In order to enable the accelerated preclinical and clinical pharmaceutical development of formulations based on nanomilling, a screening media mill was developed and evaluated for the production of nanoparticulate active pharmaceutical ingredients (API). The screening media mill is based on the principle of a conventional planetary mill, equipped with up to 24 milling beakers of 0.05-1.0 mL individual milling chamber volume. The applicability of the screening media mill was evaluated by 0.7-12.8 mg naproxen (2 wt %) per batch with a nanomilling formulation known from the literature. A case study for the preclinical formulation development is presented, applying 42 screening experiments by one operator within 5 working days, using in total 110 mg API. Promising nanomilling formulations with median particle sizes below 200 nm could be identified, suitable for preclinical in vivo studies. A second case study for the early clinical development of another proprietary API showed the successful formulation development within 12 working days. Up-scaling to a miniaturized stirred media mill of 10 mL milling chamber volume resulted in a satisfying comparability of the selected formulations, with varying performance. Further up-scaling of the most promising formulation to a laboratory-scale stirred-media mill showed the successful production of 250 g API with a median particle size of 140 nm.
In the past, drug developers in industry chose approaches mainly focusing on the drug product's efficacy, safety and quality according to the level required by regulatory expectations stipulated in guidelines, pharmacopoeia and other regulatory provisions. By putting more focus on the patient perspective, regulatory authorities are currently raising their requirements regarding successful product submissions. The increasing involvement of patients in the product development process (e.g. conduction of human factor use tests, integration of feedback from patient and patient advisory groups into clinical programmes) requires adaptations to the existing and established industrial drug development processes without compromising fast patient access to innovative therapies. This review provides an expert opinion on the emerging challenges and opportunities to implement a patient‐centric approach into new drug development programmes. The aim is to better understand the challenge of finding the right balance between bringing innovative drugs fast to the patients and to develop these in parallel in a patient‐centric product form as well as why this is an opportunity and how stakeholder parties (e.g. patients, clinicians, pharmacists, caregivers, regulators) can provide support to achieve desired outcomes.
The anaplastic lymphoma kinase (ALK) inhibitor alectinib is an effective treatment for ALK-positive non-small-cell lung cancer. This bioequivalence study evaluated the in vivo performance of test 3 formulations with the reduced wetting agent sodium lauryl sulfate (SLS) content. This randomized, 4-period, 4-sequence, crossover study compared alectinib (600 mg) as 25%, 12.5%, and 3% SLS hard capsule formulations with the reference 50% SLS clinical formulation in healthy subjects under fasted conditions (n = 49), and following a high-fat meal (n = 48). Geometric mean ratios and 90% confidence intervals (CIs) for C , AUC , and AUC of alectinib, its major active metabolite, M4, and alectinib plus M4 were determined for the test formulations versus the reference formulation. Bioequivalence was concluded if the 90%CIs were within the 80% to 125% boundaries. The 25% SLS formulation demonstrated bioequivalence to the reference 50% SLS formulation for C , AUC , and AUC of alectinib, M4, and alectinib plus M4 under both fasted and fed conditions. Further reductions in SLS content (12.5% and 3% SLS) did not meet the bioequivalence criteria. Cross-group comparisons showed an approximately 3-fold positive food effect. Reducing SLS to 25% resulted in a formulation that is bioequivalent to the current 50% SLS formulation used in alectinib pivotal trials.
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