University of Groningen. Transdermal delivery of anticholinergic bronchodilators Bosman, Ingrid Jolanda

Transcription

1 University of Groningen Transdermal delivery of anticholinergic bronchodilators Bosman, Ingrid Jolanda IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 1996 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Bosman, I. J. (1996). Transdermal delivery of anticholinergic bronchodilators: methodological and clinical aspects Groningen: s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 Chapter 8 Effects of transdermal scopolamine on pulmonary function and symptoms in patients with (partially) reversible airways obstruction 8.0. Summary In a double-blind cross-over study, transdermal scopolamine (Scopoderm TTS) was compared with transdermal placebo in ten patients with reversible airways obstruction ( FEV 1 9 %pred). We found neither significant effects of transdermal scopolamine on pulmonary function nor on symptoms. However, there was a trend in reduction of bronchodilators and symptoms during daytime in the scopolamine phase. During the study, blood and urine samples were taken from the patients and analysed for scopolamine levels to correlate these with the effects and/or side effects. In 24-hours urine, we measured 6.3 (± 2.2) µg free and 83.4 (± 27.3) µg total scopolamine. In plasma the concentrations of free and total scopolamine were 43.6 (± 15.0) pg/ml and (± 56.9) pg/ml, respectively. In the placebo phase no scopolamine was detected in either urine or plasma. We found no correlation between the concentrations of free scopolamine in plasma and the changes in FEV 1 or PEF values. However, the measurement of total scopolamine in urine showed that the drug is adequately taken up from the patch into the systemic circulation. Because no therapeutic effects were seen, further studies with a higher dose of transdermal scopolamine are necessary to find out if higher levels of scopolamine will cause improvements on pulmonary function and symptoms.

3 110 Chapter Introduction Bronchodilators, like ß 2 -agonists and anticholinergics, are used world-wide to prevent or diminish airways obstruction in patients with obstructive airways diseases (asthma and chronic obstructive pulmonary disease (COPD)). Both inhaled ß 2 - agonists (salbutamol, terbutaline) and inhaled anticholinergics (ipratropium bromide) are available in short acting form [1-5]. Long-acting ß 2 -agonists are now available for clinical practice as well [6-9]. In the oral form, side effects of ß 2 -agonists are larger than by inhalation [10]. Long-acting ß 2 -agonists have been proven to be effective, to reduce symptoms and improve patient compliance by their convenient twice daily dosing [2, 4, 11]. Long-acting anticholinergics are not yet available, though Ba 679 Br with 10 to 15 hours of action is under development [12]. A new approach to drug administration is the transdermal route, aiming to achieve systemic delivery [13-16]. Application of patches to the skin enables a constant influx of drugs over a prolonged period of time (up to a number of days), thus producing sustained, constant, and controlled drug plasma concentrations. Moreover, bioavailability may be enhanced and more constant for drugs that undergo first-pass metabolism. This may be accompanied by a reduction in dose frequency and more convenience for the patients thereby increasing patient compliance [17]. Several transdermal drug delivery systems of ß 2 -agonists have been developed and evaluated by in vitro permeation and/or pharmacokinetic studies in animals or humans [18-21]. Concomitant evaluation of the bronchodilating effects after transdermal delivery has been done in only two cases. Transdermal terbutaline was administered to ten patients with chronic, reversible airways obstruction; a constant and therapeutically effective terbutaline concentration could be maintained for 24 hours [21]. Also, transdermal broxaterol exerted a bronchodilating effect and had a protective effect on bronchial constriction induced by ultrasonically nebulized distilled water [19]. Transdermal scopolamine (Scopoderm TTS), a tertiary anticholinergic, is marketed for the prevention of nausea and vomiting associated with motion sickness. Like other anticholinergics, it can cause relaxation of the smooth muscle of the bronchi and bronchioles [22, 23]. Demeter and Cordasco [24] showed that the transdermal delivery of scopolamine appeared to be effective in a small group of patients having diverse types of lung diseases, but this study was not placebo-controlled. One unwanted side effect of scopolamine in patients with airways obstruction, is depression of the central nervous system. However, wide-spread use in the population has shown side effects to be small and well acceptable after transdermal application [22]. Therefore, we used this marketed product to test if transdermal administration of an anticholinergic drug provides adequate drug plasma levels and prolonged therapeutic efficacy, which may be especially useful in the prevention of nocturnal symptoms. The aim of the present study is to determine the therapeutic effects of transdermal scopolamine as compared to transdermal placebo treatment in patients with reversible airways obstruction. At the same time, blood and urine samples were

4 Effects of transdermal scopolamine on pulmonary function 111 taken and analysed for scopolamine levels (free and total), to correlate these with the effects and/or side effects Patients and Methods Patients We selected ten patients of either sex, aged between 25 and 60 years, with (partially) reversible airways obstruction. The absolute lower limit of the forced expiratory volume in one second (FEV 1 ) was 1.00 l. Reversibility of airways obstruction had to be at least 9% of the patients predicted FEV 1 after 80 µg ipratropium bromide (Atrovent ) ( FEV 1 9 %pred). Exclusion criteria related to the study medication were pregnancy, hypersensitivity to scopolamine, use of anticholinergics or agents having effects on the central nervous system, open angle glaucoma, pyloric obstruction, obstruction of the neck of the urinary bladder, obstruction of the intestines, severe renal, hepatic or cardiovascular disease, epilepsy, or (a history of) psychiatric diseases. Other exclusion criteria were the use of oral corticosteroids, beta-blocking agents, anticoagulants, or nitrates, continuous use of antibiotics, a history of angina pectoris, previous myocardial infarct, previous stroke, diastolic blood pressure persistently > 100 mm Hg, occupational asthma, other serious lung diseases requiring continuous medical care (e.g. tuberculosis, sarcoidosis, lung cancer), or ongoing hyposensitization program. The study was approved by the Hospital Medical Ethics Committee, and all subjects gave their written informed consent to participate Medication The transdermal therapeutic system (Scopoderm TTS, size 2.5 cm 2 ) was used, which contains a drug reservoir of 1.5 mg of scopolamine and is programmed to deliver 0.5 mg of scopolamine over a 3-day period. A priming dose (140 µg) is incorporated in the adhesive layer (to saturate certain binding sites within the skin and to accelerate achievement of steady state blood levels) and the remainder is released at a constant rate of approximately 5 µg/hour [22]. The placebo patch contained no scopolamine and was identical with the scopolamine patch. The patches (placebo or Scopoderm TTS) were kindly provided by Ciba Geigy, Arnhem, The Netherlands, and applied on the hairless skin behind the ear for 72 hours. Figure 8.1. Study design of the double-blind, placebo-controlled, cross-over study.

5 112 Chapter Study design This double-blind, placebo-controlled, cross-over study was divided into two consecutive phases of six days; each phase consisted of three patch days and a three days wash-out period (Figure 8.1). During the study, patients discontinued the use of ipratropium bromide. The use of a ß 2 -agonist by inhalation was allowed, only if necessary. Patients kept a diary card, recording cough, expectoration, daytime and nighttime symptoms (dyspnea and/or wheeze), on a four-point severity scale (0 = no symptoms and 3 = severe symptoms). The number of ß 2 -agonist inhalations during the day and night, and the highest of three measurements of morning and evening peak expiratory flow (PEF) using a Wright mini peak flow meter (Clement Clarke International, Ltd., London, UK) were noted as well. Urine was collected every second patch day during 24 hours. Every third patch day at 9.00 a.m., blood was collected and spirometry measurements were performed before and 45 min after 80 µg ipratropium bromide Spirometry measurements Spirometry measurements were performed using a calibrated water-sealed

6 Effects of transdermal scopolamine on pulmonary function 113 spirometer according to standardized guidelines [25]. The forced expiratory volume in one second (FEV 1 ) and the inspiratory vital capacity (VC) were measured until three suitable recordings were obtained. The highest values were used for analysis. FEV 1 and VC were measured between 8.00 and hours and expressed as a percentage of the predicted value (FEV 1 %pred and VC %pred, respectively). ß 2 -agonists were withheld at least 8 hours before the test. Reversibility of airways obstruction was assessed by measuring FEV 1 before and 45 minutes after inhalation of 80 µg of ipratropium bromide, and expressed as a percentage of the predicted value ( FEV 1 %pred) Scopolamine analysis Urine and plasma samples were analysed to determine the levels of free (unconjugated) and total (free plus conjugated) scopolamine. The procedure included a semi-automated solid-phase extraction followed by the analysis of scopolamine using radioreceptor assays. For urine samples of 1 ml, the limit of detection (LOD) of the assay was 550 pg/ml and the limit of quantitation (LOQ) was 610 pg/ml. For plasma samples of 1.5 ml, the LOD was 16 pg/ml and the LOQ was 38 pg/ml [26] Data analysis All variables were checked for normal distribution with Kolmogorov-Smirnov tests (p < 0.05). Differences in characteristics between patients who received scopolamine in the first phase (group 1) and patients who received scopolamine in the second phase (group 2) were analysed using Student t-tests for continuous variables or Chi-squared tests for dichotomous variables. Data of day 2 and 3 of the patch days were used to calculate mean morning and mean evening PEF, as well as mean diurnal PEF variation: ( morning PEF - evening PEF / mean PEF) * 100%. Diary cards were analysed using Wilcoxon signed rank sum tests. For comparison of the treatments, total scores of day 2 and 3 of the patch days were used for each symptom. Before comparing the treatment effects of transdermal placebo or scopolamine on pulmonary function parameters, a period effect was tested by a two sample Student t-test to compare the differences between the periods in the two groups of patients. To test a treatment-period interaction, a two sample Student t-test was used comparing patient s average response to the two treatments. No statistically significant period effect and/or treatment-period interaction were found (level of significance p < 0.05). Therefore, the effects of the two treatments were simply compared using paired Student t-tests [27]. All data were analysed using the statistical package SPSS/PC+ (Norusis MJ, SPSS Inc., 1990, Chicago).

7 114 Chapter 8 Table 8.1. Patient characteristics. Group 1 Group 2 No. Male, no. Age (years), mean (sd) Use of inhaled steroids, no (5) (11) Smoking habits Current/ex/never, no. 1/3/0 3/2/1 Pulmonary function, mean (sd) FEV 1 (%pred), pre ipr.br. *1 FEV 1 (%pred), post ipr.br. FEV 1 (%pred) (16.0) (17.7) (2.7) (13.4) (11.0) (6.1) FEV 1 /VC (%), pre ipr.br. FEV 1 /VC (%), post ipr.br (12.8) (11.0) (11.9) (13.6) *1 ipr.br. = ipratropium bromide Results Patients Ten patients aged years, fulfilled the entry criteria, no one had an exacerbation on to 6 weeks prior to the study. Four patients received the scopolamine patch in the first phase (group 1), the other six patients in the second phase (group 2). Baseline patient characteristics are presented in Table 8.1. There were no differences between the groups in age, sex and smoking habits. Although not statistically significant, the patients of group 1 had lower values of FEV 1 (%pred) before and 45 minutes after inhalation of 80 µg of ipratropium bromide. The difference in FEV 1 (%pred) between the two groups was 17.0% (p = 0.10) and 18.3% (p = 0.08), pre and post ipratropium bromide, respectively Scopolamine analysis Urine collected over 24 hours during the second patch day, contained 6.3 µg (range µg) of free scopolamine and 83.4 µg (range µg) of total scopolamine. In plasma, collected at 9.00 a.m. on the third patch day, the concentrations of free and total scopolamine were 43.6 pg/ml (range pg/ml) and pg/ml (range pg/ml), respectively. In the placebo phase no scopolamine was detected in either urine or plasma.

8 Effects of transdermal scopolamine on pulmonary function 115 Table 8.2. Effects of scopolamine and placebo on pulmonary function parameters. Scopolamine Placebo Difference p-value Pulmonary function, mean (sd) FEV 1 (%pred), pre ipr.br. *1 FEV 1 (%pred), post ipr.br. FEV 1 (%pred) (19.1) (19.0) (6.3) (18.7) (19.2) (5.8) (6.2) (5.3) (7.2) FEV 1 /VC (%), pre ipr.br. FEV 1 /VC (%), post ipr.br (15.7) (16.1) (14.0) (15.1) (5.1) (4.1) Mean PEF (l/min) morning evening variation (89) (86) (7) (92) (81) (10) (44) (29) (11) *1 ipr.br. = ipratropium bromide Effects of transdermal scopolamine treatment There were no significant differences between the placebo and scopolamine phase, in spirometry, PEF parameters, symptom scores and the use of extra bronchodilators during the night (Table 8.2). However, a trend was found in the daytime use of extra bronchodilators and the symptoms. Four patients used less bronchodilators (p = 0.07) and three had less symptoms at daytime (p = 0.11) in the scopolamine phase compared to the placebo phase, while the other patients (six and seven, respectively) showed no differences. We found no correlation between the plasma concentrations of free scopolamine and changes in FEV 1 or PEF (regression statistics, p > 0.05) Discussion and Conclusions This cross-over study assessed the therapeutic effects of transdermal scopolamine in patients with reversible airways obstruction. We found no significant effects of transdermal scopolamine on pulmonary function and symptoms (cough, expectoration, daytime and nighttime symptoms). Nevertheless, it is important to note that during daytime the decrease in use of bronchodilators and the decrease in symptoms was larger when using the scopolamine patch than when using the placebo patch. The lack of clinical effects might have been due to inadequate uptake of scopolamine from the patch. However, this did not seem to be the case since the measurement of total scopolamine in urine shows that the drug is adequately taken up. It has been shown before that during steady state, which is reached within 24

9 116 Chapter 8 hours, about 120 µg of scopolamine is delivered to the patient in one day [22]. We found that about 5% of the dose is excreted unchanged, whereas 65% of the dose is excreted as glucuronide and sulphate conjugates, in 24 hours urine. These results correspond with the programmed rate of drug release (5 µg/hour) and the described biotransformation which results in less than 10% of the administered dose excreted unchanged [22]. The measured plasma concentrations of free and total scopolamine were 43.6 pg/ml and pg/ml, respectively. Up till now, plasma concentrations of scopolamine have rarely been reported because a sensitive method for the measurement of such low levels was not available [22]. This means that correlations between plasma concentrations and effects, in particular effects on pulmonary function, are not known. However, the dose given during this study was probably too low to produce therapeutically effective plasma levels. Higher dosing may be possible because all patients were able to complete the study and no severe side effects were reported. In three patients dry mouth was reported during the scopolamine phase and one patient complained about skin irritation in both the scopolamine and placebo phase. This is a first study showing that transdermal application of an anticholinergic drug is feasible. It suggests that a higher dose of scopolamine may provide a useful and easy alternative in the treatment of patients with reversible airways obstruction. Further studies have to assess whether a higher dose can be applied without side effects Acknowledgement Ciba Geigy is thanked for financial support References [1] Shenfield GM, Brodgen RN, Ward A. Pharmacology of bronchodilators. In: Bronchodilator therapy, Auckland, Adis Press, 1984, [2] Hetzel MR. Bronchodilators in the prevention of nocturnal asthma. In: Bronchodilator therapy, Auckland, Adis Press, 1984, [3] Gern JE, Lemanske RF. Beta-adrenergic agonist therapy. Immunology and allergy clinics of North America 13 (4); , [4] Ferguson GT, Cherniack RM. Management of chronic obstructive pulmonary disease. N. Eng. J. Med. 328; , [5] Pakes GE, Brodgen RN, Heel RC, Speight TM, Avery GS. Ipratropium bromide: A review of its pharmacological properties and therapeutic efficacy in asthma and chronic bronchitis. Drugs 20; , [6] Ball DI, Brittain RT, Coleman RA, Denyer LH, Jack D, Johnson M, Lunts LHC, Nials AT, Sheldrick KE, Skidmore IF. Salmeterol, a novel, long-acting beta2-adrenoreceptor agonist: Characterization of pharmacological activity in vitro and in vivo. Br. J. Pharmacol. 104; , [7] Butchers PR, Vardey CJ, Johnson M. Salmeterol: A potent and long-acting inhibitor of inflammatory mediator release from human lung. Br. J. Pharmacol. 104; , 1991.

10 Effects of transdermal scopolamine on pulmonary function 117 [8] Breslin ABX. New developments in anti-asthma drugs. Med. J. Australia 158; , [9] Ullman A, Svedmyr N. Salmeterol, a new long-acting inhaled beta2-adrenoreceptor agonist: Comparison with salbutamol in adult asthmatic patients. Thorax 43; , [10] Barnes PJ. A new approach to the treatment of asthma. N. Eng. J. Med. 321 (22); , [11] Storms WW. Patient compliance with bronchodilator therapy in asthma. Current Therapeutic Research - clinical and experimental 55 (9); , [12] Maesen FPV, Smeets JJ, Costongs MAL, Wald FDM, Cornelissen PJG. Ba 679 Br, a new long-acting antimuscarinic bronchodilator: a pilot dose-escalation study in COPD. Eur. Respir. J. 6; , [13] Vlasses PH, Ribeiro LG, Rotmensch HH, Bondi JV, Loper AE, Hichens M, Dunlay MC, Ferguson RK. Initial evaluation of transdermal timolol: serum concentrations and betablockade. J. Cardiovasc. Pharmacol. 7; , [14] Drewe J, Meier R, Timonen U, Thumshirn M, Munzer J, Kissel T, Gyr K. Pharmacokinetics and pharmacodynamics of a new transdermal delivery system for bopindolol. Br. J. Clin. Pharmac. 31; , [15] Westerling D, Höglund P, Lundin S, Svedman P. Transdermal administration of morphine to healthy patients. Br. J. Clin. Pharmac. 37; , [16] Levy A, Brandeis R, Treves TA, Meshulam Y, Mawassi F, Feiler D, Wengier A, Glikfeld P, Grunwald J, Dachir S, Rabey JM, Levy D, Korczyn AD. Transdermal physostigmine in the treatment of Alzheimer s disease. Alzheimer Disease and Associated Disorders 8 (1); 15-21, [17] Guy RH, Hadgraft J. Transdermal drug delivery: the ground rules are emerging. Pharmacy International May; , [18] Gokhale R, Schmidt C, Alcorn L, Stolzenbach J, Schoenhard G, Farhadieh B, Needham T. Transdermal drug delivery systems of albuterol: in vitro and in vivo studies. J. Pharm. Sci. 81 (10); , [19] Robuschi M, Gambaro G, Spagnotto S, Scuri M, Fai V, Lodola E, Pisati R, Bianco S. Bronchodilating activity of broxaterol transdermal patch and its protective effect on bronchial constriction induced by inhaled distilled water mist. Int. J. Clin. Pharmacol. Therapy Tox. 29 (10); , [20] Uematsu T, Nakano M, Kosuge K, Kanamaru M, Nakashima M. The pharmacokinetics of the beta2-adrenoreceptor agonist, tulobuterol, given transdermally and by inhalation. Eur. J. Clin. Pharmacol. 44; , [21] Jain SK, Vyas SP, Dixit VK. A new approach towards the development of a transdermal terbutaline releasing system. J. Contr. Rel. 22; , [22] Clissold SP, Heel RC. Transdermal hyoscine (scopolamine). A preliminary review of its pharmacodynamic properties and therapeutic efficacy. Drugs 29; , [23] Mintzer MJ. Asthma therapy: present trends and future prospects. Comprehensive Therapy 16 (3); 12-16, [24] Demeter SL, Cordasco EM. Transdermal scopolamine in the treatment of asthma: a preliminary report. J. Asthma 23 (4); , [25] Quanjer PhH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault YC. Lung volumes and forced ventilatory flows. Eur. Respir. J. 6 (Suppl. 16); 5-40, [26] Bosman IJ, Douma WR, Ensing K, de Zeeuw RA. A semi-automated solid-phase extraction and radioreceptor assay for the analysis of scopolamine in urine and plasma. Submitted for publication in Eur. J. Pharm. Sci. (Chapter 7, this thesis). [27] Altman DG. Crossover trials. In: Practical statistics for medical research, Chapman & Hall, 1992,