In vitro release of nonoxynol-9 from silicone matrix intravaginal rings
Introduction
Nonoxynol-9 (N9) is a non-ionic surfactant that has been used widely as a spermicidal agent in intravaginal contraceptives. Recently, there has been much debate regarding the potential of N9 to prevent the transmission of the herpes simplex virus (HSV) and the human immunodeficiency virus (HIV) through disruption of the viral envelope. Although in vitro studies have demonstrated N9 activity against HSV and HIV [1], in vivo data in monkeys and humans has been less conclusive [2], [3], [4], [5]. One issue in particular that needs to be clarified is the possibility that use of N9 might increase the rate of transmission of HIV by causing lesions to form on vaginal epithelial tissue. A number of studies have suggested that such tissue damage is dose-related [6], [7], [8].
In a clinical study investigating the duration of vaginal retention and potential antiviral activity of a number of N9-containing intravaginal contraceptives, Witter et al. reported several important findings [9]. Firstly, and as expected, the retention of N9 creams, foams, suppositories and films in the vagina decreased with increasing time from application. For example, Deflon®, a 100 mg N9 foam preparation, provided median values for retained N9 of 19, 18, 8 and 5 mg at 2, 4, 8, and 12 h, respectively, post-application. This poor retention is a characteristic of most traditional vaginal drug delivery systems. Secondly, the authors estimated that at least 2.0 mg of N9 is required in the vagina to protect against HIV, based on in vitro data indicating that 0.025% of N9 in vaginal fluid is required [1] and a conservative estimate of 8 ml for the volume of vaginal fluid [10]. Although most of the N9 products investigated in the study provided >2 mg of retained N9 for up to 12 h, several disadvantages with these traditional vaginal delivery systems are apparent. The poor degree of retention is likely to be further compromised by coital activity. Also, longer-term protection will require multiple dosing which introduces issues of patient compliance. And finally, a single application of these products provides a dose of between 50 and 108 mg N9. Although such high doses are necessary to provide protection over an 8-h period, given the poor retention characteristics in the vagina, they might also be considered too high, particularly in longer term use, given recent concerns about vaginal epithelial damage by N9 [6], [7], [8].
Many of the potential problems associated with vaginal N9 administration might be overcome by optimising its delivery regime. The delivery of small, therapeutically efficacious doses of N9 in a more controlled manner through the use of a specifically designed vaginal drug delivery system could, in particular, surmount the problems of vaginal retention and dose-dependent incidence of epithelial damage associated with current N9 formulations. To this end, we report here the in vitro release characteristics of a number of matrix-type N9-releasing silicone intravaginal rings (IVR). The IVR is a flexible, doughnut-shaped, controlled-release drug delivery system that is placed by the user in the vagina where it resides next to the cervix and is capable of releasing continuous amounts of drug(s) for up to 12 months at a time. Although originally designed for the intravaginal administration of steroidal drugs for contraceptive and hormone replacement therapies [11], [12], [13], [14], [15], [16], it is apparent that IVRs might also offer possibilities in a wider range of women’s health care issues. Acceptability of IVRs is high compared with traditional vaginal drug delivery systems owing to their convenience, non-messiness, the fact that they rarely interfere with intercourse and their potential for long-term retention within the vagina until removal is required [14], [15], [16], [17], [18], [19], [20]. Thus, an N9-releasing IVR may offer a new female-controlled method for protection against HIV and other sexually transmitted diseases.
Section snippets
Materials
Analytical grade water was prepared by passing distilled water through a Milli-Q® Reagent Water System (Millipore®). Nonoxynol-9 (nonylphenolethoxylate) was supplied by Taresh (Banbridge, Northern Ireland, UK). AnalaR® grade acetic acid and GPR grade sodium hydroxide pellets were purchased from Davidson and Hardy (Belfast, UK). Stannous-2-ethyl hexanoate (stannous octoate) and poly(dimethylsiloxane) oil (20 cst, 25 °C) were obtained from Sigma (Poole, UK). Silicone elastomer base (MED-6382) and
Theory
The release of solid drugs from silicone matrix-type IVRs (where the drug is homogeneously dispersed) is described by the following two equations [21]:where Q is the cumulative amount of drug released from a unit surface area of drug (mg cm−2), A is the initial drug loading per unit volume (mg cm−3), Cp is the drug solubility in the silicone elastomer (mg cm−3), hp is the thickness of the drug depletion zone (cm), hd is the thickness of the
Silicone solubility of N9
The polymer solubility of a drug substance (Cp) is one of several rate-controlling factors influencing the release characteristics of a drug from a polymeric, diffusion-controlled, matrix, drug-delivery device, as indicated in , , , , , , , . Given that direct determination of a substance’s solubility in a polymer is difficult to measure, indirect methods such as permeation/partition studies or use of a model solvent whose solvation characteristics are similar to those of the polymer, are
Conclusions
The results of the study clearly demonstrate the potential for the intravaginal controlled delivery of nonoxynol-9 from silicone matrix intravaginal rings. Furthermore, the in vitro release rate suggests that vaginal nonoxynol-9 concentrations may be maintained at clinically optimised levels for the prevention of sexually transmitted diseases such as HIV infection. In particular, the study demonstrates that the release kinetics that apply to the release of solid permeants from silicone
References (29)
- et al.
The effect of contraceptives containing nonoxynol-9 on the genital transmission of simian immunodeficiency virus in rhesus macaques
Fertil. Steril.
(1992) - et al.
Duration of vaginal retention and potential duration of antiviral activity for five nonoxynol-9 containing intravaginal contraceptives
Int. J. Gynecol. Obstet.
(1999) - et al.
Design of an intravaginal ring for the controlled delivery of 17β-estradiol as its 3-acetate ester
J. Control. Release
(1999) - et al.
High performance liquid chromatographic determination of 17β-estradiol and 17β-estradiol-3-acetate solubilities and diffusion coefficients in silicone elastomeric intravaginal rings
J. Chromatogr. Biomed. B
(2000) - et al.
A one-year multicenter study of efficacy and safety of a continuous, low-dose, estradiol-releasing vaginal ring (Estring) in postmenopausal women with symptoms and signs of urogenital aging
Am. J. Obstet. Gynecol.
(1996) - et al.
A comparative study of two contraceptive vaginal rings releasing norethindrone acetate and differing doses of ethinyl estradiol
Contraception
(1999) - et al.
The acceptability of a combined oestrogen/progestogen contraceptive vaginal ring
Contraception
(1995) - et al.
A contraceptive vaginal ring releasing norethindrone acetate and ethinyl estradiol
Contraception
(1994) - et al.
Continuous low dose estradiol released from a vaginal ring versus estriol vaginal cream for urogenital atrophy
Eur. J. Obstet. Gynecol.
(1997) - et al.
Clinical acceptability of an ethylene-vinyl-acetate non-medicated vaginal ring
Contraception
(1999)
Controlled drug release from polymeric devices V. Hydroxy group effects on drug release kinetics and thermodynamics
J. Pharm. Sci.
A dynamic mechanical method for determining the silicone elastomer solubility of drugs and pharmaceutical excipients in silicone intravaginal drug delivery devices
Biomaterials
Controlled drug release from polymeric delivery devices II. Differentiation between partition-controlled and matrix-controlled drug release mechanisms
J. Pharm. Sci.
Spermicide permeation through biocompatible polymers
Contraception
Cited by (51)
Polymers in Vaginal Drug Delivery: Recent Advancements
2020, Applications of Polymers in Drug DeliveryIn vitro release testing methods for drug-releasing vaginal rings
2019, Journal of Controlled ReleaseCitation Excerpt :These equations have been reported many times for modelling drug release from matrix-type vaginal rings [41,49,55,62,64,65,89,92,95,116–122]. Only one matrix-type vaginal ring device has been reported containing a liquid drug at room temperature, and for which release kinetics are significantly modified compared to matrix-type ring containing solid drugs due to the absence of a drug depletion zone [56]. By comparison, reservoir-type rings, comprising a drug-loaded core surrounded by a rate-contolling polymeric membrane, generally offer controlled release of drug(s) at a near constant rate of release.
Implantable drug delivery systems
2019, Engineering Drug Delivery SystemsManufacturing and characterization of long-acting levonorgestrel intrauterine systems
2018, International Journal of PharmaceuticsMonolithic polydimethylsiloxane-modified silica composites prepared by a low-temperature sol–gel micromolding technique for controlled drug release
2017, Reactive and Functional Polymers