Inhalational techniques

Inhalational Route of Drug
Administration

Asthma/ COPD
Disease Epidemiology – Indian
Scenario
Asthma COPD
Prevalence 38 million 55 million
Age Group All age groups > 40 years
Salvi S. Lancet Glob Health 2018; 6: e1363–74

Role of Inhaled therapy: Asthma and COPD

Inhaled Drug Delivery
Cornerstone Treatment for Asthma & COPD
• Inhalation- A cornerstone of treatment for patients with asthma &
COPD
• Better Drug Delivery
• Safe & effective
• Rapid & assured results
Rogliani P, Calzetta L, Coppola A, Cavalli F, Ora J, Puxeddu E, Matera MG, Cazzola M. Optimizing drug delivery in COPD: the role of inhaler devices. Respiratory medicine.
2017 Mar 1;124:6-14.
Gregoriano C, Dieterle T, Breitenstein AL, Dürr S, Baum A, Maier S, Arnet I, Hersberger KE, Leuppi JD. Use and inhalation technique of inhaled medication in patients with asthma and COPD:
data from a randomized controlled trial. Respiratory research. 2018 Dec;19(1):237.

PulmonaryDeliveryof Drug
Pulmonary delivery of drug has become an attractive target and of tremendous
scientific and biomedical interest in the health care research area as the lung is
capable of absorbing pharmaceuticals either for local deposition or for systemic
delivery.
The respiratory epithelial cells have a prominent role in the regulation of airway
tone and the production of airway lining fluid.
In this respect, growing attention has been given to the potential of a pulmonary
route as a non-invasive administration for systemic and local delivery of therapeutic
agents.
Because the high permeability and large absorptive surface area of lungs,
(approximately 70-140 m2in adult humans having extremely thin absorptive
mucosal membrane) and good blood supply.
Lung India. 2012 Jan-Mar; 29(1): 44–49

PulmonaryDeliveryof Drug (contd..)
• The alveolar epithelium of the distal lung has been shown to be an
absorption site for most of the therapeutics and various
macromolecules.
• Advantages over peroral applications are the comparatively low
enzymatic activity, rapid absorption of drug and the capacity for
overcoming first-pass metabolism.
• It has been already reported that, the local respiratory disorders and
some systemic diseases can be well treated by delivering the drugs
through pulmonary route.
• This includes the topical treatment of asthma,COPD, local infectious
diseases, pulmonary hypertension, the systemic use of insulin,
human growth hormones, and oxytocin
Lung India. 2012 Jan-Mar; 29(1): 44–49

Originof Inhalers
• The word ‘inhaler’ was first
used by the English physician,
John Mudge.
• In his 1778 book, A Radical
and Expeditious Cure for a
recent Catarrhous Cough,he
discloses to us his invention
of an inhaler.
• It was adapted from a pewter
tankard and the use of opium
vapour to treat cough.
Sanders M. Primary Care Respiratory Journal (2007) 16(2): 71-81

Inhalation Therapy In Ancient Times
• Long before Bennet, Stern and Mudge were describing inhalers
and advocating inhalation therapy, inhalation was being
practised in many parts of the world.
• The inhalation of the vapour of black henbane is recorded in
the ancient Egyptian Ebers papyrus (1,554 BC)
• Egyptian physicians threw the weed onto hot bricks.
• It caused caused the alkaloid contents of the plant to
vapourise so that the breathless patient could inhale.

The First PressurisedInhaler
• The first ‘powered’ or pressurised
inhaler was invented in France by
Sales-Girons in 1858.

• In 1860, Henry Hyde Salter published his famous text, On
Asthma its Pathology and Treatment.
• He systematically reviewed the treatment options of the
period, including inhaled therapies, and distinguished between:
• Depressants (ipecacuanha, tobacco, tartar-emetic),
stimulants (coffee, alcohol), and
• Sedatives (tobacco, chloroform, opium, stramonium, lobelia
and indian hemp).

The First Dry PowderInhaler
• In London in 1864, Newton patented an inhaling apparatus for
the delivery of dry powder medications.
• He observed that the powder needed to be finely pulverised
and that it had to be kept dry — principles that still apply to dry
powder inhalers today.
• This device is probably the earliest recorded dry powder
inhaler.

The Nelson Inhaler
• In 1865, a new invention
was reported in The
Lancet.
• The Improved Nelson
Inhaler from the well-
known pharmacy supplier
S.Maw & Sons in London.
• The Nelson inhaler is still
manufactured to this day,
with very few
modifications

TheFormalRecognitionOfInhalationTherapy
• The 1867 edition of the British Pharmacopoeia was the first to
formularise inhalation therapies.
• It listed five medications:
• Vapor acidi hydrocyanici
• Vapor chlori
• Vapor coniae
• Vapor creasoti
• Vapor iodi
• Inhalation therapy had won its spurs and had been formally
accepted as a means of medical treatment.

The First NebulisationDevices
• Da Costa published a fine account of inhalation medications
and devices in 1867.
• Among the devices described are the hand-ball spray and the
Siegle’s steam spray inhaler — a German invention from the
early 1860’s.
• Siegle’s steam spray used the Venturi principle to atomise liquid
medication, and this was, in effect, the beginning of nebuliser
therapy.

Siegle'ssteam spray inhaler,early1860

NotableInhalers And Inhaled Therapies
From A HundredYears Ago

Ceramicinhalers.
• Numerous versions of the Nelson
inhaler and other ceramic inhalers
appeared to deliver medicinal products.
• In Europe the enamel inhalers fulfilled a
similar purpose

PillowInhaler
• This clever approach involved the use
of a small shallow pot in a specially
made pillow.
• Volatile inhalants were put into the
pot.
• These were vapourised through the
night, delivering medication to the
sleeping patient.

Combustiblepowders
• These were to be burnt and the arising vapour inhaled.
• Most contained stramonium plus other alkaloids such as
belladonna and lobelia.
• Well known examples include Braters Powder, Kinsman Powder,
Green Mountain Powder, Kellogg’s Powder, Schiffmann’s
Powder, and Himrod’s .
• Many were also produced as asthma cigarettes and as a pipe
mixture

MentholInhalers
• In 1774, Gaubius first extracted crystals from peppermint oil.
• Later to be known as menthol, inventors have been finding
ways of delivering its cooling vapours to the respiratory tract.
• Menthol and eucalyptus oil are well known today as over-the-
counter therapies for cough and cold relief.

Maxim Inhaler
• Sir Hiram Maxim, an American living in London, was an
inveterate inventor.
• Most famous for the Maxim machine gun, he also invented a
steam driven flying machine.
• In August 1909, plagued by the effects of the London
atmosphere, he developed and patented his own inhaler.
• It resembled a glass retort and delivered a combination of
menthol and pine essence and was known as the Pipe of Peace.

Maxim Inhaler

Aerohalor
• Abbott launched the Aerohalor with a preparation of penicillin
for inhalation.
• Additionally a further presentation of the bronchodilator
Norethisderone was also made available.
• The Abbott Aerohalor, a DPI, used a lactose-based formulation
to deliver penicillin from small capsules known as ‘sifters’

The AbbottAerohaler,1948

pMDI
• Undoubtedly the most significant event of the 1950’s was the
development in 1955 of the pressurised metered dose inhaler
(pMDI).
• Nowadays, pMDIs have become a very important inhalation
technology with annual sales currently in excess of 400 million
units.
• The drugs, of course, have been updated and the propellant
technology improved through the use of less environmentally-
damaging HFAs.

Spinhaler
• Dr. Roger Altounyan ,a former Spitfire pilot who was very familiar
with aerodynamics, he invented the Spinhaler.
• It is a capsule inhaler that used a small propeller to create
turbulence.
• It was necessary to find alternatives to the standard pMDI
technology because the dose to be delivered exceeded the capability
of pMDI metering valves.
• Sodium cromoglycate was launched in 1967 as a Spinhaler device.
• Some years later a pMDI version was created, using a lower dose.

SalbutamolInhaler
• Salbutamol was the first of the selective bronchodilators,
relatively free from secondary effects on other systems.
• Salbutamol was formulated :
• In a pMDI, as a dry powder inhaler in the rotahaler and the
diskhaler and
• Was also produced as nebulised, tablet and syrup
formulations.

Rotahaler
• It is a dry powder capsule inhaler simply required twisting for a
loaded capsule to be pulled apart and the powder to be
inhaled through a mesh.

Diskhaler
• The Diskhaler represented an
important step forward.
• It did not require reloading for every
dose, so it was the first multi-unit
dose dry powder inhaler.
• This inhaler used a cartridge with
foiled sealed pre-measured doses.
• These are perforated at the time of
use to permit the drug to be inhaled

Beclomethasone
• In 1972 Allen & Hanbury’s marketed the first inhaled steroid,
beclomethasone, in the same inhalers as salbutamol.
• Numerous steroids have subsequently been developed, and
some have led to new inhaler developments.

Budesonide
• In 1987, Astra Zeneca launched a novel steroid, budesonide, in
a new multi-dose dry powder inhaler.
• It did not depend on each dose being isolated.
• Rather, the drug substance was kept in a reservoir from which
individual doses were taken at administration.
• This device, the Turbuhaler, has also proved very popular.
• In a similar way is now used to administer bronchodilators,
inhaled steroid, and combinations of the two.

Turbohaler

Contd..
• Subsequent development of dry powder inhalers has followed
the three themes described above:
• Capsule inhalers
• The multiple-unit dose inhalers and
• The reservoir devices.

SmallAirwaysContributeSignificantlyToTotal
LungResistance
Beam SD P T. 2010 Jul;35(7):377-416.

Advantages and Disadvantages of
Inhalational route

Advantagesand Disadvantagesof Inhalational
route
• These can be reviewed under the following :
• Compliance with inhalers
• Pharmacokinetic Issues
• Efficacy and safety

Breath-actuatedMDI
• Population:
• Aged ≥5 years
• May be particularly useful for patients unable to coordinate
inhalation and actuation or for elderly patients

Breath-actuatedMDI: Advantages
• Indicated for patients unable to coordinate inhalation and
actuation
• May be particularly useful in the elderly
• Less variation in emitted dose due to reproducible actuation

Breath-actuatedMDI: Disadvantages
• Patients may incorrectly stop inhalation at actuation
• Cannot be used with available spacer/valved-holding chamber
devices

Dry PowderInhalers (DPI)
• Population:
• Aged ≥4 years
• Most children aged < 4 years may not generate sufficient
inspiratory flow

DPI: Advantages
• Breath actuated
• Less patient coordination required compared with a pMDI
device
• No need for propellant
• Portable and compact
• Can be used quickly
• No preparation of drug required
• Dose counters in newer designs

DPI: Disadvantages
• Some units are single dose
• Loss of dose if patient exhales through the device
• Can result in high pharyngeal deposition
• Upper limit to unit dose content

Spacer/holdingchamber
• Aged ≥4 years (< 4 years old, valved holding chamber with face
mask)
• Indicated for patients who have difficulty performing adequate
MDI technique

Spacer/holdingchamber:Advantages
• Reduced need for coordination
• Reduced pharyngeal deposition

Spacer/holdingchamber:Disadvantages
• Complexity of inhalation may be increased for some patients
• Increases expense and decreases portability compared with
MDI alone
• Development of static charge on the inner walls can attract
aerosol particles to the walls and reduce lung delivery
• Integral actuator devices may alter aerosol properties
compared with native actuator

Nebulizers
• Population:
• Patients of any age who cannot use a metered-dose inhaler
with a valved holding chamber and a face mask

Nebulizers:Advantages
• Patient coordination not required
• Effective with tidal breathing
• May be able to administer multiple medications
• Dose modification is possible
• May be used at any age

Nebulizers:Disadvantages
• Lack of portability (jet nebulizers)
• Lengthy treatment times
• Device cleaning required and contamination possible
• Lack of availability of some medications in a preparation that
can be nebulized
• Suspensions not aerosolized well (ultrasonic nebulizers)
• Variability of performance efficiency among different
nebulizers

Nebulizers:Disadvantages(contd..)
• Less efficient than other
devices (waste)
• Expensive (ultrasonic
nebulizers)
• More effective if triggering
the device is coordinated
with inspiration
• Face mask must fit
appropriately

Advantages of Using MDIs
Allows
more
medicatio
n to reach
your
lungs
Prevents
medicatio
n from
escaping
into the
air if used
with
Spacer
Fewer
side
effects
from
corticoste
roid
residue in
the mouth
Compact,
portable,
convenient
Suitable for
an
emergency
American Thoracic Society

Compliance with Inhalers
• Compliance with asthma therapy has the added dimension that
treatment frequently includes the use of inhalers:
• Which are relatively complicated devices and
• Which many patients (especially children and the elderly)
find difficult to use
• Indeed, it has been shown that the great majority of elderly
patients cannot use inhalers properly, despite adequate
instructions.
Leonardo MF et al. Drugs. 1996;52 Suppl 6:20-8.

Despiteof using MDI, outcomesare not as
expected…
As we face many challenges

Adherence Remains a Key Challenge..
Aggarwal D et al. Journal of Clinical and Diagnostic Research. 2017 Dec, Vol-11(12):OC14-OC18
Conclusion: Monitoring of medication adherence seems to be a better tool
than self reported adherence for the evaluation of adherence to ICS in
asthma

Non-adherence - A Troublemaker!
• Accidental and intentional non-adherence with therapy at least twice a week was
reported by 27% and 24%, respectively.
• Lack of perceived symptoms was the main reason for non-adherence.
• Some of the patient’s belief which are the cause of non-adherence:
1. Fear of adverse effects and addiction
2. Complexity of therapy
3. Psychological factors
• It is estimated that nearly 45% patients do not adhere to therapy (in terms of
filling/refilling prescriptions or maintaining prescribed medication schedule), which
adversely impacts clinical outcomes and patient quality of life.

In Inhalation therapy, non-adherence is very
common
63
Complete adherence to Inhaled Therapy
occurs only in 33.6%*
* Humenberger, M., Horner, A., Labek, A. et al. Adherence to inhaled therapy and its impact on chronic obstructive pulmonary disease (COPD).
BMC Pulm Med 18, 163 (2018) doi:10.1186/s12890-018-0724-3

GINA & GOLD-
RecommendstoCheck theAdherence
Non- Adherence to be assessed for gaining optimal clinical outcome
GINA 2020 Guidelines GOLD 2020 Guidelines
https://goldcopd.org/wp-content/uploads/2018/11/GOLD-2019-POCKET-GUIDE-
FINAL_WMS.pdf

Useof DigitalTechnologyforAdherence-Makingthe
ChangetoDataDrivenTreatment
Digital monitoring has been shown to have a positive impact on adherence in both
asthma and COPD and is rising in popularity because of its precision and
objectiveness.
Dekhuijzen R, Lavorini F, Usmani OS, van Boven JF. Addressing the impact and unmet needs of nonadherence in asthma and chronic obstructive
pulmonary disease: where do we go from here?. The Journal of Allergy and Clinical Immunology: In Practice. 2018 May 1;6(3):785-93.

• For patients, clinicians and researchers, digital technologies such as those addressing adherence
and inhaler technique offer the opportunity to advance personalized care for patients with
respiratory diseases.
• Longitudinal, real-time data collected through digital platforms can provide
• Precise understanding of the interaction of a patient’s adherence
• Symptoms
• Disease course, which can be used to develop and support adherence
management strategies
Blakey JD, Bender BG, Dima AL, Weinman J, Safioti G, Costello RW. Digital technologies and adherence in respiratory diseases: the road ahead. European
Respiratory Journal. 2018 Nov 1;52(5).

Conclusion
• The inhaled route of administration features prominently in
current treatment guidelines for the management of patients
with asthma.
• Inhaled short-acting beta 2 agonists are effective, well
tolerated and have a rapid onset of action, making them agents
of choice as rescue therapy.
• However, some patients find it difficult to use inhalers, and a
number of different types of errors in inhalation technique that
can impair efficacy.
Leonardo MF et al. Drugs. 1996;52 Suppl 6:20-8.

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