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 Patients and study design Enrollment Medication and MRI proceedings Evaluation Patients scheduled for MRI desiring anxiolysis because of general anxiety and/or claustrophobia Information Written consent Inclusion and exclusion criteria Treatment (MD) 1mg midazolam nasal + 1mg Randomization VAS before MRI examination VAS after comparator (UD) 1mg midazolam nasal Interview after MRI examination Assessment of radiologic technician Image quality + 1mg Figure 7-1: Study design of multicenter trial with nasal low-dose midazolam. Anxious and/or claustrophobic patients, scheduled for MRI examinations at the study centers (A, B, C, and D), were invited to participate in this multicenter trial with nasal low-dose midazolam. MD: multidose nasal spray (treatment), UD: unit dose nasal spray (comparator). Patients, scheduled for MRI examinations at the study centers and desiring anxiolysis, because of general anxiety and/or claustrophobia, were invited to participate in this clinical trial with nasal low-dose midazolam. Radiologists conclusively informed the interested patients and handed out written information about the clinical study protocol. Before enrollment, patients gave written consent. Figure 7-1 displays the study design of the multicenter study with nasal low-dose midazolam. Exclusion criteria were age
7. Project III: Transmucosal nasal delivery of low-dose midazolam – evaluation of two preparations for procedural anxiolysis Midazolam MD Nasal Spray 5 mg/ml was produced according to the NRF monograph for nasal midazolam preparation [NRF 2002]. Midazolam MD Nasal Spray 5 mg/ml (preservative: benzalconium chloride and sodium ethylenediaminetetraacetic acid) was provided in a multidose nasal spray, delivering 0.1 ml per pump (0.5 mg midazolam base per pump). To prepare the multidose nasal spray for exact dosing, the pump had to be pressed five times previous to first nasal administration. The application had to be provided in sitting patients, because the upright position of the multidose nasal spay is essential for exact dosing. Patients were administered 1 pump (0.1 ml) per nostril of Midazolam MD Nasal Spray 5 mg/ml immediately prior to MRI examination (total administered dose: 1 mg midazolam base). If the administered dose of 1 mg midazolam was not enough to provide sufficient anxiolysis to perform MRI examination, administration was allowed to be repeated (1 pump per nostril, additional administration of 1 mg midazolam). Midazolam UD Nasal Spray 1 mg (preservative-free, solubilizer: 4% RMβCD) was provided in unit dose nasal sprays (Pfeiffer GmbH, Radolfzell, Germany), delivering 1 single pump of 0.1 ml (1 mg midazolam base per pump), independent of the actual position. Therefore, the application was provided to the patients lying on the MRI table. For detailed information about the nasal midazolam preparations see Table 5-4, Table 5-5 (Project I), and Appendix 10.2.4 to 10.2.9. Additional dose and therapy failure If anxiolysis of the initial treatment with 1 mg midazolam was not enough to provide MRI examination an additional dose of 1 mg midazolam was offered to patients of both groups (MD and UD). Administration of the additional dose was no exclusion criteria. Anxiety score and subjective experience Patients were asked to rate their anxiety on a visual analog scale (VAS) before medication (VAS before ) and after completing MRI examination (VAS after ). VAS to rate anxiety was a nongraduated 100 mm line, the left end labeled ‘not anxious at all’ and the right end labeled ‘extremely anxious’. In addition, after completing the MRI examination patients were interviewed about their experiences and whether they would repeat the MRI examination again with analog anxiolytic treatment receiving during the study. Assessment of radiologic technician The radiologic technician rated the comportment and cooperation of the patient during the proceedings (calm and good cooperation, agitated insufficient cooperation, patient felt asleep, slightly anxious, and very anxious) and classified the proceeding as normal proceedings, interruption of the examination, or MRI examination not feasible and named the reasons for incomplete examinations. If MRI examination was not feasible or had to be interrupted, the therapy was judged as failed (therapy failure). Katja Suter-Zimmermann Page 85 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 Katja Suter-Zimmermann
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10 Appendix 10.3.2 Case report form
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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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