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Alternative buffer systems in biopharmaceutical formulations and their effect on formulation stability
No full textFormulation of biopharmaceutical drug is supposed to eliminate chemical instabilities, increase conformational and colloidal stability of protein, and optimize interfacial stability. This is achieved by combination of many excipients, among which buffer composition is one of the most important one. However, reference buffer, such as conventionally used histidine and phosphate buffers, may not always be the most optimal choice for all mAbs. In this study we tested seven mAbs with multiple alternative buffer systems, alternating combinations of ionic strengths, main buffer component concentrations, mAb concentration and stress condition. Protein stability was correlated to aggregates formation, which was detected by size exclusion chromatography. At low protein concentration, only bis-TRIS/glucuronate buffer formulation displayed protein instability after temperature stress, while freeze-thaw stress was best mitigated by arginine/citrate buffer. Addition of arginine to histidine buffer systems further stabilized proteins during temperature stress, whereas same was not true for histidine/HCl buffer during freeze thaw. Interestingly, five out of seven reference formulations displayed higher aggregate content after freeze-thaw stress at lower protein concentration, rather than higher. Mechanism of action was proposed.At high protein concentration, histidine/citrate buffer proved to be one of the best choices at temperature and light stress. Former was successfully mitigated by histidine buffers, probably due to histidine molecule light-absorbing capabilities. Our results demonstrate that biopharmaceutical formulation development should not limit itself to conventional buffer systems for many alternatives perform just as good if not even better
Buchwald-Hartwig Aminations of Aryl Halides Using Nitroaromatics as Coupling Partners: Overcoming Hydrodehalogenation Pathway in Water
No full textAn aqueous micellar strategy is developed for the C–N cross-coupling of nitroarenes with aryl halides. The reaction pathway in-cludes the domino aminations of in-situ generated amines from nitroaromatics with aryl halides achieved by overcoming unwanted hydrodehalogenation. A bimetallic palladium (Pd)-copper (Cu) nanocatalyst design achieves the desired reactivity by promoting the amination pathway assisted by Cu-hydride formation and suppressing Pd-hydride-mediated hydrodehalogenation. The nano-catalyst was characterized by 31P and 1H nuclear magnetic resonance and X-ray absorption spectroscopies to understand metal-ligand and metal-metal interactions, respectively. High-resolution transmission electron microscopy was performed to obtain the particle size, shape, distribution, and morphology. X-ray photoelectron spectroscopic studies confirmed the oxidation states of Cu and Pd. Control experiments revealed the significance of amphiphile PS-750-M and each component of the nanocatalyst on the desired coupling. This aqueous strategy applies to many substrates and exhibits excellent functional and protecting group tolerance. The scalability of this methodology is demonstrated on a gram-scale reaction. This approach represents greener and step-economic ways to access arylamines
Continuous manufacturing: Implementation of multiple, deliberate interruptions of a virus removal filtration process
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Adapting Deep Learning QSPR Models to Specific Drug Discovery Projects
No full textMedicinal chemistry and drug design efforts can be assisted by machine learning (ML) models that relate the molecular structure to compound properties. Such quantitative structure–property relationship models are generally trained on large data sets that include diverse chemical series (global models). In the pharmaceutical industry, these ML global models are available across discovery projects as an “out-of-the-box” solution to assist in drug design, synthesis prioritization, and experiment selection. However, drug discovery projects typically focus on confined parts of the chemical space (e.g., chemical series), where global models might not be applicable. Local ML models are sometimes generated to focus on specific projects or series. Herein, ML-based global models, local models, and hybrid global-local strategies were benchmarked. Analyses were done for more than 300 drug discovery projects at Novartis and ten absorption, distribution, metabolism, and excretion (ADME) assays. In this work, hybrid global-local strategies based on transfer learning approaches were proposed to leverage both historical ADME data (global) and project-specific data (local) to adapt model predictions. Fine-tuning a pretrained global ML model (used for weights’ initialization, WI) was the top-performing method. Average improvements of mean absolute errors across all assays were 16% and 27% compared with global and local models, respectively. Interestingly, when the effect of training set size was analyzed, WI fine-tuning was found to be successful even in low-data scenarios (e.g., ∼10 molecules per project). Taken together, this work highlights the potential of domain adaptation in the field of molecular property predictions to refine existing pretrained models on a new compound data distribution
Towards more tolerable and painless subcutaneous administration: review of contributing factors for improving combination product design
No full textSubcutaneous (SC) injections can be associated with a subjective level of local pain and discomfort, which may affect treatment adherence and overall patient experience. With innovations increasingly focusing on finding ways to deliver higher doses and volumes (≥2 mL), there is a need to better understand the multiple intertwined factors that influence SC injection pain. As part of the work of the SC Drug Delivery and Development Consortium, this manuscript provides a comprehensive review of known attributes from published literature that contribute to SC injection pain/discomfort from three perspectives: (1) device and delivery factors that cause physical pain, (2) formulation factors that trigger biophysical/biochemical pain responses, and (3) human factors impacting pain perception. Leveraging the Consortium’s collective expertise, we also provide an assessment of the comparative and interdependent factors likely to impact SC injection pain, and offer expert insights and future perspectives to fill identified gaps in knowledge to help advance the development of patient-centric and well tolerated high dose/high volume SC drug delivery solutions
AHR activation accelerates the resolution of TGF-β1 induced fibroblast activation and promotes alveolar type 1 cell regeneration in alveolar organoids
No full textRegeneration of the alveolar epithelium is necessary to restore tissue architecture and gas exchange capabilities in chronic pulmonary diseases such as fibrosing interstitial lung disease. While it is known alveolar type 2 (AT2) cells give rise to alveolar type 1 (AT1) cells to repair the alveolar epithelium after injury, methods to promote this process under pathological settings are poorly understood. Here, using a complex 3D organoid culture with TGF-β1 dependent impaired AT1 spheroid formation, we performed a high-throughput screen (HTS) with ~16,800 compounds to identify small molecules that increase number of AT1 spheroids. Longitudinal single cell RNA sequencing (scRNA-seq) revealed that DB-11-BE87 increased AT1 regeneration by reducing TGF-β1 induced fibroblast activation, concurrently with AHR activation in those cells. These studies highlight a novel HTS system to identify factors that can promote AT1 differentiation and suggest AHR activation as a method to counteract pathological TGF-β1 signaling in pulmonary disease
Consensus Recommendations for ex vivo Anterior Segment Studies of Intraocular Pressure Facility and Regulation
No full textIntraocular pressure (IOP) elevation is the primary risk factor and currently only treatable parameter for progression of glaucomatous optic nerve damage. Since aqueous humor outflow regulation remains only partially understood at a basic science level and is the focus of much of clinical glaucoma activity, additional studies in these areas are of high importance. Aside from direct clinical studies, perfused anterior segment organ culture remains the primary model system for studying IOP regulation, although some in vitro animal models have been developed and are useful in certain cases. Perfused whole globes and stationary anterior segment organ culture provided the basis for perfused anterior segment organ culture. Although this approach can be applied to several other species, human tissue is the most common. Herein, we address the protocols for the most common methodological ex vivo human approaches, variations used in other species or in partial anterior segments and the viability and limitations of these approaches
Effect of particle size on the dispersion behavior of magnesium stearate blended with microcrystalline cellulose.
No full textThe majority of tablets manufactured contain lubricants to reduce friction during ejection. However, especially for plastically deforming materials, e.g., microcrystalline cellulose (MCC), the internal addition of lubricants is known to reduce tablet tensile strength. This reduction is caused by the surface coverage by lubricant particles, the extent of which depends on both process and formulation parameters. Previously published models to predict the lubrication effect on mechanical strength do not account for changes in the excipient particle size. In this study, the impact of both lubricant concentration and mixing time on the tensile strength of tablets consisting of three different grades of MCC and four grades of magnesium stearate (MgSt) was evaluated. By taking into account the particle size of the applied excipients, a unifying relationship between the theoretically estimated surface coverage and compactibility reduction was identified. Evaluating the dispersion kinetics of MgSt as a function of time reveals a substantial impact of the initial surface coverage on the dispersion rate, while the minimal tensile strength was found to be comparable for the majority of formulations. In summary, the presented work extends the knowledge of lubricant dispersion and facilitates the reduction of necessary experiments during the development of new tablet formulations
Novel 6-Hydroxy Picolinohydrazide Ligands Promoted a Highly Efficient Cu(I)-Catalyzed Hydroxylation Reaction with Water
No full textHydroxylated (hetero)arenes are prevalent in natural products, materials, small-molecule pharmaceuticals and serve as versatile intermediates in synthetic organic chemistry. Herein, we report an efficient Cu/6-hydroxy picolinohydrazide-catalyzed hydroxylation reaction of (hetero)aryl halides (Br, Cl) in water. By establishing machine learning (ML) models, the design of ligands and optimization of reaction conditions were effectively facilitated. L31 (6-HPA-DMCA) demonstrated high efficiency in bromide substrates, promoting hydroxylation reactions with a minimal catalyst loading of 0.01 mol% (100 ppm) at 80 °C, or under near-room temperature conditions for substrates containing sensitive functional groups (3.0 mol%); L42 (6-HPA-DTBCA) displayed superior reaction activity for chloride substrates, enabling hydroxylation reactions at 100°C. These represent the currently lowest catalyst loading and temperature for copper-catalyzed hydroxylation reactions. Furthermore, this method features a sustainable and environmentally friendly solvent system, accommodates a wide range of substrates, and shows potential for developing robust and scalable synthesis processes for key pharmaceutical intermediates