Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

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3. Midazolam Table 3-2: Benefits and limitations of different administration routes for midazolam application Administration Benefit Oral (solid form) Oral (liquid preparation) - convenient, painless application - well accepted by patients - individual dosing of syrup or drops - well accepted (if bitter taste of midazolam is masked) - convenient, painless application Limitation - dose: 7.5 mg or 15 mg - delayed onset of therapeutic effect - inappropriate for emergency care - only 30-50% bioavailability (relevant interindividual variability) - delayed onset of therapeutic effect - children sometimes refuse oral medication - inappropriate for emergency care - only 30-72% bioavailability (relevant interindividual variability) - no liquid oral midazolam preparation commercially available in Europe Rectal - no swallowing - not well accepted (adults and children) - 10-20% of children refuse rectal administration Intravenous Intramuscular Nasal - fast onset of therapeutic effect - no swallowing - emergency care (if veins are accessible) - fast onset of therapeutic effect - no swallowing - fast onset of therapeutic effect - no swallowing - painful - veins are not accessible during status epilepticus - children and some adults detest injections - painful - risk of tissue necrosis at the site of injection - individual dosing is limited - no nasal preparation commercially available 3.4.1 Pharmacokinetic parameters of transmucosal delivered midazolam In Table 3-3 pharmacokinetic parameters of transmucosal delivered midazolam are summarized. It has to be taken in consideration, that for transmucosal nasal midazolam delivery different formulations were used. Several clinical investigators have used midazolam solution for injection at a concentration of 5 mg/ml (Dormicum ® , 5 mg/ml) for nasal delivery [Bjorkman et al., 1997; Burstein, et al. 1997; Connors and Terndrup 1994; Fösel 1996; Goepfert 1996; Ljung and Andreasson 1996; Ljungman 2000; Malinovsky et al., 1995; Münte 2002; Tolksdorf and Eick 1991; Uygur-Bayramicli et al., 2002]. In the cited studies, doses of 0.06 mg/kg to 0.6 mg/kg midazolam were administered by instilling Dormicum ® (5 mg/ml) into the nose. The administered volume reached from 0.1 ml to 5 ml according to the bodyweight of patients. By exceeding the commonly recommended application volumes of 0.05 ml to 0.2 ml, the excess formulation tends draining off into the nasopharynx, where it is swallowed. The swallowed portion of the nasally delivered midazolam dose is absorbed in the Katja Suter-Zimmermann Page 28 of 188 University of Basel, 2008
3. Midazolam gastrointestinal tract and due to considerable first-pass effect bioavailability is impaired. Furthermore, the absorption is delayed and depends on ingestion [Burstein, et al. 1997]. Pharmacokinetic parameters of transmucosal nasally delivered drugs depend on many-sided interaction of different preparation and administration related parameters. Therefore, to compare the outcome of different investigations of nasal midazolam delivery, it is not enough to consider the administered doses. It is important to compare also the administered volume and the drug delivery device (spray or droplets), which determine the swallowed portion. In nasal drug delivery, the impact on pharmacokinetic parameters of the vehicle and other administration related characteristics (e.g., drug delivery device) is enormous. Therefore, the cited pharmacokinetic parameters are only of trend-setting character and cannot be generally assigned to transmucosal nasal midazolam delivery. In Appendix 10.1.1 published data on nasal midazolam delivery is summarized. Table 3-3: Dose, bioavailability, and onset of therapeutic effect of transmucosal administered midazolam. This parameters were assessed by nasal delivery of different preparations (in some publications the administered preparation was no specified). Delivery Dose per kg body weight Bioavailability Onset of effect Reference Oral 0.3-0.6 mg 31-72% 10-20 min [Allen 1991; Connors and Terndrup 1994; Cote et al., 2002; Gizurarson 1993; Goepfert 1996; Malinovsky, et al. 1995; Tolksdorf et al., 1989; Tolksdorf and Eick 1991] Nasal 0.2-0.4 mg 50-83% 5-10 min [Connors and Terndrup 1994; Fösel 1996; Goepfert 1996; Malinovsky, et al. 1993; Münte Sinikka 2002; Münte 2002; Roelofse, et al. 2000; Tolksdorf and Eick 1991] Rectal 0.3-0.5 mg no data 10-16 min [Documed 2006; Goepfert 1996; Malinovsky, et al. 1995; Tolksdorf, et al. 1989; Tolksdorf and Eick 1991] Katja Suter-Zimmermann Page 29 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
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6. Project II: Pharmacokinetic of t
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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 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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