iBCS: 4. Application of the Inhalation Biopharmaceutics Classification System to the Development of Orally Inhaled Drug Products.

This is the fourth paper in a series describing an inhalation biopharmaceutics classification system (iBCS), an initiative supported by the Product Quality Research Institute. The paper examines the application of the inhalation Biopharmaceutics Classification System (iBCS) through the drug discovery, development, and postapproval phases for orally inhaled drug products (OIDP) and for the development of generic OIDPs. We consider the implication of the iBCS class in terms of product performance and identify the practical gaps that must be filled to enable the classification system to be adopted into day-to-day practice.

Targeted nasal delivery of LNP-mRNAs aerosolised by Rayleigh breakup technology.

The nasal delivery of mRNA vaccines attracts great interests in both academia and industry. While the lipid nanoparticle (LNP)-mRNA complexes are vulnerable and need a subtle process for aerosolisation. In this study, a new nasal atomizer, based on the working rationale of Rayleigh breakup, was employed to aerosolise LNP-mRNAs.

Brain distribution study of [C]-Riluzole following intranasal administration in mice.

Amyotrophic lateral sclerosis (ALS) presents a substantial challenge due to its complex nature, limited effective treatment options, and modest benefits from current therapies in slowing disease progression. This study explores the potential of intranasal (IN) delivery to enhance the CNS delivery of riluzole (RLZ), a standard ALS treatment which is subject to blood-brain barrier efflux mechanisms. Additionally, the impact of elacridar (ELC), an efflux pump inhibitor, on IN RLZ CNS bioavailability was examined.

High Content Image Analysis of Cellular Responses of the Murine J774A.1 Cell Line and Primary Human Cells Alveolar Macrophages to an Extended Panel of Pharmaceutical Agents.

Introduction: In vitro screening of macrophages for drug-induced effects, such as phospholipidosis, is useful for detecting potentially problematic compounds in the preclinical development of oral inhaled products. High-content image analysis (HCIA) is a multi-parameter approach for cytotoxicity screening. This study provides new insights into HCIA-derived response patterns of murine J774A.

Manufacture and Initial Characterisation of RAPID Biodynamic Haematogel, an Autologous Platelet and Leukocyte-Rich Plasma Gel for Diabetic Foot Ulcers.

This observational study reports the process for the manufacture of RAPID Biodynamic Haematogel and explores the properties of the platelet and leukocyte-rich plasma gels formed. Gels were manufactured from 60 mL of human blood using the protocol of Biotherapy Services. Platelet and leukocyte content, time-to-gel, gel weight and the temporal profile of liquid exudation from the gels were measured, along with the content of growth factors VEGF and PDGF in the releasate.

Integration of mucus and its impact within in vitro setups for inhaled drugs and formulations: Identifying the limits of simple vs. complex methodologies when studying drug dissolution and permeability.

Traditionally, developing inhaled drug formulations relied on trial and error, yet recent technological advancements have deepened the understanding of 'inhalation biopharmaceutics' i.e. the processes that occur to influence the rate and extent of drug exposure in the lungs.

Pullulan-Based Spray-Dried Mucoadhesive Microparticles for Sustained Oromucosal Drug Delivery.

Mucoadhesive microparticles for oromucosal drug delivery offer several advantages, including intimate contact with the mucosa, delivery to less accessible regions, extended residence time, sustained drug release, reduced irritation, and improved patient compliance. In this study, pullulan was used to prepare mucoadhesive spray-dried microparticles for delivering benzydamine hydrochloride (BZH) to oral mucosa. The BZH-pullulan spray-dried microparticles had a mean size of <25 μm with an angle of repose values between 25.

Particulate bioaerogels for respiratory drug delivery.

The bioaerogel microparticles have been recently developed for respiratory drug delivery and attract fast increasing interests. These highly porous microparticles have ultralow density and hence possess much reduced aerodynamic diameter, which favour them with greatly enhanced dispersibility and improved aerosolisation behaviour. The adjustable particle geometric dimensions by varying preparation methods and controlling operation parameters make it possible to fabricate bioaerogel microparticles with accurate sizes for efficient delivery to the targeted regions of respiratory tract (i.

iBCS: 3. A Biopharmaceutics Classification System for Orally Inhaled Drug Products.

In this article, we specify for the first time a quantitative biopharmaceutics classification system for orally inhaled drugs. To date, orally inhaled drug product developers have lacked a biopharmaceutics classification system like the one developed to navigate the development of immediate release of oral medicines. Guideposts for respiratory drug discovery chemists and inhalation product formulators have been elusive and difficult to identify due to the complexity of pulmonary physiology, the intricacies of drug deposition and disposition in the lungs, and the influence of the inhalation delivery device used to deliver the drug as a respirable aerosol.

PPAR Gamma Receptor: A Novel Target to Improve Morbidity in Preterm Babies.

Worldwide, three-quarters of a million babies are born extremely preterm (<28 weeks gestation) with devastating outcomes: 20% die in the newborn period, a further 35% develop bronchopulmonary dysplasia (BPD), and 10% suffer from cerebral palsy. Pioglitazone, a Peroxisome Proliferator Activated Receptor Gamma (PPARγ) agonist, may reduce the incidence of BPD and improve neurodevelopment in extreme preterm babies. Pioglitazone exerts an anti-inflammatory action mediated through Nuclear Factor-kappa B repression.

Profiling alveolar macrophage responses to inhaled compounds using in vitro high content image analysis.

One of the main hurdles in the development of new inhaled medicines is the frequent observation of foamy macrophage (FM) responses in non-clinical studies in experimental animals, which raises safety concerns and hinders progress into clinical trials. We have investigated the potential of a novel multi-parameter high content image analysis (HCIA) assay as an in vitro safety screening tool to predict drug induced FM. Rat (NR8383) and human U937-derived alveolar macrophages were exposed in vitro to a panel of model compounds with different biological activity, including inhaled bronchodilators, inhaled corticosteroids (ICS), phospholipidosis inducers and proapoptotic agents.

How to engineer aerosol particle properties and biopharmaceutical performance of propellant inhalers.

Given the environmental compulsion to reformulate pressurised metered dose inhalers (pMDI) using new propellants with lower global warming potential, this study investigated how non-volatile excipients can be used to engineer aerosol particle microphysics and drug release. The dynamics of change in particle size, wetting and physical state were measured for single particles (glycerol/ethanol/beclomethasone dipropionate; BDP) in the aerosol phase at different relative humidity (RH) using an electrodynamic balance. BDP dissolution rates were compared for aerosols from pMDI containing different ratios of BDP:glycerol or BDP:isopropyl myristate (IPM).

Imaging drug delivery to the lungs: Methods and applications in oncology.

Direct delivery to the lung via inhalation is arguably one of the most logical approaches to treat lung cancer using drugs. However, despite significant efforts and investment in this area, this strategy has not progressed in clinical trials. Imaging drug delivery is a powerful tool to understand and develop novel drug delivery strategies.

Comprehensive Study of Antiretroviral Drug Permeability at the Cervicovaginal Mucosa an In Vitro Model.

Modulation of drug transporter activity at mucosal sites of HIV-1 transmission may be exploited to optimize retention of therapeutic antiretroviral drug concentrations at target submucosal CD4+ T cells. Previously, we showed that darunavir was a substrate for the P-glycoprotein efflux drug transporter in colorectal mucosa. Equivalent studies in the cervicovaginal epithelium have not been reported.

Design and manufacture of a lyophilised faecal microbiota capsule formulation to GMP standards.

Faecal microbiota transplant (FMT) is an established and effective treatment for recurrent Clostridioides difficile infection (CDI) and has many other potential clinical applications. However, preparation and quality of FMT is poorly standardised and clinical studies are hampered by a lack of well-defined FMT formulations that meet regulatory standards for medicines. As an alternative to FMT suspensions for administration by nasojejunal tube or colonoscopy, which is invasive and disliked by many patients, this study aimed to develop a well-controlled, standardised method for manufacture of lyophilised FMT capsules and to provide stability data allowing storage for extended time periods.

The influence of insulin on anticipation and consummatory reward to food intake: A functional imaging study on healthy normal weight and overweight subjects employing intranasal insulin delivery.

Aberrant responses within homeostatic, hedonic and cognitive systems contribute to poor appetite control in those with an overweight phenotype. The hedonic system incorporates limbic and meso-limbic regions involved in learning and reward processing, as well as cortical regions involved in motivation, decision making and gustatory processing. Equally important within this complex, multifaceted framework are the cognitive systems involved in inhibitory control and valuation of food choices.

iBCS: 2. Mechanistic Modeling of Pulmonary Availability of Inhaled Drugs versus Critical Product Attributes.

This work is the second in a series of publications outlining the fundamental principles and proposed design of a biopharmaceutics classifications system for inhaled drugs and drug products (the iBCS). Here, a mechanistic computer-based model has been used to explore the sensitivity of the primary biopharmaceutics functional output parameters: (i) pulmonary fraction dose absorbed () and (ii) drug half-life in lumen () to biopharmaceutics-relevant input attributes including dose number (Do) and effective permeability (). Results show the nonlinear sensitivity of primary functional outputs to variations in these attributes.

iBCS: 1. Principles and Framework of an Inhalation-Based Biopharmaceutics Classification System.

For oral drugs, the formulator and discovery chemist have a tool available to them that can be used to navigate the risks associated with the selection and development of immediate release oral drugs and drug products. This tool is the biopharmaceutics classification system (giBCS). Unfortunately, no such classification system exists for inhaled drugs.

Thermosensitive in situ hydrogels of rivastigmine-loaded lipid-based nanosystems for nose-to-brain delivery: characterisation, biocompatibility, and drug deposition studies.

Acetylcholinesterase inhibitors are the most used drugs to manage Alzheimer's disease, although they show low bioavailability in the brain. In this sense, nasal administration has been considered as a promising route for the direct delivery of these drugs to the brain (nose-to-brain delivery). In this work, in situ thermosensitive nasal gels with nanostructured lipid carriers (NLC) and nanoemulsion loaded with an acetylcholinesterase inhibitor (rivastigmine- RVG) were tested.

RespiCell: An Innovative Dissolution Apparatus for Inhaled Products.

To overcome some of the shortfalls of the types of dissolution testing currently used for pulmonary products, a new custom-built dissolution apparatus has been developed. For inhalation products, the main in vitro characterisation required by pharmacopoeias is the deposition of the active pharmaceutical ingredient in an impactor to estimate the dose delivered to the target site, i.e.

In vitro Fourier transform infrared spectroscopic study of the effect of glycerol on the uptake of beclomethasone dipropionate in living respiratory cells.

The quantification of drug in living cells is of increasing interest in pharmaceutical research because of its importance in understanding drug efficacy and toxicity. Label-free in situ measurement methods are advantageous for their ability to obtain chemical and time profiles without the need of labelling or extraction steps. We have previously shown that Fourier transform infrared (FTIR) spectroscopy has the potential to quantify drug in situ within living cells at micromolar level when a simple solution of drug was added to the medium.

Digital Image Disintegration Analysis: a Novel Quality Control Method for Fast Disintegrating Tablets.

Measuring tablet disintegration is essential for quality control purposes; however, no established method adequately accounts for the timeframe or small volumes of the medium associated with the dissipation process for fast disintegrating tablets (FDTs) in the mouth. We hypothesised that digital imaging to measure disintegration in a low volume of the medium might discriminate between different types of FTD formulation. A digital image disintegration analysis (DIDA) was designed to measure tablet disintegration in 0.

Regulation, risk and safety of Faecal Microbiota Transplant.

From its origins as a left-field, experimental, and even "maverick" intervention, faecal microbiota transplantation (FMT) is now a well-recognised, accepted, and potentially life-saving therapeutic strategy, for the management of recurrent Clostridiodes difficile infection (rCDI). It is being investigated as a treatment for a growing number of diseases including hepatic encephalopathy and eradication of antimicrobial resistant organisms, and the list of indications will likely expand in the future. There is no universally accepted definition of what FMT is, and its mechanism of action remains incompletely understood; this has likely contributed to the breadth of approaches to regulation depending on interpretation.