Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

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6. Project II: Pharmacokinetic of transmucosal nasal delivered midazolam – impact of adjuvants 100 Preparation 4 80 60 40 Midazolam serum concentration [ug/l] 20 0 100 80 0 60 120 180 240 300 360 420 Preparation 5 60 40 20 0 0 60 120 180 240 300 360 420 Time [min] Figure 6-9: Modeling of the midazolam concentration time profile was performed by applying a two-compartment pharmakokinetic model for midazolam serum concentrations after administration of Preparation 4 (n=7) and Preparation 5 (n=7). Katja Suter-Zimmermann Page 72 of 188 University of Basel, 2008
6. Project II: Pharmacokinetic of transmucosal nasal delivered midazolam – impact of adjuvants Bioequivalence testing was performed for nasal delivery of 1 mg (Preparation 2 and 3) and 3 mg (Preparation 5) with reference Preparation 1 and Preparation 4, respectively (Table 6-4 and Table 6-5). Nasal delivery of 1 mg midazolam by administration of Preparation 1, 2 and 3 was bioequivalent, according to the requirements for bioequivalence defined by the EMEA [EMEA 26. July 2001] (see Table 6-4). Table 6-4: Bioequivalence testing for nasal delivery of 1 mg midazolam. Boundaries (lower 80% and upper 125% for AUC 0-∞, C max,) and mean are indicated for reference (Preparation 1), 90% confidence intervals and means of AUC 0-∞, C max of Preparation 2 and 3 are listed. wb: within boundaries, : 90% confidence interval and mean of test preparation fulfill the requirements of EMEA for bioequivalence. Parameter Boundaries of reference (mean) 90% confidence interval (mean) Preparation 1 Preparation 2 wb Preparation 3 wb AUC 0-∞, [µg*min/l] 1969 – 3076 (2461) 2140 – 3052 (2596) 2148 – 2873 (2510) C max [µg/l] 22.5 – 35.2 (28.1) 25.6 – 34.5 (30.5) 25.3 – 32.5 (28.9) None of the tested pharmacokinetic parameters (AUC, C max , and t max ) Preparation 4 and 5 did fulfill the requirements for bioequivalence, see Table 6-5. The difference between AUC following administration of Preparation 4 and 5 was not significant, whereas differences of C max (p=0.008) and t max (p=0.008) were significant. The range of AUC (4349.7 µg*min/l), C max (38.8 µg/l), and t max (1.9 min) following nasal administration of Preparation 5 were closer than the range of AUC (4668.4 µg*min/l), C max (52.5 µg/l), and t max (6.7 min) following nasal administration of Preparation 4. Table 6-5: Bioequivalence testing for nasal delivery of 3 mg midazolam. Boundaries (lower 80% and upper 125% for AUC 0-∞, C max,) and mean are indicated for reference (Preparation 4), 90% confidence intervals and means of AUC 0-∞, C max of Preparation 5 are listed. wb: within boundaries, no: 90% confidence interval and mean of test preparation does not comply with the requirements of EMEA for bioequivalence. Parameter Boundaries of reference (mean) 90% confidence interval (mean) Preparation 4 Preparation 5 wb AUC 0-∞, [µg*min/l] 5860 - 9156 (7325) 5583 – 7578 (6581) no C max [µg/l] 58.1 – 90.8 (72.6) 68.3 – 88.6 (78.5) no t max [min] 9.3 – 14.6 (11.7) 6.6 – 7.5 (7.1) no Katja Suter-Zimmermann Page 73 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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2. Impact of anatomy and physiology
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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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Page 53 and 54: 5. Project I: Development of prepar
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Page 70 and 71: 6. Project II: Pharmacokinetic of t
Page 91 and 92: 7. Project III: Transmucosal nasal
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Page 106 and 107: 8 Overall discussion pharmacokineti
Page 108 and 109: 8 Overall discussion considered as
Page 111: Appendix
Page 114 and 115: 10 Appendix 10.2 Project I 10.2.1 R
Page 116 and 117: 10 Appendix 10.2.4 Specification: M
Page 118 and 119: 10 Appendix 10.2.6 Specification: C
Page 120 and 121: 10 Appendix Katja Suter-Zimmermann
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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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