University of Groningen

Dry powder inhalationKoning, Johannes Petrus de

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.

Document VersionPublisher's PDF, also known as Version of record

Publication date:2001

Link to publication in University of Groningen/UMCG research database

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

CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.

Download date: 09-04-2020

��

&+$37(5�

&KDSWHU��

'DLO\�XVH�RI�D'U\�3RZGHU�,QKDOHU�,QFUHDVHV

3HDN�0D[LPDO�,QVSLUDWRU\�3UHVVXUH

J.P. de Koningu, Th.W. van der Mark&, P.M.J. Coenegracht#,

Th.F.J. Tromp,, H.W. Frijlinku

Groningen University Institute for Drug Exploration (GUIDE), Department of Pharmacy,uPharmaceutical Technology and Biopharmacy, #Chemometrics, , Pharmacy Practice, University of Groningen,

&Department of Pulmonology, University Hospital Groningen, The Netherlands

$EVWUDFW

Generated peak inspiratory flow rate through a dry powder inhaler (DPI) depends on the

subject-generated peak maximal inspiratory pressure (P·MIP). Inhalation through a high

resistance DPI can be considered as low intensity inspiratory muscle training (IMT), which

can increase P·MIP against time. In this study, the influence of daily use of a DPI on the

P·MIP was investigated. P·MIP and peak inspiratory flow rate through a resistance to airflow

(PIFR) were monitored in a group of 16 healthy volunteers, during an eight-week period.

Eight volunteers (intervention group) followed a simulated inhalation therapy, while the other

eight subjects were controls. The simulated inhalation therapy consisted of five forceful and

deep inhalations, performed twice daily, through a dummy DPI. In the intervention group,

P·MIP had increased by 16% after four weeks to 24% after eight weeks of simulated

inhalation therapy. The increase in P·MIP also resulted in an increase in PIFR of 4% after four

weeks to 8% after eight weeks. In the control group, MIP and PIFR remained unchanged. In

conclusion, the simulated inhalation therapy with a high resistance to airflow DPI resulted in

an increase of P·MIP and PIFR.

��

'$,/<86(2)$'3,�,1&5($6(63�0,3

&RQWHQWV�RI�FKDSWHU��

5.1 Introduction............................................................................................................725.2 Material and Methods ............................................................................................73

5.2.1 Study subjects ........................................................................................................735.2.2 Study design...........................................................................................................735.2.3 Methods..................................................................................................................74

5.2.3.1 Simulated inhalation therapy..................................................................................745.2.3.2 Respiratory muscle strength...................................................................................745.2.3.3 Flow measurements................................................................................................74

5.2.4 Analysis..................................................................................................................755.3 Results....................................................................................................................75

5.3.1 Change in respiratory muscle strength...................................................................755.3.2 Change in inspiratory flow rate through an external resistance to airflow ............765.3.3 Relationship between PIFR and P·MIP ..................................................................76

5.4 Discussion ..............................................................................................................785.5 Acknowledgements................................................................................................795.6 References..............................................................................................................79

��� ,QWURGXFWLRQ

Inspiratory flow through a breath-controlled dry powder inhaler (DPI) is the result of an

inspiratory pressure generated by the respiratory muscles. Inspiratory flow rate will increase

with increased inspiratory muscle strength (chapter 3 and chapter 4). Moreover, the

performance of breath-controlled DPI's depends on the peak inspiratory flow rate through the

inhaler device (chapter 6). Therefore, an increased inspiratory muscle strength increases the

fine particle output from the DPI. This will have a positive clinical effect. Peak maximal

inspiratory pressure (P·MIP) is a parameter for inspiratory muscle strength(1). The respiratory

muscles are striated skeletal muscles, and can be trained like other striated muscles, in order

to increase their strength and endurance. This was demonstrated in healthy volunteers(2, 3) as

well as in patients(4-7). Training with high force contractions increases maximal force, whereas

training with high velocity (low force contractions) increases maximal shortening velocity(8, 9).

Current methods to increase respiratory muscle strength are resistive breathing and threshold-

load breathing. Inspiratory muscle training (IMT) is a type of training in which the patient

inhales against resistive loads or pressure threshold-loads, while the expiration is unloaded(5,

6). The currently available DPI's have different resistances to airflow. Inhalation through these

DPI's can be simulated by inhalation through orifices with corresponding resistance to

airflow. In this respect IMT resembles daily use of a DPI. Therefore, the question was raised

how much increase in respiratory muscle strength can be obtained by the sole use of a dummy

DPI (training device) (figure 5.1) without active drug. And how much increase in peak

inspiratory flow through a resistance to airflow (PIFR), simulating a DPI, can be obtained.

��

&+$37(5�

Figure 5.1: Dummy DPI (Training-device). Mouthpiece with high resistance to airflow.

��� 0DWHULDO�DQG�0HWKRGV

����� 6WXG\�VXEMHFWV

Sixteen healthy subjects (8 female / 8 male) volunteered for the study, which was approved by

the medical ethics committee of the University Hospital Groningen. The healthy subjects were

without respiratory symptoms according to the MRC-ECSC questionnaire(10). Subjects were

matched by gender for the intervention group (4 female / 4 male) and the control group (4

female / 4 male). Median age for the intervention group was 24 years (range 20-37), and

median age for the control group was 26 years (range 22-34). Lung function data for

intervention group and control group are given in table 5.1.

Table 5.1: Lung function data.

Intervention group Control group

Mean ± SEM Mean ± SEM

PEF (%pred) 101.3 5.9 94.2 4.6

FEV1 (%pred) 103.2 5.2 95.8 2.8

FVC (l) 4.67 0.23 4.91 0.33

P·MIPbaseline (kPa) 12.0 0.4 13.7 0.7

P·MIPt8 weeks (kPa) 14.9 0.9 13.9 0.7

����� 6WXG\�GHVLJQ

During an eight-week period, peak maximal inspiratory pressure (P·MIP) and peak

inspiratory flow through the used resistance to airflow (PIFR) were monitored. For all

subjects, baseline measurements of P·MIP and PIFR were performed at time point t0. Eight

healthy subjects in the intervention group followed a simulated inhalation therapy. No drugs

��

'$,/<86(2)$'3,�,1&5($6(63�0,3

were administered during the simulated inhalation therapy. Each week, P·MIP was measured

for the intervention group. PIFR was measured four (t4) and eight (t8) weeks after the start of

the simulated inhalation therapy. Five (t+5) and ten (t+10) weeks after finishing the simulated

inhalation therapy, P·MIP was measured again. The eight healthy subjects in the control

group did not follow any simulated inhalation therapy. In the control group, P·MIP and PIFRwere measured at time point t4 and t8.

����� 0HWKRGV

������� 6LPXODWHG�LQKDODWLRQ�WKHUDS\

In accordance with the commonly used inhalation-instruction for DPI's, the simulated

inhalation therapy consisted of five forceful and deep inhalations, taken twice daily. The first

series was performed in the morning and the second series was performed in the afternoon.

Each inhalation was carried out with maximal performance with at least 10-15 seconds rest

between each inhalation. The training-device consisted of an oval flanged hard plastic

mouthpiece (Jaeger, type 892103, Germany), covered by a rubber stopper with a metal pipe of

3.5-mm internal diameter (figure 5.1). The resistance to airflow of the training-device was

140 Pa0.5·s·l-1, which is relatively high. This resistance to airflow is in between the resistance

to airflow of DPI's and the training loads in commonly used IMT methods.

������� 5HVSLUDWRU\�PXVFOH�VWUHQJWK

Peak maximal inspiratory pressure (P·MIP) is a parameter for inspiratory muscle strength(1).

P·MIP was measured with a differential pressure gauge (HBM, Germany, type PD1 (range

100 kPa)). The three highest achievable pressures were used for further analysis. All subjects

wore a noseclip and carried out their maximal inspiratory manoeuvres from residual volume

(RV). They performed their efforts against a closed shutter through an oval flanged

mouthpiece with a leak of 2.1 mm diameter and 33.8 mm length to prevent the use of the

buccinator muscles(1). At least eight maximal inspiratory manoeuvres were carried out with at

least 20-30 seconds rest between each effort. Each effort was displayed on a monitor, and the

subjects were coached to better their efforts. All measurements were carried out in such a way

that no extra leakage occurred. The three highest pressures recorded were within a range of

5% of each other, and later attempts did not yield higher results.

������� )ORZ�PHDVXUHPHQWV

Inhalation characteristics were measured during inhalation through an orifice disk, with a

cylindrical bore of 4 mm in diameter. The resistance to airflow of the orifice disk was 74.9

��

&+$37(5�

Pa0.5·s·l-1, which is comparable with a high resistance to airflow DPI. The external inspiratory

resistance to airflow consisted of an Y-valve (Jaeger, Germany) with, on the inlet site, a

housing for the exchangeable orifice disk. Pressure drop over the resistance to airflow was

measured with a differential pressure gauge connected to the Y-valve. The three highest

achievable curves were processed into flow curves and used for further analysis. All subjects

wore a noseclip and carried out their maximal inspiratory manoeuvres from residual volume

(RV) to total lung capacity (TLC). Each effort was displayed on a monitor, and the subjects

were coached to improve their efforts. All measurements were carried out in such a way that

no extra leakage occurred. The three highest flows recorded were within a range of 5% of

each other, and later attempts did not yield higher results.

����� $QDO\VLV

Changes in P·MIP or PIFR are expressed as percent of baseline results (time point t0). Mean

changes in P·MIP and PIFR were calculated for the intervention group and the control group.

Significance in differences in P·MIP and PIFR between intervention group and control group

was calculated using the Student t-test (p<0.05), for time points t4 and t8.

Linear relationship between PIFR and the square root of P·MIP was calculated based on the

general relationship between flow through an orifice disk and the pressure drop across an

orifice disk (chapter 3).

��� 5HVXOWV

����� &KDQJH�LQ�UHVSLUDWRU\�PXVFOH�VWUHQJWK

Daily use of the dummy DPI (training-device), in a simulated inhalation therapy, results in an

increase in P·MIP for the intervention group (figure 5.2). Compared to the baseline results,

P·MIP was increased by 16% and 24%, respectively, at four and eight weeks after starting the

simulated inhalation therapy. The increase in P·MIP was significant (p<0.05) compared to the

control group. The highest P·MIP-value of 22.1 kPa was measured in a male subject at t7,

which was an increase of 63.4%. The individual increase in P·MIP could be categorised in

three groups. After eighth weeks of simulated inhalation therapy, two male subjects had an

increase of approximately 54%. The majority of the subjects, 2 male and 3 female, had an

increase of approximately 18% and one female subject did hardly benefit from the simulated

inhalation therapy. Five and ten weeks after finishing the simulated inhalation therapy, P·MIP

had slightly decreased but remained still 23% and 22% above the baseline, respectively

(figure 5.2). In the control group, P·MIP remained unchanged.

��

'$,/<86(2)$'3,�,1&5($6(63�0,3

Time (weeks)

0 2 4 6 8 12 16 20

Per

cent

age

chan

ge in

PÃM

IP (

%)

0

5

10

15

20

25

30

M

M

Figure 5.2: Percentage change of P·MIP in time. (� = intervention group, � = intervention

group after the simulated therapy period, � = control group, presented are the means ±

SEM. M = significant increase (p<0.05) compared to control group).

����� &KDQJH�LQ�LQVSLUDWRU\�IORZ�UDWH�WKURXJK�DQH[WHUQDO�UHVLVWDQFH�WR�DLUIORZ

Peak inspiratory flow rate through the external resistance to airflow (PIFR) was measured four

and eight weeks after starting the simulated inhalation therapy. In the intervention group, an

increase in PIFR was found of 4.2% and 7.9%, respectively, compared to the baseline results

(figure 5.3). After eight weeks this increase in PIFR was significant (p<0.05) compared to the

control group. In the control group, PIFR remained unchanged.

����� 5HODWLRQVKLS�EHWZHHQ�3,)5�DQG�3�0,3

For the intervention group, a linear relationship between PIFR and the square root of P·MIP

was calculated (figure 5.4). In figure 5.4, each subject is represented by a symbol. Open

symbols are female subjects and solid symbols are male subjects.

��

&+$37(5�

0

2

4

6

8

10

Per

cent

age

chan

ge in

PIF

R (%

)

4 weeks

M

8 weeks

Figure 5.3: Percentage change of PIFR, after four and eight weeks of simulated inhalation

therapy. Presented are the means ± SEM for the control group (open bars) and the

intervention group (solid bars). M = significant increase (p<0.05) compared to control

group.

1.2

1.3

1.4

1.5

1.6

100 110 120 130 140 150

Square root P·MIP (Pa 0.5)

PIF

R (l

·s-1

)

80.0

32.0P·MIP1030.9PIF2

3R

=

+⋅⋅= −

r

Figure 5.4: Relationship between peak inspiratory flow rate and square root of P·MIP. Each

symbol represents one subject. Open symbols are female, solid symbols are male.

��

'$,/<86(2)$'3,�,1&5($6(63�0,3

��� 'LVFXVVLRQ

This study shows that daily use of a high resistance DPI in a simulated inhalation therapy

results in a significant increase in P·MIP, and therefore, an increase in PIFRx.

Previous studies(11-15) reported the occurrence of a learning effect during the measurement of

P·MIP. The learning effect is mainly an improvement in inspiratory co-ordination. This effect

was also found in this study, each time a series of P·MIP measurements was performed.

However, after 6 to 8 manoeuvres a maximal value of P·MIP was achieved in all series

measured, which was in line with the previous studies(11-15). A series of at least eight P·MIP

manoeuvres were performed, in both groups of participants, to avoid the learning effect. In the

control group, P·MIP remained unchanged. Therefore, the increase in P·MIP in the

intervention group is not the result of a learning effect.

Training load and time in the simulated inhalation therapy was relatively low (five forceful

and deep inhalations, taken twice daily) compared to commonly used IMT programs for

COPD patients (continuous training for 30 minutes a day(5, 6)). However, a training effect was

expected, based on the effects of low intensity training with other striated skeletal muscles as

the arm or leg muscles(16).

The increase in P·MIP with 24% resulted in an increase in PIFR of 7.9%. The found increase

in PIFR is in the same order of magnitude as can be expected based on the linear relationship

between PIFR and the square root of P·MIP. The calculated relationship between PIFR and the

square root of P·MIP (figure 5.4) are comparable to those found in an earlier study in a large

group of healthy subjects, asthmatics and COPD patients (chapter 3). This relationship shows

the dependence of the generated PIFR through a resistance to airflow on the P·MIP. In

addition, the individual effect of the increased P·MIP on the inhalation performance is shown.

The present study was performed in healthy subjects. Results might be similar in asthmatics

without any DPI experience. Whether the same results would be obtained in moderate to

severe COPD patients is questionable, because physiological changes in lung structure are

involved.

In conclusion, the daily use of a high resistance to airflow DPI has a similar effect as low

intensity IMT. It results in a significant increase in P·MIP and therefore, in an increases in

PIFR.

The used resistance to airflow in the dummy DPI (training-device) was relatively high

compared to marketed DPI's. Therefore, comparable research with different training

resistances to airflow is needed, before a direct translation to commonly used DPI's can be

made.

The results of this study might have consequences for clinical trial studies with DPI's. The

results show that the training effect in healthy subjects and powder inhaler naive asthmatics is

likely to result in an increase in PIFR. During a clinical trail, a better inhalation performance

increases the deposition of inhaled drugs in the airways. This might result in an increase of the

��

&+$37(5�

clinical effect of the administrated drugs. Therefore, it is recommended to monitor the peak

inspiratory flow rates through the inhaler device frequently during these studies in order to

check whether the inspiratory manoeuvre of the patient is constant.

��� $FNQRZOHGJHPHQWV

The authors thank the Groningen Centre for Drug Research (GCDR) for their financial support.

��� 5HIHUHQFHV

1. L.F. Black, R.E. Hyatt. Maximal respiratory pressures: Normal values and relationship to age and sex. Am

Rev Respir Dis 1969;99:696-702.

2. D.E. Leith, M. Bradley. Ventilatory muscle strength and endurance training. J Appl Physiol

1976;41(4):508-516.

3. J.A. O'Kroy, J.R. Coast. Effects of Flow and Resistive Training on Respiratory Muscle Endurance and

Strength. Respiration 1993;60:279-283.

4. C. Villafranca, G. Borzone, A. Leiva, C. Lisboa. Effect of inspiratory muscle training with an

intermediate load on inspiratory power output in COPD. Eur Respir J 1998;11(1):28-33.

5. P.N.R. Dekhuizen, H.T.M. Folgering, C.L.A. Herwaarden. Target-flow inspiratory muscle training during

pulmonary rehabilitation in patients with COPD. Chest 1991;99:128-133.

6. W.D. Reid, G. Dechman. Considerations When Testing and Training the Respiratory Muscles. Phys Ther

1995;75(11):971-982.

7. W.D. Reid, B. Samrai. Respiratory Muscle Training for Patients with Chronic Obstructive Pumonary

Disease. Phys Ther 1995;75(11):996-1005.

8. G.E. Tzelepis, D.L. Vega, M.E. Cohen, A.M. Fulambarker, K.K. Patel, F.D. McCool. Pressure-flow

specificity of inspiratory muscle training. J Appl Physiol 1994;77(2):795-801.

9. G.E. Tzelepis, V. Kadas, F.D. McCool. Inspiratory muscle adaptations following pressure or flow training

in humans. Eur J Appl Physiol 1999;79:467-471.

10. A. Minette. Questionnaire of the European Community for Coal and Steel (ECSC) on respiratory

systems: 1987-updating of the 1962 and 1967 questionnaires for studying chronic bronchitis and

emphysema. Eur Respir J 1989;2:165-177.

11. J.A. Fiz, J.M. Montserrat, C. Picado, V. Plaza, A. Agusti-Vidal. How many manoeuvres should be done

to measure maximal inspiratory mouth pressure in patients with chronic airflow obstruction? Thorax

1989;44:419-421.

12. J.L. Larson, M.K. Covey, C.A. Vitalo, C.G. Alex, M. Patel, M.J. Kim. Maximal inspiratory pressure.

Learning effect and test-retest reliability in patients with chronic obstructive pulmonary disease. Chest

1993;104:448-453.

13. T.L. Clanton, P.T. Diaz. Clinical Assessment of the Respiratory Muscles. Phys Ther 1995;75(11):983-

995.

14. P.J. Wijkstra, Th.W.van der Mark, M. Boezen, R. Altena, D.S. Postma, G.H. Koëter. Peak Inspiratory

Mouth Pressure in Healthy Subjects and in Patients With COPD. Chest 1995;107(3):652-656.

15. A.S. Wen, M.S. Woo, T.G. Keens. How many maneuvers are required to measure maximal inspiratory

pressure accurately. Chest 1997;111:802-807.

16. P-O Åstrand, K Rodahl. Textbook of work physiology: physiological bases of exercise. 2nd ed. New

York, McGraw-Hill, 1977; 403.

��

'$,/<86(2)$'3,�,1&5($6(63�0,3