Blog: Nasal delivery of drugs – applications and DMPK considerations

Our recent guest blog from Upperton Pharma Solutions, one of our preferred CDMO partners, explored the considerations when developing dry powder formulations for nasal locally delivered drugs. In this follow-up blog, we will look at the applications for nasal delivery of drugs along with the key DMPK considerations.

While developing formulations for intranasal delivery, there are a number of factors to think about when designing pharmacokinetic (PK) studies. XenoGesis supports clients in their selection of compounds at discovery phase, as well as helping with their PK design, modelling and dose prediction.

We work with Upperton Pharma Solutions to evaluate different formulations and support clients as they choose which formulation to progress into clinical studies.

Nasal delivery of drugs

Oral delivery remains the most popular route of drug administration, followed by intravenous and sub-cutaneous administration. Yet despite the relatively low numbers of drugs being delivered using intra-nasal formulations, this route is gaining increased investment as a route to deliver therapeutics for a range of modalities including, but not limited to, small molecules, biologics and vaccines.

Ignoring the compounds which have been discontinued or are inactive, 449 drugs are being developed that use an intranasal delivery route. 36 are in discovery, 173 pre-clinical. 9 IND/CTA filed, 1 Phase I, 90 Phase I, 85 Phase II, 39 Phase III and 16 are in pre-registration.

These span a wide range of disease areas including ear, nose and throat, cardiovascular, dermatology, gastrointestinal, genetic disorders, immunology, ophthalmology, oncology, metabolic diseases, musculoskeletal disorders, and women’s and men’s health. The most popular disease areas are infectious disease, central nervous system (CNS) and respiratory with 153, 114 and 39 drugs currently being developed respectively.

The nasal pathway provides a non-invasive route to deliver drugs for local and systemic action. There is the added benefit that it provides an administration route which can avoid the blood brain barrier via nose-to-brain transport, and this has resulted in the increase in CNS drugs being delivered this way. The nasal epithelial barrier is not as ‘tight’ as the blood brain barrier; there is extensive vascularisation of the nasal mucosa and lamina propria. Together, these biological features provide a surface that facilitates drug absorption. Drugs delivered into the nasal cavity can enter the brain directly via the olfactory pathway. The avoidance of issues relating to GI tract absorption, first pass metabolism and the blood brain barrier can result in favourable pharmacokinetic (PK) and pharmacodynamic (PD) profiles.

Factors to consider when designing PK studies for intranasal delivery

The potential that can be delivered via the intranasal (IN) route is reduced compared to that for oral delivery. For drugs that are being delivered and acting locally, such as decongestants, antihistamines or corticosteroids, this is not a problem as relatively low doses are effective when delivered topically.

If a compound is being delivered via the IN route for systemic exposure, the lower dose that is available means that there is no equivalent to a ‘high oral dose’. To counteract this limitation, compounds with a high potency at the relevant target(s) should be selected.

Understanding the bioavailability from the nasal route is important and this will require both IN and in vitro (IV) dosing. Suck studies are typically undertaken in rodents. When designing PK studies, it is important to also dose PO; the PO ‘arm’ of the study will provide data to determine if any swallowed dose from IN dosing is absorbed and contributes to systemic exposure. Getting this full understanding will also help towards planning toxicity studies in the future. For example, a “top-up” via IV or other routes may be required to push systemic exposure to allow a safety margin to be established.

Whether you are selecting for brain exposure or against brain exposure, measuring the compound in cerebral spinal fluid (CSF) and the brain can be useful. Only unbound drugs can exert a pharmacological and toxicological effect, so understanding the free brain concentration relative to free plasma concentration is important. An ideal scenario is that the Kpuu (the ratio of the unbound tissue brain concentration over the unbound plasma concentration, at steady state) is close to one in two rodent species.

Selecting compounds in the discovery phase

Assessing passive permeability is important to be confident that the compound will cross the nasal epithelium and also the blood:brain barrier if required. For the latter, a very high passive permeability can give fast access to the brain and target, and thus the potential for fast onset.

Determining solubility and dissolution rate (if dosed not in solution) will also be important initially with kinetic solubility and ultimately with thermodynamic solubility of the final form.

Assuming systemic exposure is required, then ensuring sufficient metabolic stability will also be important if the compound is primarily metabolised by the liver. Using either liver microsomes or “gold standard” hepatocytes of the relevant species will be the key assay as part of the design-make-test cycle.

Determining efflux against relevant brain transporters e.g. MDR1 (P-gp) and BCRP can be important to ensure that the transporters do not limit brain penetration, assuming this is required. Typically Caco-2™ cells or MDCK cell-lines are used.

PK modelling and dose prediction

As with any other route of administration, fitting and modelling all relevant pre-clinical species’ PK data will be essential for successful translation and confidence to human. Typically, in vitro – in vivo extrapolation (IVIVE) should be assessed and understood, along with building a physiologically based PK (PBPK) model incorporating specific nasal delivery. PBPK models are mathematical models that predict the absorption, distribution, metabolism and excretion of drugs. They are usually multi-compartmental models with compartments relating to organs that have interconnections corresponding to blood flow. Including a brain compartment will also be important for understanding the relationship between free systemic exposure and free brain exposure. Finally, known physiological differences between rodents and humans will need to be factored in.

Evaluating formulations for IN delivery

The first step in the formulation process is to determine what the matrix of the dry powder particles needs to be as they will subsequently make up the bulk of the formulation. Typical excipients include sugars (mannitol and lactose) and polymers (PVP), which are often used as matrices for stabilising the active ingredients within the dry powder; this provides suitable bulking properties to allow aerosolisation of the powder emitted from the metered dose and enhance drug stability both during production and within the nasal device.

Clearance of formulation by the cilia within the nose to the back of throat is typically 8 to 10 minutes, giving a relatively short therapeutic window in which, the drug can be absorbed across the nasal mucosa. Mucoadhesives such as alginates, chitosans and hyaluronic acid are useful excipients that have the property of lengthening the residence time.

Other agents, such as those that change hydrophilicity (surfactants, bile salts) or aid absorption across the membrane (carbopols), can also be added to the formulation to modify pharmacokinetics.

Working in seamless partnership

XenoGesis works with preferred formulation partner CDMO’s, including Upperton Pharma Solutions, to evaluate the various formulations and determine the systemic exposure that each formulation delivers. For these PK studies, additional considerations include the volume that can be administered per nostril (the lower the volume the lower the risk of sneezing), the maximum frequency of dosing per day, and the time that administration takes.

This seamless partnership with our CDMO partners helps expedite clients drug discovery projects, saving time and money. Click here to find out more about our Formulation Services and get in touch with one of the team to find out how we can help you with your formulation development.

Combining capabilities

Upperton Pharma Solutions is a specialist CDMO focused on the development and manufacture of dry powder dosage forms including nasal powders. XenoGesis offers DMPK services on APIs in preparation for the clinic. By partnering together, XenoGesis can check there are no biological liabilities stopping an API going forward to formulation development, whilst Upperton can offer formulation and process optimisation for the API. Combining these two key service options prior to FIH and beyond will allow a prospective client the ideal opportunities to achieve clinical success.

This partnership will mainly comprise of Upperton providing a range of initial formulations developed with a range of enabling technologies, particle engineering and process understanding; followed by a parallel DMPK analysis from XenoGesis. The DMPK analysis will ensure that our clients will have in vivo data on which to base their decisions about which formulation to select for clinical evaluation. They will therefore will be able to proceed with a higher degree of confidence, minimising the time and resource spent on formulations that are likely to fail.

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