Elsevier

Journal of Controlled Release

Volume 91, Issue 3, 4 September 2003, Pages 355-364
Journal of Controlled Release

In vitro release of nonoxynol-9 from silicone matrix intravaginal rings

https://doi.org/10.1016/S0168-3659(03)00260-8Get rights and content

Abstract

The controlled-release characteristics of matrix silicone intravaginal rings loaded with between 100 and 971 mg of nonoxynol-9 have been investigated with a view to developing a ring that may offer a new female-controlled method for the prevention of transmission of sexually transmitted diseases, particularly HIV. Intravaginal rings containing 253, 487 and 971 mg of nonoxynol-9 provided a daily release of 2 mg or more over the 8-day release period, the minimal amount of nonoxynol-9 considered to provide an effective vaginal concentration for the prevention of HIV. Furthermore, the maximum daily release of N9 was about 6 mg, an amount significantly smaller than that observed for other nonoxynol-9 products whose large daily doses may in fact increase the occurrence of HIV by causing epithelial damage to the vaginal tissue. The release mechanism of the liquid nonoxynol-9 from the intravaginal rings has also been investigated and compared to models describing the release of solid drugs from the rings. It has been demonstrated through release studies and surface microscopy that a drug depletion zone is not established in such liquid-loaded intravaginal ring systems, with implications for the release kinetics.

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]:Q=A−Cp2hphp2+2(A−Cp)DphphdA−Cp2DdkK=2CpDptA−Cp2where 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)

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