BENGTSSON, T

BORGSTROM, L

Derom, Eric

Pauwels, Romain

English

Ghent University Academic Bibliography

International Journal of Pharmaceutics 193 (2000) 227–230Variability in lung deposition of inhaled drug, within andbetween asthmatic patients, with a pMDI and a dry powderinhaler, Turbuhaler®Lars Borgstro¨m a,*, Thomas Bengtsson a, Eric Derom b, Romain Pauwels ba Astra Zeneca R&D, S-221 87 Lund, Swedenb Department of Respiratory Diseases, Uni6ersity Hospital Ghent, De Pintelaan 185, B-9000 Ghent, BelgiumReceived 11 August 1999; accepted 5 October 1999AbstractIn vitro analysis of inhaled formulations measures, among other parameters, the variability in delivered dose, whilea corresponding in vivo analysis also includes the variability caused by patient performance and distribution of drugbetween the oropharynx and the lungs. In vitro, the dose variability is higher for Turbuhaler® than for thecorresponding pMDI, whereas in vivo, the converse is true: the variability in lung deposition is significantly higher,both between and within subjects, for pMDI than for Turbuhaler. The observation can be due to several factors suchas the non-continuous working principle of inhalation via pMDI as opposed to the continuous working principle ofinhalation via Turbuhaler. © 2000 Elsevier Science B.V. All rights reserved.Keywords: Inhalers; Variability; Lung deposition; Patientswww.elsevier.com:locate:ijpharm1. IntroductionThe amount of drug reaching the effector sitedetermines the elicited effect (Borgstro¨m et al.,1996; Pauwels et al., 1997). Thus, for inhaleddrugs, it is of interest to evaluate the amount ofdrug reaching the lungs. Not only the absolutevalue of, but also the variability in, lung deposi-tion is of interest, as a large variability in lungdeposition could be reflected in the exerted effects.The overall delivery of inhaled drugs to the effec-tor site can be described by a number of steps:dose metering, aerosol generation, dose delivery(from inhaler to patient), partition of delivereddose between oropharynx and lungs, and, finally,regional deposition of drug reaching the lung.Variability in the different steps will add up to anoverall variability in the amount of drug reachingthe lungs. The variability in lung deposition thusdepends on a large number of in vitro and in vivofactors, e.g. device performance, handling of thedevice, co-ordination of actuation and inhalation,inhalation flow, patient anatomy etc. In vitroanalysis is done to ascertain a good quality of themanufactured product and the analyses are doneunder strictly standardised conditions. The abso-* Corresponding author.0378-5173:00:$ - see front matter © 2000 Elsevier Science B.V. All rights reserved.PII: S0 378 -5173 (99 )00341 -5L. Borgstro¨m et al. : International Journal of Pharmaceutics 193 (2000) 227–230228lute amount of drug leaving the inhaler and itsvariability are typical in vitro parameters. The invivo analysis includes lung deposition and itsvariability, but also the clinical outcome of thedose reaching the lungs. The measured in vitrovariability thus is only a small portion of theoverall in vivo variability observed in the clinicalsituation.Lung deposition of inhaled drug can be mea-sured with different methods, gamma-scintigraphyand pharmacokinetic methods being the mostwidely used (Borgstro¨m and Nilsson, 1990; New-man et al., 1995; Pauwels et al., 1997). In thepresent study the pharmacokinetic charcoal-blockmethod was used. The method takes advantage ofthe fact that if the uptake of the oral and gas-trointestinal portion of an inhaled drug is blockedby activated charcoal, then the amount of activedrug reaching the systemic circulation equals theamount of active drug absorbed over the lungmembrane. This amount equals the lung deposi-tion. Pharmacokinetic methods are based on mea-surements of plasma and urine concentrations andthus the variability in the bioanalytical methodadds to the overall variability. This methodologi-cal variability is probably of minor importancecompared with variability in the other factorsdiscussed above. A previous study investigated thevariability in lung deposition in healthy volunteers(Beckman et al., 1996). From that study it wasconcluded that both variability between subjects(intervariability) and variability within subjects(intravariability) in lung deposition were lower forthe dry powder inhaler, DPI, Turbuhaler than fora pressurised metered dose inhaler, pMDI.The aim of the present investigation was todetermine the intra-, and intervariability in lungdeposition in asthmatic patients when they in-haled terbutaline sulphate (Bricanyl®) via two dif-ferent kinds of inhalers, a pMDI and a DPI,Turbuhaler. The results from the previous studyin healthy volunteers are given for reference. Thepresent investigation was part of a more extensivestudy. The main aim of this study was to investi-gate if differences in the amount of terbutalinesulphate reaching the lungs were reflected in adifference in protective effect against a metha-choline or a histamine provocation.2. Material and methodsThirteen asthmatic patients (nine men) wereincluded in the study. Their mean age was 28years (range 19–48) and their mean FEV1 was 3.4L (2.6–4.6), corresponding to 85% of predicted, atinclusion. Patients were asked to inhale terbuta-line sulphate (Bricanyl®) from a pMDI or Tur-buhaler at nominal doses of 0.25 or 0.5 mg and itsprotective effect against methacholine or his-tamine provocation was tested. The study wasdouble-blind, crossover and randomised with re-spect to the provocative agent. The amount ofdrug reaching the lungs, lung deposition, wascalculated at each inhalation, with the aid of apharmacokinetic method (Borgstro¨m and Nilsson,1990). The 0.5 mg dose was given as two doses of0.25 mg. Thus, the measured lung deposition val-ues, in percentage of dose, for the 0.5 mg doses isthe mean of two 0.25 mg doses. For each patienteight determinations of lung deposition were gen-erated, making it possible to calculate the intra-,as well as the intervariability in lung deposition ofthe inhaled drug. The results from the lung depo-sition versus effect part of the study have beenreported elsewhere (Derom et al., 1999). Lungdeposition was compared between devices using amultiplicative ANOVA model with factors pa-tient, visit, device, dose and interaction device bydose. A multiplicative model means that datawere analysed on a logarithmic scale. The intra-and intervariability in lung deposition with eachdevice was assessed using a linear mixed effectsmodel (LINMEM) accounting for device and visitas fixed factors. Differences in the doses withinthe same device for asthmatic patients were as-sumed to be part of the variability. The estimatedvariances on the logarithmic scale were expressedas coefficients of variation (CV) on the linearscale.3. ResultsThe absolute amount of drug reaching thelungs differed significantly between the two in-halers (Table 1). The value given for the ratio ofTurbuhaler:pMDI is the ratio between the meanL. Borgstro¨m et al. : International Journal of Pharmaceutics 193 (2000) 227–230 229Table 1Lung deposition (percentage of nominal metered dose) after inhalation of terbutaline sulphate via pMDI or Turbuhaler in theasthmatic patients groupTreatment 95% conf. lim. (%)Lung deposition (%) Range (%)20.8Turbuhaler 0.25 mg 16.4–26.6 9.7–54.113.2–21.716.9 7.3–50.7Turbuhaler 0.5 mg3.8–6.1 0.2–15.9pMDI 0.25 mg 4.85.8–9.5 1.1–53.77.4pMDI 0.5 mg2.46–4.01Turbuhaler:pMDI ratio 3.14deposition for Turbuhaler and pMDI, respec-tively.The absolute values for Turbuhaler were aboutthree times higher than the pMDI values. This isat accord with a previous study where similarvalues were observed (Borgstro¨m et al., 1996).The values obtained for inter- and intravariabil-ity are given in Table 2.4. DiscussionThe intra- and interindividual variability inlung deposition for pMDI and Turbuhaler waspreviously assessed in 12 healthy subjects in anopen, crossover and randomised study (Beckmanet al., 1996). A re-calculation of the variabilityfrom that study with the LINMEM technique,giving more consistent estimates of the influenceof the intravariability on the intervariability, aregiven together with the results from the presentstudy in Table 2. In the previous study the Tur-buhaler and pMDI inhalers were also analysed invitro. Intra-device variability expressed as CV,was 6.4% for pMDI and 18.2% for Turbuhaler, asignificant (PB0.001) difference. Also the inter-device variability was significantly higher for Tur-buhaler than for pMDI; the ratio of CVs was 2.0(P0.023).It should be observed that in vitro analyses arenot primarily designed to predict the in vivobehaviour of a tested formulation. The in vitroanalyses are designed to judge if an individualbatch of the pharmaceutical formulation complieswith the approved specifications. The in vitroanalyses can be regarded as a final evaluation ofall the steps in the manufacturing process. Thus,one should not expect the in vitro behaviour of aninhaled formulation to be a predictor of its in vivobehaviour unless this has been shown to be thecase for a specific set of in vitro:in vivo parame-ters. This is the case for the relation between fineparticle dose (FPD) and lung deposition. It hasbeen shown that FPD, measured with an in vivolike inlet on the impactor, can be used to predictthe lung deposition for different DPIs and pMDIs(Olsson et al., 1996).In the present study, the intravariability in lungdeposition in patients was similar for the twodevices, while for the healthy subjects it washigher for the pMDI. Taken together this con-firms that factors other than the generation of theinhaled aerosol are of importance for the overallvariability seen in lung deposition. It also suggeststhat day to day variability, if anything, is lowerfor the DPI than for the corresponding pMDI.The resulting lung dose is probably only to asmall degree dependent on the variability in theproperties of the generated aerosol cloud, and isTable 2Inter- and intravariability in lung deposition of terbutalineinhaled via pMDI or TurbuhaleraPatientsDevice Healthy volunteersInter IntraIntraInterTurbuhaler 8.17 39.3 18.5 47.161.2 39.1PMDI 73.046.7a Values are expressed as coefficients of variation (%). Val-ues for healthy volunteers are given for comparison and arere-calculated from reference (Beckman et al., 1996)L. Borgstro¨m et al. : International Journal of Pharmaceutics 193 (2000) 227–230230more dependent on the interaction between theaerosol cloud and the oral cavity of the inhalingsubject.The observed difference in intervariability, be-tween pMDI and Turbuhaler, seen both in pa-tients and healthy volunteers, indicates that theperformance of Turbuhaler is more subject inde-pendent than the corresponding pMDI. In thecase of a patient, the lung deposition is morepredictable when prescribing Turbuhaler thanwhen prescribing the corresponding pMDI. Theobserved difference in variability in lung deposi-tion between the DPI Turbuhaler and the pMDIprobably represents a class difference betweenbreath actuated DPIs and pMDIs. This is becausethe generation of aerosol and inhalation is acontinuous process with breath actuated DPIs incontrast to pMDIs where aerosol generation andinhalation of the generated aerosol are two dis-tinct processes that need to be co-ordinated by theinhaling subject. This difference can explain theresults obtained.Collectively, we have shown that in an asth-matic patient population the inhalation of terbu-taline sulphate from Turbuhaler gives a morereproducible dose to the effector organ, the lungs,than inhalation of an equivalent dose from thecorresponding pMDI.ReferencesBorgstro¨m, L., Derom, E., Sta˚hl, E., Wa˚hlin-Boll, E.,Pauwels, R., 1996. The inhalation device influences lungdeposition and bronchodilating effect of terbutaline. Am.J. Respir. Crit. Care Med. 153, 1636–1640.Pauwels, R., Newman, S., Borgstro¨m, L., 1997. Airway de-position and airway effects of antiasthma drugs deliveredfrom metered-dose inhalers. Eur. Resp. J. 10, 2127–2138.Borgstro¨m, L., Nilsson, M., 1990. A method for deter-mination of the absolute pulmonary bioavailabilityof inhaled drugs: terbutaline. Pharm. Res. 7, 1068–1070.Newman, S.P., Steed, K.P., Hooper, G., Brickwell, J., 1995.Scintigraphic assessment of the oropharyngeal and nasaldepositions of fusafungine from a pressurized inhaler andfrom a novel pump spray device. J. Pharm. Pharmacol.47, 818–821.Beckman, O., Bondesson, E., Asking, L., Ka¨lle´n, A.,Borgstro¨m, L., 1996. Intra- and interindividual variationsin pulmonary deposition via Turbuhaler and a pMDI. J.Aer. Med. 9, 449.Derom, E., van Schoor, J., Borgstro¨m, L., Pauwels, R.,1999. Lung deposition and clinical effect of terbutalinedelivered from pMDI and Turbuhaler on airway respon-siveness in patients with asthma. Am. J. Respir. Crit.Care Med. 159, A859.Olsson, B., Borgstro¨m, L., Asking, L., Bondesson, E., 1996.Effect of inlet throat on the correlation between mea-sured fine particle dose and lung deposition. In: Dalby,R., Byron, P., Farr, S. (Eds.), Respiratory DrugDelivery V. Interpharm Press, Buffalo Grove, pp. 273–281..

Variability in lung deposition of inhaled drug, within and between asthmatic patients, with a pMDI and a dry powder inhaler, Turbuhaler (R)

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Variability in lung deposition of inhaled drug, within and between asthmatic patients, with a pMDI and a dry powder inhaler, Turbuhaler (R)

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