Download Breathe In, Breathe Out: Redesigning Inhalers for Asthma Patients

Breathe In, Breathe Out: Redesigning Inhalers for Asthma Patients
Gina El Nesr
Massac8husetts Academy of Math and Science
Version as of January 4, 2016
Abstract
--Introduction
-Literature Review
The Respiratory System
The system in humans that takes up oxygen and expels carbon dioxide is known as the
human respiratory system. The human respiratory system consists of two parts: the upper and the
lower airway systems. The upper airway system comprises of the nose, sinuses, pharynx, and
partly the oral cavity while the lower airway system consists of the larynx, trachea, stem bronchi,
and all parts of the lung (Britannica, 2015).
Figure QQQ. A depiction of the respiratory system. (Britannica, 2015).
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The Upper Airway
The nose is subdivided into a left and right canal. Each canal opens to the face by the
nostril and into the pharynx by the nostril. The nasal cavity is lined by a respiratory mucosa
containing mucus-secreting glands. The design of it reflects the functions of the nose and the
upper airways in general with respect to respiration. They clean, moisten, and warm the inspired
air, preparing it for contact with delicate tissues of the lung.
The pharynx is divided into three floors. The upper floor is known as the nasopharynx
and is primarily a passageway for air and secretions from the nose to the oropharynx. The middle
floor, the oropharynx, connects anteriorly to the mouth. The lower floor, the hypopharynx is the
anterior wall formed by the posterior part of the tongue. It represents the site where the pathways
of air and food cross each other. The epiglottis functions as a lid to the larynx and controls the
movement of air and food when swallowing (Britannica, 2015).
The Lower Airway System
The division of the lower airway system determines the internal lung structure. The
conducting airways comprise the larynx, trachea, the two stem bronchi, the bronchi, and the
bronchioles. They serve to further warm, moisten and clean the air and distribute it to the lung.
The larynx serves dual functions as an air canal to the lungs and an organ of phonation.
The larynx measures Below the larynx is the trachea, a tube of about ten to twelve centimeters
long and one centimeter wide (O’Rahilly et. al, 2004). At its lower end, the trachea divides in an
inverted “Y” into the two stem bronchi, one each for the left and right lung. The right main
bronchus has a larger diameter, is oriented more vertically, and is shorter than the left main
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bronchus. The consequence of this arrangement is that foreign bodies passing beyond the larynx
will usually slip into the right lung.
The bronchi are the main passageways into the lung. They are lined with cilia and move
in a wave-like pattern to carry mucus upward and out of the throat. Mucus catches and holds
much of the dust, germs, and other unwanted matter that has invaded the lungs (O’Rahilly et. al,
2004). The smallest branches of the bronchial tubes are called bronchioles. At the end of the
bronchioles are the air sacs called alveoli. The alveoli hold capillaries that pass through blood.
The blood enters through the pulmonary artery and leaves via the pulmonary vein. While in the
capillaries, blood gives off carbon dioxide through the capillary wall into the alveoli and takes up
oxygen from air in the alveoli (Britannica, 2015).
Lungs and Diaphragm
The lung, a gas-exchanging organ, is located in the rib cage and provides humans with a
continuous flow of oxygen, clearing the blood of carbon dioxide. To function, air is regularly
pumped in and out through the conducting airways. The diaphragm, the main respiratory muscle,
and the intercostal muscles generate the pumping action of the lung. It expands and contracts
within the space of the thorax. The two lungs rest with their bases on the diaphragm.
Each lung is subdivided into smaller units called pulmonary segments. The right lung is
composed of three lobes – a superior, middle, and inferior lobe – and ten pulmonary segements.
Comparatively, the left lung is smaller in volume because of the asymmetrical position of the
heart, so it only has two lobes. The number of pulmonary segments in the left lung range from
eight to ten (Rogers, 2011).
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Asthma
Asthma is a chronic lung disease that temporarily inflames, and thus narrows, the airways
that carry oxygen. This results in symptoms such wheezing, chest tightness, shortness of breath
and coughing. Asthma affects people of all ages, although it most often starts during childhood
(“Asthma,” 2014). Of the 26 million people who suffer from asthma in the United States, 7
million of them are children (“Asthma,” 2014). Each year, approximately 1.7 million emergency
department visits, 10.6 million physician office visits, 440,000 hospitalizations and 3,616 deaths
are a result of asthma (Sevum et. al, 2012).
Over the past 110 years, our understanding of asthma has evolved greatly. What was long
considered a disease of “twitchy” airways and minor ailment is now known to be a disease of
chronic fluctating airways inflammation (Kasper & Harrison, 2005). Even though asthma’s
exact cause is still unknown, the disease is characterized by reversible airflow obstruction;
airway inflammation; increase in secretions of mucus; and/or airway hyperesponsivness in
response to allergens, environmental irritants, viral infections, or exercise (Sevum et. al, 2012). It
manifests as inflammation in the centeral and peripheral airways resulting in structual changes in
the airways called remodelling. These changes degrade airway function, causing the common
asthmatic symptoms (Kasper & Harrison, 2005).
Figure QQQ. A depiction of the pathology of the airwyas normally, of an asthmatic,
and of an asthmatic during an attack. (xxx, xxx)
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Diagnosis of Asthma
Establishing the diagnosis of asthma primarily rests on obtaining a solid clinical history
that suggests airway hyperreactivity. There must be objective evidence of reversible airway
obstruction by either a spirometry test or peak flow meter. A spirometry tests records how much
air is exhaled (forced vital capacity) and how fast (forced expiratory volume). Similarly, a peak
flow meter is an inexpensive calibrated device that measures the forced expiratory volume.While
many disease share similar clinical symptoms, diagnosis should not rely solely on symptoms and
should always consider alternative causes. Some evidence suggests that many patients are
incorrectly diagnosed and treated for asthma when they have an alternative diagnosis (“Clinical
Practice,” 2009).
Figure QQQ. Right: A spirometry testing device that measures the forced vital capacity and forced expiratory volume.
Left: A peak flow meter measures the forced expiratory volume. Both are commonly used to diagnose asthma.
Treatement of Asthma
Asthma is a long-term disease without a cure, so asthma treatment is centered around
controlling the diease. The goal of asthma treatements is to prevent the chronic symptomes,
reduce the need for quick-relief medications, aid in maintaining good lung function and normal
activity level, and prevent fatal asthma attacks. Management of asthma should be done in
partnership with a doctor. Parts of managing asthma include avoiding all triggers besides
physical activity and taking daily peak-flow meter tests to track the movement of asthma.
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Treatments for asthma fall into one of two categories: long-term control or quick-relief
medicines. Long-term control medicine help reduce airway inflammation and prevent asthma
sysmptoms while quick-relief or rescue medicines relieve flare-up asthma symptoms. Most
treatment plans involve some form of inhalation therapy. With an inhaler, patients are better able
to quickly deliver the medication to the lung. However, asthma medicines can also be taken in
pill form.
History of Inhalation Therapy
While inhalation therapy for medicinal purposes dates back to at least 4,000 years, one of
the earliest inhaler devices is a design attributed to Hippocrates (Crompton, 2006). His design
consisted of a simple pot with a reed in the lid to inhale vapor. Variations on Hippocrates’s
design were used in the late 18th and early 19th century. Dr. John Mudge, an English physician,
coined the term “inhaler” after inventing a device designed for the inhalation of opium vapor.
Numerous models of ceramic inhalers followed Dr. Mudge’s design in which air was either
drawn through warm water or infusion prior to inhalation. One of the most popular models was
Nelson’s inhaler. Manufactured by S. Maw and Sons in London, Nelson’s inhaler was declared
“the most efficient apparatus for the inhalation either of simple steam or of medicated vapors” in
a Lancet article in 1863. Its envrionmental-friendliness, clealiness, portability, and cheapness
became the qualities that are now most valued in modern inhalers.
Redesigning Inhalers 6
Figure QQQ. Left: The Mudge inhaler, invented by Dr. John Mudge in 1776. Right: Nelson’s
inhaler without a stopper and tube extending down into the liquid (Anderson, 2005).
Nebulizers, or atomizers, were an outgrowth of the perfume industry and an evolution of
inhalation treatement of thermal water. Dr Auphon Euget-Les Bain invented the atomizer in
1849, and Jean Sales-Girons introduced a portable nebulizer in 1858. The portable nebulizer won
the silver prize at the Paris Academy of Science. The design uses a pump handle to draw liquid
and forces the liquid through a nozzle. This was later improved by Bergsen, of Berlin in an
apparatus consisting of two glass tubes perpendicularly relative to each other. The more open
end of the perpendicular tube is immersed in the medication. Compressed air is forced through
the horizontal tube, causing the air in the other tube to be exhausted and the medication to
evenutally rise and disperse in fine spray. This system similar to that currently utilized by today’s
nebulizers. Medication was later nebulized via glass-bulb nebulizers, such as the Parke-Davis
Glaseptic, and via plastic-bulb nebulizers, such as the AsthmaNefrin. The AsthmaNefrin
disperses the medication into fine mist that floats in air. The Pneumostat, the first compressor
nebulizer, was manufactured in Germany in the early 1930s and had a rheostat for the power
supply.
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Figure QQQ. AsthmaNefrin hand-bulb nebulizer from the 1940s. (Anderson, 2005)
Around the turn of the 20th century, combustible powders and cigarettes for the treatment
of asthma and other lung complaints became popular. Powder was placed in a saucer and burned.
Its smoke was inhaled through the mouth or a funnel. The instructions for the asthma cigarette
are similar to that given in modern clinics for pressurized metered-dose inhalers and dry powder
inhalers: exhale, fill the mouth with smoke, breathe in and draw the smoke down into the lungs,
hold for a few seconds, and exhale. Abbot Laboratories developed the Aerohaler in 1948 for
inhaled penicillin powder. Each medication-filled cartridge was inserted in the inhaler. When
there was an intake of air, a metal ball would strike the cartridge and shake out powder into the
airstream (Anderson, 2005).
However, inhalation therapy was revolutionized by the invention of the pMDI. In 1955,
Dr. George Maison, president of Riker Labs, saw his daughter’s difficulties using the hand bulb
nebulizer (Crompton, 2006). He developed a metered-dose valve and worked with DuPont to
manufactured propellants for an alcohol-based solution MDI. In 1957, the first oral suspension
pMDIs of epinephrine and isoproterenol were produced. Technology of the devices and
formulations for the inhaled drugs in the past 60 years has made remarkable advancements since
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the first pMDI was developed (Anderson, 2005). Several new devices are now breath-enhanced,
breath-actuated, and dosimetric.
pMDI development has proceeded in several directions to address the problems posed by
improper inhalation technique and coordination, high oropharyngeal deposition, and the need to
replace chlorofluorocarbon (CFC) propellants.
Figure QQQ. Evolution of inhalation therapy.
Spacer Devices
Spacer devices are add-on holding chamber that attach to pMDI actuators. Their volumes
can range from 20 mL to 750 mL in commercially available models. By placing some distance
between the point of aerosol generation and the patients mouth, the spacer reduces the
oropharyngeal deposition. Spacers make pMDIs easier to use by reducing the need for
coordination between actuation and inhalation. However, these benefits are made to the expense
of the pMDI’s size and convenience. Drug delivery from spacers depend on the patient’s
inhalation technique, and in the chase of plastic spacers, may be affected by static-charge buildup
on the spacer walls. The delivery of medicine from plastic spacers can be exchanged by antistatic
linings on the internal walls.
Redesigning Inhalers 9
Figure QQQ. Inhaler inserted into a spacer. (AAFA, 2015).
The amount of drug available from the spacer increases with diameter and length of the
spacer. While smaller spacers are more convenient for patients, there is a reduction in the dose
available for inhalation. The dose with some large-volume spacers is higher than that from a
pMDI alone. But increasing the spacer volume to be greater than one liter would most likely be
counterproductive (Newman, 2005).
Pressurized Metered-Dose Inhaler
For the first half of the 20th century, inhaled drugs for the treatment of asthma and
chronic obstructive pulmonary disease were mostly delivered via nebulizers. However, after the
development of bronchodilator drugs in pressurized containers, there was a gradual shift in
preference. The pressurized metered-dose inhaler (pMDI) became the most important device in
delivering inhaled drugs. For almost fifty years, pMDIs have been favored by patients for its
practical benefits: small size, portability, convenience, and unobtrusiveness. Its multi-dose
capability means that a dose is immediately available when needed (Newman, 2005).
Figure QQQ. Different types of inhalers. (AAFA, 2015).
Redesigning Inhalers 10
The pMDI comprises of several components, each of which is important to the whole
device. These components are the container, propellant, drug formulation, metering valve, and
actuator.
Figure QQQ. Schematic of a typical pressurized metered-dose inhaler. (Newman, 2005).
Container
The pMDI container must be able to withstand the high pressure generated by the
propellant, made of inert materials, and sufficiently robust. Aluminum is preferred, although
stainless steel has also been used. The advantages of aluminum include its light weight, compact
structure, less fragility and its light-proof characteristics. Coatings on the internal container
surface are useful in preventing adhesion of drug chemicals and chemical degradation.
The canister is used in the inverted position with the valve below the container so it refill
sunder gravity. It is also important to ensure that the emitted dose of medicine is reproducible,
regardless of the last time the inhaler was actuated or its orientation (Newman, 2005).
Propellants
The propellants of pMDIs are liquified compressed gases that form a liquid when
compressed. To ensure constant dosage, the vapor pressure is held constant, ruling out the use of
Redesigning Inhalers 11
carbon dioxide. Chlorofuourcarbons (CFC) meet the required criteria for a propellant but in
2008, the use of CFCs was banned under international agreement. The nature of CFC causes it to
release chlorine and damage the ozone layer in the stratosphere.
Figure QQQ. Standard propellant mechanism of pMDIs. (Newman,
2005).
Formulations of hydofluoroalkanes (HFA) are now popular, leading to many challenges
involving the development of new excipients and metering valves. HFAs are greenhouse gases
but their contribution to global warming is likely very small (Newman, 2005).
Metering Valve
The metering valve is the most important component of the pMDI. While there are a wide
range of designs for metering valves, they all operate on the same basic principle. Before firing,
a channel between the body of the container and the metering chamber is open. As the pMDI is
fired, the channel closes and another channel connecting the metering chamber to the atmosphere
opens. The medicine is expelled into the valve stem which forms an expansion chamber in which
the propellant begins to boil (Newman, 2005).
Redesigning Inhalers 12
Actuator
The pMDI is fitted into a plastic actuator. The design of the actuator is important,
because the aerosol particle size is determined by the nozzle diameter, which ranges from 0.14
mm and 0.6 mm. Aerosol particle size varies directly with nozzle diameter, which also
influences lung deposition. By reducing the actuator nozzle diameter, the spray force will
decrease.
The final atomization process is described as a two phase gas/liquid air-blast. When the
dose leaves the nozzle, the liquid ligaments embedded in the propellant vapor are puled part by
aerodynamic forces to form a dispersion of liquid droplets. Evaporation of propellant cools the
droplets (Newman, 2005).
Limitations of and Problems with pMDIs
There are many limitations to pMDIs. Drug delivery in pMDIs is highly dependent on the
patient’s inhaler technique. Failure to coordinate or synchronize actuation with inhalation is the
most popular and most important problem patients have with pMDIs. The improper technique
when using pMDIs can resulting in suboptimal, or even zero, lung deposition. By misusing
corticosteroid pMDIs, there has been an associated decrease in asthma stability, especially when
misses involves poor coordination.
Even with good inhaler technique, only about 10 - 20% of the dose enters the lung. The
rest of the dose is deposited in the oropharynx. This can cause localized and systematic adverse
effects. While the low lung deposition and dependence on inhaler technique may be acceptable
in cases of asthma and COPD, they are not acceptable for targeted therapies that have narrow
therapeutic windows (Newman, 2005).
Redesigning Inhalers 13
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