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A clinically relevant modification to existing inhaler therapy
Respiratory Medicine (1992) 86, 237-241
A clinically relevant modification to existing inhaler therapy A. J. M.
WARD*,N.
KASSEM'~,J. M. EVANS*, J. MOXHAM*~ AND D. GANDERTONt
*Department of Thoracic Medicine, King's College School of Medicine and Dentistry, Bessemer Rd, London SE5 and'~Department of Pharmacy, King's College, Manresa Rd, London SW3, U.K.
A modified formulation of inhaled salbutamol and a new inhaler device were studied in a group of 1 1 moderateto-severe asthmatic patients. Changes in airway calibre (FEVI, Vmax30) were measured before and after inhalation of the new formulation, and compared with changes following inhalation of conventional salbutamol. A standard Rotahaler was used as a reference for the new inhaler. The study was conducted as a two-part randomized, double-blind cross-over trial. We found a significantly greater bronchodilatation of the larger airways using the modified drug in the Rotahaler. The new inhaler did not show any superiority over the Rotahaler, contrary to expectations from in vitro work. A slightly shorter model may better reflect the in vitro results. The study has implications for inhalation therapy in general.
Introduction
The aim of inhaler therapy is to deliver the maximum amount of drug to the airway with as little systemic absorption as possible, and preferably at the relatively low flow rates often attained in clinical practice. Approximately 10% of inhaled drug is deposited in the lung (1), and so improved delivery could be of clinical and economic benefit. Both the formulation of the drug and the inhaler device used affect delivery, and also influence the site of drug deposition within the airway (2,3,4,5). In an earlier study (6), the surface of lactose particles was modified by crystallization and it was shown in an in vitro model of the lung that this gave greater detachment and penetration of the drug particles. The same model has been used to assess different inhalers using flow rates of 601 min- ~ and 150 1 min- ~ to represent low and high inspirational effort. The inhalers contained an internal nozzle with grids at either end; the optimal internal nozzle diameter (from a range of four tested) was found to be 5 mm, and the best grid mesh size was 0.5 mm. The design was chosen to generate a deeply inspirable aerosol cloud with minimum effort by the user. Changes in FEVj have been used to supply most of our current knowledge of bronchodilator drugs, whereas Vmax30 may reflect more subtle changes in the peripheral airways (7,8), not reflected in the FEV~ measurements (9). It has been shown that the maximal Received26 April 1991and acceptedin revisedform2 October 1991. JiTowhomcorrespondenceshouldbe addressed. 0954-6111/92/030237 + 05 $03.00/0
bronchodilator response to salbutamol occurs within 15 min, and is stable for 2 h (7).
Materials and Methods MATERIALS
The Rotahaler (Allen & Hanburys Ltd, U.K.) was used in conjunction with a new delivery device made from glass (Fig. 1). This consisted of a glass tube with an internal nozzle. A capsule containing a unit dose of drug could be inserted at the end oftbe inhaler, and by turning that end the capsule would be split into two halves as in the standard Rotahaler. Two tint-mesh grids were placed at positions b (Fig. l), enclosing the internal nozzle. The capsule content of Ventolin Rotacaps, 200 #g (Allen & Hanburys Ltd), was transferred to hard gelatin capsules similar to those used in our formulation, in order to preserve blindedness. Salbutamol sulphate: lactose blends were prepared in a ratio of 1:67.5. The lactose was first modified by crystallization, as determined by earlier work (6). FEV l was measured on a dry wedge bellows spirometer (Vitalograph, U.K.). Flow-volume loops were recorded on a transfer factor rolling field spirometer with a flow-volume differentiator (P.K. Morgan, U.K.), connected to a Rikadenki X-Y recorder. METHODS
The study was a two-part, double-blind, randon~zed, cross-over trial carried out over four visits. © 1992 Bailli6reTindail
238
A. J. M. Ward et al.
b
b
Fig. 1 Sketch of the inhaler pointing out. (a) Internal nozzle; (b) mesh grids; (c) opening for drug insertion; (d) mouthpiece.
Eleven patients (six male, five female) with moderateto-severe asthma (FEV~ < 8 0 % of predicted, > 15% reversibility) were recruited from the chest clinic at King's College Hospital. Mean age was 37 years (range 23-62). All were non-smokers, and all had positive skin-prick tests to common allergens. No oral steroids had been taken for at least 4 weeks prior to recruitment, and all other anti-asthmatic medications were stable over that period. Beta2-agonists were withheld for at least 6 h prior to each test session. Each patient was requested to attend at the same time of day on four occasions. On arrival, the patient rested for I0 min and then performed five maximum expiratory flow-volume (MEFV) loops, each separated by 1 min. These were followed after 2 min by five partial expiratory flow-volume (PEFV) loops and three FEV~s, each separated by 30 s. The mean FEV~ on day 1 acted as baseline, and values on subsequent d a y s were required to be within 10% of this. The MEFV loops were not repeated after, drug inhalation in order to avoid the change in bronchomotor tone following a full inflation (9). Thus the pre-inhalation MEFV loops provided the vital capacity readings for all subsequent calculations of Vmax30. In part 1 of the study (visits I and 2), 200/ag of Ventolin Rotacaps was tested against 200/zg of salbutamol on the modified lactose carrier, each inhaled via a conventional Rotahaler. The process was randomized and double-blind, drug 'A' being inhaled in visit 1 and drug 'B' on visit 2. Baseline FEV, and Vmax30 values were calculated as above, followed by drug inhalation. FEV, (mean of 3) and Vmax30 (mean of 3, calculated from PEFV loops) were recorded at 5, 10, 15 and 30 min post-inhalation. In part 2 (visits 3 and 4), the order of drugs was reversed (to correct for a learning effect on the measurements), and the new inhaler device was used. Ideally, all four visits would have been randomized; however, the difficulty of maintaining stability over this period in a group of moderate-to-severe asthmatic patients made the current design more practical. After each study day, chemical analysis of the amount of drug remaining in either inhaler was performed.
The study was approved by the ethical committee at King's College Hospital. STATISTICAL ANALYSIS
We looked at changes in FEV~ and Vmax30. As there was no particular pattern of response at the different timepoints, the time-averaged percent change from baseline (t = 0) was calculated for each patient. To look at the effect of modifying the salbutamol carrier, day 1 was compared with day 2, and day 3 with day 4. To compare the two inhaler devices, day I was compared with day 4, and day 2 with day 3. Data were normally distributed, therefore paired t-tests were used in these comparisons. Results DRUG COMPARISON
Eleven patients entered and completed part 1 of the study. The mean (SEM) percentage increase in FEV~ post-inhalation of drug via Rotahaler (Table la) was significantly greater using the new formulation: 27.5 (5.9) versus 21.4 (4.5) (paired t-test for differences, P=0"03; 95% confidence interval, 0.90-11.27). Vmax30 was not significantly different between the two groups (Table 2a). Seven of the 11 patients completed part 2 of the study. The other four did not remain within 10% of their baseline FEVI, despite returning on a further occasion to see if stability had been regained, and so were excluded from further testing. Differences in mean FEV t and Vmax30 using the new inhaler were not significant (Table 1a and b). INHALER COMPARISON
There was no significant difference found between the two inhaler devices using either drug preparation (Table 1a versus b, Table 2a versus b). Discussion
In dry powder aerosols, the detachment of drug particles from the carriers normally used, and their penetration into the lung, is determined by the strength
Modification inhaler therapy
239
Table I FEV~(1) results obtained with the different inhalers: Rotacaps versus study formulation Study formulation
Rotacaps No.
Predicted*
%Differencet
Predicted
%Difference
I 2 3 4 5 6 7 8 9 10 11
3"73 1"37 1"33 1"73 2"54 1"51 2"65 2"41 2"23 1"01 1"98
10"7 51"8 14"9 46"5 11"8 23"2 4"7 9'7 19-2 26"0 17"I
3"38 1'21 1"20 1"72 2"63 1"49 2'52 2"34 2-29 0"98 2"12
15-5 64-5 26"7 63"7 7"1 28'4 15"3 20"5 13"7 33"9 13"2
Mean SD~/SEM2
2.04 0"78'
21.4 4"5-"
1.99 0"74'
27-5 5"9:
3 4 5 6 9 10 II
1.44 1-56 2-54 1"35 2"49 0'97 2.02
2.4 27,4 9.4 55'9 6"8 25.3 11"0
1-24 I'58 2-65 1.62 2.45 1"01 1"97
22-8 66"t 7-7 25"8 3"3 24"3 10-9
Mean
1.77 0.60~
19.7 7-02
1.79 0.60~
23.0 7.92
(a) Rotahaler
(b) Study inhaler
SD'/SEM 2
*Mean baseline reading. "l'Meanpercentage increase after salbutamol.
of interparticulate forces and the fluid regime established within the inhaler during inspiration. The surface properties of the carrier influence the adhesion of the fine drug particles, rough surfaces forming stronger interparticulate bonds due to entrapment in surface clefts and indentations. Our results comparing reversibility of FEV~ with the two drug formulations showed a small but statistically significant benefit with modification of the carrier. The improvement occurred despite the fact that a higher percent of modified drug was retained in the Rotahaler in almost every case (Table 3). Controlling the moisture content of the modified powder formulation may improve fluidization. The clinical relevance of these findings is best appreciated by examination of individual data (Table la). Three patients did not improve and eight improved with the new formulation. Among the
responders, the increase in reversibility ranged from 4.8 to 17-2% of the initial baseline FEV~, with five patients achieving greater than 10% additional reversibility with the modified drug. This degree of improvement in a group of moderate-to-severe asthmatics is likely to be of clinical benefit, and suggests that the drug modification may have a role in the therapy of asthma. Because Vmax30 did not show the same pattern, and because this measurement reflects changes in the peripheral airways (9), we might surmize that our formulation confers no advantage at these sites. Alternatively, as Vmax30 is a less reproducible (though more sensitive) measurement than FEV~ (Tables 2a and b), larger numbers of patients may be necessary to demonstrate a difference (9). Air flow and the form of the inhaler combine to create high levels of turbulence within the inhaler, thus
240
A. J. M. Ward et al. Table 2 Vmax30 (l s -~) results obtained with the different inhalers: Rotacaps versus study formulation Study formulation
Rotacaps No.
Predicted
%Difference
Predicted
%Difference
1 2 3 4 5 6 7 8 9 10 11
2.38 0-82 1-12 0.84 2-44 1-34 2.72 1.84 2.56 0.44 0-66
42-9 67-1 --34-8 I2-5 45-7 42-2 13~2 64. I 30-9 26-1 --0-8
1.96 0.72 0-58 1-12 2-16 1.06 2.82 1.94 2-76 0.38 0.54
20,9 60.4 6.9 4-5 58.1 84.4 8.7 36.6 41 '9 59.2 6.5
Mean SD'/SEr,!2
1-56 0'85'
28.1 9.02
1.46 0.90'
35.3 8.42
-- 8- I 3-2 34-0 92"9 23"9 15"0 16-5
(a) Rotahaler
(b) Study inhaler 3 4 5 6 9 10 11
0"60 0'90 2"18 0"78 2-22 0"30 0"90
3-3 8"9 57"8 62"2 29'3 26-7 16"7
0'68 1"26 2"56 1"20 3" 12 0-40 0"76
Mean SD'/SEM2
1.13 0'76'
29-3 8"72
1-43 1"02'
25-3 12'42
Table 3 Percent o f drug remaining in inhaler Rotacaps
No.
Rotahaler
1 2 3 4 5 6 7 8 9 10 II
13-9 20-0 30-9 I0.0 19.7 16.4 24.0 22'3 25.8 28.3 20-6
Mean SEM
21-1 1.9
Study formulation Study inhaler
Rotahaler
Study inhaler
92-0 58.9 62-0
23"7 42-0 81-3 27-0 43'5 48"1 38"0 52.0 23-3 44.7 27.4
--86"8 66"9 51 "8 61-6 --71.0 90.7 68.7
53.9 9"5
41 '0 5.1
71.1 5.2
--74-0 38"8 24"2 27'I --
-
Modification inhaler therapy
breaking up aggregates into singly dispersed particles. The turbulence level can be increased without varying the flow rate by varying the diameter of an internal nozzle, and by inserting grids at various positions along the inhaler. Insertion of the grids did not contribute to the pressure drop created as air flowed through the device, indicating that turbulence could be maximized without an increase in resistance of the inhaler to air flow. The in vitro work with the inhaler was not reflected in the clinical study, where large amounts ofdrug were retained in the device after inspiration (Table 3). This may be due to the material used (glass), which could alter the electrostatic forces induced on the powder particles and hence cause greater adhesion of these to the inhaler wall. The emptying efficiency was also influenced by the length of the device which was longer than the standard Rotahater, causing particles to travel a longer distance before reaching the mouthpiece. The use of another material or the construction of a shorter device was not feasible due to technical difficulties. Modifications are required to facilitate emptying of the device. The importance of these results is that we have demonstrated an improved drug delivery to the airways by modification of the lactose molecule, and that
241
the improvement may be of clinical benefit. This opens up possibilities for other drugs and for other therapeutic arenas. References
I. Newman SP. Aerosol deposition considerations in inhalation therapy. Chest 1985;88 (suppl.): 152S-160S. 2. Simonsson BOG. Anatomical and pathophysiological considerations in aerosol therapy. Eur J Respir Dis 1982; 63 (suppl.): 7-14. 3. Moren F. Different techniques of aerosol administration to the lower respiratory tract. Eur J Respir Dis 1982; 63 (suppl.): 15-18. 4. Moren F. Drug deposition of pressurised inhalation aerosols. Eur J Respir Dis 1982;63 (suppl.): 51-55. 5. Svedmyr N, Lofdahl C, Svedmyr K. The effect of powder aerosol compared to pressurised aerosol. Eur J Respir Dis 1982; 63 (suppl.): 81-88. 6. Kassem NM, Ganderton D. The influence of carrier surface on the characteristics ofinspirablepowder aerosols. J Pharm Pharmacol 1990;42 (suppl.): 1IP. 7. Barnes PJ, Gribbin HR, Osmanliev D, Pride NB. Partial flow-volume curves to measure bronchodilator doseresponse curves in normal humans. J Appl Physiol 1981; 50:1193-1197.
8. Bouhuys A, Hunt VR, Kim BM, Zapletal A. Expiratory flow rates in induced bronchoconstriction in man. J Clin Invest 1969;48:1159-1168. 9. Pride NB. Assessment of changes in airway calibre. Br J Clin Pharmaco11979; 8: 193-203.
A clinically relevant modification to existing inhaler therapy A. J. M.
WARD*,N.
KASSEM'~,J. M. EVANS*, J. MOXHAM*~ AND D. GANDERTONt
*Department of Thoracic Medicine, King's College School of Medicine and Dentistry, Bessemer Rd, London SE5 and'~Department of Pharmacy, King's College, Manresa Rd, London SW3, U.K.
A modified formulation of inhaled salbutamol and a new inhaler device were studied in a group of 1 1 moderateto-severe asthmatic patients. Changes in airway calibre (FEVI, Vmax30) were measured before and after inhalation of the new formulation, and compared with changes following inhalation of conventional salbutamol. A standard Rotahaler was used as a reference for the new inhaler. The study was conducted as a two-part randomized, double-blind cross-over trial. We found a significantly greater bronchodilatation of the larger airways using the modified drug in the Rotahaler. The new inhaler did not show any superiority over the Rotahaler, contrary to expectations from in vitro work. A slightly shorter model may better reflect the in vitro results. The study has implications for inhalation therapy in general.
Introduction
The aim of inhaler therapy is to deliver the maximum amount of drug to the airway with as little systemic absorption as possible, and preferably at the relatively low flow rates often attained in clinical practice. Approximately 10% of inhaled drug is deposited in the lung (1), and so improved delivery could be of clinical and economic benefit. Both the formulation of the drug and the inhaler device used affect delivery, and also influence the site of drug deposition within the airway (2,3,4,5). In an earlier study (6), the surface of lactose particles was modified by crystallization and it was shown in an in vitro model of the lung that this gave greater detachment and penetration of the drug particles. The same model has been used to assess different inhalers using flow rates of 601 min- ~ and 150 1 min- ~ to represent low and high inspirational effort. The inhalers contained an internal nozzle with grids at either end; the optimal internal nozzle diameter (from a range of four tested) was found to be 5 mm, and the best grid mesh size was 0.5 mm. The design was chosen to generate a deeply inspirable aerosol cloud with minimum effort by the user. Changes in FEVj have been used to supply most of our current knowledge of bronchodilator drugs, whereas Vmax30 may reflect more subtle changes in the peripheral airways (7,8), not reflected in the FEV~ measurements (9). It has been shown that the maximal Received26 April 1991and acceptedin revisedform2 October 1991. JiTowhomcorrespondenceshouldbe addressed. 0954-6111/92/030237 + 05 $03.00/0
bronchodilator response to salbutamol occurs within 15 min, and is stable for 2 h (7).
Materials and Methods MATERIALS
The Rotahaler (Allen & Hanburys Ltd, U.K.) was used in conjunction with a new delivery device made from glass (Fig. 1). This consisted of a glass tube with an internal nozzle. A capsule containing a unit dose of drug could be inserted at the end oftbe inhaler, and by turning that end the capsule would be split into two halves as in the standard Rotahaler. Two tint-mesh grids were placed at positions b (Fig. l), enclosing the internal nozzle. The capsule content of Ventolin Rotacaps, 200 #g (Allen & Hanburys Ltd), was transferred to hard gelatin capsules similar to those used in our formulation, in order to preserve blindedness. Salbutamol sulphate: lactose blends were prepared in a ratio of 1:67.5. The lactose was first modified by crystallization, as determined by earlier work (6). FEV l was measured on a dry wedge bellows spirometer (Vitalograph, U.K.). Flow-volume loops were recorded on a transfer factor rolling field spirometer with a flow-volume differentiator (P.K. Morgan, U.K.), connected to a Rikadenki X-Y recorder. METHODS
The study was a two-part, double-blind, randon~zed, cross-over trial carried out over four visits. © 1992 Bailli6reTindail
238
A. J. M. Ward et al.
b
b
Fig. 1 Sketch of the inhaler pointing out. (a) Internal nozzle; (b) mesh grids; (c) opening for drug insertion; (d) mouthpiece.
Eleven patients (six male, five female) with moderateto-severe asthma (FEV~ < 8 0 % of predicted, > 15% reversibility) were recruited from the chest clinic at King's College Hospital. Mean age was 37 years (range 23-62). All were non-smokers, and all had positive skin-prick tests to common allergens. No oral steroids had been taken for at least 4 weeks prior to recruitment, and all other anti-asthmatic medications were stable over that period. Beta2-agonists were withheld for at least 6 h prior to each test session. Each patient was requested to attend at the same time of day on four occasions. On arrival, the patient rested for I0 min and then performed five maximum expiratory flow-volume (MEFV) loops, each separated by 1 min. These were followed after 2 min by five partial expiratory flow-volume (PEFV) loops and three FEV~s, each separated by 30 s. The mean FEV~ on day 1 acted as baseline, and values on subsequent d a y s were required to be within 10% of this. The MEFV loops were not repeated after, drug inhalation in order to avoid the change in bronchomotor tone following a full inflation (9). Thus the pre-inhalation MEFV loops provided the vital capacity readings for all subsequent calculations of Vmax30. In part 1 of the study (visits I and 2), 200/ag of Ventolin Rotacaps was tested against 200/zg of salbutamol on the modified lactose carrier, each inhaled via a conventional Rotahaler. The process was randomized and double-blind, drug 'A' being inhaled in visit 1 and drug 'B' on visit 2. Baseline FEV, and Vmax30 values were calculated as above, followed by drug inhalation. FEV, (mean of 3) and Vmax30 (mean of 3, calculated from PEFV loops) were recorded at 5, 10, 15 and 30 min post-inhalation. In part 2 (visits 3 and 4), the order of drugs was reversed (to correct for a learning effect on the measurements), and the new inhaler device was used. Ideally, all four visits would have been randomized; however, the difficulty of maintaining stability over this period in a group of moderate-to-severe asthmatic patients made the current design more practical. After each study day, chemical analysis of the amount of drug remaining in either inhaler was performed.
The study was approved by the ethical committee at King's College Hospital. STATISTICAL ANALYSIS
We looked at changes in FEV~ and Vmax30. As there was no particular pattern of response at the different timepoints, the time-averaged percent change from baseline (t = 0) was calculated for each patient. To look at the effect of modifying the salbutamol carrier, day 1 was compared with day 2, and day 3 with day 4. To compare the two inhaler devices, day I was compared with day 4, and day 2 with day 3. Data were normally distributed, therefore paired t-tests were used in these comparisons. Results DRUG COMPARISON
Eleven patients entered and completed part 1 of the study. The mean (SEM) percentage increase in FEV~ post-inhalation of drug via Rotahaler (Table la) was significantly greater using the new formulation: 27.5 (5.9) versus 21.4 (4.5) (paired t-test for differences, P=0"03; 95% confidence interval, 0.90-11.27). Vmax30 was not significantly different between the two groups (Table 2a). Seven of the 11 patients completed part 2 of the study. The other four did not remain within 10% of their baseline FEVI, despite returning on a further occasion to see if stability had been regained, and so were excluded from further testing. Differences in mean FEV t and Vmax30 using the new inhaler were not significant (Table 1a and b). INHALER COMPARISON
There was no significant difference found between the two inhaler devices using either drug preparation (Table 1a versus b, Table 2a versus b). Discussion
In dry powder aerosols, the detachment of drug particles from the carriers normally used, and their penetration into the lung, is determined by the strength
Modification inhaler therapy
239
Table I FEV~(1) results obtained with the different inhalers: Rotacaps versus study formulation Study formulation
Rotacaps No.
Predicted*
%Differencet
Predicted
%Difference
I 2 3 4 5 6 7 8 9 10 11
3"73 1"37 1"33 1"73 2"54 1"51 2"65 2"41 2"23 1"01 1"98
10"7 51"8 14"9 46"5 11"8 23"2 4"7 9'7 19-2 26"0 17"I
3"38 1'21 1"20 1"72 2"63 1"49 2'52 2"34 2-29 0"98 2"12
15-5 64-5 26"7 63"7 7"1 28'4 15"3 20"5 13"7 33"9 13"2
Mean SD~/SEM2
2.04 0"78'
21.4 4"5-"
1.99 0"74'
27-5 5"9:
3 4 5 6 9 10 II
1.44 1-56 2-54 1"35 2"49 0'97 2.02
2.4 27,4 9.4 55'9 6"8 25.3 11"0
1-24 I'58 2-65 1.62 2.45 1"01 1"97
22-8 66"t 7-7 25"8 3"3 24"3 10-9
Mean
1.77 0.60~
19.7 7-02
1.79 0.60~
23.0 7.92
(a) Rotahaler
(b) Study inhaler
SD'/SEM 2
*Mean baseline reading. "l'Meanpercentage increase after salbutamol.
of interparticulate forces and the fluid regime established within the inhaler during inspiration. The surface properties of the carrier influence the adhesion of the fine drug particles, rough surfaces forming stronger interparticulate bonds due to entrapment in surface clefts and indentations. Our results comparing reversibility of FEV~ with the two drug formulations showed a small but statistically significant benefit with modification of the carrier. The improvement occurred despite the fact that a higher percent of modified drug was retained in the Rotahaler in almost every case (Table 3). Controlling the moisture content of the modified powder formulation may improve fluidization. The clinical relevance of these findings is best appreciated by examination of individual data (Table la). Three patients did not improve and eight improved with the new formulation. Among the
responders, the increase in reversibility ranged from 4.8 to 17-2% of the initial baseline FEV~, with five patients achieving greater than 10% additional reversibility with the modified drug. This degree of improvement in a group of moderate-to-severe asthmatics is likely to be of clinical benefit, and suggests that the drug modification may have a role in the therapy of asthma. Because Vmax30 did not show the same pattern, and because this measurement reflects changes in the peripheral airways (9), we might surmize that our formulation confers no advantage at these sites. Alternatively, as Vmax30 is a less reproducible (though more sensitive) measurement than FEV~ (Tables 2a and b), larger numbers of patients may be necessary to demonstrate a difference (9). Air flow and the form of the inhaler combine to create high levels of turbulence within the inhaler, thus
240
A. J. M. Ward et al. Table 2 Vmax30 (l s -~) results obtained with the different inhalers: Rotacaps versus study formulation Study formulation
Rotacaps No.
Predicted
%Difference
Predicted
%Difference
1 2 3 4 5 6 7 8 9 10 11
2.38 0-82 1-12 0.84 2-44 1-34 2.72 1.84 2.56 0.44 0-66
42-9 67-1 --34-8 I2-5 45-7 42-2 13~2 64. I 30-9 26-1 --0-8
1.96 0.72 0-58 1-12 2-16 1.06 2.82 1.94 2-76 0.38 0.54
20,9 60.4 6.9 4-5 58.1 84.4 8.7 36.6 41 '9 59.2 6.5
Mean SD'/SEr,!2
1-56 0'85'
28.1 9.02
1.46 0.90'
35.3 8.42
-- 8- I 3-2 34-0 92"9 23"9 15"0 16-5
(a) Rotahaler
(b) Study inhaler 3 4 5 6 9 10 11
0"60 0'90 2"18 0"78 2-22 0"30 0"90
3-3 8"9 57"8 62"2 29'3 26-7 16"7
0'68 1"26 2"56 1"20 3" 12 0-40 0"76
Mean SD'/SEM2
1.13 0'76'
29-3 8"72
1-43 1"02'
25-3 12'42
Table 3 Percent o f drug remaining in inhaler Rotacaps
No.
Rotahaler
1 2 3 4 5 6 7 8 9 10 II
13-9 20-0 30-9 I0.0 19.7 16.4 24.0 22'3 25.8 28.3 20-6
Mean SEM
21-1 1.9
Study formulation Study inhaler
Rotahaler
Study inhaler
92-0 58.9 62-0
23"7 42-0 81-3 27-0 43'5 48"1 38"0 52.0 23-3 44.7 27.4
--86"8 66"9 51 "8 61-6 --71.0 90.7 68.7
53.9 9"5
41 '0 5.1
71.1 5.2
--74-0 38"8 24"2 27'I --
-
Modification inhaler therapy
breaking up aggregates into singly dispersed particles. The turbulence level can be increased without varying the flow rate by varying the diameter of an internal nozzle, and by inserting grids at various positions along the inhaler. Insertion of the grids did not contribute to the pressure drop created as air flowed through the device, indicating that turbulence could be maximized without an increase in resistance of the inhaler to air flow. The in vitro work with the inhaler was not reflected in the clinical study, where large amounts ofdrug were retained in the device after inspiration (Table 3). This may be due to the material used (glass), which could alter the electrostatic forces induced on the powder particles and hence cause greater adhesion of these to the inhaler wall. The emptying efficiency was also influenced by the length of the device which was longer than the standard Rotahater, causing particles to travel a longer distance before reaching the mouthpiece. The use of another material or the construction of a shorter device was not feasible due to technical difficulties. Modifications are required to facilitate emptying of the device. The importance of these results is that we have demonstrated an improved drug delivery to the airways by modification of the lactose molecule, and that
241
the improvement may be of clinical benefit. This opens up possibilities for other drugs and for other therapeutic arenas. References
I. Newman SP. Aerosol deposition considerations in inhalation therapy. Chest 1985;88 (suppl.): 152S-160S. 2. Simonsson BOG. Anatomical and pathophysiological considerations in aerosol therapy. Eur J Respir Dis 1982; 63 (suppl.): 7-14. 3. Moren F. Different techniques of aerosol administration to the lower respiratory tract. Eur J Respir Dis 1982; 63 (suppl.): 15-18. 4. Moren F. Drug deposition of pressurised inhalation aerosols. Eur J Respir Dis 1982;63 (suppl.): 51-55. 5. Svedmyr N, Lofdahl C, Svedmyr K. The effect of powder aerosol compared to pressurised aerosol. Eur J Respir Dis 1982; 63 (suppl.): 81-88. 6. Kassem NM, Ganderton D. The influence of carrier surface on the characteristics ofinspirablepowder aerosols. J Pharm Pharmacol 1990;42 (suppl.): 1IP. 7. Barnes PJ, Gribbin HR, Osmanliev D, Pride NB. Partial flow-volume curves to measure bronchodilator doseresponse curves in normal humans. J Appl Physiol 1981; 50:1193-1197.
8. Bouhuys A, Hunt VR, Kim BM, Zapletal A. Expiratory flow rates in induced bronchoconstriction in man. J Clin Invest 1969;48:1159-1168. 9. Pride NB. Assessment of changes in airway calibre. Br J Clin Pharmaco11979; 8: 193-203.