Development of a buccal doxepin platform for pain in oral mucositis derived from head and neck cancer treatment

Abstract

This study describes the development of semisolid formulations containing doxepin (DOX) for pain relief in oral mucositis, frequently related to chemotherapy and/or radiotherapy treatments in patients with head and neck cancer. Chemical permeation enhancers were evaluated and selected according to the results obtained from rheological studies, drug release, and drug permeation and retention through buccal mucosa. Finally, the selected formulation was compared in vivo, with a reference DOX mouthwash, whose clinical efficacy had been previously reported. The obtained findings showed that an orabase® platform loading transcutol® (10%) and menthol (5%) for the buccal vehiculization of DOX exhibited a decreased elastic and viscous behavior improving its application. The main drug release mechanism could be considered as diffusion according to Higuchi model. Obtained DOX permeation rates were considered optimal for an analgesic effect and far below to an antidepressant activity. Similar in vivo plasma concentrations were found for the semisolid formulation and the reference mouthwash. However, DOX amounts retained in the mucosa of animals for the semisolid formulation were higher than the reference, which let us hypostatize even stronger potential local therapeutic effect with additional advantages such as, mucoadhesive properties, absence of alcohol, some degree of freshness, as well as, drug palatability improvement.

Introduction

Oral mucositis (OM) is a common acute reaction after chemotherapy and/or radiotherapy in head and neck cancer treatment. Although being of ordinary occurrence, current literature reports highly variable incidence (fluctuating from 75% to 99%) [1]. Severity of OM ranges from superficial sore erythema to complete mucosal ulceration in the oral cavity, pharynx and esophagus. Therefore, patient’s quality of life is affected since OM is associated with considerable pain and dysphagia, which also complicates the nutritional intake, increases susceptibility to infections and leads to the cancer treatment interruption [2]. All these problems are reflected in the clinical management of cancer, without undertaking any evaluation of associated cost of medical resources [3], [4]. Currently, there is no Food and Drug Administration (FDA)-approved intervention for the prevention of OM induced by chemotherapy and/or radiotherapy [5]. Current strategies against OM are directed to limit its extent and to manage its symptomatology, mainly pain relief. Different alternatives are used to alleviate the acute pain in OM and highly severe cases may imply the use of systemic opioids. For mild and less-severe cases, therapeutic alternatives include cryotherapy, use of mouthwashes, coating agents, low laser therapy and topical anesthetic and/or analgesic agents [1], [3], [4]. Notwithstanding, topical anesthetics and analgesics typically provide less than 30 min of pain relief [6]. In this context, doxepin (DOX), a dibenzoxepin-derivate tricyclic antidepressant (TCA), without being analgesic has shown effective results in the treatment of pain [7], [8]. Concretely, some clinical studies have focused on OM pain relief caused by head and neck cancer therapy with DOX oral rinses [9], [10], [11]. Its therapeutic effect is believed to be caused by the blockade of sodium channels at local level in cutaneous nociceptors [10].

Considering the promising result of DOX oral rinses and the need of new well supported therapies to manage the OM pain induced by chemotherapy and/or radiotherapy in the treatment of head and neck cancer [12], [13], the present study was initiated with the intention to develop a new dosage form for DOX to be administered in OM. For this purpose, a semisolid buccal formulation was developed to extend the contact time with the affected tissue, to achieve some degree of coating effect and to provide sustained release of DOX. For this task, mucoadhesive paste Orabase® was selected as the DOX platform for the developed formulations.

Equally, in order to enhance its analgesic effect different penetration enhancers were evaluated. Rheological properties of formulations were assayed, as well as, in vitro release and ex vivo permeation from which main parameters were calculated. Finally, the semisolid formulation to be tested in vivo against the reference mouthwash was selected according to the results obtained from previously mentioned studies.