Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

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4. Compounding of nasal midazolam preparations 4.4.2 Applications of chitosan Chitosan is a multifunctional excipient with a wide rang of industrial applications (e.g., flocculant for wastewater clarification, chelating of heavy metals, clarification of fruit juices and beers, and fungicide in agriculture) [Shahidi and Abuzaytoun 2005]. Further, in food industry, chitosan is a popular dietary supplement, particularly in Japan. In addition, chitosan is used for ophthalmic applications, such as contact lens coating or as the contact lenses material itself and in cosmetic industry chitosan is also a very popular excipient (e.g., for hair care products). Chitosan is a versatile excipient for miscellaneous pharmaceutical applications. Chitosan is adjuvant in direct compressed tablets, for controlled release matrix tablets, in the process of wet granulation, in gels, films, and emulsions, as well as wetting and coating agent, and for the production of microspheres and microcapsules. Chitosan is used also in newer research areas like nasal vaccine delivery and DNA delivery [van der Lubben et al., 2001; Xu et al., 2004]. The European Pharmacopoeia describes the requirements for chitosan hydrochloride used in pharmaceutical products. 4.4.3 Chitosan in transmucosal nasal drug delivery Davis et al. were the first to demonstrate the cationic polymer chitosan to promote the transmucosal adsorption of challenging drugs, particularly with regard to improved nasal delivery. In animal and human models, chitosan generated a remarkably higher bioavailability [Davis and Illum 2003]. Illum et al found, that the addition of chitosan to a nasal formulation of insulin caused plasma glucose to fall to 43% of basal level compared to 83% without the addition of chitosan [Illum et al., 1994]. Similar effects on bioavailability have been achieved for polar low-molecular-weight drugs (e.g., morphine and antimigraine drugs). Chitosan is an effective nasal absorption enhancer in liquid and powder formulations. Chitosan improve bioavailability in nasal and pulmonal drug delivery [Illum 1998; Illum et al., 2002; Martinac et al., 2005; Yu et al., 2004]. In liquid formulations for nasal drug delivery, concentrations of 0.5-1.0% chitosan proved to promote absorption [Davis and Illum 2003]. Unlike common penetration enhancers, chitosan is neither membrane active nor a classical surfactant and is not transmucosal absorbed. The clearance of chitosan formulations from the nasal cavity of sheep and humans has been shown to be significantly slower compared with aqueous solutions [Soane et al., 1999; Soane et al., 2001]. The mucoadhesion results of the interaction between the linear cationic polysaccharide chitosan and the negatively charged mucosa. This mechanism decelerates the nasal clearance [Aspden et al., 1997]. The extended time of contact of the formulation and the nasal mucosa favors the transmucosal drug absorption [Pavis et al., 2002]. Studies with CaCo-2 cell monolayer suggest cationic polymers (e.g., chitosan) to modify permeability of the monolayer by interaction with the gating mechanism of tight junction, causing a transient opening [Artursson et al., 1994]. Dodane et al. demonstrated Katja Suter-Zimmermann Page 40 of 186 University of Basel, 2008
4. Compounding of nasal midazolam preparations complete reversibility of the transient opening of the tight junctions and showed the function of the nasal mucosa to be unimpaired [Dodane et al., 1999]. Consequently, the impact of chitosan on pharmacokinetics of transmucosal delivered drugs results of the prolonged drug mucosa contact by bioadhesion [Soane et al. 1999; Soane et al. 2001] and a transient completely reversible opening of tight junctions [Dodane et al. 1999]. 4.4.4 Safety and toxicology of chitosan In a review Dodane and Vilivalam characterized chitosan as safe and effective permeation enhancer for nasal drug delivery of systemic drugs [Dodane and Vilivalam 1998]. Concentrations of 0.5% chitosan hydrochloride improved absorption of different nasally administered compounds. The nasal mucosa was not affected. Illum et al. demonstrated, that neither nasal nor intravenous delivered chitosan caused any humoral immune reaction [Illum 1998]. It has been shown that the absorption-promoting effect of chitosan on the mucosal membrane is transient, with the effect declining between 30 minutes and 45 minutes after application of a liquid formulation [Illum 1998]. In a clinical trial with 14 cancer patients, break-through pain was treated with morphine nose sprays containing chitosan. All observed adverse effects (bitter taste, tiredness) were correlated with morphine [Pavis et al. 2002]. Aspden et al. examined the effect of an aqueous chitosan solution (0.25%) on the nasal mucosa in vitro and in vivo with 10 healthy volunteers. After 7 days treatment with aqueous chitosan solution (0.25%) no markers of inflammation were detected neither by endoscopic investigation of the nasal mucosa (in vivo), nor by light-microscopic investigation (in vitro). All treated volunteers tolerated nasal application well. Furthermore, Aspeden et al. showed that chitosan has a transient and completely reversible effect on mucocilliary transport rate. Chitosan is bioadhesive and able to interact with the nasal mucus layer and with the nasal epithelial cells [Aspden, et al. 1997] Chitosan is not absorbed, non toxic, biocompatible, and neither irritating nor allergenic [Dodane and Vilivalam 1998]. Katja Suter-Zimmermann Page 41 of 186 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
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
Page 47: 4. Compounding of nasal midazolam p
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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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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