29th April 2021 - Formulation Options in Nasal Drug Delivery
In our first article, we looked at the basic anatomy of the nasal cavity and considered why it was such a good target for delivering a wide range of therapeutics and vaccines, and in our second article we discussed some of the formulation choices that need to be taken into account when developing dosage forms for the nasal route.
In this, our third and final article in the series, we examine some of the analytical techniques that are used to analyse the drug product and subsequent device performance, both for characterisation purposes and for assessing stability.
Testing Liquid or Dry Powder Devices
Liquid nasal dosage forms are the most prevalent and provide the simplest and most flexible formulation approach. They also offer the option of either a unit-dose or multi-dose delivery. Analysis of the dosage form delivered by liquid devices, will include:
- Comprehensive testing of the liquid in the device (including the API and key excipients).
- Device performance testing such as droplet size, plume geometry, spray pattern and the quantity of liquid/drug delivered.
- Comprehensive testing of the dry powder drug product within the device.
- The particle size, plume geometry and quantity of dry powder delivered from the device.
During development of nasal products, a wide range of performance attribute tests are recommended and/or stipulated by the regulatory authorities in addition to the more typical; and expected specified final product release testing.
EP guidance notes, found here and similarly FDA, found here detail a lot of these tests which are often dependant on both the formulation and the device and can be used to discriminate between formulation variants. These include: Delivered dose throughout the life of the product, Priming requirements, Effect of dosing orientation on emitted dose. Plume geometry and spray pattern. Another tool that has proven useful in comparing and selecting formulations during development is the transparent nasal cavity.
The effect of formulation changes, delivery device and orientation can all be visualised by use of the transparent nasal cavity. The cavity is coated such that a colour change occurs when the delivered formulation is dosed from the nasal device. By examination of the colour the specific areas of deposition in the nasal cavity can be identified and key performance failures modes such as excessive formulation run-off to the throat or excessive deposition in the nasal vestibule resulting in the formulation “dripping out” can be observed.
Transparent Nasal Cast coated with water-reacting paste. Formulation fired into cast with multidose liquid device
The exhaustive list of tests needed for commercial products are generally not required for first in human/Phase 1 studies, instead a more pragmatic approach can be taken. In Table 1 below are typical assays that Upperton Pharma Solutions would suggest are suitable for supporting Phase 1 studies.
Testing Nasal Formulations: Regulatory Requirements
The range and extent of testing will mainly be dictated by the development stage of the formulation to be tested. In simple terms, products earmarked for use in early-stage clinical testing (Phase I) will require significantly less testing than products being tested for commercial use.
In early (Phase I) studies key tests will be those that impact on product safety, such as particle size/droplet size (impact on pulmonary toxicity) and emitted dose will provide key safety and delivery information to support use in first in human studies.
As the drug product moves further down the development process, the extent of testing will be required to increase to allow the drug to be sold/used commercially and more stringent tests such as device compatibility (extractables/leachables) will become necessary.
This series of articles has outlined the logistics and considerations associated with developing a drug/vaccine for nasal delivery. We have discussed the advantages the anatomy of the nasal cavity provides for drug delivery, the challenges of developing both liquid and dry powder formulations, and analytical techniques alongside regulatory testing requirements.
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