Sexually transmitted infections (STIs), including HIV, present a significant health problem worldwide and are spread predominantly through unprotected intercourse. Intravaginal rings (IVRs) have recently been successfully loaded with microbicides for the prevention of HIV transmission. This thesis describes the development of polycaprolactone (PCL) matrix devices loaded with either antibacterial or antifungal or antiviral agents intended for the production of vaginal inserts for prevention or treatment of heterosexual transmission of HIV and other STIs.
Intravaginal PCL matrices incorporating an antibiotic, ciprofloxacin, or the antifungal agent, miconazole (Chapter 2), an anti-HIV agent, tenofovir (Chapter 3) or nevirapine (Chapter 4) or a combination of these two drugs (Chapter 5) were produced using a rapid cooling method. PCL displays advantages over other conventional polymers used in IVR production since PCL does not require high temperatures during the manufacturing process and therefore enables biological activity retention in heat sensitive drugs.
Chapter 2 describes PCL matrices loaded with ciprofloxacin and miconazole, respectively, to investigate their potential as controlled vaginal delivery devices. Ciprofloxacin displays potent bactericidal activity against a broad range of pathogens and has been used to treat a variety of bacterial infections including sexually transmitted infections. Miconazole, an antifungal agent, is used to treat topical mucosal fungal and yeast infections including candidiasis. The differences in aqueous solubilities between ciprofloxacin and miconazole resulted in differences in their matrix loading (ciprofloxacin 15% w/w and miconazole 3.2% w/w) as well as their release kinetics. However, after their release into simulated vaginal fluid (SVF), both drugs demonstrated high levels of antimicrobial activity, in excess of 80% of the activity of the free drug.
PCL matrices loaded with tenofovir were investigated in Chapter 3 and were designed for the production of vaginal devices to prevent HIV transmission. Tenofovir is a nucleoside reverse transcriptase inhibitor which has been recently under clinical trial as a microbicide in various dosage forms (gel, IVR). Tenofovir loadings of up to 12% (w/w) and high incorporation efficiencies in excess of 90% were obtained. The release behaviour of tenofovir in SVF demonstrated high delivery efficiency of 85%–99% over 30 days and could be described effectively by a first-order kinetic model giving a mean value of 0.126 day-1 for the release constant (k1). Tenofovir released from PCL matrices into SVF exhibited high relative activities ranging from 70 to 90%, against pseudo-typed HIV-1-infected HeLa cells. In addition to confirming high levels of in vitro antiviral activity, the predicted concentrations of tenofovir, which would be released from a PCL intra-vaginal ring in vivo, exceeded the IC50 value for HIV-1 by a factor of 35–200 and clinically protective concentrations by a factor of 50.
Chapter 4 discusses PCL matrices loaded with nevirapine intended for the production of vaginal inserts. Nevirapine, a non-nucleoside reverse transcriptase inhibitor, is an inexpensive antiretroviral drug and is widely used in resource-poor areas for both treating HIV and for preventing mother-to-child transmission. However, NVP’s low water solubility (0.7046 mg/L) can hinder drug dissolution and thus drug release into vaginal fluid from an IVR. In this study, polyethylene glycol (PEG6000) was utilised as a hydrophilic carrier for nevirapine in a solid dispersion. Nevirapine was molecularly mixed with PEG6000 and distributed as amorphous clusters in solid dispersions; these significantly improved the drug loading and release properties of nevirapine into SVF. In addition, nevirapine released from PCL using solid dispersions of nevirapine and PEG retained over 80% anti-HIV activity compared with the non-formulated nevirapine control.
The fabrication of simultaneously loaded tenofovir (TFV) and nevirapine (NVP) polycaprolactone matrices was assessed in Chapter 5. These were designed to provide synergistic activities of antiretroviral agents thereby preventing transmission of HIV through the vaginal route. The combination of two or more drugs has been shown to provide potential advantages over single microbicide approaches by maximizing activity through synergistic effects and potentially allowing for lower effective microbicide concentrations. After their release from PCL matrices, combinations of tenofovir and nevirapine in collected samples were confirmed to have a potential synergistic/additive effect on pseudo HIV-1.
Chapter 6 compares the similarity between a microporous PCL IVR and a PCL matrix in cylindrical form produced using the rapid cooling method. TFV or NVP or a mixture of the two drugs was loaded into the matrix and IVR for comparison. Despite a slight increase of hardness value for cylindrical TFV-loaded matrices compared with TFV-loaded IVRs, the loading efficiencies of the drugs were not significantly different between cylindrical matrices and IVRs. Release curves of the drugs from both IVR and matrix were considered equivalent on consideration of the difference factor f1 and similarity factor f2. Overall, the findings of these investigations confirmed the potential of PCL matrices loaded with microbicides for controlling heterosexual transmission of HIV and STIs through the vaginal route.