Method for supporting amenorrhea in women subjecting constant administration of progestin and pharmaceutical composition for its realization

FIELD: medicine, gynecology, pharmacy.

SUBSTANCE: invention relates to a method for supporting amenorrhea in women subjecting the constant progestin therapy providing to induce endometrial atrophy and to avoid significant unfavorable adverse effects that accompanying administration of progesin usually. Invention provides the complete amenorrhea without intermittent bleeding or secretion of small blood amount from vagina and without significant unfavorable adverse effects as can be occur in other methods. The curative effect is attained due to the constant intravaginal administration of progestin in water-insoluble, water-swelling cross-linked polymer based on polycarboxylic acid.

EFFECT: improved supporting method, valuable medicinal properties of composition.

7 cl, 3 dwg, 2 ex

 

The technical field to which the invention relates.

The present invention relates to medicine, in particular to a method of maintaining amenorrhea in women undergoing constant projectnature, allowing to cause endometrial atrophy and to avoid significant adverse side-effects that usually accompany the introduction of progestin.

The level of technology

Progesterone is a natural steroid, which is the main steroid secreted by women during their reproductive age. This steroid has been well studied, it was found that it is the main precursor in the biosynthesis of most other steroids, particularly glucocorticoids, androgens and estrogens. Progesterone stimulates the development of the uterus and the number of specific changes in the endometrium and the myometrium. He is vanim for the growth of decidual tissue and differentiation luminaries and glandular epithelial tissue. The progesterone plays a special role in pregnancy, including breast development, inhibition of the contractility of the uterus, the continuation of the pregnancy, the immune protection of the embryo and the inhibition of prostaglandin synthesis.

Progestins include natural progestin, progesterone and synthetic progestins, such as medroxyprogesterone (MPA). Progestin use is in the pharmaceutical industry for the treatment of a number of clinical disorders, such as luteal phase deficiency, dysfunctional uterine bleeding, endometriosis, endometrial carcinoma, benign breast disease, pre-eclampsia, and to facilitate in vitro fertilization, prevention of premature miscarriage and reduce the spread of endometrial hyperplasia in estrogensensitive therapy (ERT).

Usually the most used agents related to gestagenna funds are synthetic progestins, the application of which is accompanied by undesirable side effects, such as depression and water retention. In addition, many of the synthetic progestins, taking place from 19-nortestosterone reverse the positive effects of estrogen on the levels of high density lipoprotein (HDL). In contrast, natural progesterone does not cause water retention, is rarely associated with depression and has no adverse effects on lipid profiles.

There are many difficulties when administered to patients natural progesterone in maintaining appropriate levels in serum and tissue. With the introduction of oral progesterone is rapidly metabolized (see, for example, Adlecruz N. and Martin F. J. Steroid Biochem., 13, 231-244 [1980]; and Maxson W.S. and Hargrove J.T., Fertil. Steril., 44, 622-626 [1985]).

Attempts were made to introduce progestins rectally in a dose of 25 mg is 100 mg of natural progesterone, the peak plasma levels were reached after 4-8 hours after administration, followed by a gradual decrease. Maintaining the stable level of plasma with the introduction of this way was, however, difficult (Maxson W.S., Clinical Obstet. Gynecol., 30, 465-477 [1987]; Nillius S.J. Johansson and E.D.B., Am. J. Obstet. Gynecol., 110. 470-479 [1971]). The result sublingual injection was rapid emergence of progesterone in serum, reaching peak values up to ten times greater than baseline levels, however, return to background levels occurred within twenty-four hours (Villanueva V. and others, Fertil. Steril., 35, 433-437 [1981]). When introduced through the nose doses of 20 mg and 30 mg, reached lower maximum concentrations of 2.1 and 4.1 ng/ml, preferably at least 30 and 240 minutes, respectively.

Attempts were made to introduce progesterone intramuscularly in doses of 100 mg, which made it possible to achieve concentrations in the serum of 40-50 ng/ml for two to eight hours (Nillius S.J. Johansson and E.D.B., Am. J. Gynecol., 110. 470-479 [1971]). This introduction has shown that injections need to be done every day or every other day to achieve results (Whitehead M. and Godfree V. Hormone Replacement Therapy, Churchill Livingston Edinburg, 1992, 91 C.). It was also tested subcutaneous administration using six pills containing 100 mg progesterone implanted women after childbirth (Croxatto NV and others, Acta Endocrinol., 100, 630 [1982]). Progesterone levels reached peak values of 4.4 ng/im the first week after injection, the average peak level was 1.9 ng/ml within six months after implantation. Progestin-only implants were useful in cyclic therapy and thus, were not reached physiological levels progestin (under the "circular" therapy understand that from time to time impose progestin, usually during part of each 28-day cycle or each calendar month). For example, the cyclic introduction can be daily or every other day, only on days 15 and 20 of each 28-day cycle or only during the first five days of each month. (Under "continuous" or "continuous" therapy understand what the drug is administered regularly, at least it is introduced, whatever, every day, every other day, once a week or in some other way, for example, in the case of a 28-day cycle or calendar month).

It is shown that locally applied radioactive progesterone can be absorbed through the skin (Mauvais-Jarvis and others, Progesterone, J. Clin. Endocrinol. Metab., 29. 1580-1587 [1969]). Labeled metabolites were separated in the urine within 48 hours after local injection. However, absorption was only 10% of the used dose. High jirorastvorimogo progesterone is responsible for the prolonged retention this steroid, and extensive local metabolism reduces the systemic effect of the steroid. It is shown that the processing of the shackles of the m local application of progesterone on the breast does not cause significant endometrial effects (Sitruk-Ware R. and others, J. Clin. Endocrin. Metab., 44. 771-774 [1977]).

Progestins have also introduced vaginally postmenopausal women receiving estrogensensitive therapy. Administration of a 50 mg/ml of progesterone in the suspension containing the carboxymethylcellulose and methylcellulose, which was introduced in the vagina, characterized by rapid absorption of progesterone through the vaginal mucosa. Was to appear immediately hormone in the peripheral circulation (blood flow), resulting in a 10-fold excess of base levels in serum (0.34 ng/ml) after 15 minutes. Peak levels were reached after 1 or 2 hours after injection and this meant 30-40 times higher base levels (12,25 ng/ml). Levels in serum remained at this value during the next seven hours, falling in the next 10 hours to 3.68 ng/ml (Villanueva V. and others, Fertil. Steril., 35, 433-437 [1981]). These results suggest that the absorption of progestins increases in women at estrogensensitive therapy.

In U.S. patent 5 543 150, which is included in the present description by reference, it is shown that is used according to the invention bioadhesive composition can provide local vaginal introduction of progestins to achieve significant local levels medicines, while the levels of serum under arrivalsa sufficiently low in order to avoid the highly undesirable side effects (see also Warren M.P. and others, Evaluation of Crinone®, a Transvaginally Administered Progesterone Containing Bioadhesive Gel in Women wich Secondary Amenorrhea, Abstract presented at the eighth International Congress on the menopause, Sydney, Australia, 1996). In the application for U.S. patent 08/743153, which is incorporated into this description by reference, also shown that progesterone can be introduced to cure or ameliorate ischemia or reduction of cardiovascular disorders.

Treatment of menopausal and postmenopausal women, including the introduction of progestins in cyclic Association with estrogen, causes physiological sequence of endometrial changes, which are usually encountered in the menstrual cycle. By such treatments is usually injected progestins daily for a period of time about days from 10th to 14th of each month. However, withdrawal bleeding, which is a result of such introduction is usually irregular and unpredictable and often begins early on about the fourth day after the first dose progestin (see D.F. Archer and others, Bleeding Patterns in Post-menopausal Women Taking Continuous Combined or Sequential Regimens of Conjugated Estrogens with Medroxyprogesterone Acetate, Obstet. Gynecol., 83, 686-692 [1994]).

The invention

The present invention relates to a method of constant vaginal injection to maintain full amenorrhoea with the exception of a significant negative is retnuh side effects. The invention provides complete amenorrhea without periodic intermittent bleeding or discharge a small amount of blood from the vagina that is often observed when using other methods, during the time from three to six months, and without significant adverse side effects, often resulting from other methods.

This method maintain amenorrhea in women exposed to constant introduction of progestin, includes constant vaginal introduction progestin through the delivery system lekarstvennogo means to the site of action in sufficient quantity to cause endometrial atrophy and to avoid significant adverse side effects, the system of delivery of drug to the site of action involves water-insoluble cross-linked polymer-based polycarboxylic acid and 4 wt.% progestin.

In a specified way as polymer preferably used polycarbophil and a progestin, preferably, is progesterone.

The method provides that the progestin is administered, preferably twice a week.

This invention relates also to pharmaceutical compositions for permanent vaginal injection of progestin to induce endometrial atrophy order to maintain amenorrhea, stereoselection together with water-insoluble, however, swelling in water, bioadhesive crosslinked polymer based on polycarboxylic acids, and specified the pharmaceutical composition contains 4 wt.% progestin.

Specified pharmaceutical composition as progestin preferably contains progesterone, as well as polymer - polycarbophil.

This invention relates also to the method of constant vaginal injection of progestin to induce endometrial atrophy order to maintain amenorrhea, including the introduction of the composition described above in a therapeutically effective amount.

Brief description of drawings

Figure 1 illustrates the nature of bleeding caused by a dose of 45 mg progestin (CRINONE®the gel with 4% progesterone), cyclically injected vaginally every day.

Figure 2 illustrates the nature of bleeding caused by a dose of 45 mg progestin (CRINONE®the gel with 4% progesterone), cyclically injected vaginally every other day, as reported Warren MR and others, Evaluation of Crinone®, a Transvaginally Administered Progesterone Containing Bioadhesive Gel in Women wich Secondary Amenorrhea, Abstract presented at the eighth International Congress on the menopause, Sydney, Australia, 1996).

Figure 3 illustrates the nature of bleeding caused by a dose of 90 mg progestin (CRINONE®the gel with 8% progesterone), cyclically injected vaginally through d is Ni, as reported M.P. Warren and others, Evaluation of Crinone®a Transvaginally Administered Progesterone Containing Bioadhesive Gel in Women with Secondary Amenorrhea, Abstract presented at the eighth International Congress on the menopause, Sydney, Australia, 1996).

Information confirming the possibility of carrying out the invention

The present invention relates to a method for processing progestins, including the use of a therapeutically effective amount of progestin for vaginal introduction of menopausal and postmenopausal women in enhanced mode to maintain amenorrhea. In this embodiment, the system of delivery of drug to the site of action involves water-insoluble, swellable in water cross-linked polymer-based polycarboxylic acid containing 4 wt.% progestin. Features preferably constant, and not circular, the Association of estrogens and progestins for menopausal and postmenopausal women to completely avoid monthly withdrawal bleeding (Azzawi A.J., de Ziegler D., Vaginal Progesterone Gel-based Continuous Combined HRT as an Amenorrehic Regimen presented at the IV European Congress on menopause, Vienna, October 1977). Permanent or regular, the introduction of progestins during the entire month without a break stimulates amenorrhea, or the absolute absence of bleeding. However, precisely because of the occurring is Yu amenorrhoea, the continuous introduction of progestins does not cause often desirable physiological endometrial changes associated with the menstrual cycle, during which the endometrium is exposed to monthly transformation and growth. Instead, the endometrium is in a continuing state of atrophy.

Even when endometrial atrophy and, thus, it is desirable to maintain amenorrhea, continuous daily vaginal introduction progestins impossible and difficult. The authors also studied the properties of a long selection of gel with a progestin, as described in U.S. patent 5 543 150, and reached a constant uterine "exposure" with the continued administration of progesterone by reducing vaginal injections to an acceptable injection twice a week. CRINONE®the gel with 8% progesterone, produced by Wyeth-Ayerst Laboratories, Philadelphia, Pennsylvania, is shown to maintain amenorrhea by dosing twice a week to women already receiving permanent percutaneous estrogen. Achieved and supported by the introduction endometrial atrophy is also expressed by the high prevalence of amenorrhea and a thin endometrium, as shown by ultrasound. This simple, easy treatment, devoid of the commonly known side effects and problems faced when using the synthetic progestins or with the drug orally, represents a new clinical choice for menopausal and postmenopausal women who want to completely avoid withdrawal bleeding while receiving progestins (see Fanchin R, de Ziegler D., and others, Transvaginal Administration of Progesterone: Dose-response Data Support a First Uterine Pass Effect, Obstet. Gynecol., 90, 396-401 [1997]).

In contrast to other ways of introducing progestin, known in the prior art, continuous treatment with progestin quickly maintains complete amenorrhea. This provides convenience for women who want to amenorrhea, without periodic intermittent bleeding or discharge a small amount of blood from the vagina, which is usually only three to six months, when using other treatment.

The invention relates to the use of a composition with a progestin for permanent vaginal introduction the purpose of maintaining complete amenorrhea. Preferably, the composition contains progestin progesterone and bioadhesive media, which may be in the form of a gel composition comprising a polymer base, designed to achieve a controlled and prolonged excretion of progesterone through the vaginal mucosa. This route of administration also avoid primarily with the problems of the metabolism, as well as many significant adverse events.

The crust is ASEE the invention relates to a regimen and method of processing a progestin in hormone replacement therapy. Preferably introduced at a time of about 45-90 mg of progesterone. Composition for continuous administration is preferably introduced about twice a week. Highly preferably use only the natural progesterone.

Preferred specific, delivering the drug to the site of action of the composition, which is selected and used in examples 1 and 2, CRINONE®that gels with 8% and 4% progesterone, produced by Wyeth-Ayerst Laboratories, Philadelphia, Pennsylvania, include compositions with crosslinked polymer based on polycarboxylic acids generally described in U.S. patent 4 615 697, Robinson, and in U.S. patent 5 543 150, each of which is introduced in the present description by reference. Typically, at least about eighty percent of monomer units of the polymer in such compositions should contain at least one carboxyl group. Crosslinking agent should be present in such quantity, to ensure sufficiently bioadhesion so that the system can remain attached to employees target epithelial surfaces for sufficient time to achieve the desired dosage.

For vaginal administration, such as in the examples below, preferably the composition remains attached to the epithelial surfaces during the period of time, at least from approximately twenty-four hours to forty-eight hours. Such results can be obtained clinically for various periods of time. This preferred level of bioadhesive usually reached when a crosslinking agent is present in amount of about 0.1 to 6.0 wt.% in the calculation of the weight of the polymer, more preferably about 1.0-2.0 wt.%, while the result will not be achieved the appropriate level of bioadhesive. Bioadhesive can be determined using a commercially available surface tensiometer used for measuring the strength of adhesion.

Composition based polymer can be adjusted to regulate the rate of release of progesterone by changing the amount of cross-linking agent in the polymer. Suitable crosslinking agents include Divinington, divinylbenzene, N,N-diallylamine, 3,4-dihydroxy-1,5-hexadiene, 2,5-dimethyl-1,5-hexadiene and similar agents.

The preferred polymer for use in such compositions is polycarbophil, according to the US Pharmacopoeia, which is produced in the sale of the company B.F. Goodrich Speciality Polymers of Cleveland, HE, under the trade name of a Noveon®-AA1. In the US Pharmacopoeia, edition 1995.. United States Pharmacopeial Convention, Inc., Rockville, Maryland, pages 1240-1241, indicates that polycarbophil is a polyacrylic acid, crosslinked with POM the override diphenylglycine.

Other suitable bioadhesive polymers that can be used in such a composition, which is the system for delivering drugs to the site of action, stated in U.S. patent 4 615 697. For example, they include polymers based on polyacrylic acid, crosslinked, for example, using 3,4-dihydroxy-1,5-hexadiene, and polymers based on poly (methacrylic acid, crosslinked, for example, using divinylbenzene.

Typically, these polymers cannot be used in their salt form, as this may lead to a reduction in their bioadhesive abilities. Such bioadhesive polymers can be obtained by means of conventional free-radical polymerization using initiators such as benzoyl peroxide, azobisisobutyronitrile, and the like. The examples of the preparation of suitable bioadhesives described in U.S. patent 4 615 697.

Bioadhesive the composition may be in the form of a gel, cream, pill, pills, capsules, suppository, film, or any other pharmaceutically acceptable form, which adheres to the mucosa and is not easily washed away. Various compositions are described in U.S. patent 4615 697, which is included in the present description by reference.

Additionally, additives specified in U.S. patent 4615 697, can be mixed with the crosslinked polymer in the composition for maximum or desirable for the efficiency of the delivery system or for patient comfort. Such additives include, for example, softening components, plasticizing agents, preservatives, gelling components, contributing to the formation of tablets, pills, suppositories components, film-forming components, kremoobraznaya components, disintegrators, components for coating shell, binders, carriers, colorants, regulatory taste and/or odor additives, vlagouderzhivatel substances that regulate the viscosity of the components, additives to establish a pH-values, and similar components.

Preferred containing progestin composition is CRINONE®the gel with 4% or 8% progesterone, which consists of the following ingredients listed, in addition, U.S. patent 5 543 150: 4 or 8 wt.% progesterone is 12.9 wt.% glycerin, 4.2 wt.% mineral oil, 2 wt.% polycarbophil (manufactured by a company B.F. Goodrich Specialty Polymers of Cleveland, Ohio), 1 wt.% the glycerides hydrogenated palm oil, 1 wt.% carbomer R (manufactured by a company B.F. Goodrich), 0.08 wt.% sorbic acid, 0-2 wt.% sodium hydroxide, and the remainder is purified water. (This is the same basic components, specified in U.S. patent 5 543 150, in column 6, lines 44-52, except that in this case is not included methylparaben).

Sorbic acid is a preservative, which can be replaced by any other approved (the past is dsim tested) preservative, such as methylparaben, benzoic acid or propionic acid.

Carbomer R is a gel-forming component, which can be replaced by other gel-forming components, such as carbomer R, carbomer 980, methylcellulose or propylethylene.

Glycerin is a water-retaining substance; alternative blagoder living substances include, for example, propylene glycol or dipropyleneglycol.

Mineral oil and glycerides hydrogenated palm oil are mitigating components; alternative softening components include, for example, any mineral or vegetable oil, such as canola oil, palm oil or light mineral oil.

Sodium hydroxide is a strong base for the purposes of the regulation of pH; it can be replaced by other bases, usually used for this purpose.

The preparation of the composition includes the hydration of polymers, separate mixing a water-soluble ingredients (polymer phase) and fat-soluble ingredients ("oil phase"), the heating and mixing of both phases and homogenization of the mixture. All these ingredients are well known and readily available from well-known industry suppliers.

Polymer phase can usually be obtained by the masiania water, sorbic acid, polycarbophil adding carbomer. Polymers hydratious by stirring for several hours, usually about 2-3 hours, until, until you get a uniform, homogeneous, homogeneous, devoid of lumps gel-like polymer mixture. When the polymer is fully gidratirovana add progesterone and mix to obtain a homogeneous suspension.

The oil phase is usually obtained by melting together of glycerin and mineral oil by heating to a temperature of 75-78°C. the Mixture is cooled to a temperature of about 60°while the polymer phase is heated to approximately the same temperature. Then the polymer phase is added to the heated oil phase. Both phases are thoroughly mixed, obtaining a homogeneous product is a creamy white color. If you mix sodium hydroxide to achieve a pH of about 2.5 to 3.5, usually about 3. When the mixture cooled, it dearyou. The resulting product is aseptic due to the nature of the preparation and pH-values, as well as due to the presence of the preservative.

As obvious to the specialist, the composition can be modified to influence certain properties of the composition. For example, it is possible to adjust the concentration bioadhesive polymer to provide more or less bioadhesive. The viscosity can change is by varying the pH or by changing the concentration of the polymer or gelling component. You can change the relative concentrations of oil compared to water for modulating the rate of release of progestin from the system of delivery of drug to the site of action. The pH value can also be changed, as needed, or to influence the allocation rate or bioadhesives composition.

Composition with a progestin can be entered vaginally by any of numerous methods known in the prior art, such as the introduction with the help of a plunger device, by spraying, using a suppository or manually. The preferred method of introduction is the use of a device such as described in U.S. patent number Des. D345211 or in U.S. patent number Des. D375352, the disclosure of which is incorporated into this description by reference. Such a device is an elongated hollow container, one end of which is capable of opening and the other end contains most of the input composition and is able to compress. Such devices allow you to pre-determine the quantity of a product, administered in a single dose with the help of the hermetically sealed container which is relatively simple to be used. Containers also keep the product in an aseptic environment to use. During use of the container opening and the open end is inserted into the vagina, then the AK the other end of the squeeze to eject the contents from the container into the vagina. "Set" with the product may contain, therefore, a single dose or multiple doses of the product.

Example 1

Daily, against cyclic twice a week, and the continuous introduction of progesterone

This study is intended for research use CRINONE®, gel progesterone in menopause as part of hormone replacement therapy ("HRT") in cyclic Association with estrogen therapy, and continuous combined Association with estrogen mode without bleeding. This example presents the results obtained in the case of the first groups of studied subjects. (The study was continued with an additional number of subjects; the final results obtained in the case of all subjects, including those listed in example 1 are given below in example 3).

Were collected from two groups of women, each of which consisted of 20 women. Group I was comprised of women aged from 38 to 55 years, and every woman showed menopausal symptoms or have received hormone replacement therapy. Group II was comprised of women aged 50 to 64 years old, and every woman for more than three years was in menopause (amenorrhea) or received hormone replacement therapy with cyclic bleeding. None of the women in each group had no abnormal bleeding or any other related Mat is e, pathology.

Group I continuously received estrogen (PREMARIN®(0.625 mg), conjugated estrogens (Wyeth-Ayerst Laboratories, Philadelphia, Pennsylvania), PROGYNOVA®(2 mg), estradiolvalerate (Schering AG, Berlin, Germany), or ESTRADERM®TTS (50 mg) or ESTRADERM®MX 0,05 (0,050 mg), estrogen "patches" (Novartis Pharmaceutical, Basel, Switzerland), and CRINONE®the gel with 4% progesterone (45 mg progesterone), every day in the morning in the days of the cycle 15-24. (For practical purposes and for the convenience of the administration was carried out once a month in calendar days 1-10, corresponding to the days of the cycle 15-24). Group II received ESTRADERM®Mx (50 mg), estrogen "patch" (Novartis Pharmaceutical), twice a week, continuously (or, if it was found intolerance towards "the patch", OESTROGEL®the gel with estrogen (Besins-Iscovesco Laboratories, Paris, France) every day) and CRINONE®the gel with 8% progesterone (90 mg progesterone), continuously twice a week in the morning.

For all subjects, the baseline in the clinical evaluation, including clinical examination and vaginal ultrasound examination for the purpose of screening for women without pre-processing carried out was of a thickness of less than 5 mm, and for women after HRT or resistant ovarian function of thickness less than 10 mm In group I, women were informed that they reported any vagina is enom bleeding, other than withdrawal bleeding, defined as a withdrawal bleed bleeding beginning after the last (tenth) dose of progesterone.

Processing was carried out 6-12 months after it was set a baseline for 0-6 months. In conclusion, all the women again were examined, including vaginal ultrasound and endometrial sampling when an ultrasound revealed for women in group I, endometrium thickness more than 10 mm, or for women of group II endometrium thickness more than 5 mm the Results are presented in tables 1 and 2 and figure 1.

Table 1:

The thickness of the endometrium according to the ultrasound (mm; mean±standard error in the measurements)
BaselineAfter treatment (months 6-12)
group I4,5±1,54,5±0,8
group IIwithout HRT 3,2±0,6

HRT 6,3±1,9
no bleeding 3,3±1,0

bleeding 3,5±1,1

Table 2

The nature of bleeding
The average ageThe type of bleeding n%Disposition
Group I46,8±4,1Expected: only withdrawal19/2095100%; nepreryvnaya HRT
abnormal: intermittent and/or other abnormal bleeding1/205n=1;

discontinued HRT
Group II57,5±4,6Expected: amenorrhea (no bleeding)15/2075n=13 (87 %);

continuous HRT
n=1:

the modified mode

n=1: discontinued HRT
acceptable: a separate allocation of a small amount of blood from the vagina / light bleeding4/2020n=4:

all continuous
unacceptable: heavy bleeding/frequent allocation of a small amount of blood from the vagina1/205n=1: D and With benign histology

The figure 1 shows the proportion of patients with bleeding and chronometry of such bleeding for the subjects of group I,which was administered daily progesterone. In contrast, in figures 2 and 3 show the proportion of patients with bleeding and chronometry of such bleeding for patients receiving, respectively, 45 mg and 90 mg of progesterone (CRINONE®the gel with 4% and 8% progesterone) in a day, as reported by Warren and others, cited above.

As presented in detail in table 2 and on figure 1, the cyclic introduction to the subjects of group I daily CRINONE®, gel progesterone, resulting in 95% of exposed experiment subjects causes withdrawal bleeding only after periods of dosing monthly progestin. Thus, daily administration completely changes the nature of the bleeding, which is expressed in the regular bleeding within 1-4 days after completion of processing monthly progesterone, without any other form of bleeding, if 95% of patients. All of these patients with regular bleeding continued its program of HRT, while the only patient with irregular bleeding completely stopped HRT.

In contrast CRINONE®the gel progesterone cyclically inserted through the day, is the character of bleeding, similar to that reached with synthetic progestins (MPA), regardless of the number of used CRINONE®, gel progesterone (4% (45 mg) or 8% (90 mg)). (see Warren and others, as described in the above in the present description regarding CRINONE ®, gel progesterone, and reflected on figures 2 and 3, compared with Archer and others, as described above in the present description regarding MPA). This daily regime, therefore, very attractive, when it is desirable for precise control of bleeding.

For group II, with the constant introduction of CRINONE®, gel progesterone, 75% of the subjects did not experience withdrawal bleeding and only 5% (one in twenty of the subjects experienced severe bleeding or frequent allocation of a small amount of blood from the vagina. Of the 15 patients without bleeding 13 continued its program of HRT (all 4 patients with a separate allocation of a small amount of blood from the vagina or weak bleeding), 1 patient changed his mode and 1 patient stopped HRT. The only subject with severe bleeding or frequent allocation of a small amount of blood from the vagina were subjected to dilatation (D) and curettage (C), in benign histology; his HRT was discontinued.

Thus, CRINONE®the gel progesterone, administered twice a week continuously astroenterology menopausal woman, supports full amenorrhea in most patients. Other experimental data show similar efficiency when using CRINONE®that gel with 4% progesterone (45 mg progesterone). Away the of side effects makes this mode very privlekatelnim choice for menopausal women who do not wish to have menstruation. Previous regimes often led to periodic intermittent bleeding or the allocation of a small amount of blood from the vagina for a period of 3-6 months.

Example 2

Daily, against cyclic twice a week, and the continuous introduction of progesterone

In continuation of the study reported above in example 1, in this study continued to explore the use of CRINONE®, gel progesterone in menopause as part of hormone replacement therapy ("HRT") in cyclic Association with estrogen therapy, and continuous combined Association with estrogen mode without bleeding. Group I included in General 69 women, and group II included in General 67 women. Women of group II more than three years was in menopause, or over the age of 53 years and had no bleeding disorders.

Women in both groups were evaluated after treatment for six months and thereafter at six-month intervals. The thickness of the endometrium was evaluated using ultrasound, and the results of processing, eighteen months, are presented in table 3. The nature of bleeding after six months are presented in table 4. In the subgroup of the fourteen women who were evaluated within eighteen months, twelve were still in a state of amenorrhea in accordance with what their whole observation period.

Table 3:

The thickness of the endometrium according to the ultrasound (mm; mean±standard error in the measurements)
BaselineAfter treatment (months 6-18)
group I4,1±1,54,9±0,9
group IIwithout HRT 3,7±0,7

HRT 6,7±1,45
no bleeding 3,9±1,2

bleeding 3,8±1,76

Table 4:

The nature of bleeding
The average ageThe type of bleedingn%
Group I50±1,5Expected: only withdrawal63/69for 91.3
abnormal: intermittent and/or other abnormal bleeding6/698,7
Group II58±5,3Expected: amenorrhea (no bleeding)54/6780,6
acceptable: a separate allocation of a small amount of blood from the vagina / weak blood is Uchenie 9/67the 13.4
unacceptable: heavy bleeding/ frequent allocation of a small amount of blood from the vagina4/676

In accordance with table 2 and figure 1, discussed above in example 1, table 4 shows that the introduction to the subjects of group I daily CRINONE®, gel progesterone, in 93.3% (sixty-three of the sixty-nine) subjects exposed experiment, causes withdrawal bleeding only after each of the six-month periods introduction progestin. Thus, the daily dosage completely changes the nature of the bleeding, which is expressed in the regular bleeding within 1-4 days after completion of processing monthly progesterone, without any other form of bleeding in the case of 91.3% of patients. Of these sixty-three subjects fifty-eight, or 92%, are assigned the continued introduction of vaginal progesterone for HRT, two assigned to other selected processing and in the case of three terminated any hormone treatment.

For the subjects of group II with postoyannim a dose of CRINONE®, gel progesterone, 80.6% of subjects did not experience withdrawal bleeding, only 6% had experienced severe bleeding or frequent allocation of a small amount of blood in agelisa and 13.4% had experienced a separate allocation of a small amount of blood from the vagina or light bleeding at any time during the six-month evaluation period.

Thus, the results obtained in the study of a larger number of test subjects (with respect to the first group, reported above in example 1), then show that the progestin that is injected twice a week continuously astroenterology menopausal women, supports full amenorrhea in most of the tested patients. And cyclic daily introduction progestin in women undergoing HRT, provokes a much more reliable and regular withdrawal bleeding. Especially in combination with the sharp decrease in side effects, each mode must lead respectively to improved HRT.

Any and all publications, patents and patent applications mentioned in the present description, show a professional level of equipment covered by the present patent. All publications, patents and patent applications included in the present description by reference to the same extent as if each individual publication, patent or patent application is specifically and individually indicated, was included by reference.

Acceptable changes, such as changes that are desirable to a specialist, can be done without deviating from the essence and without leaving the scope of the invention.

1. Way to keep amenorrhea in women exposed to constant introduction of progestin, which with constant vaginal introduction progestin through the system of delivery of drug to the site of action in the amount sufficient to induce endometrial atrophy, while avoiding significant adverse effects, where the system of delivery of drugs to the site of action involves water-insoluble cross-linked polymer-based polycarboxylic acid and 4 wt.% progestin.

2. The method according to claim 1, where the polymer is polycarbophil.

3. The method according to claim 1, where the progestin is progesterone.

4. The method according to claim 1, where the progestin is administered two times per week.

5. Pharmaceutical composition for constant vaginal injection of progestin to induce endometrial atrophy order to maintain amenorrhea, containing a progestin together with water-insoluble, but swellable in water, bioadhesives crosslinked polymer based on polycarboxylic acids, where this pharmaceutical composition comprises 4 wt.% progestin.

6. The pharmaceutical composition according to claim 5, where the progestin is progesterone and the polymer is polycarbophil.

7. Method of constant vaginal injection of progestin to induce endometrial atrophy order to maintain amenorrhea, including the introduction of a composition according to claim 5 in therapeutically effective amounts.



 

Same patents:

FIELD: gynecology.

SUBSTANCE: synthoxic program activity adaptation factor (SPAAF) is derived from following equation: SPAAF = (Cst%+Aat-III%+Agoap%+ Cts%)/(Cad%+Ca2mg%+Cmda%+Cth%), where Cst signifies blood concentration of serotonin, Aat-III antithrombin III activity, Agoap general oxidation activity of plasma, Cts T-suppressor concentration, Cad blood concentration of adrenaline, Ca2mga2-macroglobulin concentration, Cmd malonic dialdehyde concentration, and Cth T-helper concentration. Above concentrations and activity are expressed in % based on reference values found in sound males and females 45 to 55 years of age. When SPAAF equals 0.7, pyroxane in dose 0.015 g twice a day over a 7 days period and 0.005-0.01% phytoecdisterone in 40% alcohol in dose 30 drops thrice a day before meal over 2 weeks period are simultaneously administered. When SPAAF equals 0.5, the same treatment is prescribed but pyroxane is administered for 2 weeks and on the 15th day after the last administration the course is repeated.

EFFECT: stabilized arterial pressure, normalized metabolism, and improved cerebral blood circulation.

2 ex

FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

in which R1 represents H, halogen, OCH3, or OH; R2 represents (a) -X-(CH2)n-CH2-N(R4)R5, where (i) X represents NH or S; n is integer from 1 to 4; R4 and R5, the same or different, represent C1-C4-alkyl, H, -CH2C≡CH, or -CH2CH2OH; or R4 and R5, together, form nitrogen-containing five- or six-membered cycle or heteroaromatic cycle; or where (ii) X represents O; n is integer from 1 to 4; one of R4 and R5 is CH2C≡CH, or -CH2CH2OH and the other H or C1-C4-alkyl; or R4 and R5, together, form imidazole cycle or nitrogen-containing six-membered cycle or heteroaromatic cycle; or R2 represents (b) -Y-(CH2)nCH2-O-R5, where (i) Y represents O; n is integer from 1 to 4; and R6 represents -CH2CH2OH or -CH2CH2Cl; or where (ii) Y represents NH or S; n is integer from 1 to 4; and R6 represents H, -CH2CH2OH, or -CH2CH2Cl; or R2 represents (c) 2,3-dihydroxypropoxy, 2-methylsulfamylethoxy, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, or 2,2-diethyl-2-hydroxy-ethoxy; R3 represents H. halogen, OH, or -OCH3. Claimed compounds are novel selective estrogen receptor modulators. Invention also discloses pharmaceutical composition and a method for production of tissue-specific estrogenic and/or antiestrogenic effect in patient, for whom indicated effect is required.

EFFECT: increased choice of estrogen receptor modulators.

19 cl, 7 tbl, 11 ex

FIELD: medicine.

SUBSTANCE: before applying substitute hormonal therapy (SHT) on should evaluate antithrombogenic activity of vascular wall in women. For this purpose one should determine quantitative values of ADP-induced aggregation of thrombocytes, activity of antithrombin III in blood and fibrinolytic blood activity both before and after "cuff"-test. Then one should detect the indices calculated as the ratio of mentioned values both before and after carrying out the mentioned test. If mentioned indices are decreased against the norm by 20-40% women should be prescribed to undergo SHT at additional introduction of aspirin and supradin. The method provides prophylaxis of cardio-vascular diseases in this category of female patients due to correcting affected functional activity of vascular endothelium.

EFFECT: higher efficiency of prophylaxis.

1 cl, 1 ex, 4 tbl

The invention relates to medicine and refers to the treatment and prevention of normalizing the functions of the genital organs, acute amenorrhea, neurological development and osteoporotic manifestations in premenopausal or menopausal periods

The invention relates to the field of medicine and relates to self-adhesive drug composition for percutaneous use of estrogen combined with progestogen containing 25-90 wt.% self-adhesive acrylate copolymer, 1-15 wt

The invention relates to medicine, in particular to the pharmaceutical industry for the production of drugs therapeutic and prophylactic purposes, and can be used as a means to reduce the risk of symptoms of menopausal syndrome
The invention relates to medicine and for new ways of correction of oestrogen deficiency in natural or artificial menopause
The invention relates to medicine, gynecology, and can be used for the treatment of menopausal syndrome

FIELD: agriculture, animal science.

SUBSTANCE: the present innovation deals with introducing medicinal preparation as a complex compound of ferric iron sulfate with beet sugar and zinc oxide. The remedy should be introduced intrauterinely as 2-5%-solution in distilled water at the dosage of 25-35 ml. Application of the present method enables to restore reproductive function in cows due to removing inflammatory processes in reproductive sphere along with some diseases caused by pathogenic microflora and its mixed forms and, also, liquidate prolonged groundless terms of sterility in cows.

EFFECT: higher efficiency of stimulation.

2 tbl

FIELD: veterinary science.

SUBSTANCE: one should apply a selenium-containing preparation named selecor: it should be introduced on the 80-90th d of swine gestation twice at 10-15-d-long interval parenterally at the dosage of 20 mg/kg animal body weight. Application of low-toxic antioxidant as selecor enables to improve functional properties of cell membranes of placental system and endometrium and increase inspecific immune resistance in sows. It, also, enables to increase fertility in sows, values of uncomplicated deliveries and puerperal period.

EFFECT: higher viability of off-spring.

2 ex, 3 tbl

FIELD: veterinary science.

SUBSTANCE: the suggested preparation contains the following ratio of components, weight%: dioxidine 0.48-0.52, furacrylin 0.021-0.027, dimethylsulfoxide 38-50, distilled water - the rest.

EFFECT: higher therapeutic efficiency.

3 ex, 3 tbl

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of 8-phenyl-6,9-dihydro[1,2,4]-triazolo[3,4-I]purine-5-one of the general formula:

wherein R1 means hydrogen atom, group -CH2-R6 wherein R6 means phenyl; R2 means (C1-C5)-alkyl or group -(CH2)n-R6 wherein n= 1 or 2; R6 means (C1-C4)-alkoxy-group or pyridyl group; R3 means (C1-C6)-alkyl; R4 means hydrogen atom or (C1-C4)-alkyl; R5 means -(CH2)n-R7 wherein n = 0-4; R7 means 3-7-membered ring comprising 1-3 heteroatoms taken among nitrogen atom (N) and oxygen atom (O), (C3-C7)-cycloalkyl or phenyl wherein indicated groups can be substituted with different substitutes; or R4 and R5 mean independently hydrogen atom (H), (C2-C6)-alkynyl or (C1-C6)-alkyl that can be substituted possibly; or R4 and R5 in common with nitrogen atom (N) form 4-7-membered ring comprising 1-2 heteroatoms taken among N and O and substituted possibly. Also, invention relates to their pharmaceutically acceptable salts, methods for preparing these compounds, intermediate substances, pharmaceutical composition and a to a method for treatment of different diseases mediated by activity of phosphodiesterase-5 (PDE-5). Described compounds of the formula (I) are inhibitor of PDE-5.

EFFECT: improved preparing method and treatment, valuable properties of compounds.

20 cl, 5 tbl, 149 ex

FIELD: veterinary science.

SUBSTANCE: one should apply liniment that contains an active substance being "Todicamp-ideal" and a vegetable foundation as a mustard-pumpkin fuse obtained while manufacturing "Volgogradskoe" vegetable oil at weight ratio of mustard and pumpkin oils being 1:9 weight portions. Moreover, "Todicamp-ideal" and mustard-pumpkin fuse are at weight ratio of 10-12 : 90-88 weight portions. In some cases of liniment application upon affected part of cow's udder should be combined with peroral intake of "Todicamp-ideal". The innovation provides simultaneous antiphlogistic, antimicrobial and immunostimulating effect.

EFFECT: higher efficiency of therapy.

2 cl, 2 ex, 1 tbl

FIELD: gynecology.

SUBSTANCE: synthoxic program activity adaptation factor (SPAAF) is derived from following equation: SPAAF = (Cst%+Aat-III%+Agoap%+ Cts%)/(Cad%+Ca2mg%+Cmda%+Cth%), where Cst signifies blood concentration of serotonin, Aat-III antithrombin III activity, Agoap general oxidation activity of plasma, Cts T-suppressor concentration, Cad blood concentration of adrenaline, Ca2mga2-macroglobulin concentration, Cmd malonic dialdehyde concentration, and Cth T-helper concentration. Above concentrations and activity are expressed in % based on reference values found in sound males and females 45 to 55 years of age. When SPAAF equals 0.7, pyroxane in dose 0.015 g twice a day over a 7 days period and 0.005-0.01% phytoecdisterone in 40% alcohol in dose 30 drops thrice a day before meal over 2 weeks period are simultaneously administered. When SPAAF equals 0.5, the same treatment is prescribed but pyroxane is administered for 2 weeks and on the 15th day after the last administration the course is repeated.

EFFECT: stabilized arterial pressure, normalized metabolism, and improved cerebral blood circulation.

2 ex

FIELD: medicine, gynecology, contraceptives, pharmaceutical chemistry.

SUBSTANCE: invention proposes vaginal suppository comprising benzalconium chloride, benzoic acid, purified water and the preparation vitespol taken in the definite content of components. Invention provides the reliable inhibition of fungal microflora being especially against fungus Candida albicans and the absence of irritation and symptoms in vagina drying. Invention can be used as an individual agent for prophylaxis of undesirable pregnancy.

EFFECT: valuable properties of suppository.

5 tbl

FIELD: animal science.

SUBSTANCE: the method deals with applying dry pantohematogen at 3:1000 dilution rate at the dosage of 0.15-0.25 ml preparation/250-300 g fodder. Preparation should be introduced for male sables since the onset of estrus for 21-28 d, and for female sables - on the 13th - 15th d against the onset of estrus till the 2nd - 4th d after coupling. The method enables to increase the quantity of female sables being in heat by the moment of coupling, decrease the number of inactive male sables among 2-yr-aged ones, increase the load per 1 male sable. The method is simple, cheap and highly available at usage.

EFFECT: higher efficiency.

2 cl, 2 ex, 4 tbl

FIELD: veterinary science.

SUBSTANCE: the suggested preparation includes an active substance as a lipophilic fraction of porcine placenta and a solvent as sterile vegetable oil at the following ratio of components, weight%: lipophilic fraction of porcine placental tissues 0.5 - 1; vegetable oil. The preparation provides decreased sickness rate with postnatal gynecological diseases in cows and sows along with increased conception rate during the first insemination.

EFFECT: higher efficiency of prophylaxis and therapy.

3 tbl

FIELD: medicine, gynecology.

SUBSTANCE: invention relates to treatment of endometriosis and state associated with it. Method involves administration of LHRH antagonist by courses for 4-12 weeks. Also, method involves additional simultaneous and successive administration of nonsteroid anti-inflammatory agents, analgesic agents, contraceptive preparations and androgens. Invention provides prophylaxis of relapses of endometriosis symptoms in the absence of symptoms of estrogenic insufficiency.

EFFECT: improved and valuable method for treatment.

17 cl, 2 dwg

FIELD: medicine, cardio-vascular surgery.

SUBSTANCE: one should apply a catheter into left radial artery up to subclavian one, moreover, it should be connected with a measuring device of arterial pressure and an infusomat. One should put on cuffs with connected manometers and delivery pumps onto both patient's shoulders, then during aortal squeezing and that of left subclavian artery both cuffs should be delivered with air till values of manometers' cuffs would be 5-10 mm mercury column above those of arterial pressure measuring device. After that through infusomat one should introduced chilled solution of medicinal preparations decreasing the intensity of metabolic processes in the cells of spinal cord. After removing a clamp from aorta and left subclavian artery both a catheter and cuffs should be removed, as well. The innovation increases the number of means necessary to protect cerebrum and cervico-suprathoracic department of spinal cord at reconstructive operations upon thoracic aorta.

EFFECT: higher efficiency of protection.

1 ex

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