In vitro release testing methods for drug-releasing vaginal rings

Abstract

Drug-releasing vaginal rings are torus-shaped devices, generally fabricated from thermoplastics or silicone elastomers, used to administer pharmaceutical drugs to the human vagina for periods typically ranging from three weeks to twelve months. One of the most important product performance tests for vaginal rings is the in vitro release test. Although it has been fifty years since the a vaginal ring device was first described in the scientific literature, and despite seven drug-releasing vaginal rings having been approved for market, there is no universally accepted method for testing in vitro drug release, and only one non-compendial shaking incubator method (for the estradiol-releasing ring Estring ®) is described in the US Food and Drug Administration's Dissolution Methods Database. Here, for the first time, we critically review the diverse range of test methods that have been described in the scientific literature for testing in vitro release of drugreleasing vaginal rings. Issues around in vitro-in vivo correlation and modelling of in vitro release data are also discussed.

In Vitro–In Vivo Correlation (IVIVC) Population Modeling for the In Silico Bioequivalence of a Long-Acting Release Formulation of Progesterone

“…These findings were in agreement with the PK variability reported for the drug administered through the vaginal route and represented an intrinsic characteristic and limitation of this type of administration (28). Indeed, several physiological factors, such as changes in the epithelial thickness, alteration of the volume and pH of the vaginal fluids, can potentially affect progesterone release from the ring and alter its absorption rate [20,28,34]. A population (nonlinear-mixed effect) approach was used to account for this relevant in vivo variability.…”

“…An initial burst phase was observed in the release profile of the two lower dose levels (125 and 375 mg) for which early sampling timepoints were available. This immediate faster release is due to the progesterone at or near the surface of the matrix ring that has a relatively small diffusional pathway to overcome in order to be released [28]. The parameter P0 of the in vitro model was introduced to provide an estimate of this quantity.…”

“…Adequately predicting the in vivo performances from in vitro release data for vaginal drug delivery systems, such us PVRs, is extremely challenging due to a multitude of factors including the vaginal physiology, the complex dynamics of vaginal absorption, the significant inter-individual variability of the PK, the absence of compendial apparatus and methods for the in vitro release testing [28], as well as the inability of directly measuring the in vivo release in the vagina during the whole study period. For this reason, as in the majority of IVIVC applications, the progesterone serum concentration-time profiles were used as surrogates to reflect the in vivo drug release.…”

Co-drug delivery of regorafenib and cisplatin with amphiphilic copolymer nanoparticles: enhanced in vivo antitumor cancer therapy in nursing care

“…By stirring at 100 rpm on a detour shakers at 37 °C, the drug release medium was removed and an equivalent size of new medium was added. The drug-releasing profiles of PT and REGO were examined using an UV − vis spectrometer (Boyd et al., 2019 ; Ibrahim et al., 2020 ; Li et al., 2020 ).…”

The Vaginal Microbiota, Bacterial Biofilms and Polymeric Drug-Releasing Vaginal Rings

“…Drug-releasing VRs-the focus of this review article-are torus-shaped devices designed to administer drugs over extended time periods to the human vagina for therapeutic benefit [1][2][3][4]. To date, seven drug-releasing VRs-Estring ® , Femring ® , NuvaRing ® (and generics EluRyng™, Myring™), Progering ® , Fertiring ® , Ornibel ® (also known as SyreniRing and Kirkos ® ) and Annovera™ (Table 1)-have reached market, with total estimated annual sales of $1.8 billion, and many others are in preclinical or clinical development [5][6][7][8][9]. Each marketed ring provides either 'sustained release' (drug release maintained over an extended period but not at a constant rate) or 'controlled release' (drug release maintained over an extended period at constant or near-constant rate) of one or more steroidal drugs for hormonal contraception (either progestin-only or progestin + estrogen combinations), estrogen replacement therapy, or luteal-phase support for assisted reproduction.…”