In Vivo Testing of Nasal Dosage Forms
Interest in developing nasal dosage forms has increased significantly in the last two years, with a number of high-profile products receiving FDA approval. Indeed, the rapid systemic uptake and the ease of dosing have made this an attractive dosing option for a wide range of drugs that have previously been administered by injection.
The Upperton development platform (UpperNose™) has been designed to help guide customers towards identifying and subsequently a nasal dosage form that is ready for scale-up and in vivo testing in as little as 12 weeks. This tried and tested approach guides customers towards choosing the best nasal delivery device (for example, liquid or dry powder; single- or multidose devices) and subsequently developing the optimal formulation for successful nasal delivery of their molecule (including device deposition in nasal models and stability testing).
Lead formulations that achieve acceptable product stability (ideally in the nasal device) and reproducible in vitro device delivery performance can then be scaled up and manufactured in quantities required for in vivo testing in animal models.
Animal tests are required for a number of reasons. In early-stage development, in vivo tests are required to determine the pharmacokinetics of drug molecules that are delivered into the nasal cavity. A portion of the delivered dose will cross the nasal epithelium, providing rapid systemic delivery (and potentially directly into the brain) or be lost via the mucociliary clearance mechanism, which can be species specific. Once PK data has been generated and shown to meet dose delivery needs, safety/toxicology studies will then be performed to determine if the nasal route of administration is appropriate for human studies.
There are a number of challenges presented when considering the dosing and testing of nasal dosage forms in animal models. These include:
- Significant anatomical differences between humans and animal nasal anatomies
- Challenges related to delivery into the nasal cavity (particularly for small animals)
Indeed the general layout of nasal anatomy varies widely between species and no animal model perfectly replicates the complete morphological and physiological characteristics of the human nasal structure.
Various physiological and anatomical features of the nasal cavity will affect the distribution of the delivered dose and subsequent absorption/clearance. These include relative surface area, ciliary activity, tight junctions, pH profile, residence time, and enzymatic activity. All of vary from species to species and will impact on drug absorption.
Small rodents are usually the first animal species chosen for testing nasal formulations but beceasue of their size, they offer the greatest challenge for successful dosing. For example, dry powder delivery devices are attracting increasing attention in clinical studies but there remains significant hurdles with regards to successful delivery of powders into the nasal cavity of small rodent species. As a result, nasal drug formulations are typically administered to small rodents as a liquid using a pipette or using a polyethylene tube attached to a micropipette. The volume administered is usually 4 to 10 µL/nostril in mice and 4 to 40 µL/nostril in rats .
In larger animals (rabbits, dogs or non-human primates) nasal drug formulations can be administered as a powder or liquid, depending on the device targeted for human studies. For liquid doses, a nasal pump can be urtilised, whilst dry powders can also be dosed using delivery devices (such as the UniDose powder device (Aptar Pharma) or the Nosatron device (Therakind) which has been specifically designed to deliver powder doses in animals.
This article looks at a range of animal models that are available and compares and contrasts the benefits and shortfalls of each.
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