Lyophilization stabilizes clinical‐stage core‐crosslinked polymeric micelles to overcome cold chain supply challenges

Abstract

Background CriPec technology enables the generation of drug‐entrapped biodegradable core‐crosslinked polymeric micelles (CCPM) with high drug loading capacity, tailorable size, and drug release kinetics. Docetaxel (DTX)‐entrapped CCPM, also referred to as CPC634, have demonstrated favorable pharmacokinetics, tolerability, and enhanced tumor uptake in patients. Clinical efficacy evaluation is ongoing. CPC634 is currently stored (shelf life > 5 years) and shipped as a frozen aqueous dispersion at temperatures below −60°C, in order to prevent premature release of DTX and hydrolysis of the core‐crosslinks. Consequently, like other aqueous nanomedicine formulations, CPC634 relies on cold chain supply, which is unfavorable for commercialization. Lyophilization can help to bypass this issue. Methods and results Freeze‐drying methodology for CCPM was developed by employing CPC634 as a model formulation, and sucrose and trehalose as cryoprotectants. We studied the residual moisture content and reconstitution behavior of the CPC634 freeze‐dried cake, as well as the size, polydispersity index, morphology, drug retention, and release kinetics of reconstituted CPC634. Subsequently, the freeze‐drying methodology was validated in an industrial setting, yielding a CPC634 freeze‐dried cake with a moisture content of less than 0.1 wt%. It was found that trehalose‐cryoprotected CPC634 could be rapidly reconstituted in less than 5 min at room temperature. Critical quality attributes such as size, morphology, drug retention, and release kinetics of trehalose‐cryoprotected freeze‐dried CPC634 upon reconstitution were identical to those of non‐freeze‐dried CPC634. Conclusion Our findings provide proof‐of‐concept for the lyophilization of drug‐containing CCPM and our methodology is readily translatable to large‐scale manufacturing for future commercialization.

Core Cross‐Linked Polymeric Micelles for Specific Iron Delivery: Inducing Sterile Inflammation in Macrophages

“…Importantly, the narrow size distribution (PDI ≤ 0.16) of SPION-CCPMs Cy5 remained identical when particles were lyophilized and re-constituted in water (SPION-CCPM Cy5 -Lyo), which facilitates their scalability and pharmaceutical use. [38] Morphological analysis of SPION-CCPMs by atomic force microscopy (AFM) revealed spherical structures with sizes below 100 nm (Figure 1C), congruent with DLS and fluorescence correlation spectroscopy (FCS) (Table 1; Figure S10, Supporting Information). Transmission electron microscopy (TEM) was used to elucidate the encapsulated SPION cores.…”

Complex Structures Made Simple – Continuous Flow Production of Core Cross‐Linked Polymeric Micelles for Paclitaxel Pro‐Drug‐Delivery

“…Each process can thus be optimized separately with the potential to achieve higher yields at reduced synthetic effort and cost. [ 67 ] Nevertheless, whenever lead compound have been identified drug loading can be easily implemented by adding a third micromixer.…”

Profiling target engagement and cellular uptake of cRGD-decorated clinical-stage core-crosslinked polymeric micelles

“…In addition, we [13,18,31] and others [23,46,53,58] have observed that low decoration densities (i.e., 1 mol% or lower) are sufficient for significantly altering the in vivo behavior between ligand-decorated and non-decorated analogs. Of note, and considering our goal to evaluate this drug delivery system in vivo, the used nanoformulation has already undergone extensive investigation regarding shelf stability [59], and serum stability and protein binding examined via asymmetrical flow field-flow fractionation [57]. Regarding the latter, the crosslinking principle has assured the serum stability as can be illustrated by the extensive circulation upon intravenous administration, both preclinically [4,6] and clinically [7,8].…”