Drug Development Considerations for Additives to Organ Preservation Solutions.

The addition of a novel therapeutic agent to an organ preservation solution has the potential to address unmet needs in organ transplantation and enhance outcomes for transplant recipients. However, the development expectations for novel therapeutic agents in this context are unclear because of limited precedence and published regulatory guidance documents. To address these gaps, we have articulated a drug development strategy that leverages expectations for parenteral drug products administered via more conventional routes (eg, intravenous) and provided considerations for when deviations may be justified.

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.

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.

Optimizing Spray-Dried Porous Particles for High Dose Delivery with a Portable Dry Powder Inhaler.

This manuscript critically reviews the design and delivery of spray-dried particles for the achievement of high total lung doses (TLD) with a portable dry powder inhaler. We introduce a new metric termed the product density, which is simply the TLD of a drug divided by the volume of the receptacle it is contained within. The product density is given by the product of three terms: the packing density (the mass of powder divided by the volume of the receptacle), the drug loading (the mass of drug divided by the mass of powder), and the aerosol performance (the TLD divided by the mass of drug).

Idealhalers Versus Realhalers: Is It Possible to Bypass Deposition in the Upper Respiratory Tract?

This review discusses how advances in formulation and device design can be utilized to dramatically improve lung targeting and dose consistency relative to current marketed dry powder inhalers (DPIs). Central to the review is the development of engineered particles that effectively bypass deposition in the upper respiratory tract (URT). This not only reduces the potential for off-target effects but it also reduces variability in dose delivery to the lungs resulting from anatomical differences in the soft tissue in the mouth and throat.

The use of condensational growth methods for efficient drug delivery to the lungs during noninvasive ventilation high flow therapy.

Purpose: The objective of this study was to evaluate the delivery of nasally administered aerosols to the lungs during noninvasive ventilation using controlled condensational growth techniques.

Methods: An optimized mixer, combined with a mesh nebulizer, was used to generate submicrometer aerosol particles using drug alone (albuterol sulfate) and with mannitol or sodium chloride added as hygroscopic excipients. The deposition and growth of these particles were evaluated in an adult nose-mouth-throat (NMT) model using in vitro experimental methods and computational fluid dynamics simulations.

Evaluation and modification of commercial dry powder inhalers for the aerosolization of a submicrometer excipient enhanced growth (EEG) formulation.

The aim of this study was to evaluate and modify commercial dry powder inhalers (DPIs) for the aerosolization of a submicrometer excipient enhanced growth (EEG) formulation. The optimized device and formulation combination was then tested in a realistic in vitro mouth-throat - tracheobronchial (MT-TB) model. An optimized EEG submicrometer powder formulation, consisting of albuterol sulfate (drug), mannitol (hygroscopic excipient), l-leucine (dispersion enhancer) and poloxamer 188 (surfactant) in a ratio of 30:48:20:2 was prepared using a Büchi Nano spray dryer.

Aerodynamic factors responsible for the deaggregation of carrier-free drug powders to form micrometer and submicrometer aerosols.

Purpose: To employ in vitro experiments combined with computational fluid dynamics (CFD) analysis to determine which aerodynamic factors were most responsible for deaggregating carrier-free powders to form micrometer and submicrometer aerosols from a capsule-based platform.

Methods: Eight airflow passages were evaluated for deaggregation of the aerosol including a standard constricted tube, impaction surface, 2D mesh, inward radial jets, and newly proposed 3D grids and rod arrays. CFD simulations were implemented to evaluate existing and new aerodynamic factors for deaggregation and in vitro experiments were used to evaluate performance of each inhaler.

Aerosolization characteristics of dry powder inhaler formulations for the excipient enhanced growth (EEG) application: effect of spray drying process conditions on aerosol performance.

The aim of this study was to develop a spray dried submicrometer powder formulation suitable for the excipient enhanced growth (EEG) application. Combination particles were prepared using the Buchi Nano spray dryer B-90. A number of spray drying and formulation variables were investigated with the aims of producing dry powder formulations that were readily dispersed upon aerosolization and maximizing the fraction of submicrometer particles.

High-efficiency generation and delivery of aerosols through nasal cannula during noninvasive ventilation.

Background: Previous studies have demonstrated the delivery of pharmaceutical aerosols through nasal cannula and the feasibility of enhanced condensational growth (ECG) with a nasal interface. The objectives of this study were to develop a device for generating submicrometer aerosols with minimal depositional loss in the formation process and to improve aerosol delivery efficiencies through nasal cannulas.

Methods: A combination of in vitro experiments and computational fluid dynamics (CFD) simulations that used the strengths of each method was applied.

Preparation of sustained release rifampicin microparticles for inhalation.

Objectives: The aim of this research was to develop a novel carrier-free dry powder formulation of rifampicin for inhalation with controlled-release properties.

Methods: Rifampicin dihydrate (RFDH) microcrystals were prepared by a polymorphic transformation of rifampicin. The prepared RFDH microcrystals were coated with poly (DL-lactide-co-glycolide) or poly (DL-lactide), using a spray-dryer equipped with two different types of three-fluid (3F) spray nozzles.

Performance of combination drug and hygroscopic excipient submicrometer particles from a softmist inhaler in a characteristic model of the airways.

Excipient enhanced growth (EEG) of inhaled submicrometer pharmaceutical aerosols is a recently proposed method intended to significantly reduce extrathoracic deposition and improve lung delivery. The objective of this study was to evaluate the size increase of combination drug and hygroscopic excipient particles in a characteristic model of the airways during inhalation using both in vitro experiments and computational fluid dynamic (CFD) simulations. The airway model included a characteristic mouth-throat (MT) and upper tracheobronchial (TB) region through the third bifurcation and was enclosed in a chamber geometry used to simulate the thermodynamic conditions of the lungs.

Production of Inhalable Submicrometer Aerosols from Conventional Mesh Nebulizers for Improved Respiratory Drug Delivery.

Submicrometer and nanoparticle aerosols may significantly improve the delivery efficiency, dissolution characteristics, and bioavailability of inhaled pharmaceuticals. The objective of this study was to explore the formation of submicrometer and nanometer aerosols from mesh nebulizers suitable for respiratory drug delivery using experiments and computational fluid dynamics (CFD) modeling. Mesh nebulizers were coupled with add-on devices to promote aerosol drying and the formation of submicrometer particles, as well as to control the inhaled aerosol temperature and relative humidity.

A new respirable form of rifampicin.

The aim of this research was to investigate a novel dry powder formulation of rifampicin (RF) that presents an improved lung deposition profile by means of a polymorphic transformation into a flake-like crystal hydrate. Rifampicin dihydrate (RFDH) was prepared by recrystallization of RF in anhydrous ethanol. A control formulation, amorphous RF (RFAM) was prepared by spray drying.

Development of a standardized dissolution test method for inhaled pharmaceutical formulations.

The aim of this research was to investigate a potential standardized test method to characterize the dissolution properties of formulations intended for pulmonary delivery. A commercially available dissolution tester was adapted to be used as a testing apparatus by incorporation of a membrane containing cassette. The cassette was designed to enclose previously air-classified formulations, so that they could be uniformly tested in the dissolution apparatus.

Characterization and pharmacokinetic analysis of aerosolized aqueous voriconazole solution.

Invasive fungal infections in immunocompromised patients have high mortality rates despite current treatment modalities. This study was designed to evaluate the suitability of an aqueous solution of voriconazole solubilized with sulfobutyl ether-beta-cyclodextrin for targeted drug delivery to the lungs via nebulization. A solution was prepared such that the inspired aerosol dose was isotonic with an acceptable mass median aerodynamic diameter of 2.

Advancements in dry powder delivery to the lung.

The dry powder inhaler (DPI) has become widely known as a very attractive platform for drug delivery. Many patients have traditionally used DPIs to treat asthma and chronic obstructive pulmonary disease. Recently, the development of new DPIs for delivering therapeutic proteins such as insulin has been accelerated by patient demands, and innovative research.

Biodistribution and anti-tumor efficacy of doxorubicin loaded glycol-chitosan nanoaggregates by EPR effect.

An in vivo tumor targeting test of glycol-chitosan nanoaggregates was carried out with FITC-conjugated glycol-chitosan nanoaggregates (FTC-GC) and the doxorubicin conjugated glycol-chitosan (GC-DOX). To investigate its biodistribution in tumor-bearing rats, glycol-chitosan was labeled with fluorescein isothiocyanate (FITC), which formed nanoaggregates with a diameter of about 250 nm in aqueous media. GC-DOX nanoaggregates containing acid-sensitive spacers were prepared.