Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

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3. Midazolam Table 3-4: Indications and clinical situations where nasal administration of midazolam is beneficial Indication/clinical situation Premedication before anesthesia Reference Emergency children: [Goepfert 1996] children: [Davis, et al. 1995; Geldner et al., 1997; Griffith, et al.; Jaennet 1999; Kogan et al., 2002; Lejus, et al. 1997; Ljung and Andreasson 1996; Rey et al., 1991; Rose, et al. 1990] adults: [U.Haas 1998] adults: [Wolfe and Bernstone 2004] Status epilepticus children: [Fisgin et al., 2000; Fisgin et al., 2002; Jaennet 1999; Kutlu et al., 2000; Lahat, et al. 1998] adults: [Gilat et al., 2003; Kendall et al., 1997; Lahat et al., 1992; Scheepers et al., 2000; Scheepers et al., 1998; Scott et al., 1999; Scott et al., 1997] (Febrile) childhood seizure [Johnson 2001; Koren 2000; Lahat et al., 2000] Short surgical procedures adults: [Ljungman 2000; Malinovsky, et al. 1993; Saint-Maurice et al., 1990] MRI examinations adults: [Moss et al., 1993; Münte Sinikka 2002; Schweizer et al., 1992] Upper gastrointestinal endoscopy adults: [Uygur-Bayramicli, et al. 2002] Dental surgery children:[Abrams et al., 1993; al-Rakaf et al., 2001; Fuks et al., 1994; Hartgraves and Primosch 1994; Kaufman et al., 1994; Kupietzky et al., 1996; Lloyd et al., 2000] adults: [Burstein, et al. 1996; Fukuta et al., 1993; Fukuta et al., 1994; Fukuta et al., 1997; Kaufman, et al. 1994; Roelofse et al. 2000] Katja Suter-Zimmermann Page 30 of 188 University of Basel, 2008
4. Compounding of nasal midazolam preparations 4 Compounding of nasal midazolam preparations 4.1 Regulatory requirements for nasal preparations [Ph. Eur. 5.5] Nasal preparations are liquid, semi-solid, or solid preparations intended for administration to the nasal cavities for systemic or local effect. Nasal preparations are, as far as possible, non-irritating and do not adversely affect the function of the nasal mucosa and its cilia. Aqueous nasal preparations are usually isotonic and may contain adjuvants to modify the viscosity of the preparation, to adjust or stabilize the pH, to increase the solubility of the active compound, or for other technological purposes. 4.2 Excipients for nasal midazolam preparations In nasal preparations, adjuvants have different purposes. Beside adjuvants to solubilize the active substance and excipients to adapt the preparation to the local physiological conditions, viscosity modifiers, bioadhesives, and penetration enhancers are added to modify bioavailability. Viscosity enhancers and mucoadhesive excipients transiently modify mucociliary clearance. But, the modification of the mucociliary function needs to be reversible and should not adversely affect the functions of the nasal mucosa and its cilia. All drugs must possess some degree of aqueous solubility to be pharmacologically active, and most drugs need to be lipophilic to be able to permeate biological membranes by passive diffusion. How water-soluble a given drug needs to be is determined by its potency (i.e., the required dose) and type of formulation. 4.2.1 Solubilizers Due to restricted residence time (mucociliary clearance) and limited solvent (water) in nasal cavities, drugs are preferably administered in solutions. The ideal volume range is 25 µl to 150 µl with an upper limit of 200 µl per nostril [Romeo, et al. 1998]. Therefore, the entire dose of a nasal delivered drug is to be administered in a volume of 50 µl to 400 µl (25 µl to maximal 200 µl per nostril). If the delivered volume exceeds the recommended volume, particularly liquid, little viscous preparations, tend to flow in the nasopharynx and are swallowed. Different approaches have been explored to enhance drug solubility in nasal preparations. The use of solubilizers increases the aqueous solubility of insoluble compounds and some can even promote nasal drug absorption. The challenge in compounding nasal midazolam preparations is the limited and highly pH dependent midazolam solubility (see chapter 3) Katja Suter-Zimmermann Page 31 of 186 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
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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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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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