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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., На сегодня наиболее частым осложнением фармакотерапии является аллергическая реакция, так называемая лекарственная, или медикаментозная, аллергия. Аллергическую реакцию могут вызывать как действующие вещества, так и вспомогательные компоненты, входящие в состав препарата для обеспечения определенной лекарственной формы и его физико-химических свойств. Для вагинальных препаратов прогестерона характерно большое разнообразие лекарственных форм: гели, таблетки и желатиновые капсулы для интравагинального введения. Известно, что безопасность и эффективность фармакотерапии зависят от активного действующего вещества, лекарственной формы и основы препарата для интравагинального введения, а также показателей приверженности медикаментозной терапии. В то же время основа (вспомогательные вещества) может служить причиной развития побочных реакций.Авторами статьи на основе аналитического обзора отечественной и зарубежной литературы проанализирована эффективная, безопасная и рациональная фармакотерапия эндогенного дефицита прогестерона.Показано, что для улучшения биодоступности натурального прогестерона сегодня применяется микронизация – способ повышения растворимости с помощью уменьшения размера частиц лекарственного вещества. Благодаря высокой степени растворимости вещества снижается риск возможных побочных эффектов, что позволяет увеличить безопасность препарата.Описана особенность лекарственной формы для вагинального введения. На основе проведенного анализа различных форм прогестерона обоснована клиническая эффективность натурального прогестерона для вагинального введения.Авторами установлено, что применение прогестерона в сублингвальной и вагинальной формах является наиболее рациональным с точки зрения удобства, эффективности и безопасности., На сьогодні найбільш частим ускладненням фармакотерапії є алергічна реакція, так звана лікарська, або медикаментозна, алергія. Алергічну реакцію можуть викликати як діючі речовини, так і допоміжні компоненти, що входять до складу препарату для забезпечення певної лікарської форми і його фізико-хімічних властивостей. Для вагінальних препаратів прогестерону характерна велика різноманітність лікарських форм: гелі, таблетки і желатинові капсули для інтравагінального введення. Відомо, що безпека й ефективність фармакотерапії залежать від активної діючої речовини, лікарської форми та основи препарату для інтравагінального введення, а також показників прихильності до медикаментозної терапії. Водночас основа (допоміжні речовини) може слугувати причиною розвитку побічних реакцій.Авторами статті на підставі аналітичного огляду вітчизняної та зарубіжної літератури проаналізовано ефективну, безпечну і раціональну фармакотерапію ендогенного дефіциту прогестерону.Показано, що для поліпшення біодоступності натурального прогестерону сьогодні застосовують мікронізацію – спосіб підвищення розчинності за допомогою зменшення розміру часток лікарської речовини. Завдяки високому ступеню розчинності речовини знижується ризик можливих побічних ефектів, що дозволяє збільшити безпеку препарату.Описано особливість лікарської форми для вагінального введення. На підставі проведеного аналізу різних форм прогестерону обґрунтовано клінічну ефективність натурального прогестерону для вагінального введення.Авторами встановлено, що застосування прогестерону в сублінгвальній і вагінальній формах є найбільш раціональним з точки зору зручності, ефективності та безпеки.

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.

Chelidonium majus (also known as celandine) contains pharmacologically active compounds such as isoquinoline alkaloids (e.g., chelidonine, sanguinarine), flavonoids, saponins, carotenoids, and organic acids. Due to the presence of isoquinoline alkaloids, Chelidonii herba extracts are widely used as an antibacterial, antifungal, antiviral (including HSV-1 and HIV-1), and anti-inflammatory agent in the treatment of various diseases, while chitosan is a biocompatible and biodegradable carrier with valuable properties for mucoadhesive formulations preparation. Our work aimed to prepare mucoadhesive vaginal drug delivery systems composed of Chelidonii herba lyophilized extract and chitosan as an effective way to treat vaginitis. The pharmacological safety of usage of isoquinoline alkaloids, based on MTT test, were evaluated for the maximum doses 36.34 &plusmn, 0.29 &micro, g/mL and 0.89 &plusmn, 1.16 &micro, g/mL for chelidonine and sanguinarine, respectively. Dissolution rate profiles and permeability through artificial membranes for chelidonine and sanguinarine after their introduction into the chitosan system were studied. The low permeability for used save doses of isoquinoline alkaloids and results of microbiological studies allow confirmation that system Chelidonii herba lyophilized extract chitosan 80/500 1:1 (w/w) is a promising strategy for vaginal use. Ex vivo studies of mucoadhesive properties and evaluation of tableting features demonstrated that the formulation containing Chelidonii herba lyophilized extract (120.0 mg) with chitosan (80/500&mdash, 100.0 mg) and polymer content (HPMC&mdash, 100.0 mg, microcrystalline cellulose&mdash, 50.0 mg, lactose monohydrate&mdash, 30.0 mg and magnesium stearate&mdash, 4.0 mg) is a vaginal dosage form with prolonging dissolution profile and high mucoadhesion properties (up to 4 h).

Based on numerous written works of Persian scholars of Middle ages, Traditional Persian Medicine (TPM) has its own capabilities and strengths. According to TPM, vaginal drug delivery was prioritized to treat gynecological disorders because of the adjacency of uterine and cervix to vagina. This study was carried out to introduce and extract vaginal multi-component dosage forms, suggested by eight key medicinal manuscripts. Traditional terms of abzan, bakhour, fetileh, forzjeh, jalous, hamoul, hoghneh, and shiaf were sought as keywords. More than 670 vaginal formulations had been found for various gynecological disorders such as abortion, amenorrhea, and cervical stenosis. Vaginal dosage forms were categorized based on three physical conditions including solid (forzjeh, fetileh, hamoul, and shiaf), liquid (abzan, jalous, and hoghneh), and gas or smoke (bakhour). More detailed analysis of each vaginal dosage form based on traditional documents is suggested.

Sildenafil citrate (SIL), a type 5-specific phosphodiesterase inhibitor, demonstrates valuable results in the management of infertility in women; however, the absence of vaginal dosage form in addition to the associated oral adverse effects minimize its clinical performance. The present study is concerned with SIL uterine targeting following intravaginal administration via optimization of cubosomal in situ gelling sponges (CIS). An emulsification method was employed for preparation of cubosomal dispersions incorporating glyceryl monooleate as a lipid phase and poloxamer 407 as a surfactant with or without polyvinyl alcohol as a stabilizer. Cubosomes were estimated regarding entrapment efficiency (EE%), particle size, and in vitro drug release. Chitosan (2% w/w) was incorporated into the optimum formulation and then lyophilized into small sponges. For the CIS, in vivo histopathological and pharmacokinetic studies were conducted on female Wistar rats and compared with intravaginal free SIL sponges (FIS) and oral SIL solution. SIL-loaded cubosomes showed EE% ranging between 32.15 and 72.01%, particle size in the range of 150.81–446.02 nm and sustained drug release over 8 h. Histopathological study revealed a significant enlargement in endometrial thickness with congestion and dilatation of endometrial blood vessels in intravaginal CIS compared to intravaginal FIS and oral-treated groups. The pharmacokinetic study demonstrated higher AUC0–∞ and Cmax with oral administration compared to intravaginal CIS or intravaginal FIS indicating potential involvement of first uterine pass effect after intravaginal administration. Finally, intravaginal CIS could be considered as a promising platform for SIL uterine targeting with minimized systemic exposure and side effects.

Vaginal rapidly disintegrating tablets (RDTs) containing tenofovir (TFV) or TFV and emtricitabine (FTC) were evaluated for safety and pharmacokinetics in pigtailed macaques. Two separate animal groups ( n = 4) received TFV (10 mg) or TFV-FTC (10 mg each) RDTs, administered near the cervix. A third group ( n = 4) received 1 ml TFV gel. Blood plasma, vaginal tissue biopsy specimens, and vaginal fluids were collected before and after product application at 0, 0.5, 1, 4, and 24 h. A disintegration time of 4 to 10 5 ng/g (147 to 571 μM) and 10 6 ng/g (12 to 34 mM), respectively, at 1 to 4 h postdose. At 24 h, however, TFV vaginal tissue levels were more sustained after RDT dosing, with median TFV concentrations being approximately 1 log higher than those with gel dosing. FTC pharmacokinetics after combination RDT dosing were similar to those of TFV, with peak median vaginal tissue and fluid levels being on the order of 10 4 ng/g (374 μM) and 10 6 ng/g (32 mM), respectively, at 1 h postdose with levels in fluid remaining high at 24 h. RDTs are a promising alternative vaginal dosage form, delivering TFV and/or FTC at levels that would be considered inhibitory to simian-human immunodeficiency virus in the macaque vaginal microenvironment over a 24-h period.

In vitro testing and quantitative analysis of a matrix, hydrophilic polyether urethane (HPEU) intravaginal ring (IVR) for sustained delivery of the anti-HIV agent tenofovir (TFV) are described. To aid in device design, we employed a pseudo-steady-state diffusion model to describe drug release, as well as an elastic mechanical model for ring compression to predict mechanical properties. TFV-HPEU IVRs of varying sizes and drug loadings were fabricated by hot-melt extrusion and injection molding. In vitro release rates of TFV were measured at 37 °C and pH 4.2 for 30 or 90 days, during which times IVR mechanical properties and swelling kinetics were monitored. Experimental data for drug release and mechanical properties were compared to model predictions. IVRs loaded with 21% TFV (w/w) released greater than 2mg TFV per day for 90 days. The diffusion model predicted 90 day release data by extrapolating forward from the first 7 days of data. Mechanical properties of IVRs were similar to NuvaRing, although the matrix elastic modulus decreased up to three-fold following hydration. This is the first vaginal dosage form to provide sustained delivery of milligram quantities of TFV for 90 days. Drug release and mechanical properties were approximated by analytical models, which may prove useful for the continuing development of IVRs for HIV prevention or other women's health indications.

Carbamazepine indicated for the control of epilepsy, undergoes extensive hepatic first-pass metabolism after oral administration. A vaginal dosage form of carbamazepine is not commercially available. Conventional suppository having poor retention in the vaginal tract, as they are removed in a short time by the tract's self-cleansing action, having poor patient compliance. To overcome such problems, delivery system with mucoadhesive polymers polyox WSR N-60K and Ucarflock 302 that prolong drug permanence on the vaginal mucosa were developed. In the present study the suitability of gelucires to formulate vaginal pesseries was investigated. The possible modification of carbamazepine release kinetics by using gelucires blends and hydrophilic additives in the pesseries was evaluated. It was observed that among gelucire grades melting point higher than 37 degrees C, the release rate proved to be highly dependant on HLB value and matrix composition. In most of the formulations carbamazepine release occurred by disintegration and erosion of the matrices which is depending upon the vehicle employed. The aging study revealed that the formulations containing G50/13 and G50/13-G44/14 blends undergo some changes during one year of shelf aging. From the results obtained it can be concluded that different gelucire grades and their blends along with hydrophilic polymer could be successesively used to formulate prolong release carbamazepine pesseries.

One of the main stages in new medicines creation is the development of their making technology. Technological process of suppository making includes ratherlongthermal treatment during preparation and homogenization of suppository base, active substancesaddition. These factors create danger of chemical and physical transformation of active substances and excipients in suppository up to their destruction and change of pharmacological and physical-chemical properties. Use of thermogravimetric analysis in pharmaceutical technology allows to studythepossibility of chemical interaction in dosage forms over the wide temperature range. The aim of this work is study of thermal treatmenteffects of suppository base with thyme oil over the temperature range of suppository manufacturing. Methods and results. As an object of thermogravimetric study vaginal suppository with thyme oil 0,2 g, suppository-placebo containing propylenglycol, polyethylene glycol 400, proxanol 268, twin 80 and the active ingredient of «Царствоароматов», Ukraine, production were used. Thermogravimetric analysis was carried out on the derivatograph«Shimadzu DTG-60», Japan, with the platinum and platinum-rhodiumthermopair with samples heating in aluminiumcrucibles from 25 to 200oС. As standard α-Al 2 O 3 was used.Heating rate was 10oСper min.Mass of the samples was 23,45– 39,63 mg. Obtained data were registered by the derivatograph as curves T, DTA, TGA. The T curve on the derivatogramm shows the temperature change and the TGA curve demonstrates the sample mass change during investigation. The DTA curve reflects differentiation of thermal effects and contains information about endothermic and exothermal maximum and is used for qualitative valuation of derivatogramm. According to results of thermogravimetric investigation the thyme oil is thermostable substance which is gradually evaporating during heating. So, at the beginning of study the test sample mass was 23,45 mg at 26,14o С, then the thyme oil mass has been decreased on 1,41% at 50,2o С and on 4,14% at 69,48 oСaccordingly. In accordance with results of thermogravimetric study of suppository with thyme oil and placebo vaginal dosage form (base) it was revealed that both objects of investigation don’t reach the critical temperature within 100oС. That fact isindicated by the insignificant mass loss (3,35% and 3,44%accordingly). Derivatography of compositions upper 100oС wasn’t carried out because such high temperatures aren’t used in technological process of suppository manufacturing. Melting process of suppository base is going at 53,41°С. Addition of thyme oil in suppository base insignificantly decrease melting temperature of composition to 51,25°С, moreover the mass loss of sample is practically absent (0,04%). Conclusion. Character of the thermal effects of vaginal suppository with thyme oil on the derivatogrammcoincides with the thermal effects of suppository base. This fact indicates the absence of any chemical interactions between active substance and excipients of application dosage form.

The wide use of microbicide is mainly depends on its effectiveness, less frequent application, ready availability and most importantly cost. The aim of this work was to develop affordable microbicide mucoadhesive gel formulation of synthetic anti HIV drug, stavudine and to characterise it in terms of its physical properties, mucoadhesiveness and spreadability. The purpose of the present study was also to compare different dissolution media used for in vitro release of vaginal dosage form. The gels were tested for antimicrobial, spermicidal and anti-HIV activity. Gels prepared using Carbopols and Polycarbophil were transparent and homogenous and had excellent mucoadhesion index - and showed fast drug release profile. Gels showed very good antimicrobial action against pathological microorganism.

Background For any new vaginal dosage form, the distribution and retention in the vagina has to be assessed by in vivo evaluation. We evaluated the vaginal distribution and retention of starch-based pellets in sheep as live animal model by gamma scintigraphy (using Indium-111 DTPA as radiolabel) and in women via magnetic resonance imaging (MRI, using a gadolinium chelate as contrast agent). A conventional cream formulation was used as reference in both studies. Method Cream and pellets were administered to sheep ( n = 6) in a two period-two treatment study and to healthy female volunteers ( n = 6) via a randomized crossover trial. Pellets (filled into hard gelatin capsule) and cetomacrogol cream, both labeled with Indium-111 DTPA (for gamma scintigraphy) or with gadolinium chelate (for MRI) were evaluated for their intravaginal distribution and retention over a 24 h period. Spreading in the vagina was assessed based on the part of the vagina covered with formulation (expressed in relation to the total vaginal length). Vaginal retention of the formulation was quantified based on the radioactivity remaining in the vaginal area (sheep study), or qualitatively evaluated (women study). Results Both trials indicated a rapid distribution of the cream within the vagina as complete coverage of the vaginal mucosa was seen 1 h after dose administration. Clearance of the cream was rapid: about 10% activity remained in the vaginal area of the sheep 12 h post-administration, while after 8 h only a thin layer of cream was detected on the vaginal mucosa of women. After disintegration of the hard gelatin capsule, the pellet formulation gradually distributed over the entire vaginal mucosa. Residence time of the pellets in the vagina was longer compared to the semi-solid formulation: after 24 h 23 ± 7% radioactivity was detected in the vaginal area of the sheep, while in women the pellet formulation was still detected throughout the vagina. Conclusion A multi-particulate system containing starch-based pellets was identified as a promising novel vaginal drug delivery system, resulting in complete coverage of the vaginal mucosa and long retention time.

MucoCept is a biotherapeutic for prevention of HIV-1 infection in women and contains a human, vaginal Lactobacillus jensenii that has been genetically enhanced to express the HIV-1 entry inhibitor, modified cyanovirin-N (mCV-N). The objective of this study was to develop a solid vaginal dosage form that supports sustained vaginal colonization of the MucoCept Lactobacillus at levels previously shown, with freshly prepared cultures, to protect macaques from SHIV infection and to test this formulation in a macaque vaginal colonization model. Vaginally disintegrating tablets were prepared by lyophilizing the formulated bacteria in tablet-shaped molds, then packaging in foil pouches with desiccant. Disintegration time, potency and stability of the tablets were assessed. For colonization, non-synchronized macaques were dosed vaginally with either one tablet or five tablets delivered over five days. Vaginal samples were obtained at three, 14, and 21 days post-dosing and cultured to determine Lactobacillus colonization levels. To confirm identity of the MucoCept Lactobacillus strain, genomic DNA was extracted from samples on days 14 and 21 and a strain-specific PCR was performed. Supernatants from bacteria were tested for the presence of the mCV-N protein by Western blot. The tablets were easy to handle, disintegrated within two minutes, potent (5.7x1011 CFU/g), and stable at 4°C and 25°C. Vaginal administration of the tablets to macaques resulted in colonization of the MucoCept Lactobacillus in 66% of macaques at 14 days post-dosing and 83% after 21 days. There was no significant difference in colonization levels for the one or five tablet dosing regimens (p=0.88 Day 14, p=0.99 Day 21). Strain-specific PCR confirmed the presence of the bacteria even in culture-negative macaques. Finally, the presence of mCV-N protein was confirmed by Western blot analysis using a specific anti-mCV-N antibody.