Treatment of vaginal atrophy in women with risk of cardiovascular pathology

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine, namely to gynaecology, and can be used for a method of prevention and/or treatment of urogenital atrophy in women, including the vaginal introduction of pharmaceutical compositions with estriol, as well as for the application of estriol in the production of a pharmaceutical composition with a possibility of self-restriction of estriol absorption. The said women have the high possibility of development of a cardiovascular pathology, or suffer or suffered from the cardiovascular pathology. Estriol is introduced in a dose, smaller or equal to 0.1 mg/day. An area under the estriol concentration curve depending on the time constitutes less than 500 pg/ml·h after the introduction of repeated doses one time per day for the time period from 1 to 4 weeks.

EFFECT: group of inventions provides efficient and safe treatment.

24 cl, 7 tbl, 1 dwg

 

This invention relates to the use of estriol in the manufacture of a pharmaceutical composition for vaginal administration with the possibility of limiting the absorption of estriol. This composition is used in the prevention and/or treatment of urogenital atrophy in women who have a high likelihood of developing or who are suffering or have suffered from cardiovascular disease.

The level of technology

Estrogen and other female sex hormones mainly produced in the ovaries and function throughout life in a variety of tissues and organs. The cells of these organs, among which are the mammary glands and uterus, have receptors for estrogen and other hormones. Estrogen hormones exert their effects by binding to these receptors and initiating various physiological or pathological processes. Among other physiological functions they are responsible for the development and changes that occur in the Breasts and uterus at different periods of life (puberty, pregnancy, lactation, menopause). But estrogen can also participate in pathological processes, causing, for example, ischemic heart disease, cerebrovascular or thromboembolic disease.

During female menopause occurs a progressive decrease in estrogen production in aicn�Kah which is usually accompanied by a series of signs, symptoms and pathologies. The main symptom is the disappearance of menses (menopause) and the occurrence of multiple hormonal and mental symptoms, the most common among which are vasomotor disorders (hot flashes and sweats) and urogenital atrophy.

When the production of estrogen is reduced, the gradual depletion of vaginal, urethral mucosa and the mucosa of the bladder. When atrophy becomes more pronounced, you experience genital symptoms - vaginal itching and burning, atrophic vaginitis, dyspareunia and bleeding and urological symptoms are repeated infections, dysuria and incontinence. In addition, a deficiency of the hormone causes contraction of the supporting tissues, which can cause prolapse and stress urinary incontinence.

Although urogenital atrophy is a natural consequence of menopause and menopause related disorders often affect the quality of life of women, it is therefore important that doctors sooner discovered their presence and was prescribed treatment.

Note that the symptoms of vaginal atrophy and the need for treatment is greater the longer a woman is post-menopausal. However, the more the age, the greater the likelihood of developing heart�about cardiovascular disease, so the risk of embolism, coronary and cerebrovascular diseases increases with age.

Although estrogen therapy is usually very effective inverse development of urogenital atrophy caused by hormonal deficiency, its use in women with vaginal atrophy, which in history have venous thromboembolic pathology (e.g., deep vein thrombosis or pulmonary thromboembolism) or coronary or cerebrovascular disease (such as myocardial infarction or stroke), it is not recommended due to the risks that it entails. For the same reason it is also not recommended its use in women who have a high probability of developing cardiovascular diseases, and in elderly postmenopausal women.

Although urogenital atrophy due to estrogen deficiency does not always require systemic treatment with oral hormone replacement therapy, and it is rather preferable to the vaginal route of administration of estrogens, but you need to take into account that this path is not safe. Topically introduced estrogen hormones can be absorbed and move to the system level, increasing the risk of coronary heart disease, cerebrovascular disorders (stroke) and/or thromboembolic disease�any.

Estriol is a estrogen used in the treatment of urogenital atrophy, especially in the vaginal route of administration. Currently offered on the market vaginal formulations with astrila typically administered at a dose of 0.5 mg/day (500 mcg/day) for the first 2-3 weeks of treatment, and then at a dose of 0.5 mg 2 or 3 times/week, but due to the risk they entail, their introduction is not recommended for women suffering from cardiovascular diseases or with high probability of their development.

Therefore, urogenital atrophy due to estrogen deficiency in women suffering from coronary heart disease, stroke, or venous thromboembolic disease, or in women with a high likelihood of developing cardiovascular disease, an issue that is still not resolved. In particular, this unresolved problem for those postmenopausal women who have long, menopause, i.e. in elderly women.

Brief description of the invention

The inventors of the present invention unexpectedly found that some vaginal formulations with astrila form a system that is able to constrain the absorption of estriol.

They found that after the start of treatment with compositions of this invention, when the vaginal epithelium is atrophied, there is a low absorption of estriol, Thu� shown by the area under the curve (AUC) of plasma estriol concentration depending on time of 1000 PG/ml × h, preferably less than 750 PG/ml x hour. After the re-introduction of these compounds was observed the development of vaginal atrophy that suddenly happened after a few days (2 to 15 days, in particular from 2 to 10 days, more specifically from 2 to 7 days, even more specifically from 2 to 5 days) after the start of treatment, the absorption of estriol was low and the area under the curve was significantly decreased compared with baseline, becoming less than 500 PG/ml × h, preferably less than 250 PG/ml × h. Thus, the compositions of this invention can be used without risk or with a significantly reduced risk for the treatment or prevention of urogenital atrophy in women with a high likelihood of developing cardiovascular disease or in women who suffer or have suffered from cardiovascular disease.

The inventors of this invention also unexpectedly found that in the treatment of vaginal atrophy using commercially available formulations systemic effects estriol does not cause significant changes throughout the treatment (although in the end the epithelium became eutrophy), while in the treatment compositions of this invention, as already mentioned, the systemic effect is significantly reduced during treatment.

Therefore, by administration of vaginal formulations of this invented�I astrila to prevent and/or treat urogenital atrophy due to estrogen deficiency, at the same time it prevents or substantially reduces the risk associated with estrogen therapy, which causes cardiovascular disease.

Thus, the first aspect of the invention is the use of estriol in the manufacture of a pharmaceutical composition for vaginal administration with the possibility of limiting the absorption of estriol, for the prevention and/or treatment of urogenital atrophy in women with a high likelihood of developing cardiovascular disease or of suffering or suffering from cardiovascular disease.

In other words, the present invention relates to a pharmaceutical composition containing estriol for vaginal administration with the possibility of limiting the absorption of estriol, which will be used for the prevention and/or treatment of urogenital atrophy in women with a high likelihood of developing cardiovascular disease or of suffering or suffering from cardiovascular disease.

The second aspect of this invention relates to a method for prevention or treatment of urogenital atrophy in women, which includes vaginal administration of the composition astrila with the possibility of limiting the absorption of this hormone, however these women have a high likelihood of developing cardiovascular disease, or they are suffering or have suffered from with�techno cardiovascular disease.

Brief description of graphic materials Fig.1. Plasma estriol concentration depending on time.

Detailed description of the invention

In the context of this invention are the women who have a history of cardiovascular disease and/or at least one of the known risk factors, namely: increasing age (e.g., women over 50 years old 60 years or older), genetic predisposition (e.g., cardiovascular disease, family history, genetic mutations associated with cardiovascular disease), comorbidities (severe migraines with aura, high blood pressure, hypercholesterolemia, hypertriglyceridemia, and insulin-dependent diabetes, cardiomyopathy, valvular heart diseases, etc.) and lifestyle (Smoking, sedentary lifestyle, obesity, diet rich in fats, etc.) are considered to be women with a high likelihood of developing cardiovascular disease (SS3).

In particular, in the context of this invention are cardiovascular disease includes any disease or disorder of the cardiovascular system that are associated with the effects of estrogen, or which may be regarded as a contraindication to estrogen therapy. For example, ischemic heart disease (or coronary cardiopathy), cerebrovascular accident (CEP�ecno cardiovascular disease or stroke), venous thromboembolism (including deep vein thrombosis and embolism of the pulmonary artery), superficial thrombophlebitis or thrombophilia.

In particular, women in postmenopausal women, preferably older than 55, more preferably over the age of 60, even more preferably above 65 years, are at a high risk of developing cardiovascular diseases associated with estrogen therapy and may benefit from treatment with compositions of the present invention to enhance absorption of estriol.

On the other hand, women who have a history of venous thromboembolic pathology (e.g., deep vein thrombosis, pulmonary embolism, superficial thrombophlebitis or thrombophilia), coronary and cerebrovascular disease (such as myocardial infarction or stroke) or migraine with aura, can also benefit from treatment with compositions of the present invention to enhance absorption of estriol.

It should be clearly understood that when referring to "the absorption of estriol, this means the absorption of estriol in the blood plasma.

The embodiment of this invention relates to the application of said composition to enhance absorption of estriol, for the prevention and/or treatment of urogenital atrophy in women with a high likelihood of developing cardiovascular disease.

It t�the realm of human relates to a method of prevention and/or treatment of urogenital atrophy in women with a high likelihood of developing cardiovascular disease using the compositions of the present invention to enhance absorption estriol.

The preferred embodiment relates to the use of these formulations in women, the long-standing postmenopausal women (older women). In private embodiments of these women menopause began at least 5 years, preferably 10, more preferably 15, even more preferably from 20 years ago or more before treatment.

Another embodiment relates to the application of these formulations to enhance absorption of estriol, for the prevention and/or treatment of urogenital atrophy in women who suffer or have suffered from cardiovascular disease.

It also relates to a method of prevention and/or treatment of urogenital atrophy in women who suffer or have suffered from cardiovascular diseases, using the compounds of this invention with the limitation of the absorption of estriol.

The preferred embodiment relates to the use of these formulations in women, preferably in postmenopausal women who suffer or have suffered from coronary heart disease, stroke, deep vein thrombosis, pulmonary embolism, superficial thrombophlebitis, thrombophilia and/or severe migraine with aura.

Another embodiment also relates to a method for prevention of cardiovascular disease at the system level associated with estrogen tera�Oia, which includes vaginal administration of the composition astrila with the possibility of limiting the absorption of the hormone.

As already mentioned, the pharmaceutical compositions used in the method of treatment of this invention, are those compounds, which constitute a system with self-limitation of the absorption of estriol. In the context of this invention the composition with the possibility of limiting the absorption of estriol is such that it provides low absorption of this hormone peaks estriol in the plasma of less than 150 PG/ml, preferably less than 125 PG/ml), when the vaginal mucosa is atrophied, and negligible absorption (which shows the peaks of plasma estriol close to basal physiological values in postmenopausal women), when atrophy develops back due to the local action of estriol.

In particular, the pharmaceutical composition may be any, which, when used vaginally delivers a peak plasma estriol less than 50 PG/ml, preferably less than 30 PG/ml, more preferably less than 25 PG/ml, even more preferably less than or equal to 20 PG/ml after repeated administration once daily for 1 to 4 weeks, in particular from 2 to 3 weeks and after this period, if the introduction continues.

In accordance with a preferred embodiment of the pharmaceutical industry�ski the composition of this invention can be any, which can significantly reduce the systemic effect of estriol (quantitatively assessed using AUC plasma concentrations of estriol depending on time) after repeated daily administration for several days, when vaginal atrophy subjected to reverse development. In particular, it can be any structure which provides an AUC less than 1000 PG/ml·h, preferably less than 750 PG/ml·h, more preferably less than 600 PG/ml·h, at the beginning of treatment, more specifically in the first day of treatment, and AUC of less than 750 PG/ml·h, preferably less than 500 PG/ml·h, more preferably less than 300 PG/ml·h, even more preferably less than 250 PG/ml·h, after the re-introduction of once a day during the time from 1 to 4 weeks, in particular from 2 to 3 weeks and after this period, if the introduction continues.

In a particularly preferred embodiment of the pharmaceutical composition of this invention may be any that allows almost negligible systemic effects and simultaneously reverse the development of urogenital atrophy. In particular, it can be one that provides an AUC less than or equal to 150 PG/ml·h after re-injection once a day for 1 to 4 weeks, especially from 2 to 3 weeks and after this period, if the introduction continues.

Pharmaceutical comp�in maybe for example, in solid (suppositories, tablets, etc.), semi-solid (gels, creams, etc.), liquid form or in the form of foam. It can also contain any of excipients known to specialists in this field.

In accordance with a preferred embodiment of the pharmaceutical compositions of this invention are semi-solid formulations, such as gels, cream gels or creams.

In the preferred embodiment they are mucoadhesive gels, cream gels or creams containing at least one bioadhesive polymer (gelling agent and/or thickener) and this amount of estriol, which allows you to enter less than 0.5 mg/day.

In a more preferred embodiment mucoadhesive the compositions of this invention contain at least two bioadhesive of the polymer and the amount of estriol, which allows you to enter less than 0.3 mg/day, preferably less than 0.1 mg/day, more preferably from 0.07 to 0.002 mg/day. For example, the compositions may contain estriol in quantities less than or equal to 0.03 percent by weight, preferably less than or equal to 0.01% by weight, more preferably from 0007 up to 0.0002% by weight, even more preferably from to 0001 0005% by weight of the composition.

Bioadhesive polymers used for the compositions of this invention, selected from among cellulose polymers, natural resins, sodium alginate, Poliak�of etileno, acrylic Homo - or copolymers and mixtures thereof.

Cellulosic polymers may be selected from methylcellulose, carboxymethylcellulose sodium (CMC), hydroxyethyl cellulose (NES), hydroxypropyl cellulose (HPC) and hydroxypropylmethylcellulose (HPMC). Natural resins may be selected, for example, among the guar gum, gum karaya gum, xanthan resin and drug Veegum. Acrylic polymers are preferably selected from among polymers of the type of acrylic acid, cross stitched with diphenylglycine (supplied under the trademark of a Noveon® AA-1 Polycarbophil), and polymers derived from acrylic acid, cross stitched with allinsecurity or allinterfaces, referred to as polymers carbamatnogo type (supplied under the trademark Carbopol®).

Carbomer is the common name adopted by a number of agencies, including the Pharmacopoeia and National formulary, U.S. (USP-NF), the Council for assigned names (USAN) and the European Pharmacopoeia for the determination of various types of high molecular transversely crosslinked polymers based on acrylic acid, which are presented on the market as polymers Carbopol®. U.S. patent№№2798053, 4267103, 5349030, 4996274, 4509949, 5373044 describe these polymers are polyacrylic acid, including the type of Carbopol®, which are incorporated herein by reference. Handbook of Pharmaceutical Excipients, 2006, describes polymers T.�and Carbopol® under the heading "Carbomer", furthermore, this monograph also included in this document by reference.

Polymers carbamatnogo type and polycarbophil polymer produced by the process of cross-linkage. Depending on the degree of crosslinking and of the conditions of production there are different classes of HPMC. Carbopol® 934 P cross stitched with allinsecurity and polymerized in solvent benzene. Carbopol 5984 EP cross stitched with allinsecurity and polymerized in ethyl acetate and tikokino. Carbopol® 71 G, 971 R 974 R cross stitched with allinterfaces and polymerized in ethyl acetate. Carbopol® 980 and 981 cross stitched with allinterfaces and polymerized in a solvent mixture of ethyl acetate and cyclohexane. Polycarbophil is transversely crosslinked polymer in diphenylglycine and polymerized in solvent benzene or ethyl acetate. All polymers made in ethyl acetate, neutralized 1-3% potassium hydroxide.

Although Carbopol® 971 P and Carbopol® 974 P are produced in the same process under similar conditions, the difference between them is that Carbopol® 971 P (USP29/NF24 of carbomer homopolymer type A) has a slightly lower level of cross-linking agent than Carbopol® 974 P (USP29/NF24 of carbomer homopolymer type B). As a result Carbopol® 971 NF P has a viscosity of from 4,000 to 11,000 CP (measured in Brookfield viscometer RTV at 20 rpm, 25°C, in 0.5% by weight of mucus, neutralizou�Noah to pH 7,3-7,8), while Carbopol® 974 NF P has a viscosity between 29400 and of 39,400 CP (measured in Brookfield viscometer RTV at 20 rpm, 25°C, in 0.5% by weight of mucilage, neutralized to pH 7.3-7.8) to. For the same reasons, Carbopol® 981 NF has a viscosity between 4000 and 10000 CP (measured in Brookfield viscometer RTV at 20 rpm, 25°C, in 0.5% by weight of mucilage, neutralized to pH 7.3 to 7.8), while Carbopol® 980 NF has a viscosity between 40000 and 60000 CP (measured in Brookfield viscometer RTV at 20 rpm, 25°C, in 0.5% by weight of mucilage, neutralized to pH 7.3-7.8) to.

In an even more preferred embodiment mucoadhesive the compositions used in the methods of this invention contain at least one polymer carbamatnogo type selected from among polymers of acrylic acid, a transversely cross-linked with allyl ethers of pentaerythritol, at least one of polyacrylic acid, cross stitched with diphenylglycine, and estriol in such quantity that it allows you to type less than or equal to 0.1 mg/day.

Polymer carbamatnogo type preferably chosen among these polymers, the synthesis of which does not require the use of benzene as the solvent, for example, Carbopol® 71 G NF, Carbopol® 971 P NF, Carbopol® 974 P NF, Carbopol® 980 NF, Carbopol® 981 NF and Carbopol® 5984 EP. More preferably, the polymer carbamatnogo type choose among polymerized in ethyl acetate or in a mixture of ethyl acetate and cyclohexane. �still more preferably, the polymer carbamatnogo type choose among polymerized in ethyl acetate or in a mixture of ethyl acetate and cyclohexane and having a viscosity between 4000 and 11000 CP.

In a particularly preferred embodiment the compositions contain at least two bioadhesive polymer is a homopolymer carbamatnogo type selected from among Carbopol® 971 P NF and Carbopol® 981 NF, and the other is a Noveon® AA-1 Polycarbophil, and the amount of estriol less than or equal to 0.03 percent by weight of the composition.

In a more preferred embodiment, the compositions contain at least polycarbophil a Noveon® AA-1 and Carbopol® 971 P NF and the amount of estriol less than or equal to 0.03 percent by weight of the composition.

Each polymer included in an amount necessary to create a composition, physico-chemical and organoleptic properties, suitable for vaginal administration. In the case of acrylic polymers, the amount will range from 0.05 to 5% by weight of the preparation, preferably from 0.1 to 2%, more preferably from 0.25 to 1.5%.

The composition may also contain other pharmaceutically acceptable excipients, such as wetting agents, wetting agents, solubilizers agents, emulsifiers, preservatives, fatty or lipophilic substances, etc., in amounts known to specialists in this field.

These compounds may be made in the processes known to specialists in this field.

The compositions used in the methods of this invention, preferably administered in an amount sufficient to form layer over the entire vaginal p�surface and to obtain effective and safe dosage. For example, in the case of semi-solid compositions, as a rule, from 1 to 5 grams.

Devices that can be used for the introduction of semi-solid compositions used in the method of this invention, are any of applicators for a single dose, known in this field, e.g. the applicator with piston or diaphragm.

Dose estriol for administration to patients receiving treatment according to the methods of this invention, will be less than 0.5 mg/day, preferably less than 0.3 mg/day, more preferably less than 0.1 mg/day.

In the private embodiment of the present invention estriol is administered in doses of from 0.002 to 0.07 mg/day (2 to 70 mg/day), preferably from 0.002 to 0.05 mg/day (2 to 50 μg/day), more preferably from 0.01 to 0.05 mg/day (10 to 50 µg/day), particularly preferably from 0.02 to 0.05 mg/day (20 to 50 mcg/day), for the prevention and/or treatment of urogenital atrophy due to estrogen deficiency in women with a high likelihood of developing cardiovascular disease, preferably women, long in postmenopausal women.

In another private embodiment, estriol is administered in doses of from 0.002 to 0.07 mg/day (2 to 70 mg/day), preferably from 0.002 to 0.05 mg/day (2 to 50 μg/day), more preferably from 0.01 to 0.05 mg/day (10 to 50 µg/day), particularly preferably from 0.02 to 0.05 mg/day (20 to 50 mcg/day), for the treatment�Oia urogenital atrophy due to estrogen deficiency in women who suffered or suffer from cardiovascular disease, preferably in women who suffered or are suffering from coronary heart disease, cerebrovascular and venous thromboembolism.

Given the high safety of compounds used in the methods of this invention, the treatment and/or prevention of vaginal atrophy can be performed simultaneously with the treatment of cardiovascular diseases.

The duration of treatment and/or prevention of urogenital atrophy and mode of introduction of these compositions will depend on the patient's condition, response to treatment and concomitant therapy. For example, a dose of from 0.002 to 0.07 mg, preferably from 0.01 to 0.05 mg, will be administered every day for 2 or 3 weeks, and will continue to be a dose of from 0.002 to 0.07 mg, preferably from 0.01 to 0.05 mg, two times per week during the time required to maintain the trophic status of the vaginal mucosa, without a break in the treatment. Alternative will be entered dose from 0.002 to 0.07 mg per day, preferably from 0.01 to 0.05 mg, within 2 or 3 weeks, and will continue to be a dose of from 0.002 to 0.07 mg, preferably from 0.01 to 0.05 mg, two times a week for several weeks, for example from 6 to 10 weeks, so with a break in treatment as long until symptoms reappear. Alternative, given �high security compounds, used in the methods of this invention, their introduction may continue daily or twice a week, at a dose of from 0.002 to 0.07 mg, preferably from 0.01 to 0.05 mg, for more than 3 weeks or more than 10 weeks, respectively.

An illustrative example of the invention described below. In any case, it should not be construed as limiting the interpretation of the claims.

Analysis

Comparative pharmacokinetics and efficacy of two astrology compositions of the invention in comparison with commercial astrology composition (cream Ovestinon®, Organon) in postmenopausal women.

Description

The analyzed compositions were two vaginal gel based on estriol T1 (0,002% ITFE) and T2 (0,005% ITFE) with the following composition:

Active ingredientConnectionnumbernumber
Estriol0,002%0,005%
ExcipientiCarbopol®971 (0.5%) Polycarbophil a Noveon® AA-1 (1,5%)2%2%
glycerin10%10%
methylparaben0,16%0,16%
propylparaben0,02%0,02%
sodium hydroxideto pH=4,5to pH=4,5
waterto 100%to 100%

These formulations were compared with the composition of the placebo without estriol and commercially available composition (cream Ovestinon® with 0.1% estriol).

In the analysis participated seventy postmenopausal women with vaginal atrophy, which were randomly divided into four groups, three of 20 patients each, and one with 10 patients:

Women were treated daily and continuously for 21 days. 1 g of gel per day vaginal transmission was administered to each patient of group b, C and D, and 0.5 g of cream per day vaginal transmission was administered to each patient of group A.

Group a: treated Ovestinon (labeled "R") (n=20)

Group b: treated 0,005% ITFE (n=20)

Group C: treated 0,002% ITFE (n=20)

Group D: treated with 0% ITFE (indicated by "P") (n=10)

The pharmacokinetic study was performed in the subgroup of 42 women, educated 12 patients�mi from each group, who received active treatment (n=12 group a, n=12, n=12).

The day before the start of treatment the patients underwent gynecological examination and cervical-vaginal cytologic analysis.

On the first day of treatment a composition corresponding to the designated group, vaginally was administered to all patients, and blood samples were taken at time points 0 (before administration), 0, 5, 1, 2, 3, 4, 6, 8, 12 and 24 h (after the introduction), only 42 volunteers pharmacokinetic studies.

On the second day all the patients repeated the introduction and only 42 volunteers took blood samples.

3 to 20 days of treatment daily for all patients was administered vaginally respective lineups. On the 7th and 14th days immediately before the introduction of the assessed subjective efficacy and tolerability.

On day 21, all patients were injected the last dose of treatment and only 42 volunteers pharmacokinetic studies were obtained blood samples at time 0 (before administration), 0, 5, 1, 2, 3, 4, 6, 8, 12 and 24 h (after the introduction). Local tolerance was assessed 12 hours after injection.

On the 22nd day, all the patients underwent gynecological examination and cervical-vaginal Cytology, and 42 volunteers were given blood samples in the above-described points in time.

Evaluation of the effect on vaginal atrophy

Vaginal mask�, obtained during a pelvic examination in the 0-th and 22 th days, fixed with an aqueous solution to cytodiagnostic (ethanol/methanol EDTA) and stained by the Papanicolaou technique for qualitative assessment of cytological status and the number of superficial cells (SC, superficial cells), intermediate cells (1C, intermediate cells) and parabasal cells (PC, parabasal cells) that is used in subsequent determination of the maturation index (Ml, maturation index) and the values of maturation (MV, maturation value).

The maturation value (MV) is calculated based on the index of maturation (Ml) as follows: = 0,2·% parabasal cells +0,6·% intermediate cells +1,0·% of surface cells.

The qualitative and quantitative estimation (Ml and MV) are shown in tables I, II and III.

Table I
The frequency of cytological patterns in day 0 (basal level) and 22 day (after administration of formulations T1, T2, R or placebo)
Cytological modelT1T2RP
Day 0Day 22Day 0 Day 22Day 0Day 22Day 0Day 22
Atrophic71707022
Low proliferative55455344
Proliferative12010300
Highly proliferative05050600
Total 13131111121266

Table II
Index of maturation (Ml) based on the differential number of superficial cells (SC), intermediate cells (IC) and parabasal cells (PC) in the 0-th and 22 th days, and the difference with the basal levels (ΔSC, ΔIC and Δ) after administration of formulations T1, T2, R and R
SC/300:mean ±SDIC/300: mean ±SDRS/300:mean ±SD
Day 0Day 22ASCDay 0Day 22DSDay 0Day 22ARS
T112,92±23,67 110,08±79,8097,15±79,44177,00±117,11174,00±72,36-3,00±107,71110,08±126,8315,92±43,98-94,15±118,65
T210,75±12,17111,25±71,45100,50±76,84207,00±105,51187,75±71,25-19,25±71,3882,25±112,731,00±3,46-81,25±111,46
R9,50±14,00150,75±73,55141.25 bar±66,39209,00±95,82149,25±73,55Was 59.75±126,0681,50±102,240,00±0,00-81,50±102,24
P15,50±14,6323,00±of 18.267,50±4,55198,00±123,90206,50±94,218,50±34,1286,50±135,4870,50±109,2-16,00±32,40

Table III
The maturation value (MV) in the 0-th and 22 th days and the difference with the basal level (AMV) after administration of formulations T1, T2, R and R
TreatmentMV: mean value ±SD
Day 0Day 22AMV
T147,12±18,7372,51±14,3425,38±22,85
T250,13±15,8974,70±9,57A 24.57±LK 23: 43
R50,50±14,4780,08±9,8429,58±15,63
P50,53±19,B853,67±16,683,13±4,17

Thus, we can conclude that the method of treatment of this invention is effective in the reverse development of vaginal atrophy.

Assessment of plasma levels of estriol

The concentration of estriol in plasma were determined using liquid chromatography/mass spectrometry (LC-MS/MS) obrazca blood received from 42 voluntary patients at time points 0 (before the introduction), 0, 5, 1, 2, 3, 4, 6, 8, 12 and 24 h (after the introduction) in the 0-th, 1-th, 21 th and 22 th days.

Plasma levels obtained on the first day and 21-day treatment, are shown in tables IV and VI and 1 on the chart.

The pharmacokinetic parameters calculated from these values, shown in tables V and VII.

Table IV
Plasma levels of estriol after the administration of a single dose of formulations T1, T2 and R. Day 1
Time (h)Plasma estriol levels: mean ±SD (PG/ml)
T1T2R
01,48±3,46Of 5.17±17,9010,33±35,80
0,565,24±45,54Of 87.59±79,2462,45±78,01
172,43±45,46108,57±79,7683,36±72,14
248,63±25,79105,20±64,12 161,40±98,58
335,53±30,0592,81±64,15180,88±85,98
420,46±12,2757,78±25,77165,34±68,88
65,57±6,3021,82±17,83106,43±46,98
81,56±3,679,02±10,8265,02±52,91
121,65±3,863,86±10,0234,20±45,02
241,89±5,123,85±9,250,56±1,92

Table V
Pharmacokinetic parameters (± standard deviation) of estriol after the administration of a daily single dose of formulations T1, T2 and R. Day 1
Cmax(PG/ml) Adjusted doseTmax (h)AUCO-t(ng/ml×h) Adjusted doset½ (h)MRT(h)
T1ą0. 57±27,21,29±0,171,65±80,1194,29±73,81,59±0,3,99±3,
T2106,40±63,2,38±1,406,75±199,461,53±17B;1,65±0,4,57±2,
R210,06±82,3,04±1,1221,97±541431,21±802,52±2,5,79±3,

Table VI
Plasma levels of estriol after the administration of daily doses of formulations T1, T2 and R. Day 21
Time (h)Plasma estriol levels: mean ±SD (PG/ml)
T1T2R
0BLQL4,98±6,45
0,55,18±8,072,48±6,144,92±6,54
18,40±10,2910,56±14,39To 7.33±8,28
211,20±9,9217,79±17,0123,94±11,60
313,00±7,25For 19.32±13,8838,58±21,40
4Of 8.47±6,2816,30±9,1660,08±25,51
61,63±4,217,28±to 5.6272,36±39,18
80,87±3,001,85±3,4376,17±34,78
12BLQLBLQL74,81±41.68 per
24BLQLBLQL3,47±7,40
BLQL = below n�life quantitative limit (5 PG/ml)

Table VII
Pharmacokinetic parameters (± standard deviation) of estriol after the administration of daily doses of formulations T1, T2 and R. Day 21
Cssmax(PG/ml) Adjusted doseTssmax(h)Cssmin(PG/ml)AUCssmax(PG/ml×h) Adjusted dose
T113,77±8,032,17±0,940,0±0,036,33±30,52
T222,80±15,783,25±1,140,0±0,073,71±46,86
R89,95±38,557,67±3,062,97±5,49800,11±363,51

Thus, we can conclude that the safety profile of the compositions of this invention are very favorable, because the systemic effect of estriol after the re-introduction is very minor (very weak). In addition, the system impact� significantly lower than impacts that occur after the administration of drug control.

In addition, although systemic effects estriol significantly below, the compositions of this invention cause the same increase in the value of maturation on the 22nd day compared to day 0, indicating that the effect similar to the effect of control drug on the vaginal mucosa.

1. The use of estriol in obtaining pharmaceutical composition for vaginal administration in a dose of less than or equal to 0.1 mg/day, where the pharmaceutical composition provides an area under the curve of plasma concentration of estriol depending on time of less than 500 PG/ml·h after the administration of repeated doses once a day for 1 to 4 weeks, for the prevention and/or treatment of urogenital atrophy in women, where the women have a high likelihood of developing cardiovascular disease or suffered or suffer from cardiovascular disease.

2. The use according to claim 1, wherein the pharmaceutical composition provides an area under the curve less than 300 PG/ml·h.

3. The use according to claim 2, where the pharmaceutical composition provides an area under the curve less than 250 PG/ml·h.

4. The use according to claim 3, wherein the pharmaceutical composition provides an area under the curve less than or equal to 150 PG/ml·h after the administration of repeated doses once a day for a time from 2 to 3 weeks.

5. PR�the use according to claim 1, where the pharmaceutical composition provides a plasma estriol levels less than 50 PG/ml after repeated administration once daily for 1 to 4 weeks.

6. The use according to claim 5, where the pharmaceutical composition provides a plasma estriol levels less than 25 ng/ml after repeated administration once daily at a period of time of 2 to 3 weeks.

7. The use according to claim 6, where the pharmaceutical composition provides a plasma levels of estriol less than or equal to 20 PG/ml.

8. The use according to claim 1, where the absorption of estriol is low, when the vaginal epithelium is atrophic, and the absorption of estriol becomes insignificant when repeated administration of the composition causes return development of vaginal atrophy.

9. The use of estriol according to claim 8, wherein the area under the curve plasma concentration of estriol in time is less than 1000 PG/ml·h, when the vaginal epithelium is atrophic, and less than 500 PG/ml·h, when vaginal atrophy subjected to reverse development.

10. The use of estriol according to claim 9, where the area under the curve plasma concentration of estriol in a time less than 750 PG/ml·h, when the vaginal epithelium is atrophic, and less than 250 PG/ml·h, when vaginal atrophy subjected to reverse development.

11. The use according to claim 8, wherein the vaginal atrophy subjected to reverse development within 2-10 days more specifically within 2-7 days, even more specifically within 2-5 days after the start of treatment.

12. The use of estriol according to claim 1, where women having a high probability of having cardiovascular disease are women in postmenopausal women over the age of 55 years and/or women with a family history of coronary heart disease, stroke, deep vein thrombosis, pulmonary embolism, superficial thrombophlebitis, thrombophilia and/or severe migraine with aura.

13. The use of estriol according to claim 1, where women suffer or have suffered from coronary heart disease, stroke, deep vein thrombosis, pulmonary embolism, superficial thrombophlebitis, thrombophilia and/or severe migraine with aura.

14. The use according to claim 1, wherein the dose of estriol is from 0.002 to 0.07 mg/day.

15. The use according to claim 14, where the dose of estriol is from 0.01 to 0.05 mg/day.

16. The use of estriol according to claim 1, wherein the pharmaceutical composition is mucoadhesive gel, cream-gel or cream containing at least one bioadhesive polymer.

17. The use according to claim 16, where the specified bioadhesive polymer selected from the group consisting of cellulosic polymers, natural resins, sodium alginate, polyoxyethylene, acrylic polymers and mixtures thereof.

18. The use according to claim 17, where the specified bioadhesive polymer selected from �the group, consisting of methylcellulose, carboxymethylcellulose sodium (CMC), hydroxyethyl cellulose (NES), hydroxypropyl cellulose (HPC) and hydroxypropylmethylcellulose (HPMC).

19. The use according to claim 17, where the specified bioadhesive polymer selected from the group consisting of polymers of acrylic acid type, cross stitched with diphenylglycine, and polymers derived from acrylic acid, cross stitched with allinsecurity or allinterfaces.

20. The use according to claim 16, where the pharmaceutical composition contains at least one of polyacrylic acid, cross stitched with diphenylglycine, and at least one polymer of acrylic acid, a transversely cross-linked with allyl ethers of pentaerythritol.

21. The use according to claim 20, wherein acrylic acid, a transversely cross-linked with allyl ethers of pentaerythritol, polymerized in ethyl acetate or in a mixture of ethyl acetate and cyclohexane.

22. The use according to claim 21, where acrylic acid, a transversely cross-linked with allyl ethers of pentaerythritol and polymerized in ethyl acetate or in a mixture of ethyl acetate and cyclohexane, has a viscosity of from 4,000 to 11,000 CP.

23. The use according to claim 19, where the amount of said acrylic polymer, cross stitched with diphenylglycine, and/or the aforementioned polymers obtained from acrylic acid, a transversely cross-linked with allyl ethers of sucrose or allyl ethers pentameric�ITA, individually comprise from 0.05 to 5% by weight of the composition, preferably from 0.1 to 2%, more preferably from 0.25 to 1.5%.

24. Method of prevention and/or treatment of urogenital atrophy in women, including vaginal administration of pharmaceutical compositions with astrila with the possibility of limiting the absorption of estriol, where these women have a high likelihood of developing cardiovascular disease, or suffer or suffered from cardiovascular disease and where estriol is administered in a dose of less than or equal to 0.1 mg/day, and where the pharmaceutical composition provides an area under the curve of plasma concentration of estriol depending on time of less than 500 PG/ml·h after the administration of repeated doses once a day for 1 to 4 weeks.



 

Same patents:

FIELD: medicine.

SUBSTANCE: presented egg-shaped vaginal suppositories contains the following mass ratio in 1 capsule (egg-shaped vaginal suppository): sulphadimine 0.05 g; metronidazole 0.01 g, potato starch 0.02 g, glucose 0.04 g, 5% polyvinyl alcohol 0.07 g, 15% oily extract of propolis 1.0 g; gelatine 0.2 g; dimethicone 0.04 g; glycerol 0.4 g; purified water 0.37 g.

EFFECT: using the invention increases the therapeutic effect and bioavailability of the capsules, increases the prolonged action time, provides the control release of the active substances.

3 cl, 1 dwg, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents a topical composition containing a combination of natural salt or pure sodium chloride and glucose mixed in ratio 1:1-30 (wt/wt) as an active ingredient in an amount effective for treating bacterial vaginosis caused by Cardnerella vaginalis together with a pharmaceutically acceptable carrier.

EFFECT: invention provides the higher pharmacological activity.

4 cl, 4 ex, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, namely to homeopathic suppositories for treatment of fungal colpitis, vulvovaginitis, endometriosis, papillomas, cervical erosion, candidosis and vaginal dryness (versions). Homeopathic suppositories for treatment of fungal colpitis, vulvovaginitis, endometriosis, papillomas, cervical erosion, candidosis and vaginal dryness, contain Sea buckthorn oil, homeopathic oil extract, thuya oil, melaleuca oil, juniper oil, homeopathic essence of eucalyptus, homeopathic essence of elder flower, homeopathic essence of wormwood, thick extract of galium, thick extract of cimicifuga, base, taken in specified quantity. Homeopathic suppositories for treatment of fungal colpitis, vulvovaginitis, endometriosis, papillomas, cervical erosion, candidosis and vaginal dryness, containing Sea buckthorn oil, homeopathic oil extract, valerian oil, Melissa oil, Humulus lupulus oil, homeopathic essence of Viscum album, homeopathic essence of jaborandi, thick extract of galium, thick extract of cimicifuga, base, taken in specifies quantity. Homeopathic suppositories for treatment of fungal colpitis, vulvovaginitis, endometriosis, papillomas, cervical erosion, candidosis and vaginal dryness, containing homeopathic oil extract, beggar-ticks oil, homeopathic essence of lycopodium, homeopathic essence of cantharis, thick extract of galium, thick extract of cimicifuga, base, taken in specified quantity.

EFFECT: suppositories are efficient for treatment of fungal colpitis, vulvovaginitis, endometriosis, papillomas, cervical erosion, candidosis and vaginal dryness.

3 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to a method for preparing a therapeutic hydrogel material involving mixing an aqueous solution of sodium alginate and a drug preparation, dispersing a cross-linking agent that is presented by calcium sulphate in glycerol in the concentration of 0.8-2.5%, mixing the dispersion with the prepared mixture of sodium alginate with the drug preparation in ratio 1-2:4-6, placing the prepared product into a tiling pattern and keeping it till form-stable, conducting gamma sterilisation; the formation process involves the mechanical stability measurements with the diametral compression of the formed hydrogel; the hydrogel is considered to be formed once a thickness of the formed hydrogel varies with the diametral compression by 10-30%.

EFFECT: invention provides the wider medical variation of the drug concentrations, preparing high-thixotropy soft hydrogel materials (tablets) easy to administer, including through rectum, preparing the materials that preserve its all their physical-technical and mechanical properties after the gamma sterilisation along with the sterility.

4 cl, 10 ex

FIELD: biotechnologies.

SUBSTANCE: group of inventions refers to microbiology and biotechnology. Proposed strains Lactobacillus crispatus "ВКМ" B-2727D, Lactobacillus gasseri "ВКМ" B-2728D and Lactobacillus plantarum "ВКМ" B-2731D have antagonistic activity in relation to pathogenic and semi-pathogenic microorganisms. Besides, the invention proposes a consortium based on the above strains for production of a bacterial preparation, a biologically active additive, and direct inoculation for obtaining fermented milk product of functional nutrition.

EFFECT: consortium has higher antagonistic activity against pathogenic and semi-pathogenic microorganisms in relation to individual strains of lactobacilli, use of a consortium will allow enlarging the range of devices intended for prophylaxis and treatment of urogenital infections of females.

4 cl, 1 dwg, 7 tbl, 12 ex

FIELD: medicine.

SUBSTANCE: what is presented is using oestriol for preparing a pharmaceutical dosage form for the vaginal administration of oestriol in a dose of 0.1 mg/day or less for preventing and/or treating urogenital atrophy in females prone to a high probability of the development of oestrogen-dependent tumour or the patients suffering or suffered from oestrogen-dependent tumour.

EFFECT: it is shown that oestriol has the limited absorption from the declared dosage form that reduces its systemic exposure as compared to the control preparation that is "Ovestinon®" cream containing oestriol 0,1% with the effective elimination of vaginal atrophy.

24 cl, 1 dwg, 7 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a composition for local application for treating vaginitis of various origins and related inflammatory inflammations. The above composition contains benzophenanthridine alkaloids, benzofuran compounds and optionally Zanthoxylum bimgeanum or Echinacea angustifolia extract.

EFFECT: composition possesses antibacterial, antifungal and antienzymic activity and reduces vaginal infections fast, eliminates the presence of saprophytes, relieves inflammation, itch and vaginal pH.

12 cl, 3 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a composition for oral hygiene and for treating and preventing pathological conditions related to the dentofacial system, implants and complications following the oral surgeries. The above composition contains benzophenanthridine alkaloids, benzofuran compounds and catechine polyphenols.

EFFECT: composition possesses antibacterial, antifungal and antienzymic activity that exceeds total activities of the different ingredients if used separately.

14 cl, 2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely gynaecology and may be used for individual selection of the preparations containing the probiotic lactic bacterial strains for effective intravaginal therapy. For this purpose, vaginal epithelial cells are recovered from the patient, released from the accompanying microflora. That is followed by preparing an epithelial cell suspension in a culture medium, and mixed with a suspension of thermally-activated probiotic lactic bacterial strains. Then, the suspension is incubated; the epithelial cell culture fluid filtrate is prepared and added to the suspension of the tested probiotic lactic bacterial strains in ratio 1:7. Concurrently, a reference of the mixture of the epithelial cell culture medium and the suspension of the tested probiotic lactic bacterial strains in ratio 1:7 is prepared. The test and reference samples are incubated, measured for optical density; and a degree of biomass increase in the test sample is related to that in the reference. The preparation containing the probiotic lactic bacterial strains the biomass increase of which under the influence of patient's vaginal epithelial cells is stimulated most is selected form the effective intravaginal therapy.

EFFECT: invention enables the individual selection of the preparations containing the probiotic lactic bacterial strains for the effective intravaginal therapy.

3 ex, 1 tbl, 2 dwg

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine and is intended for treatment of vaginal infections. Method includes complex therapy with application of immunocorrector. As immunocorrector solution of medicine Betaleukin, introduced intravaginally during 40-90 minutes daily at least during 5 days, is applied.

EFFECT: method is highly efficient in complex therapy of vaginal infections.

3 ex

FIELD: agriculture.

SUBSTANCE: group of inventions relates to the field of animal husbandry and is intended for stimulation of energy metabolic processes and to the method of prevention of patrimonial pathologies and postnatal diseases at cows. The offered composition for stimulation of energy metabolic processes includes the use of amber acid as an energy stimulator. A carbohydrate component is beet treacle, it is used in the following ratio of components per 1 litre: amber acid - 15 g, beet treacle - 500 g, water - the rest. The offered method includes the administration of the named composition a days before calving and during the first hours after calving.

EFFECT: use of the offered group of inventions allows to provide high power activity in organisms of animals during the predicted periods of risk of development of serious pathobiochemical processes, in particular in prenatal and postnatal periods.

2 cl, 2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: combined phyto- and physiotherapy is conducted. The phytotherapy involves administering Prolit Super 2 capsules two times a day (at 8 and 14 o'clock) for one month; the physiotherapy provides rectal electrical stimulation by means of AndroGyn for 8 minutes a day, 15 procedures in the therapeutic course.

EFFECT: invention enables improving the sexual function and prostatic microcirculation, and can be used in ambulance situation.

1 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: invention relates to a method of treating a mammal with endometriosis. The claimed method includes the pulse or interrupted peroral introduction of an N-acetyl-L-cysteine-containing pharmaceutical composition for 3-5 successive days with the following 2-4-day break or for 1-3 successive days with the following 1-2-day break, for at least a two-month time period. N-acetyl-L-cysteine in the said method is introduced in a dose, constituting from 20 to 90 mg/kg/day.

EFFECT: claimed method provides the more significant effect with respect to endometriosis symptoms in comparison with the traditional daily introduction of N-acetyl-L-cycteine.

11 cl, 7 dwg, 2 tbl, 3 ex

FIELD: veterinary medicine.

SUBSTANCE: method comprises intramuscular administration in the body of the medicinal drug of antioxidant action prior to anticipated calving twice. The first administration is performed 50÷60 days before. The second administration is carried out 15÷20 days prior to anticipated calving. The medicinal drug is used as immunofan which is administered in a dose of 4÷5 ml per animal.

EFFECT: invention is highly effective for prevention of postpartum inflammatory diseases of uterus and mammary gland.

3 tbl, 1 ex

FIELD: veterinary medicine.

SUBSTANCE: method comprises intramuscular administration of the tylosin-containing preparation at a dose of 0.05 ml/kg body weight once a day for 3-4 days in all forms of mastitis. The tylosin-containing preparation is used as the preparation of the following composition, wt %: colistin sulphate - 4.0-6.0; tylosin base - 4.0-6.0; benzyl alcohol - 4.0; water for injection - 15.0; 1,2-propylene glycol - 100.0%.

EFFECT: use of the claimed invention enables to improve the therapeutic efficacy of treatment of mastitis.

3 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine and concerns a stable composition of nanostructured Sildenafil inhibiting cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDEV) containing a nanostructured Sildenafil base or its pharmaceutically acceptable salts having an average particle size of less than approximately 500nm, a stabilising agent, wherein the composition is prepared in a microfluidics-based continuous-flow tank reactor, and the composition possesses a semi-amorphous structure. The group of inventions also concerns a method for preparing the composition of nanostructured Sildenafil; using the above composition for preparing the pharmaceutical composition for treating male or female sexual dysfunction and pulmonary arterial hypertension.

EFFECT: group of inventions provides the improved solubility of the composition.

8 cl, 11 ex, 14 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula (I), which can be used for treating diseases mediated by an androgen receptor. In formula (I), R1 means (C2-6)alkyl, (C1-6)alkyloxy, -S(O)m-(C1-6)alkyl, (C1-6)fluoroalkyl, CN or halogen, R2 and R3 are identical or different and mean a hydrogen atom or (C1-9)alkyl, R4, R5, R6, R7 are identical or different and mean a hydrogen or halogen, X means CH or N, Y means either a nitrogen atom, or a carbon atom substituted by (C1-6)alkyl, (C1-6)alkyloxy, (C1-6)fluoroalkyl, a hydrogen atom or halogen; m is equal to 0, 1 or 2.

EFFECT: invention refers to using the compounds for preparing a therapeutic agent for preventing and/or treating hirsutism, androgenetic alopecia, hypertrichosis, atopic dermatitis, disordered sebaceous gland, such as hyperseborrhea, acne, greasy skin or seborrheic dermatitis.

8 cl, 2 tbl, 26 ex

FIELD: veterinary medicine.

SUBSTANCE: method comprises intravaginal administration of probiotic preparation "Giprolam" (Lactobacillus fermentum 44/1 and Lactococcus lactis subsp. Lactis 574). "Giprolam" is administered for 5-7 days prior to calving daily at a dose of 100 cm3.

EFFECT: use of the claimed invention promotes to maintain the amount of lactobacilli and bifidobacteria at the physiological level, prevents the colonisation of the genital tract with potentially pathogenic microflora and prevents the occurrence of postpartum infections.

6 tbl, 2 ex

FIELD: veterinary medicine.

SUBSTANCE: method comprises the combined use of the tissue preparation on the 1, 3 and 5 days of treatment, and 15% solution of ASD-2f on tetrahydrovit at a dose of 10 ml intramuscularly on the 2, 4 and 6 days of treatment. The tissue preparation is used as biogenic stimulator aminoseleton which is administered subcutaneously into the upper third of the neck in increasing dose of 40-45-50 ml.

EFFECT: method is highly effective for treatment of subclinical mastitis in lactating cows.

3 tbl, 1 ex

FIELD: veterinary medicine.

SUBSTANCE: chemotherapeutic agent is used as N,N-dimethylamino-propylamides of fatty acids of the formula 1 which are used in the form of salts with pharmacologically acceptable acids.

EFFECT: use of the claimed invention is highly effective for treatment of animals with postpartum endometritis.

4 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to racemic 3-hydroxy-16-methyl-2-fluoro-13α-estra-1,3,5(10),8,15-pentaen-17one of formula , which is used as an inducer of high-density lipoproteids, as well as to a method of its obtaining. The method includes reaction of 6-hydroxy-7-fluorotetralone-1 with vinylmagnesium bromide, condensation of formed vinylcarbinol with 2,4-dimethylcyclopentan-1,3-dion with further cyclohydration of the obtained secocompound under action of p-toluenesulfonic acid in toluene.

EFFECT: improved properties of compounds.

2 cl, 1 ex

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