Combining SNAC and C10 in oral tablet formulations for gastric peptide delivery: A preclinical and clinical study.

Current oral formulations of macromolecules including peptides typically rely on single permeation enhancer (PE) to promote absorption and thus bioavailability. In this work, we combined two PEs, namely sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) and sodium caprate (C10), in one tablet formulation to potentially gain a synergistic effect for enhanced gastric absorption of a GLP-1 analogue and a PCSK9 inhibitor. Permeability tests on a gastric organoids-based cell model showed that the combination of SNAC and C10 can significantly improve peptide permeability compared to either SNAC or C10 alone.

Salcaprozate-based ionic liquids for GLP-1 gastric delivery: A mechanistic understanding of in vivo performance.

Oral delivery of peptides requires formulations with high concentrations of permeation enhancer (PE) to promote absorption, and often necessitates fasting time between dosing and food ingestion. Improved formulations promoting a more rapid absorption would increase convenience of use but requires a faster onset of action. We have developed a salcaprozate-based ionic liquid (IL) formulation, namely choline salcaprozate (CHONAC), for oral delivery of a glucagon-like peptide-1 (GLP-1) analogue via gastric absorption.

SSEmb: A joint embedding of protein sequence and structure enables robust variant effect predictions.

The ability to predict how amino acid changes affect proteins has a wide range of applications including in disease variant classification and protein engineering. Many existing methods focus on learning from patterns found in either protein sequences or protein structures. Here, we present a method for integrating information from sequence and structure in a single model that we term SSEmb (Sequence Structure Embedding).

Simulation of roller compaction by combination of a compaction simulator and oscillating mill - A material sparing approach.

This study investigates the feasibility of a compaction simulator and oscillating mill to mimic a roller compactor as a material sparing approach for process development. Microcrystalline cellulose and dicalcium phosphate dihydrate were selected to represent soft and hard materials, respectively. The relative density of ribbons and riblets was determined using a pycnometer and granules size distribution was determined by laser diffraction.

Influence of Polyvinylpyrrolidone Molecular Weight and Concentration on the Precipitation Inhibition of Supersaturated Solutions of Poorly Soluble Drugs.

Supersaturating drug delivery systems such as solid dispersions of a drug in a polymer are frequently used in pharmaceutical development to enable oral delivery of poorly soluble drugs. In this study, the influence of the concentration and molecular weight of polyvinylpyrrolidone (PVP) on the precipitation inhibition of the poorly soluble drugs albendazole, ketoconazole and tadalafil is investigated to expand the understanding of the mechanism of PVP as a polymeric precipitation inhibitor. A three-level full-factorial design was used to delineate the influence of polymer concentration and viscosity of the dissolution medium on precipitation inhibition.

Rapid protein stability prediction using deep learning representations.

Predicting the thermodynamic stability of proteins is a common and widely used step in protein engineering, and when elucidating the molecular mechanisms behind evolution and disease. Here, we present RaSP, a method for making rapid and accurate predictions of changes in protein stability by leveraging deep learning representations. RaSP performs on-par with biophysics-based methods and enables saturation mutagenesis stability predictions in less than a second per residue.

The Use of Capsule Endoscopy to Determine Tablet Disintegration In Vivo.

The preferred delivery route for drugs targeted for systemic effect is by oral administration. Following oral administration, a solid dosage form must disintegrate and the drug dissolve, thereafter permeating the intestinal mucosa. Several different in vitro methods are used to investigate these processes, i.

Influence of Glass Forming Ability on the Physical Stability of Supersaturated Amorphous Solid Dispersions.

In this study, the influence of the glass-forming ability (GFA) of a drug on its physical stability in a supersaturated solid dispersion was investigated. Nine drugs were classified according to their GFA using their respective critical cooling rate. Their respective solubility in poly(vinylpyrrolidone-co-vinyl acetate) 6:4 (PVPVA64) was predicted using the melting point depression method based on the Flory-Huggins lattice theory.

The Influence of Polymers on the Supersaturation Potential of Poor and Good Glass Formers.

The increasing number of poorly water-soluble drug candidates in pharmaceutical development is a major challenge. Enabling techniques such as amorphization of the crystalline drug can result in supersaturation with respect to the thermodynamically most stable form of the drug, thereby possibly increasing its bioavailability after oral administration. The ease with which such crystalline drugs can be amorphized is known as their glass forming ability (GFA) and is commonly described by the critical cooling rate.

Is there a correlation between the glass forming ability of a drug and its supersaturation propensity?

The use of an enabling formulation technique, such as amorphization of a poorly water-soluble crystalline drug, can result in supersaturation with respect to the crystalline form of the drug and thus potentially in a higher degree of absorption after oral administration. The ease with which such drugs can be amorphized is known as their glass forming ability (GFA). In this study, a potential correlation between GFA and supersaturation propensity is investigated.

Influence of preparation pathway on the glass forming ability.

The glass forming ability (GFA), i.e. the ease of amorphization of drugs, is mostly investigated using the critical cooling rate upon melt quenching to generate an amorphous product via the thermodynamic pathway.

Glass Forming Ability of Amorphous Drugs Investigated by Continuous Cooling and Isothermal Transformation.

The aim of this study was to investigate the glass forming ability of 12 different drugs by the determination of continuous cooling and isothermal transformation diagrams in order to elucidate if an inherent differentiation between the drugs with respect to their the glass forming ability can be made. Continuous-cooling-transformation (CCT) and time-temperature-transformation (TTT) diagrams of the drugs were developed in order to predict the critical cooling rate necessary to convert the drug from the melt into an amorphous form. While TTT diagrams overestimated the actual critical cooling rate, they allowed an inherent differentiation of glass forming ability for the investigated drugs into drugs that are extremely difficult to amorphize (>750 °C/min), drugs that require modest cooling rates (>10 °C/min), and drugs that can be made amorphous even at very slow cooling rates (>2 °C/min).

Preparation and characterization of spray-dried co-amorphous drug-amino acid salts.

Objectives: Recently, co-amorphous drug-amino acid mixtures were introduced as a promising alternative to other amorphous stabilization approaches such as the use of polymers to form glass solutions. So far, these co-amorphous mixtures have been mainly prepared via vibrational ball milling on a lab scale. In this study, spray-drying was investigated as a scale up preparation method for co-amorphous indomethacin (IND)-amino acid mixtures.

Solid-state properties and dissolution behaviour of tablets containing co-amorphous indomethacin-arginine.

Co-amorphous drug formulations provide the possibility to stabilize a drug in its amorphous form by interactions with low molecular weight compounds, e.g. amino acids.