Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

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5. Project I: Development of preparations for transmucosal nasal midazolam delivery 5.2 Materials and methods 5.2.1 Materials Midazolam hydrochloride was purchased from Fährhauspharma (Hamburg, Germany), RMβCD (methylated-β-cyclodextrin, Cavasol ® W7M Pharma), HPβCD (hydroxypropyl-β-cyclodextrin, Cavasol ® W7HP Pharma), and HPγCD (hydroxypropyl-γ-cyclodextrin, Cavasol ® W8HP Pharma) from Wacker Chemicals (München, Germany), chitosan hydrochloride for preliminary testing from Kraeber GmbH & Co (Ellerbek, Germany), chitosan hydrochloride for pharmaceutical preparations from NovaMatrix FMC BioPolymer (Oslo, Norway). For the preliminary experiments all chemicals were of analytical reagent grade and obtained from commercial sources. Preparations for stability testing, were produced with chemicals of pharmaceutical quality (see also Project II and Project III). Semi-permeable cellophane membranes (Spectra/Por ® Dialysis Tubing, MWCO 2000 from regenerated cellulose) were obtained from Spectrum Europe (Breda, The Netherlands). Unit dose nasal sprays, delivering 0.1 ml, were obtained from Ing. Erich Pfeiffer GmbH (Radolfzell, Germany) and multidose nasal sprays, delivering 0.1 ml per pump, from E. Anwander & Cie. AG (Oberwil, Switzerland). 5.2.2 HPLC-Method The quantification of midazolam was performed by HPLC, Waters Alliance HPLC System (2690 Separation Module, 996 Photodiode Array Detector, Millenium 32 Software), Waters Corporation, (Millford, Massachusetts, USA). Table 5-1 shows the chromatographic conditions. Table 5-1: Chromatographic condition for midazolam analysis Parameter Setting column ACE RP18 3µm, 4.0 x 75 mm mobile Phase buffer pH 5.5/ACN flow rate 0.8 ml/min running time 10 min temperature 30°C injection volume 10 µl midazolam quantification wavelength 223 nm 5.2.3 Solubility studies To assess the pH-dependent solubility and the effects of different cyclodextrins, midazolam hydrochloride was added in excess amounts to Britton-Robinson buffer (BR buffer, 40 mM boric acid, 40 mM acetic acid, 40 mM phosphoric acid pH, adjusted to pH 3.0, 3.5, 4.0, 4.5, 5.0, and 7.4 Katja Suter-Zimmermann Page 46 of 188 University of Basel, 2008
5. Project I: Development of preparations for transmucosal nasal midazolam delivery with 1.0 M sodium hydroxide), containing no solubilization enhancer, 10% RMβCD, 10% HPβCD, or 10% HPγCD. The suspensions were equilibrated at room temperature for 3 days. The suspensions were filtered (0.45 µm) and midazolam content assessed by HPLC. All samples were prepared in triplicates. 5.2.4 Drug Release For drug release of midazolam from RMβCD-midazolam complexes aqueous solutions trough semi-permeable cellophane membranes, diffusion cells (see Figure 5-1) were used. A semipermeable cellophane membrane (Spectra/Por ® Dialysis Tubing, MWCO 2000 from regenerated cellulose) was inserted into diffusion cells with a surface area of 2.3 cm 2 . In a preliminary drug release study Dormicum ® 5 mg/ml, 10 mg/ml midazolam solubilized with 20% RMβCD, and 10 mg/ml midazolam solubilized with equimolar amount of RMβCD (4%) were filled in donor compartments. For drug release 5 mg/ml midazolam in water; 5 mg/ml, 15 mg/ml, and 30 mg/ml midazolam solved with equimolar amount of RMβCD; and 5 mg/ml and 30 mg/ml midazolam with threefold molar amount of RMβCD were filled into donor compartment. Osmolality of all preparations for midazolam release studies was adjusted to 300mOsmol/kg with sodium chloride. The receiver compartment contained 0.9% sodium chloride in water. Both compartments contained 8.0 ml and were stirred during the release experiments (see Figure 5-1 A and B). The diffusion cells were immersed in a water bath maintained at 37°C. Samples were withdrawn from the receptor compartment replaced with aliquots of 0.9% sodium chloride. Midazolam release per minute was assessed from the slope of the midazolam concentration time plot. A B Figure 5-1 A and B: Picture of a diffusion cell (A) and 2 diffusion cells mounted, ready for drug release experiment. The arrow indicates the position of the cellulose membrane. Katja Suter-Zimmermann Page 47 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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Page 53: 5. Project I: Development of prepar
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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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