Drug delivery system via

nasal route

Humaedi, A
 Introduction

The nasal cavity can be used as a route of entry:

➢ Local effect: nasal drops or sprays
Drugs: decongestants, antibiotics, mucolytics
➢ Systemic sirculation:
@ Absorption profile of the drug is appropriate
to its clinical application
@ Compounds which cannot be given orally:
The reasons that compounds cannot be
administered orally:
➢ Destroyed in the GI fluids
➢ Metabolized in the wall of GI tract
➢ Undergo extensive biotransformation by
the liver (FPE)
Structure and physiology of the nasal cavity
The nasal cavity extends 12-14 cm, from nostrils
to the nasopharynx (throat)

Lateral wall of the nasal

cavity
A. Nasal vestibule
B. Inferior turbinate
C. Middle turbinate
D. Superior turbinate
Hatched area: the
olfactory region
The nasal mucosa is highly vascular
Between the venules and capillaries:
numerous sinuses

Olfaction
➢ The olfactory region of the nose: containing
the smell receptors
➢ Approximately 20% of the air flowing
through the nasal cavity directed upwards
to the olfactory region
Diagram 4 jenis sel pada sel epitel respirasi

A. Sel kolumnar silia

B. Sel basal
C. Sel goblet
D.Sel kolumnar
nonsilia
Cilia
Composition of nasal secretion
 Physiological factors affecting
nasal bioavailability

Area
The total surface area of both nasal cavities:
160 cm2
The area available for absorption is enhanced
by: @ the convolutions of the turbinate
@ the microvilli present

Blood supply
The nasal mucosa is highly vascular →
potential for drug absorption → rapid onset
Contact time and mucociliary clearance
➢The length of time the drug is in contact
with the absorbing tissue → influence amount
of drug crosses the mucosa.
➢The site of deposition in the nasal cavity →
affects the rate of mucociliary clearance of
drug:
➢Particles deposited on ciliated regions (ex.
Turbinates) → clearanced immediately
➢Particles deposited on non-ciliated regions
(ex. the anterior) → move slowly
➢ Particles deposit on the nasopharyngeal
regions → immediately swallowed & no nasal
absorption
➢ Clearance of the bulk of the mucus from the
nose to the nasopharynx → 10-20 minutes
➢ 40% radiolabeled solution → administered
either as a nasal spray or as drops → cleared
rapidly within 20 minutes
➢ following phase: clearance of the nasal spray
is slower than that of the drops → most of
the spray has deposited on non-ciliated
regions of the nasal cavity.
Implications:
Drug absorption that is administered via drops
may only be suitable if drug molecule → rapidly
absorbed.
Drugs → diffuse across the nasal epithelium
more slowly will need a longer contact time →
may be better administered as sprays.

Further consideration:
Drug molecules that are cleared by the
mucociliary clearance from the nasal cavity to
the GI tract → absorbed from the GI tract if
they are not metabolized.
Disease
The rate of mucociliary clearance → affected by
the pathophysiological condition of the nasal
cavity → affect the rate of clearance of
administered drug.
Ex. Rhinitis, cold, hayfever, sinusitis, asthma,
nasal polyposis.

Phenomena in common cold: mucus

hypersecretion & nasal congestion
Former phase: < 10% of a dose administered
as a nasal spray → remain in the nasal cavity
after 25 minutes
After administration during the nasal
congestion phase: drug still present at the site
of deposition up to 90 minutes.

Enzymatic activity
The nasal mucosa and fluids → possess
exopeptidases & endopetidases
Exopeptidases cleave at N- & C-termini include
aminopeptidases, carboxypeptidases & dipepti-
dyl peptidase
Endopeptidases cleave at an internal peptide
bond including enkephalinase & cathepsin B
Small peptides → resistant to action of endo-
Enzymatic activity in the nasal → generally
lower than that of the GI tract → alternative to
the oral delivery of enzymatically labile drugs:
peptides & proteins.

Immunological clearance
The immune system functions: to recognize &
eliminate foreign materials.
Foreign proteins → eliciting an immune
response
Antibodies → secreted in the nasal cavity (high
conc. in the mucus) → neutralize antigens
Molecule → undergo degradation & cause
allergic disease such as hayfever
Mucus barrier
Mucus affects drug delivery by interacting with
nasally administered drugs by:
@ acting as a physical barrier to drug diffusion
@ binding to drugs

Mucus protects the nasal epithelium by acting as

a physical barrier.
Mucus is retarded the diffusion of water
Mucolytics → alter the viscoelasticity of mucus
→ absorption increased
Binding of drugs to mucin can account for their
limited diffusion.
Positively charged drug molecules bind to mucus
glycoproteins via electrostatic interaction
Mucus contains negatively charged sialic acid &
sulfate ester residues.
Drugs and the hydroxyl groups on the sugar and
O- & N-containing groups on the protein
backbone → hydrogen bonding
Drugs and a globular protein region of the
glycoprotein molecule → hydrophobic interaction
Ex.
Tetracycline binds to mucus by hydrogen-
bonding, electrostatic and hydrophobic
interactions.
Transport routes & mechanisms
Epithelial mucosae restrict drug permeation
acrosss the epithelial barrier to 2 routes:
1. The paracellular route: between adjacent
epithelial cells via the mechanism passive
diffusion or solvent drug
2. The transcellular route: across the epithelial
cells by passive diffusion, carrier-mediated
transport and via endocytic processes
The paracellular route
Small hydrophilic molecules passively diffuse
between adjacent cells
Driven by a concentration gradient

The transcellular route

Transcellular passive diffusion
Small & lipophilic drugs
Dependent on the pKa of the drug & pH of the
environment
pH of nasal secretions is 5.5-6.5
Carrier-mediated process
Endocytic process

Formulation factors affecting nasal

bioavailability

Physical factors associated with the drug

Two mechanisms of absorption exist for nasal
drug delivery:
@ a fast rate: dependent on lipophilicity of drugs
@ a slower rate: dependent on molecular weight
Ex. Propranolol, progesterone, estradiol,
naloxone & testosterone
The slower rate absorption → provide
absorption of low MW polar compounds
Above a MW of 1000 Da the nasal absorption of
compounds declines
Absorption of hydrophilic drugs → variable than
that of lipophilic compounds

Concentration
Drugs across the nasal mucosa via passive
diffusion (paracellular or transcellular).
Rate of absorption → affected by the
concentration of drug in solution at the
absorbing membrane.
➢ The higher the drug concentration → the steeper
the concentration gradient driving the absorption
process → the faster the drug will be absorbed.
➢ Drug solution → choose the highest concentration.
➢ Note: high local drug concentrations → cause
severe local irritation or adverse tissue reactions.

Factors associated with the dosage form

Commonly formulated as:
@ nasal drops → deposit a film of drug solution
@ nasal sprays → deposit an aerosol of particles
suspended in droplets
Site of deposition of an aerosol from a nasal spray
depends on:
- The diameter of the particle
- the particle charge
- the velocity at which the particle is moving

➢ Particles in the size range 5-10 m

➢ Deposition mechanisms in the nose include:
Inertial impaction, sedimentation, diffusion,
interception & electrostatic attraction.
➢ Inertial impaction → the most significant
mechanism
Deposition & clearance in the nose

1 min after 4 min after

administration administration
nasal spray nasal drops
➢ Nasal drops disperse a drug solution throughout
the length of the nasal cavity from atrium to
nasopharynx → offering a large area for
immediate absorption
➢ Nasal sprays → tend to deposit at the front of the
nasal cavity → little dose reaching the turbinates
 Advantages & disadvantages of nasal drug delivery

Advantages:
@ Large surface area, approximately 160 cm2
@ Rich blood supply → ensures rapid absorption &
onset, maintenance of sink conditions
@ Low metabolic activity compare to that in GI tract
→ alternative route to deliver peptides & proteins
@ Ease of administration, ex. MD (metered dose)
nasal sprays
@ Intestine alternative, when the GI route is
unfeasible due to:
- Patients with nausea and vomiting
- Patients with swallowing difficulties
- Drugs that are unstable in the GI fluids
- Drugs that undergo extensive first-pass effect in
the liver

Disadvantages:
@ Mucociliary clearance → reduces the retention
time of drugs
@ Mucus barrier → provide binding drugs to mucins
→ inhibit drug diffusion
@ Metabolic activity, the nasal mucosa & secretions
may degrade drugs
@ Lack of reproducibility, absorption is unreliable →
affected by diseases such cold, hayfever →
change in mucociliary clearance & permeability of
mucosa
@ Adverse reactions
Locally irritating or sensizing drugs

@ Epithelial nasal, cilia → sensitive & fragile →

sensitive to adverse reaction of penetration
enhancer
 Current technologies for nasal drug delivery
Concerned with:
@ the local delivery of drug → ex. Decongestants,
antibiotics & mucolytics
@ the systemic delivery of low MW drugs (<500 Da)
including peptides

Nasal sprays
@ Available as squeeze bottles → not expected to
give reproducible dosing
@ Metered-dose devices → more reproducible dose
@ Dose of drug received by the patient → depends
on the concentration of drug in the formulation
@ Deposit at the impaction site: in the anterior
(unciliated regions). Airflow associated with
inspiration is high & mucociliary clearance is slow
@ Drug is cleared slowly & is transported over a
large area en route to the pharynx → promote
drug absorption

Nasal drops
@ Rely on the instillation of drops of drug solution
→ from a dropper or directly from squeezeable
plastic container
@ Deposit throughout the nasal cavity
@ Provide a large effective area for immediate
absorption compare to nasal sprays
@ Some drugs is deposited on ciliated regions of the
mucosa → immediately clearanced
@ A proportion of the dose deposits at the
nasopharynx → immediately swallowed → not
available for nasal absorption
Illustration of administration of nasal drop-bottle
Teknologi saat ini pada penghantaran obat via nasal

Nasal sprays
➢ Tersedia dalam bentuk squeeze bottle →
dosis tidak reprodusibel
➢ Cenderung untuk terdeposit di anterior
(tidak bersilia) → lambat terbuangkan →
menginduksi absorpsi obat
Nasal sprays vs. nasal drops
➢ 40% of administered dose → rapid clearly
within 20 minutes (sprays & drops)
➢ Slower phase: clearance of the drops → faster
than that of the spray → probably most of the
spray deposits on non-ciliated regions
➢ Due to faster clearance, nasal drops are more
suitable for drug that rapidly absorbed
➢ Drug across the nasal epithel slowly → need
longer contact time → better administered as
sprays
Absorpsi obat secara sistemik yang diberikan
secara intranasal
Absorpsi obat secara sistemik yang diberikan
secara intranasal
Teknologi baru dalam penghantaran nasal

Obat konvensional → sistemik via nasal (BM

rendah < 500 Da)
Peptida & protein (BM > 1000 Da) → tdk
diabsorpsi melalui mukosa nasal tanpa
intervensi
Teknologi dalam penghantaran via nasal →
strategi utk meningkatkan absorpsi obat
Pendekatan untuk meningkatkan absorpsi obat
via intranasal (1)
Pendekatan untuk meningkatkan absorpsi obat
via intranasal (2)
1. Meningkatkan permeabilitas epitelial nasal

➢ Merubah lapisan mukus

➢ Menurunkan viskoelastik mukus
Ex. Surfaktan anionik atau kationik, garam
empedu
➢ Perubahan tight junction
2. Meningkatkan waktu kontak pada tempat
absorpsi
Waktu kontak ditingkatkan → bioavailabilitas
zat aktif meningkat
Obat dapat dihilangkan dari lubang hidung dg
cara:
➢ Mucociliary clearance
➢ Metabolisme
2.a. Memodifikasi tempat deposisi
Turbinate → tempat utama absorpsi sistemik
Peningkat viskositas, ex. MC, hyaluronan →
lokalisasi deposisi di bag. anterior (low
clearance site) →absorpsi meningkat
 2.b. Penggunaan bioadhesif

Bioadhesif atau mukoadhesif → menempel

pada substrat such as mukus. Pengaruh
bioadhesif pada bioavailabilitas:
➢ Menurunkan kecepatan clearance dari
tempat absorpsi
➢ Meningkatkan konsentrasi lokal obat
➢ Melindungi obat dari degradasi oleh sekresi
nasal
2.c. Menurunkan kecepatan mucociliary clearance

→Meningkatkan waktu kontak obat

Ex. Eksipien dengan efek ciliostatic reversibel
STDHF, laureth, Na-deoksikolat
 3. Inhibisi degradasi enzim

Degradasi enzimatik obat oleh sekresi nasal

dan mukosa
Ex. Sitokrom P450-dependent
monooksigenase memetabolisme
dekongestan nasal, nikotin, kokain &
progresteron
 4. Metode lain untuk peningkatan absorpsi

Merubah tekanan osmotik formulasi

Simpangan dari isotonisitas →
meningkatkan absorpsi salmon kalsitonin 4-
5x
Penghantaran obat sbg serbuk kering
Menghantarkan obat dalam bentuk serbuk
(tanpa carier bioadhesif)
Ex. Absorpsi insulin freeze-dried (serbuk)
lebih baik dibanding dalam bentuk larutan
Terima kasih