Clinical Re-evaluation on Bioequivalence and Relative Bioavailability of Micronized Progesterone Hard Capsule (Yimaxin) and Micronized Progesterone Soft Capsule (Utrogestan) under Vaginal and Oral Administration Routes

Background and Objective: To clinically re-evaluate relative bioavailability and bioequivalence of micronized progesterone (hard capsule) Yimaxin and micronized progesterone (soft capsule) Utrogestan under vaginal and oral administration routes. Methods: From December 2017 to June 2018, a total of 16 postmenopausal healthy women were recruited and received a total of four rounds of drug treatment with cross-over design, respectively Yimaxin and Utrogestan under vaginal and oral administration routes. Changes in the subjects’ hormone levels after medication were monitored and an endometrial biopsy after a course of treatment was performed in our hospital. Result: The Geomeans of AUC0-t of Yimaxin and Utrogestan under vaginal administration route were 252.15 and 115.46, respectively, with a ratio of 2.19, and under oral administration route were 244.64 and 413.68, respectively, with a ratio of 0.59. The Geomeans of Cmax of Yimaxin and Utrogestan under vaginal administration route were 28.11 and 12.21, respectively, with a ratio of 2.30, and under oral administration route were 53.12 and 129.85, respectively, with a ratio of 0.41. Conclusion: Yimaxin was not bioequivalent to Utrogestan. Yimaxin had higher exposure to the drug in vivo at the same dose when administered vaginally, and Utrogestan had higher exposure to the drug in vivo at the same dose when administered orally. doi: https://doi.org/10.12669/pjms.37.7.3949 How to cite this:Wang H, Liu M, Chen R, Deng C. Clinical Re-evaluation on Bioequivalence and Relative Bioavailability of Micronized Progesterone Hard Capsule (Yimaxin) and Micronized Progesterone Soft Capsule (Utrogestan) under Vaginal and Oral Administration Routes. Pak J Med Sci. 2021;37(7):---------. doi: https://doi.org/10.12669/pjms.37.7.3949 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Subcutaneous progesterone versus vaginal progesterone for luteal phase support in in vitro fertilization: A retrospective analysis from daily clinical practice

Objective: Progesterone application for luteal phase support is a well-established concept in in vitro fertilization (IVF) treatment. Water-soluble subcutaneous progesterone injections have shown pregnancy rates equivalent to those observed in patients receiving vaginal administration in randomized controlled trials. Our study aimed to investigate whether the results from those pivotal trials could be reproduced in daily clinical practice in an unselected patient population.Methods: In this retrospective cohort study in non-standardized daily clinical practice, we compared 273 IVF cycles from 195 women undergoing IVF at our center for luteal phase support with vaginal administration of 200 mg of micronized progesterone three times daily or subcutaneous injection of 25 mg of progesterone per day.Results: Various patient characteristics including age, weight, height, number of oocytes, and body mass index were similar between both groups. We observed no significant differences in the clinical pregnancy rate (CPR) per treatment cycle between the subcutaneous (39.9%) and vaginal group (36.5%) (p=0.630). Covariate analysis showed significant correlations of the number of transferred embryos and the total dosage of stimulation medication with the CPR. However, after adjustment of the CPR for these covariates using a regression model, no significant difference was observed between the two groups (odds ratio, 0.956; 95% confidence interval, 0.152–1.786; p=0.888).Conclusion: In agreement with randomized controlled trials in study populations with strict selection criteria, our study determined that subcutaneous progesterone was equally effective as vaginally applied progesterone in daily clinical practice in an unselected patient population.

Recent Advances in Polymer-Based Vaginal Drug Delivery Systems

The vagina has been considered a potential drug administration route for centuries. Most of the currently marketed and investigated vaginal formulations are composed with the use of natural or synthetic polymers having different functions in the product. The vaginal route is usually investigated as an administration site for topically acting active ingredients; however, the anatomical and physiological features of the vagina make it suitable also for drug systemic absorption. In this review, the most important natural and synthetic polymers used in vaginal products are summarized and described, with special attention paid to the properties important in terms of vaginal application. Moreover, the current knowledge on the commonly applied and innovative dosage forms designed for vaginal administration was presented. The aim of this work was to highlight the most recent research directions and indicate challenges related to vaginal drug administrations. As revealed in the literature overview, intravaginal products still gain enormous scientific attention, and novel polymers and formulations are still explored. However, there are research areas that require more extensive studies in order to provide the safety of novel vaginal products.

Comparison of Various Progesterone Drugs in Reducing Miscarriages

Background: Threatened abortion is a common complication of pregnancy. In order to prevent miscarriage progesterone in various forms is administered in patients. This is done to allow pregnancy to proceed further beyond twenty week of gestation. Aim: To compare gravibinan (injected) with utrogestan/cyclogest (intra vaginal administration) in reduction of miscarriages. Study design: Case control study Place and duration of study: Department of Obstetrics & Gynecologiy, Mohtrama Benzair Bhutto Shaheed Medical College Mirpur and Department of Pediatric, Shaikh Zayed Hospital Lahore from 1st April 2020 to 30th September 2020. Methodology: Pregnant women, who had vaginal bleeding until 20 weeks of their pregnancy, were assessed for inclusion. Participants were divided into three groups. Group A was given gravibinan, Group B was given utrogestan and Group C was given cyclogest. Results: Women infested with gravibinan had 20% those who still had miscarriage while the number of miscarriages significantly decreased to 14.2% in utrogestan group and 13.63% in cyclogest group (p<0.005). Conclusion: Cyclogest proved a better drug of choice for reducing miscarriages. Keywords: Miscarriages, progesterone, pregnancy

Effective, safe and rational pharmacotherapy of endogenic progesterone deficiency

Today, the most frequent complication of pharmacotherapy is an allergic reaction, the so-called drug or drug allergy. An allergic reaction can be caused both by the active ingredients and by the excipients included in the composition of the drug to provide a certain dosage form and its physicochemical properties. Vaginal progesterone preparations are characterized by a large variety of dosage forms: gels, tablets and gelatin capsules for intravaginal administration. It is known that the safety and efficacy of pharmacotherapy depend on the active substance, the dosage form, and the base of the intravaginal preparation, as well as the indices of adherence to medication therapy. At the same time, the base - excipients can cause the development of adverse reactions.The authors of the article, based on an analytical review of domestic and foreign literature, analyzed effective, safe and rational pharmacotherapy of endogenous progesterone deficiency.It is shown that micronization is currently used to improve the bioavailability of natural progesterone – a method of increasing solubility by reducing the particle size of the drug substance. Due to the high solubility of the substance, the risk of possible side effects is reduced, which allows increasing the safety of the drug.The peculiarity of the dosage form for vaginal administration is described. On the basis of the analysis of various forms of progesterone, the clinical efficacy of natural progesterone for vaginal administration has been substantiated.The authors found that the use of progesterone in sublingual and vaginal forms is the most rational in terms of convenience, efficacy and safety.

Electrospun fibers for vaginal administration of tenofovir disoproxil fumarate and emtricitabine in the context of topical pre-exposure prophylaxis

Women are particularly vulnerable to sexual HIV-1 transmission. Oral pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) is highly effective in avoiding new infections in men, but protection has only been shown moderate in women. Such differences have been associated, at least partially, to poor drug penetration of the lower female genital tract and the need for strict adherence to continuous daily oral intake of TDF/FTC. On-demand topical microbicide products could help circumventing these limitations. We developed electrospun fibers based on polycaprolactone (PCL fibers) or liposomes associated to poly(vinyl alcohol) (liposomes-in-PVA fibers) for the vaginal co-delivery of TDF and FTC, and assessed their pharmacokinetics in mice. PCL fibers and liposomes-in-PVA fibers were tested for morphological and physicochemical properties using scanning electron microscopy, differential scanning calorimetry and X-ray diffractometry. Fibers featured organoleptic and mechanical properties compatible with their suitable handling and vaginal administration. Fluorescent quenching of mucin in vitro – used as a proxy for mucoadhesion – was intense for PCL fibers, but mild for liposomes-in-PVA fibers. Both fibers were shown safe in vitro and able to rapidly release drug content (15-30 min) under sink conditions. Liposomes-in-PVA fibers allowed increasing genital drug concentrations after a single intravaginal administration when compared to continuous daily treatment with 25-times higher oral doses. For instance, the levels of tenofovir and FTC in vaginal lavage were around 4- and 29-fold higher, respectively. PCL fibers were also superior to oral treatment, although to a minor extent (approximately 2-fold higher drug concentrations in lavage). Vaginal tissue drug levels were generally low for all treatments, while systemic drug exposure was negligible in the case of fibers. These data suggest that proposed fibers may provide an interesting alternative or an ancillary option to oral PrEP in women.