The Clinical Respiratory Journal
ORIGINAL ARTICLE
Clinical equivalence of budesonide dry powder inhaler and pressurized metered dose inhaler Teerapol Srichana1, Siwasak Juthong2, Ekawat Thawithong1, Supot Supaiboonpipat3 and Suchada Soorapan4 1 Nanotec-PSU Excellence Center on Drug Delivery System and Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla, Thailand 2 Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand 3 Department of Medicine, Nopparat Rajathanee Hospital, Bangkok, Thailand 4 Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla, Thailand
Abstract Introduction: A delivery device is the most important factor that determines the local/systemic bioavailability of inhaled corticosteroids. Dry powder inhalers (DPIs) and pressurized metered dose inhalers (pMDIs) are the most commonly used delivery devices for localized drug delivery to the airways. Objective: This study was to compare the clinical equivalence of budesonide delivered by the Pulmicort TurbuhalerTM (DPI) and the AeronideTM inhaler (pMDI). Materials and Methods: The two inhalers were compared for their pharmaceutical equivalence and clinical equivalence. The in vitro test included the uniformity of the delivered dose and determination of the aerodynamic particle size of budesonide. The in vivo test was carried out in 36 patients with mild to moderate asthma. This was a randomized, single-blinded study conducted for a period of 3 months. This included assessment of the spirometric parameters [forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), peak expiratory flow rate (PEFR), forced expiratory flow 25–75% (FEF25–75)], the severity of asthma symptoms, adverse events, frequency of short-acting inhaled bronchodilator usage and measurement of urinary cortisol levels. Results: The aerodynamic particle size was slightly different between the two inhalers (2.3 ± 0.2 µm for Pulmicort TurbuhalerTM and 2.2 ± 0.2 µm for AeronideTM inhaler). Both inhalers passed the uniformity of delivered dose (95.4% and 97.4%) specified in the British Pharmacopoeia. There was no statistically significant difference observed between the two inhalers in terms of the spirometric parameters, symptom-free days, frequency of bronchodilator usage and the level of urinary cortisol. Conclusion: In addition to pharmaceutical equivalence, no clinical difference observed between the two budesonide inhalers. Please cite this paper as: Srichana T, Juthong S, Thawithong E, Supaiboonpipat S and Soorapan S. Clinical equivalence of budesonide dry powder inhaler and pressurized metered dose inhaler. Clin Respir J 2014; ••: ••–••. DOI:10.1111/crj.12188.
Key words Andersen cascade impactor – budesonide – clinical equivalence – dry powder inhaler – metered dose inhaler – spirometric parameters Correspondence Teerapol Srichana, PhD, Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University Hat Yai, Songkhla, 90112, Thailand. Tel: +66 74 288979 Fax: +66 74 288979 email: [email protected] Received: 20 May 2013 Revision requested: 23 June 2014 Accepted: 03 July 2014 DOI:10.1111/crj.12188 Authorship and contributorship T. Srichana was responsible for concept and design of experiment, data analysis and interpretation. S. Juthong and S. Supaiboonpipat were responsible for clinical investigation. E. Thawithong was responsible for data tabulation and statistical analysis. S. Soorapan was responsible for concept and design of experiment. Ethics The study was approved by the ethics committee of the Faculty of Medicine, Prince of Songkla University. All patients gave informed consent. The manuscript has been read and approved by all coauthors. Conflict of interest The authors have stated explicitly that there are no conflicts of interest in connection with this article.
The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
1
Clinical strudy of budesonide DPI and MDI
Introduction Asthma results from a chronic inflammatory disorder of the airways with variable and often reversible airflow obstruction and is now recognized as being a major worldwide health problem with 300 million people affected (1). It has been well established that clinical manifestations of asthma can be controlled with appropriate treatment (2). The extensive inflammation of the airway has warranted the use of glucocorticoids for asthma therapy. Due to various adverse effects associated with the long-term administration of systemic glucocorticoids, inhaled corticosteroids have become the mainstay of treatment for all patients with persistent asthma owing to their profile of proven safety and efficacy (3–6). The search for a corticosteroid with desirable physical and pharmacokinetic properties for administration by inhalation resulted in the development of budesonide, a synthetic glucocorticosteroid with a well-documented efficacy in the management of asthma (2). The unique structural features like the lipophilic acetal groups on the 16α and 17α positions enhance glucocorticoid receptor binding and prolong airway retention (6). Furthermore, the absence of a halogen atom on the corticosteroid nucleus contributes to the optimal topical to systemic activity ratio of budesonide. The distinctive physical and pharmacokinetic properties of budesonide results in a favorable efficacy and tolerability profile, and because of its high therapeutic index, this makes it an ideal inhaled corticosteroid (ICS) for the long-term treatment of asthma for all categories of patients (6, 7). The delivery device is the most important factor that determines the local bioavailability of the ICS (8). Consequently, it is imperative to measure the clinical equivalence of the ICS from different delivery devices. The pressurized metered dose inhaler (pMDI) is a safe, convenient, inexpensive and reliable delivery device for providing localized drug delivery to the airways and is used by about 80% of asthmatics worldwide (9, 10). Conversely, these devices are associated with a number of problems like under dosing owing to poor hand breath coordination and airway irritation from the lubricants or propellants used and their propensity for a high oral deposition (11). A spacer device attached to a metered dose inhaler will reduce oropharyngeal deposition and increase lung deposition. Breath-actuated dry powder inhalers (DPI) were developed to overcome the above drawbacks, but the deposition efficiency of DPI was dependent on the patient’s inspiratory airflow and the drug was wasted if patients inadvertently exhaled into the DPI. Hence the availability of data on
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the clinical equivalence of these two devices will certainly give clinicians greater freedom to select the most cost-effective therapy that suits the needs and preferences of individual patients and clinicians. The purpose of this study was to compare the clinical equivalence of budesonide delivered from the Pulmicort TurbuhalerTM DPI and the AeronideTM pMDI. The in vitro analysis included tests for the uniformity of the delivered dose and the aerodynamic particle size distribution. A randomized, singleblinded parallel study design was employed for the in vivo evaluation of the budesonide aerosols. Thirty-six subjects with asthma in the study received either DPI or pMDI for a study period of 3 months. The lung function tests [forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), peak expiratory flow rate (PEFR) and forced expiratory flow 25–75% (FEF25–75)] were monitored before and after drug administration at 2 weeks, 1 month, 2 months and 3 months of the study period. The vital signs, differential hematology, electrolytes, metabolic variables and 24-h urinary cortisol levels were recorded at the beginning and the end of the study period. Any adverse events and the number of bronchodilator needed were also assessed during the study period.
Materials and methods Materials The devices used in the study include the AeronideTM pMDI (lot no 0180), which was kindly donated by AeroCare Co., Ltd. (Bangkok, Thailand) and the Pulmicort TurbuhalerTM DPI (lot no NB 1575), which was obtained from AstraZeneca (Stockholm, Sweden). All chemicals (analytical grade) used in the study were purchased from local suppliers in Thailand.
Analysis of budesonide inhaler formulations Budesonide was analyzed by high performance liquid chromatography (HPLC). The HPLC system consisted of a Spectra System SCM 1000 and Spectra System Pump P2000 plus an Auto-sampler. Spectra System AS 3000 equipped with a Spectra System SN4000 and a Spectra System UV 1000 detector (Thermo Fisher Scientific, Inc., Waltham, MA, USA). A BDS Hypersil C18 column (150 × 4.6 mm id, 5 µm) (Thermo Scientific, Leicester, UK) was used in this study. The mobile phase used in the analysis consisted of 25-mM phosphate buffer pH 3.2 and acetonitrile in the ratio of 65:35 (v/v) at a flow rate of 1.5 mL/min at ambient temperature. The injection volume was 50 µL and the ultraviolet detector was operated at 240 nm.
The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
Srichana et al.
Clinical strudy of budesonide DPI and MDI
Uniformity of delivered dose
In vivo evaluation of budesonide aerosols
The uniformity of the delivered dose from the MDI was assessed by using the apparatus specified in the British Pharmacopoeia (12). The apparatus consisted of a filter support base with an open mesh filter support, a collection tube that was clamped to the filter support base and a mouthpiece adapter to ensure an airtight seal between the collection tube and the mouthpiece. The vacuum connector was connected to a system comprising a vacuum pump and a flow regulator. The pump was adjusted to draw air through the entire assembly at 28.3 L/min. The pressurized inhaler was shaken for 5 s prior to dose collection and the first dose was discharged to waste. Three deliveries at the beginning (2nd–4th), four deliveries at the middle (100th–103rd) and three deliveries at the end (198th–200th) were quantitatively collected and analyzed for the amount of budesonide. The above procedure was slightly modified to accommodate the DPI. The apparatus was modified by connecting a differential pressure meter to the sample collection tube that was used to measure the pressure drop across the inhaler. The pressure drop was set to 4.0 kPa by adjusting the flow control valve placed between the sample collection apparatus and the vacuum pump.
The study was approved by the Faculty of Medicine Ethics Committee, Prince of Songkla University, Thailand (EC 52-274-14-13). All patients provided written informed consent, and the study was conducted in accordance with the principles of good clinical practice. A total of 36 patients with mild to moderate asthma were randomized to use budesonide via the Pulmicort TurbuhalerTM or AeronideTM pMDI with a spacer. The sample size was calculated according to Equations 1 and 2 (14).
Assessment of aerodynamic particle size distribution The measurement of the aerodynamic particle size distribution was performed on an eight-stage Andersen cascade impactor (ACI) (Copley Scientific, Atlanta, GA, USA) stated in the British Pharmacopoeia as Apparatus D. The inhaler was shaken for 5 s and then actuated to waste before it was introduced into the impactor. The inhaler was connected to the metal inlet of the ACI using an adaptor. Air was drawn through the apparatus and the flow rate was adjusted to a desired value (28.3 L/min and 60 L/min for the MDI and the DPI, respectively). The MDI was then discharged into the apparatus for two consecutive doses and shaken for 5 s between each delivery. For the DPI, the drug was drawn into the ACI after activation. The metal inlet and stages were washed with the mobile phase. Each fraction was adjusted to a specified volume and analyzed for the amount of the drug by the HPLC. The mass median aerodynamic diameter (MMAD) and the fine particle fraction (FPF) were calculated according to the method described by Srichana et al. (13).
The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
σ=
(n1 − 1)S12 + (n 2 − 1)S22 = 0.58 n1 + n 2 − 2
(1)
2(z1−α + z β )2 σ 2 = 18 (x1 − x 2 )2
(2)
N=
Where the power of analysis is 80%, α = 0.01, Z1α = 1.28, Zβ = 0.84, the mean difference of PEFR is 0.41. From Equation 2, the number of subjects is 18 and it is enough to detect differences. Similar studies have been carried out with a similar number of patients (15, 16). The ‘null hypothesis (H0)’, shows that there is no difference between the two inhaler products and for the ‘alternative hypothesis (HA), there is a significant difference between the two products. Patients (18 men and 18 women) with mild to moderate persistent asthma (1) aged 18–60 years were selected for the study. Other inclusion criteria were an improvement in their FEV1 of at least 12% following salbutamol 100 µg for 2 puffs within the past 6 months or at the baseline visit. The patients were excluded if they met any of the following criteria: the presence or recent history of any chronic diseases of liver, kidney, heart, any type of carcinoma or psychosis, history of smoking within 3 months or more than 10 pack/year, allergic to budesonide or any excipients in the formulation, history of a severe asthma exacerbation/ hospitalization, receiving oral or parenteral corticosteroids in the previous 6 weeks, use of ICS in a dose greater than 400-µg budesonide, 500-µg beclomethasone dipropionate or 250-µg fluticasone during the 4 weeks preceding the study period and any female patients who were pregnant or lactating. Patients were not included if they had taken sodium cromolyn, ketotifen, leukotriene antagonists and an oral β2 agonist or theophylline or long-acting β2 agonist 4 weeks preceding the study. The volunteers were in a normal fed state throughout the study period. All subjects received instructions on the technique for using the pMDI with spacer or the DPI and peak flow meter before being recruited into the study. 3
Clinical strudy of budesonide DPI and MDI
The study was designed as a randomized, singleblinded parallel study conducted in two centers for a period of 3 months. The eligible patients were randomly assigned to one of the two treatments. The patients in one block were instructed to take the AeronideTM pMDI with spacer 1 puff twice daily and the patients in the other group took the Pulmicort TurbuhalerTM 1 puff twice daily. The AeronideTM pMDI and the Pulmicort TurbuhalerTM were designed to deliver budesonide at 200 µg/inhalation. The lung function tests (FEV1, FVC, PEFR, FEF25–75) as primary outcomes were recorded with a Compact II Spirometer (Vitalograph, Buckingham, UK) at the beginning of the study and after 2 weeks, 1 month, 2 months and 3 months during the study period. The level of difference was set at P < 0.05. Secondary outcomes were assessed from the daily diary card data during each clinical visit. Patients were provided with a peak flow meter and instructed to record the best of three in the morning (6.00–8.00 am) and in the evening (8.00–10.00 pm) peak expiratory flow values. The patients were asked to record asthma symptoms during day and night (4-point scale where 0 = no symptom, 1 = minor symptom, 2 = moderate symptom and 3 = very severe symptom), night awakenings due to asthma symptoms and the number of days that the bronchodilator was needed. No other medications were taken together with budesonide except when the subjects had an asthma attack. Then they were allowed to use their bronchodilator. Safety was investigated by assessing the nature, incidence and severity of any adverse events reported by the patient. Estimation of 24-h urinary cortisol levels was carried out at the beginning and after 3 months of the study period. Clinical laboratory results of complete blood count, electrolytes, metabolic variables, enzymes and vital signs (blood pressure and pulse rate) were recorded at the beginning and the end of the study period. At each study, visit physicians recorded whether patients had oral candidiasis or not.
Statistical analysis Data were managed and analyzed with SPSS software (Version 17, IBM, Armonk, NY, USA). The baseline parameters were compared between the two groups. Data were expressed as means ± standard deviation. The Student t-test was employed for continuous variables with normal distribution. The Mann–Whitney U-tests were used for comparison in the case of a nonnormal distribution. A statistically significant difference was set at P value of less than 0.05 unless otherwise stated.
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Results Uniformity of the delivered dose of budesonide aerosols Tests for the uniformity of the delivered dose were carried out for the Pulmicort TurbuhalerTM and the AeronideTM inhaler according to the procedure specified in the British Pharmacopoeia (12) and the percentage of the labeled amount was 95.4 ± 2.7 (n = 10) and 97.4 ± 7.3 (n = 10) for the Pulmicort TurbuhalerTM and AeronideTM pMDI, respectively. The percentage of the labeled amount indicated the actual amount of active ingredient in comparison with the claim on the label. Both inhalers satisfied the criteria given in the British Pharmacopoeia (12) for the uniformity of the delivered dose (criteria: all values should lie between 75% and 125% of the average value).
In vitro deposition of drugs by the ACI The in vitro deposition of the Pulmicort TurbuhalerTM and AeronideTM pMDI were studied using the ACI. The MMADs for the Pulmicort TurbuhalerTM inhaler and the AeronideTM inhaler were calculated and found to be around 2 µm for both inhalers for which 1–5 µm was considered to be the optimum size for deposition in the deep airways. There was no significant difference between the MMAD values obtained for the Pulmicort TurbuhalerTM (2.3 ± 0.2 µm) and the AeronideTM pMDI (2.1 ± 0.2 µm). The percentage FPFs were 29.3 ± 2.6 and 27.4 ± 2.8 for the Pulmicort TurbuhalerTM and AeronideTM inhaler, respectively. Both inhalers exhibited FPFs that met the standards specified in the British Pharmacopoeia (12) (>25%) and there was no significant difference in the values of FPF between the two inhalers (P > 0.05). This result indicated that the two formulations produced depositions of almost the same amount of the FPF (stage 2 to terminal filter of the ACI). The Particle size distributions of the Pulmicort TurbuhalerTM and the AeronideTM pMDI on each stages of the ACI are shown in Fig. 1. Both formulations delivered budesonide as far as stage 7 so the drug particles are likely to reach the alveoli.
In vivo evaluation of the budesonide inhalers Of the 36 patients enrolled in the study, 33 completed the study and 3 discontinued prematurely: 2 patients (1 in the Pulmicort TurbuhalerTM group and 1 in the AeronideTM pMDI group) discontinued due to side effects and 1 patient in the AeronideTM MDI group
The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
Srichana et al.
Clinical strudy of budesonide DPI and MDI
Figure 1. The particle size distribution of the (□) Aeronide and (■) Pulmicort inhalers on each stage of the Andersen cascade impactor (Mean ± standard deviation, n = 3).
could not complete the study due to personal problems. The enrolment details of the study subjects are summarized in Fig. 2. The mean age of the patients in the Pulmicort TurbuhalerTM group was 49.7 years and 50.2 years in the AeronideTM pMDI group. The male/female ratios were 5/13 for the Pulmicort TurbuhalerTM group and 7/11 for the AeronideTM group. There was no statistically significant difference in the baseline demographic characteristics between the two treatment groups (P > 0.05). The baseline spirometric values (FEV1, FEV1/FVC (%), FEF25–75, PEFR) were also comparable
between the two groups. The patient demographics and baseline characteristics are summarized in Table 1. Intragroup analysis showed significant improvement in FEV1, FEV1/FVC, FEF25–75 values at 1 month, 2 months and 3 months compared with the baseline in the two groups (Fig. 3A–C), but there was no significant improvement in PEFR observed during the study period compared with their baseline values in both groups (Fig. 3D). Table 2 showed that there was no statistically significant difference between the Pulmicort TurbuhalerTM and AeronideTM pMDI groups in terms of the FEV1, FEF25–75 and PEFR values. There were no significant differences in the FEV1/FVC (%)
Table 1. Demographic and baseline characteristics of patients in two treatment groups
Figure 2. Patient flow chart.
The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
Parameters
Pulmicort TurbohalerTM DPI
AeronideTM pMDI
P value
Age (year) Weight (kg) Sex (male/female) FEV1 (L) FEV1/FVC (%) FEF25–75 (L/s) PEFR (L/min)
49.7 ± 12.2 65.7 ± 14.3 5/13 1.8 ± 0.4 67.4 ± 0.5 1.13 ± 0.5 346 ± 108
50.2 ± 12.2 65.9 ± 9.3 7/11 1.9 ± 0.7 67.1 ± 0.6 1.26 ± 0.9 318 ± 132
0.903 0.953 0.725 0.754 0.112 0.596 0.488
DPI, dry powder inhaler; pMDI, pressurized metered dose inhaler; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; FEF25–75, forced expiratory flow 25–75%; PEFR, peak expiratory flow rate.
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Clinical strudy of budesonide DPI and MDI
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Figure 3. (A) Forced expiratory volume in 1 s (FEV1) values at different time points in the two groups; (B) FEV1 /forced vital capacity [FVC (%)] in two groups at different time points; (C) forced expiratory flow 25–75% (FEF25–75) at different time points in the two groups; (D) change in peak expiratory flow rate (PEFR) from the baseline at different points. *Significant difference compared with the baseline value (♦, Pulmicort; ■, Aeronide).
values between the Pulmicort TurbuhalerTM group and the AeronideTM group at the 95% confidence level. The number of symptom-free days during the study period (90 days) was found to be 65.5 ± 25.1 for the Pulmicort TurbuhalerTM group and 58.9 ± 25.4 for the AeronideTM group. There was no significant difference observed in symptom-free days between the two groups (Fig. 4A). The number of days of bronchodilator usage in the Pulmicort TurbuhalerTM and the AeronideTM group were 12.3 ± 22.7 and 25.1 ± 30.1,
respectively, and there was no statistically significant difference between the two groups (Fig. 4B). The baseline urinary cortisol level for the Pulmicort TurbuhalerTM and the AeronideTM group were 36.0 ± 19.4 and 51.2 ± 30.6, and after 3 months, it was reduced to 15.6 ± 14.9 and 32.5 ± 28.6, respectively. There was no statistically significant difference in the urinary cortisol level at the baseline and after 3 months between the two groups. Changes in the laboratory parameters, vital signs and physical examination were
Table 2. Comparison of different spirometric parameters between the two groups Spirometric data of [Pulmicort TurbohalerTM DPI, AeronideTM pMDI] and P value from t-test Spirometric parameters
Baseline
1 Month
2 Month
3 Month
FEV1 (L) FEF25–75 (L/s) FEV1/FVC (%) PEFR (L/min)
[1.80, 1.77] 0.7541 [1.13, 1.14] 0.5956 [69.50, 64.88] 0.8885 [346.2, 309.6] 0.4878
[2.11, 1.96] 0.4323 [1.76, 1.56] 0.5052 [75.33, 68.91] 0.0670 [323.6, 299.8] 0.5856
[2.12, 1.93] 0.3227 [1.60, 1.51] 0.7551 [72.72, 69.89] 0.4436 [329.5, 312.2] 0.6035
[2.04, 1.89] 0.4618 [1.57, 1.40] 0.4923 [74.16, 68.89] 0.0995 [324.0, 309.8] 0.7271
DPI, dry powder inhaler; pMDI, pressurized metered dose inhaler; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; FEF25–75, forced expiratory flow 25–75%; PEFR, peak expiratory flow rate.
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The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
Srichana et al.
Clinical strudy of budesonide DPI and MDI
Figure 4. (A) Symptom-free days during the study period in two groups; (B) Bronchodialator usage in two groups during the study period.
unremarkable and no oral candidiasis was observed in any patient. Two patients (one patient treated with Pulmicort TurbuhalerTM and one with AeronideTM) left the trial because of adverse events that occurred during the study. Both of them complained about having similar adverse events (cough and feeling uncomfortable). One other patient dropped out from the AeronideTM group for a personal reason.
Discussion The in vitro testing of the Pulmicort TurbuhalerTM DPI and the AeronideTM pMDI were conducted at the Drug Delivery System Excellence Centre of the Prince of Songkla University, Hat Yai campus. Both inhalers passed the test for the uniformity of the delivered dose according to criteria given in the British Pharmacopoeia (12). The aerodynamic particle size distribution was assessed by the ACI for both inhalers. There was no statistically significant difference in the in vitro mean FPF values between the two inhalers. However, it was observed that the deposition of budesonide in stages 1–3 from the Pulmicort TurbuhalerTM was significantly higher than that from the AeronideTM. However, the opposite situation occurred in stages 4–6 of the AeronideTM as the deposition of budesonide was significantly higher than that of the PulmicortTM. This may imply that the budesonide in the AeronideTM may go deeper into the small airways and lead to greater systemic absorption and side effects. According to Islam and Gladki (17), stage 3 of the ACI corresponded to particle sizes of ≥2.3 µm to 3.2 µm, which is an The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
optimum size for topical delivery, as particle sizes greater than 5 µm were considered to be deposited in the oropharyngeal region and have the potential for oral absorption and systemic adverse events, whereas particle sizes
ORIGINAL ARTICLE
Clinical equivalence of budesonide dry powder inhaler and pressurized metered dose inhaler Teerapol Srichana1, Siwasak Juthong2, Ekawat Thawithong1, Supot Supaiboonpipat3 and Suchada Soorapan4 1 Nanotec-PSU Excellence Center on Drug Delivery System and Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla, Thailand 2 Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand 3 Department of Medicine, Nopparat Rajathanee Hospital, Bangkok, Thailand 4 Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla, Thailand
Abstract Introduction: A delivery device is the most important factor that determines the local/systemic bioavailability of inhaled corticosteroids. Dry powder inhalers (DPIs) and pressurized metered dose inhalers (pMDIs) are the most commonly used delivery devices for localized drug delivery to the airways. Objective: This study was to compare the clinical equivalence of budesonide delivered by the Pulmicort TurbuhalerTM (DPI) and the AeronideTM inhaler (pMDI). Materials and Methods: The two inhalers were compared for their pharmaceutical equivalence and clinical equivalence. The in vitro test included the uniformity of the delivered dose and determination of the aerodynamic particle size of budesonide. The in vivo test was carried out in 36 patients with mild to moderate asthma. This was a randomized, single-blinded study conducted for a period of 3 months. This included assessment of the spirometric parameters [forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), peak expiratory flow rate (PEFR), forced expiratory flow 25–75% (FEF25–75)], the severity of asthma symptoms, adverse events, frequency of short-acting inhaled bronchodilator usage and measurement of urinary cortisol levels. Results: The aerodynamic particle size was slightly different between the two inhalers (2.3 ± 0.2 µm for Pulmicort TurbuhalerTM and 2.2 ± 0.2 µm for AeronideTM inhaler). Both inhalers passed the uniformity of delivered dose (95.4% and 97.4%) specified in the British Pharmacopoeia. There was no statistically significant difference observed between the two inhalers in terms of the spirometric parameters, symptom-free days, frequency of bronchodilator usage and the level of urinary cortisol. Conclusion: In addition to pharmaceutical equivalence, no clinical difference observed between the two budesonide inhalers. Please cite this paper as: Srichana T, Juthong S, Thawithong E, Supaiboonpipat S and Soorapan S. Clinical equivalence of budesonide dry powder inhaler and pressurized metered dose inhaler. Clin Respir J 2014; ••: ••–••. DOI:10.1111/crj.12188.
Key words Andersen cascade impactor – budesonide – clinical equivalence – dry powder inhaler – metered dose inhaler – spirometric parameters Correspondence Teerapol Srichana, PhD, Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University Hat Yai, Songkhla, 90112, Thailand. Tel: +66 74 288979 Fax: +66 74 288979 email: [email protected] Received: 20 May 2013 Revision requested: 23 June 2014 Accepted: 03 July 2014 DOI:10.1111/crj.12188 Authorship and contributorship T. Srichana was responsible for concept and design of experiment, data analysis and interpretation. S. Juthong and S. Supaiboonpipat were responsible for clinical investigation. E. Thawithong was responsible for data tabulation and statistical analysis. S. Soorapan was responsible for concept and design of experiment. Ethics The study was approved by the ethics committee of the Faculty of Medicine, Prince of Songkla University. All patients gave informed consent. The manuscript has been read and approved by all coauthors. Conflict of interest The authors have stated explicitly that there are no conflicts of interest in connection with this article.
The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
1
Clinical strudy of budesonide DPI and MDI
Introduction Asthma results from a chronic inflammatory disorder of the airways with variable and often reversible airflow obstruction and is now recognized as being a major worldwide health problem with 300 million people affected (1). It has been well established that clinical manifestations of asthma can be controlled with appropriate treatment (2). The extensive inflammation of the airway has warranted the use of glucocorticoids for asthma therapy. Due to various adverse effects associated with the long-term administration of systemic glucocorticoids, inhaled corticosteroids have become the mainstay of treatment for all patients with persistent asthma owing to their profile of proven safety and efficacy (3–6). The search for a corticosteroid with desirable physical and pharmacokinetic properties for administration by inhalation resulted in the development of budesonide, a synthetic glucocorticosteroid with a well-documented efficacy in the management of asthma (2). The unique structural features like the lipophilic acetal groups on the 16α and 17α positions enhance glucocorticoid receptor binding and prolong airway retention (6). Furthermore, the absence of a halogen atom on the corticosteroid nucleus contributes to the optimal topical to systemic activity ratio of budesonide. The distinctive physical and pharmacokinetic properties of budesonide results in a favorable efficacy and tolerability profile, and because of its high therapeutic index, this makes it an ideal inhaled corticosteroid (ICS) for the long-term treatment of asthma for all categories of patients (6, 7). The delivery device is the most important factor that determines the local bioavailability of the ICS (8). Consequently, it is imperative to measure the clinical equivalence of the ICS from different delivery devices. The pressurized metered dose inhaler (pMDI) is a safe, convenient, inexpensive and reliable delivery device for providing localized drug delivery to the airways and is used by about 80% of asthmatics worldwide (9, 10). Conversely, these devices are associated with a number of problems like under dosing owing to poor hand breath coordination and airway irritation from the lubricants or propellants used and their propensity for a high oral deposition (11). A spacer device attached to a metered dose inhaler will reduce oropharyngeal deposition and increase lung deposition. Breath-actuated dry powder inhalers (DPI) were developed to overcome the above drawbacks, but the deposition efficiency of DPI was dependent on the patient’s inspiratory airflow and the drug was wasted if patients inadvertently exhaled into the DPI. Hence the availability of data on
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the clinical equivalence of these two devices will certainly give clinicians greater freedom to select the most cost-effective therapy that suits the needs and preferences of individual patients and clinicians. The purpose of this study was to compare the clinical equivalence of budesonide delivered from the Pulmicort TurbuhalerTM DPI and the AeronideTM pMDI. The in vitro analysis included tests for the uniformity of the delivered dose and the aerodynamic particle size distribution. A randomized, singleblinded parallel study design was employed for the in vivo evaluation of the budesonide aerosols. Thirty-six subjects with asthma in the study received either DPI or pMDI for a study period of 3 months. The lung function tests [forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), peak expiratory flow rate (PEFR) and forced expiratory flow 25–75% (FEF25–75)] were monitored before and after drug administration at 2 weeks, 1 month, 2 months and 3 months of the study period. The vital signs, differential hematology, electrolytes, metabolic variables and 24-h urinary cortisol levels were recorded at the beginning and the end of the study period. Any adverse events and the number of bronchodilator needed were also assessed during the study period.
Materials and methods Materials The devices used in the study include the AeronideTM pMDI (lot no 0180), which was kindly donated by AeroCare Co., Ltd. (Bangkok, Thailand) and the Pulmicort TurbuhalerTM DPI (lot no NB 1575), which was obtained from AstraZeneca (Stockholm, Sweden). All chemicals (analytical grade) used in the study were purchased from local suppliers in Thailand.
Analysis of budesonide inhaler formulations Budesonide was analyzed by high performance liquid chromatography (HPLC). The HPLC system consisted of a Spectra System SCM 1000 and Spectra System Pump P2000 plus an Auto-sampler. Spectra System AS 3000 equipped with a Spectra System SN4000 and a Spectra System UV 1000 detector (Thermo Fisher Scientific, Inc., Waltham, MA, USA). A BDS Hypersil C18 column (150 × 4.6 mm id, 5 µm) (Thermo Scientific, Leicester, UK) was used in this study. The mobile phase used in the analysis consisted of 25-mM phosphate buffer pH 3.2 and acetonitrile in the ratio of 65:35 (v/v) at a flow rate of 1.5 mL/min at ambient temperature. The injection volume was 50 µL and the ultraviolet detector was operated at 240 nm.
The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
Srichana et al.
Clinical strudy of budesonide DPI and MDI
Uniformity of delivered dose
In vivo evaluation of budesonide aerosols
The uniformity of the delivered dose from the MDI was assessed by using the apparatus specified in the British Pharmacopoeia (12). The apparatus consisted of a filter support base with an open mesh filter support, a collection tube that was clamped to the filter support base and a mouthpiece adapter to ensure an airtight seal between the collection tube and the mouthpiece. The vacuum connector was connected to a system comprising a vacuum pump and a flow regulator. The pump was adjusted to draw air through the entire assembly at 28.3 L/min. The pressurized inhaler was shaken for 5 s prior to dose collection and the first dose was discharged to waste. Three deliveries at the beginning (2nd–4th), four deliveries at the middle (100th–103rd) and three deliveries at the end (198th–200th) were quantitatively collected and analyzed for the amount of budesonide. The above procedure was slightly modified to accommodate the DPI. The apparatus was modified by connecting a differential pressure meter to the sample collection tube that was used to measure the pressure drop across the inhaler. The pressure drop was set to 4.0 kPa by adjusting the flow control valve placed between the sample collection apparatus and the vacuum pump.
The study was approved by the Faculty of Medicine Ethics Committee, Prince of Songkla University, Thailand (EC 52-274-14-13). All patients provided written informed consent, and the study was conducted in accordance with the principles of good clinical practice. A total of 36 patients with mild to moderate asthma were randomized to use budesonide via the Pulmicort TurbuhalerTM or AeronideTM pMDI with a spacer. The sample size was calculated according to Equations 1 and 2 (14).
Assessment of aerodynamic particle size distribution The measurement of the aerodynamic particle size distribution was performed on an eight-stage Andersen cascade impactor (ACI) (Copley Scientific, Atlanta, GA, USA) stated in the British Pharmacopoeia as Apparatus D. The inhaler was shaken for 5 s and then actuated to waste before it was introduced into the impactor. The inhaler was connected to the metal inlet of the ACI using an adaptor. Air was drawn through the apparatus and the flow rate was adjusted to a desired value (28.3 L/min and 60 L/min for the MDI and the DPI, respectively). The MDI was then discharged into the apparatus for two consecutive doses and shaken for 5 s between each delivery. For the DPI, the drug was drawn into the ACI after activation. The metal inlet and stages were washed with the mobile phase. Each fraction was adjusted to a specified volume and analyzed for the amount of the drug by the HPLC. The mass median aerodynamic diameter (MMAD) and the fine particle fraction (FPF) were calculated according to the method described by Srichana et al. (13).
The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
σ=
(n1 − 1)S12 + (n 2 − 1)S22 = 0.58 n1 + n 2 − 2
(1)
2(z1−α + z β )2 σ 2 = 18 (x1 − x 2 )2
(2)
N=
Where the power of analysis is 80%, α = 0.01, Z1α = 1.28, Zβ = 0.84, the mean difference of PEFR is 0.41. From Equation 2, the number of subjects is 18 and it is enough to detect differences. Similar studies have been carried out with a similar number of patients (15, 16). The ‘null hypothesis (H0)’, shows that there is no difference between the two inhaler products and for the ‘alternative hypothesis (HA), there is a significant difference between the two products. Patients (18 men and 18 women) with mild to moderate persistent asthma (1) aged 18–60 years were selected for the study. Other inclusion criteria were an improvement in their FEV1 of at least 12% following salbutamol 100 µg for 2 puffs within the past 6 months or at the baseline visit. The patients were excluded if they met any of the following criteria: the presence or recent history of any chronic diseases of liver, kidney, heart, any type of carcinoma or psychosis, history of smoking within 3 months or more than 10 pack/year, allergic to budesonide or any excipients in the formulation, history of a severe asthma exacerbation/ hospitalization, receiving oral or parenteral corticosteroids in the previous 6 weeks, use of ICS in a dose greater than 400-µg budesonide, 500-µg beclomethasone dipropionate or 250-µg fluticasone during the 4 weeks preceding the study period and any female patients who were pregnant or lactating. Patients were not included if they had taken sodium cromolyn, ketotifen, leukotriene antagonists and an oral β2 agonist or theophylline or long-acting β2 agonist 4 weeks preceding the study. The volunteers were in a normal fed state throughout the study period. All subjects received instructions on the technique for using the pMDI with spacer or the DPI and peak flow meter before being recruited into the study. 3
Clinical strudy of budesonide DPI and MDI
The study was designed as a randomized, singleblinded parallel study conducted in two centers for a period of 3 months. The eligible patients were randomly assigned to one of the two treatments. The patients in one block were instructed to take the AeronideTM pMDI with spacer 1 puff twice daily and the patients in the other group took the Pulmicort TurbuhalerTM 1 puff twice daily. The AeronideTM pMDI and the Pulmicort TurbuhalerTM were designed to deliver budesonide at 200 µg/inhalation. The lung function tests (FEV1, FVC, PEFR, FEF25–75) as primary outcomes were recorded with a Compact II Spirometer (Vitalograph, Buckingham, UK) at the beginning of the study and after 2 weeks, 1 month, 2 months and 3 months during the study period. The level of difference was set at P < 0.05. Secondary outcomes were assessed from the daily diary card data during each clinical visit. Patients were provided with a peak flow meter and instructed to record the best of three in the morning (6.00–8.00 am) and in the evening (8.00–10.00 pm) peak expiratory flow values. The patients were asked to record asthma symptoms during day and night (4-point scale where 0 = no symptom, 1 = minor symptom, 2 = moderate symptom and 3 = very severe symptom), night awakenings due to asthma symptoms and the number of days that the bronchodilator was needed. No other medications were taken together with budesonide except when the subjects had an asthma attack. Then they were allowed to use their bronchodilator. Safety was investigated by assessing the nature, incidence and severity of any adverse events reported by the patient. Estimation of 24-h urinary cortisol levels was carried out at the beginning and after 3 months of the study period. Clinical laboratory results of complete blood count, electrolytes, metabolic variables, enzymes and vital signs (blood pressure and pulse rate) were recorded at the beginning and the end of the study period. At each study, visit physicians recorded whether patients had oral candidiasis or not.
Statistical analysis Data were managed and analyzed with SPSS software (Version 17, IBM, Armonk, NY, USA). The baseline parameters were compared between the two groups. Data were expressed as means ± standard deviation. The Student t-test was employed for continuous variables with normal distribution. The Mann–Whitney U-tests were used for comparison in the case of a nonnormal distribution. A statistically significant difference was set at P value of less than 0.05 unless otherwise stated.
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Results Uniformity of the delivered dose of budesonide aerosols Tests for the uniformity of the delivered dose were carried out for the Pulmicort TurbuhalerTM and the AeronideTM inhaler according to the procedure specified in the British Pharmacopoeia (12) and the percentage of the labeled amount was 95.4 ± 2.7 (n = 10) and 97.4 ± 7.3 (n = 10) for the Pulmicort TurbuhalerTM and AeronideTM pMDI, respectively. The percentage of the labeled amount indicated the actual amount of active ingredient in comparison with the claim on the label. Both inhalers satisfied the criteria given in the British Pharmacopoeia (12) for the uniformity of the delivered dose (criteria: all values should lie between 75% and 125% of the average value).
In vitro deposition of drugs by the ACI The in vitro deposition of the Pulmicort TurbuhalerTM and AeronideTM pMDI were studied using the ACI. The MMADs for the Pulmicort TurbuhalerTM inhaler and the AeronideTM inhaler were calculated and found to be around 2 µm for both inhalers for which 1–5 µm was considered to be the optimum size for deposition in the deep airways. There was no significant difference between the MMAD values obtained for the Pulmicort TurbuhalerTM (2.3 ± 0.2 µm) and the AeronideTM pMDI (2.1 ± 0.2 µm). The percentage FPFs were 29.3 ± 2.6 and 27.4 ± 2.8 for the Pulmicort TurbuhalerTM and AeronideTM inhaler, respectively. Both inhalers exhibited FPFs that met the standards specified in the British Pharmacopoeia (12) (>25%) and there was no significant difference in the values of FPF between the two inhalers (P > 0.05). This result indicated that the two formulations produced depositions of almost the same amount of the FPF (stage 2 to terminal filter of the ACI). The Particle size distributions of the Pulmicort TurbuhalerTM and the AeronideTM pMDI on each stages of the ACI are shown in Fig. 1. Both formulations delivered budesonide as far as stage 7 so the drug particles are likely to reach the alveoli.
In vivo evaluation of the budesonide inhalers Of the 36 patients enrolled in the study, 33 completed the study and 3 discontinued prematurely: 2 patients (1 in the Pulmicort TurbuhalerTM group and 1 in the AeronideTM pMDI group) discontinued due to side effects and 1 patient in the AeronideTM MDI group
The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
Srichana et al.
Clinical strudy of budesonide DPI and MDI
Figure 1. The particle size distribution of the (□) Aeronide and (■) Pulmicort inhalers on each stage of the Andersen cascade impactor (Mean ± standard deviation, n = 3).
could not complete the study due to personal problems. The enrolment details of the study subjects are summarized in Fig. 2. The mean age of the patients in the Pulmicort TurbuhalerTM group was 49.7 years and 50.2 years in the AeronideTM pMDI group. The male/female ratios were 5/13 for the Pulmicort TurbuhalerTM group and 7/11 for the AeronideTM group. There was no statistically significant difference in the baseline demographic characteristics between the two treatment groups (P > 0.05). The baseline spirometric values (FEV1, FEV1/FVC (%), FEF25–75, PEFR) were also comparable
between the two groups. The patient demographics and baseline characteristics are summarized in Table 1. Intragroup analysis showed significant improvement in FEV1, FEV1/FVC, FEF25–75 values at 1 month, 2 months and 3 months compared with the baseline in the two groups (Fig. 3A–C), but there was no significant improvement in PEFR observed during the study period compared with their baseline values in both groups (Fig. 3D). Table 2 showed that there was no statistically significant difference between the Pulmicort TurbuhalerTM and AeronideTM pMDI groups in terms of the FEV1, FEF25–75 and PEFR values. There were no significant differences in the FEV1/FVC (%)
Table 1. Demographic and baseline characteristics of patients in two treatment groups
Figure 2. Patient flow chart.
The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
Parameters
Pulmicort TurbohalerTM DPI
AeronideTM pMDI
P value
Age (year) Weight (kg) Sex (male/female) FEV1 (L) FEV1/FVC (%) FEF25–75 (L/s) PEFR (L/min)
49.7 ± 12.2 65.7 ± 14.3 5/13 1.8 ± 0.4 67.4 ± 0.5 1.13 ± 0.5 346 ± 108
50.2 ± 12.2 65.9 ± 9.3 7/11 1.9 ± 0.7 67.1 ± 0.6 1.26 ± 0.9 318 ± 132
0.903 0.953 0.725 0.754 0.112 0.596 0.488
DPI, dry powder inhaler; pMDI, pressurized metered dose inhaler; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; FEF25–75, forced expiratory flow 25–75%; PEFR, peak expiratory flow rate.
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Clinical strudy of budesonide DPI and MDI
Srichana et al.
Figure 3. (A) Forced expiratory volume in 1 s (FEV1) values at different time points in the two groups; (B) FEV1 /forced vital capacity [FVC (%)] in two groups at different time points; (C) forced expiratory flow 25–75% (FEF25–75) at different time points in the two groups; (D) change in peak expiratory flow rate (PEFR) from the baseline at different points. *Significant difference compared with the baseline value (♦, Pulmicort; ■, Aeronide).
values between the Pulmicort TurbuhalerTM group and the AeronideTM group at the 95% confidence level. The number of symptom-free days during the study period (90 days) was found to be 65.5 ± 25.1 for the Pulmicort TurbuhalerTM group and 58.9 ± 25.4 for the AeronideTM group. There was no significant difference observed in symptom-free days between the two groups (Fig. 4A). The number of days of bronchodilator usage in the Pulmicort TurbuhalerTM and the AeronideTM group were 12.3 ± 22.7 and 25.1 ± 30.1,
respectively, and there was no statistically significant difference between the two groups (Fig. 4B). The baseline urinary cortisol level for the Pulmicort TurbuhalerTM and the AeronideTM group were 36.0 ± 19.4 and 51.2 ± 30.6, and after 3 months, it was reduced to 15.6 ± 14.9 and 32.5 ± 28.6, respectively. There was no statistically significant difference in the urinary cortisol level at the baseline and after 3 months between the two groups. Changes in the laboratory parameters, vital signs and physical examination were
Table 2. Comparison of different spirometric parameters between the two groups Spirometric data of [Pulmicort TurbohalerTM DPI, AeronideTM pMDI] and P value from t-test Spirometric parameters
Baseline
1 Month
2 Month
3 Month
FEV1 (L) FEF25–75 (L/s) FEV1/FVC (%) PEFR (L/min)
[1.80, 1.77] 0.7541 [1.13, 1.14] 0.5956 [69.50, 64.88] 0.8885 [346.2, 309.6] 0.4878
[2.11, 1.96] 0.4323 [1.76, 1.56] 0.5052 [75.33, 68.91] 0.0670 [323.6, 299.8] 0.5856
[2.12, 1.93] 0.3227 [1.60, 1.51] 0.7551 [72.72, 69.89] 0.4436 [329.5, 312.2] 0.6035
[2.04, 1.89] 0.4618 [1.57, 1.40] 0.4923 [74.16, 68.89] 0.0995 [324.0, 309.8] 0.7271
DPI, dry powder inhaler; pMDI, pressurized metered dose inhaler; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; FEF25–75, forced expiratory flow 25–75%; PEFR, peak expiratory flow rate.
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The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
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Clinical strudy of budesonide DPI and MDI
Figure 4. (A) Symptom-free days during the study period in two groups; (B) Bronchodialator usage in two groups during the study period.
unremarkable and no oral candidiasis was observed in any patient. Two patients (one patient treated with Pulmicort TurbuhalerTM and one with AeronideTM) left the trial because of adverse events that occurred during the study. Both of them complained about having similar adverse events (cough and feeling uncomfortable). One other patient dropped out from the AeronideTM group for a personal reason.
Discussion The in vitro testing of the Pulmicort TurbuhalerTM DPI and the AeronideTM pMDI were conducted at the Drug Delivery System Excellence Centre of the Prince of Songkla University, Hat Yai campus. Both inhalers passed the test for the uniformity of the delivered dose according to criteria given in the British Pharmacopoeia (12). The aerodynamic particle size distribution was assessed by the ACI for both inhalers. There was no statistically significant difference in the in vitro mean FPF values between the two inhalers. However, it was observed that the deposition of budesonide in stages 1–3 from the Pulmicort TurbuhalerTM was significantly higher than that from the AeronideTM. However, the opposite situation occurred in stages 4–6 of the AeronideTM as the deposition of budesonide was significantly higher than that of the PulmicortTM. This may imply that the budesonide in the AeronideTM may go deeper into the small airways and lead to greater systemic absorption and side effects. According to Islam and Gladki (17), stage 3 of the ACI corresponded to particle sizes of ≥2.3 µm to 3.2 µm, which is an The Clinical Respiratory Journal (2014) • ISSN 1752-6981 © 2014 John Wiley & Sons Ltd
optimum size for topical delivery, as particle sizes greater than 5 µm were considered to be deposited in the oropharyngeal region and have the potential for oral absorption and systemic adverse events, whereas particle sizes
