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Purpose: Typical clinical "in use" conditions for topical semisolids involve their application as a thin film, often with rubbing that can induce metamorphic stress. Yet, product quality and performance tests often characterize the manufactured product, and may not consider product metamorphosis (e.g., shear history) during dispensing and administration. This work sought to elucidate how such metamorphosis might alter product quality and performance., Methods: We evaluated the effect of "in use" stresses on drug crystal metamorphosis in acyclovir creams by optical microscopy. The amount of dissolved acyclovir was determined by separation of the cream base by ultra-centrifugation and quantification by HPLC. IVPT was undertaken on Zovirax ® US and Aciclostad ® comparing static and "in use" application of a finite dose. A mechanistic IVPT study was also conducted to understand the influence of acyclovir particle size reduction by "in use" rubbing on skin permeation., Results: Reduction in acyclovir particle size was seen after "in use" rubbing with increases in the amount of dissolved acyclovir after rubbing (30 and 60 s) compared to static for both products. "In use" application resulted in significantly higher acyclovir permeation from both products. The mechanistic IVPT study proved the role of product metamorphosis., Conclusion: These results highlight the role of metamorphosis of product microstructure and its influence on performance., Competing Interests: Declarations. Competing Interest: The authors declare that they have no conflicts of interest., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To develop a toolkit of test methods for characterizing potentially critical quality attributes (CQAs) of topical semisolid products and to evaluate how CQAs influence the rate and extent of active ingredient bioavailability (BA) by monitoring cutaneous pharmacokinetics (PK) using an In Vitro Permeation Test (IVPT)., Methods: Product attributes representing the physicochemical and structural (Q3) arrangement of matter, such as attributes of particles and globules, were assessed for a set of test acyclovir creams (Aciclostad® and Acyclovir 1A Pharma) and compared to a set of reference acyclovir creams (Zovirax® US, Zovirax® UK and Zovirax® Australia). IVPT studies were performed with all these creams using heat-separated human epidermis, evaluated with both, static Franz-type diffusion cells and a flow through diffusion cell system., Results: A toolkit developed to characterize quality and performance attributes of these acyclovir topical cream products identified certain differences in the Q3 attributes and the cutaneous PK of acyclovir between the test and reference sets of products. The cutaneous BA of acyclovir from the set of reference creams was substantially higher than from the set of test creams., Conclusions: This research elucidates how differences in the composition or manufacturing of product formulations can alter Q3 attributes that modulate myriad aspects of topical product performance. The results demonstrate the importance of understanding the Q3 attributes of topical semisolid drug products, and of developing appropriate product characterization tests. The toolkit developed here can be utilized to guide topical product development, and to mitigate the risk of differences in product performance, thereby supporting a demonstration of bioequivalence (BE) for prospective topical generic products and reducing the reliance on comparative clinical endpoint BE studies., (© 2024. The Author(s).)

The aim was to evaluate whether an in vitro release test (IVRT) could differentiate the release rates from five pharmaceutically equivalent acyclovir cream products and one ointment compared to that from a reference product, Zovirax cream (USA), to identify a test product with an inequivalent drug release rate that could serve as negative control for bioequivalence (BE) in a separate in vivo study. The reference product showed equivalent drug release rates compared to itself. The six test products failed to show equivalent drug release rates compared to the reference product. Aciclovir 1A pharma cream was selected to serve as a negative control for subsequent BE studies, since it exhibited the greatest difference in release rate among all creams, compared to the reference product. The results of this study indicate that IVRT results can be highly sensitive and may discriminate clinically relevant differences between products. Results from an appropriately validated IVRT method can support a demonstration of BE by showing that the drug release rates from test and reference products are statistically equivalent, mitigating the risk that differences may exist between the products which may influence in vivo performance of the drug product., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The rate of release of an active pharmaceutical ingredient (API) from a topical semisolid dosage form can be influenced by its physical and structural properties. An In Vitro Release Test (IVRT) is an established method to characterize this rate of API release and compare the underlying sameness in product quality characteristics. The purpose of this work was to validate an IVRT method to compare acyclovir cream, 5% products. However, despite widespread use of the IVRT since 1997, there has been no established approach to validate an IVRT method. Our approach included: 1) qualification of the diffusion cell apparatus, 2) qualification of the laboratory, 3) validation of the HPLC analytical method, and 4) validation of numerous critical parameters of the IVRT method, itself, and resulted in a comprehensive and successful IVRT method validation. Subsequent to the IVRT validation work described here, the U.S. Food and Drug Administration (FDA) drafted a guidance on the development and validation of an IVRT method for acyclovir cream, 5%. Although there are notable differences between our approach and the approach in that guidance, this report illustrates how many of the same essential qualification parameters and validation concepts were considered and systematically addressed in our approach to IVRT validation., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The availability of generic topical dermatological drug products is constrained by the limited methods established to assess topical bioequivalence (BE). A novel cutaneous pharmacokinetic approach, dermal open-flow microperfusion (dOFM), can continuously assess the rate and extent to which a topical drug becomes available in the dermis, to compare in vivo dermal bioavailability (BA) and support BE evaluations for topical products., Objective: To evaluate whether dOFM is an accurate, sensitive, and reproducible in vivo method to characterize the intradermal BA of acyclovir from 5 % acyclovir creams, comparing a reference (R) product either to itself or to a different test (T) product., Methods: In a single-center clinical study, R or T products were applied to six randomized treatment sites on the skin of 20 healthy human subjects. Two dOFM probes were inserted in each treatment site to monitor the intradermal acyclovir concentration for 36 h. Comparative BA (of R vs. R and T vs. R) was evaluated based on conventional BE criteria for pharmacokinetic endpoints (area under the curve and maximum dermal concentration) where the 90 % confidence interval of the geometric mean ratio between the T and R falls within 0.80-1.25., Results: The positive control products (R vs. R) were accurately and reproducibly confirmed to be bioequivalent, while the negative control products (T vs. R) were sensitively discriminated not to be bioequivalent., Conclusions: dOFM accurately, sensitively, and reproducibly characterized the dermal BA in a manner that can support BE evaluations for topical acyclovir 5 % creams in a study with n = 40 (20 subjects in this study)., Competing Interests: Compliance with Ethical Standards Funding Funding for this project was made possible, in part, by the FDA through research award FD004946. The views expressed in this publication do not reflect the official policies of the FDA, or the Department of Health and Human Services; nor does any mention of trade names, commercial practices, or organization imply endorsement by the United States Government. Conflict of interest MB, KIT, RR, BT, TA, CD, TB, SK, DS, TRP, and FS are employees of Joanneum Research holding patents on OFM devices. SGR is an employee of US FDA. GS and IK declare that there are no conflicts of interest. Ethics, informed consent, research involving human participants The study was conducted with the full informed consent of all participating subjects, under the authority of the Ethical Committee of the Medical University of Graz, the Austrian health authority AGES, and the FDA’s Research Involving Human Subjects Committee (RIHSC) and was performed in accordance with Good Clinical Practice and the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. The study has been registered in the European Clinical Trials Register (EudraCT No. 2013-005062-19) and at ClinicalTrials.gov (NCT02711267).