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      Pharmaceutical Development of 5-Fluorouracil-Eluting Stents for the Potential Treatment of Gastrointestinal Cancers and Related Obstructions

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          Abstract

          Background

          Drug-eluting gastrointestinal (GI) stents are emerging as promising platforms for the treatment of GI cancers and provide the combined advantages of mechanical support to prevent lumen occlusion and as a reservoir for localized drug delivery to tumors. Therefore, in this work we present a detailed quality assurance study of 5-fluorouracil (5FU) drug-eluting stents (DESs) as potential candidates for the treatment of obstructive GI cancers.

          Methods

          The 5FU DESs were fabricated via a simple two-step sequential dip-coating process of commercial GI self-expanding nitinol stents with a 5FU-loaded polyurethane basecoat and a drug-free protective poly(ethylene-co-vinyl acetate) topcoat. The drug loading, content uniformity and drug stability were determined using a validated high-performance liquid chromatography (HPLC) method, which is also recommended in the United States Pharmacopeia. In vitro drug release studies were performed in phosphate buffered saline to determine the drug releasing properties of the two 5FU-loaded stents. Gas chromatography (GC) and HPLC were employed to determine total residual tetrahydrofuran and N,N-dimethylformamide in the stents remaining from the manufacturing process. Sterilization of the stents was performed using gamma radiation and stability testing was carried out for 3 months.

          Results

          The drug loading analysis revealed excellent uniformity in the distribution of 5FU between and within individual stents. Determination of drug stability in the biorelevant release media confirmed that 5FU remains stable over 100 d. In vitro drug release studies from the stents revealed sustained release of 5FU across two different time scales (161 and 30 d), and mathematical modeling of drug release profiles revealed a diffusion-controlled mechanism for the sustained 5FU release. GC and HPLC analysis revealed that the daily residual solvent leached from the stents was below the United States (US) Food and Drug Administration (FDA) guidelines, and therefore, unlikely to cause localized/systemic toxicities. Sterilization of the stents with gamma radiation and accelerated stability tests over a period of 3 months revealed no significant effect on the stability or in vitro release of 5FU.

          Conclusion

          Our results demonstrate that the 5FU DESs meet relevant quality standards and display favourable drug release characteristics for the potential treatment of GI cancers and related obstructions.

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          Most cited references 68

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          DDSolver: an add-in program for modeling and comparison of drug dissolution profiles.

          In recent years, several mathematical models have been developed for analysis of drug dissolution data, and many different mathematical approaches have been proposed to assess the similarity between two drug dissolution profiles. However, until now, no computer program has been reported for simplifying the calculations involved in the modeling and comparison of dissolution profiles. The purposes of this article are: (1) to describe the development of a software program, called DDSolver, for facilitating the assessment of similarity between drug dissolution data; (2) to establish a model library for fitting dissolution data using a nonlinear optimization method; and (3) to provide a brief review of available approaches for comparing drug dissolution profiles. DDSolver is a freely available program which is capable of performing most existing techniques for comparing drug release data, including exploratory data analysis, univariate ANOVA, ratio test procedures, the difference factor f (1), the similarity factor f (2), the Rescigno indices, the 90% confidence interval (CI) of difference method, the multivariate statistical distance method, the model-dependent method, the bootstrap f (2) method, and Chow and Ki's time series method. Sample runs of the program demonstrated that the results were satisfactory, and DDSolver could be served as a useful tool for dissolution data analysis.
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            Coronary stents: a materials perspective.

            The objective of this review is to describe the suitability of different biomaterials as coronary stents. This review focuses on the following topics: (1) different materials used for stents, (2) surface characteristics that influence stent-biology interactions, (3) the use of polymers in stents, and (4) drug-eluting stents, especially those that are commercially available.
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              Drug/device combinations for local drug therapies and infection prophylaxis.

              Combination devices-those comprising drug releasing components together with functional prosthetic implants-represent a versatile, emerging clinical technology promising to provide functional improvements to implant devices in several classes. Landmark antimicrobial catheters and the drug-eluting stent have heralded the entrance, and significantly, routes to FDA approval, for these devices into clinical practice. This review describes recent strategies creating implantable combination devices. Most prominent are new combination devices representing current orthopedic and cardiovascular implants with new added capabilities from on-board or directly associated drug delivery systems are now under development. Wound coverings and implantable sensors will also benefit from this combination enhancement. Infection mitigation, a common problem with implantable devices, is a current primary focus. On-going progress in cell-based therapeutics, progenitor cell exploitation, growth factor delivery and advanced formulation strategies will provide a more general and versatile basis for advanced combination device strategies. These seek to improve tissue-device integration and functional tissue regeneration. Future combination devices might best be completely re-designed de novo to deliver multiple bioactive agents over several spatial and temporal scales to enhance prosthetic device function, instead of the current 'add-on' approach to existing implant device designs never originally intending to function in tandem with drug delivery systems.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                dddt
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                09 April 2021
                2021
                : 15
                : 1495-1507
                Affiliations
                [1 ]Pharmaceutical Innovation and Development (PIDG) Group, Clinical and Health Sciences, University of South Australia , Adelaide, SA, 5000, Australia
                [2 ]Applied Chemistry and Translational Biomaterials (ACTB) Group, Clinical and Health Sciences, University of South Australia , Adelaide, SA, 5000, Australia
                [3 ]Drug Discovery and Development Group, Clinical and Health Sciences, University of South Australia , Adelaide, SA, 5000, Australia
                Author notes
                Correspondence: Sanjay Garg Pharmaceutical Innovation and Development (PIDG) Group, Clinical and Health Sciences, University of South Australia , Adelaide, SA, 5000, Australia Email Sanjay.Garg@unisa.edu.au
                Anton Blencowe Applied Chemistry and Translational Biomaterials (ACTB) Group, Clinical and Health Sciences, University of South Australia , Adelaide, SA, 5000, Australia Email Anton.Blencowe@unisa.edu.au
                Article
                299401
                10.2147/DDDT.S299401
                8043784
                © 2021 Arafat et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 5, Tables: 2, References: 74, Pages: 13
                Categories
                Original Research

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