Nasal and Lung Drug Delivery

MP508

Dr. Philipp Seib

E-Mail: Philipp.Seib@strath.ac.uk
Office: Robertson Trust Wing, Room 501
References
Text books:

FASTtrack: Pharmaceutics - Drug Delivery and Targeting Y. Perrie and T.

Rades. Publisher: Pharmaceutical Press

Aulton’s Pharmaceutics. Michael E. Aulton, Kevin M.G. Taylor. 4th Edition

(2013) Churchill Livingstone Elsevier
 Learning objectives

• Understand the physiology of the nose and lung and their

pros and cons for drug delivery

• Understand the underlying mathematics that affects lung

delivery

• Understand the principles applied to formulating

nasal/pulmonary delivery systems

• Know clinical examples of drugs administered to the

nose and lungs
 The nasal cavity

A: Lateral wall of nasal cavity

B: Cross-section through
middle of the nasal cavity
C: The respiratory epithelium
D: Olfactory epithelium

Reference: Aulton’s Pharmaceutics Chapter 38 Nasal drug delivery

 The nasal cavity
Nasal cavity
• Volume 15 ml
• Surface area 160 cm2
• pH 5.5. to 6.5
• Broad range of enzymes (e.g. proteases)
• Mucos propelled by beating cilia (mucociliary clearance).

Reference: Aulton’s Pharmaceutics Chapter 38 Nasal drug delivery

 Intranasal drug application
Local treatment
• Allergic rhinitis
• Nasal congestion
• Nasal infection
(Many products)
Systemic treatment
• Diabetes (Exubera discontinued)
• Chronic pain (fentanyl, Instanyl®)
• Postmenopausal osteoporosis (calcitonin, Miacalcic® discontinued)
• Smoking cessation (nicotine, Nicorette®)
• Migrane (sumatriptan, zolmitripan Imitrex®, Zomig®)
• Prostate cancer (buserelin, Suprefact®)
• Influenza vaccination (Fluenz®)
 Intranasal drug application - Why?
• Rapid onset of action (pain, migrane, erectile dysfunction)

• Avoid GI and hepatic pre-systemic metabolism

• Patient willingness to use this route of administration

• Low cost for manufacturer (no requirement for sterility)

• Management of chronic disorders (providing no irritation occurs)

• Improved vaccine delivery, esp. for respiratory tract infections (e.g.,

influenza)

• Presentation of antigen + adjuvant promotes cellular/humoral

response (e.g. nasal-associated lymphoid tissue)
 Intranasal buserelin Suprefact®

Gonadotropin releasing hormone (GnRH) agonist

Peptide drug- semester 2 lectures MP509 for information

• Hormone responsive prostate cancer (main indication)

• IVF treatment (specialist application)

• Treatment choice of GnRH è pharmacoeconomics

Salmon
Intranasal calcitonin - discontinued
Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro

Human
Cys-Gly-Asn-Leu-Ser-Thr-Cys-Met-Leu-Gly-Thr-Tyr-Thr-Gln-Asp-Phe-Asn-Lys-Phe-His-Thr-Phe-Pro-Gln-Thr-Ala-Ile-Gly-Val-Gly-Ala-Pro

Salmon calcitonin
• MW 3,500
• 50x more potent than human polypeptide
• Ca2+ and phosphorous metabolism
• Reduced bone turn over (êosteoclastic activity)
é Bone mineral density
• No evidence for fracture reduction

Omni die (o.d.)

Intranasal calcitonin - discontinued
 Intranasal vaccine Fluenz®
IM injection Intranasal spray (Fluenz)
Fluenz
• Live attenuate influenza vaccine
• Nasal spray
• 0.1 ml/nostril

Conventional vaccine
• Inactivated influenza vaccine
• IM injection
• 0.25 ml
Fluenz recommended vaccine:
• Live attenuate influenza vaccine
• Children >2 years to adults 49 years
• Nasal spray
• 0.1 ml/nostril

• Safe vaccines for children w/o history of

asthma and wheezing
Belshe et al. NEJM (2007) 356 685
Flu vaccination - nasal vs. IM

IM vaccine

Fluenz

Belshe et al. NEJM (2007) 356 685

 Pulmonary drug delivery – Why?

Local drug delivery è permits rapid onset of action e.g.,

Obstructive pulmonary disease

Cystic fibrosis (Dornase α, antimicrobials)
Asthma (e.g. salbutamol, betamethasone)

Systemic drug delivery:

Poor oral availability
Avoid 1st pass metabolism in liver
Large surface area for absorption

Reference: Aulton’s Pharmaceutics Chapter 37 Pulmonary drug delivery

The human airways

• O2 and CO2 exchange

between blood and inhaled
air

• Alveoli surface area 140 m2

• Airway design efficiently

prevents entry/removal of
particles/microorganisms

• Conducting airways lined

with ciliated epithelium
(i.e. mucociliary escalator)
 Pulmonary drug delivery

• Drug must be presented as aerosol

(exception are medical gases)

• Aerosol: solid particle or liquid droplet dispersed in

air or gaseous phase

• Successful aerosol deposition in lung:

Physiochemical properties of drug
Formulation
Delivery/liberating device
Patient (breathing pattern, clinical status)
The mathematics of pulmonary drug delivery
• Size of aerosol is most important physical property

• Aerodynamic radius takes into account: Size, shape & density

For log-normally distributed and approx. spherical particles:

“Large” porous particle,

da = dp (ρ/ρ0)1/2 physical diameter 20 μm

da Aerodynamic radius
dp Physical diameter
Excellent lung deposition
ρ Particle density
ρ0 Unit density 1 g/cm 3

da Defined as the diameter of a sphere of unit density (1 g/cm3) which has

the same terminal velocity as the particle in question.
The mathematics of pulmonary drug delivery
Particle deposition in the airways

Inertial impaction Gravitational Brownian diffusion

sedimentation

Vt V sinθ ρgd2 kB T
Vt = D=
gr 18 η 3πηd
Important for particles Important for particles Important for particles
> 5μm & especially > 10μm 0.5 to 3 μm (da) < 0.5 μm (da)
(da)

Vt terminal settling velocity ρ Particle density D Diffusion coefficient

V air stream velocity
θ change in airways direction
r airway’s radius
g acceleration due to gravity
d particle diameter kB Boltzmann’s constant
η air viscosity
1 to 5 μm lower airways
0.5 to 1 μm lower airways (stagnant air)
A pharmaceutical company has developed two
particulate formulation to treat asthma. The
characteristics of the formulations are:
Formulation A:
20 μm diameter
Density of the particle 0.05 g/cm3
Formulation B:
10 μm diameter
Density of the particle 0.8 g/cm3

(A) Which formulation is best suited? Justify

your answer!
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End
The mathematics of pulmonary drug delivery
Polydispersed (reality)

Frequency (%)
Private study:
Student knows how &
shows how
• Geometric mean diameter
• Geometric standard deviation
• Mass median diameter Size of aerosol droplets
• Mass median aerodynamic diameter
Monodispersed (idealised)
Apply this background to aerosols

Frequency (%)
Reference: Aulton’s Pharmaceutics,
Pulmonary drug delivery

Size of aerosol droplets

 Pressurised metered-dose inhalers (MDI)

25 – 100 μl

• Drug is dissolved or suspended in liquid propellant

• Propellant fluoralkanes (gas at room temperature, liquid at higher pressure)

Advantages Disadvantages
• Portable • Inefficient and drug delivery
• Low cost • On actuation 1st droplets very fast
• Disposability (30 m/s)
• Many doses (up to 200) • Mean droplet size 40μm – shrinks as
• Inert condition of propellant protects drug propellant evaporates
• Can take 5s to get to original size of
micronized drug
• Incorrect use of MDI use
Pressurised metered-dose inhalers + spacer

Spacer- approach
• Inhalation/actuation coordination
• Premature deposition due to large particles
• Reduces droplet velocity
• Propellant evaporation

Disadvantages (spacer)
• Bulky
Other approaches
• Breath-actuated inhalers
• (e.g. Syncroner®, Autoinhaler®)
 Dry powder inhaler (DPI)

Inhalation of finely powdered drug

Advantages
• Propellant free
• No excipient except lactose as carrier
• Breath actuated avoid inhalation/actuation
issues
• Deliver larger dose > MDIs

Disadvantages
• Patient required to inhale sufficiently to
• Deaggregate particles
• Drug exposed to ambient conditions (drug
stability, e.g. humidity powder aggregate)
• DPI less efficient at delivering drug, 2x MDI
Turbohaler®: dose required
Bricanyl (terbutaline sulfate)
Oxis (formoterol)
Pulmicort (budesonide) http://www.bbc.co.uk/programmes/p01jzdh5
Symbicort (budesonide)
Inhaled insulin Exubera® - discontinued

Marketed in USA 2006 – 2007 (Pfizer)

Discontinued due to poor sales
• Market acceptance?
• Toxicity?

http://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?id=7043
 Insulin delivery – clinical trial
PET scan: Hypometabolism Delivery of insulin to
• Olfactory bulb
• Trigeminal nerves

T0
Access to the CNS
T 4 months

Placebo Insulin
(nasal)

• Impact of insulin on cognitive abilities of non-diabetic Alzheimer’s patients.

• Measured brain metabolism (PET)
• Delayed storey recall score

Craft et al. Arch Neurol (2012) 69 29

Fun fact…