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).A five-step method development procedure was used in this study: sample preparation, particle imaging and morphology analysis, particle Raman measurements and classification, morphology filter selection, and minimum number of particles determination. Wet dispersion sample preparation method was selected to ensure that the particles were measured in their original suspended state. A training set containing over 10,000 randomly-selected particles, including both the API and excipient particles, was used to gain a comprehensive understanding of particle size, shape, and chemical ID for the nasal spray suspension. Morphology and Raman measurements were performed on each particle in the training set. The measurement results suggested that the aspect ratio and intensity mean filter combination was an appropriate morphology filter setting to selectively target API particles and exclude most of excipient particles. With further optimization of the morphology filter cutoff values and determination of minimal number of particles to be measured, the total measurement time was reduced from 90 hours to 8 hours. The morphologically screening strategy ultimately allowed us to create a time-efficient practical API-specific particle size distribution (PSD) methods for nasal spray suspensions.This study shows that MDRS is a fit for purpose analytical technique for determining ingredient-specific PSDs of the pharmaceutical formulation studied in this work.     

Predicting Pulmonary Pharmacokinetics from <Emphasis Type="Italic">In Vitro</Emphasis> Properties of Dry Powder Inhalers

Purpose

The ability of two semi-mechanistic simulation approaches to predict the systemic pharmacokinetics (PK) of inhaled corticosteroids (ICSs) delivered via dry powder inhalers (DPIs) was assessed for mometasone furoate, budesonide and fluticasone propionate.

Methods

Both approaches derived the total lung doses and the central to peripheral lung deposition ratios from clinically relevant cascade impactor studies, but differed in the way the pulmonary absorption rate was derived. In approach 1, the rate of in vivo drug dissolution/absorption was predicted for the included ICSs from in vitro aerodynamic particle size distribution and in vitro drug solubility estimates measured in an in vivo predictive dissolution medium. Approach 2 derived a first order absorption rate from the mean dissolution time (MDT), determined for the test formulations in an in vitro Transwell^® based dissolution system.

Results

Approach 1 suggested PK profiles which agreed well with the published pharmacokinetic profiles. Similarly, within approach 2, input parameters for the pulmonary absorption rate constant derived from dissolution rate experiments were able to reasonably predict the pharmacokinetic profiles published in literature.

Conclusion

Approach 1 utilizes more complex strategies for predicting the dissolution/absorption process without providing a significant advantage over approach 2 with regard to accuracy of in vivo predictions.

     

Regulatory Perspectives on Strength-Dependent Dissolution Profiles and Biowaiver Approaches for Immediate Release (IR) Oral Tablets in New Drug Applications

Dissolution profile comparisons are used by the pharmaceutical industry to assess the similarity in the dissolution characteristics of two formulations to decide whether the implemented changes, usually minor/moderate in nature, will have an impact on the in vitro/in vivo performance of the drug product. When similarity testing is applied to support the approval of lower strengths of the same formulation, the traditional approach for dissolution profile comparison is not always applicable for drug products exhibiting strength-dependent dissolution and may lead to incorrect conclusions about product performance. The objective of this article is to describe reasonable biopharmaceutic approaches for developing a biowaiver strategy for low solubility, proportionally similar/non-proportionally similar in composition immediate release drug products that exhibit strength-dependent dissolution profiles. The paths highlighted in the article include (1) approaches to address biowaiver requests, such as the use of multi-unit dissolution testing to account for sink condition differences between the higher and lower strengths; (2) the use of a single- vs. strength-dependent dissolution method; and (3) the use of single- vs. strength-dependent dissolution acceptance criteria. These approaches are cost- and time-effective and can avoid unnecessary bioequivalence studies.     

Impact of collagen-induced arthritis on the pharmacokinetic disposition of voriconazole,a widely used antifungal agent: in vitro and in vivo investigations in DBA/1J mice

1. Pharmacokinetics of voriconazole, an anti-fungal agent, was determined in collagen-induced arthritic (CIA) and healthy DBA/1J mice. CIA was confirmed in DBA/1J mice by clinical scoring and histological analysis.

2. In vivo oral pharmacokinetic study (3?mg/kg) and in vitro stability assessment in liver microsomes were performed in CIA vs. healthy DBA/1J mice. Additionally, hepatic portal vein cannulated (HPVC) CIA and healthy mice were used to clarify the role of gut first-pass effect. Voriconazole/N-oxide metabolite was measured in plasma and in vitro samples using liquid chromatography tandem-mass spectrometry method.

3. Voriconazole exposure was reduced in CIA by 27% as compared to healthy mice. Formation of voriconazole N-oxide was higher in CIA mice as evidenced by higher molar C_max ratio (i.e. metabolite/parent) of 2.08 vs. 1.66 in healthy mice. Because voriconazole was stable in microsomes, involvement of presystemic gut metabolism was suspected for decreased voriconazole exposure and formation of higher molar ratio of metabolite. HPVC work revealed higher formation of voriconazole N-oxide in CIA relative to healthy mice resulting in C_max/AUC ratios of 0.41/0.54 and 0.08/0.17, respectively, confirming first-pass effect.

4. The findings may have implications in the clinical therapy of arthritis patients who are concomitantly given voriconazole for the management of fungal infections.

     

Consequences of daily corticosteroid dosing with or without pre-treatment with quinidine on the in vivo cytochrome P450 2D (CYP2D) enzyme in rats: effect on O-demethylation activity of dextromethorphan and expression levels of CYP2D1 mRNA

1.?Present investigation was carried out in rats to study influence of corticosteroids after repeated dosing with/without pre-treatment with CYP2D inhibitor quinidine on the CYP2D1 mRNA levels and CYP2D enzyme activity using dextromethorphan as probe substrate.

2.?CYP2D1 mRNA was measured in liver homogenate using quantitative real-time polymerase chain reaction [qRT-PCR] and enzymatic reaction was studied ex vivo in liver S-9 fractions of rats treated with oral 10?mg/kg dexamethasone or prednisolone for five days or pre-treated with quinidine and followed by treatment with oral 10?mg/kg corticosteroids for five days.

3.?Five days repeat dosing of dexamethasone or prednisolone decreased the activity of the rat liver CYP2D by 37% and 34%, at 30?min incubation and decreased CYP2D1 mRNA levels by 62% and 61%, respectively.

4.?Pre-treatment of quinidine decreased the enzymatic activity of rat CYP2D by 58% and did not potentiate CYP2D inhibition by corticosteroids. This observation was further complemented by qRT-PCR data.

5.?Corticosteroids caused CYP2D inhibition in rats vs. literature evidence of CYP2D induction in human hepatocytes/pregnant humans demonstrating lack of concordance. In vivo inhibition should be factored for interpretation of pharmacokinetic data of CYP2D substrates when treated with corticosteroids in rats.     

In Vitro Biopredictive Methods: A Workshop Summary Report

This workshop report summarizes the proceedings of Day 1 of a three-day workshop on “Current State and Future Expectations of Translational Modeling Strategies to Support Drug Product Development, Manufacturing Changes and Controls”. Physiologically based biopharmaceutics models (PBBM) are tools which enable the drug product quality attributes to be linked to the in vivo performance. These tools rely on key quality inputs in order to provide reliable predictions. After introducing the objectives of the workshop and the expectations from the breakout sessions, Day 1 of the workshop focused on the best practices and challenges in measuring in vitro inputs needed for modeling, such as the drug solubility, the dissolution rate of the drug product, potential precipitation of the drug and drug permeability. This paper reports the podium presentations and summarizes breakout session discussions related to A) the best strategies for determining solubility, supersaturation and critical supersaturation; B) the best strategies for the development of biopredictive (clinically relevant) dissolution methods; C) the challenges associated with describing gastro-intestinal systems parameters such as mucus, liquid volume and motility; and D) the challenges with translating biopharmaceutical measures of drug permeability along the gastrointestinal tract to a meaningful model parameter.     

Application of the Modified Chi-Square Ratio Statistic in a Stepwise Procedure for Cascade Impactor Equivalence Testing

Equivalence testing of aerodynamic particle size distribution (APSD) through multi-stage cascade impactors (CIs) is important for establishing bioequivalence of orally inhaled drug products. Recent work demonstrated that the median of the modified chi-square ratio statistic (MmCSRS) is a promising metric for APSD equivalence testing of test (T) and reference (R) products as it can be applied to a reduced number of CI sites that are more relevant for lung deposition. This metric is also less sensitive to the increased variability often observed for low-deposition sites. A method to establish critical values for the MmCSRS is described here. This method considers the variability of the R product by employing a reference variance scaling approach that allows definition of critical values as a function of the observed variability of the R product. A stepwise CI equivalence test is proposed that integrates the MmCSRS as a method for comparing the relative shapes of CI profiles and incorporates statistical tests for assessing equivalence of single actuation content and impactor sized mass. This stepwise CI equivalence test was applied to 55 published CI profile scenarios, which were classified as equivalent or inequivalent by members of the Product Quality Research Institute working group (PQRI WG). The results of the stepwise CI equivalence test using a 25% difference in MmCSRS as an acceptance criterion provided the best matching with those of the PQRI WG as decisions of both methods agreed in 75% of the 55 CI profile scenarios.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-014-9698-0) contains supplementary material, which is available to authorized users.KEY Words: aerodynamic particle size distribution, bioequivalence, cascade impactor, chi-square ratio statistic, orally inhaled drug products     

Applications of Clinically Relevant Dissolution Testing: Workshop Summary Report

This publication summarizes the proceedings of day 3 of a 3-day workshop on “Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development.” Specifically, this publication discusses the current approaches in building clinical relevance into drug product development for solid oral dosage forms, along with challenges that both industry and regulatory agencies are facing in setting clinically relevant drug product specifications (CRDPS) as presented at the workshop. The concept of clinical relevance is a multidisciplinary effort which implies an understanding of the relationship between the critical quality attributes (CQAs) and their impact on predetermined clinical outcomes. Developing this level of understanding, in many cases, requires introducing deliberate but meaningful variations into the critical material attributes (CMAs) and critical process parameters (CPPs) to establish a relationship between the resulting in vitro dissolution/release profiles and in vivo PK performance, a surrogate for clinical outcomes. Alternatively, with the intention of improving the efficiency of the drug product development process by limiting the burden of conducting in vivo studies, this understanding can be either built, or at least enhanced, through in silico efforts, such as IVIVC and physiologically based pharmacokinetic (PBPK) absorption modeling and simulation (M&S). These approaches enable dissolution testing to establish safe boundaries and reject drug product batches falling outside of the established safe range (e.g., due to inadequate in vivo performance) enabling the method to become clinically relevant. Ultimately, these efforts contribute towards patient-centric drug product development and allow regulatory flexibility throughout the lifecycle of the drug product.