Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

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5. Project I: Development of preparations for transmucosal nasal midazolam delivery Table 5-3 and Figure 5-5 summarize midazolam release from RMβCD-midazolam complexes assessed by permeation experiments with semi-permeable cellophane membranes (SpectraPro ® , MWCO 2000). Table 5-3: Midazolam release (µg/min ± SD) from RMβCD-midazolam complexes. Total midazolam concentration was 5 mg/ml, 15 mg/ml, and 30 mg/ml and RMβCD was added in equimolar amount and threefold amount of midazolam (base). Drug release experiments were accomplished in triplicates Total midazolam Ratio RMβCD to midazolam concentration No RMβCD 1 to 1 1 to 3 5 mg/ml 1.067 ± 0.058 µg/min 0.850 ± 0.354 µg/min 0.150 ± 0.050 µg/min 15 mg/ml --- 1.133 ± 0.808 µg/min --- 30 mg/ml --- 1.375 ± 0.436 µg/min 0.567 ± 0.306 µg/min Midazolam release decrease with addition of RMβCD and is 1.067 ± 0.058 µg/min, 0.850 ± 0.354 µg/min, and 0.150 ± 0.050 µg/min for midazolam 5 mg/ml, 5 mg/ml with equimolar RMβCD, and 5 mg/ml with threefold molar amount of RMβCD, respectively. For 30 mg/ml observed midazolam release was 1.375 ± 0.436 µg/min and 0.567 ± 0.306 µg/min for 30 mg/ml midazolam with equimolar RMβCD, and 30 mg/ml with threefold molar amount of RMβCD, respectively. The observed midazolam release was not proportional to the total midazolam concentration present in the donor compartment. Half of the midazolam concentration (15 mg/ml midazolam solved with equimolar amount of RMβCD) did not result in half of midazolam release compared with the release of 30 mg/ml midazolam solved with equimolar amount of RMβCD. Midazolam release did not correlate with the total midazolam concentration in the donor compartment. Three fold amount of RMβCD did considerably reduce midazolam release for both tested (total) midazolam concentrations 5 mg/ml and 30 mg/ml. Katja Suter-Zimmermann Page 52 of 188 University of Basel, 2008
5. Project I: Development of preparations for transmucosal nasal midazolam delivery 5.3.3 Specification and stability testing Table 5-4 shows the composition of the preparations provided for Project II and III. All preparations are aqueous solutions and osmolality is adjusted with sodium chloride to 300mOsmol/kg. Table 5-5 displays the specification of all midazolam nasal sprays prepared for Project II and Project III. For all investigational products a shelf life of 6 months was proposed. Table 5-4: Preparations for nasal midazolam delivery provided for Project II and Project III. All preparations are aqueous solutions and osmolality is adjusted to 300mOsmol/kg with sodium chloride. Nr. Preparation 1a 1b 2 3 4 5 Midazolam UD Nasal Spray 0.5 mg Midazolam MD Nasal Spray 5 mg/ml Cyclodex- Midazolam UD Nasal Spray 0.5 mg Cyclodex- Midazolam UD Nasal Spray 1 mg Cyclodex- Midazolam UD Nasal Spray 3 mg Chitosan-CD- Midazolam UD Nasal Spray 3 mg Midazolam (base) RMβCD Chitosan HCl Preservatives 5 mg/ml --- --- --- Dose (Volume) 1 mg (2 x 0.1 ml) 5 mg/ml --- --- Yes 2 1 mg (2 x 0.1 ml) 5 mg/ml 2% --- --- 1 UD: unit dose system, MD: multidose nasal spray 2 benzalconium chloride and sodium EDTA 1 mg (2 x 0.1 ml) Device 1 UD MD UD Project 10 mg/ml 4% --- --- 1 mg (0.1 ml) UD II / III 30 mg/ml 12% --- --- 3 mg (0.1 ml) UD II 30 mg/ml 12% 0.5% --- 3 mg (0.1 ml) UD II II III II Table 5-5: Specification of the clinical test samples. Nr. Preparation 1a 1b 2 3 4 5 Midazolam UD Nasal Spray 0.5 mg Midazolam MD Nasal Spray 5 mg/ml Cyclodex-Midazolam UD Nasal Spray 0.5 mg Cyclodex-Midazolam UD Nasal Spray 1 mg Cyclodex-Midazolam UD Nasal Spray 3 mg Chitosan-CD-Midazolam UD Nasal Spray 3 mg Aspect Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution Clear, colorless solution Identity Midazolam Content [mg/ml] pH Osmolality [mOsmol/kg] conform 4.50-5.50 3.0-3.5 270-330 conform 4.50-5.50 3.0-3.5 270-330 conform 4.50-5.50 3.5-4.5 270-330 conform 9.00-11.0 3.5-4.5 270-330 conform 27.0-33.0 3.0-4.5 270-330 conform 27.0-33.0 3.0-4.5 270-330 Katja Suter-Zimmermann Page 53 of 188 University of Basel, 2008
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TRANSMUCOSAL NASAL DRUG DELIVERY Sy
Page 5 and 6:
Acknowledgments At the Hospital Pha
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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 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 59: 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
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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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