Effect of plasticizers on drug-in-adhesive patches containing 5-fluorouracil

Highlights

• Drug-in-adhesive patches containing 5-fluorouracil for the treatment of skin cancer.

• Pressure-sensitive adhesives using Eudragit® E and plasticizers for topical application.

• Solubility parameters and thermal analysis for polymer-plasticizer miscibility evaluation.

Abstract

Topical patches containing 5-fluorouracil (5-FU) are a feasible alternative to overcome the shortcomings of commercial cream for the treatment of non-melanoma skin cancer (NMSC). Plasticizers are a critical component of drug-in-adhesive (DIA) patches as they can significantly affect the mechanical, adhesive and drug release characteristics of the patches. Eudragit® E (EuE) is a methacrylate-based cationic copolymer capable of producing flexible and adhesive films for topical application. In this study, the effect of plasticizers on the mechanical, adhesive and 5-FU release characteristics of EuE-based patches was comprehensively evaluated. While the elongation at break (%) and adhesion of the films were significantly increased with increasing triacetin, dibutyl sebacate (DBS) and triethyl citrate (TEC) concentrations, the tensile strength showed an inverse relationship. EuE plasticized with 40% triacetin, 30% DBS or 40% w/w TEC produced elastic and adhesive films most suitable for topical application. In vitro release studies of the 5-FU-loaded patches demonstrated an initial burst release pattern during the first 10 min followed by a slow release over 120 min. In summary, this study provides important information on effect of plasticizers for preparation of EuE-based patches with desired mechanical, adhesive and release characteristics of 5-FU towards their potential application in the treatment of NMSC.

Introduction

Non-melanoma skin cancer (NMSC) is the most common form of cancer diagnosed in Australia and many other countries (Australian Institute of Health and Welfare, 2016, Eisemann et al., 2014). NMSC comprises basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and other rare types of skin cancer including Merkel cell lesions and cutaneous lymphoma (Ciazynska et al., 2021). 5-fluorouracil (5-FU) is a pyrimidine antimetabolite that inhibits DNA synthesis by blocking the activities of thymidylate synthase enzymes and is commercially available as a topical cream for the treatment of actinic keratoses and SCC in situ (Fahradyan et al., 2017). However, there are several drawbacks associated with using the semi-solid formulation for the treatment of NMSC. As appropriate dosing information for the commercial 5-FU cream is lacking, there seems to be little consensus among the clinicians in terms of topically applied doses and treatment areas – either dose not specified or recommended to spread over too small or too large areas (Berman et al., 2004, Geisse et al., 2004). Further dose variations among individual patients may also be expected due to the self-administration nature of the semi-solid products. Other practical issues may also include compromised patient adherence due to special handling procedures and a risk of accidental application leading to local or systemic toxicities (Donnelly et al., 2006).

Drug-in-adhesive (DIA) patches are a simple, stable and convenient dosage form in cutaneous and transdermal drug delivery systems (TDDS). A cutaneous patch containing 5-FU may be a feasible alternative option to overcome the shortcomings of semi-solid dosage forms for the treatment of NMSC. A DIA patch can be cut to a size and shape that cover the affected areas of the skin and deliver a fixed-dose of drugs at a controlled rate rendering it suitable for potential application in skin cancer treatment (Kathe and Kathpalia, 2017, Layek et al., 2019). However, there are only limited studies reported on the development of DIA patches for the treatment of skin cancer including imiquimod-loaded cutaneous patches (Donnelly et al., 2006, Layek et al., 2019) and 5-FU-loaded patches (Chandrashekar and Prasanth, 2008). A DIA patch consists of a drug-containing pressure-sensitive adhesive (PSA) layer that is sandwiched between a backing membrane and a release liner protecting the formulation during the storage (Fig. 1). The release liner is removed prior to patch application where the backing membrane serves as a protective layer from the external environment during the intended period of therapy (Lobo et al., 2016). A PSA is a critical component of the DIA patch, which not only provides the adhesion to the skin but also allows the drug to be directly embedded within the PSA layer to control drug release (Liu et al., 2016). Generally, acrylic copolymers, polysiloxane and polyisobutylenes are the three main types of PSA. Acrylic PSAs have been most commonly used for the preparation of drug-in-adhesive patches as they are low-cost and resistant to oxidation and color changes on exposure to sunlight (Park et al., 2020). Methyl methacrylate copolymers, also known as Eudragit® have widely been used for the development of various drug dosage forms including oral (Drašković et al., 2017), vaginal (Martín-Illana, 2021), ocular (Taghe et al., 2020), and TDDS (Chantasart et al., 2018). Eudragit® copolymers are commercially available in different grades including Eudragit® E, L, S, RS and RL depending on the monomers used. Eudragit E® (EuE) is a US Food and Drug Administration-approved cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate (2:1:1) capable of producing flexible and adhesive films, which showed good compatibility with several weak acidic drugs for oral and topical applications (Thakral et al., 2013, Li et al., 2015, Pradhan et al., 2016).

The addition of a plasticizer is crucial for providing EuE films with desired tensile strength, flexibility and adhesion (Sun et al., 2020). Plasticizers are low molecular weight resins or liquids that can improve physico-mechanical properties of polymeric films by weakening the intermolecular forces among the polymeric chains and forming new hydrogen bonds with them (Sun et al., 2020). As films produced from pure EuE are brittle and non-adhesive, EuE-based films without the addition of a plasticizer are not suitable as a PSA (Cilurzo et al., 2014). However, EuE-based films containing an appropriate amount and type of plasticizer have been used as a PSA in several TDDS such as medicated plasters (Elgindy and Samy, 2009), film-forming topical sprays (Ranade et al., 2017), cutaneous and transdermal patches (Rajabalaya, 2010).

The type of plasticizers and their concentration can significantly affect the physico-mechanical properties of polymeric films (Vieira et al., 2011). For example, EuE-based films prepared using ethylene vinyl acetate, glycerol monostearate, glycerine and polyethylene glycol (PEG) 6000 did not demonstrate suitable flexibility and adhesion for topical application (Lin et al., 1991). On the other hand, EuE-based DIA patches were successfully developed using 40% w/w acetyl tributyl citrate (ATBC) as a plasticizer (Kanikkannan et al., 2004). Similarly, dibutyl phthalate and diethyl phthalate have also been used to develop EuE-based PSAs (Rajabalaya, 2010). However, many of these studies lack detailed evaluation of the mechanical and adhesive properties of the prepared EuE-based films, in which comprehensive comparisons between the PSAs fabricated using different plasticizers were difficult to achieve.

In addition, plasticizers can significantly affect drug release characteristics of drug-in-adhesive patches. In a previous study, the release rate of verapamil hydrochloride was significantly higher from gum copal films plasticized with glycerol than those with PEG 400 and dibutyl phthalate (Mundada and Avari, 2010). In another study, the effect of glycerol and castor oil as a plasticizer on in vitro release of diltiazem hydrochloride from ethyl cellulose-based transdermal patches was evaluated (Kulkarni et al., 2010). The authors reported that the formulations plasticized with glycerol showed a significantly faster release than those containing castor oil while increasing the plasticizer concentration markedly accelerated the rate of diltiazem release. However, to the best of our knowledge, there is no previous research conducted on evaluating the effect of plasticizers on the drug release characteristics of 5-FU from EuE-based patches.

Considering the critical roles of plasticizers on determining the mechanical, adhesive and drug release characteristics of patches, this study aims to provide better insight into the effect of using different plasticizers and concentrations on the physico-mechanical, adhesive and 5-FU release characteristics of EuE-based patches. In this study, we have fabricated drug-free EuE-based PSAs using various concentrations of plasticizers including PEG 300, propylene glycol (PG), triacetin, dibutyl sebacate (DBS) and triethyl citrate (TEC) to comprehensively evaluate the effect of plasticizers on the mechanical and adhesive properties of the PSAs. In addition, various backing membranes and release liners were screened based on their affinity to the PSAs. Following the physicochemical characterization of the EuE-based patches containing 5-FU, in vitro release studies were conducted to demonstrate the effect of plasticizers on the 5-FU release characteristics of the patches.