Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

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5. Project I: Development of preparations for transmucosal nasal midazolam delivery Accelerated stability testing In Preparation 3 (10 mg/ml) midazolam content was constant and no precipitation or discoloring occurred during storage at room temperature 40°C, 5 0°C, and 60°C, for 30 days. In Preparation 4 (30 mg/ml) midazolam content was constant and no precipitation occurred during storage at room temperature 40°C, 50°C, and 60°C, f or 30 days. At storage temperature of 60°C Preparation 4, originally colorless solution turned slightly yellow. For all storage conditions pH was constant in both preparations (Preparation 3 and 4), the measured values are listed in Appendix 10.2.2 and 10.2.3. Real time stability testing To perform real-time stability testing Preparation 1 and 3 were stored for 10 months and Preparations 2, 4, and 5 were stored for 6 months at room temperature. In Table 5-5 the specification of Preparation 1a to 5 are listed. To fulfill the stability requirements all analyzed parameters had to comply with the specified limits. In Table 5-6 and Table 5-7 the outcome of stability testing of 6 months and 10 months, respectively is summarized. Stability reports, including original data, are shown in Appendix 10.2.10 to 10.2.15. Acquired stability data confirm specified shelf life of 6 months for Preparation 1a, 1b, 2, 3, and 4 but not for Preparation 5. After 10 months storage at room temperature Preparation 3 fulfills all specified quality requirements. Table 5-6: Outcome of stability testing: 6 months Nr. Preparation Aspect Identity Midazolam Content [mg/ml] pH Osmolality [mOsmol/kg] Shelf life 6 months 1a 1b 2 3 4 Midazolam UD Nasal Spray 0.5 mg Midazolam MD Nasal Spray 5 mg/ml Cyclodex-Midazolam UD Nasal Spray 0.5 mg Cyclodex-Midazolam UD Nasal Spray 1 mg Cyclodex-Midazolam UD Nasal Spray 3 mg o.k. o.k. o.k. o.k. o.k. 5 Chitosan-CD-Midazolam UD Nasal Spray 3 mg analyzed parameter fulfills specification analyzed parameter below specified limits Table 5-7: Outcome of stability testing: 10 months Identity Nr. Preparation Aspect Midazolam 1b 3 Midazolam MD Nasal Spray 5 mg/ml Cyclodex-Midazolam UD Nasal Spray 1 mg analyzed parameter fulfills specification analyzed parameter above specified limits not o.k. Content [mg/ml] pH Osmolality [mOsmol/kg] Shelf life 10 months not o.k. o.k. Katja Suter-Zimmermann Page 54 of 188 University of Basel, 2008
5. Project I: Development of preparations for transmucosal nasal midazolam delivery 5.4 Discussion Different cyclodextrin derivatives were evaluated to solubilize midazolam for development of preparations for transmucosal nasal midazolam delivery. Drug release studies were performed to assess the effect of the selected solubilizer (RMβCD) on midazolam release in vitro. Furthermore, accelerated and long term stability testing was performed. Besides presystemic drug elimination (intestinal and hepatic first-pass metabolism), the most important parameters affecting bioavailability are aqueous solubility and permeability of the drug. The Biopharmaceutical Classification System (BCS) was introduced by the FDA as binning system for oral drugs, and classifies all drugs into four groups based on their ability to permeate biologic membranes and their aqueous solubility. A given drug substance is considered ‘highly soluble’ when the highest dose strength is soluble in ≤ 250 ml water, and ‘highly permeable’ when the extent of oral absorption in humans is determined to be ≥ 90% of an administered dose (in solution). According to this definition, midazolam salts are rated as ‘highly soluble’, because the highest oral dose strength (15 mg midazolam) is soluble in ≤ 250 ml water. For transmucosal nasal drug delivery the definition of ‘high’ and ‘poor’ solubility has to be adjusted to the characteristics of the nasal cavities. Obviously, in the nose there is only very little solvent available to solubilize administered drugs. Therefore, drugs preferably are delivered as solutions. Since the capacity of the nasal cavities is limited, delivery of extended volumes results in swallowing of surplus liquid preparations. Consequently, minimizing of nasally instilled volumes is essential to provide for exclusive transmucosal nasal drug uptake. In transmucosal nasal drug delivery, drugs may be rated as ‘highly soluble’ if the highest dose to be nasally delivered is soluble in ≤ 0.2 ml aqueous solutions. According to this definition, for transmucosal nasal delivery midazolam is to be classified as poorly soluble. Transmucosal nasal drug delivery is particularly feasible for drugs with high potency. Furthermore, for efficient transmucosal nasal drug delivery the compound needs to be ‘highly permeable’. Overall ideal characteristics of drugs for transmucosal nasal delivery are: high solubility, high permeability and adequate potency. Since systemic bioavailability of transmucosal nasal absorbed midazolam is not affected by presystemic metabolization (hepatic first-pass effect), the doses to be nasally administered are lower than doses for oral application. Midazolam proved excellent permeation ability [Gudmundsdottir, et al. 2001], therefore, the key issue in compounding nasal preparations for transmucosal nasal midazolam delivery is the relatively poor and highly pH-dependent solubility of midazolam. Different approaches to enhance midazolam solubility have been described in literature. Knoester et al. proposed a nasal midazolam preparation with 26% propylene glycol, but the administration of this hypertone preparation resulted in local irritation [Knoester, et al. 2002]. Less local irritation has been reported for nasal administration of midazolam preparations with cyclodextrins as solubilizer [Gudmundsdottir, et al. 2001]. Therefore, in the presented project different cyclodextrin derivatives were evaluated to solubilize midazolam in preparations for nasal midazolam delivery. To prevent Katja Suter-Zimmermann Page 55 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
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 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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