Moving from a pre-clinical to a clinical API – A different formulation needed

Projects often have different priorities such as budget constraints, tight deadlines or just generating a key piece of data. In this case study we give an example of how the flexible, proactive approach we have at Sygnature delivered an API formulation to meet a tight deadline for the start of a preclinical toxicology study.

The Requirements

A client had an advanced Active Pharmaceutical Ingredient (API) which was moving towards preclinical toxicology studies in Non-Human Primates (NHPs). These studies would require:

• a relatively high dose
• in a well-tolerated formulation
• which could be dosed for at least 28 days.

The form of the API at that time would not have been able to deliver on these criteria. Whilst a highly stable polymorphic form was being sued, the current formulation did not deliver the required exposure due to the Biopharmaceutics Classification System (BCS) Class II nature of the compound. Low solubility and slow dissolution rates hindering the development of the promising molecule.

Time Was of the Essence

Physiologically Based Pharmacokinetic (PBPK) modelling had shown that a particle size reduction might reach sufficient exposure. However, for this project time was the critical factor and the client did not want to risk delays in potentially having to going back to an alternative formulation if the Particle Size Distribution (PSD) reduction was unsuccessful.

Our Proposal

With this in mind, our Form & Formulation team proposed to look at 2 different routes to achieve PSD reduction, a liquid formulation in parallel with a nano-suspension option, and the client agreed to this more thorough investigation.

An Intriguing Outcome

After a truly team effort, we developed a high dose lipidic formulation as well as a nano-suspension which both performed well in vitro. Testing in vivo by the client led to some interesting data. The lipidic formulation massively increased exposure compared to historical data, but the maximum blood concentration C_max and time to maximum concentration T_max didn’t fit the desired profile for human dosing. As such, whilst the lipidic formulation was a massive help and fit for purpose for the NHP toxicology study, it wasn’t going to help the molecule move forwards to clinical trials in humans.

The nano-suspension however, did have the desired C_max and T_max profile. Whilst the Sygnature team regularly prepares nano suspensions and hand them over to our in vivo pharmacology colleagues for testing, a suspension isn’t the most desirable, patient friendly formulation for Phase I clinical trials.

To that end, we looked at spray drying the nano-suspension with a carrier as a bulking agent. To achieve this, we set up a series of experiments that aimed to:

• screen a variety of carrier and surfactant options
• optimize the carrier load level
• optimize the spray drying process

What we delivered was a beautiful powder which will be much easier to transfer to GMP for clinical use, and more importantly had reconstitution properties where the nano-suspension was easily redispersed upon hitting aqueous media, without agglomeration being observed.

Impact and Next Steps

There is still more work to be done. Such as – long term stability studies to ICH guidelines in our Memmert chambers along with further optimization of the spray drying parameters for transfer to a GMP drug product manufacturer.

This piece of work shows the benefit of working on 2 options in parallel, where time is a key factor. The speed and flexibility that the Sygnature team leveraged allowed us to deliver different options to boost the performance of the API. Ultimately the approach we took shortened the project timeline, by not having to go back and revisit alternative formulation routes when the more obvious route failed.

We met the clients’ timelines and moved the project rapidly towards clinical trials and hopefully will lead to helping patients in need.

If you wish to learn more about how we can advance your molecule to the clinic please don’t hesitate to get in touch. Just use the “Get in Touch” button at the bottom of the page.