Elution from intact and broken vaginal contraceptive rings: an in vitro study.

OBJECTIVE: The in vitro elution of the active substances etonogestrel (ETO) and ethinylestradiol (EE) of Ornibel® (a vaginal delivery system) was determined after a deliberate breakage of the vaginal contraceptive ring and compared to the standard elution and hormone release of intact rings under the same experimental conditions. MATERIALS AND METHODS: Ornibel® intact and broken vaginal rings were placed in a dissolution buffer and subject to a repetitive sampling of ETO and EE following a standardized in vitro elution (IVE) procedure for 21 days. The hormone dissolution profile was determined by HPLC using a fully validated analytical method. In a second study, rings were broken after day seven, and their elution profiles were compared to that of intact rings. For all utilized batches, the stability conditions established were 24 months at 5°C. Furthermore, no special storage conditions are needed. RESULTS: The instantaneous elution on day 1 of ETO and EE for intact rings were 119±8 µg/day and 15±1 µg/day, respectively (mean ± SD), which was non-significantly different to the immediate release of ETO and EE for broken rings (118±4 µg/day and 14±1 µg/day). The average elution profile for days 2-20 were 132±5 µg/day and 18±1 µg/day (ETO/EE, intact rings) and 132±4 µg/day and 19±1 µg/day (ETO/EE, broken rings) respectively. On day 21, the elution of ETO and EE was numerically similar 111±5 (±4) µg/day and 18±1 µg/day) for both intact and broken rings. The IVE results from intact rings and vaginal rings deliberately cut on day seven similarly did not differ in their release of ETO and EE. CONCLUSIONS: Our study concludes that the hormonal release of ETO and EE from Ornibel® are similar for intact and broken vaginal rings under standardized in vitro conditions.

Residual hormone levels in used contraceptive rings as a measurement of adherence to vaginal ring use.

OBJECTIVE: This study sought to measure residual contraceptive hormone levels in vaginal rings as an adherence marker for monitoring product use in clinical trials. STUDY DESIGN: Residual etonogestrel and ethinyl estradiol levels from used NuvaRings® of 26 self-reported adherent women enrolled in a clinical trial of vaginal ring acceptability were compared to those from 16 women who used NuvaRing® as their contraceptive choice. RESULTS: Twenty-one (81%) clinical trial rings had contraceptive hormone levels within the range of those used as a contraceptive choice. Five returned rings had unused or discordant levels of residual contraceptive hormones. CONCLUSION: Residual vaginal ring drug levels could help assess adherence in clinical trials.

Improving the efficiency of ion mobility spectrometry analyses by using multivariate calibration.

The simplicity, sensitivity and expeditiousness of ion mobility spectrometry (IMS) make it especially useful for the determination of active principal ingredients (APIs) present at low concentrations in pharmaceuticals. However, the poor resolution of this technique precludes the identification and/or determination of substances with similar molecular weights, which exhibit also similar drift times and give overlapped peaks as a result. Oral contraceptives are pharmaceutical formulations containing two APIs of similar molecular weights at very low concentrations which therefore give strongly overlapped peaks hindering their determination by IMS. In this work, we assessed the potential of IMS for detecting and quantifying the contraceptives ethinylestradiol (ETE) and desogestrel (DES) in commercial tablets. To this end, we used various chemometric techniques including a second-derivative (TN2D) algorithm and the more powerful choice Multivariate Curve Resolution (MCR) to improve the resolution of IMS and enable the determination of both APIs. Quantitation was based on PLS1 models for each API. The models constructed involve a single PLS factor with a Y-explained variance above 98.4%, obtaining a RMSEP of 0.34 and 0.63 for ETE and DES, respectively. The ensuing method, which was validated for use in routine analyses, is quite expeditious (analyses take less than 1 min) and uses very small amounts of sample (a few microliters). Based on the results, IMS has a great potential for the qualitative and quantitative determination of APIs in low doses.

The contraceptive vaginal ring in women with renal and liver transplantation: analysis of preliminary results.

INTRODUCTION: Vaginal administration seems to be the best route to achieve steady and precise doses of contraceptive hormones, resulting in stable serum concentrations and low exposure. The aim of this study was to evaluate the contraceptive efficacy, cycle control, tolerability and acceptability of a contraceptive vaginal ring (NuvaRing) in renal and liver transplant recipients. MATERIAL AND METHODS: Renal or liver transplant recipients, asking for contraception, were enrolled into the study. The duration of treatment was 12 cycles, with each vaginal ring releasing an average of 120 mg etonogestrel and 15 mg ethinylestradiol daily. Study visits were scheduled at screening, in the first week following cycles 3, 6, and 12 (172 cycles). RESULTS: Among 17 females included into the study: were 9 renal (mean age, 30 +/- 7.2 years) and 8 liver transplant recipients (mean age, 32.6 +/- 6.6 years). At the onset of therapy all patients showed at least 6 months of stable graft function with no signs of allograft rejection. The mean posttransplant follow-up was 4 +/- 3.6 and 5.3 +/- 2.1 years for women with renal and hepatic transplantations respectively (P = NS). The immunosuppressive therapy was not changed for any patient. We demonstrated good cycle control: 162 cycles did not exhibit any bleeding; 7 cycles, only spotting episodes, whereas 2 cycles had 1 bleeding episode during the ring period. The estrogen-related adverse events (nausea and breast tenderness) were reported in 2 patients. One patient experienced significant bleeding related to thrombocytopenia. DISCUSSION: Nuvaring, in our preliminary findings, may be considered to be an highly effective contraceptive method for female transplant recipients that additionally regulate menstrual bleeding and seems to positively influence well-being. Vaginal administration may diminish the chance of drug interactions and therefore be safer for patients.

[Sonographic localization of non-palpable implanon hormone implants]. / Sonografische Lokalisation nicht tastbarer Implanon(R)-Hormonimplantate.

PURPOSE: Implanon is a rod-shaped hormone implant which leads to reliable contraception. The rod is implanted in the subcutis of the upper arm and is usually removed easily after its effective period. In the scenario where the rod is not palpable, the removal of the rod can be difficult or impossible. The purpose of this study was to evaluate the reliability of US in locating non-palpable Implanon implants and to investigate the optimal technical parameters for determining the location. MATERIALS AND METHODS: In a prospective study we evaluated 21 women between June 2004 and June 2008. In 14 patients previous examinations with US, radiography, CT and/or MRI were non-diagnostic. The US evaluation followed a standardized protocol in transverse and longitudinal sections. The technical parameters US frequency, position and number of focal zones and compound imaging were varied to define the optimal parameters for the visualization of the Implanon implant. RESULTS: The Implanon implant was detected in all 21 patients. Reasons for negative palpability were mainly an intramuscular or subfascial location as well as a significant migration of the Implanon implant in 2 patients. The use of a high US frequency, the position of the focal zones in the near field and the deactivation of compound imaging all facilitate visualization of the characteristic US morphology of the plastic rod. CONCLUSION: High resolution US is the method of choice for determining the location of non-palpable Implanon implants. Knowledge of US morphology and optimal technical settings as well as the use of high-resolution scan heads are essential for determining the correct location.

High performance liquid chromatography/ion-trap mass spectrometry for separation and simultaneous determination of ethynylestradiol, gestodene, levonorgestrel, cyproterone acetate and desogestrel.

A fast and highly sensitive high performance liquid chromatographic/ion-trap mass spectrometric method (LC/MS) has been developed for simultaneous determination of ethynylestradiol (EE2), gestodene (GES), levonorgestrel (LNG), cyproterone acetate (CPA) and desogestrel (DES). Among three types of sorbents tested (C8, C18 and phenyl) from two suppliers, the best separation was achieved on reverse phase Zorbax SB-Phenyl column using aqueous methanol as a mobile phase. A linear gradient profile from 70 up to 100% (v/v) in 7th min, kept constant at 100% up to 10th min and followed by a negative gradient to 70% of methanol up to 12th min was used for elution. Applicability of electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) and influence of the mobile phase composition, its flow rate, capillary/vaporizer temperature of API source and in-source fragmentor voltage ionization are discussed. The on-column limits of quantification (10S/N) were 300 pg of EE2, 14 pg of GES and LNG, 4 pg of CPA and 960 pg of DES per injection (1 microL) using APCI with data collection in selected ion monitoring (SIM) mode. The analytical performance of the method was evaluated using the determination of EE2, GES, LNG, CPA and DES in contraceptives and river water samples.

Classification and comparison of oral contraceptives containing new generation progestogens.

New generation-oral contraceptives containing desogestrel or gestodene, and possibly also norgestimate, are more or less similar with respect to contraceptive efficacy, cycle control and acceptability. They also show a more favourable metabolic profile in comparison with older preparations. The desogestrel-containing preparations Gracial and Marvelon, and possibly also the gestodene-containing preparation Gynera, have demonstrated a good efficacy in well-controlled studies in the treatment of mild to moderate acne and/or hirsutism. There may be differences between new generation oral contraceptives with respect to their effects on metabolic variables like high-density lipoprotein cholesterol and sex hormone-binding globulin. These differences are most probably modulated by variations in both the pharmacokinetics and selectivity of the progestogenic components. Of particular relevance here may be the recent finding that approximately 20% of administered norgestimate is metabolized into levonorgestrel. For use in clinical practice, it is of considerable help to have different preparations containing a range of oestrogen doses with the same progestogen. They allow the clinician to 'tailor make' the choice of oral contraceptives for those starting pill use or those switching to another combination due to symptomatology or changed circumstances, e.g. advancing age, smoking, etc. In this respect, desogestrel-containing oral contraceptives allow the most flexible approach.