Drug Delivery


is necessary for DPI-based products, to address some of the dry powder formulation and stability characteristics.


Furthermore, if the development company is not legally bound to one clinical device, this gives greater flexibility with the product for clinical use to a wider potential human population, however, strategic agreements to a specific device may give product differentiation and extend patent life for the API.


Aerosol sampling and analytical methodology


Confirmation of the amount of the dosed test material is not only good scientific practice but also a regulatory requirement.


The precise dose delivered to the animal using a syringe for oral or parenteral routes can be mea- sured exactly, based on the bodyweight of the ani- mal and the concentration of the solution being administered. With inhalation administration it is not possible to calculate the ‘dose’ given to animal in the same way.


The animal is presented with an atmosphere concentration of the test article and spontaneously breathes from that aerosol, effectively self-dosing based on the animal’s own tidal volume and fre- quency of breathing.


As a consequence the delivered dose needs to be derived based on an estimate of the air volume inhaled during the exposure period as well as the bodyweight and test atmosphere aerosol concen- tration. Finally, the proportion of inhaled test arti- cle that will enter the lungs is dependent on the particle size. The delivered dose is estimated as:


DD = (C x RMV x D x IF) W


DD Delivered dose C


Aerosol concentration of substance in air


RMV Respiratory minute volume D IF


Duration of exposure


Proportion by weight of particles that are inhalable (normally assumed as 1 if >90% of particles are <7 microns)


W Bodyweight


To verify the concentration of the delivered dose, samples are collected directly from the exposure sys- tem from locations that are representative of the


Drug Discovery World Winter 2017/18


Table 1: Typical excipient types for inhaled biopharmaceuticals (Parry, M et al http://www.intertek.com/knowledge-education/formulation-biologics-inhaled-nasal-delivery/)


EXCIPIENT Buffers Salts Amino acids Polyols/disaccharides/polysaccharides Surfactants Antioxidants FUNCTION Control of pH Control of ionic strength Control of ionic strength


Preferential hydration/exclusion to create a stabilising ‘shell’


Protection from hydrophobic interactions, such as at container surfaces


Protection from oxidation


breathing zone for the animals (generally a facemask or restraint tube attachment position) using method- ology that provides optimal trapping of the drug and to permit chemical analysis of the active component. For most liquid formulations, this comprises a glass sintered sampling trap using an appropriate trapping solvent. For powder or suspension formulations, a quartz-fibre filter is used rather than the standard glass-fibre filters for NCEs. This is used in conjunc- tion with silanising analytical glassware prior to use. As well as aerosol concentration determination, the other principle sample collection for any inhalation delivery study is for the assessment of particle size. Similarly, this sample must also be collected from the breathing zone of the non-clini- cal species being evaluated to ensure a representa- tive and compliant sample and not from the extract of the exposure system. This poor practice will compromise the validity of the study. The Marple or Mercer cascade impactors are the devices of choice for this evaluation.


For aerosol concentration and particle size assessment, standard Ultra Performance Liquid Chromatography analysis is normally employed, however, alternative methodologies may have to be used depending on the biopharmaceutical con- cerned. As mentioned earlier, biopharmaceutical products have complex structures and in many cases their activity depends on correct folding and subsequent tertiary structure. The shear forces exerted during the process of aerosol generation can impact the structure and therefore alter the bioactivity of the drug substance, with the worst case scenario being loss of potency in the test sys- tem. For feasibility studies, researchers should con- sider the inclusion of a cell-based potency assay,


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