
is low for intranasal drug administration
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PROPERTIES OF THE FORMULATION pH Viscosity Osmolarity
Pharmaceutical excipients Area of nasal mucus membrane exposed
Dosage form Device related factor Particle size of the droplet or
powder If the particle size is