Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

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8 Overall discussion pharmacokinetic characteristics to provide midazolam therapy in clinical situations where common drug delivery methods (e.g., i.v. or i.m. administration) are inappropriate but fast onset of therapeutic effect is required (e.g., anticonvulsive treatment of status epilepticus). In particular, the tested chitosan hydrochloride containing nasal midazolam preparation (Preparation 5) demonstrated fast increasing of midazolam serum concentration providing maximal midazolam serum concentrations within 7.1 ± 0.6 minutes (range t max 1.9 min). These findings are in accordance with the data published by Illum demonstrating chitosan to promote nasal absorption of morphine [Illum, et al. 2002]. Furthermore, nasal morphine preparations containing chitosan provided fast onset of therapeutic effect in the treatment of breakthrough pain in cancer patients [Pavis, et al. 2002]. As well as therapy of breakthrough pain, treatment of seizures (epileptic or febrile) is also a clinical situation where drug administration is difficult and fast onset of therapeutic effect is urgently needed. Chitosan containing nasal midazolam preparation (Preparation 5) showed most promising pharmacokinetic characteristics for the treatment of seizures. Providing anticonvulsive therapy by nasal administration of midazolam the local irritation is of secondary importance compared to the enormous benefit of this needle-free drug delivery option featuring rapid onset of therapeutic effect. However, to elongate shelf life and to reduce local irritation further optimization of chitosan containing nasal midazolam preparations is required. The performed pharmacodynamic testing during Project II (VAS and CRTT) assessed volunteer’s attention and their ability to respond. These tests aimed predicting the time needed to restore fitness to drive after procedural anxiolysis with nasally applied midazolam. However, for the quantification of the anticonvulsive effects of nasally delivered midazolam more specific pharmacodynamic characterization needs to be performed (e.g., electroencephalogram). To assess the anxiolytic effects of benzodiazepines in healthy volunteers, different testing methods have been described in literature [Visser et al., 2003]. But no testing method is specific enough to differentiate sedating from anxiolytic effects. Anxiety and panic during MRI examinations is impossible to be simulated, since these phenomena involve different components (e.g., fear of enclosed places, pain, the unknown situation, as well as apprehension about what the test might reveal) [Katz, et al. 1994]. Consequently, evaluation of therapeutic equivalence of two nasal midazolam preparations was accomplished with anxious and/or claustrophobic patients undergoing MRI examinations and not with healthy volunteers (multicenter trial, Project III). Therapeutic equivalence of multidose nasal spray (MD, Preparation 1) and unit dose nasal spray (UD, Preparation 3) demonstrated in Project III is in accordance with the congruent serum concentrations time profiles attesting bioequivalence for these two preparations. However, less required additional doses (total administration of 2 mg midazolam) in the comparator group (UD, Preparation 3) cannot be explained by serum concentration time profiles. Drug administration with the unit dose system (UD, Preparation 3) is mostly a new experience for the patients, while nasal drug administration with the multidose nasal spray (MD, Preparation 1) resembles ordinary nasal delivery of common decongestants for the treatment of rhinitis. The Katja Suter-Zimmermann Page 98 of 188 University of Basel, 2008
8 Overall discussion unusual application experience may have influenced the subjective assessment of therapeutic effect. As the impact of cyclodextrin derivatives on drug release and absorption kinetics (in vivo) is controversially discussed in literature, midazolam was nasally delivered without RMβCD (Preparation 1) and with equimolar RMβCD (Preparation 2). In aqueous solutions maximal 5 mg/ml midazolam (base) can be solubilized by dissolving midazolam hydrochloride. Therefore, the impact of RMβCD on pharmacokinetics of nasally applied midazolam was studied at the concentration of 5 mg/ml midazolam base (Preparation 1 and Preparation 2). This midazolam concentration is equal to Dormicum ® 5 mg/ml and only adequate for transmucosal delivery of low-dose midazolam. RMβCD, added in equimolar amounts to midazolam, demonstrated neither penetration enhancing nor penetration inhibiting effects on transmucosal nasal delivered midazolam. RMβCD proved to be an adequate solubilizer in preparations for transmucosal nasal midazolam delivery. Bioequivalence was confirmed for all tested nasal administration modalities for nasal delivery of 1 mg midazolam (Project II). According to Fick’s first law, absorption of 1 mg nasal delivered midazolam following nasal administration of half concentration (5 mg/ml) on doubled application area (two-sided administration) was equivalent with one-sided administration of doubled midazolam concentration (10 mg/ml, Preparation 3). Hence, transmucosal nasal midazolam absorption demonstrated direct proportionality to (total) midazolam concentration and to the application area. Unlike in vivo midazolam absorption (Project II), in vitro midazolam release was reduced by equimolar RMβCD (Project I): doubled midazolam concentration (solubilized with equimolar amount of RMβCD) did not result in doubled midazolam release from the donor compartment into the receptor compartment (in vitro). Apparently, not the total midazolam but the free midazolam concentration determined midazolam release in vitro. In the nasal cavities (in vivo) there are a lot of molecules (components of the mucus layer or of the cell surfaces) potentially interfering with the cyclodextrin-drug complexes. Therefore, midazolam release in vivo is probably facilitated by competitive displacement of complexed midazolam molecules [Stella, et al. 1999]. The in vitro drug release studies showed different midazolam release for midazolam preparations with RMβCD (equimolar) and without RMβCD. However, overall transmucosal nasal midazolam uptake, resulting of midazolam release, penetration, and permeation processes, did not reflect the differences of midazolam release observed in vitro (Project I). Apparently, in vitro drug release studies revealed differences in midazolam release, that in vivo were of inferior importance. Thus, drug release studies were not reliable models to predict absorption kinetics of nasally applied midazolam preparations. Osmolality of all proposed preparations for transmucosal nasal midazolam delivery was adjusted to physiologic conditions. For preparation proposed by Roelofse et al., containing 20% of βCD to solubilize 10 mg/ml midazolam, pH was 5.8. But as this preparation showed reduced systemic midazolam bioavailability following nasal administration, adding of excess cyclodextrin was Katja Suter-Zimmermann Page 99 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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3. Midazolam 3 Midazolam 3.1 Physic
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3. Midazolam 3.2.1 Indications and
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3. Midazolam Administration of high
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3. Midazolam gastrointestinal tract
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4. Compounding of nasal midazolam p
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5. Project I: Development of prepar
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10 Appendix 10.3.4 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 10.4.2 Case report form
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10 Appendix 10.4.3 Flowchart: multi
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10 Appendix Katja Suter-Zimmermann
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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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