Hydroxypropyl β cyclodextrins effects on self-assembly of cyclic peptide, lanreotide acetate, in water and subsequent release rate from an in vitro emulator of subcutaneous delivery.

Most of the peptide drugs are often delivered subcutaneously. The significant barrier in this type of peptide administration is the high concentration of formulation, which can lead to self-assembly and aggregation. These phenomena can negatively impact the peptide drug's bioavailability, manufacturing, and injectability.

β-Cyclodextrin derivatives bind aromatic side chains of the cyclic peptide lanreotide.

Cyclodextrin complexation has a potential to modulate the physicochemical properties of peptide drugs. The ability of peptides to form an inclusion complex can be influenced by factors such as size, amino acid sequence of peptide, and the size and charge of the cyclodextrin cavity. In this study, the inclusion complexes of the cyclic peptide drug lanreotide acetate with two common β-cyclodextrin derivatives, Sulfobutyl ether β-CD (SBEβ-CD) and hydroxypropyl β-CD (HPβ-CD) were investigated.

Characterization of macrocyclic peptide drug interactions with bile salts and biorelevant colloids via single amino acid mutations and H nuclear magnetic resonance (NMR) spectroscopy.

There is growing interest in the oral delivery of poorly permeable peptide drugs; however, the effect of biorelevant colloids found in the aqueous gastrointestinal environment on peptide drug solution behavior has been largely understudied. In this work, we detail the molecular level interactions between octreotide, a water-soluble macrocyclic peptide drug, and biorelevant colloids, i.e.

Enhanced Dissolution of Amphotericin B through Development of Amorphous Solid Dispersions Containing Polymer and Surfactants.

Amphotericin B (AmB) is the gold standard for antifungal therapy; however, its poor solubility limits its administration via intravenous infusion. A promising formulation strategy to achieve an oral formulation is the development of amorphous solid dispersions (ASDs) via spray-drying. Inclusion of surfactants into ASDs is a newer concept, yet it offers increased dissolution opportunities when combined with a polymer (HPMCAS 912).

Development of a drying method for proteins based on protein-hyaluronic acid precipitation.

This study aims to develop a new method to dry proteins based on protein-hyaluronic acid (HA) precipitation and apply the precipitation-redissolution technique to develop highly concentrated protein formulations. Lysozyme was used as a model protein and HA with various molecular weights (MW) were investigated. Under low ionic strength, low-MW HA (e.

Molecular Dynamics Simulation of an Iron(III) Binding Site on the Fc Domain of IgG1 Relevant for Visible Light-Induced Protein Fragmentation.

Molecular dynamics simulations were employed to investigate the interaction between Fe(III) and an iron-binding site composed of THR259, ASP252, and GLU261 on the Fc domain of an IgG1. The goal was to provide microscopic mechanistic information for the photochemical, iron-dependent site-specific oxidative fragmentation of IgG1 at THR259 reported in our previous paper. The distance between Fe(III) and residues of interest as well as the binding pocket size was examined for both protonated and deprotonated THR259.

Development of Drug Release Model for Suspensions in ESCAR (Emulator of SubCutaneous Absorption and Release).

We recently developed an in vitro testing system, namely, ESCAR (Emulator of SubCutaneous Absorption and Release). The objective of this work was to investigate drug release behaviors of unmilled and milled suspensions in ESCAR. A mass transport-based model was developed to describe the multi-step drug release process, including drug dissolution, particle settling, drug distribution/partition, and drug permeation through the membrane(s).

Development of an In Vitro System To Emulate an In Vivo Subcutaneous Environment: Small Molecule Drug Assessment.

A reliable in vitro system can support and guide the development of subcutaneous (SC) drug products. Although several in vitro systems have been developed, they have some limitations, which may hinder them from getting more engaged in SC drug product development. This study sought to develop a novel in vitro system, namely, mulator of ubutaneous bsorption and elease (ESCAR), to better emulate the in vivo SC environment and predict the fate of drugs in SC delivery.

Advanced Formulations/Drug Delivery Systems for Subcutaneous Delivery of Protein-Based Biotherapeutics.

Multiple advanced formulations and drug delivery systems (DDSs) have been developed to deliver protein-based biotherapeutics via the subcutaneous (SC) route. These formulations/DDSs include high-concentration solution, co-formulation of two or more proteins, large volume injection, protein cluster/complex, suspension, nanoparticle, microparticle, and hydrogel. These advanced systems provide clinical benefits related to efficacy and safety, but meanwhile, have more complicated formulations and manufacturing processes compared to conventional solution formulations.

Investigating protein diffusivities in diluted hyaluronic acid solutions using dynamic light scattering.

This study aimed to investigate the diffusivities of lysozyme (LYS), ovalbumin (OVA), and hyaluronic acid (HA) in buffered solvents using dynamic light scattering (DLS). For protein/solvent and HA/solvent binary systems, the diffusion coefficients of protein or HA were obtained from autocorrelation function (ACF) curve fitting. Whereas, for protein/HA/solvent ternary systems, the two eigenvalues of the mutual diffusion coefficient matrix were obtained from ACF curve fitting.

Particle Size Limits to Pass the Acceptance Value (AV)-Based USP Content Uniformity Test for Tablets.

The papers published by Yalkowsky et al. and Rohrs et al. offer a method to correlate the probability of passing USP content uniformity (CU) test with maximum allowed particle size and distribution.

Simulating particle movement inside subcutaneous injection site simulator (SCISSOR) using Monte-Carlo method.

This study used Monte Carlo method to simulate particle movement inside a commercialized instrument called Subcutaneous Injection Site Simulator (SCISSOR). A series of parameters related to instrument, injection device, operation, formulation, as well as medium were thoroughly investigated. Also, several events that particles may occur in the subcutaneous (SC) space, including diffusion, binding, and aggregation, were implemented in our Monte Carlo based algorithms.

Applications of Machine Learning in Solid Oral Dosage Form Development.

This review comprehensively summarizes the application of machine learning in solid oral dosage form development over the past three decades. In both academia and industry, machine learning is increasingly applied for multiple preformulation/formulation and process development studies. Further, this review provides the authors' perspectives on how pharmaceutical scientists can use machine learning for right projects and in right ways; some key ingredients include (1) the determination of inputs, outputs, and objectives; (2) the generation of a database containing high-quality data; (3) the development of machine learning models based on dataset training and model optimization; (4) the application of trained models in making predictions for new samples.

Machine Learning Attempts for Predicting Human Subcutaneous Bioavailability of Monoclonal Antibodies.

Purpose: One knowledge gap related to subcutaneous (SC) delivery is unpredictable and variable bioavailability. This study was aimed to develop machine learning methods to predict whether mAb's bioavailability was ≥70% or below, without completely knowing the mechanism and causality between inputs and outputs.

Methods: A database of mAb SC products was built.

Investigating the Influence of Tablet Location Inside Dissolution Test Apparatus on Polymer Erosion and Drug Release of a Surface-Erodible Sustained-Release Tablet Using Computational Simulation Methods.

The objective of this work was to investigate the influence of tablet location along the bottom of a USP apparatus II vessel on polymer erosion and drug release of surface-erodible sustained-release tablets using computational simulation methods. Computational fluid dynamics (CFD) methods were performed to simulate the velocity distribution. A mathematical model was developed to describe polymer erosion and tablet deformation according to the mass transfer coefficient.

Enhancing Intestinal Absorption of a Model Macromolecule via the Paracellular Pathway using E-Cadherin Peptides.

Membrane permeation enhancers have received significant attention in recent years for enabling the oral absorption of poorly permeable drug molecules. In this study, we investigated the ability of His-Ala-Val (HAV) and Ala-Asp-Thr (ADT) peptides derived from the extracellular-1 (EC1) domain of E-cadherin proteins to increase the paracellular permeation and intestinal bioavailability of the poorly permeable model macromolecule, fluorescein-isothiocyanate dextran with average molecular weight 4000 (FD4). The in vitro enzymatic stability of linear and cyclic E-cadherin peptides was characterized under simulated gastric and intestinal conditions, and the cyclic E-cadherin peptides, HAVN1 and ADTC5, which demonstrated excellent stability in vitro, were advanced to in vivo intestinal instillation studies and compared against the established surfactant membrane permeation enhancer, sodium caprate (C).

Assessing the risk of drug crystallization in vivo.

Introduction: Low intrinsic solubility leading to poor oral bioavailability is a common challenge in drug discovery that can often be overcome by formulation strategies, however, it remains a potential limitation that can pose challenges for early risk assessment and represent a significant obstacle to drug development. We identified a selective inhibitor (BMS-986126) of the IL-1 receptor-associated kinase 4 (IRAK4) with favorable properties as a lead candidate, but with unusually low intrinsic solubility of <1 μg/mL.

Methods: Conventional histopathology identified the issue of crystal formation in vivo.

The application of machine learning algorithms in understanding the effect of core/shell technique on improving powder compactability.

This study systemically investigated the application of core/shell technique to improve powder compactability. A 28-run Design-of-Experiment (DoE) was conducted to evaluate the effects of the type of core and shell materials and their concentrations on tensile strength and brittleness index. Six machine learning algorithms were used to model the relationships of product profile outputs and raw material attribute inputs: response surface methodology (RSM), Support Vector Machine (SVM), and four different types of artificial neural networks (ANN), namely, Backpropagation Neural Network (BPNN), Genetic Algorithm Based BPNN (GA-BPNN), Mind Evolutionary Algorithm Based BPNN (MEA-BPNN), and Extreme Learning Machine (ELM).

Preparation of lapatinib ditosylate solid dispersions using solvent rotary evaporation and hot melt extrusion for solubility and dissolution enhancement.

The objective of this study was to enhance solubility and dissolution of lapatinib (LB) ditosylate (DT) using solid dispersions (SD) prepared by solvent rotary evaporation (SRE) and hot melt extrusion (HME). A series of models based on solubility parameter, the solid-liquid equilibrium equation, and the Flory-Huggins equation were employed to provide insight to data and evaluate drug/polymer interactions. Experimentally, nine SD formulas were prepared and characterized by various analytical techniques including differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), scanning electron microscope (SEM), solubility, and dissolution.

The expanding role of prodrugs in contemporary drug design and development.

Prodrugs are molecules with little or no pharmacological activity that are converted to the active parent drug in vivo by enzymatic or chemical reactions or by a combination of the two. Prodrugs have evolved from being serendipitously discovered or used as a salvage effort to being intentionally designed. Such efforts can avoid drug development challenges that limit formulation options or result in unacceptable biopharmaceutical or pharmacokinetic performance, or poor targeting.