Elsevier

Carbohydrate Polymers

Volume 132, 5 November 2015, Pages 187-195
Carbohydrate Polymers

Synthesis and characterization of thiolated β-cyclodextrin as a novel mucoadhesive excipient for intra-oral drug delivery

https://doi.org/10.1016/j.carbpol.2015.06.073Get rights and content

Highlights

  • Synthesis and characterization of cysteamine conjugated β-cyclodextrin (β-CD-Cys).

  • Conjugates showed no toxic effects on Caco-2 cells at concentrations of 0.5% (m/v).

  • Maximum 34.51-fold improved mucoadhesion on the porcine buccal mucosa.

  • Inclusion complexes resulted in 150-fold increased water solubility of miconazole nitrate.

Abstract

The objective of the present study was to synthesize and characterize cysteamine conjugated β-cyclodextrin (β-CD-Cys) as a novel mucoadhesive oligomeric excipient for intra-oral drug delivery. β-CD-Cys conjugates were obtained in a two-step synthetic pathway, whereby, vicinal diol groups of the oligomer were oxidized using increasing concentrations of sodium-per-iodate (NaIO4), prior to the covalent coupling of cysteamine via reductive amination. Quantification of immobilized thiol groups through Ellman's test revealed 561.56 ± 81 μmol/g, 1054.26 ± 131 μmol/g and 1783.92 ± 201 μmol/g of free thiol groups attached to the oligomer backbone depending on the extent of oxidation. β-CD-Cys conjugates at concentrations of 0.5% (m/v) showed no toxic effects on Caco-2 cells within 72 h. Furthermore, β-CD-Cys conjugates displayed a 4-fold improved water solubility compared to the parent oligomer. β-CD-Cys conjugates (β-CD-Cys561, β-CD-Cys1054 and β-CD-Cys1783) showed 2.86-, 15.09- and 49.08-fold improved retention time on porcine intestinal mucosa and 9.66-, 16.43- and 34.51-fold improved on the porcine buccal mucosa, respectively. Formation of inclusion complexes of miconazole nitrate and β-CD-Cys1054 resulted in 150-fold increased solubility of miconazole nitrate. According to these results, it seems that β-CD-Cys conjugates might provide a new promising tool for delivery of poorly water soluble therapeutic agents, such as miconazole nitrate for intra-oral delivery.

Introduction

The intra-oral cavity is an ideal site for local drug delivery as it is open to direct visualization, which simplifies both agent placement and clinical monitoring (de Vries, Bodde, Verhoef, & Junginger, 1990). It is advantageous for the treatment of intra-oral conditions such as gingivitis, oral candidiasis, oral lesions, dental carries, xerostomia (dryness of mouth due to lack of saliva), oral cancer, mucositis and neuropathic pain. Furthermore, the mucosal linings of the oral cavity are robust, and regain rapidly after local stress or damage (Smart, 2004). The development of intra-oral drug delivery system, however, in most cases is challenging. In particularly, it is difficult to keep the drug for a prolonged period of time on the intra-oral mucosa. Swallowing of saliva can also potentially lead to the loss of dissolved or suspended drug and, ultimately, the involuntary removal of the dosage form (Salamat-Miller, Chittchang, & Johnston, 2005). To overcome these problems, mucoadhesive polymers (Andrews, Laverty, & Jones, 2009) in the form of mucoadhesive patches (Perioli et al., 2004), lozenges/tablets (Perioli et al., 2007) and mucoadhesive gums (Alur, Pather, Mitra, & Johnston, 1999) have been used, still, they bear the disadvantage of foreign sensation, leading to poor patient compliance and tongue tries to get rid of these dosage forms. Furthermore, inconvenience to the patients during eating and drinking, along with the threat of choking by involuntarily swallowing of the delivery system.

Therefore, the aim of this study was the development of a novel mucoadhesive intra-oral drug delivery system without having foreign sensation. Accordingly β-CD, the likely smallest drug carrier providing improved solubility of numerous poorly soluble drugs, was chosen. β-CD is a multifunctional excipient which is extensively being used in pharmaceutical industry (Gidwani & Vyas, 2014). β-CD was thiolated to acquire the desired mucoadhesive properties according to the synthetic pathway as outlined in Fig. 1. Thiolated polymers mimic the natural mechanism of secreted mucus glycoproteins, covalently anchored in the mucus layer by the formation of disulfide bonds, the bridging structure most commonly encountered in biological systems. Because of the protracted residence time of the mucoadhesive drug delivery systems at the site of drug action, the frequency of dosing can be reduced which can lead to an improved patient compliance.

Miconazole nitrate is a broad spectrum antifungal drug, which has poor water solubility with an octanol-water partition coefficient of about 6.25 emphasizing the lipophilic character of the nitrate salt (Bhalekar, Pokharkar, Madgulkar, Patil, & Patil, 2009). Poor water solubility and lack of absorption at the site of application makes it a challenging candidate for intra-oral use. Inclusion complexes with β-CD have been reported to increase the dissolution and solubility of miconazole nitrate paving the way for new oral and topical drug delivery systems (Pedersen et al., 1993). After thiolation of β-CD miconazole nitrate serving as model drug for intra-oral therapy was therefore, encapsulated and the potential of this novel delivery system was evaluated in vitro.

Section snippets

Materials

Beta-cyclodextrin (β-CD), Ellman's reagent (5,5-dithiobis (2-nitro-benzoic acid)), MES hydrate (4-morpholine-ethanesulfonic acid), TNBS (trinitrobenzensulfonic acid), cysteamine, cysteine HCl, ethylene glycol, t-butyl carbazate, rhodamine 123 (Rhod-123), sodium periodate (NaIO4), sodium cyanoborohydride (NaCNBH3), sodium borohydride (NaBH4), dimethyl sulfoxide (DMSO) and minimum essential medium eagle (MEM) were all purchased from Sigma-Aldrich, Vienna, Austria. Pre-treated standard grade

Characterization of β-CD-Cys conjugates

β-CD-Cys conjugates obtained via the covalent attachment of cysteamine to the oxidized β-CD were of white color and odorless having fibrous structure. Conjugation of primary amine such as cysteamine depends on the presence of carbonyl groups on β-CD, whereas, unmodified β-CD does not contain carbonyl groups necessary for the reaction with primary amines. Within this study increasing concentrations of NaIO4 were used to partially oxidize β-CD. The periodate oxidation reaction encompasses a

Conclusion

In this study cysteamine was successfully conjugated to the oxidized β-CD. It could be shown, that thiolation of β-CD can increase the potential of β-CD drug encapsulation property by imparting mucoadhesive properties. Synthesized β-CD-Cys conjugates (β-CD-Cys561, β-CD-Cys1054 and β-CD-Cys1783) displayed significantly increased intra-oral mucoadhesion along with enhanced solubilizing effects for lipophilic drugs. Mucoadhesive properties were verified by applying the β-CD-Cys conjugates onto the

Acknowledgments

All the expenses for this work were supported by the Higher Education Commission of Pakistan (HEC), the Austrian Agency for International Cooperation in Education and Research (ÖAD) and the FWF (Fonds zur Förderung der wissenschaftlichen Forschung) project No. ZFP 235150.

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