Case Study

OptiForm® Solution Suite: Improved Bioavailability Of Trio Medicines TML-2 In 12 Weeks

Source: Catalent
Improved Bioavailability

Trio Medicines Ltd (Trio) is a London-based pharmaceutical company, founded in 2005. Trio is developing treatments for unmet medical needs, including rare diseases, with the aim of improving the health and quality of life of patients worldwide. Trio’s lead compound TML-2 is the acetyl prodrug of TML-1, a novel, well tolerated G-protein coupled receptor antagonist which shows clinical promise but has limited bioavailability owing to low solubility. The prodrug approach was only partially successful in increasing the solubility and bioavailability of TML-1, so Trio turned to Catalent for help. Utilizing OptiForm Solution Suite platform, Catalent’s experts screened 3 formulation technologies, and provided 4 formulation prototypes, in only 12 weeks. In 3 of the 4 prototypes, bioavailability of TML-2 was enhanced substantially.

The Challenges

The Solution

Catalent’s Science & Technology advisors utilized Optiform Solution Suite, an integrated platform with a structured 3-step approach: assess, enhance & deliver.

Assess

Thoroughly assess the molecule’s physical and chemical properties. The team conducted a series of assessments of the molecule’s physicochemical properties.

1. Chemical Compatibility

HPLC analysis of samples stored at high temperature to monitor growth of degradation products. In some excipients, the product showed accelerated degradation highlighted in red in the table below.

2.  Molecule Solubility & DCS Classification

HPLC analysis of solubility in different buffers and biorelevant media. Recheck PXRD. Placement of molecule on DCS graph.

  1. Solid State Characterization

Analysis of Particle Size, DSC, Microscopy, DVS and PXRD

  1.  Molecule Stability

Analysis of PXRD at high RH, solid state and solution state stability (pH, light and peroxide)

The molecule was classified as a DCS IIa (limited by rate of dissolution, rather than absolute solubility) with some stability issues (not uncommon for a prodrug).

Enhance

Evaluate multiple technologies in parallel. Based on the data from the ASSESS phase, experts assessed the potential of 3 formulation technologies to enhance the molecule’s bioavailability: lipid formulation (5), amorphous solid dispersion (6) and particle size engineering (7).

Results of technology screening:

  • Lipid Formulation: TML-2 had good solubility in 4 excipients and fair solubility in another 7, providing sufficient options for development of a lipid formulation with 2.5-10% drug loading
  • Solid Dispersion: Solid dispersion formulations were viable at a 20% drug loading
  • Particle Size Reduction: TML-2 was micronized to the particle size target of D90<83μm (calculated from rearrangement of the dissolution equation)

Deliver

Provide prototypes for animal PK study, a full report with recommendations and all data, including 2 weeks’ stability. Catalent provided 4 candidate formulations and a complete report to Trio within 12 weeks. Based on the assessment of physical/chemical properties, processability and fit to DCS classification, the micronized formulation was considered the strongest candidate.

Preliminary data showed enhanced bioavailability of all 4 formulations compared with the prodrug.

Conclusion

Trio’s Medical Director commented:

“Catalent’s Optiform Solution Suite met the 12-week guarantee and provided good choices for candidate formulations with extensive supporting data. The platform represents good value for money based on the other options that we evaluated. Our early PK analysis shows improved AUC from the candidate formulations, but we need to collect data from more subjects and look to further increase AUC”.

“Over the years, in my experience of carrying out early phase I studies, large and small, worldwide, the planned start is delayed in about 25% of those studies, mostly due to formulation problems. The majority of small molecules are now coming from small- to medium-sized companies, most of which have to outsource formulation work. They are rarely aware of the potential problems. So, my advice is to start formulation work as early as possible”.

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