title: Evaluation of microporous polycaprolactone matrices for controlled delivery of antiviral microbicides to the female genital tract.
abstract: Acyclovir (ACV) as a model antiviral microbicide, was incorporated in controlled-release polycaprolactone (PCL) matrices designed for application as intra-vaginal ring inserts (IVRs). Microporous materials incorporating acyclovir up to a level of ~10 % w/w were produced by rapidly cooling suspensions of drug powder in PCL solution followed by solvent extraction from the hardened matrices. Around 21, 50 and 78 % of the drug content was gradually released from matrices over 30 days in simulated vaginal fluid at 37 °C, corresponding to drug loadings of 5.9, 7.0 and 9.6 % w/w. The release behaviour of matrices having the lowest drug loading followed a zero order model, whereas, the release kinetics of 7.0 and 9.6 % ACV-loaded PCL matrices could be described effectively by the Higuchi model, suggesting that Fickian diffusion is controlling drug release. Corresponding values of the diffusion co-efficient for ACV in the PCL matrices of 3.16 × 10(-9) and 1.07 × 10(-8) cm(2)/s were calculated. Plaque reduction assays provided an IC50 value of 1.09 μg/mL for acyclovir against HSV-2 and confirmed the antiviral activity of released acyclovir against HSV-2 replication in primate kidney cells (Vero) at levels ~70 % that of non-formulated acyclovir at day 30. Estimated minimum in vivo acyclovir concentrations produced by a PCL IVR (19 μg/mL) exceeded by a factor of 20 the IC50 value against HSV-2 and the reported ACV vaginal concentrations in women (0.5-1.0 μg/mL) following oral administration. These findings recommend further investigations of PCL matrices for vaginal delivery of antiviral agents in the treatment and prevention of sexually transmitted infections such as AIDS.
authors.affiliation: Pharmacy Australia Centre of Excellence, The University of Queensland, 20 Cornwall Street, Woolloongabba, QLD, 4102, Australia.
authors.forename: Naghme Hajarol
authors.initials: NH
authors.lastname: Asvadi
authors.forename: Nhung T T
authors.initials: NT
authors.lastname: Dang
authors.forename: Nicholas
authors.initials: N
authors.lastname: Davis-Poynter
authors.forename: Allan G A
authors.initials: AG
authors.lastname: Coombes
mesh_terms: D000212:Acyclovir / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000282:Administration, Intravaginal; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems; D005260:Female; D006244:Hardness; D018258:Herpesvirus 2, Human; D006801:Humans; D020128:Inhibitory Concentration 50; D008422:Materials Testing; D011091:Polyesters / Q000737:chemistry*; D012997:Solvents / Q000737:chemistry; D014621:Vagina / Q000187:drug effects* / Q000821:virology; D014777:Virus Diseases / Q000517:prevention & control
chemical_list: D000998:Antiviral Agents; D003692:Delayed-Action Preparations; D011091:Polyesters; D012997:Solvents; C016240:polycaprolactone; D000212:Acyclovir
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