Evaluation of the impact of the polymer end groups and molecular weight on in vitro and in vivo performances of PLGA based in situ forming implants for ketoprofen.

In situ forming implants are appealing long-acting dosage forms for both preclinical and clinical applications due to their simple manufacturing process and easy delivery. This study aims to develop extended-release in situ forming solid implants for subcutaneous administration using two types of commercially available triblock poly (lactic-co-glycolic acid)-poly (ethylene glycol)-poly (lactic-co-glycolic acid) (PLGA-PEG-PLGA) polymers, with either an acid or ester end group. Both types of polymers instantly form in situ implants when injected directly into an aqueous medium.

Unsupervised graph anomaly detection with discriminative embedding similarity for viscoelastic sandwich cylindrical structures.

In the detection of slipping anomalies in viscoelastic sandwich cylindrical structures (VSCS), conventional methods may encounter challenges due to the extremely rare and weak nature of slipping signals. This study focuses on normal signals and introduces unsupervised graph representation learning (UGRL) with discriminative embedding similarity for VSCS's detection. UGRL involves data preprocessing, model embedding, and matrix reconstructing.

Early evaluation of opportunities in oral delivery of PROTACs to overcome their molecular challenges.

PROteolysis TArgeting Chimeras (PROTACs) offer new opportunities in modern medicine by targeting proteins that are intractable to classic inhibitors. Heterobifunctional in nature, PROTACs are small molecules that offer a unique mechanism of protein degradation by hijacking the ubiquitin-mediated protein degradation pathway, known as the ubiquitin-proteasome system. Herein, we present an analysis on the structural characteristics of this novel chemical modality.

Current screening, design, and delivery approaches to address low permeability of chemically synthesized modalities in drug discovery and early clinical development.

A drug's permeability across biological membranes is a key property associated with the successful development of an orally absorbed drug candidate. Although a variety of methods are available for predicting and assessing permeability, some are more preferred than others at specific stages of drug discovery and development across the pharmaceutical industry. Permeability measurements may be interpreted differently depending on the chosen method.

Pre-clinical Formulation Development of an in situ Meglumine Salt of AZD5991: A Novel Macrocyclic Mcl-1 Inhibitor.

Purpose: AZD5991 is a potent and selective macrocyclic inhibitor of Mcl-1 in clinical development. Developing an intravenous solution formulation for AZD5991 proved to be challenging primarily due to the poor intrinsic solubility of AZD5991. In this article are described studies performed to select a suitable crystalline form and to assess physicochemical properties of AZD5991 to aid in the design of a solution formulation for preclinical studies.

Discovery of a Potent and Orally Bioavailable Zwitterionic Series of Selective Estrogen Receptor Degrader-Antagonists.

Herein, we report the optimization of a meta-substituted series of selective estrogen receptor degrader (SERD) antagonists for the treatment of ER+ breast cancer. Structure-based design together with the use of modeling and NMR to favor the bioactive conformation led to a highly potent series of basic SERDs with promising physicochemical properties. Issues with hERG activity resulted in a strategy of zwitterion formation and ultimately in the identification of .

Discovery solubility measurement and assessment of small molecules with drug development in mind.

Solubility is a key physicochemical property for the success of any drug candidate. Although the methods used and their rationales for determining solubility are subject to project needs and stages along the drug discovery-drug development pipeline, an artificial boundary can exist at the discovery-development interface. This boundary results in less effective solubility knowledge sharing and data integration among scientists in both drug discovery and drug development.

Experimental design, development and evaluation of extended release subcutaneous thermo-responsive gels for small molecules in drug discovery.

The objective of this work is to develop extended release subcutaneous thermo-responsive gel-forming delivery systems using the following commercially available triblock polymers: poly (lactic-co-glycolic acid)-poly (ethylene glycol)-poly (lactic-co-glycolic acid) (PLGA-PEG-PLGA, copolymer A & B) and poly (lactide-co-caprolactone)-poly (ethylene glycol)-poly (lactide-co-caprolactone) (PLCL-PEG-PLCL, copolymer C). Performance of two optimized formulations containing ketoprofen as a model compound, was assessed by comparing drug release profiles with performance following subcutaneous administration in rats. This work employs a Design of Experiment (DoE) approach to explore first, the relationship between copolymer composition, concentration, and gelation temperature (GT), and second, to identify the optimal copolymer composition and drug loading in the thermo-responsive formulation.

Modulating target engagement of small molecules via drug delivery: approaches and applications in drug discovery and development.

Drug-delivery technologies for modified drug release have been in existence for decades, but their utilization has been largely limited to post-launch efforts improving therapeutic outcomes. Recently, they have gained renewed importance because the pharmaceutical industry is steadily shifting to a more integrated discovery-development approach. In discovery, modulating target engagement via drug-delivery technologies can enable crucial pharmacological studies for building well-defined criteria for molecular design.

Discovery of AZD9833, a Potent and Orally Bioavailable Selective Estrogen Receptor Degrader and Antagonist.

Herein we report the optimization of a series of tricyclic indazoles as selective estrogen receptor degraders (SERD) and antagonists for the treatment of ER breast cancer. Structure based design together with systematic investigation of each region of the molecular architecture led to the identification of -[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6,8)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3-pyrazolo[4,3-]isoquinolin-6-yl]pyridin-3-amine (). This compound was demonstrated to be a highly potent SERD that showed a pharmacological profile comparable to fulvestrant in its ability to degrade ERα in both MCF-7 and CAMA-1 cell lines.

Discovery of (2)--[3-[2-[(3-Methoxy-1-methyl-pyrazol-4-yl)amino]pyrimidin-4-yl]-1-indol-7-yl]-2-(4-methylpiperazin-1-yl)propenamide (AZD4205) as a Potent and Selective Janus Kinase 1 Inhibitor.

JAK1, JAK2, JAK3, and TYK2 belong to the JAK (Janus kinase) family. They play critical roles in cytokine signaling. Constitutive activation of JAK/STAT pathways is associated with a wide variety of diseases.

The Evolving Druggability and Developability Space: Chemically Modified New Modalities and Emerging Small Molecules.

The druggability and developability space is rapidly evolving in the post-genomic era. In the past, Lipinski's rule-of-five (Ro5) emerged and served as a guide for drug-like molecule design for oral delivery in the traditional druggable target space. In contrast, in this new era, a transition is occurring in drug discovery towards novel approaches to bind and modulate challenging biological targets that have led to transformative treatments for patients.

Application and Impact of Human Dose Projection from Discovery to Early Drug Development.

The application and impact of human dose projection (HDP) has been well recognized in the late drug development phase, with increasing appreciation earlier during discovery and early development. This commentary describes the perspective of pharmaceutical scientists on the evolving application and impact of HDP at various phases from discovery to early development, including lead generation, lead optimization, lead up to candidate nomination, and early drug development. The underlying fundamental concepts and key input parameters for HDP are briefly discussed.

Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia.

Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we describe AZD5991, a rationally designed macrocyclic molecule with high selectivity and affinity for Mcl-1 currently in clinical development.

Effect of para-sulfonato-calix[n]arenes on the solubility, chemical stability, and bioavailability of a water insoluble drug nifedipine.

This study reports the use of para-sulphonato calix[8]arene to produce stable complexes with improved bioavailability for nifedipine, a calcium-channel blocker that is practically insoluble in water. Thermal analysis and electrospray ionisation mass spectroscopy confirmed that nifedipine formed complexes with the calixarenes in a size dependent way. The most stable, soluble complexes was formed with para-sulphonato calix[8]arene.

A novel method to prepare highly encapsulated interferon-alpha-2b containing liposomes for intramuscular sustained release.

A novel modified film-hydration-dilution method was employed to prepare highly encapsulated interferon-alpha-2b containing liposomes for intramuscular sustained release. The liposomes produced by this technique were a mixture of mainly unilamellar vesicles and a small number of multilamellar vesicles. The trapping efficiency was above 80%.

Effect of 4-sulphonato-calix[n]arenes and cyclodextrins on the solubilization of niclosamide, a poorly water soluble anthelmintic.

The present study investigated the effect of water-soluble 4-sulphonato-calix[n]arenes, cyclodextrins, and combinations of these macromolecules on the aqueous solubility of a poorly water-soluble drug, niclosamide. Complexation between the macromolecules and niclosamide was confirmed by thermal analysis and phase solubility studies in a pH 7.0 Mcllvaine buffer kept at 30 degrees C.

The solubilization of the poorly water soluble drug nifedipine by water soluble 4-sulphonic calix[n]arenes.

In this study, the solubilizing effect of 4-sulphonic calix[n]arenes on the poorly water soluble drug nifedipine was investigated. 4-Sulphonic calix[n]arenes are water-soluble phenolic cyclooligomers that form complexes with neutral molecules such as nifedipine. Solubility experiments were performed at 30 degrees C using the Higuchi rotating bottle method.

Aqueous solubilization of furosemide by supramolecular complexation with 4-sulphonic calix[n]arenes.

The solubilization of the practically water insoluble drug furosemide by guest:host inclusion complexation with 4-sulphonic calix[n]arenes has been reported. The 4-sulphonic calix[n]arenes are water-soluble phenolic cyclooligomers that form inclusion complexes with neutral molecules. The solubility of furosemide in acidic (pH < 4) aqueous solutions containing increasing concentrations of the calixarenes was determined at 30 degrees C and the concentration of furosemide in solution was determined by HPLC.

Improving the aqueous solubility of triclosan by solubilization, complexation, and in situ salt formation.

Triclosan, an antimicrobial, although widely incorporated into many skin care products, toothpastes, and liquid soaps, presents formulation difficulties because it is practically insoluble in water. The objective of this study was to improve the aqueous solubility of triclosan through solubilization, complexation, and salt formation. The solubility of triclosan in distilled water and in phosphate buffers (pH 7.