Microstructural Characterization of Microsponge-Based Gel Products using CryoSEM

2021 FDA Science Forum

• Authors: Mohammed, Yousuf, Therapeutics Research Group, The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Brisbane, Australia; Namjoshi, Sarika, Therapeutics Research Group, The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Brisbane, Australia; Dabbaghi, Maryam, Therapeutics Research Group, The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Brisbane, Australia; Ramezanli, Tannaz, Division of Therapeutic Performance, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, USA; Raney, Sam G, Division of Therapeutic Performance, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, USA; Jiang, Ying, Division of Therapeutic Performance, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, USA; Grice, Jeffrey, Therapeutics Research Group, The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Brisbane, Australia; Roberts, Michael S, Therapeutics Research Group, The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Brisbane, Australia

• Center: Office of the Commissioner

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Abstract

Background and Purpose

Retin-A Micro® (tretinoin) topical gel, 0.1% (Retin-A Micro® gel) contains tretinoin loaded in microsponges that are dispersed in a gel vehicle. The microstructure of the products requires assessments at levels of both the drug loaded-microsponges and the gel matrices. Internal pore size of microsponges is an important microstructure characteristic that can be correlated to their drug loading capacity. This study aimed to develop sensitive imaging techniques to evaluate the microstructure of topical products and simultaneously, to assess the size and internal microstructure of microsponges in the gel matrices.

Methods

Retin-A Micro® gel products dispensed from both the tube and pump packaging configurations were first cryo-fixed in flush nitrogen. Then, morphology of the native and sublimed forms of the frozen, fractured samples was examined using a JOEL scanning electron microscope (SEM) (JSM7100F) equipped with a secondary electron detector. Microsponges pore size in CryoSEM images taken periodically during sample sublimation was calculated using the Image J software (NIH).

Results

The CryoSEM technique could successfully assess both the overall microstructure of the gel and the internal microstructure of the microsponges within the gel. From CryoSEM images of the native form of the gel, the size of microsponges and morphological information can be gained. Periodic imaging of gels that were undergoing sublimation showed morphological changes of the microsponges and the surrounding gel matrices. The sublimation process revealed the internal pores of the microsponges and left behind a unique pattern of integrated polymers in the gel system. The average internal pore sizes of the microsponges in gels dispensed from the tube and pump were calculated to be 18.57 nm2 and 17.41 nm2 at 90 minutes sublimation, respectively (n=3), which remained constant despite further sublimation till 210 minutes. After sublimation, the gel matrix dispensed from the tube exhibited visible hollow structures between polymeric filaments, while that was not observed in the formulation that was dispensed from the pump.

Conclusion

Here we introduce the use of cryoSEM techniques to evaluate the morphology and porosity of microsponges dispersed in a gel vehicle. A carefully designed protocol may be used to provide a means for comparing reference and generic products for their microstructural differences.

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