Pharmaceutics, Drug Delivery and Pharmaceutical Technology Thiolated Cyclodextrin: Development of a Mucoadhesive Vaginal Delivery System for Acyclovir Muhammad Ijaz 1 , Julia Anita Griessinger 2 , Arshad Mahmood 1 , Flavia Laffleur 1 , Andreas Bernkop-Schnürch 1 , * 1 Department of Pharmaceutical Technology, Center for Chemistry and Biomedicine, Institute of Pharmacy, University of Innsbruck, Innsbruck 6020, Austria 2 Thiomatrix Forschungs-und Beratungs GmbH, Innsbruck 6020, Austria article info Article history: Received 15 December 2015 Revised 4 March 2016 Accepted 7 March 2016 Chemical Compounds: Cyclomaltoheptaose (PubChem CID: 444041) Cysteamine (PubChem CID: 6058) Sodium metaperiodate (PubChem CID: 23667635) Sodium cyanotrihydridoborate (PubChem CID: 20587905) Acyclovir (PubChem CID: 2022) Keywords: vaginal mucosa thiomers acyclovir beta-cyclodextrin mucoadhesion abstract The objective of this study was the development of a mucoadhesive vaginal delivery system for acyclovir (Acv). Sodium-per-iodate (NaIO 4 ) was used to introduce aldehyde substructures into beta-cyclodextrin (b-CD) by oxidative cleavage of vicinal diol bonds. Cysteamine was covalently attached to b-CD-CHO via reductive amination. Ellman’s reagent was utilized for quantification of free thiol groups attached and resazurin assay was used for cytotoxicity studies. Mucoadhesive properties were evaluated on porcine vaginal mucosa in comparison to intestinal mucosa. Quantification of thiol groups revealed 851.84 ± 107, 1040.44 ± 132, and 1563.72 ± 171 mmol/g of free thiol groups attached to the b-CD-SH851, b-CD-SH1040, and b-CD-SH1563, respectively. b-CD-SH derivatives at concentrations of 0.5% (m/v) did not show sig- nificant reduction of viability of Caco-2 cells within 24 h. Furthermore, water solubility of b-CD-SH1563 was improved 7.6-fold in comparison to unmodified b-CD. b-CD-SH851, b-CD-SH1040, and b-CD-SH1563 showed 5.84-, 15.95-, and 17.14-fold improved mucoadhesive properties on porcine vaginal mucosa and 3-,12.47-, and 32.13-fold on porcine intestinal mucosa, respectively. Inclusion complex of Acv with b-CD-SH1563 resulted in significantly improved drug dissolution. According to the results, b-CD-SH derivatives might be promising new tools for local vaginal delivery of Acv. © 2016 American Pharmacists Association ® . Published by Elsevier Inc. All rights reserved. Introduction Mucosal surfaces in the female reproductive tract and in the lower gastrointestinal tract are the main routes of viral infections like herpes simplex virus. Genital herpes, characterized by a cluster of painful vesicular or ulcerative mucocutaneous lesions, is a globally prevalent sexually transmitted disease and the most common reason of genital ulcer disease. 1 Acyclovir (Acv), one of the most effective antiviral drugs, is a drug of choice for the treatment of herpes viruses. 2 However, poor water and lipid solubility of Acv (1.3 mg/mL of solubility in water and an octanol to water partition coefficient of 0.018) may contribute to its low drug availability at the site of action. 3 To address vaginal infectious problems, local vaginal drug de- livery is the preferred choice. Local drug delivery to the vaginal mucosa is currently implemented or being developed via administration of soft and semi-solid materials (like creams, gels, etc.). However, quite a lot of issues, including leakage, messiness, low residence time, and local irritation, need to be addressed throughout the design of vaginal formulations. 4 b-CD (beta- cyclodextrin), a well-known and likely the smallest drug carrier, has an ability to increase solubility of various drug molecules 5 by the formation of relatively stable inclusion complexes. 6 Inclusion complex stability is usually higher when the dimension of the guest molecule is suitable for the dimension of b-CD’s cavity. To keep encapsulated drugs at the site of drug action for a longer period of time, unfortunately, b-CD lacks mucoadhesive proper- ties (the ability to adhere to the mucosal surfaces of the body). Thiolated polymers offer the advantage of covalent bonds with cysteine-rich subdomains in mucosal surfaces via thiol/disulfide * Correspondence to: Andreas Bernkop-Schnürch (Telephone: þ43-512-507- 58600; Fax: þ43-512-507-58699). E-mail address: andreas.bernkop@uibk.ac.at (A. Bernkop-Schnürch). Contents lists available at ScienceDirect Journal of Pharmaceutical Sciences journal homepage: www.jpharmsci.org http://dx.doi.org/10.1016/j.xphs.2016.03.009 0022-3549/© 2016 American Pharmacists Association ® . Published by Elsevier Inc. All rights reserved. Journal of Pharmaceutical Sciences 105 (2016) 1714e1720