Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

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5. Project I: Development of preparations for transmucosal nasal midazolam delivery 5.2.5 Specification and stability testing Specification and quality control of the investigational products For all investigational products (Preparation 1 to 5, see Table 5-4) GMP-conform specifications (see Appendix 10.2.4 to 10.2.9 ), instructions for manufacturing, and instructions for quality control were provided according to the quality management system of Hospital Pharmacy of the University Hospital Basel. Accelerated stability testing Accerlerated stability testing was accomplished for the Preparation 3 and 4 (see Table 5-4). The preparations were bottled in sealed vials and stored protected from light at room temperature, 40°C, 50°C, and 60°C for 30 days. Midazolam content , pH, and aspect (color, precipitate) was assessed every 3 days. Real time stability testing For stability testing the nasal sprays for Project II (Preparations 1a, 2, 4, 5) were stored at room temperature for 6 months and the nasal sprays for Project III (Preparations 1b and 3) were stored at room temperature for 10 months. Aspect (visual), pH (pH Meter 780, Metrohm AG, Herisau AR, Switzerland), tonicity (The Advanced TM Micro Osmometer Model 3300, Norwood, MA, USA), and midazolam content (HPLC, see Table 5-1), were analyzed according to the specifications (Appendix 10.2.4 to 10.2.9) of the investigational products. Katja Suter-Zimmermann Page 48 of 188 University of Basel, 2008
5. Project I: Development of preparations for transmucosal nasal midazolam delivery 5.3 Results 5.3.1 Solubility studies 80 70 BR buffer BR buffer + 10%RMbCD BR buffer + 10%HPbCD Figure 5-2 shows pH-dependent solubility of midazolam in BR buffer and in BR buffer with 10% RMβCD, Midazolam consentration [mg/ml] 60 50 40 30 20 10 BR buffer + 10%HPgCD 10% HPβCD, and 10% HPγCD. All tested cyclodextrin derivatives enhance midazolam solubility, but not independent of pH. In Table 5-2 maximal midazolam concentrations in BR buffer and BR buffer with 10% RMβCD, 10% HPβCD, and 10% HPγCD are listed. 0 2 3 4 5 6 7 pH Figure 5-2: pH-dependent solubility of midazolam. In BR buffer (40 mM boric acid, 40 mM acetic acid, 40 mM phosphoric acid; pH, adjusted with 1.0 M sodium hydrochloride) with and without solubilizer (10% RMβCD, 10% HPβCD, and 10% HPγCD). Table 5-2: Midazolam solubilized with 10% RMβCD, 10% HPβCD, and 10% HPγCD. pH Midazolam hydrochloride solubility (mg/ml) in: RB buffer (pH 3.5) + 10% RMβCD + 10% HPβCD + 10% HPγCD 3.0 56.4 68.1 70.3 68.0 3.5 3.4 --- --- --- 4.0 3.8 42.4 33.3 52.8 4.5 1.5 --- --- --- 5.0 0.5 10.0 4.4 2.6 7.4 --- 2.53 0.8 0.6 Katja Suter-Zimmermann Page 49 of 188 University of Basel, 2008
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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
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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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