Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

More documents

Recommendations

Info

6. Project II: Pharmacokinetic of transmucosal nasal delivered midazolam – impact of adjuvants Table 6-3: Pharmacokinetic parameters (mean and SD) following i.v. (Dormicum ® application of midazolam (1 mg by Preparation 1 to 3 and 3 mg by Preparation 4, 5); n=8. 1 mg/ml, 1 mg) and nasal Preparation Nr. Specification t max [min] C max [µg/l] AUC 0-∞ [µg*min/l] Cl [l/min] t 1/2 [min] F 1 mg i.v. --- Dormicum ® , Roche 2.1 (0.8) 87.6 (58.7) 2798.5 (508.9) 0.37 (0.07) 113.5 (25.9) 100% non-compartment model 1 mg nasal 1 Midazolam UD Nasal Spray 0.5 mg 2 Cyclodex-Midazolam UD Nasal Spray 0.5 mg 10.6 (5.0) 9.4 (3.2) 28.1 (9.1) 30.1 (6.6) 2461.0 (627.8) 2596.4 (680.4) 0.43 (0.11) 0.41 (0.13) 114.2 (23.0) 113.0 (22.8) 88% (17) 93% (15) 3 Cyclodex-Midazolam UD Nasal Spray 1 mg 11.3 (4.4) 28.9 (5.4) 2510.5 (541.4) 0.42 (0.11) 105.4 (17.7) 90% (16) two-compartment 1 3 mg nasal 4 Cyclodex-Midazolam UD Nasal Spray 3 mg 5 Chitosan-CD- Midazolam UD Nasal Spray 3 mg 11.7 (2.4) 7.1 (0.6) 72.6 (18.2) 82.2 (15.8) 7324.8 (1599.5) 6580.6 (1358.4) 0.43 (0.10) 0.48 (0.12) 120.9 (32.9) 113.9 (20.8) 86% (8) 78% (10) 1 for two-compartment modeling data from Subject 1 had to be excluded Mean serum concentration time profiles following nasal administration of 1 mg were congruent and demonstrated equal absorption kinetics independent of the delivered preparation (Preparation 1, 2, and 3) and the administration modality (one- versus two-sided), see Figure 6-8 A, B, and C. Intraindividual variability of midazolam serum concentration profiles following nasal administration of 1 mg midazolam (Preparation 1, 2, and 3) is shown in Appendix 10.3.9. Midazolam serum concentration time profile following nasal administration of Preparation 5 is shifted compared to the profile resulting of nasal administration of 3 mg midazolam by Preparation 4, see Figure 6-8 D. Faster increasing midazolam serum concentrations were detected in all subjects after nasal administration of Preparation 5 (3 mg midazolam plus chitosna) than after nasal administration of Preparation 4 (3 mg midazolam without chitosan), see Appendix 10.3.10. Modeling of midazolam serum concentration time profiles following nasal administration of Preparation 4 and 5 was performed by applying a two-compartment pharmacokinetic model (see Figure 6-9). Range (interindividual variability) of AUC (4349.7 µg*min/l), C max (38.8 µg/l), and t max (1.9 min) following Katja Suter-Zimmermann Page 70 of 188 University of Basel, 2008
6. Project II: Pharmacokinetic of transmucosal nasal delivered midazolam – impact of adjuvants nasal administration of Preparation 5 were closer than the range of AUC (4668.5 µg*min/l), C max (52.5 µg/l), and t max (6.7 min) following nasal administration of Preparation 4. Midazolam serum conc (ng/ml) concentration [ug/L] 40 35 30 25 20 15 10 5 0 -5 A 1mg meanconcF1 nasal, P1 1mg meanconcF2 nasal, P2 40 35 30 25 20 15 10 5 0 -5 0 60 120 180 240 300 360 time(min) conc (ng/ml) B 1mg meanconcF1 nasal, P1 1mg meanconcF3 nasal, P3 0 60 120 180 240 300 360 time(min) Midazolam serum conc (ng/ml) concentration [ug/L] 40 35 30 25 20 15 10 5 0 -5 C 1mg meanconcF2 nasal, P2 1mg meanconcF3 nasal, P3 80 70 60 50 40 30 20 10 0 0 60 120 180 240 300 360 Time time(min) [min] conc (ng/ml) D 3mg meanconcF4 nasal, P4 3mg meanconcF5 nasal, P5 0 60 120 180 240 300 360 Time time(min) [min] Figure 6-8 (A-D): Overlaid profiles of midazolam serum concentrations following administration of Preparation 1 and 2 (A), Preparation 1 and 3 (B), Preparation 2 and 3 (C), and Preparation 4 and 5 (D). The displayed midazolam serum concentrations refer to the mean serum concentrations (n=8). Katja Suter-Zimmermann Page 71 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 and 12:
Summary Summary Transmucosal nasal
Page 13:
Summary Project III: In this random
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 27 and 28: 2. Impact of anatomy and physiology
Page 29 and 30: 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
Page 49: 4. Compounding of nasal midazolam p
Page 53 and 54: 5. Project I: Development of prepar
Page 67: 5. Project I: Development of prepar
Page 70 and 71: 6. Project II: Pharmacokinetic of t
Page 91 and 92: 7. Project III: Transmucosal nasal
Page 103: 7. Project III: Transmucosal nasal
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
Page 122 and 123: 10 Appendix 10.2.9 Specification: C
Page 128 and 129:
10 Appendix Katja Suter-Zimmermann
Page 130 and 131:
Page 132 and 133:
Page 134 and 135:
Page 136 and 137:
Page 138 and 139:
Page 140 and 141:
Page 142 and 143:
Page 144 and 145:
Page 146 and 147:
Page 148 and 149:
Page 150 and 151:
10 Appendix 10.3.2 Case report form
Page 152 and 153:
Page 154 and 155:
Page 156 and 157:
Page 158 and 159:
10 Appendix Frequency 10.3.5 Intens
Page 160 and 161:
10 Appendix 10.3.7 Serumconcentrati
Page 162 and 163:
10 Appendix Identification midazola
Page 164 and 165:
Page 166 and 167:
Page 168 and 169:
10 Appendix 10.3.8 Midazolam serum
Page 170 and 171:
10 Appendix 10.3.10 Nasal delivery
Page 172 and 173:
Page 174 and 175:
10 Appendix 10.4.3 Flowchart: multi
Page 176 and 177:
Page 178 and 179:
Page 180 and 181:
Page 182 and 183:
Page 185 and 186:
11 References 11 References Abrams,
Page 187 and 188:
11 References Erjefalt, J.S., I. Er
Page 189 and 190:
11 References Irie, T. and K. Uekam
Page 191 and 192:
11 References Malinovsky, J.M., C.
Page 193 and 194:
11 References Scheepers, M., B. Sch
Page 195 and 196:
12 Curriculum vitae 12 Curriculum v
show all

Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?