Controlled delivery of antibacterials using polycaprolactone matrices for the intravaginal treatment of sexually transmitted infections

Abstract

Around 500 million cases of four of the major curable sexually transmitted infections (STIs), Chlamydia, gonorrhoea, syphilis and trichomoniasis, were recorded worldwide in 2008, an increase of 11% from 2005, confirming the need for improved prevention and treatment strategies. The chances of acquiring these infections are 8 times greater in women than men because of biological, social and cultural factors. Furthermore, the presence of these infections increases the chances of both acquisition and transmission of HIV/AIDS by causing genital ulcers and inflammation in the vagina.The human vagina is considered to be a novel, non-invasive and safe route for drug delivery because of its rich blood supply, large surface area and low enzymatic activity.There are many vaginal preparations available in the market but conventional systems such as creams and gels are criticised because of messiness and leakage, and many vaginal formulations have the disadvantage of daily dosing. Intravaginal rings (IVRs) have potential advantages over other delivery systems, in that they can be used for prolonged periods of time, avoid messiness and sustained drug delivery is possible. Previous research has focussed on the use of IVRs for the prevention of HIV. This thesis describes the development of IVRs for the treatment of vaginal bacterial and fungal infections, including STIs.The most important component of IVRs is the polymer used in their construction; currently IVRs are composed of silicone and polyethylene vinyl acetate but these require a high processing temperature and are suitable only for delivery of low molecular weight, hydrophobic drugs. In this thesis, the use of polycaprolactone (PCL) as a potential polymer for use in IVRs is investigated because of its perceived advantages over other polymers, such as low processing temperature and potential to deliver a wide range of drug molecules from hydrophobic to hydrophilic, and low-molecular to high molecular weight.Following a review of the literature in Chapter 1, the delivery of metronidazole using PCL, which could be used for the treatment of bacterial vaginosis, is considered in Chapter 2. Delivery of metronidazole in an IVR could be a better option than the vaginal gel and oral tablet formulations that are currently available because an IVR would provide long term sustained delivery and would be expected to reduce the gastrointestinal side effects associated with oral delivery. PCL matrices loaded with different concentrations of 3 metronidazole achieved an incorporation efficiency of 40-54%. The matrices were studied using a range of approaches including release into simulated vaginal fluid (SVF), morphological and drug distribution studies, thermal characterization and antibacterial activity against Gardnerella vaginalis (one of the main bacteria implicated in bacterial vaginosis). First day burst release occurred due to the presence of drug crystals at the surface of the PCL which was confirmed by scanning electron microscopy and Raman microscopy. Even consider...