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Figure 9.6 Clearance of 99mTc microspheres from the nose. □ microspheres, subject seated; ■ microspheres, subject supine; O DTPA solution control.

increase the nasal absorption and residence of insulin56, and solutions thickened with hyaluronan showed an increased residence time57.

Bioadhesive microspheres

Microsphere formulations studied include albumin, Sephadex, starch, dextran58, hyaluronan59, and chitosan60. The majority of these studies were intended for the delivery of peptides, particularly insulin, and caused increased absorption. Unfortunately there are conflicting reports concerning their nasal residence, and some workers have suggested that they are rapidly cleared but somehow increase nasal permeability58. In some cases, one is led to suspect that the isotope labelling of microspheres used for scintigraphy studies may be at fault.

The studies which demonstrate long nasal retention times for bioadhesive microspheres report that this occurs in the anterior part of the nasal cavity, which is non-ciliated and non-absorptive (Figure 9.6)15.

Excipient and drug effects on clearance

Much interest has been shown in the ciliotoxicity of formulation excipients included in nasal sprays, although recently a differentiation is being made between ciliotoxicity and cilioinhibition61.

In the early 1980's, it was recommended that mercury-containing preservatives, e.g. thiomersal, should not be employed in nasal preparations since these materials produced a rapid, irreversible inactivation of cilia in a chick tracheal preparation62. However later studies showed that thiomersal at the concentrations used in these experiments had no effect on mucociliary transport in man63. Recently, the combination of topical steroids and benzalkonium chloride has produced areas of squamous cell metaplasia in rat nostrils. This was not observed in any nasal cavities exposed to the topical nasal steroid without the preservative, or to 0.9% NaCl, suggesting that benzalkonium chloride is potentially toxic64. It obviously does disrupt the membrane, allowing large molecules to pass through, since it enhances insulin absorption three-fold (6.31% vs 1.96%)65. Benzalkonium chloride is also present in many buserelin and nafarelin formulations and has also been shown to reduce ciliary beat frequency by 35% for 20 minutes in vitro, but it appears to have little effect in vivo66. The benzalkonium chloride story is further confused by in vitro studies which compared its ciliotoxicity to that of chlorobutol using concentrations of 0.005% for both compounds67. In commercial formulations, different concentrations of both are used i.e. 0.01% benzalkonium chloride and 0.5% chlorobutol. Hence, not surprisingly, the data generated using 0.005% chlorobutol demonstrated it to be less ciliotoxic than benzalkonium chloride, whereas studies using representative concentrations of both show that the reverse is true68 69.

Many drugs administered in nasal preparations can also influence ciliary motility. The list of materials which are cilioinhibitory includes anaesthetics70 antihistamines, propranolol71 and bile salts72. However, E-adrenergic and cholinergic drugs stimulate ciliary motility. Early in vitro studies indicated that penicillin had an inhibitory effect on ciliary function, however this was not found in subsequent studies using orally administered penicillin73.

Dexamethasone nasal drops (used in the treatment of allergic rhinitis) may cause pathological changes leading to Cushing's syndrome74. Cushing's syndrome results from hypersecretion of the adrenal cortex leading to symptoms such as protein loss, fatigue, osteoporosis, amenorrhoea, impotence and oedema. The drug acts by absorption through the nasal mucosa and partly through the intestinal mucosa after a portion of the dose is swallowed. This problem does not occur with the newer intranasal steroids (e.g. beclomethasone and flunisolide) which are less readily absorbed through the nasal mucosa, and are inactivated in the liver after gastrointestinal absorption.

Care must be taken when extrapolating cilioinhibitory or toxicity data from in vitro to in vivo situations. For example, azelastine was claimed to be ciliotoxic, since it reduced in vitro ciliary beat frequency75, however, this effect was not observed in animals and in long term use in allergic rhinitis patients it actually improved the nasal clearance rate76.

Effect of formulation pH

The average baseline nasal pH is 6.4 in the anterior of the nose and 6.27 in the posterior of the nose (Figure 9.7)77. The ranges were 5.5-6.5 and 5.0-6.7 in adults and children respectively. Nasal pH varies with air temperature, sleep, emotions and food ingestion37. In acute rhinitis and sinusitis the nasal secretion is alkaline.

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