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Spray and Display

Convenient and easy to use, nasal sprays have a high degree of patient acceptability and are increasingly selected for the delivery of both locally acting and systemic drugs. Achieving clinical efficacy relies on developing a device/formulation combination that delivers droplets optimised to ensure reproducible deposition to the affected areas, in the case of local conditions such as rhinitis, or to facilitate absorption through the nasal mucosa for systemic therapies. A combination of rheological studies and laser diffraction particle size measurements can be used to support the realisation of this goal.

UNDERSTANDING NASAL DRUG DELIVERY

Covering a large surface area, and with high blood flow, the nasal mucosa offer an ideal site for drug absorption into the body. Furthermore, the nasal route is accessible and patient-friendly, preferred by many to intravenous delivery, and especially valuable for those unable to swallow, or where the formulation cannot survive the gastrointestinal route. These advantages explain the increased interest in nasal drug delivery, particularly for delicate long-chain molecules such as vaccines, proteins and peptides.

Maximising the effectiveness of drug delivery relies on developing a product that consistently delivers droplets optimally sized for deposition at target sites within the nasal passages, which will remain in the nasal cavity for sufficient time. Mucociliary clearance is a problematic issue for this route, of greatest concern for higher molecular weight, more slowly absorbed drug entities. The delivery characteristics of a product are dependent on many factors including the technique of the patient, the properties of the formulation and the performance of the spray pump. Achieving desirable clinical efficacy is therefore a complex multi-factorial exercise, heavily reliant on in vitro analytical techniques.

THE REQUIREMENT FOR DROPLET SIZE MEASUREMENT

Various studies have shown that the geometry of the nasal passages and properties of the spray strongly influence deposition behaviour (1-4). Guo, for example, demonstrated, using a nasal cast, that low viscosity sprays provide greater surface coverage than higher viscosity formulations, and attributed this observation to differences in particle size and, possibly, plume geometry (5). From this and subsequent work, it was concluded that ‘spray pattern, plume geometry and droplet size distribution all appeared to provide critical data for assessment of nasal pump performance’ as it relates to reproducible delivery from the device (6). It is therefore unsurprising that droplet size measurement, along with spray pattern and plume geometry assessment, is well-established as a valuable technique for developing an understanding of nasal spray product performance. Plume pattern and droplet size measurement are both routinely used in quality control (QC) testing.

Guidance from the US FDA describes how nasal sprays should be tested in vitro, and recommends the use of laser diffraction technology for droplet size measurement, for detailed analysis of spray atomisation behaviour (7). This guidance also highlights the necessity of automatic actuation during testing to ensure that changes in actuation force or velocity do not affect the integrity of the results. Avoiding manual actuation eliminates a source of variability that, although present in the patient community, obscures information gathering during product development and routine quality control.

THE RELEVANCE OF RHEOLOGICAL DATA

In contrast to droplet size measurement, rheological characterisation is not mentioned as an in vitro test within the FDA’s bioequivalence and bioavailability draft guidance (7). However, it is an important technique for the development of an efficient and effective product, and is recognised as such with the FDA’s Chemistry, Manufacturing and Controls guidance for nasal spray products (8), which requests that viscosity be measured as part of batch release. It is well known that a direct correlation exists between viscosity, atomisation behaviour and the size of droplets produced by a spray device. Measuring and controlling rheology enables the harmonisation of formulation properties and device characteristics, identifying a combined product that will provide good performance.

For nasal spray formulations, high viscosity at low shear is advantageous, especially where the product is a suspension. High viscosity confers stability during storage, improving spray content uniformity, and is also believed to reduce the rate of clearance from the nasal cavity, improving bioavailability and/or retention in the nasal cavity. However, for ease of atomisation, low viscosity is preferable. One option is to develop a formulation with constant viscosity somewhere between the ideal for each of these conflicting demands. An alternative is to include excipients that impart shear thinning behaviour.

Shear thinning fluids are more fully able to meet the design criteria for nasal spray formulations because they have time- and sheardependent rheological properties. Such fluids have structure at low shear that breaks down with the application of higher shear rates, rebuilding once shear is reduced. A well-tailored shear thinning nasal spray formulation will be relatively viscous under storage conditions (low shear), giving good product stability, have low viscosity when shaken and/or atomised (high shear), and will regain high viscosity when deposited in the nasal cavity.

FORMULATING NASAL SPRAYS

Formulators can choose from a wide array of ingredients when attempting to develop ideal product, and more specifically rheological, characteristics. Furthermore, the choice is expanding because of the challenge posed by delivering larger drug entities. Recent trials highlight the possibility of using liposomes, microspheres and gels as more sophisticated delivery systems for macromolecules, while bioadhesives such as chitosan are being considered for improving retention on the nasal mucosa (9-11). A range of polymers and other viscosity modifying agents are already routinely, and successfully, used in commercial products to increase the viscosity of formulations, with the aim not only of improving stability during storage, but also increasing residence time of the formulation within the nasal passages following delivery (see Table 1).

In the following studies, rheological tests and laser diffraction particle size measurement were used to investigate the impact on performance of two different polymer excipients. The first formulation tested was a model solution, where the concentration of polyvinylpyrrolidone (PVP) was changed to give Newtonian fluids of different viscosity. The second formulation is an over-the-counter product which uses carboxymethyl cellulose (CMC) and microcrystalline cellulose (MCC) to impart shear thinning behaviour, preventing the product from dripping back out of the nose following administration.


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Dr Paul Kippax has a degree in Chemistry and a PhD in Colloid and Interface Science, both obtained at the University of Nottingham in the UK. He joined Malvern Instruments in 1997 as an Applications Scientist and in 2002 became Product Manager for the company’s laser diffraction particle size analysis systems. He has worked closely with the pharmaceutical industry in understanding how laser diffraction techniques can be best applied to characterising the performance of medical devices. This has included the publication of several joint research articles relating to the optimisation of drug delivery from dry powder inhalers and nasal sprays. Email: paul.kippax@malvern.com

Dr Julie D Suman is co-founder and President of Next Breath LLC, a contract research organisation dedicated to the development and analytical testing of nasal and inhalation delivery systems. Julie directs the research division that supports product development and regulatory submissions for North American and international clients in the pharmaceutical, biotechnology and medical device markets. She holds a BS in Pharmacy from Duquesne University (1996) and a PhD in Pharmaceutical Sciences from the University of Maryland, Baltimore (2002). She is a co-editor for Respiratory Drug Delivery Proceedings, and is an adjunct assistant professor at the University of Maryland, School of Pharmacy in Baltimore, Maryland. Email: julie.suman@nextbreath.net

Dr Gerallt Williams is Director, R&D Laboratory Services for Valois France. After obtaining his PhD from the University of Wales in 1985, he has held various industrial positions at Monsanto Inc (UK), Fisons Ltd (UK), Valois (France) and Nektar Therapeutics (US). He is now in charge of R&D laboratory services and regulatory affairs for the Valois Pharmaceutical Division, Le Vaudreuil, France, and is engaged in the development of new devices for nasal and inhaled drug products. Email: gerallt.williams@valois.com

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Paul Kippax
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Julie D Suman
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Gerallt Williams
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