Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

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Summary Project II: Pharmacokinetic characteristics following nasal application of 1 mg midazolam (Preparation 1, 2, and 3) and 3 mg midazolam (Preparation 4 and 5) were compared with pharmacokinetic characteristics of 1 mg i.v. administered midazolam (Dormicum ® , Roche). The impact of RMβCD (solubilizer), chitosan hydrochloride (penetration enhancer) and the application modality (one- versus two-sided nasal administration) was investigated in this open-label study with healthy volunteers. Volunteers were asked to describe nasal midazolam administration and to classify local irritation after nasal midazolam administration. Pharmacologic effects were assessed by computer-controlled self-adjusting reaction time test (CRTT, recording reaction time and interstimulus interval) and visual analog scale (VAS). Blood samples were serially obtained until 6 hours after midazolam administration. Serum concentrations of midazolam and two metabolites (α-hydroxymidazolam and 4-hydroxymidazolam) were quantified by liquid chromatography-mass spectrometry (LC-MS). Non-compartment and two-compartment pharmacokinetic modeling was performed to estimate pharmacokinetic parameters. Bioequivalence testing was performed according to the requirements of EMEA (European Agency for the Evaluation of Medicinal Products). Systemic bioavailability of nasally applied midazolam ranged from 78% (Preparation 5) to 93% (Preparation 2), differences of bioavailability were not significant. After nasal administration of 1 mg midazolam by Preparation 1, 2, and 3 mean C max was, 28.1 ± 9.1 µg/l, 30.1 ± 6.6 µg/l and 28.9 ± 5.4 µg/l, respectively. After nasal administration of 3 mg midazolam by Preparation 4 and 5 C max was, 72.6 ± 18.2 µg/l, and 82.2 ± 15.8 µg/l, respectively. Following nasal midazolam administration t max was between 7.1 ± 0.6 minutes (Preparation 5) and 11.7 ± 2.4 minutes (Preparation 4). All tested nasal administration modalities to deliver 1 mg midazolam proved bioequivalence. For Preparation 4 and Preparation 5 bioequivalence was not confirmed. The serum concentration time profiles of the midazolam metabolites (α-hydroxymidazolam and 4- hydroxymidazolam) demonstrated exclusive transmucosal absorption of nasally applied midazolam. Swallowing of nasally delivered preparations was prevented and hepatic first-pass effect successfully circumvented. Consequently, the assessed pharmacokinetic parameters characterized pure transmucosal nasal midazolam delivery. Neither RMβCD (equimolar to midazolam) nor application modality (one- or two-sided) changed absorption kinetics of nasally administered midazolam, whereas chitosan hydrochloride promoted absorption of nasally applied midazolam. Significant higher midazolam serum concentrations were achieved faster. The outcome of the pharmacokinetic study emphasizes the decisive role of minimized nasal application volume to prevent swallowing of nasally applied preparations and to provide for exclusive transmucosal midazolam absorption. Katja Suter-Zimmermann Page 4 of 188 University of Basel, 2008
Summary Project III: In this randomized multicenter trial with 110 anxious and/or claustrophobic patients undergoing MRI examinations, two nasal preparations for low-dose midazolam delivery, Midazolam MD Nasal Spray 5 mg/ml (MD) and Midazolam UD Nasal Spray 1 mg (UD), were compared. Nasal administration of 1 mg or 2 mg midazolam was provided before MRI examination. Within both groups anxiety reduction was significant, but there was no difference in anxiety reduction between the MD and UD group. Local irritation following administration of UD nasal spray was slightly more intense than local irritation after administration of MD nasal spray. Nasal delivery of low-dose midazolam is a safe therapy to provide procedural anxiolysis in patients undergoing MRI examinations. The two compared low-dose midazolam preparations for transmucosal nasal delivery of midazolam proved therapeutic equivalence. Hence, anxious and/or claustrophobic patients equally benefit from procedural anxiolysis during MRI examinations following administration of low-dose midazolam by MD nasal spray or UD nasal spray. Concerning convenient handling, administration to laying patients, and hygienic aspects the new midazolam nasal spray (UD) is superior to the commonly used midazolam multidose nasal spray (MD). Overall, the presented nasal preparations facilitated characterization of exclusive transmucosal nasal absorbed midazolam. In vivo neither RMβCD (equimolar to midazolam) nor administration modality changed the pharmacokinetic profile of nasally applied midazolam. Chitosan hydrochloride promoted nasal midazolam absorption but clinical relevance (e.g., for the treatment of status epilepticus) is to be verified in further clinical investigations. High systemic bioavailability of nasally applied midazolam demonstrated the veritable potential of transmucosal nasal drug delivery as alternative to invasive drug administration. Katja Suter-Zimmermann Page 5 of 188 University of Basel, 2008
Page 1: TRANSMUCOSAL NASAL DRUG DELIVERY Sy
Page 5 and 6: Acknowledgments At the Hospital Pha
Page 7: Index EXPERIMENTAL SECTION 5 Projec
Page 11: Summary Summary Transmucosal nasal
Page 17: THEORETICAL SECTION
Page 20 and 21: 1. Nasal drug delivery 1.2 Transmuc
Page 22 and 23: 1. Nasal drug delivery 1.3 Challeng
Page 25 and 26: 2. Impact of anatomy and physiology
Page 31 and 32: 3. Midazolam 3 Midazolam 3.1 Physic
Page 33 and 34: 3. Midazolam 3.2.1 Indications and
Page 35 and 36: 3. Midazolam Administration of high
Page 37 and 38: 3. Midazolam gastrointestinal tract
Page 39 and 40: 4. Compounding of nasal midazolam p
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5. Project I: Development of prepar
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6. Project II: Pharmacokinetic of t
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7. Project III: Transmucosal nasal
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8 Overall discussion pharmacokineti
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8 Overall discussion considered as
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Appendix
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10 Appendix 10.2 Project I 10.2.1 R
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10 Appendix 10.2.4 Specification: M
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10 Appendix 10.2.6 Specification: C
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10 Appendix Katja Suter-Zimmermann
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10 Appendix 10.2.9 Specification: C
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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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