Microstructural Characterization of Dry Powder Inhaler Formulations Using Orthogonal Analytical Techniques.

Purpose: For locally-acting dry powder inhalers (DPIs), developing novel analytical tools that are able to evaluate the state of aggregation may provide a better understanding of the impact of material properties and processing parameters on the in vivo performance. This study explored the utility of the Morphologically-Directed Raman Spectroscopy (MDRS) and dissolution as orthogonal techniques to assess microstructural equivalence of the aerosolized dose of DPIs collected with an aerosol collection device.

Methods: Commercial DPIs containing different strengths of Fluticasone Propionate (FP) and Salmeterol Xinafoate (SX) as monotherapy and combination products were sourced from different regions.

Patient Perceptions of Switching to a Generic Dry Powder Inhaler - Increased Understanding Through Journey Mapping.

Purpose: This qualitative study explored patients' attitudes about and perceptions of generic dry powder inhaler (DPI) substitution for the brand product and patients' views of generic product quality, efficacy, design, and usability.

Methods: Forty COPD and asthma patients (36 adults, four adolescents), who were actively using a brand DPI product, participated in one of six focus groups. Participants completed a journey mapping exercise to assess attitudes and opinions about a scenario where they refill their prescription and unexpectedly receive a generic DPI instead of their brand DPI.

Considerations for the Forced Expiratory Volume in 1 Second-Based Comparative Clinical Endpoint Bioequivalence Studies for Orally Inhaled Drug Products.

Herein, we present the US Food and Drug Administration (FDA) Office of Research and Standards' current thinking, challenges, and opportunities for comparative clinical endpoint bioequivalence (BE) studies of orally inhaled drug products (OIDPs). Given the product-associated complexities of OIDPs, the FDA currently uses an aggregate weight-of-evidence approach to demonstrate that a generic OIDP is bioequivalent to its reference listed drug. The approach utilizes comparative clinical endpoint BE or pharmacodynamic BE studies, pharmacokinetic BE studies, and in vitro BE studies to demonstrate equivalence, in addition to formulation sameness and device similarity.

Systematic Evaluation of the Effect of Formulation Variables on In Vitro Performance of Mometasone Furoate Suspension-Metered Dose Inhalers.

The therapeutic benefits of metered dose inhalers (MDIs) in pulmonary disorders are mainly driven by aerosol performance, which depends on formulation variables (drug and excipients), device design, and patient interactions. The present study provides a comprehensive investigation to better understand the effect of formulation variables on mometasone furoate (MF) suspension-based MDI product performance. The effects of MF particle size (volume median diameter; X) and excipient concentration (ethanol and oleic acid, cosolvent, and surfactant, respectively) on selected critical quality attributes (delivered dose (DD), fine particle dose of particles lesser than 5 µm (FPD < 5), ex-throat dose and median dissolution time (MDT)) were studied.

Can Pharmacokinetic Studies Assess the Pulmonary Fate of Dry Powder Inhaler Formulations of Fluticasone Propionate?

In the context of streamlining generic approval, this study assessed whether pharmacokinetics (PK) could elucidate the pulmonary fate of orally inhaled drug products (OIDPs). Three fluticasone propionate (FP) dry powder inhaler (DPI) formulations (A-4.5, B-3.

Analytical method development for characterizing ingredient-specific particle size distributions of nasal spray suspension products.

Particle size characterization for active pharmaceutical ingredients (APIs) in nasal spray suspension products presents unique challenges because both the API and excipient particles are present in the final dosage form. Currently, an established method is lacking because traditional particle sizing technologies do not distinguish the chemical identity of the particles. In this study, a non-destructive, ingredient-specific particle sizing method was developed for characterization of mometasone furoate (MF) nasal spray suspensions using Morphology Directed Raman Spectroscopy (MDRS).

Development of an Aerosol Dose Collection Apparatus for In Vitro Dissolution Measurements of Orally Inhaled Drug Products.

The aim of the study was to develop a robust and standardized in vitro dissolution methodology for orally inhaled drug products (OIDPs). An aerosol dose collection (ADC) system was designed to uniformly deposit the whole impactor stage mass (ISM) over a large filter area for dissolution testing. All dissolution tests were performed under sink conditions in a sodium phosphate buffered saline solution containing 0.

Effects of Formulation Variables on Lung Dosimetry of Albuterol Sulfate Suspension and Beclomethasone Dipropionate Solution Metered Dose Inhalers.

The performance of pressurized metered dose inhalers (MDIs) is affected by formulation and device variables that impact delivered dose, aerodynamic particle size distribution, and consequently lung deposition and therapeutic effect. Specific formulation variables of relevance to two commercially available products-Proventil® HFA [albuterol sulfate (AS) suspension] and Qvar® [beclomethasone dipropionate (BDP) solution]-were evaluated to determine their influence on key performance attributes measured experimentally with in vitro cascade impaction studies. These commercial MDIs, utilized as model systems, provided mid-points for a design of experiments (DoE) plan to manufacture multiple suspension and solution MDI formulations.

Generic drug device combination products: Regulatory and scientific considerations.

Complex regulatory and scientific considerations exist for drug-device combination products submitted under an Abbreviated New Drug Application. The Agency has published several guidances to aid industry in the development of a generic drug-device combination product: providing recommendations on the types of studies necessary to establish bioequivalence, providing considerations on product quality and performance for certain types of device constituents, and most recently, providing tools to assess the proposed user interface when compared to the user interface of the Reference Listed Drug. In addition, the Office of Generic Drugs has established a regulatory science research program intended to support projects that examine scientific questions relating to the development of generic combination products and their associated regulatory review.

Influence of Formulation Factors on the Aerosol Performance of Suspension and Solution Metered Dose Inhalers: A Systematic Approach.

Metered dose inhalers (MDIs) are complex drug-device combination products widely used to treat pulmonary disorders. The efficacy, driven by aerosol performance of the products, depends on a multitude of factors including, but not limited to, the physicochemical properties of drug and nature and amount of excipient(s). Under the quality by design (QbD) paradigm, systematic investigations are necessary to understand how changes in critical quality attributes (CQAs) of formulation, device, and manufacturing process influence key product performance parameters, such as delivered dose (DD) and fine particle dose (FPD).

Post-Transcriptional Regulation of the GASC1 Oncogene with Active Tumor-Targeted siRNA-Nanoparticles.

Basal-like breast cancer (BLBC) accounts for the most aggressive types of breast cancer, marked by high rates of relapse and poor prognoses and with no effective clinical therapy yet. Therefore, investigation of new targets and treatment strategies is more than necessary. Here, we identified a receptor that can be targeted in BLBC for efficient and specific siRNA mediated gene knockdown of therapeutically relevant genes such as the histone demethylase GASC1, which is involved in multiple signaling pathways leading to tumorigenesis.

Polymeric Nanostructured Systems for Liquid Formulation of Praziquan-tel: Development and in vitro Assessment.

Praziquantel (PZQ) is widely used in the treatment of several parasitic infections in both humans and animals, and is the first choice in the treatment of Schistosomiasis in humans. However, PZQ is a hydrophobic drug, and its low aqueous solubility has been a significant barrier to the development of oral liquid formulations that may provide improved bioavailability, pharmacokinetic profile, and compliance. The aim of this study was thus (i) to develop an oil-in-water (O/W) nanoemulsion(NE)-based platform for the delivery of PZQ in liquid form; (ii) to study the transport of PZQ formulated in NEs across an in vitro model of the intestinal epithelium; and (iii) to determine the toxicity profile of the NEs and their individual components on the model epithelium.

Synthesis of PEG-PCL-based polyurethane nanoparticles by miniemulsion polymerization.

In this work biocompatible polyurethane nanoparticles for future application as noninvasive polymeric nanocarriers using propellant-based inhalers in the treatment of respiratory diseases were prepared by miniemulsion interfacial polymerization derived from isophorone diisocyanate, poly(ϵ-caprolactone), and poly(ethylene glycol). The effects of the surfactant type, nonionic Tween 80 and Brij 35, anionic sodium dodecyl sulfate, and cationic cetyltrimethyl ammonium bromide, and poly(ethylene glycol) molar mass on the stability, size and morphology of nanoparticles were evaluated. In addition, the ability of cells to proliferate in contact with polyurethane nanoparticles was assessed by MTS ([(3-(4,5-dimethylthiazole-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfo-phenyl)-2H-tetrazolium, inner salt]) assay using human lung adenocarcinoma A549 cells, an in vitro model of Type II alveolar epithelium.

Application of an oregano oil nanoemulsion to the control of foodborne bacteria on fresh lettuce.

Although antimicrobial activities of plant essential oils are well documented, challenges remain as to their application in fresh produce due to the hydrophobic nature of essential oils. Oregano oil nanoemulsions were formulated with a food-grade emulsifier and evaluated for their efficacy in inactivating the growth of foodborne bacteria on fresh lettuce. Lettuce was artificially inoculated with Listeria monocytogenes, Salmonella Typhimurium and Escherichia coli O157:H7, followed by a one-minute dipping in oregano oil nanoemulsions (0.

Poly(amidoamine) dendrimer nanocarriers and their aerosol formulations for siRNA delivery to the lung epithelium.

Small interfering RNA (siRNA)-based therapies have great promise in the treatment of a number of prevalent pulmonary disorders including lung cancer, asthma and cystic fibrosis. However, progress in this area has been hindered due to the lack of carriers that can efficiently deliver siRNA to lung epithelial cells, and also due to challenges in developing oral inhalation (OI) formulations for the regional administration of siRNA and their carriers to the lungs. In this work we report the ability of generation four, amine-terminated poly(amidoamine) (PAMAM) dendrimer (G4NH2)-siRNA complexes (dendriplexes) to silence the enhanced green fluorescent protein (eGFP) gene on A549 lung alveolar epithelial cells stably expressing eGFP.

Polymeric nanocarriers for transport modulation across the pulmonary epithelium: dendrimers, polymeric nanoparticles, and their nanoblends.

The purpose of this study was to (a) Determine the cellular transport and uptake of amine-terminated generation 3 (G3) poly(amido amine) (PAMAM) dendrimers across an in vitro model of the pulmonary epithelium, and the ability to modulate their transport by forming nanoblends of the dendrimers with biodegradable solid polymeric nanoparticles (NPs) and (b) to formulate dendrimer nanocarriers in portable oral inhalation devices and evaluate their aerosol characteristics. To that end, fluorescein isothiocyanate (FITC)-labeled G3 PAMAM dendrimer nanocarriers (DNCs) were synthesized, and also encapsulated within poly lactide-co-glycolide nanoparticles (NPs). Transport and uptake of both DNCs encapsulated within NPs (nanoblends) and unencapsulated DNCs were tracked across polarized monolayers of airway epithelial cells, Calu-3.

Solvation in hydrofluoroalkanes: How can ethanol help?

Objectives: The goal of this work was to evaluate the ability of ethanol mixed with hydrofluoroalkanes (HFAs) to improve solvation of moieties of relevance to pressurized metered-dose inhalers (pMDIs).

Methods: Chemical force microscopy was used to measure the adhesion force (F(ad)) between alkyl-based, ether-based and ester-based moieties (C8/C8, COC/COC and COOC/COOC interactions) in 2H,3H-perfluoropentane (HPFP)/ethanol mixtures. HPFP is a liquid that mimics propellant HFAs.

Propellant-based inhalers for the non-invasive delivery of genes via oral inhalation.

In this work we describe the development of a propellant-based, portable oral inhalation platform for the pulmonary delivery of genes. A core-shell strategy is utilized to efficiently disperse cationic-polymer-DNA nanoparticles in hydrofluoroalkane propellants, and to generate aerosols from the corresponding pressurized metered-dose inhaler formulations (pMDIs) that have excellent aerosol characteristics, suitable for deep lung deposition. The engineered polyplexes and core-shell structures were fully characterized, and their ability to transfect model lung alveolar epithelium cells in vitro was demonstrated.