Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

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4. Compounding of nasal midazolam preparations Figure 4-2: Release of a lipophilic drug from a cyclodextrin-drug complex in the aqueous environment of a biological membrane. Form [Loftsson et al. 2005] The solubilizing effect of cyclodextrins is usually related to improved drug absorption [Illum 2002]. But the impact of cyclodextrins on bioavailability is controversially discussed in literature. Loftsson reduces the effect of cyclodextrins on drug transport through and into skin to true carriers keeping the hydrophobic drug in solution [Loftson 1995]. In aqueous vehicles, cyclodextrins act as penetration enhancers by solubilizing lipophilic water-insoluble drug molecules. For optimal permeation Loftsson and Jarho recommend to add exactly enough cyclodextrin to solubilize the drug [Jarho et al., 1996; Loftson 1995]. This recommendation is based on the findings of in vitro studies from Jarho (Figure 4-3), demonstrating impaired permeation by excess of cyclodextrins [Jarho et al. 1996]. Katja Suter-Zimmermann Page 36 of 186 University of Basel, 2008
4. Compounding of nasal midazolam preparations Figure 4-3 : Optimal cyclodextrin concentration. Jarho et al. demonstrated exceeding cyclodextrin concentration to impair permeation of drug through cornea of pigmented rabbits. Figure modified after [Jarho et al. 1996]. Permeation of drug molecules from aqueous cyclodextrin containing vehicles through semipermeable membranes follows the same pattern as permeation through lipophilic biomembranes [Loftsson et al. 2002]. Determination of drug fluxes through semi-permeable membranes have been used to characterize release of drugs from cyclodextrin containing vehicles as well as to assess stability constants of drug-cyclodextrin complexes [Masson et al., 1999; Ono et al., 1999]. 4.3.3 Cyclodextrins in transmucosal nasal drug delivery In nasal formulations, cyclodextrins are used to increase the aqueous solubility of lipophilic drugs. However, cyclodextrins can also interact with biological membranes, acting as penetration enhancers, especially in nasal delivery of peptides [Marttin et al., 1998]. Numerous studies have demonstrated that methylated cyclodextrins are efficient absorption enhancers, and therefore well established in nasal drug delivery [Merkus 1999]. The first cyclodextrin-based nasal formulations contained steroidal hormones and peptides. The results were promising and the most effective cyclodextrins, methylated cyclodextrin derivates, increased the bioavailability of progesterone threefold with suspension of the same compound [Hermens et al., 1990; Matsubara et al. 1995; van den Berg et al. 2004]. The estradiol nasal spray Aerodiol ® (Servier S.A, Meyrin Switzerland). represents the successful use of cyclodextrins in nasal applications. Katja Suter-Zimmermann Page 37 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
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 43: 4. Compounding of nasal midazolam p
Page 49: 4. Compounding of nasal midazolam p
Page 53 and 54: 5. Project I: Development of prepar
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Page 70 and 71: 6. Project II: Pharmacokinetic of t
Page 91 and 92: 7. Project III: Transmucosal nasal
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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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