Physiological Pharmaceutics

210 Physiological Pharmaceuticsagonists and analogues which are used as contraceptive agents. Synthetic nasal salmoncalcitonin is used in Hong Kong to treat ostoporosis 40 .A nasally delivered live attenuated influenza vaccine (FluMist ) has been developedto aid annual immunisation for influenza particularly for children and the elderly 41 . Itconsists of egg allantoic fluid, primarily ovalbumin and live attenuated influenza virusestypes A and B.In the US, sufentanil and midazolam are administered intranasally for sedation. Antimigrainetreatments such as ergotamine tartate, sumatriptan and butorphanol are alsoadministered intranasally to relieve the nausea and vomiting which is associated with severemigraine.Penetration enhancersThe drive to increase the absorption of large molecular weight molecules has lead to the useof penetration enhancers. Bile salts, e.g. sodium deoxycholate, sodium glycocholate andsodium taurocholate, decrease the viscosity of mucus and create transient hydrophilic poresin the membrane bilayer. EDTA, and fatty acid salts such as sodium caprate and sodiumlaurate, increase paracellular transport by removal of luminal calcium, thus increasingpermeability of the tight junctions. Non-ionic detergents e.g. Laureth-9 alter membranestructure and permeability. It should be remembered that the penetration enhancers aregenerally non-specific and there remains the potential that any large molecule can enter thesystemic circulation once the epithelial barrier is breached. Some penetration enhancers, e.g.Laureth-9 and bile salts, have been reported to be toxic to the nasal mucosa.Cyclodextrins have been used as solubilizers and absorption enhancers for nasal drugdelivery 42 . Methylated ß-cyclodextrins have been used to promote absorption of peptidesand proteins, but mainly in animals. Limited studies show that the cyclodextrins are welltolerated in humans 43 44 .DRUG DELIVERY SYSTEMS AND DEPOSITION PATTERNSInhaled particles are deposited by five mechanisms; interception, electrostatic precipitation,impaction, sedimentation and diffusion. However, it is only the last three which areimportant in nasal drug delivery. Aerodynamic particle size is a key factor in nasaldeposition. Correlation of aerodynamic particle diameter and nasal deposition efficiency ata given flow rate shows that particles of 0.5–1 µm are the least likely to impact. Above thisparticle size deposition increases due to inertial forces, and below it due to turbulentdiffusion. Although the lung filters particles more efficiently during expiration compared toinspiration, expiratory deposition is lower than inspiratory deposition due to the loss ofparticles deposited in the lung 45 .There are four basic formulations which are suitable for nasal drug delivery. These aresolution, suspension, emulsion and dry powders. The liquid formulations are often waterbased but may contain alcohol, oils or other organic solvents. Mechanical pumps andpressurised aerosol devices may be used for accurate dosing.Liquid spray and drop preparations are most commonly used to deliver drugsintranasally. For the nasal drop to be correctly applied, some complex manoeuvres arerequired which include lying on a bed with the subject’s head at a 90° angle and the nostrilsuppermost. The drops are then applied and the head is swirled from side to side! Apart fromnot being very practical, the volume delivered cannot be easily controlled and contaminationof the formulation can easily occur. High concentrations of preservatives cannot be used asthey may damage the nasal mucosa and affect mucociliary clearance. Single use preparationsmay avoid the potential problems of contamination of the containers. The currentlyavailable devices are the bottle pack and a device which operates with an actuator and a