Development of a mucoadhesive delivery system for control release of doxepin with application in vaginal pain relief associated with gynecological surgery

Abstract

The main purpose of this study was to develop a semisolid mucoadhesive formulation for the non-invasive vaginal administration of doxepin (DOX) for relief of pain derived from the scarring process after surgery. An orafix^® platform loading DOX was tested for adequate stability, rheology and vaginal mucoadhesion capacity. The formulation exhibited appropriate pH and was microbiologically stable. The rheological studies confirmed its pseudoplastic and thixotropic nature with prevalence of the elastic behavior component over the viscous one. Appropriate syringeability and spreadability results were also confirmed. Different experiments showed adequate mucoadhesion capacity even in the presence of simulated vaginal fluid. Finally, DOX release, permeation and retention in vaginal mucosa studies were also accomplished with promising results. DOX release kinetics followed the modified Higuchi model and the permeation studies did not render such high values as to suggest potential systemic absorption which could lead to undesirable systemic side effects. Therefore, we can hypostatize that the proposed formulation may assist to fill in the therapeutic gap regarding pure pain relief at local level in vagina.

Introduction

The vagina is an expandable, longitudinally S-shaped, fibromuscular tube. It extends from the cervix of the uterus to the vestibule with dimensions of approximately 7–10 cm in length and 2–5 cm in diameter. Although commonly known as a mucosa, it does not harbor secretory glands; it does not secret fluid per se. However, its epithelium surface is covered by a thin film of fluid mainly originated by transudation and cervical glands (Vanić and Škalko-Basnet, 2013).

The vagina is a non-invasive delivery route in women for drugs formulations with systemic and local effect. Seeking a local effect, it has traditionally been used for the delivery of drugs such as prostaglandins, antibiotics, antifungals, steroids, antivirals, antiprotozoal, antichlamydial and spermicidal agents (Vermani et al., 2002). Many different vaginal delivery systems have been used over the years. However, conventional dosage forms are associated with poor retention time, leakage and messiness, causing discomfort to patients and leading to poor patient compliance and loss of therapeutic efficacy (Rençber et al., 2017). Nevertheless, semisolid formulations have been the preferred ones (Palmeira-de-Oliveira et al., 2015). An ideal vaginal delivery system should present minimal leakage, long residence on the tissue and it should uniformly distribute throughout the entire vaginal cavity (Ochoa Andrade et al., 2014). In order to improve the residence time of vaginal semisolids, the incorporation of mucoadhesive polymers to the formulations is a widely extended practice.

As regards drug administration in mucosa, researchers may be tempted to extrapolate results regarding the oral route to vaginal administration, it must be taken into account that drug delivery is tissue specific and should be studied for each specific drug and route of administration (Sanz et al., 2015a). However, considering the significant structural similarities between the oral and vaginal mucosa (Thompson et al., 2001), it was considered appropriate to study the potential use of a typical oral mucoadhesive excipient for its application in vaginal mucosa. It was also taken into account that human vaginal mucosa is a good permeability model for human buccal mucosa (Van Eyk and Van Der Bijl, 2004). Thus, it was expected that an oral formulation may also render satisfactory results at vaginal level. Orafix^®, a fat white vehicle for drug administration designed for oral application in buccal mucosa was selected as the main excipient to elaborate the proposed formulation. Orafix^® is a fat, white, odorless, uniform, and slightly grainy to the touch cream.

Doxepin (DOX) is a tricyclic antidepressant which has proven analgesic and anesthetic effect with topical application onto buccal mucosa. It is believed that its therapeutic local effect is caused by the blockade of sodium channels in cutaneous nociceptors (Leenstra et al., 2014).

Some anesthetic and anti-inflammatory topical drugs for local effect at vaginal level are commercially available. However, the field of local vaginal analgesia is not properly covered nowadays. Any surgery is a trauma to the body and the healing process involves the formation of scars. The scarring may cause pain through neuropathic pain mechanisms. Unfortunately, the treatment of scar pain in gynecology has not received much attention. Current treatment may include several injections of local anesthetics, the application of an anesthetic ointment containing lidocaine and the administration of oral tricyclic antidepressant and antiepileptic drugs (Steege and Zolnoun, 2009).

This work was undertaken with the main objective of designing a suitable mucoadhesive semisolid dosage form for DOX vaginal delivery at local level. In order to do so, rheological and bioadhesive properties of the formulation were tested, as well as its physical and microbiological stability. In vitro and ex vivo studies were also performed to assess its potential drug release and mucosal permeation, including its mucosal drug retention capacity.