Livzon Pharmaceutical Group, Inc.

Long-acting injectables (LAIs) represent promising drug delivery platforms for chronic diseases management, but their clinical translation remains constrained by extremely long trial-and-error experiments (8-10 years), limited mechanism insights, and poor in vitro-in vivo correlation (IVIVC). How can we design LAI formulations more efficiently and predictably? Here, we propose a closed-loop computational framework integrating machine learning (ML), physiologically based pharmacokinetic (PBPK) modeling, and molecular dynamics (MD) simulations to accelerate LAI formulation design. Using the commercial poly (lactic-co-glycolic acid) (PLGA)-based injectable Zilretta® as a benchmark, PBPK/PD modeling was used to define target in vitro release profiles that maximize therapeutic exposure. Guided by ML predictions, an optimized in situ forming gel (ISFG) formulation was developed for intra-articular delivery of triamcinolone acetonide, achieving a 34 % increase in drug exposure compared to commercial suspension in rat pharmacokinetic studies. MD simulations elucidated key drug-polymer interactions enabling sustained release. The transformative computational framework could significantly reduce the formulation development time during the preclinical phase from the traditional 5-7 years to approximately 1-2 years. This framework redefines the formulation paradigm: from empirical "formulate-and-test" to predictive "compute-and-validate", and offers a scalable strategy for rational, efficient development of long-acting injectables.

Ilaprazole, a proton pump inhibitor, has been approved and marketed in Korea and China for the treatment of gastric ulcer, duodenal ulcer, gastroesophageal reflux disease, and erosive esophagitis. This study evaluated the in vitro antibacterial activity of ilaprazole against Helicobacter pylori ( H. pylori ), both as a single agent and in combination with other components used in the standard quadruple therapy. The antibacterial activity of ilaprazole was tested on 25 H . pylori strains, including the clinical isolates resistant to clarithromycin (CLA), amoxicillin (AMX), levofloxacin, and/or metronidazole. Antibacterial activities and killing kinetics were evaluated by the minimal inhibitory concentration (MIC) and time-kill curve determination, respectively. Synergistic effects were assessed in checkerboard and time-kill assays. Resistance development was assessed through serial passage over 12 cycles. Ilaprazole exhibited potent in vitro antibacterial activity against H. pylori , with MIC 50 and MIC 90 values of 8 µg/mL, demonstrating activity against drug-resistant strains. When combined with CLA, ilaprazole showed synergistic effects against 36% of the tested strains. Notably, the quadruple combination of ilaprazole + AMX + CLA + bismuth potassium citrate exhibited an obvious synergistic effect. Importantly, repeated exposure to ilaprazole over 12 passages did not induce resistance. These findings highlight the promising in vitro antibacterial activity of ilaprazole against H. pylori , including drug-resistant strains, and its potential to enhance the efficacy of quadruple therapy. The study supports the inclusion of ilaprazole in treatment regimens for H. pylori infections, offering a compelling rationale for its clinical use.

H. pylori infection remains a major global health issue, contributing to a wide range of gastric diseases. Despite current treatment regimens, rising antibiotic resistance limits their effectiveness, emphasizing the need for novel therapeutic approaches. This study highlights the promising in vitro antibacterial activity of ilaprazole against H. pylori , including drug-resistant strains. Ilaprazole not only exhibits direct antimicrobial effects but also enhances the efficacy of combination therapy, particularly in quadruple therapy regimens, which are recommended as first-line treatment. The findings demonstrate that ilaprazole, in combination with clarithromycin, shows synergistic effects, offering a potential solution to overcome antibiotic resistance challenges. Importantly, repeated exposure to ilaprazole did not induce resistance, a critical factor for its long-term use. These results provide compelling evidence for ilaprazole’s inclusion in clinical treatment strategies, contributing to improved eradication rates and better patient outcomes in H. pylori management.

Macrocyclization is a compelling strategy for conventional drug design for improving biological activity, target specificity, and metabolic stability, but it was rarely applied to the design of PROTACs possibly due to the mechanism and structural complexity. Herein, we report the rational design of the first series of "Head-to-Tail" macrocyclic PROTACs. The resulting molecule SHD913 exhibited pronounced Brd4 protein degradation with low nM DC₅₀ values while almost totally dismissing the "hook effect", which is a general character and common concern of a PROTAC, in multiple cancer cell lines. Further biological evaluation revealed that the compound exhibited positive cooperativity and induced de novo protein-protein interactions (PPIs) in both biophysical and cellular NanoBRET assays and outperformed macroPROTAC-1 that is the first reported macrocyclic Brd4 PROTAC, in cellular assays. In vitro liver microsomal stability evaluation suggested that SHD913 demonstrated improved metabolic stability in different species compared with the linear counterpart. The co-crystal structure of Brd4^BD2: SHD913: VCB (VHL, Elongin C and Elongin B) complex determination and molecular dynamics (MD) simulation also elucidated details of the chemical-induced PPIs and highlighted the crucial contribution of restricted conformation of SHD913 to the ternary complex formation. These results collectively support that macrocyclization could be an attractive and feasible strategy for a new PROTAC design.