University of Groningen

Dry powder inhalationKoning, Johannes Petrus de

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Citation for published version (APA):Koning, J. P. D. (2001). Dry powder inhalation: technical and physiological aspects, prescribing and uses.n.

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1.1 Introduction..............................................................................................................21.2 Aim of this thesis .....................................................................................................31.3 Asthma and COPD...................................................................................................41.4 From powder to clinical effect .................................................................................41.5 Respiratory system...................................................................................................51.6 Pulmonary ventilation ..............................................................................................61.7 Pulmonary mechanics ..............................................................................................71.8 Inspiratory muscle strength....................................................................................101.9 Inhaler devices .......................................................................................................11

1.9.1 Nebulizers ..............................................................................................................111.9.2 Pressurised-metered dose inhalers .........................................................................121.9.3 Dry powder inhalers...............................................................................................12

1.10 Powder formulations ..............................................................................................151.11 Deposition mechanisms .........................................................................................171.12 Particle size for lung deposition.............................................................................181.13 Inhalation-instruction .............................................................................................191.14 Patient compliance .................................................................................................201.15 Prescribing .............................................................................................................211.16 References..............................................................................................................22

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The respiratory tract is one of the oldest routes for the administration of drugs. Anaesthetics,

aerosolised drugs, smoke or steam have been inhaled for medical purposes for centuries. Over

the past decades inhalation therapy has established itself as a valuable tool in the local therapy

of pulmonary diseases, such as asthma or COPD(1). Historically, the evolution of inhalation

therapy can be traced to India 4000 years ago, where the leaves of the Atropa Belladonna

plant, containing atropine as bronchodilator, were smoked as a cough suppressant(2). The

development of modern inhalation therapy began in the nineteenth-century with the invention

of the glass bulb nebulizer. The development of the first pressurised metered-dose inhaler

(p-MDI) for asthma therapy in 1956 was a major advance in the use of aerosols for drug

delivery to the lungs(3). However, the required hand-lung coordination of the patient and the

use of environmentally damaging CFC propellants, are major drawbacks of the traditional

p-MDI. Dry powder inhalers (DPI's) were introduced to overcome these drawbacks. From the

first introduction of a DPI in 1971 (Spinhaler), several DPI's have been added to the collection

of available inhalers. DPI's represent a significant advance in pulmonary delivery technology.

They are breath-controlled and so coordination problems have been overcome. DPI's are also

potentially suitable for the delivery of a wide range of drugs, such as anti-asthmatics, peptides

and proteins. DPI's can also deliver a wide range of doses from 6 µg to more than 20 mg via

one short inhalation(4, 5). This chapter gives an introduction to inhalation therapy with modern

dry powder inhalers, from the anatomy of the airways, mechanics of pulmonary ventilation,

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powder formulation, technological aspects of interest for the understanding of DPI design, to

the prescription and use of DPI's.

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It is clear that inhalation technology or inhalation therapy with dry powder inhalers is not

simply the administration of some powder to the patient which will result in a clinical effect.

Many variables are involved in the steps between powder formulation and the clinical effect

(figure 1.1). The unique combination of research groups in this multidisciplinary project

enabled investigation of variables involved in inhalation, from different perspectives.

Relevant inhalation variables include the design (resistance to airflow) of the dry powder

inhaler, the patient, and the inhalation-instruction. They represent the whole domain of dry

powder inhalation from pharmaceutical technology to inhaler use. Technological and

physiological aspects as well as prescribing and use of dry powder inhalers are investigated.

Two main questions are raised. Firstly, the question is raised to what extent the inspiratory

muscle function is a determinant for the inspiratory performance through a dry powder inhaler

and how this is related to the inhaler performance. Secondly, the question is raised to what

extent counselling at prescribing level and patient level can contribute to the correct use of the

inhaler device.

Both questions are investigated in different research settings. The first question resulted in a

research setting in the University Hospital of Groningen and the asthma centre Beatrixoord,

Haren. In this study the relation between the inspiratory flow curve and the inspiratory muscle

function was investigated in healthy subjects, asthmatics, Chronic Obstructive Pulmonary

Disease (COPD) patients and Chronic Obstructive Lung Disease (COLD) patients with

reduced peak maximal inspiratory pressure (P·MIP). Similarities between inspiratory muscle

training as applied in COLD patients with reduced P·MIP, and the inhalation through high

resistance to airflow DPI’s resulted in an additional study in which the effects of DPI use on

the inspiratory muscle strength was investigated.

To answer the second research question, the process underlying the choice of an inhaler

device for the treatment of asthma and COPD was investigated. In this study the evoked set

for prescribing inhaled medication, as well as the knowledge about the prescribed inhaler

devices, was investigated amongst chest physicians, general practitioners, and pharmacists.

Adequate knowledge is necessary for proper patient education and counselling. Therefore, an

inhalation-instruction was written with technological background regarding the inhaler

devices to improve the knowledge by the health care provider about the inhalation

technology. The use of dry powder inhalers was measured by calculating patient compliance.

Therefore, a database was developed with prescription data concerning the use of inhaled

corticosteroids. This database is developed in cooperation with pharmacists from the

pharmacists peer review group NODE (Noord-Oostpolder / IJssel-Vecht Delta, the

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Netherlands), ‘Stichting Doelmatige Farmaceutische Zorg Drenthe/Hanzeland’ (DFZ) and

Quality Institute for Pharmaceutical Care (QIPC).

The research involved in this thesis provides various perspectives concerning the complex

interactions between the variables that affect inhalation.

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Asthma is a chronic inflammatory disease of the airways characterised by reversible airway

obstruction associated with exacerbations of coughing, wheezing, chest tightness, difficult

breathing, and airway hyperresponsiveness. Asthma is predominantly a disease of young

individuals(6). Asthma has a high incidence. It is estimated, that over 100 million people

worldwide have asthma. Epidemiological studies in The Netherlands have revealed that 10 -

20% of the general population report respiratory symptoms like wheezing and shortness of

breath that could indicate the disease asthma(7).

Chronic Obstructive Pulmonary Disease (COPD), which refers primarily to chronic bronchitis

and emphysema, is characterised by chronic airway obstruction causing progressive loss of

lung function(8). COPD is associated with symptoms of chronic cough and purulent sputum(8).

COPD is strongly related to a history of smoking and is predominantly a disease of older

patients(8).

Asthma differs from COPD in that there is a greater reversibility, spontaneously and after

treatment with bronchodilators or corticosteroids. Some patients with asthma have

progressive irreversible airway obstruction and therefore have a form of COPD, and some

patients may have coexistent asthma and COPD.

The term Chronic Obstructive Lung Disease (COLD) is used as definition for combined

asthma and COPD.

The goal of respiratory therapy is to improve the patient’s quality of live by achieving and

maintaining control of symptoms, preventing exacerbations, attaining normal lung function,

maintaining normal activity levels, including exercise, and avoiding adverse effects from

respiratory medications(6, 8).

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Applying inhalation therapy in the treatment of pulmonary diseases is a form of targeted drug

delivery. It should be appreciated that a very significant improvement in the therapeutic

efficacy is achieved when drugs are delivered directly to the site of action in the respiratory

tract. The goal of inhalation therapy is to deliver medication directly to the lungs. It is an

advantage for the patient if the amount of drug reaching the lungs is maximised and the

amount deposited in other regions, like the mouth or oropharyngeal region, is minimised.

Reducing the amount of drug that is deposited in the oropharynx can reduce the likelihood of

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adverse events(9). The major advantages of inhalation therapy are, rapid onset of the

therapeutic effect, lowering of the required dose, compared to systemic administration, and

reduction in unwanted side effects.

It is well known that inhalation therapy, especially for asthma and COPD, is very successful

even though only a small fraction of the inhaled dose (typically less than 20-30%) actually

reaches the peripheral parts of the respiratory tract. The rest of the dose deposits in the mouth

and in the upper airways(1).

The dry powder inhaler device is one of the types of delivery systems that enable generation

and delivery of aerosolised drug particles into the respiratory tract. The principle of this

therapy is to transfer powdered medication into a clinical effect (figure 1.1). However, the

respiratory tract is a strongly branched system, which works excellently as filtering system to

avoid penetration of particles into the lungs. To enable penetration into the lungs, the

aerodynamic particle size of the inhaled medication has to be small, preferably below 5 to 10

µm, as will be explained in detail in paragraph 1.12. The particle size distribution of the drug

is one of the major determinants in drug delivery to the respiratory tract. Special techniques,

such as micronisation of drugs in dry powder systems, are required to produce particles (or

droplets) in this size range. Because the handling of micronised particles is very difficult, and

the amounts of drugs that have to be metered in inhalation therapy are often very low (6 µg to

500 µg), special formulations and devices have to be applied to obtain the required clinical

effect from the administered dose.

Powder InhalerPat ient

Deposi t ion EffectInstruct ion

Inhalat ion character ist ics

Figure 1.1: From powder to clinical effect.

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The human respiratory tract is a branching system of air channels with more than 23

bifurcations from the mouth to the alveoli. This human respiratory tract looks like an inverted

tree with a single trunk. The human respiratory system can be divided into four regions, each

covering one or more anatomical regions. These regions clearly differ in structure, airflow

patterns, function, and sensitivity to deposited particles. The most widely used morphologic

model for describing the structures within the lung was initially given by Weibel(5, 10) (figure

1.2). The first region is the upper respiratory tract, which includes the nose, mouth and

pharynx. The main function of this region is heating and moistening of air. Normal

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atmospheric air contains around 40 - 60% moisture and has a temperature of 20 °C. In the

mouth, nose and throat the air is heated to 37 °C and moistened till 99% relative humidity.

generation diameter(cm)

length(cm)

numbertotal crosssectional

area (cm2)

Powderdepositionby particlediameter

trachea 0 1.80 12.0 1 2.54 7 - 10 µm

1 1.22 4.8 2 2.33

2 0.83 1.9 4 2.13

bronchi

3 0.56 0.8 8 2.00 2 - 10 µm

4 0.45 1.3 16 2.48cond

uctin

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ne

bronchioles

terminal bronchioles

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0.35↓

0.06

1.07↓

0.17

32↓

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180.017

18respiratorybronchioles

19 0.05 0.10 5·105 1030.5 - 2 µm

20 and

21 < 0.25 µmalveolar ducts22

tran

sitio

nal a

ndre

spira

tory

zon

es

alveolar sacs 23 0.04 0.05 8·106 104

Figure 1.2: A schematic representation of airway branching in the human lung(5, 10).

The second region is the conduction zone. This region consists of the first 16 generations of

branching. The airways of the conducting zone are described as rigid tubes that consist

primarily of cartilage in the walls and that symmetrically divide or bifurcate beginning with

the trachea and ending with the terminal bronchioles. The third region is the transitional zone.

This region consists of the generations 17 through 19 of the branching. The respiratory

bronchioles each consist of a few alveoli in which limited gas exchange occurs. The fourth

region is the respiratory zone. This region consists of the generations 20 through 23 of the

branching, ending in the alveoli. In the highly vascularised respiratory zone gas exchange

occurs by adding oxygen to, and removing carbon dioxide from the blood passing the

pulmonary capillary bed.

With increasing generation number, the number of branches rapidly increases, while the

distance between the branches and the airway diameter decrease. The summed cross sectional

area from mouth to alveolar sacs rapidly increases and results in a trumpet shaped lung model,

with a total absorptive surface area of up to 100 m2(5).

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The inhaled air volume depends on the extent of chest enlargement. During normal breathing,

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the inhaled and exhaled volumes (tidal volume) are only a part of the total lung volume. The

different parameters describing pulmonary ventilation are shown in figure 1.3. Definitions of

the different parameters are given in table 1.1.

7

0

volu

me

(l)

VC

ERV

VT

IRV

RV

IC TLC

FRC

Figure 1.3: Spirometric tracing demonstrating different measures for

lung volumes and capacities. For definitions see table 1.1.

Table 1.1: Definitions of lung volumes and capacities describing pulmonary ventilation.

Parameter Definition

Tidal volume (VT)The volume of air inspired or expired during a normalbreath

Inspiratory reserve volume (IRV)The maximal volume of air that can be inspired after anormal tidal inspiration

Expiratory reserve volume (ERV)The maximal volume of air that can be expired after anormal tidal expiration

Residual volume (RV)The volume of air remaining in the lungs after a maximalexpiratory effort

Inspiratory capacity (IC)The maximal volume of air that can be inspired after anormal tidal expiration (IC = VT + IRV)

Functional residual capacity (FRC)The volume of air remaining in the lungs after a normaltidal expiration (FRC = ERV + RV)

Vital capacity (VC)The maximal volume of air that can be expired from thelungs after a maximal inspiration (VC = IRV + VT + ERV)

Total lung capacity (TLC)The volume of air in the lungs after a maximal inspiratoryeffort (TLC = IRV + VT + ERV + RV)

Lung volumes are given as the volume of air at body temperature (310 °K), saturated with watervapour at that temperature (BTPS-conditions)

Determination of lung volumes and capacities can provide important information on the

pathophysiological status of the lung. The amount of air moving in and out of the lungs

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(characterised by VT, IRV, ERV, VC and IC) can be measured through spirometry. Estimates

of volume of air remaining in the lungs after expiration (RV and FRC) are made by gas

dilution methods. The respiratory system of a normal adult processes 10-20 m3 of air per day.

The gas-exchange area of the lungs is about 120 - 160 m2 and is perfused with over 2000 km

of capillaries(5). At rest, about 700 ml of tidal air is inhaled and exhaled with each breath(11).

During heavy work, tidal volume may be three times as much. A resting adult breathes about

12 times per minute and this rate will triple during heavy work.

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The ventilatory apparatus consists of the lungs and surrounding chest wall. The chest wall

includes not only the rib gages but also the diaphragm and abdominal wall (figure 1.4).

Interpleural pressure(increasingly subatmospheric)

Force of muscular contraction (rib cage)

Alveolar pressure(subatmospheric)

Elastic recoil of lung(alveolar pressure minus interpleural pressure)

Elastic recoil of chest wall (interpleural pressure minus pressure at surface of chest)

Force of muscular contraction (diaphragm)

Figure 1.4: Forces and pressures during inspiration. (Illustration from the CIBA Collection

of Medical Illustrations illustrated by F.H. Netter, M.D. 1979, 1980).

Movement of air into and out of the lungs is driven by pressure differentials or gradients

across the lungs. When inspiratory muscles (diaphragm and intercostal muscles) contract to

expand the thoracic cavity, a force is applied to the lung surface, which causes expansion of

the lungs. Lung expansion occurs because the lungs are compliant and distensible. By

expanding, a negative pressure is created within the lungs, specifically in the airways and

alveoli. This results in airflow in the direction from high to low pressure, which is in the

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direction of the alveoli. Changes in lung pressures relative to atmospheric pressure can be

summarised as follows. At the start of inspiration, the alveolar pressure equals atmospheric

pressure. There is no pressure difference and thus, no driving force for airflow. In this

situation, the relative alveolar pressure is referred to as zero (figure 1.5). Interpleural pressure

is about –500 Pa because elastic recoil of the lungs counteracts the forces of the chest wall to

recoil outwards. Thus, a negative pressure is generated in the interpleural space between the

lungs and the chest wall. Upon inspiration, a greater negative intrapleural pressure is

generated as the chest wall moves outward against the elastic recoil of the lungs, reaching a

maximal value of about –700 to –800 Pa under normal conditions. The expansion of the lungs

by the greater negative intrapleural pressure causes alveolar pressure to decrease (become

0.5

0

-500

-800

0.5

0

-0.5

100

0

-100

volu

me

(l)in

trap

leur

al

pres

sure

(P

a)

flow

(l·

s-1)

alve

olar

pr

essu

re(P

a)

inspiration expiration

Figure 1.5: Ventilatory parameters during tidal breathing (single breath)(5).

negative relative to atmospheric pressure) until it reaches a maximum value of about –100 Pa

under normal conditions, providing the pressure gradient for air to flow into the airways and

alveoli (depicted as negative flow in figure 1.5). The rate of airflow does not depend on the

pressure gradient alone but also on the internal resistance to airflow of the airway system,

which is mainly a function of the airway diameters and the existence of obstructions. The

obstructions reduce the airway diameters locally, thereby increasing the resistance to airflow.

Patients suffering from obstructive diseases have to generate higher pressure differences to

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create the same airflow rate, compared to patients without lung obstructions. Consequently,

alveolar pressures have to be much lower. During inhalation, the airflow gradually decreases

as the alveoli are filled with air and the relative alveolar pressure returns to zero. The

difference between intrapleural pressure and alveolar pressure is the transpulmonary pressure,

which provides a measure of elastic lung recoil at each point of lung expansion. When

inspiration is complete and the lungs are inflated, respiratory muscles relax and elastic recoil

properties of the lung cause it to return back to its original state prior to inflation, thereby

expelling the inspired air. Intrapleural pressure returns to –500 Pa and alveolar pressure

increases to about +100 Pa, thereby creating the pressure gradient to allow air to flow out of

the lungs to the external environment (depicted as positive flow in figure 1.5). Throughout

this cycle of normal inspiration and expiration, airways remain open in order to allow air to

flow in and out of the lungs with relative ease. Expiration may be forced such as during a

cough or when blowing up a balloon, by contracting expiratory muscles (internal intercostal

muscles, external and internal oblique abdominal muscles, transversus and rectus abdominis

muscles). Such forced expiratory manoeuvres can increase intrapleural pressure to reach

positive values, causing a large increase in alveolar pressure above atmospheric pressure and

creating a large pressure gradient for air to flow out of the lungs at greater velocity.

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The maximal inspiratory mouth pressure is a measure for the inspiratory muscle strength. In

this measurement, maximal inspiratory manoeuvres from residual volume (RV) are performed

against a closed shutter. An oval flanged mouthpiece with a small leak is used to prevent the

use of the buccinator muscles(12-14). Conventionally, inspiratory muscle strength has been

assessed by maximal inspiratory mouth pressure sustained for 1 second (PImax or MIP) during

a maximal static manoeuvre against a closed shutter(12, 15-20). However, PImax is poorly

reproducible(21, 22). The peak maximal inspiratory pressure (P·PImax or P·MIP) during a

maximal static manoeuvre is a more valid assessment of inspiratory muscle strength. This

measurement is considered to be influenced less by learning effect and has a high

reproducibility(23, 24). Figure 1.6 shows a typical pressure recording during fast maximal

inhalation obtained from maximal inspiratory pressure measurement. The peak value is

referred to as the peak maximal inspiratory pressure (P·MIP) or P·PImax(23, 24). The plateau

value, which has to be maintained for at least one second, is referred to as the maximal

inspiratory pressure (MIP) or the PImax.

As shown in figure 1.5 the flow profile in the mouth follows the alveolar pressure profile

during ventilation without time delay. The commonly used inhalation-instruction for dry

powder inhalers is to inhale forcefully and deeply. Because the airflow through breath-

controlled dry powder inhalers depends on the patient-generated inspiratory pressure, the

P·MIP might be a useful measure for the peak inspiratory flow through a dry powder inhaler.

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In some studies an indication is given that the inspiratory muscle strength might be a

determinant for the peak inspiratory flow through breath-controlled DPI's, or a resistance to

airflow(25-27).

Moreover, the respiratory muscles are striated skeletal muscles, which can be trained like

other striated muscles in order to increase their strength and endurance. This is demonstrated

in healthy volunteers(28, 29) as well as in patients(30-33). Training with high force contractions

increases maximal force, whereas training with high velocity, low force contractions,

increases maximal shortening velocity(34, 35).

0

5

10

15

0 0.5 1 1.5 2 2.5Time (sec)

Pre

ssur

e (k

Pa)

P·MIP

MIP

1 sec

Figure 1.6: Diagram with definitions of peak maximal inspiratory pressure (P·MIP) and

maximal inspiratory pressure (MIP).

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For the generation of aerosol particles in the required size range for deep lung deposition,

three different types of inhalation devices are available. These are the nebulizers, pressurised

metered dose inhalers (p-MDI) and dry powder inhalers (DPI). p-MDI’s are world wide the

most frequently used system and they have proven their value in therapy. In The Netherlands,

DPI’s are the most frequently prescribed inhalation device.

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Nebulizers are the oldest systems and have been used in inhalation therapy since the early 20th

century(2). Nebulizers are applied for drug solutions or suspensions, which are aerosolised

either by air jet or ultrasonic nebulisation. To generate the aerosol from an air-jet nebulizer,

compressed air is forced through an orifice over, or in co-axial flow around the open end of a

capillary tube. The drug solution or suspension is drawn through the capillary by means of

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momentum transfer. In the nozzle region, shear forces disrupt the liquid into small particles

that are entrained by the air towards a baffle. Only the smallest droplets, in the desired size

range, are able to follow the streamlines of the air and pass the baffle, whereas larger droplets

impact on the baffle and are returned to the liquid reservoir. Ultrasonic nebulizers generate

aerosols using high-frequency ultrasonic waves by a ceramic piezoelectric crystal. The

greatest disadvantages of nebulizers are their poor deposition efficiency, the long inhalation

time and the requirement for a power supply. Nebulizers are suitable devices for acute care of

non-ambulatory patients and of infants and children(36).

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The pressurised-metered dose inhaler (p-MDI) consists of four basic functional elements,

container, metering valve, actuator and mouthpiece.

The principle of p-MDI's is based on a spray-can as used for hair spray(3). A liquefied

propellant serves both as an energy source to expel the formulation from the valve in the form

of rapidly evaporating droplets, and as a dispersion medium for the drug and other

excipients(5). Initial droplet size and droplet speed is too high for effective deposition in the

lower respiratory tract. Evaporation and deceleration in the upper respiratory tract are

essential. For p-MDI's the inhalation manoeuvre is relevant for deposition efficacy. Especially

the hand-lung coordination is of major importance. The use of spacer devices or breath-

triggered devices overcomes this coordination problem.

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In a United States patent from 1939, by W.B. Stuart, a description is given of what is called

the first dry powder inhaler. The patent describes a device, which had been designed to aid the

inhalation of aluminium dust for the chelation of inhaled silica. However, the device was

never commercialised(37). A patent from 1949, by M.R. Fields, described the first dry powder

inhaler to be used for the administration of a pharmaceutical agent. The so-called Aerohaler,

was the first commercially available dry powder inhaler for the delivery of isoprenaline

sulphate(37).

The first single dose dry powder inhaler with a hard gelatin capsule technology was initially

developed for the inhalation of relatively large amounts of drug, being 50 mg of disodium

cromoglycate (Spinhaler, 1971)(38). Later, DPI's found their application in inhalation therapy

as a CFC-free alternative for the older p-MDI's. However, nowadays DPI's seem to have a

much larger potential(4, 39), because of the high lung deposition that can be attained and their

suitability for pulmonary delivery of therapeutic peptides and proteins, which can

subsequently become systemically available.(40).

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Dry powder inhalers basically contain four functional elements, the powder container, the

dosing/metering system, the disintegration principle and a mouthpiece. Based on these

functional elements, dry powder inhalers can be divided into two major groups, single dose

and multi-dose inhalers (table 1.2). The multi-dose inhalers are divided in two different types

of design: the reservoir systems and the multiple unit-dose inhalers. An example for the

reservoir system is Turbuhaler. In this type of inhaler, the powder formulation is stored in a

container from which single doses are measured volumetrically with a special dose-metering

unit. Accurate dose metering for this type of inhaler requires careful manipulation of the

device by the patient. In the multiple unit-dose inhalers, single doses are filled by the

manufacturer into suitable dose compartments, such as blisters. Examples are Diskhaler,

having the blisters on a disk (Rotadisk), and Diskus with the blisters on a long strip. Before

inhalation, a single blister is either perforated or the cover foil is peeled off the blister foil in

order to gain access to one single dose. Another example of a multiple unit-dose inhaler is the

Eclipse. This inhaler is actually a single dose inhaler, however it can hold 4 single Spincaps at

once.

Table 1.2: Dry powder inhalers available on the Dutch market.

Inhaler device (manufacturer) Dosage forms Powder formulation

Single dose inhalersSpinhaler (Rhône-Poulenc Rorer) Spincaps Spherical pelletsRotahaler (GlaxoWellcome) Rotacaps Adhesive mixtureCyclohaler (Pharbita) Cyclocaps Adhesive mixtureForadil dry powder inhaler (Novartis Pharma) Inhalation powder (in capsules) Adhesive mixtureInhalator Ingelheim (Boehringer Ingelheim) Inhalette Adhesive mixtureMulti-dose inhalers

Multiple unit-dose inhalersDiskhaler (GlaxoWellcome) Rotadisk (4 or 8 dose) Adhesive mixtureDiskus (GlaxoWellcome) Powder on strip Adhesive mixtureEclipse (Rhône-Poulenc Rorer) Eclipse can hold 4 Spincaps Spherical pellets

Reservoir systemsTurbuhaler (AstraZeneca) Reservoir Spherical pellets

Single dose inhalers have unit-doses in individual (sealed) dose compartments, usually

capsules that have to be placed into the inhaler by the patient. Capsule cap and body must be

separated before inhalation (Rotacaps for Rotahaler) or the capsule has to be pierced at both

ends, as for the Cyclocaps for Cyclohaler, Inhalettes for Inhalator Ingelheim, or the Spincaps

for the Spinhaler.

The powders in the inhaler are in general not formulated as single particles, but as adhesive

mixtures or spherical pellets, as described in section 1.10. These mixtures or pellets are

suitable for processing and metering. However, the particle size of these mixtures or pellets is

far too large for lung deposition. Therefore, the pellet or mixture has to be disintegrated to

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make an aerosol cloud, which contains a high fraction of non-agglomerated drug particles

with the desired particle size (<5 µm). Many different disintegration principles exist. They

may vary from a simple screen (Rotahaler, Diskhaler) (figure 1.7), to twisted powder channels

(Turbuhaler) (figure 1.8). The applied disintegration concept in the design of a dry powder

inhaler largely determines the resistance to airflow of the inhaler device. In those designs, in

which the dry powder formulation is only dispersed into the inspiratory airflow, the

inspiratory flow, as energy source, is not used optimally. These type of inhaler designs use a

so-called non-specific disintegration system (figure 1.7). Inhalers without a recognisable

disintegration principle often have a low resistance to airflow. As a consequence of a non-

specific disintegration system the fine particle fraction generated by the inhaler is low. Due to

the low resistance to airflow, larger variations in peak inspiratory flow are found. However,

the fine particle output is more or less constant over a broad range of inspiratory flows at a

low level(41).

Airflow

Carrier/drugpowder bed

Carrier/drug aerosol

Disintegration mechanism

Carrier and drug aerosol after disintegration

Figure 1.7: Schematic diagram of the disintegration of micronised drug particles from

carrier crystals through a non-specific disintegration system.

Packed powder bed

Aerosol of spherical pellets

Disintegration mechanism

Disintegrated drug aerosol

Airflow

Figure 1.8: Schematic diagram of the disintegration of spherical pellets through

a specific disintegration mechanism.

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More specific disintegration systems use the inspiratory flow more optimally as energy source

for disintegration and delivery of fine particles into the airflow (figure 1.8). This usually

results in an increased resistance to airflow of the disintegration system. Due to the inhaler

design, the fine particle output depends more strongly on patient inspiratory performance. As

a result, the fine particle output is more or less flow dependent. However, the higher

resistance to airflow limits the range of possible flow rates, but reduced particle velocity

resulted in a reduced mouth and throat deposition. Due to the higher disintegration efficiency,

the fine particle output is higher compared to the non-specific disintegration systems.

The mouthpiece may be used to control resistance to airflow of the inhaler and the direction

of the aerosol cloud in the mouth and throat, in order to reduce drug deposition in the

oropharyngeal cavities(42).

Dry powder inhalers are generally described as 'breath-actuated' devices, because the

inspiratory air steam releases the dose from the dose system and supplies the energy for the

generation of fine drug particles from the powder formulation. Because the efficiency of dose

release and powder disintegration increases with increasing inspiratory flow rate for most

DPI's, it would be better to speak of 'breath-controlled' devices.

In table 1.3 some advantages and disadvantages of dry powder inhalers are summarised.

Table 1.3: Advantages and disadvantages for dry powder inhalers versus

metered dose inhalers(39).

Advantages of dry powder inhalers: Disadvantages of dry powder inhalers:• Propellant free• Less need for patient coordination• Less potential for formulation problems• Less potential problems with drug stability• Less potential for extractables from device

components

• Performance depends on the patientsinspiratory flow profile

• Resistance to airflow of the device• Potential difficulties to obtain dose uniformity• Less protection from environmental effects

and patient abuse• More expensive• Not available world wide

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For the generation of fine particles in the ideal particle size range, the used powder

formulation is essential. The flow properties of fine particles in the ideal particle size range is

usually poor. In combination with the fact that for the inhaled medication usually very small

amounts of drugs have to be accurately metered (6 µg to 500 µg), special powder

formulations are necessary to make (free flowing) powders that can be used for processing

and metering. For the many marketed dry powder inhalers, only two different types of powder

formulations are currently applied. So-called spherical pellets are used in the Turbuhaler. In

this type of formulation, the micronised drug particles are agglomerated into much larger

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spherical units without binder agent, behaving as a free flowing powder. Some micronised

diluent lactose or glucose may have been added to the active component, but the formulation

does not contain coarser carrier crystals. Spherical pellets can disintegrate nearly completely

during inhalation into much smaller agglomerates or even primary particles that have the

required size-range for deep penetration into the respiratory tract.

The Rotadisk for the Diskhaler, the blisters in the Diskus and the Cyclocaps for the

Cyclohaler are filled with adhesive mixtures. This type of formulation consists of relatively

large carrier crystals, mostly α-lactose monohydrate, carrying the micronised drug particles

distributed over their surface. During inhalation, the drug particles have to be released from

the carrier crystals to generate the aerosol with particles of the desired particle size, that are

able to enter the lower respiratory tract. The fraction of drug not detached may cause serious

local side effects, as candidiasis, in the upper respiratory tract (mouth and throat) where the

carrier crystals, and other larger particles, are deposited.

100 µmx 100

10 µmx 500

100 µm x 100

10 µmx 1000

Figure 1.9: Scanning electron micrographs (SEM-photo’s) of dry powder inhaler

formulations. Both pictures on the left hand show an adhesive mixture of 25 mg α-lactose

monohydrate with 250µg micronised fluticasone from a Flixotide 250 Diskus

(GlaxoWellcome). On the right hand, the pictures show a spherical pellet of micronised

budesonide from a Pulmicort 200 Turbuhaler (AstraZeneca).

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After inhalation, particles can be deposited at a great variety of anatomical locations. It is

generally accepted that all particles that touch the surface of the respiratory tract are deposited

on the site of initial contact. Different physical mechanisms operate on inhaled particles and

move them across streamlines of air to the surface of the respiratory tract. These mechanisms

are gravitational sedimentation, inertial impaction, Brownian diffusion, interception and

electrostatic forces. The deposition in the respiratory tract occurs in a system of changing

geometry and at flow rates that change with time and direction(11). The mechanisms that

contribute to the deposition of a specific particle depend on the particle’s aerodynamic

behaviour, the breathing pattern, geometry of the respiratory tract, and the flow and mixing

patterns of the aerosol containing particles and the remaining air in the respiratory tract.

Airflow

Airflow

Airflow

Sedimentation

Inertial impaction

Diffusion (Brownian motion)

Figure 1.10: Particle deposition mechanisms at an airway branching site.

The three major deposition mechanisms are shown in figure 1.10. During inhalation, the

inhaled air changes constantly in direction as it flows from the mouth down through the

branching airway system. Particles will have to follow the airstream in order to get deeper

into the lungs. However, particles are unable to do so when their inertia is too high, due to a

high mass or a high velocity or both, will deposit. Therefore, the largest particles are

deposited by the mechanism of inertial impaction in the throat and at the first bifurcations. As

the remaining small particles move on into the lung, the air velocity gradually decreases to

much lower values and the force of gravitation becomes important. Settling by sedimentation

is the dominant deposition mechanism in the deeper airways. The finest particles are able to

enter the periphery of the lung, where they can make contact with the walls of the airways as

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the result of Brownian motion (diffusion). Near obstructions or in the small airways, drug

deposition might occur due to particle interception, because the particles touch the airway

surface, although they do not deviate from their streamlines. A charged particle may deposit

in the respiratory tract by electrostatic forces. Though the contribution of these latter two

deposition mechanisms is considered to be low.

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For a prediction of the lung deposition of inhaled particles, two mechanisms have to be taken

into account. Firstly the penetration probability of particles into the lung, and secondly the

deposition efficiency. The penetration probability is the probability that a particle of a certain

size is able to pass the lung bifurcation’s and penetrate further into the lung. The penetration

probability for the defined target area of the terminal and respiratory bronchioles, will

increase with decreasing particle diameter (figure 1.11, dark curved area). On the other hand,

deposition efficiencies have to be taken into account. Deposition efficiencies for particles in

the respiratory tract are generally presented as function of their aerodynamic diameter. In the

definition of the aerodynamic diameter, corrections are made for density differences from

unity and shape irregularities of the particles. Large particles (>10 µm) are removed from the

airstream with nearly 100% efficiency by inertial impaction, mainly in the oropharynx. But as

sedimentation becomes more dominant, the deposition efficiency decreases to a minimum of

0

20

40

60

80

100

(%)

Deposition

Penetration in target area

Particle diameter (µm)

Per

cent

age

pene

trat

ion/

depo

sitio

n

Preferred particle size

0.1 0.5 1 2 4 6 8 10

Figure 1.11: Penetration probability and deposition efficiency dependence on particle

diameter in the respiratory tract. The black line is the deposition efficiency. The dark curved

area is the penetration probability in the terminal and respiratory bronchioles. The grey area

is the optimal particle size, of which the shaded area is mostly mentioned as preferred

particle size.

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approximately 20% for particles with an aerodynamic diameter of 0.5 µm (figure 1.11, black

line). Only when particles become smaller than 0.1 µm the deposition efficiency increases

again as a result of diffusional displacement. It is believed that 100% deposition due to

Brownian motion might be possible for particles in the nanometer range(43).

From the penetration probability and the deposition efficiency, as well as from deposition

studies and force balances, it can be derived that the optimum (aerodynamic) particle size lies

between 0.5 and 7.5 µm (figure 1.11, grey area). Within this approximate range many

different sub-ranges have been presented. The sub-range of 1 to 5 µm(44) (figure 1.11, shaded

area) is considered to be the preferred particle size range in this thesis. Particles of 7.5 µm and

larger mainly deposit in the oropharynx, whereas most particles smaller than 0.5 µm may be

exhaled again. All inhalation systems for drug delivery to the respiratory tract produce

polydisperse aerosols of which different amounts of the delivered fine particles are in the

range of the ideal particle size.

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The pulmonary delivery of drugs by inhalers is, compared to the oral delivery route, a

complex therapy for the patient. Using the oral route of administration, it may be sufficient to

give the patient a dosing schedule for taking one or more tablets at predetermined times of the

day. Using an inhaler, this is not enough, and the patient also has to receive an adequate

inhalation-instruction to ensure correct inhalation of the medication.

Differences in the inhaler-designs cause large differences in the instructions for correct use of

these inhalers. The way in which the patient uses the inhaler is also called the patients'

inhalation-technique. It has frequently been shown that patients suffer from problems with

their inhalation-technique as well as from problems regarding compliance. In a number of

studies concerning the inhalation-technique of asthma and COPD patients it is shown that 70

to 80% of the patients were able to perform the most important manoeuvres with their inhaler

correctly. A correct execution of all manoeuvres could only be performed by a much smaller

fraction of the patients(45). Mistakes are made, ranging from mistakes in loading the inhaler, to

mistakes in performing the inhalation. Exhaling through the inhaler before inhalation, not

releasing the dose before inhalation, or mistakes in storage of the inhaler have been

reported(45-48). General practitioners, chest physicians, pharmacists, and lung-function nurses

are the appropriate persons to give inhalation-instructions to patients. As a result of good

inhalation-instructions to the patient, the number of mistakes in the patients' inhalation-

technique reduces significantly, which results in an increased therapeutic efficacy of the

inhalation therapy(45-50).

The use of different types of inhalers by one patient, for the inhalation of bronchodilators and

corticosteroids, may cause many mistakes in the inhalation-technique(45). When using

different types of inhalers, the importance of a proper inhalation-instruction increases, since

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the patient has to perform the correct inhalation-technique for each inhaler. For convenience

of the patient, and to prevent the patient from making mistakes, it is recommended to give one

patient only one type of inhaler (if possible) for the bronchodilators and the corticosteroids.

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The term patient compliance in a medical context is generally defined as the extent to which

the patients' medication taking history corresponds to the prescribed drug regimens, thereby

following the instructions of the health care provider(51-55). Variable patient compliance is

recognised as a potential complication in patient care(9, 52). The compliance of patients with a

chronic disease, including respiratory diseases, is often inadequate. Compliance with

maintenance therapy, such as inhaled corticosteroids, of which the effect is noticeable only

after a period of weeks, may be less than compliance with drugs that relieve asthma

symptoms more rapidly(9). Therefore, for inhaled corticosteroids, studies mainly focus on

underuse of the medication compared with the prescribed dose.

Patient compliance can be calculated from prescription data by dividing the delivered amount

of doses by the required amount of doses in a defined period. This calculation of patient

compliance result in three classifications of compliance, as given in table 1.4.

Table 1.4: Classification of compliance.

compliance definitionappropriate use (compliant)

the patient takes the medication in a way that conformssatisfactorily to prescribed use

underuse the patient takes less medication than prescribed

overuse the patient takes more medication than prescribed

Patient compliance depends on different parameters, especially parameters directly related to

patients’ behaviour. Health care providers might influence this behaviour by appropriate

prescribing, patient education and counselling. The prescribing behaviour of the general

practitioner is directly related to the choice of the inhaler device and the prescribed number of

doses to be taken every day. An appropriate inhalation technique will significantly affect

compliance of the patient, but compliance may also depend on the age of the patient and

patients’ awareness and beliefs(56) on the need of a proper inhalation technique. The

pharmacist may influence the patient compliance by patient education and counselling.

To optimise inhalation-instruction and patient compliance, networks including general

practitioners, pharmacists and chest physicians should make agreements on these subjects. An

optimal patient education and counselling may finally improve the inhalation technique and

the patient compliance, and thereby therapeutic efficacy of the inhalation therapy.

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Besides the choice of drug in the treatment of asthma and COPD, the choice of the inhaler

device plays an important role in the success of the therapy. From several studies, it is known

that therapeutic decision making is usually based on habits(57-64). Many drug choice models

show that habitual prescribing is the most common way of prescribing. In this habitual

prescribing, each physician uses only a limited number of devices in their prescription, the so-

called evoked set.

The drug choice process for the treatment of a particular disease is divided in two steps

(figure 1.12). Firstly, a small set of possible treatment options for the proposed problem is

generated, the so-called evoked set. Secondly, a therapy is selected for a specific patient(57).

Prob lem Evoked Set Therapy choice

Figure 1.12: The drug choice process(57).

As a result of evoked set based on prescribing, only a limited number of drugs are routinely

prescribed by the individual prescriber. Once it has been decided to prescribe a drug, a few

names automatically pop-up(57, 65). The evoked set provides a number of possible treatments,

from which finally one therapy is selected for a specific patient. The physicians may choose a

drug through habitual or non-habitual choice (figure 1.13). Most of the choices for a brand are

probably done by habitual choice(62). When the therapeutic situation is new for the physician,

he will probably choose a drug non-habitually by active problem-solving (figure 1.13). This

can also be expected to occur when the therapeutic outcome of a previous prescription is

unsatisfactory, either because of insufficient efficacy, or because of side effects. After a

number of satisfactory results, the physician will choose the drug habitually when confronted

with the same situation.

Evoked Set

Active Problem-Solvingweighing pros and cons

Habitualusing reasoned rules

Habitualusing unreasoned rules

Choice of therapy

Figure 1.13: Choosing from the evoked set(57).

The concept of the evoked set is also applicable to the choice of an inhaler device. Many of

the prescriptions for the treatment of asthma or COPD are given habitual. However, the

difficult interaction between patient and inhaler device combined in the inhalation

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characteristics suggests that, for the treatment of asthma or COPD, active problem-solving is

a more appropriate choice. Besides knowledge about the applied drug in the treatment, also

technical knowledge about the applied inhaler device is necessary for an optimal choice of an

inhaler device.

���� 5HIHUHQFHV

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