Drug Delivery Systems And Deposition Patterns

Inhaled particles are deposited by five mechanisms; interception, electrostatic precipitation, impaction, sedimentation and diffusion. However, it is only the last three which are important in nasal drug delivery. Aerodynamic particle size is a key factor in nasal deposition. Correlation of aerodynamic particle diameter and nasal deposition efficiency at a given flow rate shows that particles of 0.5-1 pm are the least likely to impact. Above this particle size deposition increases due to inertial forces, and below it due to turbulent diffusion. Although the lung filters particles more efficiently during expiration compared to inspiration, expiratory deposition is lower than inspiratory deposition due to the loss of particles deposited in the lung45.

There are four basic formulations which are suitable for nasal drug delivery. These are solution, suspension, emulsion and dry powders. The liquid formulations are often water based but may contain alcohol, oils or other organic solvents. Mechanical pumps and pressurised aerosol devices may be used for accurate dosing.

Liquid spray and drop preparations are most commonly used to deliver drugs intranasally. For the nasal drop to be correctly applied, some complex manoeuvres are required which include lying on a bed with the subject's head at a 90° angle and the nostrils uppermost. The drops are then applied and the head is swirled from side to side! Apart from not being very practical, the volume delivered cannot be easily controlled and contamination of the formulation can easily occur. High concentrations of preservatives cannot be used as they may damage the nasal mucosa and affect mucociliary clearance. Single use preparations may avoid the potential problems of contamination of the containers. The currently available devices are the bottle pack and a device which operates with an actuator and a chamber with a piston. This can either be a single shot or double shot device, which enables both nasal cavities to be dosed.

Liquid formulations generally clear from the nose within 30 minutes, but the exact figure is very variable and ranges of 5 to 90 minutes have been reported. Radiolabelled nasal sprays exhibit bi-phasic clearance from their initial site of deposition46. The first phase lasts 15-20 min in which more than 50% of the administered dose is cleared. The slower clearance is the removal of material from, the non-ciliated vestibule and anterior septal area.

Dry powders are less frequently used in nasal drug delivery, even though they are preservative-free and have greatly improved stability. Powders can be administered from several devices, the most common being the insufflator. Many insufflators work with predosed powder in gelatin capsules. To improve patient compliance a multi-dose powder inhaler has been developed which has been used to deliver budesonide47.

Pressurized metered dose inhalers (pMDIs) originally developed for pulmonary delivery have been adapted for nasal use by alteration of the shape of the applicator. These have the advantage that generation of an aerosol is independent of inhalation. They are small, portable, available in a wide range of doses per actuation, provide accurate dosing and protect the contents. The disadvantages include possible irritation of the mucosa produced by the propellants and surfactants, and malfunctioning in cold conditions.

Vitamin B12 in a nasal gel for systemic delivery has recently been introduced into the marketplace. The gel has been used to prolong nasal retention, but the bioavailability may depend upon the mode and site of administration, since its viscosity prevents lateral spreading in the nose.

Care should be taken when studying bioadhesives for drug delivery to the nose. Any fraction of the dose which impacts on nasal hair will remain in the nose for exceptionally long periods, but it is however, not available for drug absorption48. Generally during studies, subjects are requested to refrain from blowing their nose, but it is this action which clears material impacted on the hair. Nasal patency will also affect the initial rate of clearance of nasal sprays from the mucosa. As would be expected, the clearance of a formulation is slower from the least patent nostril (T50—least patent 39.3±5.1 minutes vs most patent 24.2±2.9)48. Vigorous breathing during inhalation of aqueous sprays does not affect nasal deposition patterns49. Few studies have been carried out on the pharmacokinetic inter- and intrasubject variability after nasal administration of drugs50. However, there appears to be a non-linear dose-response curve for some formulations51.

The turbinates, which are covered by respiratory epithelium, are the primary sites for systemic drug absorption. Not surprisingly, drugs which are deposited posteriorly will clear faster than drugs deposited anteriorly. Nasal sprays deposit drugs more anteriorly than nasal drops and hence the type of dosing device used can affect absorption. For instance, the bioavailability of desmopressin is significantly increased when administered in a spray rather than drops. The particle size of the aerosol droplet is also very important since small particles (<10 pm) may be carried in the air into the lung whereas particles between 10 and 20 pm mainly deposit on the nasal mucosa. Aqueous sprays tend to produce droplets which are > 50 pm, with only 10% being less than 10 pm The intensity of sniffing as the nasal spray is administered does not appear to affect the deposition pattern52.

It should be remembered that regardless of the mechanism by which drug is administered to the nose, any drug which is not absorbed will either be blown out of the nose, or will clear to the gastrointestinal tract. When considering administering any drug to the nose, the consequence of gastrointestinal absorption should always be considered.

Mechanisms to increase nasal residence time of formulations

Two basic approaches have been used to increase the nasal residence times of drugs, and correspondingly to decrease intrasubject variation. These are firstly to use viscosity enhancers, and secondly to use a "bioadhesive" formulation to reduce the clearance rate. Two classes of bioadhesives have been used; firstly polymers which interact with the nasal mucus, and secondly microspheres. A large number of such formulations have been studied and many of them increase the residence time of the formulation, and alter the pharmacokinetics of the drug, causing increased bioavailability or duration of action. It is difficult to assess the exact physical mechanism by which these formulations operate. Many of the so-called bioadhesive polymers also act as viscosity modifiers, and many of the microsphere formulations hydrate to form glue-like gels which will adhere to the nasal tissues even in the absence of a specific particle-mucus interaction. As a result it is almost impossible to separate the importance of these effects in vivo and the importance of specific 'bioadhesive' interactions is questionable.

Viscosity modifiers

Spray preparations containing 0.25% methylcellulose have been reported to exhibit decreased mucociliary clearance resulting in delayed absorption of nasally administered desmopressin53 and hydroxypropylmethylcellulose increased the residence time of spray formulations54.

Smart hydrogel (poly (oxyethylene-b-oxypropylene-b-oxyethylene)-g-poly (acrylic acid) (GelMed Inc. USA) demonstrates great potential for nasal drug delivery. It is a thin liquid at room temperature, but it gels at body temperature. When administered as a spray to the nose, 80% cleared within 4 h, but 10% was still detectable at 20 hours post administration (Figure 9.5)55.

Bioadhesive polymers

A number of polyelectrolyte polymers are generally considered to show specific interactions with mucus. Polyacrylic acid and polyacrylates such as Carbopol 934 were shown to


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