Size-dependent biodistribution of thiol-organosilica nanoparticles and F4/80 protein expression in the genital tract of female mice after intravaginal administration.

Recently the vaginal route consider as an ideal route for drug delivery systems (DDS) administration. This is because, it is suitable for lower drug dosage, higher drug concentration in the genital tract tissues and lower drug concentration in pregnant women blood circulation. However, the vaginal route administration faces many challenges due to the physiology as well as the complexity of vaginal tissue histology. Here in this study, during diestrus stage (optimal condition for foreign substance internalization), single or dual size of fluorescent thiol-organosilica nanoparticles (tOS-NPs) were administrated intravaginally. The biodistribution and reactivity of tOS-NPs in different tissues of the female genital tract were investigated under the fluorescence microscope. Furthermore, using immunohistochemical staining, the expression of F4/80 protein and the role of macrophages in transport and re-location of tOS-NPs from vaginal lumen into different genital tissues or other organs were investigated. This study showed that, tOS-NPs size and type of tissue are important in biodistribution and uptake of tOS-NPs in the genital tract. Small size (100 nm) of tOS-NPs was highly accumulated in the genital tract tissues especially endometrial epithelium compared with large tOS-NPs (1000 nm). Contradictory, the large size induced the expression of F4/80 protein and the number of vaginal macrophages compared with small size. However, both small and large sizes of tOS-NPs were found co-localized with F4/80+ macrophages, located in the vaginal, endometrial and ovarian tissues. The tOS-NPs intravaginally administrated were found in the splenic tissues, indicating its ability to enter the blood circulation from the vaginal lumen. Additionally, the high accumulation of tOS-NPs in the endometrial epithelium indicated the endometrial first pass effect of tOS-NPs. As a result, high concentration of tOS-NPs in the endometrial epithelium may reduce the concentration of tOS-NPs-based DDS in the blood circulation and their side effects. Furthermore, during vaginal tissue optimal condition (diestrus stage), understanding the fate and biodistribution of tOS-NPs will introduce important data about the development of save and effective DDS for the pregnant women.

Emulsion-Based Multicompartment Vaginal Drug Carriers: From Nanoemulsions to Nanoemulgels.

In order to overcome the limitations associated with vaginal administration of drugs, e.g., the short contact time of the drug form with the mucosa or continuous carrier wash-out, the development of new carriers for gynecological use is necessary. Furthermore, high individual anatomical and physiological variability resulting in unsatisfactory therapeutic efficacy of lipophilic active substances requires application of multicompartment drug delivery systems. This manuscript provides an up-to-date comprehensive review of the literature on emulsion-based vaginal dosage forms (EVDF) including macroemulsions, microemulsions, nanoemulsions, multiple emulsions and self-emulsifying drug delivery systems. The first part of the paper discusses (i) the influence of anatomical-physiological conditions on therapeutic efficacy of drug forms after local and systemic administration, (ii) characterization of EVDF components and the manufacturing techniques of these dosage forms and (iii) methods used to evaluate the physicochemical and pharmaceutical properties of emulsion-based vaginal dosage forms. The second part of the paper presents (iv) the results of biological and in vivo studies as well as (v) clinical evaluation of EVDF safety and therapeutic efficacy across different indications.

Ovarian Folliculogenesis and Uterine Endometrial Receptivity after Intermittent Vaginal Injection of Recombinant Human Follicle-Stimulating Hormone in Infertile Women Receiving In Vitro Fertilization and in Immature Female Rats.

The uterine first-pass effect occurs when drugs are delivered vaginally. However, the effect of vaginally administered recombinant human follicle-stimulating hormone (rhFSH) on ovarian folliculogenesis and endometrial receptivity is not well established. We aimed to compare the efficacy of rhFSH administered vaginally and abdominally in clinical in vitro fertilization (IVF) treatment, pharmacokinetic study, and animal study. In IVF treatment, the number of oocytes retrieved, endometrial thickness and uterine artery blood perfusion were not different between women who received the rhFSH either vaginally or abdominally. For serum pharmacokinetic parameters, significantly lower Tmax, clearance, and higher AUC and T1/2_elimination of rhFSH were observed in women who received rhFSH vaginally, but urine parameters were not different. Immature female rats that received daily abdominal or vaginal injections (1 IU twice daily for 4 days) or intermittent vaginal injections (4 IU every other day for two doses) of rhFSH had more total follicles than the control group. In addition, the serum progesterone and progesterone receptors in the local endometrium were significantly higher in the groups treated with intermittent abdominal or vaginal injection of rhFSH, compared with those who recieved daily injection. In summary, vaginal administration of rhFSH may provide an alternative treatment regimen in women receiving IVF.

[Rheology and in vitro release properties of thermosensitive in situ gel of Yihuang Decoction and its common gel for vaginal use].

To evaluate the traits and rheological properties of thermosensitive in situ gel of Yihuang Decoction and its common gel for vaginal use, and predict the release behavior of Yihuang Decoction in situ gel in vitro. Poloxamer was used as thermosensitive material to prepare Yihuang Decoction vaginal in situ gel, and Yihuang Decoction common gel was prepared with carbopol. Then the differences of the two gels before and after diluting with vaginal fluid were compared. The rheological parameters of Yihuang Decoction in situ gel and its common gel were determined with Anton Paar MCR102 rheometer. In addition, berberine hydrochloride was selected as an index component to evaluate the in vitro release properties of Yihuang Decoction vaginal thermosensitive in situ gel. Yihuang Decoction vaginal thermosensitive in situ gel was Newtonian fluid under low-temperature conditions, which was yellow and transparent. After reaching the gelling temperature of 24.5 ℃, it became semi-solid, pseudoplastic fluid. The gelling temperature was predicted to be 37 ℃, and the phase transition time was 30 s after diluting with simulated vaginal fluid. However, the rheological properties of Yihuang Decoction common gel had no significant changes with temperature. Compared with in situ gel, the color of common gel was darker and more translucent. Besides, its mobility was stronger after diluting with simulated vaginal fluid. The in vitro release study showed that the kinetic behavior of berberine hydrochloride in Yihuang Decoction vaginal thermosensitive in situ gel was matched with the Higuchi equation. Through simulation of vaginal administration, physical properties and dynamic rheological parameters were used to intuitively and scientifically evaluate the two gels. Compared with the common gel, the thermosensitive in situ gel could quickly attached to the vaginal mucosa and release drug, and thus was more suitable for developing vaginal administration of Yihuang Decoction, which also provides references for studying new vaginal preparation of Yihuang Decoction.

Mucoadhesive In Situ Gelling Liquid Crystalline Precursor System to Improve the Vaginal Administration of Drugs.

The vaginal mucosa is a very promising route for drug administration due to its high permeability and the possibility to bypass first pass metabolism; however, current vaginal dosage forms present low retention times due to their dilution in vaginal fluids, which hampers the efficacy of many pharmacological treatments. In order to overcome these problems, this study proposes to develop a mucoadhesive in situ gelling liquid crystalline precursor system composed of 30% of oleic acid and cholesterol (7:1), 40% of ethoxylated and propoxylated cetyl alcohol, and 30% of a dispersion of 16% Poloxamer 407. The effect of the dilution with simulated vaginal fluid (SVF) on this system was evaluated by polarized light microscopy (PLM), small-angle X-ray scattering (SAXS), rheological studies, texture profile analysis (TPA), mucoadhesion study, in vitro drug release test using hypericin (HYP) as drug model, and cytotoxicity assay. PLM and SAXS confirmed the formation of an isotropic system. After the addition of three different concentrations of SVF (30, 50, and 100%), the resultant formulations presented anisotropy and characteristics of viscous lamellar phases. Rheology shows that formulations with SVF behaved as a non-Newtonian fluid with suitable shear thinning for vaginal application. TPA and mucoadhesion assays indicated the formation of long-range ordered systems as the amount of SVF increases which may assist in the fixation of the formulation on the vaginal mucosa. The formulations were able to control about 75% of the released HYP demonstrating a sustained release profile. Finally, all formulations acted as safe vaginal drug delivery systems.

Optimal Dose of Vaginal Misoprostol for Cervical Ripening before Hysteroscopy: A Randomized Double-Blind Study.

STUDY OBJECTIVE: To evaluate the optimal dose of vaginal misoprostol (200 and 400 µg) for cervical priming before operative hysteroscopy. DESIGN: A randomized, controlled, double-blind trial (Canadian Task Force classification I). SETTING: A university hospital. PATIENTS: Sixty-eight patients undergoing operative hysteroscopy. INTERVENTIONS: Patients were randomized to receive a low (200 µg) or high (400 µg) dose of misoprostol administered vaginally 8 hours before operative hysteroscopy. MEASUREMENTS AND MAIN RESULTS: The primary outcome was perioperative dilatation time, and the secondary outcome measurements included the subjective difficulty of cervical dilatation assessed by the surgeon, operative time, self-reported adverse events after vaginal administration and before the start of the operation, and complications during the procedure. A comparison of the 200-µg (n = 34) and 400-µg (n = 34) misoprostol cohorts revealed similarities when comparing time with cervical dilatation, operative difficulty, result, and time. Misoprostol-related adverse events were significantly lower in the 200-µg cohort than the 400-µg cohort (58.8% vs 85.3%, p = .015). Abdominal pain was the most common adverse event and was higher in the 400-µg cohort compared with the 200-µg cohort (73.5% vs 50.0%, p = .046). However, there were no operative delays resulting from adverse events, and all individuals reported the procedure to be tolerable and recovered without medication or treatment. CONCLUSION: Both 200 µg and 400 µg vaginally administered misoprostol are effective for cervical dilatation, and we recommend vaginal administration of 200 µg misoprostol for cervical dilatation 8 hours before operative hysteroscopy because of lower adverse events in the 200-µg group as well as similar efficacy between cohorts.

Effectiveness of high-dose transvaginal progesterone supplementation for women who are undergoing a frozen-thawed embryo transfer.

PURPOSE: To evaluate the effectiveness of high-dose progesterone supplementation for women who are undergoing a frozen-thawed embryo transfer (FET). METHODS: Among the 2010 FET cycles that were included in the present study, 1188 were 1200 mg/d of vaginal progesterone, while 822 were 900 mg/d. The dose of progesterone that was used was decided by the treatment period and additional progesterone supplementation was used when the serum progesterone levels were <9 ng/mL on luteal day 5. RESULTS: The clinical pregnancy rate was higher in the 1200 mg group than in the 900 mg group. The mean serum progesterone level on luteal day 5 in the 1200 mg and 900 mg groups was 12.6 ng/mL and 13.4 ng/mL, respectively. The rate of additional progesterone supplementation was higher in the 1200 mg group. A logistic regression analysis identified a younger age (≤37 years) and the use of 1200 mg progesterone as independent predictive factors for the clinical pregnancy outcome. The analysis of the infant outcomes revealed no significant difference in the distribution of birth ages and weights. CONCLUSION: High-dose transvaginal progesterone of 1200 mg/d as luteal support contributed to good pregnancy outcomes.

Chitosan Ascorbate Nanoparticles for the Vaginal Delivery of Antibiotic Drugs in Atrophic Vaginitis.

The aim of the present work was the development of chitosan ascorbate nanoparticles (CSA NPs) loaded into a fast-dissolving matrix for the delivery of antibiotic drugs in the treatment of atrophic vaginitis. CSA NPs loaded with amoxicillin trihydrate (AX) were obtained by ionotropic gelation in the presence of pentasodium tripolyphosphate (TPP). Different CSA:TPP and CSA:AX weight ratios were considered and their influence on the particle size, polydispersion index and production yield were investigated. CSA NPs were characterized for mucoadhesive, wound healing and antimicrobial properties. Subsequently, CSA NPs were loaded in polymeric matrices, whose composition was optimized using a DoE (Design of Experiments) approach (simplex centroid design). Matrices were obtained by freeze-drying aqueous solutions of three hydrophilic excipients, polyvinylpirrolidone, mannitol and glycin. They should possess a mechanical resistance suitable for the administration into the vaginal cavity and should readily dissolve in the vaginal fluid. In addition to antioxidant properties, due to the presence of ascorbic acid, CSA NPs showed in vitro mucoadhesive, wound healing and antimicrobial properties. In particular, nanoparticles were characterized by an improved antimicrobial activity with respect to a chitosan solution, prepared at the same concentration. The optimized matrix was characterized by mechanical resistance and by the fast release in simulated vaginal fluid of nanoparticles characterized by unchanged size.

Biological Effects of Drug-Free Alginate Beads Cross-Linked by Copper Ions Prepared Using External Ionotropic Gelation.

External ionotropic gelation offers a unique possibility to entrap multivalent ions in a polymer structure. The aim of this experimental study was to prepare new drug-free sodium alginate (ALG) particles cross-linked by Cu2+ ions and to investigate their technological parameters (particle size, sphericity, surface topology, swelling capacity, copper content, release of Cu2+ ions, mucoadhesivity) and biological activity (cytotoxicity and efficiency against the most common vaginal pathogens-Herpes simplex, Escherichia coli, Candida albicans) with respect to potential vaginal administration. Beads prepared from NaALG dispersions (3 or 4%) were cross-linked by Cu2+ ions (0.5 or 1.0 M CuCl2) using external ionotropic gelation. Prepared mucoadhesive beads with particle size over 1000 µm exhibited sufficient sphericity (all ˃0.89) and copper content (214.8-249.07 g/kg), which increased with concentration of polymer and hardening solution. Dissolution behaviour was characterized by extended burst effect, followed by 2 h of copper release. The efficiency of all samples against the most common vaginal pathogens was observed at cytotoxic Cu2+ concentrations. Anti-HSV activity was demonstrated at a Cu2+ concentration of 546 mg/L. Antibacterial activity of beads (expressed as minimum inhibition concentration, MIC) was influenced mainly by the rate of Cu2+ release which was controlled by the extent of swelling capacity. Lower MIC values were found for E. coli in comparison with C. albicans. Sample ALG-3_1.0 exhibited the fastest copper release and was proved to be the most effective against both bacteria. This could be a result of its lower polymer concentration in combination with smaller particle size and thus larger surface area.

Aerosolized Non-viral Nucleic Acid Delivery in the Vaginal Tract of Pigs.

PURPOSE: The human pathogen Chlamydia trachomatis is worldwide the leading cause of bacterial sexually transmitted disease. Nasal or vaginal nucleic acid vaccination is a promising strategy for controlling genital Chlamydia trachomatis infections. Since naked nucleic acids are generally not efficiently taken up by cells, they are often complexed with carriers that facilitate their intracellular delivery. METHODS: In the current study, we screened a variety of commonly used non-viral gene delivery carriers for their ability to transfect newborn pig tracheal cells. The effect of aerosolization on the physicochemical properties and transfection efficiency of the complexes was also evaluated in vitro. Subsequently, a pilot experiment was performed in which the selected complexes were aerosolized in the vaginal tract of pigs. RESULTS: Both mRNA and pDNA containing lipofectamine and ADM70 complexes showed promise for protein expression in vitro, before and after aerosolization. In vivo, only lipofectamine/pDNA complexes resulted in high protein expression levels 24 h following aerosolization. This correlates to the unexpected observation that the presence of vaginal mucus increases the efficiency of lipofectamine/pDNA complexes 3-fold, while the efficiency of lipofectamine/mRNA complexes and ADM70/mRNA and ADM70/pDNA complexes decreased. CONCLUSIONS: As aerosolization was an easy and effective method to deliver complexes to the vaginal tract of pigs, we believe this application technique has future potential for both vaginal and perhaps nasal vaccination using non-viral gene delivery vectors.

Sublingual versus vaginal misoprostol for cervical dilatation 1 or 3 h prior to surgical abortion: a double-blinded RCT.

STUDY QUESTION: Can sublingual administration of misoprostol 1 h prior to vacuum aspiration be more effective than vaginal administration and as effective as either route three 3 h prior to surgery? SUMMARY ANSWER: Sublingually administered misoprostol is superior to vaginally administered misoprostol when given 1 h pre operatively, and it is as effective as after a three 3 h priming interval with either route of administration. WHAT IS KNOWN ALREADY: Misoprostol reduces complications and morbidity when used for cervical priming prior to surgical dilatation and vacuum aspiration in first trimester pregnancy. Despite the widespread use and extensive studies, the optimal route of administration of misoprostol before surgical abortion remains to be defined. The optimal priming interval after vaginal and sublingual administration of 400 mcg misoprostol has been reported to be 3 h. A longer interval will not improve dilatation but will increase the risk for bleeding and expulsion of the uterine contents before surgical evacuation. The pharmacokinetic properties of misoprostol indicate that sublingual compared with vaginal administration of misoprostol may result in a more rapid cervical priming effect. STUDY DESIGN, SIZE, DURATION: Women were randomized to four treatment groups and received 400 mcg misoprostol sublingually, or vaginally, 1 or 3 h prior to surgery. The study was a double-blinded RCT with regard to route of misoprostol administration but not the timing interval. The primary outcome was baseline cervical dilatation after misoprostol priming. The study was conducted between June 2007 and March 2014 and 184 women aged 18 years or older were recruited. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women were recruited among nulliparous women undergoing elective surgical first trimester abortion. Exclusion criteria were any contraindication for misoprostol, untreated genital infection, previous history of surgery to the cervix, or abnormal pregnancy. Gestational age was established by endovaginal ultrasound examination. The trial was conducted in a university hospital outpatient clinic. The allocated medication (misoprostol and placebo) was self-administered 1 h or 3 h prior to surgery. All women received 2 tablets of 200 mcg misoprostol and 2 identical looking placebo tablets. Prophylactic pain medication, 100 mg oral diclofenac, was administered at the time of misoprostol. Side effects were recorded immediately before surgery and women were asked which administration route of administration they found most convenient and which they would have preferred. The exact priming time (from misoprostol administration to initiation of dilatation) and signs of bleeding prior to dilatation were recorded. Vacuum aspiration was performed under general anaesthesia according to clinical routine. Dilatation was performed using tapered Pratt-dilatators and the resistance of the cervix was assessed objectively using a tonometer. All surgery was performed by two investigators, experienced in using the tonometer. The cumulative force required to dilate the cervix was calculated by adding the peak force needed for each dilatator up to 9.7 mm. The time needed for surgery including cervical dilatation and vacuum aspiration, was recorded. Intra-operative blood loss was measured and any surgical complications noted. MAIN RESULTS AND THE ROLE OF CHANCE: Six women were excluded retrospectively from the analysis. Multivariate analysis of the primary outcome baseline dilatation showed a significant influence on route of administration (P = 0.034, 95% confidence interval (CI) -2.202, -0.086) as well as the interaction variable between route of administration and total priming time (P = 0.042, 95% CI 0.00, 0.016), with the vaginal route becoming more effective with longer priming time. These factors also had a significant influence on the peak force (administration route P = 0.042, 95% CI 0.221, 12.427, interaction P = 0.049, 95% CI -0.089, 0.000) and cumulative force (administration route P = 0.023, 95% CI 3.142, 40.877, interaction P = 0.026, 95% CI -0.293, -0.019) used for dilatation. The total priming time had a significant influence on bleeding before surgery, with more women bleeding the longer the total priming time (P = 0.003, 95% CI 2.203, 49.706). For abdominal pain before surgery there was a significant influence of administration route (P = < 0.001 95% CI 0.028, 0.235) and the interaction variable between administration route and priming time (P = 0.003, 95% CI 2.005, 30.757) with more women in the sublingual group experiencing abdominal pain the longer the priming time. The groups did not differ regarding duration of surgery, amount of bleeding and rate of side effects, such as nausea and shivering. Women in our study preferred vaginal treatment, as they disliked the taste of the misoprostol tablets. Vaginal treatment was also perceived as quicker to administer (P = 0.0001). LIMITATIONS, REASONS FOR CAUTION: The cervical tissue has viscoelastic properties, i.e. tissue resistance to mechanical dilatation depends also on the rate at which dilatation is performed. The ideal measurement of dilatation force should therefore also record the rate and time of dilatation. To ensure comparability, only nulliparous women without prior cervical surgery were recruited. In addition, time of dilatation was recorded and did not differ between the groups, and it is therefore assumed that dilatation took place at approximately the same rate. A limitation is that the study was conducted over a long time period because there was only one tonometer, decreasing numbers of surgical abortions and the fact that the main author was on a rotation schedule. In addition, the study was not powered to detect differences in side effects. WIDER IMPLICATIONS OF FINDINGS: Priming with misoprostol is recommended prior to surgical abortion. The priming interval of misoprostol may be reduced to 1 h after sublingual administration but not after vaginal administration. The results of the present study will increase choice and flexibility in cervical priming. STUDY FUNDING/COMPETING INTERESTS: The Swedish research council (521-2009-2605), Swedish Council for Working Life and Social Research (1404/08), Stockholm County Council and Karolinska Institutet (ALF 2009-2012). All authors declare that they have no conflicts of interest. TRIAL REGISTRATION NUMBER: www.clincaltrials.gov, NCT 01933360.

Vaginally Administered Danazol: An Overlooked Option in the Treatment of Rectovaginal Endometriosis?

Danazol has been used in the treatment of endometriosis and heavy menstrual bleeding for more than 40 years. This medication has both central antigonadotropic actions and direct atrophic effects on endometriotic tissue. Although it demonstrates a high-efficacy profile, the associated side effects have resulted in limited usage. Vaginal administration of the drug may prove favourable specifically in rectovaginal endometriosis. This targeted mode of delivery is associated with a significant reduction in both pain symptoms and nodule size. The relative persistence of these therapeutic benefits is likely related to the direct tissue effects after absorption through the vaginal mucosa. Vaginal administration would also limit systemic propagation of danazol and thus should minimize androgenic side effects. Use of vaginal danazol also improves heavy menstrual bleeding and may even restore fertility in some patients. In this review we provide a critical analysis of the existing literature on the use of vaginal danazol.

Le danazol est utilisé dans la prise en charge de l'endométriose et des saignements menstruels abondants depuis plus de 40 ans. Ce médicament exerce tant des effets antigonadotropes centraux que des effets atrophiques directs sur le tissu endométriotique. Bien qu'il présente un profil solide d'efficacité, les effets indésirables qui lui sont associés en ont limité l'utilisation. L'administration de ce médicament par voie vaginale pourrait s'avérer favorable, particulièrement dans les cas d'endométriose rectovaginale. Ce mode d'administration ciblée est associé à une atténuation significative des symptômes de douleur et de la taille des nodules. La persistance relative de ces avantages thérapeutiques est probablement associée aux effets tissulaires directs qui sont constatés à la suite de l'absorption au travers de la muqueuse vaginale. L'administration par voie vaginale permettrait également de limiter la propagation générale du danazol, ce qui devrait en minimiser les effets indésirables androgéniques. L'utilisation de danazol par voie vaginale entraîne également une atténuation des saignements menstruels abondants et pourrait même restaurer la fertilité chez certaines patientes. Dans le cadre de cet article, nous offrons une analyse critique de la littérature existante sur l'utilisation du danazol par voie vaginale.

Impact of prolonged dinoprostone cervical ripening on the rate of artificial induction of labor: a prospective study of 330 patients.

AIM: The aim of this study was to evaluate two regimens of administration of sustained-release dinoprostone on the need for oxytocin induction of labor. MATERIAL AND METHODS: We carried out an open prospective study comparing labor, maternal and neonatal outcomes after 12 h of prostaglandin cervical ripening insert versus 24 h of prostaglandin cervical ripening insert in 284 patients (142 ripenings at 12 h [P12 group] and 142 ripenings at 24 h [P24 group]). RESULTS: The two groups were demographically similar. There was a significant difference in the need for artificial rupture of membranes/oxytocin induction of labor between the groups (49.3% for the P12 group vs 38% for the P24 group, P = 0.03). The delay between the beginning of ripening and delivery was significantly decreased in the P12 group, but the duration of active labor (6.6 h), the dose of oxytocics used (1326 UI), the rate of cesarean section, the rate of uterine hyperstimulation, the rates of hemorrhaging from delivery, the neonatal state and the experience of induction were similar in the two groups. CONCLUSION: This study allows us to show for the first time that sustained-release of dinoprostone leads to spontaneous induction of labor without increasing the obstetrical risk in a majority of patients.

Resveratrol-loaded microemulsion based thermosensitive hydrogel for potential topical treatment of the vaginal inflammation.

BACKGROUND: Vaginal inflammation is a prevalent gynecological condition. If left untreated, it can potentially spread to the urinary and reproductive systems. METHODS: In this study, we propose a resveratrol-loaded microemulsion-based thermosensitive hydrogel (Res-Me-Tsgel) and compare it with a chitosan hydrogel-based Res-Me-Cogel. We characterized the different characters of Res-Me-Tsgel. The safety of Res-Me-Tsgel was also evaluated in vitro and in vivo. Finally, we measured the retention of Res in the vagina after drug administration. RESULTS: The Res-Me-Tsgel we prepared is a transparent liquid solution at room temperature that rapidly forms a gel at 37oC. Compared to Res solution and Res-Me, both Res-Me-Cogel and Res-Me-Tsgel demonstrate superior sustained release properties. Both in vitro and in vivo studies confirm the excellent biosafety profile of Res-Me-Cogel and Res-Me-Tsgel. Vaginal administration of these formulations in rats results in prolonged retention of resveratrol within the vagina. Notably, due to its improved flow into vaginal folds after administration, the retention of Resveratrol was approximately three times higher for the Res-Me-Tsgel group compared to the Res-Me-Cogel group at 24 h post-administration. Overall, these findings highlight the potential application of Res-Me-Tsgel as an effective means for vaginal inflammation. CONCLUSIONS: We developed a novel micromulsion based thermosensitive hydrogel for the delivery of Res. The sustained release of Res and favorable vaginal retention from Res-Me-Tsgel make them promise as a potential candidate for local intravaginal therapy.

Efficacy and safety of oral and vaginal administration of misoprostol for induction of labor in high-risk obese pregnant women with hypertension or diabetes mellitus.

OBJECTIVE: This study aims to compare the safety and efficacy of misoprostol administered orally and vaginally in obese pregnant women at term with either gestational hypertension or diabetes. METHODS: A total of 264 pregnant women were enrolled and categorized into two groups based on their primary condition: hypertension (134 cases) or diabetes mellitus (130 cases) and were further divided into subgroups for misoprostol administration: orally (Oral group) or vaginally (Vaginal group). The primary outcomes measured were changes in the Bishop score following treatment, induction of labor (IOL) success rates, requirement for oxytocin augmentation, duration of labor, mode of delivery, and cesarean section rates. RESULTS: Significant enhancements in Bishop scores, decreased cesarean section rates and increased success rates of IOL were noted in both administration groups. The incidence of vaginal delivery within 24 h was significantly higher in the Vaginal group compared to the Oral group. Adverse effects, including nausea, uterine overcontraction, hyperfrequency of uterine contraction and uterine hyperstimulation without fetal heart rate deceleration, were significantly more prevalent in the Vaginal group than in the Oral group. CONCLUSION: Misoprostol administration, both orally and vaginally, proves effective for labor induction in obese pregnant women with hypertension or diabetes. However, the oral route presents a lower risk of adverse maternal and neonatal outcomes, suggesting its preference for safer labor induction in this demographic.

Comparing the effects of low-dose contraceptive pills to control dysfunctional uterine bleeding by oral and vaginal methods.

UNLABELLED: Background and Objective : Contraceptive pills are generally taken orally and can cause side effects such as nausea, vomiting and hypertension. The vaginal use of these pills can reduce such complications. Our objective was to compare the efficacy and side effects of low dose contraceptive pills by oral and vaginal route in the management of dysfunctional uterine bleeding-(DUB) Methods: This comparative observational study was conducted at Beheshti and Alzahra (SA) teaching hospitals, affiliated to Isfahan University of Medical Sciences in 2010-2011. One hundred women who presented with DUB were randomly assigned into two groups of equal number, receiving the low dose oral contraceptive pills by oral or vaginal route for three month. The amount and duration of bleeding were compared at the beginning and at the end of the study and side effects by these two methods compared. RESULTS: The results of this study showed that both oral and vaginal routes effectively reduced the duration and amount of bleeding due to DUB after three courses of treatment. This effect was better in the vaginal method compared with oral administration (P = 0.03). Regarding the side effects, nausea and vomiting were significantly higher in the oral group than in the vaginal group (P = 0.03). Vulvovaginitis infection was more frequent in the vaginal group than in the oral group (P = 0.03). CONCLUSION: Low dose contraceptive pills are effective in reducing the amount, time, and duration of bleeding in patients with DUB. In addition, reduction of gastrointestinal side effects by vaginal route helps to use these pills by the patient with proper training of physicians, midwives and patients.

pH-triggered polymeric nanoparticles in gel for preventing vaginal transmission of HIV and unintended pregnancy.

Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/ AIDS) and unplanned pregnancy affect female reproductive health globally. A single product providing a dual purpose of HIV prophylaxis and contraception may improve adherence to the therapy. Thus, we formulated a female-centric multipurpose prevention technology (MPT) comprising of nanoparticle loaded vaginal gel formulation acting as a contraceptive and microbicide. Eudragit® S100 nanoparticles of Atazanavir sulphate (ATZ; antiviral) and Fluoxetine hydrochloride (FLX; repurposed spermicide) were prepared for pH dependent drug release and loaded in carrageenan and HPMC K200M gel. The particle size of ATZ and FLX nanoparticles was 396.7 ± 20.64 nm and 226.5 ± 2.08 nm respectively. The in vitro release of the gel formulation in simulated seminal fluid (pH 7.6) showed 96.16% and 95.98% release of ATZ and FLX respectively at the end of 8 h. The in vitro anti-HIV and spermicidal activity of the formulation was above 80% for low drug concentrations. In vivo studies on murine model showed no signs of inflammation or vaginal epithelial injury. Curcumin based imaging confirmed the retention of the formulation in the reproductive tract of mice with minimal leakage. Nanoparticles in gel enabled non-invasive and localised delivery with minimal side effects and can be an effective prophylactic therapy.

The Potential of Films as Transmucosal Drug Delivery Systems.

Pharmaceutical films are polymeric formulations used as a delivery platform for administration of small and macromolecular drugs for local or systemic action. They can be produced by using synthetic, semi-synthetic, or natural polymers through solvent casting, electrospinning, hot-melt extrusion, and 3D printing methods, and depending on the components and the manufacturing methods used, the films allow the modulation of drug release. Moreover, they have advantages that have drawn interest in the development and evaluation of film application on the buccal, nasal, vaginal, and ocular mucosa. This review aims to provide an overview of and critically discuss the use of films as transmucosal drug delivery systems. For this, aspects such as the composition of these formulations, the theories of mucoadhesion, and the methods of production were deeply considered, and an analysis of the main transmucosal pathways for which there are examples of developed films was conducted. All of this allowed us to point out the most relevant characteristics and opportunities that deserve to be taken into account in the use of films as transmucosal drug delivery systems.

Evaluation of vaginal brachytherapy for treating early-stage endometrial cancer according to the European Society of Medical Oncology 2020 risk stratification.

Objective: The aim was to evaluate vaginal brachytherapy (VB) after surgery in early-stage endometrial cancer. Materials and Methods: The patients with Stage I-II endometrial adeno-cancer operated between 1998 and 2018 and whose adjuvant therapies had been arranged were evaluated retrospectively. Results: A total of 618 patients were enrolled. In 409 patients in the low-risk group, the vaginal, pelvic recurrence, and distant metastasis rates were found to be higher in the VB group. When the results of 112 patients in the intermediate-risk group were evaluated, there was no statistically significant difference between the vaginal, pelvic recurrence, and distance metastasis rates. In 89 patients in the intermediate-high risk group, vaginal recurrence rates were 0%, 4.8%, 0%, and 25% for VB, external beam radiotherapy, combination radiotherapy, and the follow-up groups, respectively (p=0.010), and pelvic recurrence rates were found to be 18.2%, 0%, 1.9% and 0% (p=0.036). Distant metastasis rates were 0%, 0%, 9.6% and 0% (p=0.229). When the overall survival in all groups was examined, no significant difference was found between the groups. Conclusion: In conclusion, no adjuvant treatment is a proper approach for low-risk patients. Brachytherapy can be considered a suitable option for the intermediate risk group. Combined treatments instead of VB in the high-intermediate risk group would be preferred in terms of local control.

Vaginal progesterone for preterm birth prevention in women with arrested preterm labor.

OBJECTIVE: We tested the hypothesis that administration of vaginal progesterone in women with arrested preterm labor would result in lower rates of preterm birth <37 weeks compared to placebo. STUDY DESIGN: We performed a randomized, placebo-controlled trial comparing vaginal progesterone to placebo in women with arrested preterm labor. Our trial included women with a singleton or twin gestation at 240/7-336/7 weeks' gestation who presented with preterm labor with cervical dilation ≥1 centimeter but remained undelivered. Participants were randomized to receive vaginal progesterone 200 mg daily or an identical placebo. The primary outcome was preterm birth <37 weeks. We performed an updated systematic review and meta-analysis of clinical trials, including our results. We searched MEDLINE, EMBASE, CINHAL, Scopus, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov using the key terms to identify relevant trials. The risk of bias was appraised using the Cochrane risk-of-bias tool. Data were synthesized using random-effects models. Heterogeneity was assessed using Higgins I2. RESULTS: The randomized trial was prematurely terminated due to slow recruitment. There were 18 women randomized to receive vaginal progesterone who had complete follow-up data and 18 women in the placebo group. The risk of preterm birth <37 weeks was not significantly different in the groups (RR 1.10, 95% CI 0.63-1.19). Secondary outcomes were also similar. Thirteen trials with 1658 women (835 in the vaginal progesterone and 823 in the control groups) were included in the meta-analysis. Risk of preterm birth <37 weeks was similar in women who received progesterone and those in the control group (pooled RR 1.06, 95% CI 0.83-1.35). Latency was significantly longer among women with arrested preterm labor who received vaginal progesterone (weighted mean difference: 9.2 d, 95% CI 3.2-15.1), but further analysis showed that prolonged latency was only observed in the subgroup of studies that were not placebo-controlled. CONCLUSIONS: This randomized controlled trial and meta-analysis do not support the use of vaginal progesterone for the prevention of preterm birth in women who present in preterm labor.