A New Approach for Preparing Stable High-Concentration Peptide Nanoparticle Formulations.

The subcutaneous administration of therapeutic peptides would provide significant benefits to patients. However, subcutaneous injections are limited in dosing volume, potentially resulting in high peptide concentrations that can incur significant challenges with solubility limitations, high viscosity, and stability liabilities. Herein, we report on the discovery that low-shear resonant acoustic mixing can be used as a general method to prepare stable nanoparticles of a number of peptides of diverse molecular weights and structures in water without the need for extensive amounts of organic solvents or lipid excipients.

Utilizing Molecular Simulations to Examine Nanosuspension Stability.

Drug nanosuspensions offer a promising approach to improve bioavailability for poorly soluble drug candidates. Such formulations often necessitate the inclusion of an excipient to stabilize the drug nanoparticles. However, the rationale for the choice of the correct excipient for a given drug candidate remains unclear.

Development of Nanosuspension Formulations Compatible with Inkjet Printing for the Convenient and Precise Dispensing of Poorly Soluble Drugs.

The pharmaceutical industry has been challenged by the increasing number of poorly soluble drug candidates, resulting in significant issues with obtaining sufficient absorption and bioavailability, risk of exposure variability, and difficulties in achieving a safe therapeutic index. Additionally, the rapid and precise dispensing of specific drug dosages is an important aspect that can enable personalized medicines for the patient. Herein, we report on the development of inkjet printing as a method for delivering precise quantities of poorly soluble drug molecules using commercially available equipment.

Effect of magnesium stearate surface coating method on the aerosol performance and permeability of micronized fluticasone propionate.

In this study, we evaluated the aerodynamic performance, dissolution, and permeation behavior of micronized fluticasone propionate (FP) and magnesium stearate (MgSt) binary mixtures. Micronized FP was dry mixed with 2% w/w MgSt using a tumble mixer and a resonant acoustic mixer (RAM) with and without heating. The mixing efficacy was determined by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) analysis.

Impact of surfactant selection and incorporation on in situ nanoparticle formation from amorphous solid dispersions.

Spray dried amorphous solid dispersions (ASDs) stand as one of the most effective formulation strategies to address issues of low aqueous solubility when developing new chemical entities.An emerging research topic focusing on the formation of amorphous nanoparticles or nanodroplets from ASD formulations has attracted attention recently. These ASD nanoparticlescan be highly beneficial and able to further increase oral bioavailability.

Targeting KRAS Mutant Cancers via Combination Treatment: Discovery of a Pyridopyridazinone pan-RAF Kinase Inhibitor.

Structure-based optimization of a set of aryl urea RAF inhibitors has led to the identification of Type II pan-RAF inhibitor GNE-9815 (), which features a unique pyrido[2,3-]pyridazin-8(7)-one hinge-binding motif. With minimal polar hinge contacts, the pyridopyridazinone hinge binder moiety affords exquisite kinase selectivity in a lipophilic efficient manner. The improved physicochemical properties of GNE-9815 provided a path for oral dosing without enabling formulations.

Targeting KRAS Mutant Cancers via Combination Treatment: Discovery of a 5-Fluoro-4-(3)-quinazolinone Aryl Urea pan-RAF Kinase Inhibitor.

Optimization of a series of aryl urea RAF inhibitors led to the identification of type II pan-RAF inhibitor GNE-0749 (), which features a fluoroquinazolinone hinge-binding motif. By minimizing reliance on common polar hinge contacts, this hinge binder allows for a greater contribution of RAF-specific residue interactions, resulting in exquisite kinase selectivity. Strategic substitution of fluorine at the C5 position efficiently masked the adjacent polar NH functionality and increased solubility by impeding a solid-state conformation associated with stronger crystal packing of the molecule.

A novel method for preparing stabilized amorphous solid dispersion drug formulations using acoustic fusion.

A diverse set of drug and polymer combinations have been effectively evaluated utilizing a newly developed method called acoustic fusion to form amorphous solid dispersions (ASD) on the mg-scale, indicating that this approach is a general procedure that can be applied for ASD drug formulations. We have demonstrated the effectiveness of this acoustic fusion process by generating amorphous solid dispersions of various BCS class 2 and 4 drug candidates, including torcetrapib, itraconazole, and lopinavir, with a variety of polymer systems, including HPMCAS (L, M, and H), copovidone, Soluplus®, PEG1500, Vitamin-E TPGS, Kolliphor EL, and Eudragit, etc. Formulations of these ASD drug products demonstrated significantly elevated solubility of the drug substance compared to the solubility of the crystalline form of the drug.

Towards an improved understanding of drug excipient interactions to enable rapid optimization of nanosuspension formulations.

Suspensions of drug nanoparticles known as nanosuspensions have emerged as a successful enabling formulation approach for poorly soluble drug candidates. These nanoparticles typically require stabilization with specific polymer or surfactant excipients to prevent aggregation from occurring. This study demonstrates the necessity of formulating drug nanosuspensions with amphiphilic excipients possessing long hydrophobic alkyl or polymer block chains to produce stable nanoparticles.

Design, Synthesis, and Evaluation of Novel and Selective G-protein Coupled Receptor 120 (GPR120) Spirocyclic Agonists.

Type 2 diabetes mellitus (T2DM) is an ever increasing worldwide epidemic, and the identification of safe and effective insulin sensitizers, absent of weight gain, has been a long-standing goal of diabetes research. G-protein coupled receptor 120 (GPR120) has recently emerged as a potential therapeutic target for treating T2DM. Natural occurring, and more recently, synthetic agonists have been associated with insulin sensitizing, anti-inflammatory, and fat metabolism effects.

Development of a Convenient In Vitro Gel Diffusion Model for Predicting the In Vivo Performance of Subcutaneous Parenteral Formulations of Large and Small Molecules.

Parenteral delivery remains a compelling drug delivery route for both large- and small-molecule drugs and can bypass issues encountered with oral absorption. For injectable drug products, there is a strong patient preference for subcutaneous administration due to its convenience over intravenous infusion. However, in subcutaneous injection, in contrast to intravenous administration, the formulation is in contact with an extracellular matrix environment that behaves more like a gel than a fluid.

Modulating Drug Release and Enhancing the Oral Bioavailability of Torcetrapib with Solid Lipid Dispersion Formulations.

The development of drug dispersions using solid lipids is a novel formulation strategy that can help address the challenges of poor drug solubility and systemic exposure after oral administration. The highly lipophilic and poorly water-soluble drug torcetrapib could be effectively formulated into solid lipid microparticles (SLMs) using an anti-solvent precipitation strategy. Acoustic milling was subsequently used to obtain solid lipid nanoparticles (SLNs).

A new and improved method for the preparation of drug nanosuspension formulations using acoustic mixing technology.

Drug discovery and development is a challenging area. During the drug optimization process, available drug compounds often have poor physicochemical and biopharmaceutical properties, making the proper in vivo evaluation of these compounds difficult. To address these challenges, drug nanoparticles of poorly soluble compounds have emerged as a promising formulation approach.

Axial donating ligands: a new strategy for late transition metal olefin polymerization catalysis.

An alpha-diimine ligand (1) containing an axial donating pyridine group is developed for late metal polymerization catalysis. Despite having no substitution on the bottom face of the ligand, the nickel and palladium complexes of 1 are highly active for ethylene polymerization, producing linear high molecular weight polymers. For example, 1-NiBr2 (3) forms PE with a Mn of up to 109 224 g/mol with 1.

Enthalpy-entropy compensation reveals solvent reorganization as a driving force for supramolecular encapsulation in water.

A chiral self-assembled M4L6 host assembly has been shown to be a suitable host for the supramolecular encapsulation of a series of guests in polar solvents, ranging from simple organic ammonium cations to more complex organometallic species. This molecular recognition process creates highly selective reactivity within the host cavity. In order to understand the factors driving the molecular recognition process, the standard thermodynamic parameters for encapsulation were determined for a series of protiated and fluorinated iridium guests in a variety of polar solvents using van't Hoff analysis.

Scope and mechanism of the C-H bond activation reactivity within a supramolecular host by an iridium guest: a stepwise ion pair guest dissociation mechanism.

A chiral self-assembled supramolecular M(4)L(6) assembly has been shown to be a suitable host for a series of reactive monocationic half-sandwich iridium guests 1, 3, and 4 that are capable of activating C-H bonds. Upon encapsulation, selective C-H bond activation of organic substrates occurs. Precise size and shape selectivity are observed in the C-H bond activation of aldehydes and ether substrates.

Selective molecular recognition, C-H bond activation, and catalysis in nanoscale reaction vessels.

Supramolecular chemistry represents a way to mimic enzyme reactivity by using specially designed container molecules. We have shown that a chiral self-assembled M4L6 supramolecular tetrahedron can encapsulate a variety of cationic guests with varying degrees of stereoselectivity. Reactive iridium guests can be encapsulated, and the C-H bond activation of aldehydes occurs with the host cavity controlling the ability of substrates to interact with the metal center based upon size and shape.

Cost-effectiveness of pulmonary resection and systemic chemotherapy in the management of metastatic soft tissue sarcoma: a combined analysis from the University of Texas M. D. Anderson and Memorial Sloan-Kettering Cancer Centers.

Background: We sought to determine the cost-effectiveness of different treatment strategies for patients with pulmonary metastases from soft tissue sarcoma.

Methods: We constructed a decision tree to model the outcomes of 4 treatment strategies for patients with pulmonary metastases from soft tissue sarcoma: pulmonary resection, systemic chemotherapy, pulmonary resection and systemic chemotherapy, and no treatment. Data from 1124 patients with pulmonary metastases from soft tissue sarcoma were used to estimate disease-specific survival for pulmonary resection and no treatment.

Enantioselective guest binding and dynamic resolution of cationic ruthenium complexes by a chiral metal-ligand assembly.

A supramolecular metal-ligand assembly encapsulates a variety of cationic half-sandwich ruthenium complexes. Due to the chirality of both host and guest, chiral recognition is observed with diastereomeric excesses up to 70%. The chiral cavity can be used to carry out a dynamic resolution of the rapidly equilibrating enantiomers of the chiral organometallic guest.