Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

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2. Impact of anatomy and physiology on transmucosal nasal drug delivery nasopharynx, the transported mucus layer with the trapped inhaled particles is swallowed or expectorated. Cilia in isolation are sensitive to temperature, optimally working at 35-40°C, and below these temperatures, the natural beat frequency drops [Jones 2001]. Increased mucus production in the respiratory tract is a symptom of many common diseases, such as the common cold. Nasal mucociliary clearance describes the removal of inhaled particles, viruses and bacteria by the combined function of cilia and mucus layers. Nasal mucociliary clearance is important for the protection of the respiratory system [Merkus, et al. 1998]. It takes approximately 20-30 minutes to remove the whole mucus layer [Bommer 2002]. Mucociliary clearance is independent of age and sex [Kao et al., 1994]. Extend of transmucosal nasal drug absorption is related to contact time of the delivered drug with the nasal mucosa. Nasal mucociliary clearance limits the residence time of drugs administered into the nasal cavities, decreasing the time available for the drug to be absorbed [Merkus, et al. 1998]. In the nasopharynx, not absorbed compounds are swallowed, followed by gastrointestinal degradation, gastrointestinal absorption, and/or hepatic metabolization. Mucociliary clearance can be modified by nasally administered drugs or components of the vehicle (viscosity enhancers, mucoadhesive excipients). Evaluation of the effects of drugs and additives on nasal mucociliary clearance is an important issue, especially in developing preparations for long-term treatments. The measurement of ciliary beat frequency in vitro is a very accurate and reproducible technique to determine the effects on ciliated epithelium. Therefore, assessment of ciliary beat frequency is a screening method to estimate potential toxicity of drugs and excipients and to compare nasal preparations. However, ciliary beat frequency data have to be interpreted carefully, because effects of nasal formulations in vitro are usually stronger than effects in vivo [Merkus, et al. 1998]. In vivo, the mucus layer protects cilia and dilutes the nasally delivered preparations, whereas in vitro, the cilia are in direct contact with the formulations. Furthermore, the nasal mucosa continuously regenerates. Consequently, it is difficult to predict the effects of chronic application on mucociliary clearance in vivo based on ciliary beat frequency assessment in vitro. For the term ‘ciliotoxic’ no defined criteria exist and the classification depends on the performed in vitro assays. Furthermore, the cilioinhibitory effects of compound or vehicle depend on the applied concentration and are often additive [Merkus, et al. 1998]. To predict the safety of nasal drug formulations for human use, it is important to investigate the effects of therapeutic concentrations, both in vitro and in vivo. Katja Suter-Zimmermann Page 20 of 188 University of Basel, 2008
2. Impact of anatomy and physiology on transmucosal nasal drug delivery 2.3 Drug metabolism in the nasal mucosa Nasal biotransformation enzymes are responsible for the metabolism of airborne xenobiotics. Geravasi et al. demonstrated the human respiratory epithelium of the nose containing a wide array of oxidative and non-oxidative enzymes, responsible for bioactivation or detoxication of inhaled xenobiotics [Gervasi et al., 1991]. Despite recent progresses in identification and characterization of numerous nasal biotransformation enzymes in animal models, metabolism in human nasal mucosa has not been conclusively characterized [Rahmel 2004; Zhang et al., 2005]. Some carcinogens or toxicants arise from metabolic transformation of originally nontoxic xenobiotic compounds. Most studies on metabolizing Cytochromes P450 monooxigenases (CYPs) in the respiratory tract focus on the role of these enzymes in metabolic toxicity [Ding and Kaminsky 2003]. CYPs, detected in extrahepatic tissues, usually, are also expressed in the liver at higher levels. Bereziat and Su characterized the sensitivity of tissues to a certain xenobiotic compound by the tissue-specific profile of exprimed CYP enzymes [Bereziat et al., 1995; Su et al., 2000]. However, the regulation mechanisms, responsible for tissue-specific CYP expression, have not been resolved. In human nasal respiratory epithel, Rahmel identified different isoforms of CYPs (such as CYP 1A1, 1B1, 2A6/7, 2A13, 2B6, 2C8, 2C9, 2C18, 2C19, 2E1, 2F1, 2J2, 2S1, 3A4, 3A5, and 4B1) by RT-PCR 1 . Furthermore, traces of CYP 1A2, 2D6, 3A7, and 4A11 were detected and enhanced expression of CYP 1A1, 1B1, and 2S1 was demonstrated in nasal mucosa of smokers. But, only the translation of CYP 2A proteins has been confirmed by western blot [Rahmel 2004]. To estimate the metabolic capacity of nasal mucosa, the actual transcription level of the metabolic enzymes or even the metabolic activity should be specified. For loteprednol-etabonate (CYP 3A4 substrate), testosterone, and ethoxyresorufin (CYP 1A1 substrate) Rahmel demonstrated minimal biotransformation in nasal microsomal preparations [Rahmel 2004]. For nasally delivered substrates of enzymes, expressed in nasal mucosa, metabolism preceding systemic absorption is to be expected. To what extend this ‘nasal first-pass effect’ affects the systemic bioavailability of nasally delivered drugs, depends on actual enzyme expression. Expression of CYP 3A4, mainly responsible for midazolam metabolism, has not been detected in human nasal mucosa. Therefore, for nasally delivered midazolam no nasal fist-pass metabolism has to be expected. 1 Reverse Transcription Polymerase Chain Reaction Katja Suter-Zimmermann Page 21 of 188 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
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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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