The three main disadvantages of nasal delivery lie in:
1) The smaller volume of the nasal cavity compared to gastric intestinal tract limits the maximum dose delivered into the nose, which makes drugs for continuous and frequent administration.
2) The rapid removal of drug formulations deposited in the nasal cavity by nasal mucociliary clearance is an important limiting factor.
3) High variability in the amount of drug absorbed reported due to the variation in patient’s actuation technique and the complexity involving both the formulations and the devices.
1.4 Nasal anatomy and physiology
Fig 1.2: Structure of the internal nasal cavity, and the oral cavity. The nasopharynx, oropharynx, and laryngopharynx, they are three main subdivisions of the pharynx
1.4.1 Nasal anatomy (27Proctor DF et al;1985, 28Mygind N 1998; 29Ugwoke MI et al 2001)
General anatomy. The nose is divided basically in the two compartments, containing similar structures. The one-third of nose and nasal cavity is externally visible, rest is well hidden centrally in the frontal skull. The nose is 5cm high and 9-10cm long dual chamber with a total surface area of about 150 cm2 and with total volume of about 15-20ml. Each half of the nasal cavity is limited by the septal wall and the lateral wall. The frontal part, the vestibule, a middle part, containing three turbinates and just before the nasopharynx a posterior part, the choanae (fig 1.2).
The presence of these chonchae creates a turbulent air flow through the nasal passages which thereby ensures a better contact between the mucosa and the inspired air, thus facilitating its humidification and temperature regulation.
The nasal vestibule, is covered with skin and has hairs (vibrissae), and narrows down towards the middle part of the nasal cavity. The narrowest point is referred as the nasal valve or internal ostium, which is located approximately 1.5 cm from the nasal tip. The cross-sectional area of the valve is 30mm2 (about 5 – 6 mm) on each side.
The middle part of the nose has on the medial side the nasal septum and on the lateral side, from top to bottom, three turbinates’, a superior, a middle and an inferior turbinate. These turbinates are important in the regulation of airflow, humidity and temperature of the inspired air. The middle meatus is important in local disease and drug delivery, called the osteomeatal complex. Most of the sinuses have their opening and drainage in this area, referred as nasolachrymal duct and the paranasal sinuses. This region is essential in the cause and treatment of disease.
The nasal septum divides the nasal cavity in two half’s, and the frontal third is highly vascularized. The region around the superior turbinate is a sort of narrow ‘roof’ and contains the area of olfaction.
Epithelial layers and cells. The nose is considered to have the large surface area, especially within the relative small cavity. The surface epithelium contains three epithelial layers that is squamous epithelium, respiratory epithelium and olfactory epithelium. The vestibule is covered with keratinized squamous epithelium. Almost the septum, middle and inferior turbinates, just like rest of the airway, is lined well with respiratory epithelium.
This epithelium layer contains columnar cells next to goblet cells. Each columnar cell has about 300 microvilli, which are short fingerlike cytoplasmic expansions, thereby increases the surface area of the epithelium. Here the microvilli promote exchange processes and prevent the surface drying merely by retaining the moisture over it. Columnar cells are ciliated or non-ciliated. The cilia are motile hair like appendages extending from the surface of epithelial cells. There are 200 cilia per cell, and beats in the direction of nasopharynx at the frequency of 10-15Hz (30Marttin E 1997).
All particles larger than 10 ??m are retained in the nose during breathing at rest, while particles smaller than 2 ??m passes through nose. The mucus layer and foregin particles are swept towards the back of the nasal cavity where they can be swallowed and subsequently destroyed in the GIT. Cilia beat about 1000 times per minute in the backward direction
Non-ciliated columnar cells are presents in the first one-third part of the nose, while ciliated cells are seen at the whole posterior part, which starts at the inferior turbinate head. Lesser amount of cilia are seen in the areas where there is increased airflow, low humidity and low temperature exist (27 Proctor DF 1985).
Fig 1.3: Nasal mucosa: ciliated, non-ciliated and goblet cells under a blanket of mucus. a.Mucus gel/top layer; b.Mucus sol layer; c.Non-ciliated columnar cell; d.Ciliated columnar cell; e.Supporting cell; f.Basal membrane; g.Goblet cell ; h.Cilia ; i.Microvilli
Goblet cells produces mucus which increasingly located posteriorly in the nasal cavity (fig 1.3). Approximately 20-40 ml of mucus are produced from the normal ‘resting’ nose per day (31 Quraishi, 1998).
Their volume of secretion is probably small as compared to that of submucosal glands. Goblet cells are less interconnected because of discontinuity of tight junctions (33 Carson JL et al 1987). These tight-junctions opening or discontinuity could play a role in nasal drug absorption (30 Marttin E 1997)
Olfactory epithelium. The top part of the nose is covered with olfactory epithelium and comprises about 10- 20cm2 (8%) of the nasal surface epithelium in humans. The potential role of this area is the transport of certain drugs to the brain.
Blood vessels. Several types of blood vessels are located within the nose and differ from the rest of the airway vasculature. First, there is venous sinusoids blood vessel, mainly located in the inferior turbinates. They are normally found in a semi-contracted state but can swell in some conditions. Secondly, nasal vasculature shows cyclical changes of congestion.
Third, there are arterio-venous anastomoses, which probably related to temperature and water control and thereby creates a shunted blood flow of at least 50% of the total nasal blood flow. Therefore, total blood flow through the nose per cm3 is greater than in muscle, brain or liver (33 Drettner B et al 1974).
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