(W0930-09-60) High Drug Load Nanocrystalline Formulations Matching the Performance of Supersaturating Amorphous Solid Dispersions and Offering Reduced Pill Burden

Purpose: Tyrosine kinase inhibitors, androgen antagonists and other targeted anti-cancer therapies have revolutionized the treatment of several malignancies. [1] However, many compounds in these groups need enabling technologies, typically amorphous solid dispersions (ASDs), to overcome solubility and bioavailability issues. Whilst ASDs improve apparent solubility, they usually sacrifice drug loading: two thirds of the marketed ASD intermediates contain >65% stabilizing polymers (Fig 1). Low drug loading can lead to large pill size and high pill burden, neglecting patient centricity and ultimately resulting in therapy discontinuation.

Methods: The key methodology for this work is Controlled Expansion of Supercritical Solutions (CESS^®). During CESS^® nanoforming, controlled precipitation is performed from supercritical carbon dioxide (scCO₂) based API solutions. CESS^® was shown to be a robust and reproducible method to produce nanoparticles offering control over particle size distribution, crystalline form and morphology. [2-4] In this work we selected three anti-cancer small molecules, enzalutamide (ENZ), apalutamide (APA) and API X, all marketed as amorphous solid dispersions. Whilst the spray dried dispersions enabled druggability, by increasing the apparent solubility of the APIs, it came at a cost of sacrificing drug loading in the final dosage form, yielding large pills and a high overall pill burden.

Results: Herein we present the successful nanoforming of ENZ, APA and API X using the CESS^® technology Nanocrystalline API X formulation produced by this technique has been shown to achieve pharmacokinetic profiles outperforming micronized material by an order of magnitude and equivalent to supersaturating ASDs (Fig 2), with significant reductions in required polymers / excipients. Therefore, our platform enables reduction in pill size and overall pill burden empowering the development of patient centric nanocrystal-based tablets with high drug loading. Production of nanocrystals of ENZ enabled us to increase the drug loading within nanoenzalutamide tablets by more than 3x compared with the commercial Xtandi^® product, leading to the generation of a single 160 mg / day tablet to replace the current 4 pill regimen (Fig 3). A pivotal Phase III clinical study of this product is ongoing, with readout expected in Q3 2025. Using our approach for APA, we were able to decrease the size of nanoapalutamide once daily tablets by up to 60% compared to commercial ASD product Erleada®.

Conclusion: CESS^® nanoforming is a clinically validated new tool in the hands of formulators challenged by poor API dissolution/solubility. The resultant high drug load nanocrystalline formulations can offer new final dosage forms and administration routes earlier disabled by suboptimal API properties. For preclinical candidates with poor solubility and projected dosages of >100mg, CESS® offers a viable path to generating patient centric dosage forms, paving the way for single-pill formulations to enhance patient convenience and adherence.

References: 1. Zhong et al, Sig Transduct Target Ther, 2021, DOI: 10.1038/s41392-021-00572-w
2. Pessi et al, J Pharm Sci, 2016, DOI: 10.1016/j.xphs.2016.05.022
3. Kauppinen et al, J Pharm Biomed Anal, 2021, DOI: 10.1016/j.jpba.2022.115169
4. Lakio et al, Pharm Res, 2023, DOI: 10.1007/s11095-023-03624-8

Acknowledgements: The authors wish to acknowledge funding assistance from Business Finland.

Figure 1: Drug loadings of marketed ASD drug product intermediates.

Figure 2: Rodent PK study of micronized, nanoformed and ASD formulations.

Figure 3: Comparison of Xtandi® and nanoenzalutamide tablets.