Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

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7. Project III: Transmucosal nasal delivery of low-dose midazolam – evaluation of two preparations for procedural anxiolysis 7.4 Discussion This multicenter trial was accomplished to compare two preparations for transmucosal nasal delivery of low-dose midazolam. This trial was implemented at three radiologic departments and one private radiologic institution. The indication of interest was procedural anxiolysis during MRI examinations. The purpose was to investigate therapeutic equivalence of the two preparations. Midazolam (oral, i.v., or nasal) is commonly used for procedural anxiolysis during MRI examinations. In several radiologic departments (e.g., Institute of Diagnostic Radiology, University Hospital Zurich Institute of Radiology, Kantonsspital Winterthur) midazolam nasal spray, prepared according to the monograph of NRF [NRF 2002], is routinely offered to anxious and/or claustrophobic patients for procedural anxiolysis. The presented study was designed to compare two preparations (today’s routine nasal spray MD and new UD nasal spray) and not for the quantitative assessment of efficacy in prevention of claustrophobia during MRI examinations. The design of a clinical trial to prove efficacy of nasal delivered low-dose midazolam in prevention of procedural anxiety and/or claustrophobia, is supposed to be randomized, placebo controlled, and preferably double blinded. For such a placebo-controlled study it would be essential, that the administration of the placebo nasal spray is identical concerning sensation of application and local irritation. For the present trial, blinding was not feasible, due to different shapes of the two nasal sprays (MD and UD nasal spray). Furthermore, the application characteristics were integral part of the comparison of the two nasal sprays. The only option for blinding would have been a double-dummy study design, and consequently simultaneous nasal administration with both nasal sprays: in treatment group midazolam by multidose nasal spray and placebo by unit dose nasal spray and in comparator group vice versa, placebo by multidose nasal spray and midazolam by unit dose nasal spray. But because of the limited volumetric capacity of the nose, double-dummy design is not reasonable for nasal administration of liquid preparations. Hence, doubled application volume (placebo and treatment or placebo and comparator) would certainly result in swallowing of the midazolam preparation diluted by placebo. Patients, self-assessing to be anxious and/or claustrophobic, were invited for participation in this trial with nasal midazolam. No standardized diagnostic tool was applied to identify claustrophobic patients. Intensity of anxiety and/or claustrophobia was rated by visual analog scale. McIsaac et al. assumed one single item to detect claustrophobia to be insufficient for predicting intense anxiety reactions during MRI examinations [Mc Isaac et al., 1998]. An elaborate claustrophobia questionnaire (with 29 items) for diagnosis of claustrophobia was proposed by Randomsky et al. [Radomsky et al., 2001], but in day-to-day operations at radiologic departments interviewing patients by this extensive questionnaire is to time-consuming. To help anxious patients to complete MRI examinations successfully it is not necessary to conclusively diagnose their claustrophobia. Therefore, Mc Isaac et al. reduced the extensive claustrophobia questionnaire to 6 items and suggested this screening tool for the identification of patients who are Katja Suter-Zimmermann Page 92 of 188 University of Basel, 2008
7. Project III: Transmucosal nasal delivery of low-dose midazolam – evaluation of two preparations for procedural anxiolysis most likely to experience claustrophobic fear or panic during MRI examinations. But this reduced questionnaire has not been validated yet and therefore reliability is still unsettled. Because day’s schedule in radiologic departments is tight, the accomplishment of a clinical trial should not affect work flow. Therefore, to successfully run a clinical trial in clinical everyday life it is crucial to deliver well structured self-explanatory study material. The documentation should be as less time-consuming as possible. Schweizer et al. demonstrated in a pilot study the anxiolytic effect of low-dose midazolam (0.5- 1 mg) in prevention of panic reactions [Schweizer, et al. 1992]. In addition, nasal delivery of lowdose midazolam proved to be efficient and safe for conscious sedation during MRI examinations [Tschirch, et al. 2006]. Nasally administered doses of 1 mg to 2 mg midazolam provided anxiolysis without sedation (i.e., conscious sedation) and therefore the patients were able to follow the instructions given during MRI examinations. Based on these findings for the present study the dose of 1 mg nasal midazolam (initial dose) was set with the possibility of delivering another 1 mg nasal midazolam if anxiolysis was not provided. The composition and the multidose delivery device of the test preparation (Midazolam MD Nasal Spray 5 mg/ml) refer to the commonly used midazolam nasal spray, prepared by the local hospital pharmacies. Complying with monograph for nasal preparations of Ph.Eur., this aqueous nasal preparation, supplied in multidose delivery systems, is preserved. The multidose nasal spray used in this trial, delivers 0.1 ml per pump. But for correct dosing at least 1 ml preparation has to be filled into the delivery device. As for the administration of 1 mg to 2 mg midazolam only 0.2 ml to 0.4 ml are delivered, the major portion of the preparation is wasted. Furthermore, to get the multidose nasal spray ready for exact dosing, the pump needs to be prepared by pressing the pump several times previous to nasal administration. Preparing the pump inhalation of the atomized midazolam preparation is to be prevented. Since the upright position of the multidose nasal spay is essential for exact dosing, administration to lying patients is not possible. As used multidose nasal sprays do not look different from unused multidose nasal sprays, there is a certain risk for unhygienic multiple application to different patients. The comparator (Midazolam UD Nasal Spray 1 mg) is supplied in a single-dose delivery device and is preservative-free. The dose of 1 mg midazolam is delivered within 0.1 ml by one-sided administration. For the administration of an additional dose, 0.1 ml is sprayed into the opposite nostril by applying a second unit dose nasal spray. The unit dose nasal spray system contains 0.125 ml nasal preparation, thereof 0.1 ml is delivered independent of the position. Therefore, the unit dose system allows nasal administration of the anxiolytic treatment directly to patients lying on MRI table, ready to be introduced into the MRI tunnel. As often patients declare their anxiety only at the moment they are introduced into the MRI tunnel, administration independent of position is advantageous. Many patients presenting to radiologists for MRI examination admit anxiety and/or claustrophobia, but only few of them are willing to participate in a clinical trial. Finally, 110 patients gave consent to enter the trial with nasal midazolam. One patient dropped out because of withdrawal of consent. Katja Suter-Zimmermann Page 93 of 188 University of Basel, 2008
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TRANSMUCOSAL NASAL DRUG DELIVERY Sy
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Acknowledgments At the Hospital Pha
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Index EXPERIMENTAL SECTION 5 Projec
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Summary Summary Transmucosal nasal
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Summary Project III: In this random
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THEORETICAL SECTION
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1. Nasal drug delivery 1.2 Transmuc
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1. Nasal drug delivery 1.3 Challeng
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2. Impact of anatomy and physiology
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3. Midazolam 3 Midazolam 3.1 Physic
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3. Midazolam 3.2.1 Indications and
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3. Midazolam Administration of high
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3. Midazolam gastrointestinal tract
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4. Compounding of nasal midazolam p
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10 Appendix 10.3.2 Case report form
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10 Appendix Katja Suter-Zimmermann
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10 Appendix Frequency 10.3.5 Intens
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10 Appendix 10.3.7 Serumconcentrati
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10 Appendix Identification midazola
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10 Appendix 10.3.8 Midazolam serum
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10 Appendix 10.3.10 Nasal delivery
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10 Appendix 10.4.3 Flowchart: multi
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11 References 11 References Abrams,
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11 References Erjefalt, J.S., I. Er
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11 References Irie, T. and K. Uekam
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11 References Malinovsky, J.M., C.
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11 References Scheepers, M., B. Sch
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12 Curriculum vitae 12 Curriculum v
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