Critical quality attributes, in vitro release and correlated in vitro skin permeation—in vivo tape stripping collective data for demonstrating therapeutic (non)equivalence of topical semisolids: A case study of “ready-to-use” vehicles

Abstract

This work aimed to prove the ability of “ready-to-use” topical vehicles based on alkyl polyglucoside-mixed emulsifier (with/without co-solvent modifications) to replace the conventionally used pharmacopoeial bases (e.g., non-ionic hydrophilic cream) in compounding practice. For this purpose, considering the regulatory efforts to establish alternative, scientifically valid methods for evaluating therapeutic equivalence of topical semisolids, we performed a comparative assessment of microstructure, selected critical quality attributes (CQAs) and in vitro/in vivo product performances, by utilizing aceclofenac as a model drug. The differences in composition between investigated samples have imposed remarkable variances in monitored CQAs (particularly in the amount of aceclofenac dissolved, rheological properties and water distribution mode), reflecting the distinct differences in microstructure formed, as partially observed by polarization microscopy and confocal Raman spectral imaging. Although not fully indicative of the in vivo performances, in vitro release data (vertical diffusion vs. immersion cells) proved the microstructure peculiarities, asserting the rheological properties as decisive factor for obtained liberation profiles. Contrary, in vitro permeation results obtained using pig ear epidermis correlated well with in vivo dermatopharmacokinetic data and distinguished unequivocally between tested formulations, emphasizing the importance of skin/vehicle interactions. In summary, suggested multi-faceted approach can provide adequate proof on topical semisolids therapeutic equivalence or lack thereof.

Introduction

Despite the progress achieved in pharmaceutical and regulatory science, the availability of generic topical semisolid products on the market is still constrained due to the difficulty in demonstrating bioequivalence (BE) with innovator’s products (Raney et al., 2015). As the target site of the most topical formulations is the skin or underlying tissue, due to none or very low measurable amounts of drug in the systemic circulation, establishing BE in the most cases entails conducting comparative clinical trials. Generally, the clinical studies are expensive, time-consuming and importantly, often associated with a high degree of variability and a low sensitivity in detecting formulation differences (Krishnaiah et al., 2014, Raney et al., 2015, Yacobi et al., 2014). Therefore, to facilitate development, approval and ultimately availability of high-quality generic semisolids to patients at more reasonable cost, pharmaceutical scientists are intensively exploring whether BE may be demonstrated by integrating collective evidence related to product quality and performance, based on multiple, scientifically valid in vitro/in vivo methods, tailored to drug and disease (EMA, 2014, FDA, 2017, Yacobi et al., 2014).

Depending on the formulation composition and manufacturing process, the generic semisolid product may exhibit differences in the microstructure and arrangement of matter (Q3) compared to the reference listed drug (RLD) that may impact its performance in vivo (Shah et al., 2015). Therefore, it is of particular interest to identify and develop a reliable toolkit to characterize these microstructural differences (Murthy, 2016). The US Food and Drug Administration (FDA), inter alia, is currently interested in defining the specific quality attributes of different topical semisolid dosage forms that needed to be closely monitored to gain an assurance of microstructural similarity (Chang et al., 2013, Shanley, 2016). At this moment, quality attributes potentially critical for therapeutic performance usually encompass pH, globule size, drug particle size, rheological behavior, drug polymorphic form, dissolved/undissolved drug ratio, water activity, to name a few (Chang et al., 2013, Murthy, 2016), but experts in the field still fail to agree on an exhaustive list. The understanding of the relationship between critical quality attributes (CQAs) that define the microstructure of semisolid products, their in vitro and in vivo performances and/or failure modes possibly arising from differences in CQAs is believed to enable an efficient comparison of the proposed generic product with RLD (Shanley, 2016).

On the other hand, the absence or unavailability of authorized semisolid drug products required to meet the specific needs of individual patients, over the past several years, have led to a remarkable increase in compounding practice (Nornoo et al., 2016). As a result, there are growing needs for the “ready-to-use” topical vehicles/bases on the market which could ensure effective delivery of a broad variety of actives into/through the skin, showing at the same time acceptable physicochemical stability, satisfactory safety profile as well as optimal sensorial properties (Savić et al., 2009; Surber and Smith, 2005). In addition, considering that a substantial number of actives intended for topical application is poorly water soluble, the compounding base should be capable of incorporating different co-solvents, which act as penetration enhancers as well (Jaksic et al., 2012). Moreover, taking into account a number of drawbacks typical for traditional ionic or non-ionic emulsifiers (e.g., skin irritation potential, postponed system’s structuring) employed for stabilization of conventional pharmaceutical vehicles, as well as increasing affinity of modern patients towards “green” products, it is indispensable to innovate the composition of topical vehicles via introduction of skin- and environmental-friendly emulsifiers,. As a result, naturally derived alkyl polyglucoside (APG) surfactants have been recently recognized as promising in formulating “ready-to-use” topical vehicles (Jaksic et al., 2012, Pantelic et al., 2014a, Pantelic et al., 2014b, Savić et al., 2009).

Therefore, in this study, we were interested to verify the viability of a “ready-to-use” topical vehicle based on APG mixed emulsifier (cetearyl glucoside and cetearyl alcohol) as an appropriate surrogate of the pharmacopoeial one for widespread use in extemporaneous compounding. In the absence of suitable regulatory guidance for such an issue, we opted for an approach similar to the one currently under development for the prospective application in formulation of generic semisolid drug products. Namely, the selection of suitable characterization methods employed in our study was based on the relevance of quality attributes that we anticipated as critical: amount of drug dissolved in the vehicle, pH value, rheology, water distribution mode. Moreover, since the tested (APG-stabilized) vehicle had qualitatively (Q1) and quantitatively (Q2) different composition relative to the reference pharmacopoeial vehicle, in vitro and in vivo tests were utilized to evaluate the formulations’ effect on drug skin absorption. For this purpose, aceclofenac (ACF), a relatively new nonsteroidal anti-inflammatory drug (NSAID), was selected as a model of poorly water soluble drugs because no topical product of ACF has yet obtained the market authorization in Europe and USA, and therefore, it may be available only through compounding practice.

To be precise, we were interested to understand how formulation composition of APG-stabilized base and a corresponding one of pharmacopoeial quality (as a reference), alongside with the presence of ACF, affect the formation of complex microstructure (using the polarization microscopy and confocal Raman spectral imaging), and how such microstructure further influences the selected CQAs and ultimately, in vitro release/permeation profiles and in vivo dermatopharmacokinetics. Additionally, taking into account the poor water solubility of ACF, it was intriguing to evaluate whether and to which extent two co-solvents (isopropyl alcohol (IPA), glycerol) with different proposed penetration enhancement mechanisms alter the colloidal structure of APG-based vehicle and consequently CQAs, as well as whether or not that affects the in vitro and in vivo fate of ACF. In this context, we also aimed to assess whether in vitro permeation test using pig ear epidermis and in vivo tape stripping could individually differentiate the rate and extent of ACF delivery from the different investigated formulations, and thereby, to evaluate the utility of their combination for comparative assessment of drug’s bioavailability and/or BE from semisolid products, which are not Q1/Q2/Q3 equivalent. Therefore, we strongly believe that the results of this study may contribute to accumulating knowledge on the relationship between the selected CQAs and in vitro/in vivo performances of topical semisolid products.