Form and Formulation to the rescue

In this short case study, we present how our legendary Form & Formulation (F&F) team delivered a new formulation for a drug. This allowed higher dosage and thereby opened up the option for a wider therapeutic profile for a client’s product.

The Starting Point

Our client had run some early Phase 1 clinical trials for their oncology small molecule drug. As an intravenous product, they had sensibly gone down the well-trodden path of a lyophilised presentation. Delivery in the clinic was via reconstitution prior to addition to an infusion bag for patients. At this stage oral delivery was not required as an option for this molecule.

The dose was two vials, each one requiring dissolution, extraction into a syringe and then addition to an IV bag. This worked relatively well. The product was stable, dissolved relatively easily and with this process dosing the patients was straightforward.

Early results were very promising. Patients had positive responses, PK data looked as expected but then something was flagged…….

Opportunity Knocks

 ……The safety profile of their API was much better than expected. The anticipated issues at high dose (based on historical data) were not observed. This presented the possibility of an exciting option. Could the dose be increased? The anticipation was that if it could, there would be beneficial effects for patients in terms of allowing a wider therapeutic window. The client was obviously keen to explore this option.

But There Was a Hurdle

This is where the lyo cake fell over. The initial dose was 2 vials. The new dose would require 8 vials which now became unfeasible – no clinician would want to shake 8 vials for addition to an IV bag.

Our Solution (pun very much intended)

Time to reformulate. The aqueous solubility was good enough for a 100 mL IV bag, but even so that still wasn’t a viable route for a lyo cake. We therefore proposed to explore a liquid concentrate option. This would entail investigating the use of IV compatible organic concentrates. We designed and executed a series of experiments to explore and evaluate the following factors.

• To improve solubility: A range of 5 suitable organic concentrates were investigated
• To improve stability as a solution: We trialled a range of 3 other potential excipients, such as anti-oxidants

Throughout these experiments we were mindful of the fact that a liquid formulation for dilution brings a whole set of particular challenges, such as:

• Physical stability – did the drug precipitate over time
• Chemical stability – did we see known degradants form, or even new ones considering the introduction of a new set of excipients.
• Viscosity of the concentrate – as it would still need to be extracted with a syringe and needle.
• Sterile filtration – viscous solution present challenges along with filter compatibility

Accordingly, we ran stability studies in our International Council for Harmonisation (ICH) stability chambers to evaluate these factors.

The Outcome

After 8 weeks and dozens of experiments, the F&F team had developed a successful formulation that had suitable solubility, stability and viscosity that could be delivered as a liquid concentrate. This allowed our client to explore the higher dose option, with the potential to provide an enhanced cancer drug for patients.

Actually, the study was significantly harder than it sounds, and we are proud of the determination and resilience required by the team to deliver this outcome.

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.