Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

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5. Project I: Development of preparations for transmucosal nasal midazolam delivery midazolam concentration [mg/ml] 50.0 45.0 40.0 35.0 30.0 25.0 20.0 15.0 10.0 5.0 0.0 w ater 10% HPbCD 10% RMbCD 10% HPgCD midazolam 9.1 26.2 33.1 40.8 Figure 5-3: Saturated midazolam concentration in water, 10% RMβCD, 10% HPβCD, and 10% HPγCD (n=3). Midazolam solubility was 9.1 mg/ml, 26.2 mg/ml, 33.1 mg/ml, and 40.8 mg/ml in water, 10% HPβCD, 10% RMβCD, and 10% HPγCD, respectively. The calculated ratio of cyclodextrin and midazolam in the saturated solutions was 1 to 1.13, 1 to 1.33, and 1 to 1.97 for HPβCDmidazolam, RMβCD-midazolam, and HPγCD-midazolam complexes, respectively. Figure 5-3 displays the solubility of midazolam without and with solubilization enhancer (10% HPβCD, 10% RMβCD, and 10% HPγCD). Midazolam release [ug/min] 5.3.2 Drug Release 2.00 1.80 1.60 1.40 1.20 1.00 0.80 0.60 0.40 0.20 0.00 Dormicum (5mg/ml) . 10mg/ml midazolam, equimolar RMbCD 10mg/ml midazolam, 20% RMbCD Midazolam release in preliminary drug release studies was 1.258 µg/min, 1.150 µg/min, and 0.461 µg/min from Dormicum ® (5 mg/ml midazolam), 10 mg/ml midazolam solubilized with equimolar amount of RMβCD (4%) and 10 mg/ml midazolam solubilized with 20% RMβCD, respectively. Midazolam release did not correlate with the total midazolam concentration. In Figure 5-4 the results of the preliminary drug release study is displayed. Figure 5-4: Midazolam Release from Dormicum ® (5 mg/ml midazolam), 10 mg/ml midazolam solubilized with equimolar amount of RMβCD (4%) and 10 mg/ml midazolam solubilized with 20% RMβCD. Katja Suter-Zimmermann Page 50 of 188 University of Basel, 2008
5. Project I: Development of preparations for transmucosal nasal midazolam delivery 2.00 1.80 1.60 5mg/ml midazolam A 2.00 1.80 1.60 5mg/ml midazolam 30mg/ml midazolam B Midazolam release [ug/min] 1.40 1.20 1.00 0.80 0.60 . Midazolam release [ug/min] 1.40 1.20 1.00 0.80 0.60 . 0.40 0.40 0.20 0.20 0.00 no RMbCD 1 to 1 3 to 1 Ratio RMbCD to midazolam 0.00 no RMbCD 1 to 1 3 to 1 Ratio RMbCD to midazolam Midazolam release [ug/min] 2.00 1.80 1.60 1.40 1.20 1.00 0.80 0.60 0.40 0.20 0.00 . . 1 to 1 Ratio RMbCD to midazolam 5mg/ml midazolam 15mg/ml midazolam 30mg/ml midazolam C Figure 5-5 (A, B, and C): Midazolam release (µg/min ± SD) from RMβCD-midazolam complexes through semi-permeable cellophane membrane (SpectraPor ® , MWCO 2000). Total midazolam concentration was 5 mg/ml, 15 mg/ml, and 30 mg/ml and RMβCD was added in equimolar (2%, 6%, and 12%) amount and threefold (6%, 36%) amount of midazolam (base). Drug release experiments were accomplished in triplicates. Figure 5-5 (A-C) show the midazolam release from preparations with and without solubilization enhancer (RMβCD). Midazolam release does not correspond to the total midazolam concentration available in the donor compartment. With increasing excess of RMβCD, midazolam release decreases. Katja Suter-Zimmermann Page 51 of 188 University of Basel, 2008
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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 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 57: 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
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Page 106 and 107: 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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