Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

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5. Project I: Development of preparations for transmucosal nasal midazolam delivery local irritation, preparations for nasal administration should as far as possible be adapted to the intranasal physiology concerning pH as well as tonicity. In aqueous solutions cyclodextrin derivatives spontaneously form water-soluble complexes with a wide range of compounds. Since increased compound solubility stands for effectual complexation, verification of cyclodextrin-midazolam complexes was not performed. In order to successfully generate midazolam solutions, by complexation with different cyclodextrin derivatives (RMβCD, HPβCD, and HPγCD), it was essential to solubilize cyclodextrins first and then to add midazolam hydrochloride. Hardly soluble agglomerates resulted by inverting the procedure (adding cyclodextrins to midazolam suspensions). All tested cyclodextrins (RMβCD, HPβCD, and HPγCD) improved the solubility of midazolam in aqueous solutions. Despite successful complexation with RMβCD, HPβCD, or HPγCD midazolam solubility remained pH-dependent and above pH 4 to 5 midazolam precipitated. Despite superior solubilization ability of 10% HPγCD (midazolam concentration 40.8 mg/ml) compared to RMβCD (midazolam concentration 33.1 mg/ml solubilized with 10% RMβCD), RMβCD was selected to compound preparations for nasal midazolam delivery, because RMβCD is adjuvant in Aerodiol ® (Servier, Meyrin, Switzerland) and approved by the authorities of several European countries. The calculated ratio of different cyclodextrin derivatives and midazolam (1 to 1.13, 1 to 1.33, and 1 to 1.97 for saturated midazolam solutions with 10% RMβCD, 10% HPβCD, and 10% HPγCD, respectively) indicates that in saturated midazolam solutions not only 1 to 1 complexes are formed. The 1 to 1.97 ratio calculated for HPγCD-midazolam complexes implies the formation of 1 to 2 complexes (one HPγCD molecule complexes two midazolam molecules). But complex characteristics can not conclusively be described by calculated ratios of cyclodextrin and solubilized compound. The effect of cyclodextrins on drug release, absorption kinetics, and consequently bioavailability of transmucosal delivered drugs is controversially discussed. Based on Fick’s first law, the fundamental equation describing passive diffusion is represented by Equation 1: J = P * A * (c 1 – c 2 ) (Equation 1) Where J is the resulting drug flux through the membrane, P is the permeability coefficient of the drug through the membrane (characterizing the ability of a given drug to permeate a specific membrane), c 1 refers to the drug concentration in the donor compartment, c 2 refers to the drug concentration in the receptor compartment, and A is the area of the membrane available for drug flux. As usually c 2
5. Project I: Development of preparations for transmucosal nasal midazolam delivery Assuming constant permeability coefficient (identical membrane and drug) and indifferent area, doubling the drug concentration in the donor compartment (2 * c 1 ) results in doubled drug flux (2 * J), according to Equation 2. Generally, Equation 1 and 2 describe passive diffusion (in vitro and in vivo) of any substance (e.g., drug, adjuvant) through any membrane (e.g., biomembrane or artificial membrane), for in vitro and in vivo situations. Roelofse et al. published pharmacokinetic characterization of nasal midazolam (dose 7.5 mg) delivered by a test preparation (20% βCD to solubilize 10 mg/ml midazolam, nasal administration volume 0.75ml) or Dormicum ® 5 mg/ml (nasal administration volume 1.5 ml) [Roelofse, et al. 2000]. The maximal midazolam plasma concentration and the systemic bioavailability were considerably lower for midazolam delivered by the test preparation (20% βCD, 10 mg/ml midazolam). Based on the solubility study, the published data from Loftsson et Jarho [Loftsson 1995, Jarho, 1996], and the outcome of the in vivo study of Roelofse et al., the excess of cyclodextrin was supposed to reduce midazolam release. To confirm this assumption (in vitro) midazolam release studies were performed with preparations containing 20% RMβCD and 4% RMβCD (equimolar amount) to solubilize 10 mg/ml midazolam and compared with midazolam release from Dormicum ® 5 mg/ml (no RMβCD). Despite half midazolam concentration, midazolam release from Dormicum ® 5 mg/ml was superior to midazolam release from RMβCD containing preparations (total midazolam concentration 10 mg/ml). Furthermore, midazolam release from preparations with 20% RMβCD (10 mg/ml midazolam) was lower as midazolam release from preparation with equimolar RMβCD (4%) to solubilize 10 mg/ml midazolam. In further drug release studies with semi-permeable cellophane membranes (in vitro) the effect of RMβCD on midazolam release was investigated with 5 mg/ml, 15 mg/ml, and 30 mg/ml midazolam solubilized with equimolar and threefold amounts of RMβCD. Due to limited midazolam solubility drug release studies without RMβCD were performed only for 5 mg/ml midazolam. Midazolam release from RMβCD containing preparations did not correlate with the absolute midazolam concentration in the donor compartment (5 mg/ml, 15 mg/ml, and 30 mg/ml). The impaired midazolam release from preparations with higher RMβCD concentrations (ratio RMβCD to midazolam, 3 to 1) indicated that less free midazolam molecules are available for permeation. According to the law of mass action, high concentration of one educt (i.e., RMβCD) promotes the formation of the product (i.e., RMβCD-midazolam complexes), see Equation 3. In addition, huge excess of cyclodextrins is reported to promote non-conventional cyclodextrin complexes (i.e., noninclusion complexes) and molecular aggregation [Loftsson, et al. 2005], consequently reducing free midazolam concentration available for permeation. [RMβCD] + [free midazolam] ↔ [RMβCD-midazolam complexes] + [RMβCD] + [free midazolam] (Equation 3) Katja Suter-Zimmermann Page 57 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
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
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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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Page 106 and 107: 8 Overall discussion pharmacokineti
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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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