Exploration of the potential impact of batch-to-batch variability on the establishment of pharmacokinetic bioequivalence for inhalation powder drug products.

Batch-to-batch variability in inhalation powder has been identified as a potential challenge in the development of generic versions. This study explored the impact of batch-to-batch variability on the probability of establishing pharmacokinetic (PK) bioequivalence (BE) in a two-sequence, two-period (2 × 2) crossover study. A model-based parametric simulation approach was employed, incorporating batch-to-batch variability through the relative bioavailability (RBA) ratio.

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.

Anatomically-detailed segmented representative adult and pediatric nasal models for assessing regional drug delivery and bioequivalence with suspension nasal sprays.

In vitro nasal models can potentially facilitate development and approval of nasal drug products. This study aims to evaluate the potential for using regional deposition measurements from in vitro nasal models to evaluate nasal spray performance across several products. To accomplish this, the posterior regions of six anatomically realistic nasal airway models of adult and pediatric subjects, representing Low (L), Mean (M) and High (H) posterior drug deposition (PD) for each of the two age groups, were segmented with high anatomical precision into five regions of interest.

CFD-PK model for nasal suspension sprays: Validation with human adult in vivo data for triamcinolone acetonide.

The objectives of this study were to expand and implement a Computational Fluid Dynamics (CFD)-Dissolution, Absorption and Clearance (DAC)-Pharmacokinetics (PK) multi-physics modeling framework for simulating the transport of suspension-based nasal corticosteroid sprays. The mean CFD-predicted peak plasma concentration (C) and area under the curve (AUC) of the plasma concentration-time profile, based on three representative nasal airway models (capturing low, medium and high posterior spray deposition), were within one standard deviation of available in vivo PK data for a representative corticosteroid drug (triamcinolone acetonide). The relative differences in mean C between predictions and in vivo data for low dose (110 µg) and high dose (220 µg) cases were 27.

Pharmacokinetic Models for Inhaled Fluticasone Propionate and Salmeterol Xinafoate to Quantify Batch-to-Batch Variability.

Advair Diskus is an essential treatment for asthma and chronic obstructive pulmonary disease. It is a dry powder inhaler with a combination of fluticasone propionate (FP) and salmeterol xinafoate (SX). However, the pharmacokinetics (PK) batch-to-batch variability of the reference-listed drug (RLD) hindered its generic product development.

Advancements in the Design and Development of Dry Powder Inhalers and Potential Implications for Generic Development.

Dry powder inhalers (DPIs) are drug-device combination products where the complexity of the formulation, its interaction with the device, and input from users play important roles in the drug delivery. As the landscape of DPI products advances with new powder formulations and novel device designs, understanding how these advancements impact performance can aid in developing generics that are therapeutically equivalent to the reference listed drug (RLD) products. This review details the current understanding of the formulation and device related principles driving DPI performance, past and present research efforts to characterize these performance factors, and the implications that advances in formulation and device design may present for evaluating bioequivalence (BE) for generic development.

Mechanistic modeling of generic orally inhaled drug products: A workshop summary report.

In silico mechanistic modeling approaches have been designed by various stakeholders with the goal of supporting development and approval of generic orally inhaled drug products in the United States. This review summarizes the presentations and panel discussion that comprised a workshop session concentrated on the use of in silico models to predict various outcomes following orally inhaled drug product administration, including the status of such models and how model credibility may be effectively established.

Scientific and regulatory activities initiated by the U.S. Food and drug administration to foster approvals of generic dry powder inhalers: Bioequivalence perspective.

Regulatory science for generic dry powder inhalers (DPIs) in the United States (U.S.) has evolved over the last decade.

Scientific and regulatory activities initiated by the U.S. food and drug administration to foster approvals of generic dry powder inhalers: Quality perspective.

Regulatory science for generic dry powder inhalation products worldwide has evolved over the last decade. The revised draft guidance Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Products - Quality Considerations [1] (Revision 1, April 2018) that FDA issued summarizes product considerations and potential critical quality attributes (CQAs). This guidance emphasizes the need to apply the principles of quality by design (QbD) and elements of pharmaceutical development discussed in the International Conference for Harmonisation of (ICH) guidelines.

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.

Medication Cost-Savings and Utilization of Generic Inhaled Corticosteroid (ICS) and Long-Acting Beta-Agonist (LABA) Drug Products in the USA.

Background: In the USA, drug costs associated with the inhaled corticosteroid (ICS) and long acting β agonist (LABA) combination products have been increasing since 2001. In January 2019, the first generic ICS/LABA drug product was approved by the U.S.

Cyclosporine release and distribution in ophthalmic emulsions determined by pulsatile microdialysis.

An in vitro release test based on pulsatile microdialysis (PMD) is presented for the purpose of measuring the release of cyclosporine from ophthalmic emulsions, along with a method to determine the drug distribution within the oil-rich globule, surfactant-rich micelle and aqueous phases of the emulsion formulation. Compositionally equivalent formulations containing 0.05% cyclosporine were prepared with similar physical parameters (globule size, viscosity, surface tension zeta potential, osmolality, pH) but made with different manufacturing conditions.

A Systematic Approach in the Development of the Morphologically-Directed Raman Spectroscopy Methodology for Characterizing Nasal Suspension Drug Products.

Demonstrating bioequivalence (BE) of nasal suspension sprays is a challenging task. Analytical tools are required to determine the particle size of the active pharmaceutical ingredient (API) and the structure of a relatively complex formulation. This study investigated the utility of the morphologically-directed Raman spectroscopy (MDRS) method to investigate the particle size distribution (PSD) of nasal suspensions.

Addressing the Regulatory and Scientific Challenges with Generic Orally Inhaled Drug Products.

Generic products offer a considerable cost savings for American consumers and the US healthcare industry. While generics for many products have become available, the approval and adoption of generics for orally inhaled drug products (OIDPs) has lagged behind, owing to the difficulties in bringing these complex generic products to the market. As a complex product, OIDP performance is impacted by numerous factors derived from the product's formulation, delivery to a local site of action within the lung, the performance of the device, and the patient population that uses the medication.

In vitro and ex vivo correlation of drug release from ophthalmic ointments.

In vitro drug release testing and ex vivo transcorneal drug permeation can provide valuable information on the performance of the Q1/Q2 equivalent ointments prior to any animal studies. Good correlation between in vitro and ex vivo drug release may be indicative of good in vitro and in vivo correlation. Accordingly, it is important to investigate in vitro as well as ex vivo drug release from Q1/Q2 equivalent ophthalmic ointments and evaluate whether a correlation between these release profiles can be established.

On the Road to Development of an in Vitro Permeation Test (IVPT) Model to Compare Heat Effects on Transdermal Delivery Systems: Exploratory Studies with Nicotine and Fentanyl.

Purpose: At elevated temperatures, the rate of drug release and skin permeation from transdermal delivery systems (TDS) may be higher than at a normal skin temperature. The aim of this study was to compare the effect of heat on the transdermal delivery of two model drugs, nicotine and fentanyl, from matrix-type TDSs with different formulations, using in vitro permeation tests (IVPT).

Methods: IVPT experiments using pig skin were performed on two nicotine and three fentanyl TDSs.

In vitro release testing method development for ophthalmic ointments.

It is essential as well as challenging to develop a reliable in vitro release testing method for determining whether differences in release profiles exist between qualitatively and quantitatively equivalent ophthalmic ointment formulations. There is a lack of regulatory guidance on in vitro release testing methods for ophthalmic formulations. Three different in vitro release testing methods 1) USP apparatus 4 with semisolid adapters; 2) USP apparatus 2 with enhancer cells; and 3) Franz diffusion cells were investigated.

Physicochemical attributes and dissolution testing of ophthalmic ointments.

The investigation of semisolid ophthalmic ointments is challenging due to their complex physicochemical properties and the unique anatomy of the human eye. Using Lotemax as a model ophthalmic ointment, three different manufacturing processes and two excipient sources (Fisher (OWP) and Fougera (NWP)) were used to prepare loteprednol etabonate ointments that were qualitatively and quantitatively the same across the manufactured formulations. Physicochemical properties including drug content and uniformity, particle size and distribution, as well as rheological parameters (onset point, crossover modulus, storage modulus and Power law consistency index) were investigated.

Navigating sticky areas in transdermal product development.

The benefits of transdermal delivery over the oral route to combat such issues of low bioavailability and limited controlled release opportunities are well known and have been previously discussed by many in the field (Prausnitz et al. (2004) [1]; Hadgraft and Lane (2006) [2]). However, significant challenges faced by developers as a product moves from the purely theoretical to commercial production have hampered full capitalization of the dosage forms vast benefits.

Heat effects on drug delivery across human skin.

Introduction: Exposure to heat can impact the clinical efficacy and/or safety of transdermal and topical drug products. Understanding these heat effects and designing meaningful in vitro and in vivo methods to study them are of significant value to the development and evaluation of drug products dosed to the skin.

Areas Covered: This review provides an overview of the underlying mechanisms and the observed effects of heat on the skin and on transdermal/topical drug delivery, thermoregulation and heat tolerability.

Trastuzumab resistance induces EMT to transform HER2(+) PTEN(-) to a triple negative breast cancer that requires unique treatment options.

Although trastuzumab is an effective treatment in early stage HER2(+) breast cancer the majority of advanced HER2(+) breast cancers develop trastuzumab resistance, especially in the 40% of breast cancers with loss of PTEN. However, HER2(+) breast cancer patients continue to receive trastuzumab regardless PTEN status and the consequence of therapy in these patients is unknown. We demonstrate that continued use of trastuzumab in HER2(+) cells with loss of PTEN induces the epithelial-mesenchymal transition (EMT) and transform HER2(+) to a triple negative breast cancer.