Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

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4. Compounding of nasal midazolam preparations Table 4-2: Unsubstituded cyclodextrins and some derivates Cyclodextrin Abbr. R Substitution 1 MW [Da] Solubility in water [mg/ml] Delivery α-cyclodextrin αCD -H - 972 145 oral, parenteral, topical β-cyclodextrin βCD -H - 1135 18.5 oral, topical randomly methylated β-cyclodextrin β-cyclodextrin sulfobutyl ether sodium salt RMβCD -CH 3 1.7-1.9 1310 > 500 oral 2 , topical HPβCD -CH 2CHOHCH 3 0.65 1400 > 600 oral, parenteral, topical SBEβCD -(CH 2) 4SO - 3 Na + 0.9 2163 > 500 oral, parenteral, topical γ-Cyclodextrin γCD -H - 1297 232 oral, parenteral 3 , topical 2-Hydroxypropyl-βcyclodextrin 2-Hydroxypropyl-γcyclodextrin 1 degree of substitution (per anhydroglucose unit) HPγCD -CH 2CHOHCH 3 0.6 1576 > 500 oral, parenteral, topical 2 maximal 1 mg per kg body weight, Wacker Chemie AG, Burghausen, Germany 3 limited amounts 4.3.2 Pharmaceutical application of cyclodextrins Due to the hydrophilic outer surface and the lipophilic central cavity, cyclodextrins are able to form inclusion complexes with lipophilic molecules in aqueous solutions. Inclusion complexes are chemical complexes, where one molecule is enclosed within another. This kind of complexation enhances the apparent solubility of lipophilic molecules in aqueous solutions [Davis and Brewster 2004; Loftsson et al., 2002]. If any molecule entirely or at least partially enters into the cavity of a cyclodextrin, an inclusion complex is formed [Manosroi et al., 2005]. In pharmaceutical preparations cyclodextrins are added to improve the solubility and dissolution rate of hardly water soluble drugs, to enhance physical and chemical stability of the active compound, and to modify the bioavailability. In aqueous solutions, cyclodextrins form inclusion complexes by taking up some hydrophobic moieties of drug molecules into the central cavity. No covalent bonds are formed or broken during the complex formation. In solution, drug molecules complexed with cyclodextrins are in dynamic equilibrium with free molecules [Irie and Uekama 1997; Loftsson and Brewster 1996; Rajewski and Stella 1996]. Katja Suter-Zimmermann Page 34 of 186 University of Basel, 2008
4. Compounding of nasal midazolam preparations The driving force of complex formation is the release of enthalpy rich water molecules from the cyclodextrin cavity. The total energy of the drug-cyclodextrin complex decreases by displacing enthalpy rich water molecules by hydrophobic guest molecules [Loftson 1995]. Van der Waals forces, hydrogen bonds, and hydrophobic interactions stabilize the drug-cyclodextrin complex. The complexation ratio depends on the physicochemical properties, especially surface character and size of the guest molecule. Most of the drugs form 1:1 complexes with cyclodextrin [Szente and Szejtli 1999]. Generating of solid cyclodextrin-drug complexes is more sophisticated, 3 methods (complexation in solution followed by freeze drying, complexation as a paste, and complexation in organic solvents) are proposed by Wacker Fine Chemicals (Burghausen, Germany). Before applying solid drugcyclodextrin complexes, for compounding of solid preparations (e.g., tablets) the complex formation needs to be verified (e.g., by X-ray diffractometry). Benefit of solid cyclodextrin-drug complexes in compounding of solid preparations are improved chemical stability, modified dissolution characteristics, or masking of unpleasant taste and/or odor. Due to chemical structure of cyclodextrins (i.e., the large number of hydrogen donors and acceptors), the molecular weight and their low octanol/water partition coefficient cyclodextrins and the drug-cyclodextrin complexes do not readily permeate biological membranes. Only the free form of the drug is able to permeate the biological membrane. The drug-cyclodextrin complex diffuses to the lipophilic membrane, where the drug (without hydratisation) penetrates directly into the membrane, whereas the cyclodextrin remains in the aqueous phase [Gröger 2001]. Figure 4-2 shows the equilibrium drug complexation and drug release in the aqueous environment of a lipophilic biologic membrane. Competitive displacement of the drug molecule contributes to efficient release of the drug from drug-cyclodextrin complexes [Stella et al., 1999]. Katja Suter-Zimmermann Page 35 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 41: 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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