Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

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2. Impact of anatomy and physiology on transmucosal nasal drug delivery 2.2 Nasal mucosa and mucociliary clearance 2.2.1 Morphology of the nasal mucosa All mucous membranes are linings of ectodermic origin and are involved in absorption and secretion processes. Mucous membranes cover various body cavities exposed to internal organs or external environment. At the nostrils, the lips, the ears, the genital area, and the anus, tissue changes in a smooth transition from skin (epidermis, dermis) to mucosa. From the nostrils to the nasopharynx, the predominant cell types of the nasal mucosa lining are changing. Stratified squamous, respiratory (pseudostratified columnar), and transitional epithelium, are the different epithelia linings of the nasal mucosa. In the anterior third of the nasal cavity, stratified squamous and transitional epithelium precedes respiratory epithelium, which is predominant in the posterior two-thirds of the cavity. The human olfactory region, situated in the superior conchae, covers only about 10% (about 10 cm 2 ) of the nasal cavity, while in mice and rats about 50% of the nasal cavity is covered by olfactory epithelium [Gizurarson 1993]. The olfactory epithelium is a pseudo stratified columnar structure. It consists of specialized olfactory cells, supporting cells, and serous and mucosal glands [Romeo, et al. 1998]. The respiratory epithelium is the major lining of the human nasal cavity and is essential for cleaning of nasal mucosa by the mucociliary clearance. The respiratory epithelium comprises of five cell types; ciliated and non-ciliated columnar cells, goblet cells, basal cells, and low numbers of neurosecretory cells in the basement membrane, see Figure 2-2. The apical side of the columnar and goblet cells reaches the lumen of the nasal cavity. Approximately 20% of the cells in the lower turbinante area are ciliated cells, with about 100-300 cilia on the apical surface. Cilia are hair-like projections (5-10 µm) on the apical surface of the columnar cells. All cilia beat in a coordinated fashion, transporting the mucus towards the nasopharynx. Basal cells are adjacent to the basal lamina, on the basolateral side of the epithelium. The lamina propria is located beneath the basal lamina and contains many blood vessels, nerves and glands. The functions of epithelial cells in the nose can be summarized as follows: (1) building a physical barrier for particles and allergens; (2) secretion of mucus, to protect the mucosa and to provide efficient conditioning of the inspired air; and (3) responding to various stimuli by producing mediators to recruit lymphocytes, eosinophils, and mast cells to the nasal mucosa [Takeuchi et al., 2006]. The intense blood flow in the arteriovenous anastomosis and the large surface of the respiratory epithelium favors transmucosal nasal drugs absorption. Drug absorption in the olfactory region is possibly resulting in direct nose to brain-transport through the nervus olfactorius (q.v. chapter 1.4.) [Gizurarson 1993]. Katja Suter-Zimmermann Page 18 of 188 University of Basel, 2008
2. Impact of anatomy and physiology on transmucosal nasal drug delivery gel layer sol layer mucus layer ciliated cell basement membrane with neurosecretory cells Non-ciliated cell with microvilli goblet cell basal cell Figure 2-2: Respiratory epithelium. The respiratory epithelium is covered by a mucus layer (gel and sol layer) and the cell types arising from the basement membrane are: ciliated and non-ciliated cells (with microvilli), goblet cell, and basal cell. Modified after [Sakane et al., 1991]. 2.2.2 Mucus and mucociliary clearance The goblet cells and the submucosal glands secrete about 20 ml to 40 ml mucus per day [Quraishi et al., 1998]. The mucus layer protects the underlying tissue from various environmental influences and the metabolic effects of enzymes. The mucus layer and hairs in the anterior nose filter 80% of particles larger than 12.5 µm out from the inhaled air stream [Jones 2001]. The pH of the mucus layer varies from 5.5 to 6.5 in adults and from 5.0 to 7.0 in infants [Arora, et al. 2002]. The principal component of the mucus is water (90-95%) containing mucin (2%), electrolytes (1%), proteins (1%, mainly albumin, immunoglobulins, and lysozymes), and lipids [Merkus et al., 1998; Schipper et al., 1991]. Small molecules not interacting with the components of the mucus layer diffuse freely through the water network of the mucous gel. Khanvilkar et al. demonstrated that for many compounds, nasal mucus layer adds as little additional resistance as an unstirred water layer of equal thickness [Khanvilkar et al., 2001]. The mucus layer consists of two films with different rheological properties, a preciliary layer (sol layer) and a more viscous upper layer (gel layer) covering the tips of the cilia. Responsible for the rheological properties are two forms of mucin; soluble mucin and membrane bound mucin. Soluble mucin forms viscous gels by intermolecular disulfide bridges [Khanvilkar, et al. 2001]. The sol layer with low viscosity is slightly less thick than the length of an extended cilium (5 µm to 10 µm). The extended cilia dip into the gel layer and, with effective beats, transports the layer to the nasopharynx. During the recovery stroke, the cilia move backward through the sol layer. In the Katja Suter-Zimmermann Page 19 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
Page 22 and 23: 1. Nasal drug delivery 1.3 Challeng
Page 25: 2. Impact of anatomy and physiology
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Page 31 and 32: 3. Midazolam 3 Midazolam 3.1 Physic
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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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