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Nasal drug delivery

Dr. Herman J. Woerdenbag

Department of Pharmaceu1cal Technology and Biopharmacy
University of Groningen
The Netherlands
h.j.woerdenbag@rug.nl

2016 H.J.Woerdenbag
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Drug administra8on in the nasal cavity

Local eect
Acute rhini1s
Allergic rhini1s
Sinusi1s
Nasal ves1buli1s
Systemic eect
Small pep1des
Vaccine delivery
Direct nose-brain delivery
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Nasal cavity
Volume circa 15 mL
Surface area about 160 cm2
Major part respiratory epithelium
Around 10 cm2 olfactory epithelium
pH around 6.5
Limited buer capacity
Contains mucus
Propelled by cilia to nasopharynx
Contains enzymes
Phase I and II metabolism
Inac1va1on of API
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Nasal prepara8ons (1)

NASALIA (Ph. Eur.)

Liquid, semi-solid or solid prepara1ons for administra1on to

the nasal cavi1es to obtain a systemic or local eect

Are as far as possible non-irrita1ng and do not adversely

eect func1ons of nasal mucosa and its cilia
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Nasal prepara8ons (2)

Nasal drops and liquid nasal sprays
Nasal powders
Semi-solid nasal prepara1ons
Nasal washes
Nasal s1cks
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Ingredients
One or more ac1ve substances
Solubility API is key determinant
Excipients
To adjust tonicity to isotonic
To adjust viscosity
To adjust or stabilise pH
To increase solubility of ac1ve substance
To stabilise the prepara1on
Preserva1ve
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Ciliotoxicity
Nega1ve inuence on the natural movement of the ciliated
epithelium (mucociliar clearance)
Reversible
Irreversible
Causes
Drugs or excipients (especially preserva1ves)
Oily solvents
pH values beyond physiological value
Osmo1c value devia1ng from from physiological value
Low humidity or high temperature of air

Nasal prepara8ons should, as much of possible, maintain the

integrity of the ciliated epithelium
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Cilia on nasal mucosa

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Biopharmacy nasal medica8on

Way of applica1on
Number of nasal drops
Loss due to mucociliary clearance
Gastrointes1nal absorp1on
Loss to to enzyma1c degrada1on
Absorp1on through epithelial cell layer systemic eect
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Use of nasal drops or spray

Blow nose and clean before using nasal drops or spray
Sni aeer applica1on
Avoid contamina1on
Temporary irrita1on may occur
Systemic ac1on aeer absorp1on via nasal mucosa
Children
Posi1on head is important
Less for nasal spray
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Requirements for nasal drops

Isohydric (pH 6.5-8.3)
Iso-osmo1c (around 0.9% NaCl)
Void (as much as possible) from ciliotoxic substances
Always preserved

Suitable weak buers in range 6.5-8.3:

Phosphate
Trometamol
Not: borate, citrate
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Typical drugs for the nose (local delivery)

Decongestants
Xylometazoline, NaCl 0.9%
(Ephedrine)
An1histamines
Azelas1ne, sodium cromoglycate
Cor1costeroids
Flu1casone, beclomethasone
An1bio1cs (cream or ointment)
Mupirocin
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Poor nasal availability (1)

Low aqueous solubility API
Improve solubility
- Prodrugs, co-solvents, cyclodextrins, novel delivery systems
(nanotechnology)

Enzyma1c degrada1on API

Reduce anity of API for nasal enzymes, inhibit nasal enzymes, limit
access of enzymes to API
- Prodrugs, enzyme inhibitors, encapsula1on (liposomes, nanopar1cles,
microspheres)
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Poor nasal availability (2)

Short contact 1me
Increase residence 1me of API
- Increase viscosity of formula1on, use adhesive formula1on

Low permeability API across nasal epithelium

Increase permeability, increase solubility, modify nasal epithelium
- Prodrugs, co-solvents, cyclodextrins, novel delivery systems, permea1on
enhancers

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Systemic ac8on via the nose: why?

Rapid onset of ac1on
Pain, migraine, emergency situa1ons
Avoidance rst-pass eect aeer oral administra1on
Avoidance gastrointes1nal problems
Galantamine: emesis
Route beler accepted than rectal, parenteral
Management of chronic diseases
No irrita1on should occur
Lower costs for produc1on
Compared to parenterals
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Systemic delivery of nasal drugs

Pep1des
Desmopressin, calcitonin, buserelin
Bioavailability poor
Fentanyl
Nico1ne
Sumatriptan

Vaccines
Inuenza (live alenuated virus)
- Airways site of exposure to airborne viruses
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Nasal sprays - examples

Metered dose Single-dose

Mul1ple use
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Nasal delivery to central nervous system

Nerve cells olfactory epithelium go to Route from olfactory region of nasal cavity
olfactory bulb of brain that bypasses blood-brain barrier
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Respiratory and
olfactory region
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Op8Nose system
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Final remarks
The nose as site of drug administra1on for systemic ac1on is
interes1ng and oers (limited) perspec1ves
Not yet fully explored
Future possibili1es, mainly for vaccines and olfactory delivery
Not as subs1tute for oral administra1on
- Limita1ons in dose that can be delivered and the frequency
- Metabolism in nasal cavity
- Mucociliar elimina1on
- Ciliotoxicity
Development of novel and improved devices
- Proper use: pa1ent counseling
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