Performance of Multiple-Batch Approaches to Pharmacokinetic Bioequivalence Testing for Orally Inhaled Drug Products with Batch-to-Batch Variability.

Batch-to-batch pharmacokinetic (PK) variability of orally inhaled drug products has been documented and can render single-batch PK bioequivalence (BE) studies unreliable; results from one batch may not be consistent with a repeated study using a different batch, yet the goal of PK BE is to deliver a product comparison that is interpretable beyond the specific batches used in the study. We characterized four multiple-batch PK BE approaches to improve outcome reliability without increasing the number of clinical study participants. Three approaches include multiple batches directly in the PK BE study with batch identity either excluded from the statistical model ("Superbatch") or included as a fixed or random effect ("Fixed Batch Effect," "Random Batch Effect"). A fourth approach uses a bio-predictive in vitro test to screen candidate batches, bringing the median batch of each product into the PK BE study ("Targeted Batch"). Three of these approaches (Fixed Batch Effect, Superbatch, Targeted Batch) continue the single-batch PK BE convention in which uncertainty in the Test/Reference ratio estimate due to batch sampling is omitted from the Test/Reference confidence interval. All three of these approaches provided higher power to correctly identify true bioequivalence than the standard single-batch approach with no increase in clinical burden. False equivalence (type I) error was inflated above the expected 5% level, but multiple batches controlled type I error better than a single batch. The Random Batch Effect approach restored 5% type I error, but had low power for small (e.g., <8) batch sample sizes using standard [0.8000, 1.2500] bioequivalence limits.

Impact of simulated lung fluid components on the solubility of inhaled drugs and predicted in vivo performance.

Orally inhaled products (OIPs) are gaining increased attention, as pulmonary delivery is a preferred route for the treatment of various diseases. Yet, the field of inhalation biopharmaceutics is still in development phase. For a successful correlation between various in vitro data obtained during formulation characterization and in vivo performance, it is necessary to understand the impact of parameters such as solubility and dissolution of drugs. In this work, we used in vitro-in silico feedback-feedforward approach to gain a better insight into the biopharmaceutics behavior of inhaled Salbutamol Sulphate (SS) and Budesonide (BUD). The thorough characterization of the in vitro test media and the impact of different in vitro fluid components such as lipids and protein on the solubility of aforementioned drugs was studied. These results were subsequently used as an input into the developed in silico models to investigate potential PK parameter changes in vivo. Results revealed that media comprising lipids and albumin were the most biorelevant and impacted the solubility of BUD the most. On the contrary, no notable impact was seen in case of SS. The use of simple media such as phosphate buffer saline (PBS) might be sufficient to use in solubility studies of the highly soluble and permeable drugs. However, its use for the poorly soluble drugs is limited due to the greater potential for interactions within in vivo environment. The use of in silico tools showed that the model response varies, depending on the used media. Therefore, this work highlights the relevance of carefully selecting the media composition when investigating solubility and dissolution behavior, especially in the early phases of drug development and of poorly soluble drugs.

Measuring The Bipolar Charge Distributions of Fine Particle Aerosol Clouds of Commercial PMDI Suspensions Using a Bipolar Next Generation Impactor (bp-NGI).

PURPOSE: To measure the charge to mass (Q/M) ratios of the impactor stage masses (ISM) from commercial Flixotide™ 250 µg Evohaler, containing fluticasone propionate (FP), Serevent™ 25 µg Evohaler, containing salmeterol xinafoate (SX), and a combination Seretide™ 250/25 µg (FP/SX) Evohaler metered dose inhalers (MDIs). Measurements were performed with a purpose built bipolar charge measurement apparatus (bp-NGI) based on an electrostatic precipitator, which was directly connected below Stage 2 of a Next Generation Impactor (NGI). METHODS: Five successive shots of the respective MDIs were actuated through the bp-NGI. The whole ISM doses were electrostatically precipitated to determine their negative, positive and net Q/m ratios. RESULTS: The ISM doses collected in the bp-NGI were shown to be equivalent to those collected in a standard NGI. FP particles, actuated from Flixotide™ and Seretide™ MDIs, exhibited greater quantities of negatively charged particles than positive. However, the Q/m ratios of the positively charged particles were greater in magnitude. SX particles from Serevent™ exhibited a greater quantity of positively charged particles whereas SX aerosol particles from Seretide™ exhibited a greater quantity of negatively charged particles. The Q/m ratio of the negatively charged SX particles in Serevent™ was greater in magnitude than the positively charged particles. CONCLUSIONS: The bp-NGI was used to quantify the bipolar Q/m ratios of aerosol particles collected from the ISMs of commercial MDI products. The positive charge recorded for each of the three MDIs may have been enhanced by the presence of charged ice crystals formed from the propellant during the aerosolisation process.