Understanding the In Vitro-In Vivo Nexus: Advanced correlation models predict clinical performance of liposomal doxorubicin.

In the century of precision medicine and predictive modeling, addressing quality-related issues in the medical supply chain is critical, with 62 % of the disruptions being attributable to quality challenges. This study centers on the development and safety of liposomal doxorubicin, where animal studies alone often do not adequately explain the complex interplay between critical quality attributes and in vivo performances. Anchored in our aim to elucidate this in vitro-in vivo nexus, we compared TLD-1, a novel liposomal doxorubicin delivery system, against the established formulations Doxil® and Lipodox®. Robust in vitro-in vivo correlations (IVIVCs) with excellent coefficients of determination (R2 > 0.98) were obtained in the presence of serum under dynamic high-shear conditions. They provided the foundation for an advanced characterization and benchmarking strategy. Despite the smaller vesicle size and reduced core crystallinity of TLD-1, its release behavior closely resembled that of Doxil®. Nevertheless, subtle differences between the dosage forms observed in the in vitro setting were reflected in the bioavailabilities observed in vivo. Data from a Phase-I clinical trial facilitated the development of patient-specific IVIVCs using the physiologically-based nanocarrier biopharmaceutics model, enabling a more accurate estimation of doxorubicin exposure. This advancement could impact clinical practice by allowing for more precise dose estimation and aiding in the assessment of the interchangeability of generic liposomal doxorubicin.

Encapsulation and release of hydrocortisone from proliposomes govern vaginal delivery.

Topical preparations of hydrocortisone can be used for the anti-inflammatory treatment of the female genital area. Although the drug is a low-strength corticosteroid, systemic absorption and distribution of the drug are the most common safety risks associated with this therapy. In the current investigation, we elucidate the physicochemical properties of lipid-based drug carrier systems that govern the local bioavailability of hydrocortisone for intravaginal administration. For this purpose, we compared various proliposome formulations with a commercial cream. Depending on the availability of physiological acceptors, encapsulation and drug release from the lipid phase were found to be the most important drivers of drug bioavailability. The high permeability of hydrocortisone leads to rapid transport of the drug across the mucosal cell layer as indicated by experiments using HEC-1-A and CaSki cell monolayer models. Under sink conditions, differences in the release from the liposomes as determined in the Dispersion Releaser were almost negligible. However, under non-sink conditions, the drug release plateaued at levels corresponding to the encapsulation efficiency. After redispersion, all liposomal formulations performed better than the commercial drug product indicating that the encapsulation into the lipid phase is the main driver sustaining the release.

Biopredictive tools for the development of injectable drug products.

INTRODUCTION: Biopredictive release tests are commonly used in the evaluation of oral medicines. They support decision-making in formulation development and allow predictions of the expected in-vivo performances. So far, there is limited experience in the application of these methodologies to injectable drug products. AREAS COVERED: Parenteral drug products cover a variety of dosage forms and administration sites, including subcutaneous, intramuscular, and intravenous injections. In this area, developing biopredictive and biorelevant methodologies often confronts us with unique challenges and knowledge gaps. Here, we provide a formulation-centric approach and explain the key considerations and workflow when designing biopredictive assays. Also, we outline the key role of computational methods in achieving clinical relevance and put all considerations into context using liposomal nanomedicines as an example. EXPERT OPINION: Biopredictive tools are the need of the hour to exploit the tremendous opportunities of injectable drug products. A growing number of biopharmaceuticals such as peptides, proteins, and nucleic acids require different strategies and a better understanding of the influences on drug absorption. Here, our design strategy must maintain the balance between robustness and complexity required for effective formulation development.