Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

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Summary Summary Transmucosal nasal drug delivery is a drug delivery option for challenging clinical situations where common drug administrations (e.g., intravenous, intramuscular, or oral) are inapplicable. For drugs with constricted oral bioavailability, due to degradation in the intestinal tract or hepatic first-pass metabolism, transmucosal nasal delivery is a convenient alternative to intravenous and intramuscular drug administration. The considerable blood flow, actually responsible for breath conditioning, benefits efficient systemic drug uptake and provides direct access to the systemic circulation for transmucosal absorbed drugs. Often, in nasal drug delivery the limited nasal capacity is disregarded and the instilled volumes exceed the limited capacity of the nose. Consequently, the administered preparations are partially swallowed and resulting pharmacokinetic characteristics refer to a combination of transmucosal nasal and gastrointestinal drug absorption. Due to low midazolam concentration, the commercially available preparations for intravenous administration (e.g. Dormicum ® , Roche) is inappropriate for transmucosal nasal midazolam delivery. For the optimization of transmucosal nasal midazolam delivery minimized administration volumes are essential to prevent swallowing of nasally administered preparations. Therefore, nasal preparations with enhanced midazolam concentrations need to be provided. In Project I different preparations for transmucosal nasal midazolam delivery were developed. The impact of vehicle and application modality on the pharmacokinetics of nasally applied midazolam was studied by administration of the developed preparations to healthy volunteers (Project II). The benefit of two nasal midazolam preparations for procedural anxiolysis in anxious patients undergoing MRI examinations was compared (Project III). Project I: Midazolam solubilization with RMβCD (randomized methylated-β-cyclodextrin, a cyclodextrin derivative) facilitated compounding of midazolam preparations adjusted to the limited volumetric capacity of the nose. RMβCD (added in equimolar or higher concentration to solubilize midazolam) reduced midazolam release in drug release studies with semi-permeable cellophane membranes (in vitro). Stability data affirmed shelf life of at least 6 months for RMβCD containing nasal midazolam preparations. Addition of chitosan hydrochloride (penetration enhancer) affected midazolam stability; therefore shelf life of the chitosan containing nasal midazolam preparation was reduced. The developed preparations for transmucosal nasal midazolam delivery were the basis to study the influence of the vehicle and the application modality on pharmacokinetics and systemic bioavailability of nasally applied midazolam (Project II). Katja Suter-Zimmermann Page 3 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 12 and 13: Summary Project II: Pharmacokinetic
Page 15: Background and objectives Backgroun
Page 19 and 20: 1. Nasal drug delivery 1 Nasal drug
Page 21 and 22: 1. Nasal drug delivery Table 1-1: C
Page 23: 1. Nasal drug delivery 1.4 Nose to
Page 26 and 27: 2. Impact of anatomy and physiology
Page 32 and 33: 3. Midazolam 3.2 Pharmacologic effe
Page 34 and 35: 3. Midazolam 3.2.2 Conscious sedati
Page 36 and 37: 3. Midazolam Table 3-2: Benefits an
Page 38 and 39: 3. Midazolam Table 3-4: Indications
Page 40 and 41: 4. Compounding of nasal midazolam p
Page 51: EXPERIMENTAL SECTION
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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 8 Overall disc
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8 Overall discussion unusual applic
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8 Overall discussion 9 Final conclu
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10 Appendix 10.1.1 Pharmacokinetic
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10 Appendix 10.2.3 Accelerated stab
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10 Appendix 10.2.5 Specification: M
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10 Appendix 10.2.7 Specification: C
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10 Appendix 10.2.8 Specification: C
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10 Appendix 10.2.10 Stability repor
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10 Appendix Project II 10.3.1 Study
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10 Appendix Katja Suter-Zimmermann
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10 Appendix 1.3.3 Case report form:
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10 Appendix Frequency 10.3.6 Intens
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10 Appendix Identification midazola
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10 Appendix 10.3.9 Nasal delivery o
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10 Appendix 10.4. Project III 10.4.
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10 Appendix 10.4.4 Instruction mate
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11 References Cote, C.J., Md, I.T.
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11 References Griffith, N., S. Howe
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11 References Lahat, E., M. Goldman
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11 References Mygind, N. and R. Dah
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11 References Tschirch, F.T., K. Go
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12 Curriculum vitae During my acade
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