WO2012145809A1 - Pharmaceutical compositions and uses thereof for the treatment and/or prevention of diseases caused by hypoestrogenism in the lower genital tract of women - Google Patents

Pharmaceutical compositions and uses thereof for the treatment and/or prevention of diseases caused by hypoestrogenism in the lower genital tract of women Download PDF

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Publication number
WO2012145809A1
WO2012145809A1 PCT/BR2012/000101 BR2012000101W WO2012145809A1 WO 2012145809 A1 WO2012145809 A1 WO 2012145809A1 BR 2012000101 W BR2012000101 W BR 2012000101W WO 2012145809 A1 WO2012145809 A1 WO 2012145809A1
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Prior art keywords
glycine
pharmaceutical composition
composition according
genistein
isoflavone
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PCT/BR2012/000101
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French (fr)
Portuguese (pt)
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Sônia Maria Rolim Rosa . Lima
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Hebron Farmacêutica Pesquisa, Desenvolvimento E Inovação Tecnológica Ltda
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Publication of WO2012145809A1 publication Critical patent/WO2012145809A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens

Definitions

  • the present invention relates to pharmaceutical compositions comprising a phytoestrogen selected from a natural organic compound of plant origin.
  • Said pharmaceutical compositions may be used in the treatment and / or prevention of diseases resulting from female lower genital tract hypoestrogenism, as a feminine hygiene product, as a skin tightening and rejuvenating cosmetic, and in the preparation of medicaments for vaginal administration. .
  • Symptoms of hypoestrogenism Decreased estrogen level - may be due to various situations that occur with the female organism, affecting women in the postpartum period; those diagnosed with premature or climacteric menopause.
  • Hormonal changes to which the female organism is prone may lead to systemic changes, and the most remarkable period of these changes occurs with the onset of the climacteric period and continues after menopause.
  • women may present physical and neurovegetative changes with symptoms of hot flushes, mood swings, irritation, emotional lability, among others.
  • vaginal dryness which associated with thinning of the epithelium can often lead to vaginal irritation, pain and bleeding during intercourse - dyspareunia, pruritus, burning or vulvar and vaginal burning.
  • vaginal irritation pain and bleeding during intercourse - dyspareunia, pruritus, burning or vulvar and vaginal burning.
  • vaginal irritation pain and bleeding during intercourse - dyspareunia, pruritus, burning or vulvar and vaginal burning.
  • vaginal irritation atrophic vaginitis
  • yellowish and purulent vaginal discharge leukorrhea
  • hypoestrogenism With the progression of hypoestrogenism come other important changes such as decreased vascular flow, pale mucosa and thinning of the epithelium (atrophy of the urethral mucosa). However, in situations of prolonged hypoestrogenism, more complex changes may occur, such as narrowing of the vaginal diameter and reduction of roughness, leading to sexual dysfunction, in addition to erythema and local petechiae.
  • vaginal epithelium In the female organism, atrophy of the vaginal epithelium induces a decrease in glycogen production produced by these cells. As a result there is an increase in vaginal pH and a decrease in Dördelein bacilli.
  • estrogen deficiency promotes the profusion of the urethral mucosa, which assumes the appearance of a reddish lesion, called urethral caruncle that, in situations of prolonged hypoestrogenism, may have a tumoral appearance.
  • the lower urinary tract and vagina have the same embryological origin and therefore have properties similar histochemical studies.
  • the vaginal, urethral and bladder trigone epithelium are rich in estrogen receptors.
  • hypoestrogenism is also associated with worsening distopias' genital (drop in internal genitals) and urinary incontinence in women after menopause.
  • HRT hormone replacement therapy
  • Estrogens may be administered orally, vaginally, subcutaneously, injectable, intramuscular, sublingual, intranasal and transdermal and percutaneous devices and at doses capable of maintaining sufficient serum concentrations to relieve vasomotor symptoms and revert to urogenital atrophy, among others.
  • HRT hormone replacement therapy
  • estrogen replacement treatment may cause liver and biliary lesions, and in the case of vaginal administration, may modify the vaginal epithelium and lead to endometrial proliferative effects.
  • HRT hormone replacement therapy
  • equine conjugated estrogens This therapy has shown significant improvement in quality of life and sexuality compared to estrogen therapy alone.
  • this type of therapy has the disadvantage that estrogens are absorbed and cause systemic manifestations, among them the actions on the breast and the uterus (endometrium - mucosa lining the uterus), which can lead to hyperplasia and even symptoms. to endometrial adenocarcinoma.
  • phytoestrogens are compounds with estrogenic properties found in plants with activity and chemical structure similar to natural estrogens. They present as characteristic the property of binding to estrogen receptors, leading to the induction of specific gene products.
  • phytoestrogens are classified into phenolics, steroids, saponins and terpenoids.
  • Phenolic derivatives include isoflavones, lignans, coumestanas, flavonoids, flavonone, chalcones and flavones.
  • the estrogenic power of these substances is variable.
  • the isoflavone group has the highest estrogenic activity and highest affinity for receptors.
  • the isoflavones stand out daidzein, genistein, glycitein, daidizine, glycitin, formonetin and biochanin A.
  • the racemose-rich Cimicifuga species which has estrogenic and dopaminergic properties, stands out.
  • Isoflavones are found in large quantities in soybean (Glycine max) and its derivatives, and in plants such as Trifolium pratense.
  • the major limitation in studies of phytoestrogen metabolism is the complexity of these substances, with at least 15 different chemical forms of isoflavones found in food, soybean, and plants, even at low plasma concentrations.
  • the main phytoestrogens present in soybean are: genistein, daidzein and their glycosides - genistine and daidzine respectively.
  • Trifolium pratense-derived phytoestrogens are daidzein, genistein and its methylated forms: formononetin and biochanin.
  • flavonoids exhibit antiviral, anticarcinogenic, bactericidal, antifungal, antioxidant, anti-mutagenic, antihypertensive, antiinflammatory, and antiproliferative activity.
  • Flavonoid-derived substances when administered to postmenopausal patients are known to reduce symptoms and could prevent some chronic diseases occurring in the climacteric.
  • EP 1348439 discloses a composition for herbal use vaginal use. More specifically, it is a product utilizing the extract of the species Mimosa tenuiflora associated with soy isoflavone. Mentioned in that document is the surprising effect obtained when the composition comprising Mimosa tenuiflora and isoflavones is compared to compositions containing only a single substance.
  • the isoflavone concentration used in said composition ranges from 0.01 to 3% and even more preferably 0.1%.
  • One skilled in the art, upon reviewing said document, will readily appreciate that the effect of said composition on the disorders it is intended to address should not be attributed to the presence of isoflavone. since its concentration is much lower than the concentration of Mimosa tenuiflora.
  • isoflavone as a phytotherapic is widely discussed in the art, those skilled in the art still note a lack of work related to the use of a simple, unassociated phytotherapic, such as isoflavone, used as alternative hormone replacement therapy, mainly regarding the treatment of disorders of the vaginal epithelium due to hypoestrogenism, or even studies that have analyzed the effects of phytoestrogens on the endometrium and vaginal cytology.
  • the present invention is shown as a promising alternative for improving women's quality of life.
  • compositions comprising a pharmacologically active amount of a substance of plant origin selected from the group of substances called endocrine disruptors and at least one pharmaceutically acceptable carrier. More specifically, said active substance is a phytoestrogen selected from of natural organic compounds of plant origin.
  • the pharmaceutical compositions - objects of the present embodiment - may be used in the treatment and / or prevention of diseases arising from hypoestrogenism in the female lower genital tract, as a feminine hygiene product, as a skin tightening and rejuvenating cosmetic, and in the preparation of of medications for topical vaginal administration. Therefore, it is an object of the present invention to use pharmaceutical compositions for the preparation of a medicament for the treatment and / or prevention of diseases resulting from hypoestrogenism in the female lower genital tract, as well as for women's personal hygiene.
  • the present invention further relates to the analysis of the action of the exclusively local pharmaceutical composition, thereby preventing absorption of the undesirable product into other tissues and may be used for a prolonged period without leading to systemic changes in the female organism.
  • Figure 1 shows the Meisels index distribution in the Isoflavone group at times 0, 30 and 90 days.
  • Figure 2 shows the Meisels index distribution in the placebo group at times 0, 30 and 90 days.
  • Figure 3 shows the Meisels index distribution at times 0, 30 and 90 days in the EEC group.
  • Figure 4 shows the distribution of the Meisels index at times 0, 30 and 90 days in the 3 groups. DETAILED DESCRIPTION OF THE INVENTION;
  • compositions comprising a pharmacologically active amount of a substance of plant origin, selected from the group of substances called endocrine disruptors, and at least one pharmaceutically acceptable carrier.
  • Said active substance of plant origin is capable of binding to hormone receptors and interfering with the endocrine chain. More specifically, said active substance is a phytoestrogen.
  • the phytoestrogen referred to in the present invention is selected from natural organic compounds of plant origin. Specifically, this phytoestrogen is extracted from species of the legume group (Fabaceae). More specifically, from the Glycine genre group.
  • the plant species of the genus Glycine which may be selected as a phytoestrogen are: Glycine albicans, Glycine aphyonota, Glycine arenaria, Glycine argyrea, Glycine canescens, Glycine clandestine, Glycine curvata, Glycine cyrtolc, Glycine grace, Glycine grace, Glycine hirticaulis, Glycine hirticaulis subsp.
  • Phytoestrogens are found in large quantities in soybean and its derivatives, in other grains such as as green peas, lentils, beans and their derivatives, in vegetables, red clover, alfalfa sprouts, and other plants, among which stands out the Trifol ⁇ um pratense.
  • the selected plant species belongs to the glycine genus. In particular, it was extracted from the species Glycine max Merr.
  • the active substance of the pharmaceutical compositions of the present invention was obtained from the dried vegetable extract of the soybeans belonging to the flavonoid class and rich in genistein and daidzein.
  • the stages of the soybean isoflavone extraction process are usual to those with knowledge of the technique, as revealed by Vigo, CLS; Marques, LC Preparation and standardization of plant extracts.
  • Phytotherapy Scientific and technological bases Chapter 7, Pg. 167-205, Sao Paulo: Ed. Atheneu, 2009; Polko ski, K. & Mazurek, AP (2000) Biological properties of genistein.
  • the selected isoflavone must be soluble or partially soluble in water so as to be absorbed by the vaginal epithelium and further comprise both the glycoside form and the aglycone form.
  • Said plant extract should comprise from 0.5% to 80% of total isoflavones, i.e. comprising genistein, dadzein and glycitein. More specifically, said plant extract comprises between 30% to 50% of total isoflavones. More specifically, said plant extract comprises about 40% total isoflavones. However, more particularly, for the pharmaceutical composition of a first preferred embodiment of the present invention, said plant extract comprises about 10% total isoflavones.
  • the isoflavone extract used has partial solubility in water.
  • the biological and structural activity similar to the natural estrogens of this phytoestrogen is due to the presence of genistein in the crude isoflavone grain extract.
  • Genistein is highly active by the ⁇ receptor, which approximates it to natural estrogen.
  • a second object of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of pharmacologically active ingredient of a substance of plant origin and at least one pharmaceutically acceptable carrier. More specifically, said plant composition comprises as an active principle the total genistein isolated from the crude isoflavone extract and at least one pharmaceutically acceptable carrier.
  • the total genistein (glycone and aglycone) of the present embodiment was isolated from the commercial crude isoflavone extract obtained from soybeans.
  • the substance isolation procedure comprises steps usual for those skilled in the art and for this reason will not be detailed in the present invention. However, for better reference, the description of such a procedure can be found in Porter, P.M .; Banwart, W.L .; Hassett, J.J.HPLC isolation and GC-MS identification of genistein, daidzein, and coumestrol from unhydrolyzed soybean root extracts; Environmental and Experimental Botany, Volume 25, Issue 3, August 1985, Pages 229-232; and G ⁇ ES-FAVONI, S.P .; BELÉIA, A. D.
  • the concentration of total genistein (aglycone and glycone) in the extract may range from 0.1 to 100%. However, but specifically, for the present extract, the total genistein concentration ranges from 5 to 95%. Side effects that may occur upon application of the product, such as irritation, itching, etc., are reduced, more specifically, absent when total genistein is present in this concentration range. More preferably, the total genistein concentration (aglycone and glycone) in said extract is about 60% - 70%.
  • the concentration of glycoside genistein ranges from 40 to 80%, preferably 55 to 65%.
  • the concentration of genistein in the glycol form ranges from 58 to 62%. More preferably, the concentration of glycoside genistein in said extract is about 60%.
  • the concentration of genistein in the aglycone form ranges from 0.1 to 10%, preferably from 0.5 to 1.5%, more preferably from 0.8 to 1.2%. Even more preferably, the concentration of genistein in the aglycone form is around 1.0%.
  • a third object of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmacologically active amount of a substance of plant origin and at least one pharmaceutically acceptable carrier.
  • said plant composition comprises, as an active principle, aglycone genistein isolated from total genistein extract and at least one pharmaceutically acceptable carrier.
  • the aglycone form of the total genistein extract of the present embodiment was obtained by substance isolation procedures, comprising steps usual for those skilled in the art and for this reason will not be detailed in the present invention. However, for better reference, the description of such a procedure may be found in (FERRARI, RA; DEMIATE, IM Soy Isoflavones. Biological and Health Sciences .7 (1): 39-46, 2001.).
  • the concentration of aglycone genistein ranges from 0.1 to 10%, preferably from 0.5 to 1.5%. More preferably, the concentration of aglycone genistein in said extract is about 0.8 to 1.2%. More preferably, it is around 1.0%.
  • the pharmaceutically acceptable carriers for use are the same. More specifically, for the present embodiment, non-toxic and inactive excipient substances such as stabilizers, emollients, diluents, solubilizers, thickeners, preservatives, dyes and antacid substances are selected from the pharmaceutically acceptable carriers.
  • excipients from the group of stabilizers that may be used are selected from the group of water soluble polymers to stabilize the solutions and improve their viscosity.
  • water-soluble polymers include carbopol, or any other substance with characteristics similar to those described above, such as cellosize, sodium chloride, trietolamine, propylene glycol.
  • excipients from the group of preservatives that may be used are selected from methylparaben and / or propylparaben, or any other substance with characteristics similar to those described above. More specifically, as preservative substances for the present embodiment, nipagin and nipazole were used.
  • the antacid substance selected for use is sodium hydroxide, or any other substance with similar characteristics such as ammonium hydroxide.
  • the substances selected for use may be propylene glycol, sorbitol, glycerin, or any other substance with similar characteristics to those cited.
  • the substances selected for use may be of natural and / or artificial origin, preferably of the same color as the mucosa and which do not influence the pH and stability of the product.
  • the substances selected for use may be water, alcohol, glycerin, among others with polar and non-polar function to dilute the formulation compounds.
  • the present invention is not limited to the above described substances.
  • One of ordinary skill in the art is able to replace any of the above substances with an equivalent one provided that the substance has functional characteristics similar to the one he or she replaces.
  • the pharmaceutical compositions - objects of the present embodiment - may be used in the treatment and / or prevention of diseases resulting from hypoestrogenism in the female lower genital tract, as a product for female personal hygiene and as a cosmetic for firmness and skin rejuvenation.
  • compositions namely: total isoflavone based pharmaceutical composition, total genistein based pharmaceutical composition and aglycone or glycone genistein pharmaceutical composition in the preparation of effective medicaments. in the treatment and / or prevention of diseases resulting from hypoestrogenism in the female lower genital tract.
  • Said drug is also used as a product for personal hygiene of women, balancing the local flora, as it has a pH similar to the vaginal pH of the woman (pH between 3.5 to 4.5), especially the vaginal pH in the period. reproductive.
  • Preferred pharmaceutical forms of said medicament may be pasty and liquid.
  • said medicament is in pasty form, more specifically in the form of ointment, cream, paste, gel, lotion or ointments, providing for local application thereof.
  • pharmaceutical forms such as suppositories, emulsions, adhesives, tablets or vaginal ring may also be envisaged in the present embodiment.
  • the medicament is in the preferred pharmaceutical form of a gel.
  • Said "shape provides an emollient, refreshing effect, quick drying when in contact with air and good skin penetration.
  • vaginal gel The option of the pharmaceutical form, vaginal gel, was chosen because it has numerous advantages over other pharmaceutical forms, among which we mention: it is the least cumbersome pharmaceutical form for local application, it is easy to apply, enables local lubrication aiding in the protection of the Good penetration, facilitating local action of the active ingredient, is one of the most hygienic options, since it less soils the garments, is easy to clean and allows the product to have indication of continuous use.
  • the drug now developed by the present invention has been physiochemically analyzed and the results obtained for its physicochemical and microbiological characteristics are shown in Table 1.
  • the product obtained presents excellent rheological indices, such as good viscosity and good dispersion of the active principle, which means excellent characteristics for the phytotherapic developed here. Such characteristics provide a pleasant sensation at the time of application on the fabric and a smaller amount of the product to use, ensuring therapeutic efficiency.
  • the final product has an acceptable pH and good stability at room temperature (about -25 ° C).
  • the product According to the accelerated stability and long term tests, the product has safety and efficacy for 2 years in the proposed formulation.
  • the route of administration of the drug in the form of vaginal gel is topical, applied directly to the vagina in order to improve various aspects related to local symptoms of hypoestrogenism, such as dyspareunia, vaginal dryness, pruritus, pain / burning, burning and vaginal discharge.
  • Said gel should preferably be applied with the aid of a suitable mechanical device, such as an applicator of about 5.0 mL.
  • the drug in gel form should be applied to women preferably 1 (once) a day. Each application of said gel should be about 5.0mL.
  • the daily dose of the pharmaceutical composition comprising total isoflavones of the present invention should be about 40.0mg.
  • each 1.0 ml of isoflavone gel for treating / preventing local symptoms of hypoestrogenism comprises about 8.0 Omg of total isoflavones.
  • the daily dose of the total genistein-based pharmaceutical composition of the present invention should be about 24 ⁇ g and the daily dose of the genistein-aglycone-based pharmaceutical composition of the present invention should be about 0.25 ⁇ g. 40mg.
  • the present invention further relates to the analysis of the action of the exclusively local pharmaceutical composition, avoiding
  • the absorption of the product with undesirable action in other tissues can be used for a prolonged period, without leading to systemic changes.
  • Example 1 Formulation of the present invention
  • composition object of the present embodiment comprises:
  • Example 2 Selection of women to undergo the study:
  • the diagnosis of menopause was based on clinical data provided by fully autonomous women with at least 12 months of amenorrhea and confirmed by elevation of gonadotropin-stimulating follicle (FSH) measured by blood collected by forearm vessel venipuncture. Inclusion criteria were those with FSH> 30 mIU / mL.
  • vaginal pH was measured using acid-base indicators such as litmus tape and local material was collected for oncological and hormonal cytology reading.
  • the hormonal vaginal cytology was evaluated by smears and for the collection of the material the women were instructed to avoid sexual intercourse, creams, showers, talc and vaginal washes at least about 48 hours before the collections.
  • a vaginal speculum without lubricants was used, and the vaginal material was collected with Ayre's wooden spatula from the posterior vaginal fornix and brushed with saline from the lateral vaginal walls.
  • the collected material was placed on a glass slide and fixed in absolute alcohol, stained by Papanicolaou method and referred for study under optical microscope, aiming to observe the intensity of maturation of the epithelium.
  • the women were submitted to complementary exams, which included: blood count, blood glucose, lipoprotein profile, renal and liver function tests, fecal occult blood test, serum levels of FHS and estradiol, basal TSH and T4L, ultrasonography transvaginal and mammography.
  • the examination initially consisted of the morphological evaluation of the uterus and the uterine cavity and the uterine volume through measurements in the direction of their longitudinal, anteroposterior and transverse axes.
  • Endometrial echo measurement was performed, with the frozen image, anteroposteriorly, in longitudinal sections of the uterus, including the two endometrial layers, from the echogenic interface of the myometrium-endometrium junction from side to side.
  • the largest possible thickness was measured from the myometrium-endometrium interface of the anterior wall of the uterus to the myometrium-endometrium interface of the posterior wall.
  • the examination also morphologically evaluated the ovaries and . ovarian volume through measurements on the longitudinal, anteroposterior, and transverse axis (Kepple, 2000).
  • Example 3 Analysis of laboratory tests and distribution of women into two groups.
  • the groups formed were homogeneous as to the age of the patients undergoing treatment, time after menopause and body mass index.
  • Group 1 comprised women selected for use and application of isoflavone vaginal gel, comprising genistein (5%).
  • the application was local to the vaginal epithelium by means of plastic vaginal applicators with a lg printed marker. The recommendation was that the application should be performed daily and preferably in the evening.
  • this Group also served to evaluate the acceptance of the product and consequently the final color of the product.
  • Group 2 comprised women selected for placebo use, ie Group 2 served as a control group for the analysis and follow-up of treatment outcomes and effects.
  • the women in the control group used and applied a vaginal gel, which was exempt from the active ingredient.
  • the application was local to the vaginal epithelium by means of plastic vaginal applicators with a lg printed marker.
  • the recommendation was that the application should be performed daily and preferably in the evening.
  • the women proceeded with the daily application of vaginal gel for a period of 30 (thirty) days, after which they returned to the outpatient clinic to evaluate the use of the drug.
  • the fourth visit to the outpatient clinic occurred ninety (90) days after the start of vaginal gel use.
  • a new evaluation of clinical symptoms and adverse effects was performed in addition to the women being again submitted to hormonal cytology tests and pH evaluation, following the same protocol used in the first visit, of these, to the outpatient clinic.
  • the data obtained as results throughout the treatment period were tabulated in Microsoft Excel® spreadsheets for information archiving and field counting.
  • the data were submitted to statistical analyzes performed by means of a computer program usual to those with knowledge in the art.
  • the program selected for use was the SPSS statistical package for Windows.
  • Isoflavone FSH 0 60, 5 80.0 48.0
  • Table 3 shows the data obtained in the evaluation of the vaginal action of the product, through the values of vaginal epithelial maturation index (Meisels index), in the two groups of women undergoing treatment in 3 (three) different times, namely: : Time 0 (To) - start of treatment; Time 1 (Ti) - after 30 days and Time 2 (T 2 ) after 90 days.
  • Meisels index vaginal epithelial maturation index
  • Placebo 30 10.0 85.0 0.0 0.008
  • the results obtained regarding the vaginal action of the product confirm the fact of the local action of the drug.
  • the action of the product on the vaginal epithelium is observed. This is important when referring to women who have some contraindication to the use of hormone therapy and who cannot use any product that presents absorption.
  • Example 7 Selection of women to undergo isoflavone, placebo and conjugated equine estrogen:
  • the exams requested at the first visit of the women to the outpatient clinic were evaluated and those that met the inclusion criteria, laboratory imaging and normal cytology tests were randomly assigned to three groups to begin treatment.
  • the groups formed were homogeneous as to the age of the patients undergoing treatment, time after menopause and body mass index.
  • Group 1 comprised women selected for use and application of isoflavone vaginal gel comprising genistein (5%).
  • the application was local to the vaginal epithelium by means of plastic vaginal applicators with a lg printed marker.
  • the recommendation was that the application should be performed daily and preferably in the evening.
  • Group 2 comprised women selected for placebo use, ie Group 2 served as a control group for the analysis and follow-up of treatment outcomes and effects.
  • the women in the control group used and applied a vaginal gel, which was exempt from the active ingredient.
  • the application was local to the vaginal epithelium by means of plastic vaginal applicators with a lg printed marker. The recommendation was that the application should be performed daily and preferably in the evening.
  • Group 3 comprised women selected for use and application of conjugated estrogens or positive control. Approximately 0.3 mg of conjugated estrogen vaginal cream was applied locally to the vaginal epithelium by means of plastic vaginal applicators with a lg marker. The recommendation was that the application should be performed daily and preferably in the evening.
  • the women proceeded with the daily application of vaginal gel for periods of 30 (thirty) days, 90 (ninety) days and 120 (one hundred and twenty) days, according to the previous protocol. described. At the end of each period, the women returned to the outpatient clinic to evaluate their medication use.
  • the data obtained as results throughout the treatment period were tabulated in Microsoft Excel® spreadsheets for information archiving and field counting.
  • the data were submitted to statistical analyzes performed by means of a computer program usual to those with knowledge in the art.
  • the program selected for use was the SPSS statistical package for Windows.
  • the Meisels index results obtained for Group III are shown in Table 8 and also showed a statistically significant difference between the Meisels index medians in the EEC group between the 3-stroke times (Friedman, p ⁇ .001). Dunn's POST HOC test shows that only the differences between the medians of pairs 0-30 and 0-90 are statistically significant.
  • estrogens used vaginally are effective in treatment, but have the drawback of systemic absorption with often undesirable effects.
  • the number of women who reject for some reason hormone therapy and opt for alternative therapy increasingly affects a larger number of patients, given the increase in life expectancy and also because of the new strategies used for the treatment. diagnosis and treatment of conditions, in which hormone therapy is contraindicated, especially women with hormone-dependent cancer.
  • Embodiments of the present invention are shown to be an effective and safe alternative to the use of estrogens in the treatment of genital atrophic disorders.
  • the proposed drugs have an exclusively local action, preventing the absorption of the product by the vaginal epithelium and causing an undesirable action in other tissues and may be used for a prolonged period, without leading to systemic changes.

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Abstract

The present invention relates to the preparation of pharmaceutical compositions containing a substance of plant origin selected from the group of so-called endocrine disruptors, and at least one pharmaceutically acceptable carrier. More specifically, the active substance is a phytoestrogen selected from natural organic compounds of plant origin. The pharmaceutical compositions which form the object of the invention can be used for the treatment and/or prevention of diseases caused by hypoestrogenism in the lower genital tract in women and also for preparing medicaments for vaginal administration.

Description

COMPOSIÇÕES FARMACÊUTICAS E SEUS USOS PARA TRATAMENTO E/OU PREVENÇÃO DE DOENÇAS DECORRENTES DO HIPOESTROGENISMO NO TRATO GENITAL INFERIOR FEMININO  PHARMACEUTICAL COMPOSITIONS AND ITS USES FOR TREATMENT AND / OR PREVENTION OF DISEASES ARISING FROM HYPOESTROGENISM IN THE FEMININE LOWER GENITAL TRACT
CAMPO DA INVENÇÃO FIELD OF INVENTION
A presente invenção refere-se a composições farmacêuticas compreendendo um fitoestrogênio selecionado a partir de um composto orgânico natural de origem vegetal. As referidas composições farmacêuticas podem ser utilizadas no tratamento e/ou prevenção das doenças decorrentes do hipoestrogenismo no trato genital inferior feminino, como produto para higiene pessoal feminina, como cosmético para firmeza e rejuvenescimento da pele e, ainda, na preparação de medicamentos para administração vaginal.  The present invention relates to pharmaceutical compositions comprising a phytoestrogen selected from a natural organic compound of plant origin. Said pharmaceutical compositions may be used in the treatment and / or prevention of diseases resulting from female lower genital tract hypoestrogenism, as a feminine hygiene product, as a skin tightening and rejuvenating cosmetic, and in the preparation of medicaments for vaginal administration. .
FUNDAMENTOS DA INVENÇÃO BACKGROUND OF THE INVENTION
Os sintomas decorrentes do hipoestrogenismo diminuição do nive.l de estrogênio - podem ser decorrentes de diversas situações que ocorrem com o organismo feminino, acometendo as mulheres no período após o parto; aquelas com diagnóstico de menopausa prematura ou no período do climatério .  Symptoms of hypoestrogenism Decreased estrogen level - may be due to various situations that occur with the female organism, affecting women in the postpartum period; those diagnosed with premature or climacteric menopause.
As alterações hormonais a que o organismo feminino está propenso podem levar a alterações sistémicas, sendo que o período mais marcante dessas alterações ocorre com o início do período do climatério e continua após a menopausa.  Hormonal changes to which the female organism is prone may lead to systemic changes, and the most remarkable period of these changes occurs with the onset of the climacteric period and continues after menopause.
Nesta fase da vida, as mulheres podem apresentar alterações físicas e neurovegetativas com sintomas de fogachos, alterações de humor, irritação, labilidade emocional, dentre outros. No período do climatério, há maior risco de perda de massa óssea, diminuição da qualidade do colágeno, acelerando o envelhecimento dos tecidos e atrofia de estruturas como as mamas, sendo notória a atrofia urogenital. At this stage of life, women may present physical and neurovegetative changes with symptoms of hot flushes, mood swings, irritation, emotional lability, among others. In the climacteric period, there are greater risk of bone loss, decreased collagen quality, accelerating tissue aging and atrophy of structures such as the breasts, with urogenital atrophy notorious.
As principais queixas genitais associadas a esta fase de vida relacionam-se à secura vaginal, que associada à diminuição da espessura do epitélio podem frequentemente levar à irritação vaginal, dor e sangramento por ocasião do coito - dispareunia, prurido, ardor ou queimação vulvar e vaginal (vaginite atrófica) , secreção vaginal amarelada e purulenta ( leucorréia) .  The main genital complaints associated with this phase of life relate to vaginal dryness, which associated with thinning of the epithelium can often lead to vaginal irritation, pain and bleeding during intercourse - dyspareunia, pruritus, burning or vulvar and vaginal burning. (atrophic vaginitis), yellowish and purulent vaginal discharge (leukorrhea).
Com a progressão do hipoestrogenismo advêm outras alterações importantes como a diminuição do fluxo vascular, palidez da mucosa e adelgaçamento do epitélio (atrofia da mucosa uretral) . No entanto, em situações de hipoestrogenismo prolongado, podem ocorrer alterações mais complexas, tais como estreitamento do diâmetro vaginal e redução da rugosidade, levando a disfunção sexual, além de eritemas e petéquias locais.  With the progression of hypoestrogenism come other important changes such as decreased vascular flow, pale mucosa and thinning of the epithelium (atrophy of the urethral mucosa). However, in situations of prolonged hypoestrogenism, more complex changes may occur, such as narrowing of the vaginal diameter and reduction of roughness, leading to sexual dysfunction, in addition to erythema and local petechiae.
No organismo feminino, a atrofia do epitélio vaginal induz a diminuição da produção de glicogênio produzido por estas células. Em consequência há elevação do pH vaginal e diminuição dos bacilos de Dõrdelein.  In the female organism, atrophy of the vaginal epithelium induces a decrease in glycogen production produced by these cells. As a result there is an increase in vaginal pH and a decrease in Dördelein bacilli.
Além dessas questões sabe-se, ainda, que a deficiência de estrogênios propicia a profusão da mucosa uretral, que assume o aspecto de uma lesão avermelhada, denominada de carúncula uretral que, em situações de hipoestrogenismo prolongado, pode ter aparência tumoral.  In addition to these issues, it is also known that estrogen deficiency promotes the profusion of the urethral mucosa, which assumes the appearance of a reddish lesion, called urethral caruncle that, in situations of prolonged hypoestrogenism, may have a tumoral appearance.
O trato urinário inferior e a vagina têm a mesma origem embriológica e, portanto, apresentam propriedades histoquímicas semelhantes. O epitélio vaginal, uretral e do trigono vesical são ricos em receptores estrogênicos . The lower urinary tract and vagina have the same embryological origin and therefore have properties similar histochemical studies. The vaginal, urethral and bladder trigone epithelium are rich in estrogen receptors.
0 hipoestrogenismo está associado também ao agravamento das distopias ' genitais (queda dos órgãos genitais internos) e incontinência urinária nas mulheres após a menopausa. 0 hypoestrogenism is also associated with worsening distopias' genital (drop in internal genitals) and urinary incontinence in women after menopause.
Com o aumento da expectativa de vida e, ao mesmo tempo, com o crescimento dos fatores que agravam as doenças crónicas - fumo, estresse, vida sedentária, hábito alimentar rico em gordura, entre outros - a terapia de reposição hormonal (TRH) tem sido a indicação mais efetiva para tratar e/ou prevenir os sintomas moderados e severos do hipoestrogenismo, em especial a atrofia vulvar e vaginal.  With the increase in life expectancy and, at the same time, with the growth of factors that aggravate chronic diseases - smoking, stress, sedentary lifestyle, high fat eating habits, among others - hormone replacement therapy (HRT) has been the most effective indication for treating and / or preventing moderate and severe symptoms of hypoestrogenism, especially vulvar and vaginal atrophy.
Os estrogênios podem ser administrados por via oral, vaginal, implantes subcutâneos, injetável, intramuscular, sublingual, intranasal e dispositivos transdérmicos e percutâneos e em doses capazes de manter as concentrações séricas suficientes para aliviar os sintomas vasomotores e reverter à atrofia urogenital, dentre outros.  Estrogens may be administered orally, vaginally, subcutaneously, injectable, intramuscular, sublingual, intranasal and transdermal and percutaneous devices and at doses capable of maintaining sufficient serum concentrations to relieve vasomotor symptoms and revert to urogenital atrophy, among others.
Entretanto, muitas mulheres apresentam algum tipo de resistência à Terapia de Reposição Hormonal (TRH), seja por apresentarem contra-indicações e efeitos colaterais, por medo a esse tipo de tratamento ou, ainda, por não perceberem melhora após o uso, mantendo os sintomas vulvo- vaginais e infecções urinárias recidivantes.  However, many women have some resistance to hormone replacement therapy (HRT), either because they have contraindications and side effects, for fear of this type of treatment or because they do not notice improvement after use, maintaining symptoms. vulvovaginal and recurrent urinary tract infections.
Além disso, o tratamento de reposição de estrogênio por via oral, por exemplo, pode causar lesões hepáticas e biliares, e no caso de administração vaginal, podem modificar o epitélio vaginal e acarretar efeitos proliferativos endometriais . Uma alternativa à Terapia de Reposição Hormonal (TRH) tem sido a utilização de estrogênios conjugados equinos. Essa terapia tem mostrado melhora significativa na qualidade de vida e na sexualidade em relação à estrogenioterapia isolada. Entretanto, esse tipo de terapia, apresenta, a desvantagem dos estrogênios serem absorvidos e causarem manifestações sistémicas, destacando-se entre elas as ações nas mamas e no útero (endométrio - mucosa que reveste o útero) podendo levar a quadros de hiperplasias e até mesmo ao adenocarcinoma do endométrio . In addition, oral estrogen replacement treatment, for example, may cause liver and biliary lesions, and in the case of vaginal administration, may modify the vaginal epithelium and lead to endometrial proliferative effects. An alternative to hormone replacement therapy (HRT) has been the use of equine conjugated estrogens. This therapy has shown significant improvement in quality of life and sexuality compared to estrogen therapy alone. However, this type of therapy has the disadvantage that estrogens are absorbed and cause systemic manifestations, among them the actions on the breast and the uterus (endometrium - mucosa lining the uterus), which can lead to hyperplasia and even symptoms. to endometrial adenocarcinoma.
As opções para o tratamento dos sintomas do climatério têm constituído tema de grande preocupação entre as mulheres e profissionais de saúde. Embora o tratamento convencional, com o uso de hormônios sintéticos, permaneça ainda como o mais apropriado, o interesse por outros produtos continua crescendo.  Options for the treatment of climacteric symptoms have been a matter of great concern among women and health professionals. Although conventional treatment with the use of synthetic hormones remains the most appropriate, interest in other products continues to grow.
A despeito dos efeitos clínicos atribuídos ao uso da terapia hormonal (TH) após a menopausa, a taxa de aderência ao tratamento varia de 10 a ,50%, e a grande maioria das mulheres após a menopausa (80% ou mais) não faz uso da TH por tempo suficiente para obter impacto na prevenção das doenças crónicas. Assim, o estudo de terapias alternativas torna-se interessante para mulheres que se recusam ou não aderem ao tratamento, ou ainda, apresentem contraindicações a ele .  Despite the clinical effects attributed to the use of hormone therapy (HT) after menopause, treatment adherence rates range from 10 to 50%, and the vast majority of postmenopausal women (80% or more) do not use it. long enough to impact on chronic disease prevention. Thus, the study of alternative therapies becomes interesting for women who refuse or do not adhere to treatment, or even have contraindications to it.
Nesse intuito, o reino vegetal, rico em substâncias que possuem atividade farmacológica, entre as quais se destacam os fitohormônios , tem sido um amplo campo de pesquisa na busca de alternativas ao uso dos hormônios sintéticos. To this end, the plant kingdom, rich in substances with pharmacological activity, among which phytohormones stand out, has been a broad field of research in search of alternatives to the use of synthetic hormones.
Mais especificamente, os fitoestrogênios são compostos com propriedades estrogênicas encontrados em plantas com atividade e estrutura química semelhante aos estrogênios naturais. Apresentam como característica a propriedade de se unir a receptores de estrogênio, levando à indução de produtos gênicos específicos.  More specifically, phytoestrogens are compounds with estrogenic properties found in plants with activity and chemical structure similar to natural estrogens. They present as characteristic the property of binding to estrogen receptors, leading to the induction of specific gene products.
De uma maneira geral, os fitoestrogênios classificam-se em fenólicos, esteróides, saponinas e terpenóides. Entre os derivados fenólicos encontram-se as isoflavonas, lignanas, coumestanas, flavonóides, flavonona, calconas e flavonas. 0 poder estrogênico destas substâncias é variável.  Generally speaking, phytoestrogens are classified into phenolics, steroids, saponins and terpenoids. Phenolic derivatives include isoflavones, lignans, coumestanas, flavonoids, flavonone, chalcones and flavones. The estrogenic power of these substances is variable.
O grupo das isoflavonas é o que possui maior atividade estrogênica e maior afinidade pelos receptores. Dentre as isoflavonas destacam-se a daidzeína, genisteína, gliciteína, daidizina, glicitina, formonetina e biochanina A. Entre os derivados terpenóides destaca-se a espécie Cimicifuga racemosa , rica em terpenóides, que apresenta propriedades estrogênicas e dopaminérgicas .  The isoflavone group has the highest estrogenic activity and highest affinity for receptors. Among the isoflavones stand out daidzein, genistein, glycitein, daidizine, glycitin, formonetin and biochanin A. Among the terpenoid derivatives, the racemose-rich Cimicifuga species, which has estrogenic and dopaminergic properties, stands out.
As isoflavonas são encontradas em grande quantidade na soja {Glycine max) e seus derivados, e em plantas como a Trifolium pratense .  Isoflavones are found in large quantities in soybean (Glycine max) and its derivatives, and in plants such as Trifolium pratense.
A maior limitação nos estudos do metabolismo dos fitoestrogênios é a complexidade destas substâncias, com pelo menos 15 diferentes formas químicas de isoflavonas encontradas nos alimentos, no feijão da soja, e em plantas, mesmo em baixas concentrações plasmáticas. Os principais fitoestrogênios presentes na soja são: genisteina, daidzeina e seus glicosideos - genistina e daidzina respectivamente. Os fitoestrogênios derivados do ■Trifolium pratense são a daidzeina a genisteina e suas formas metiladas: a formononetina e biochanina . The major limitation in studies of phytoestrogen metabolism is the complexity of these substances, with at least 15 different chemical forms of isoflavones found in food, soybean, and plants, even at low plasma concentrations. The main phytoestrogens present in soybean are: genistein, daidzein and their glycosides - genistine and daidzine respectively. ■ Trifolium pratense-derived phytoestrogens are daidzein, genistein and its methylated forms: formononetin and biochanin.
Aqueles com conhecimento na técnica reconhecem que os flavonóides apresentam atividade antiviral, anticarcinogênica, bactericida, antifúngica, antioxidante, anti-mutagênica, anti-hipertensiva, anti-inflamatória e anti-proliferativa .  Those skilled in the art recognize that flavonoids exhibit antiviral, anticarcinogenic, bactericidal, antifungal, antioxidant, anti-mutagenic, antihypertensive, antiinflammatory, and antiproliferative activity.
Sabe-se, ainda, que as substâncias derivadas dos flavonóides, quando administradas a pacientes na pós- menopausa, são capazes de reduzir os sintomas e poderiam prevenir algumas doenças crónicas que ocorrem no climatério Flavonoid-derived substances when administered to postmenopausal patients are known to reduce symptoms and could prevent some chronic diseases occurring in the climacteric.
É possível encontrar, no estado da técnica, diversas discussões sobre o assunto. A título ilustrativo, encontra-se a matéria discorrida no documento EP1348439. It is possible to find, in the state of the art, several discussions on the subject. By way of illustration, the subject matter is disclosed in EP1348439.
O documento EP 1348439 revela uma composição para uso vaginal à base de fitoterápicos . Mais especificamente, trata-se de um produto que utiliza o extrato da espécie Mimosa tenuiflora associado com a isoflavona de soja. É mencionado no referido documento o efeito surpreendente obtido quando a composição compreendendo Mimosa tenuiflora e isoflavonas é comparada com composições contendo apenas uma única das substâncias. A concentração de isoflavona utilizada na referida composição varia entre 0,01 a 3% e ainda mais preferencialmente seria de 0,1%. Um técnico no assunto, ao analisar o referido documento, facilmente perceberá que o efeito da referida composição sob as desordens a que ela se propõe a tratar, não deve ser atribuído à presença da isoflavona,. uma vez que a sua concentração é muito menor que a concentração de Mimosa tenuiflora . EP 1348439 discloses a composition for herbal use vaginal use. More specifically, it is a product utilizing the extract of the species Mimosa tenuiflora associated with soy isoflavone. Mentioned in that document is the surprising effect obtained when the composition comprising Mimosa tenuiflora and isoflavones is compared to compositions containing only a single substance. The isoflavone concentration used in said composition ranges from 0.01 to 3% and even more preferably 0.1%. One skilled in the art, upon reviewing said document, will readily appreciate that the effect of said composition on the disorders it is intended to address should not be attributed to the presence of isoflavone. since its concentration is much lower than the concentration of Mimosa tenuiflora.
Atualmente, tem-se uma preocupação significativa com a saúde e a qualidade de vida futura das mulheres. Os aspectos diagnósticos, preventivos e terapêuticos são úteis como referências para os profissionais da área da saúde, as pacientes e seus familiares.  There is currently a significant concern for women's health and future quality of life. The diagnostic, preventive and therapeutic aspects are useful as references for health professionals, patients and their families.
Embora o uso de isoflavona como fitoterápico seja amplamente discutido na técnica, aqueles com conhecimento no assunto, ainda notam uma carência de trabalhos relacionados com o uso de um fitoterápico simples, sem associações, tal como a isoflavona, utilizado como terapia de reposição hormonal alternativa, principalmente quando se refere ao tratamento de desordens do epitélio vaginal decorrentes do hipoestrogenismo, ou ainda, trabalhos que tenham analisado os efeitos dos fitoestrogênios no endométrio e na citologia vaginal.  Although the use of isoflavone as a phytotherapic is widely discussed in the art, those skilled in the art still note a lack of work related to the use of a simple, unassociated phytotherapic, such as isoflavone, used as alternative hormone replacement therapy, mainly regarding the treatment of disorders of the vaginal epithelium due to hypoestrogenism, or even studies that have analyzed the effects of phytoestrogens on the endometrium and vaginal cytology.
Frente ao exposto acima, a presente invenção mostra-se como uma alternativa promissora para melhorar a qualidade de vida das mulheres.  In view of the above, the present invention is shown as a promising alternative for improving women's quality of life.
SUMÁRIO DA INVENÇÃO SUMMARY OF THE INVENTION
É objetivo da presente concretização, prover a técnica com composições farmacêuticas, compreendendo uma quantidade farmacologicamente ativa de uma substância de origem vegetal selecionada do grupo de substâncias chamadas de disruptores endócrinos e pelo menos um veículo farmaceuticamente aceitável. Mais especificamente, referida substância ativa é um fitoestrogênio selecionado a partir de compostos orgânicos naturais de origem vegetal. As composições farmacêuticas - objetos da presente concretização - podem ser utilizadas no tratamento e/ou prevenção das doenças decorrentes do hipoestrogenismo no trato genital inferior feminino, como produto para higiene pessoal feminina, como cosmético para firmeza e rejuvenescimento da pele e, ainda, na preparação de medicamentos para administração tópica vaginal. Portanto, é um dos objetivos da presente invenção o uso das composições farmacêuticas para a preparação de um medicamento para o tratamento e/ou prevenção das doenças decorrentes do hipoestrogenismo no trato genital inferior feminino, bem como, para a higiene pessoal da mulher. It is an object of the present embodiment to provide the art with pharmaceutical compositions comprising a pharmacologically active amount of a substance of plant origin selected from the group of substances called endocrine disruptors and at least one pharmaceutically acceptable carrier. More specifically, said active substance is a phytoestrogen selected from of natural organic compounds of plant origin. The pharmaceutical compositions - objects of the present embodiment - may be used in the treatment and / or prevention of diseases arising from hypoestrogenism in the female lower genital tract, as a feminine hygiene product, as a skin tightening and rejuvenating cosmetic, and in the preparation of of medications for topical vaginal administration. Therefore, it is an object of the present invention to use pharmaceutical compositions for the preparation of a medicament for the treatment and / or prevention of diseases resulting from hypoestrogenism in the female lower genital tract, as well as for women's personal hygiene.
A presente invenção ainda refere-se à análise da ação da composição farmacêutica, exclusivamente local, evitando assim a absorção do produto com ação indesejável em outros tecidos, podendo ser utilizado por período prolongado, sem levar a alterações sistémicas no organismo feminino.  The present invention further relates to the analysis of the action of the exclusively local pharmaceutical composition, thereby preventing absorption of the undesirable product into other tissues and may be used for a prolonged period without leading to systemic changes in the female organism.
BREVE DESCRIÇÃO DAS FIGURAS: BRIEF DESCRIPTION OF THE FIGURES:
A Figura 1 mostra a distribuição de índice de Meisels no grupo Isoflavona nos tempos 0, 30 e 90 dias.  Figure 1 shows the Meisels index distribution in the Isoflavone group at times 0, 30 and 90 days.
A Figura 2 mostra a distribuição de índice de Meisels no grupo placebo nos tempos 0, 30 e 90 dias.  Figure 2 shows the Meisels index distribution in the placebo group at times 0, 30 and 90 days.
A Figura 3 mostra a distribuição de índice de Meisels nos tempos 0, 30 e 90 dias no grupo EEC .  Figure 3 shows the Meisels index distribution at times 0, 30 and 90 days in the EEC group.
A Figura 4 mostra a distribuição do índice Meisels nos tempos 0, 30 e 90 dias, nos 3 grupos. DESCRIÇÃO DETALHADA DA INVENÇÃO; Figure 4 shows the distribution of the Meisels index at times 0, 30 and 90 days in the 3 groups. DETAILED DESCRIPTION OF THE INVENTION;
É objetivo da presente concretização, prover a técnica com composições farmacêuticas compreendendo uma quantidade farmacologicamente ativa de uma substância de origem vegetal, selecionada do grupo de substâncias chamadas de disruptores endócrinos, e pelo menos um veiculo farmaceuticamente aceitável.  It is an object of the present embodiment to provide the art with pharmaceutical compositions comprising a pharmacologically active amount of a substance of plant origin, selected from the group of substances called endocrine disruptors, and at least one pharmaceutically acceptable carrier.
A referida substância ativa de origem vegetal é capaz de ligar-se aos receptores hormonais e interferir na cadeia endócrina. Mais especificamente, referida substância ativa é um fitoestrogênio .  Said active substance of plant origin is capable of binding to hormone receptors and interfering with the endocrine chain. More specifically, said active substance is a phytoestrogen.
O fitoestrogênio referido na presente invenção é selecionado a partir de compostos orgânicos naturais de origem vegetal. Especificamente, este fitoestrogênio é extraído de espécies do grupo das leguminosas (Fabaceae) . Mais especificamente, do grupo do género Glycine.  The phytoestrogen referred to in the present invention is selected from natural organic compounds of plant origin. Specifically, this phytoestrogen is extracted from species of the legume group (Fabaceae). More specifically, from the Glycine genre group.
Mais particularmente, as espécies vegetais do grupo do género Glycine, que podem ser selecionadas como fitoestrogênio são: Glycine albicans, Glycine aphyonota , Glycine arenaria, Glycine argyrea, Glycine canescens, Glycine clandestina , Glycine curvata, Glycine cyrtoloba , Glycine falcata, Glycine gracei, Glycine hirticaulis, Glycine hirticaulis subsp. leptosa, Glycine lactovirens, Glycine latifolia , Glycine latrobeana , Glycine microphylla , Glycine montis-douglas, Glycine peratosa , Glycine pescadrensis, Glycine pindanica , Glycine pullenii , Glycine rubiginosa , Glycine stenophita , Glycine syndetika , Glycine tabacina, Glycine tomentella e Glycine max.  More particularly, the plant species of the genus Glycine, which may be selected as a phytoestrogen are: Glycine albicans, Glycine aphyonota, Glycine arenaria, Glycine argyrea, Glycine canescens, Glycine clandestine, Glycine curvata, Glycine cyrtolc, Glycine grace, Glycine grace, Glycine hirticaulis, Glycine hirticaulis subsp. leptosa, Glycine lactovirens, Glycine latifolia, Glycine latrobeana, Glycine microphylla, Glycine montis-douglas, Glycine peratosa, Glycine pescadrensis, Glycine pindanica, Glycine rubenin, Glycine rubiginosa, Glycine tomy, Glycine latifolia
Os fitoestrogênios são encontrados em grande quantidade na soja e seus derivados, em outros grãos tais como, ervilha verde, lentilha, feijão e seus derivados, em legumes, trevo vermelho, brotos de alfafa, além de outras plantas, entre as quais se destaca o Trifolíum pratense . Nos exemplos da presente invenção que serão demonstrados a seguir, a espécie vegetal selecionada pertence ao género glycine. Em especial, foi extraído da espécie Glycine max Merr. Phytoestrogens are found in large quantities in soybean and its derivatives, in other grains such as as green peas, lentils, beans and their derivatives, in vegetables, red clover, alfalfa sprouts, and other plants, among which stands out the Trifolíum pratense. In the following examples of the present invention, the selected plant species belongs to the glycine genus. In particular, it was extracted from the species Glycine max Merr.
A substância ativa das composições farmacêuticas da presente invenção foi obtida a partir do extrato vegetal seco dos grãos de soja pertencentes à classe dos flavonoides e ricos em genisteína e daidzeína. As etapas do processo de extração da isoflavona dos grãos de soja são usuais àqueles com conhecimento da técnica, conforme revelado por Vigo,C.L.S; Marques, L.C. Preparação e padronização de extratos vegetais. Fitoterapia Bases Científicas e Tecnológicas. Capítulo 7, Pg. 167-205, São Paulo: Ed. Atheneu, 2009; Polko ski, K. & Mazurek, A. P. (2000) Biological properties of genistein. A review of in vitro and in vivo data. Acta Pol. Pharm. 57: 135-155.; Setchell, K.D.R., Brown, N. M. , Desaj, P., Zimmer-Nechemias , L., Wolf, B. E., Brahear, W. T . , Kirschner, A. S., Cassidy, A. & Heubi, J. E. (2001); Bioavailability of pure isoflavones in healthy humans and analysis of commercial soy isoflavone supplements. J. Nutr. 131: 1362S-1375S e; Shelnutt, S. R. , Cimino, C. O., Wiggins, P. A., Ronis, M.J.J. & Badger, T. M. (2002) Pharmacokinetics of the glucuronide and sulfate conjugates of genistein and daidzein in men and women after consumption of a soy beverage.Am. J. Clin. Nutr. 75: 588-594 e, portanto, não serão descritas em detalhes pela presente concretização. A forma química em que a isoflavona se apresenta tem importância capital em sua atividade biológica, em sua biodisponibilidade e, ainda, sobre seus efeitos fisiológicos. The active substance of the pharmaceutical compositions of the present invention was obtained from the dried vegetable extract of the soybeans belonging to the flavonoid class and rich in genistein and daidzein. The stages of the soybean isoflavone extraction process are usual to those with knowledge of the technique, as revealed by Vigo, CLS; Marques, LC Preparation and standardization of plant extracts. Phytotherapy Scientific and technological bases. Chapter 7, Pg. 167-205, Sao Paulo: Ed. Atheneu, 2009; Polko ski, K. & Mazurek, AP (2000) Biological properties of genistein. A review of in vitro and in vivo data. Acta Pol. Pharm. 57: 135-155 .; Setchell, KDR, Brown, NM, Desaj, P., Zimmer-Nechemias, L., Wolf, BE, Brahear, W. T. Kirschner, AS, Cassidy, A. & Heubi, JE (2001); Bioavailability of pure isoflavones in healthy humans and analysis of commercial soy isoflavone supplements. J. Nutr. 131: 1362S-1375S and; Shelnutt, SR, Cimino, CO, Wiggins, PA, Ronis, MJJ & Badger, TM (2002). J. Clin. Nourish 75: 588-594 and therefore will not be described in detail by the present embodiment. The chemical form in which isoflavone is of major importance in its biological activity, its bioavailability and also its physiological effects.
Para uma primeira concretização da presente invenção, a isoflavona selecionada deve ser solúvel ou parcialmente solúvel em água, de maneira a ser absorvida pelo epitélio vaginal e, ainda, compreender tanto a forma glicosada quanto a forma aglicona.  For a first embodiment of the present invention, the selected isoflavone must be soluble or partially soluble in water so as to be absorbed by the vaginal epithelium and further comprise both the glycoside form and the aglycone form.
0 referido extrato vegetal deve compreender entre 0,5% a 80% de isoflavonas totais, ou seja, compreendendo genisteína, dadzeína e gliciteína. Mais especificamente, o referido extrato vegetal compreende entre 30 % a 50% de isoflavonas totais. Mais especificamente, o referido extrato vegetal compreende cerca de 40% de isoflavonas totais. Entretanto, mais particularmente, para a composição farmacêutica de uma primeira concretização preferencial da presente invenção, o referido extrato vegetal compreende cerca de 10% de isoflavonas totais.  Said plant extract should comprise from 0.5% to 80% of total isoflavones, i.e. comprising genistein, dadzein and glycitein. More specifically, said plant extract comprises between 30% to 50% of total isoflavones. More specifically, said plant extract comprises about 40% total isoflavones. However, more particularly, for the pharmaceutical composition of a first preferred embodiment of the present invention, said plant extract comprises about 10% total isoflavones.
Particularmente, na referida concretização preferencial, o extrato de isoflavona utilizado possui uma solubilidade parcial em água.  Particularly, in said preferred embodiment, the isoflavone extract used has partial solubility in water.
Mais especificamente, a atividade biológica e estrutural semelhante aos estrogênios naturais do presente fitoestrogênio se deve devido à presença da genisteína no extrato bruto dos grãos de isoflavonas. A genisteína apresenta grande atividade pelo receptor β, o que a aproxima do estrogênio natural.  More specifically, the biological and structural activity similar to the natural estrogens of this phytoestrogen is due to the presence of genistein in the crude isoflavone grain extract. Genistein is highly active by the β receptor, which approximates it to natural estrogen.
Um segundo objetivo da presente invenção, consiste em uma composição farmacêutica compreendendo uma quantidade farmacologicamente ativa de uma substância de origem vegetal e pelo menos um veiculo farmaceuticamente aceitável Mais especificamente, a referida composição vegetal compreende como principio ativo a genisteina total isolada do extrato bruto de isoflavona e pelo menos um veiculo farmaceuticamente aceitável. A second object of the present invention is a pharmaceutical composition comprising an amount of pharmacologically active ingredient of a substance of plant origin and at least one pharmaceutically acceptable carrier. More specifically, said plant composition comprises as an active principle the total genistein isolated from the crude isoflavone extract and at least one pharmaceutically acceptable carrier.
A genisteina total (glicona e aglicona) da presente concretização foi isolada do extrato bruto comercial de isoflavona obtida dos grãos de soja. O procedimento de isolamento da substância compreende etapas usuais para aqueles com conhecimento na técnica e por esse motivo não será detalhado na presente invenção. Entretanto, para melhor referência, a descrição de tal procedimento pode ser encontrada em Porter, P.M.; Banwart, W.L.; Hassett, J.J.HPLC isolation and GC-MS identification of genistein, daidzein, and coumestrol from unhydrolyzed soybean root extracts; Environmental and Experimental Botany, Volume 25, Issue 3, August 1985, Pages 229-232; e GÓES-FAVONI, S.P.; BELÉIA, A. D. P. ; CARRÃO- PANI Z ZI , M.C.; MANDARINO, J.M.G. ISOFLAVONAS EM PRODUTOS COMERCIAIS DE SOJA. Ciênc. Tecnol. Aliment., Campinas, 24(4) : Pg .582-586, 2004.  The total genistein (glycone and aglycone) of the present embodiment was isolated from the commercial crude isoflavone extract obtained from soybeans. The substance isolation procedure comprises steps usual for those skilled in the art and for this reason will not be detailed in the present invention. However, for better reference, the description of such a procedure can be found in Porter, P.M .; Banwart, W.L .; Hassett, J.J.HPLC isolation and GC-MS identification of genistein, daidzein, and coumestrol from unhydrolyzed soybean root extracts; Environmental and Experimental Botany, Volume 25, Issue 3, August 1985, Pages 229-232; and GÓES-FAVONI, S.P .; BELÉIA, A. D. P.; CARTON-PANI Z ZI, M.C .; MANDARINO, J.M.G. ISOFLAVONES IN SOY TRADE PRODUCTS. Science Technol. Aliment., Campinas, 24 (4): P.582-586, 2004.
A concentração de genisteina total (aglicona e glicona) no extrato pode variar entre 0,1 e 100%. Entretanto, mas especificamente, para o presente extrato, a concentração de genisteina total varia entre 5 e 95%. Os efeitos colaterais que podem ocorrer quando da aplicação do produto, tais como, irritação, prurido etc, são reduzidos, mais especificamente, ausentes, quando a genisteina total está presente nessa faixa de concentração. Mais preferencialmente, a concentração de genisteina total (aglicona e glicona) no referido extrato é em torno de 60% - 70%. The concentration of total genistein (aglycone and glycone) in the extract may range from 0.1 to 100%. However, but specifically, for the present extract, the total genistein concentration ranges from 5 to 95%. Side effects that may occur upon application of the product, such as irritation, itching, etc., are reduced, more specifically, absent when total genistein is present in this concentration range. More preferably, the total genistein concentration (aglycone and glycone) in said extract is about 60% - 70%.
Para a composição farmacêutica ora objeto da presente concretização baseada em genisteina total, a concentração de genisteina na forma de glicona varia entre 40 e 80%, preferencialmente entre 55 e 65%. Preferencialmente, a concentração de genisteina na forma de glicona varia entre 58 a 62%. Mais preferencialmente, a concentração de genisteina na forma de glicona no referido extrato é em torno de 60%. Já a concentração de genisteina na forma de aglicona varia entre 0,1 e 10%, preferencialmente, varia entre 0,5 e 1,5%, mais preferencialmente entre 0,8 e 1,2%. Ainda, mais preferencialmente, a concentração de genisteina na forma de aglicona é em torno de 1,0%.  For the pharmaceutical composition herein subject to the total genistein-based embodiment, the concentration of glycoside genistein ranges from 40 to 80%, preferably 55 to 65%. Preferably, the concentration of genistein in the glycol form ranges from 58 to 62%. More preferably, the concentration of glycoside genistein in said extract is about 60%. The concentration of genistein in the aglycone form ranges from 0.1 to 10%, preferably from 0.5 to 1.5%, more preferably from 0.8 to 1.2%. Even more preferably, the concentration of genistein in the aglycone form is around 1.0%.
Um terceiro objetivo da presente invenção consiste em uma composição farmacêutica compreendendo uma quantidade farmacologicamente ativa de uma substância de origem vegetal e pelo menos um veículo farmaceuticamente aceitável. A third object of the present invention is a pharmaceutical composition comprising a pharmacologically active amount of a substance of plant origin and at least one pharmaceutically acceptable carrier.
Mais especificamente, a referida composição vegetal compreende, como princípio ativo, a genisteina aglicona isolada do extrato de genisteina total e pelo menos um veículo farmaceuticamente aceitável. More specifically, said plant composition comprises, as an active principle, aglycone genistein isolated from total genistein extract and at least one pharmaceutically acceptable carrier.
A forma aglicona do extrato de genisteina total da presente concretização foi obtida por meio de procedimentos de isolamento da substância, compreendendo etapas usuais para aqueles com conhecimento na técnica e por esse motivo não será detalhado na presente invenção. Entretanto, para melhor referência, a descrição de tal procedimento pode ser encontrada em (FERRARI, R.A.; DEMIATE, I.M. Isoflavonas de soja. Biological and Health Sciences .7 ( 1 ) : 39-46, 2001.). The aglycone form of the total genistein extract of the present embodiment was obtained by substance isolation procedures, comprising steps usual for those skilled in the art and for this reason will not be detailed in the present invention. However, for better reference, the description of such a procedure may be found in (FERRARI, RA; DEMIATE, IM Soy Isoflavones. Biological and Health Sciences .7 (1): 39-46, 2001.).
No extrato da presente concretização baseado apenas na forma aglicona da genisteína, a concentração de genisteína aglicona varia entre 0,1 a 10%, preferencialmente entre 0,5 a 1,5%. Mais preferencialmente, a concentração de genisteína aglicona no referido extrato é em torno de 0,8 a 1,2%. Mais preferencialmente, é em torno de 1,0%.  In the extract of the present embodiment based only on the aglycone form of genistein, the concentration of aglycone genistein ranges from 0.1 to 10%, preferably from 0.5 to 1.5%. More preferably, the concentration of aglycone genistein in said extract is about 0.8 to 1.2%. More preferably, it is around 1.0%.
Para ambas as composições farmacêuticas, objeto da presente concretização, os veículos farmaceuticamente aceitáveis para uso são os mesmos. Mais especificamente, para a presente concretização, são selecionados, dentre os veículos farmaceuticamente aceitáveis, as substâncias excipientes não tóxicas e inativas, tais como substâncias estabilizadoras, emolientes, diluentes, solubilizantes , espessantes, conservantes, corantes e substâncias antiácidas .  For both pharmaceutical compositions, object of the present embodiment, the pharmaceutically acceptable carriers for use are the same. More specifically, for the present embodiment, non-toxic and inactive excipient substances such as stabilizers, emollients, diluents, solubilizers, thickeners, preservatives, dyes and antacid substances are selected from the pharmaceutically acceptable carriers.
Mais especificamente, os excipientes do grupo dos estabilizadores que podem ser utilizados, são selecionados dentre o grupo dos polímeros hidrossolúveis, para que estabilizem as soluções e melhorem a sua viscosidade. Dentre os polímeros hidrossolúveis possíveis de uso, tem-se o carbopol, ou ainda, qualquer outra substância com características semelhantes às substâncias acima descritas, tais como cellosize, cloreto de sódio, trietolamina, propilenoglicol . Mais especificamente, os excipientes do grupo dos conservantes que podem ser utilizados, são selecionados dentre as substâncias metilparabeno e/ou propilparabeno, ou ainda, qualquer outra substância com características semelhantes às substâncias acima descritas. Mais especificamente, como substâncias conservantes para a presente concretização, foram utilizados nipagin e nipazol. More specifically, excipients from the group of stabilizers that may be used are selected from the group of water soluble polymers to stabilize the solutions and improve their viscosity. Among the possible water-soluble polymers are carbopol, or any other substance with characteristics similar to those described above, such as cellosize, sodium chloride, trietolamine, propylene glycol. More specifically, excipients from the group of preservatives that may be used are selected from methylparaben and / or propylparaben, or any other substance with characteristics similar to those described above. More specifically, as preservative substances for the present embodiment, nipagin and nipazole were used.
Mais especificamente, a substância antiácida selecionada para uso, é o hidróxido de sódio, ou ainda, qualquer outra substância com características semelhantes tais como hidróxido de amónio.  More specifically, the antacid substance selected for use is sodium hydroxide, or any other substance with similar characteristics such as ammonium hydroxide.
Mais especificamente, como emolientes, as substâncias selecionadas para o uso podem ser o proprilenoglicol , sorbitol, glicerina, ou quaisquer outras substâncias com características semelhantes a essas citadas.  More specifically, as emollients, the substances selected for use may be propylene glycol, sorbitol, glycerin, or any other substance with similar characteristics to those cited.
Mais especificamente, como corantes, as substâncias selecionadas para o uso podem ser de origem natural e/ou artificial, preferencialmente da mesma cor da mucosa e que não influenciem no pH e na estabilidade do produto.  More specifically, as dyes, the substances selected for use may be of natural and / or artificial origin, preferably of the same color as the mucosa and which do not influence the pH and stability of the product.
Adicionalmente, mais especificamente, como diluentes, as substâncias selecionadas para o uso podem ser água, álcool, glicerina, entre outros com função polar e apolar para diluir os compostos da formulação.  Additionally, more specifically, as diluents, the substances selected for use may be water, alcohol, glycerin, among others with polar and non-polar function to dilute the formulation compounds.
Cabe salientar que a presente invenção não está limitada às substâncias acima descritas. Uma pessoa com conhecimento na técnica é capaz de substituir qualquer uma das substâncias acima descritas, por outra equivalente, desde que essa substância apresente características funcionais semelhantes àquela que vai substituir. As composições farmacêuticas - objetos da presente concretização - podem ser utilizadas no tratamento e/ou prevenção das doenças decorrentes do hipoestrogenismo no trato genital inferior feminino, como produto para higiene pessoal feminina e, ainda, como cosmético para firmeza e re uvenescimento da pele. It should be noted that the present invention is not limited to the above described substances. One of ordinary skill in the art is able to replace any of the above substances with an equivalent one provided that the substance has functional characteristics similar to the one he or she replaces. The pharmaceutical compositions - objects of the present embodiment - may be used in the treatment and / or prevention of diseases resulting from hypoestrogenism in the female lower genital tract, as a product for female personal hygiene and as a cosmetic for firmness and skin rejuvenation.
Adicionalmente, é ainda objetivo da presente invenção, o uso das referidas composições farmacêuticas, a saber: composição farmacêutica à base de isoflavona total, composição farmacêutica à base de genisteina total e composição farmacêutica à base de genisteina aglicona ou glicona, na preparação de medicamentos eficazes no tratamento e/ou prevenção das doenças decorrentes do hipoestrogenismo no trato genital inferior feminino.  Additionally, it is a further object of the present invention to use said pharmaceutical compositions, namely: total isoflavone based pharmaceutical composition, total genistein based pharmaceutical composition and aglycone or glycone genistein pharmaceutical composition in the preparation of effective medicaments. in the treatment and / or prevention of diseases resulting from hypoestrogenism in the female lower genital tract.
Referido medicamento é ainda utilizado como um produto para a higiene pessoal da mulher, equilibrando a flora local, uma vez que apresenta um pH semelhante ao pH vaginal da mulher (pH entre 3,5 a 4,5), principalmente o pH vaginal no período reprodutivo.  Said drug is also used as a product for personal hygiene of women, balancing the local flora, as it has a pH similar to the vaginal pH of the woman (pH between 3.5 to 4.5), especially the vaginal pH in the period. reproductive.
As formas farmacêuticas preferenciais do referido medicamento podem ser a pastosa e a líquida. Entretanto, preferencialmente, o referido medicamento está sob a forma pastosa, mais especificamente, sob a forma de pomada, creme, pasta, gel, loção ou unguentos, proporcionando a aplicação local do mesmo. Entretanto, formas farmacêuticas como supositórios, emulsões, adesivos, comprimidos ou anel vaginal também podem ser previstas na presente concretização .  Preferred pharmaceutical forms of said medicament may be pasty and liquid. Preferably, however, said medicament is in pasty form, more specifically in the form of ointment, cream, paste, gel, lotion or ointments, providing for local application thereof. However, pharmaceutical forms such as suppositories, emulsions, adhesives, tablets or vaginal ring may also be envisaged in the present embodiment.
Para a presente concretização, o medicamento encontra-se sob a forma farmacêutica preferencial de um gel. Referida " forma proporciona um efeito emoliente, refrescante, secagem rápida quando em contato com o ar e boa penetração cutânea. For the present embodiment, the medicament is in the preferred pharmaceutical form of a gel. Said "shape provides an emollient, refreshing effect, quick drying when in contact with air and good skin penetration.
A opção da forma farmacêutica, gel vaginal, foi escolhida por apresentar inúmeras vantagens sobre as outras formas farmacêuticas, dentre as quais, citamos: é a forma farmacêutica menos incómoda para aplicação local, é de fácil aplicação, possibilita a lubrificação local auxiliando na proteção do tecido, boa penetração facilitando a ação local do principio ativo, é uma das opções mais higiénicas, uma vez que menos suja as vestes, é de fácil limpeza e permite que o produto tenha indicação de uso continuo.  The option of the pharmaceutical form, vaginal gel, was chosen because it has numerous advantages over other pharmaceutical forms, among which we mention: it is the least cumbersome pharmaceutical form for local application, it is easy to apply, enables local lubrication aiding in the protection of the Good penetration, facilitating local action of the active ingredient, is one of the most hygienic options, since it less soils the garments, is easy to clean and allows the product to have indication of continuous use.
0 medicamento ora desenvolvido pela presente invenção, foi analisado fisico-quimicamente e os resultados obtidos quanto as suas características físico-químicas e microbiológicas, são mostradas na Tabela 1.  The drug now developed by the present invention has been physiochemically analyzed and the results obtained for its physicochemical and microbiological characteristics are shown in Table 1.
Tabela 1 - Especificações de análise físico-química e microbiológica do produto Table 1 - Specifications of product's physicochemical and microbiological analysis
Figure imgf000019_0001
Coliformes totais < 10000 UFC/g
Figure imgf000019_0001
Total coliforms <10000 CFU / g
Salmonella sp. Ausente  Salmonella sp. Absent
E. coli Ausente  E. coli Missing
P. auruginosa Ausente  P. auruginosa Absent
S. aureus Ausente  S. aureus Absent
Adicionalmente, o produto obtido, apresenta excelentes índices reológicos, tais como boa viscosidade e boa dispersão do princípio ativo, o que significa ótimas características para o fitoterápico ora desenvolvido. Tais características proporcionam uma sensação agradável no momento de sua aplicação sobre o tecido e uma menor quantidade do produto para uso, garantindo a eficiência terapêutica. O produto final, apresenta um pH aceitável e boa estabilidade a temperatura ambiente (cerca de -25 °G) . Additionally, the product obtained presents excellent rheological indices, such as good viscosity and good dispersion of the active principle, which means excellent characteristics for the phytotherapic developed here. Such characteristics provide a pleasant sensation at the time of application on the fabric and a smaller amount of the product to use, ensuring therapeutic efficiency. The final product has an acceptable pH and good stability at room temperature (about -25 ° C).
De acordo com os ensaios de estabilidade acelerada e longa duração, o produto apresenta segurança e eficácia por 2 anos na formulação proposta.  According to the accelerated stability and long term tests, the product has safety and efficacy for 2 years in the proposed formulation.
A via de administração do referido medicamento sob a forma de gel vaginal é tópica, aplicado diretamente na vagina, de modo a se objetivar a melhora de vários aspectos relacionados aos sintomas locais de hipoestrogenismo, tais como a dispareunia, a secura vaginal, o prurido, a dor/ardor, a queimação e a secreção vaginal.  The route of administration of the drug in the form of vaginal gel is topical, applied directly to the vagina in order to improve various aspects related to local symptoms of hypoestrogenism, such as dyspareunia, vaginal dryness, pruritus, pain / burning, burning and vaginal discharge.
Entretanto, referida via de administração deve ser alterada conforme a forma de apresentação do medicamento.  However, this route of administration should be changed according to the presentation of the drug.
Como forma de garantia da ação terapêutica do fármaco, outro ponto importante a observar é o modo como este medicamento será aplicado. A forma de aplicação interfere direta e proporcionalmente no sucesso da terapia.  As a guarantee of the therapeutic action of the drug, another important point to note is the way this drug will be applied. The form of application directly and proportionally interferes with the success of therapy.
A fim de facilitar a aplicação local do gel na vagina e garantir a ação local terapêutica do medicamento, referido gel deve ser preferencialmente aplicado com o auxilio de um dispositivo mecânico adequado, tal como um aplicador de cerca de 5,0 mL. In order to facilitate local application of the gel to the vagina and to ensure local therapeutic action of the drug, Said gel should preferably be applied with the aid of a suitable mechanical device, such as an applicator of about 5.0 mL.
. O fármaco na forma de gel deve ser aplicado à mulher preferencialmente 1 (uma) vez ao dia. Cada aplicação do referido gel deve ser de cerca de 5,0mL.  . The drug in gel form should be applied to women preferably 1 (once) a day. Each application of said gel should be about 5.0mL.
Mais especificamente, a dose diária da composição farmacêutica, compreendendo isoflavonas totais, da presente invenção, deve ser de cerca de 40,0mg.  More specifically, the daily dose of the pharmaceutical composition comprising total isoflavones of the present invention should be about 40.0mg.
Mais especificamente, para as concretizações preferidas da presente invenção, cerca de cada l,0mL do gel de isoflavona para tratamento/prevenção de sintomas locais de hipoestrogenismo compreende cerca de 8 , Omg de isoflavonas totais. A dose diária da composição farmacêutica, à base de genisteina total, da presente invenção, deve ser de cerca de 24, Omg e a dose diária da composição farmacêutica, à base de genisteina aglicona, da presente invenção, deve ser de cerca de 0,40mg.  More specifically, for preferred embodiments of the present invention, about each 1.0 ml of isoflavone gel for treating / preventing local symptoms of hypoestrogenism comprises about 8.0 Omg of total isoflavones. The daily dose of the total genistein-based pharmaceutical composition of the present invention should be about 24 µg and the daily dose of the genistein-aglycone-based pharmaceutical composition of the present invention should be about 0.25 µg. 40mg.
As vantagens do uso tópico para o tratamento das doenças decorrentes do hipoestrogenismo no trato genital inferior feminino consistem no fato de ser uma via alternativa ao trato gastrointestinal, evitando o efeito de primeira passagem hepática, permitindo o controle da absorção de determinada quantidade de fármaco. Ainda, possibilita a aplicação em diferentes locais do corpo, aumenta a adesão do paciente ao tratamento, devido à facilidade de administração e diminuição da toxicidade sistémica .  The advantages of topical use for the treatment of diseases due to hypoestrogenism in the female lower genital tract are that it is an alternative route to the gastrointestinal tract, avoiding the first-pass hepatic effect, allowing the control of absorption of a certain amount of drug. It also enables application in different body sites, increases patient compliance with treatment due to ease of administration and decreased systemic toxicity.
A presente invenção ainda se refere à análise da ação da composição farmacêutica, exclusivamente local, evitando assim a absorção do produto com ação indesejável em outros tecidos, podendo ser utilizado por período prolongado, sem levar a alterações sistémicas. The present invention further relates to the analysis of the action of the exclusively local pharmaceutical composition, avoiding Thus, the absorption of the product with undesirable action in other tissues can be used for a prolonged period, without leading to systemic changes.
Para que a matéria da presente invenção possa ser melhor visualizada, serão apresentados exemplos. Entretanto, os exemplos aqui descritos possuem caráter puramente ilustrativo, não se tornando formas limitativas da invenção .  In order that the subject matter of the present invention may be better visualized, examples will be given. However, the examples described herein are purely illustrative and not limiting forms of the invention.
Exemplo 1 : Formulação da presente invenção Example 1: Formulation of the present invention
Particularmente, cerca de 60g da composição farmacêutica, objeto da presente concretização, compreende:  Particularly, about 60g of the pharmaceutical composition, object of the present embodiment, comprises:
Isoflavona 10% 3,00g Isoflavone 10% 3.00g
Carbopol 0 , 6gCarbopol 0.6g
Nipagin 0 , 09gNipagin 0.09g
Nipazol 0, 048gNipazole 0.048g
Hidróxido de sódio 0,3gSodium hydroxide 0.3g
Água osmose Q.S.P.60, 00g Osmosis Water Q.S.P.60.00g
Exemplo 2 : Seleção das mulheres a serem submetidas ao estudo : Example 2: Selection of women to undergo the study:
Realizou-se ensaio clínico, placebo-controlado, randomizado, por período de três meses, em um grupo de mulheres após a menopausa.  We conducted a randomized, placebo-controlled clinical trial over a period of three months in a group of postmenopausal women.
As mulheres, que foram selecionadas para fazer parte do estudo clínico, apresentavam queixa de pelo menos um dos sintomas a seguir: secura vaginal e/ou presença de prurido, dor/ardor ou queimação vulvar e vaginal, dispareunia, útero intacto, sem o uso de terapia hormonal atual, ou por pelo menos 6 meses, e sem indicação para terapia hormonal. Women, who were selected to be part of the clinical study, complained of at least one of the following symptoms: vaginal dryness and / or pruritus, vaginal / vaginal pain / burning, dyspareunia, uterus intact, without the use of current hormone therapy, or for at least 6 months, and without indication for hormone therapy.
Na primeira visita das mulheres ao ambulatório, estas foram submetidas à anamnese geral e, a seguir, encaminhadas para o exame físico geral e . ginecológico de rotina e subsequente solicitação de exames complementares.  On the first visit of the women to the outpatient clinic, they were submitted to a general anamnesis and then referred to the general physical exam. gynecological examination and subsequent request for further examinations.
O diagnóstico de menopausa foi baseado nos dados clínicos fornecidos por mulheres com autonomia plena, com pelo menos 12 meses de amenorréia e confirmado pela elevação da gonadotrofina folículo estimulante (FSH) aferida através do sangue colhido por punção venosa de vaso do antebraço. Considerou-se como critério de inclusão aque'las que apresentaram FSH > 30 mUI/mL.  The diagnosis of menopause was based on clinical data provided by fully autonomous women with at least 12 months of amenorrhea and confirmed by elevation of gonadotropin-stimulating follicle (FSH) measured by blood collected by forearm vessel venipuncture. Inclusion criteria were those with FSH> 30 mIU / mL.
Para atender às formalidades exigidas, as mulheres foram informadas do protocolo a ser adotado e assinaram um termo de consentimento livre e esclarecido.  To meet the required formalities, the women were informed of the protocol to be adopted and signed a free and informed consent term.
Durante o exame citológico, foi realizada a aferição do pH vaginal por meio do uso de indicadores ácido-base, tal como a fita de tornassol e colhido material local para leitura da citologia oncológica e hormonal.  During the cytological examination, vaginal pH was measured using acid-base indicators such as litmus tape and local material was collected for oncological and hormonal cytology reading.
A citologia vaginal hormonal foi avaliada por esfregaços e para a coleta do material as mulheres foram orientadas a evitar relação sexual, cremes, duchas, talcos e lavagens vaginais pelo menos cerca de 48 horas antes das coletas. Foi utilizado um espéculo vaginal sem lubrificantes, e o material vaginal foi colhido com espátula de madeira de Ayre do fórnice vaginal posterior e retirado por escovinha com soro fisiológico das paredes vaginais laterais. O material colhido foi acomodado em lâmina de vidro e fixado em álcool absoluto, corados pelo método de Papanicolaou e encaminhado para estudo sob microscópio ótico, visando observar a intensidade de maturação do epitélio. The hormonal vaginal cytology was evaluated by smears and for the collection of the material the women were instructed to avoid sexual intercourse, creams, showers, talc and vaginal washes at least about 48 hours before the collections. A vaginal speculum without lubricants was used, and the vaginal material was collected with Ayre's wooden spatula from the posterior vaginal fornix and brushed with saline from the lateral vaginal walls. The collected material was placed on a glass slide and fixed in absolute alcohol, stained by Papanicolaou method and referred for study under optical microscope, aiming to observe the intensity of maturation of the epithelium.
Em seguida, as mulheres foram submetidas aos exames complementares, que compreenderam: hemograma, glicemia, perfil lipoproteico, provas de funções renais e hepáticas, pesquisa de sangue oculto nas fezes, dosagens sérica de FHS e estradiol, TSH e T4L basais, ultrassonografia por via transvaginal e mamografia.  Then, the women were submitted to complementary exams, which included: blood count, blood glucose, lipoprotein profile, renal and liver function tests, fecal occult blood test, serum levels of FHS and estradiol, basal TSH and T4L, ultrasonography transvaginal and mammography.
Nos exames ultrassonográficos foram realizados três movimentos primários do transdutor: movimento de lado a lado para imagens no plano sagital, movimentos ântero- posteriores para imagens em plano coronal e variação de profundidade para imagens do útero e anexos em vários graus de planos semicoronais .  In the ultrasound exams, three primary transducer movements were performed: side-by-side movement for sagittal plane images, anteroposterior movements for coronal plane images, and depth variation for uterus images and attachments at various degrees of semicoronal planes.
O exame consistiu inicialmente da avaliação morfológica do útero e da cavidade uterina e do volume uterino, através das medidas no sentido dos seus eixos longitudinais, ântero-posterior e transverso.  The examination initially consisted of the morphological evaluation of the uterus and the uterine cavity and the uterine volume through measurements in the direction of their longitudinal, anteroposterior and transverse axes.
A mensuração do eco endometrial foi realizada, com a imagem congelada, no sentido ântero-posterior, em secções longitudinais do útero, incluindo as duas camadas endometriais , a partir da interface ecogênica da junção miométrio-endométrio, de um lado ao outro. Foi realizada medida, na maior espessura possível, desde a interface miométrio-endométrio da parede anterior do útero até a interface miométrio-endométrio da parede posterior.  Endometrial echo measurement was performed, with the frozen image, anteroposteriorly, in longitudinal sections of the uterus, including the two endometrial layers, from the echogenic interface of the myometrium-endometrium junction from side to side. The largest possible thickness was measured from the myometrium-endometrium interface of the anterior wall of the uterus to the myometrium-endometrium interface of the posterior wall.
O exame ainda avaliou morfologicamente os ovários e. o volume ovariano através das medidas no eixo longitudinal, ântero-posterior e transverso (Kepple, 2000) . Exemplo 3 - Análise dos exames laboratoriais e distribuição das mulheres em dois grupos The examination also morphologically evaluated the ovaries and . ovarian volume through measurements on the longitudinal, anteroposterior, and transverse axis (Kepple, 2000). Example 3 - Analysis of laboratory tests and distribution of women into two groups.
Os exames solicitados na primeira visita das mulheres ao ambulatório foram avaliados e aquelas que preencheram os critérios de inclusão, exames laboratoriais de imagens e citológicos normais, foram distribuídas aleatoriamente em dois grupos para início do tratamento.  The exams requested at the first visit of the women to the outpatient clinic were evaluated and those that met the inclusion criteria, laboratory imaging and normal cytology tests, were randomly assigned to two groups to begin treatment.
Os grupos formados foram homogéneos quanto à idade das pacientes submetidas ao tratamento, tempo transcorrido após a menopausa e índice de massa corpórea.  The groups formed were homogeneous as to the age of the patients undergoing treatment, time after menopause and body mass index.
0 Grupo 1 compreendeu as mulheres selecionadas para uso e aplicação do gel vaginal de isoflavona, compreendendo genisteína (5%). A aplicação foi local no epitélio vaginal, por meio de aplicadores vaginais de plástico, com marcador impresso de lg. A recomendação foi que a aplicação fosse realizada diariamente e preferencialmente na parte da noite.  Group 1 comprised women selected for use and application of isoflavone vaginal gel, comprising genistein (5%). The application was local to the vaginal epithelium by means of plastic vaginal applicators with a lg printed marker. The recommendation was that the application should be performed daily and preferably in the evening.
Adicionalmente, esse Grupo também serviu para avaliar a aceitação do produto e consequentemente a coloração final do mesmo.  Additionally, this Group also served to evaluate the acceptance of the product and consequently the final color of the product.
O Grupo 2 compreendeu as mulheres selecionadas para uso e aplicação do placebo, ou seja, o Grupo 2 serviu como grupo controle para a análise e acompanhamento dos resultados e efeitos obtidos com o tratamento. As mulheres do grupo controle fizeram uso e aplicação de um gel vaginal, o qual era isento do princípio ativo. A aplicação foi local no epitélio vaginal, por meio de aplicadores vaginais de plástico, com marcador impresso de lg. A recomendação foi que a aplicação fosse realizada diariamente e preferencialmente na parte da noite. As mulheres procederam com a aplicação diária do gel vaginal por um período de 30 (trinta) dias, período após o qual, retornaram ao ambulatório para avaliação do uso do medicamento . Group 2 comprised women selected for placebo use, ie Group 2 served as a control group for the analysis and follow-up of treatment outcomes and effects. The women in the control group used and applied a vaginal gel, which was exempt from the active ingredient. The application was local to the vaginal epithelium by means of plastic vaginal applicators with a lg printed marker. The recommendation was that the application should be performed daily and preferably in the evening. The women proceeded with the daily application of vaginal gel for a period of 30 (thirty) days, after which they returned to the outpatient clinic to evaluate the use of the drug.
Exemplo 4 - Avaliação do uso do gel vaginal após 30 (trinta) dias de uso Example 4 - Evaluation of vaginal gel use after 30 (thirty) days of use
Na terceira visita das mulheres ao ambulatório, estas foram novamente submetidas a exames citológicos e a aferição do pH vaginal, seguindo o mesmo protocolo utilizado na primeira visita, dessas, ao ambulatório.  In the third visit of the women to the outpatient clinic, they were again submitted to cytological exams and the vaginal pH measurement, following the same protocol used in the first visit of the outpatient clinic.
Os resultados obtidos nos exames, juntamente com a análise dos sintomas clínicos apresentados pelas mulheres e os efeitos adversos, foram indicativos para avaliação do efeito do medicamento fitoterápico à base de genisteina.  Examination results, together with analysis of clinical symptoms presented by women and adverse effects, were indicative for the evaluation of the effect of the genistein-based herbal medicine.
Exemplo 5 - Avaliação do uso do gel vaginal após 90 (noventa) dias de uso Example 5 - Evaluation of vaginal gel use after ninety (90) days of use
A quarta visita ao ambulatório ocorreu 90 (noventa) dias após o início do uso do gel vaginal. Nessa visita, nova avaliação dos sintomas clínicos e efeitos adversos foi realizada além das mulheres serem novamente submetidas aos exames de citologia hormonal e avaliação do pH, seguindo o mesmo protocolo utilizado na primeira visita, dessas, ao ambulatório .  The fourth visit to the outpatient clinic occurred ninety (90) days after the start of vaginal gel use. At this visit, a new evaluation of clinical symptoms and adverse effects was performed in addition to the women being again submitted to hormonal cytology tests and pH evaluation, following the same protocol used in the first visit, of these, to the outpatient clinic.
Nessa visita, as mulheres foram encaminhadas para a realização de exame de imagem, ultrassonografia via transvaginal , para avaliação endometrial e dosagens séricas de estradiol e FSH. Exemplo 6 - Avaliação do uso do gel vaginal após 120 (cento e vinte) dias de uso During this visit, the women were referred for imaging, transvaginal ultrasound, endometrial evaluation, and serum estradiol and FSH measurements. Example 6 - Evaluation of vaginal gel use after 120 (one hundred and twenty) days of use
Após 120 (cento e vinte) dias do inicio do tratamento, as mulheres fizeram nova visita ao ambulatório para entrega dos resultados dos exames realizados nas visitas anteriores e orientação.  120 (one hundred and twenty) days after the beginning of the treatment, the women made another visit to the outpatient clinic to deliver the results of the exams performed in the previous visits and orientation.
Os dados obtidos, como resultados durante todo o período de tratamento, foram tabulados em planilhas do Microsoft Excel® para arquivamento de informações e contagem de campos. Os dados foram submetidos a análises estatísticas realizadas por meio de um programa de computador usual àqueles com conhecimento na técnica. Para a presente invenção, o programa selecionado para uso foi o pacote estatístico SPSS para Windows.  The data obtained as results throughout the treatment period were tabulated in Microsoft Excel® spreadsheets for information archiving and field counting. The data were submitted to statistical analyzes performed by means of a computer program usual to those with knowledge in the art. For the present invention, the program selected for use was the SPSS statistical package for Windows.
Por meio da análise dos resultados obtidos, nota-se que não houve alteração significativa nas concentrações séricas de FSH (mUI/mL) , estradiol (mg/dL) e do eco endometrial (mm) quando da comparação dos resultados obtidos do início ao final do tratamento, conforme mostra a Tabela 2.  By analyzing the results obtained, it was noted that there was no significant change in serum concentrations of FSH (mUI / mL), estradiol (mg / dL) and endometrial echo (mm) when comparing the results obtained from beginning to end. treatment as shown in Table 2.
Tabela 2. Valores de FSH (mUI/mL) , Estradiol (mg/dL) e Eco endometrial (mm) nos tempos 0 e 90 dias nos 2 grupos. Table 2. FSH (mIU / mL), Estradiol (mg / dL) and Endometrial Echo (mm) values at times 0 and 90 days in the 2 groups.
Grupo Variável Tempo Mediana V. V. Mann- Variable Group Median Time V. V. Mann-
(dias) máximo mínimo Whitney (days) minimum maximum Whitney
~ P* ~ P *
Isoflavona FSH 0 60, 5 80,0 48,0 Isoflavone FSH 0 60, 5 80.0 48.0
Placebo FSH 0 57, 0 70,0 48,0 0, 138 Placebo FSH 0 57,0 0 70,0 48,0 0, 138
Isoflavona FSH 90 52, 5 75, 0 42, 0 Isoflavone FSH 90 52,575 75,0 42,0
Placebo FSH 90 52, 0 66, 0 40, 0 0, 347 Placebo FSH 90 52,0 66 0 40 0 0 347
Isoflavona Estradiol 0 30 48 20 Isoflavone Estradiol 0 30 48 20
Placebo Estradiol 0 30 49 20 0, 689 Placebo Estradiol 0 30 49 20 0, 689
Isoflavona Estradiol 90 31 48 24 Isoflavone Estradiol 90 31 48 24
Placebo Estradiol 90 30 52 24 0,287 Placebo Estradiol 90 30 52 24 0,287
Isoflavona Eco 0 3 5 1 Isoflavone Eco 0 3 5 1
endometrial Placebo Eco 4 1 0, 625 endometrial endometrial Placebo Eco 4 1 0, 625 endometrial
Isoflavona Eco 3 1 Isoflavone Eco 3 1
endometrial  endometrial
Placebo Eco 3 1 0,269 endometrial Placebo Eco 3 1 0,269 endometrial
* as diferenças entre as medianas mostram resultado não estatisticamente significantes para o FSH, Estradiol e para o Eco endometrial (Mann-Whitney) .  * Differences between medians show non-statistically significant results for FSH, Estradiol and endometrial echo (Mann-Whitney).
Os dados apresentados na Tabela 2 demonstram que não houve absorção do medicamento, assim como o eco endometrial não sofreu alteração, isto é, não houve ação no endométrio. Esse fato é de extrema relevância para análise da ação e efeito do medicamento, uma vez que não há interesse que o referido medicamento tenha outra ação exceto a ação vaginal local . The data presented in Table 2 show that there was no absorption of the drug, as well as the endometrial echo did not change, that is, there was no action on the endometrium. This fact is extremely relevant for the analysis of the action and effect of the drug, since there is no interest in the drug having any action other than local vaginal action.
A Tabela 3 mostra os dados obtidos na avaliação da ação vaginal do produto, por meio dos valores de indice de maturação do epitélio vaginal (indice de Meisels) , nos dois Grupos de mulheres submetidos ao tratamento em 3 (três) tempos distintos, a saber: Tempo 0 (To) - inicio do tratamento; Tempo 1 (Ti) - após 30 dias e Tempo 2 (T2) após 90 dias. Table 3 shows the data obtained in the evaluation of the vaginal action of the product, through the values of vaginal epithelial maturation index (Meisels index), in the two groups of women undergoing treatment in 3 (three) different times, namely: : Time 0 (To) - start of treatment; Time 1 (Ti) - after 30 days and Time 2 (T 2 ) after 90 days.
Tabela 3. Valores de indice de Meisels nos grupos isoflavona e placebo nos 3 tempos Table 3. Meisels index values in the isoflavone and placebo groups at 3 times
Grupo Tempo Mediana V. V. Mann- Median Time Group V. V. Mann-
(dias) máximo mínimo Whitney(days) minimum maximum Whitney
Isoflavona 0 3,7 20,0 0,0 Isoflavone 0 3.7 20.0 0.0
(n=30)  (n = 30)
Placebo 0 0,0 15,0 0,0 0, 302 Placebo 0 0.0 15.0 0.0 0, 302
(n=25) (n = 25)
Isoflavona 30 27,5 65,0 0,0  Isoflavone 30 27.5 65.0 0.0
(n=30)  (n = 30)
Placebo 30 10, 0 85,0 0,0 0, 008 Placebo 30 10.0 85.0 0.0 0.008
(n=25) (n = 25)
Isoflavona 90 46,2 85, 0 2,5  Isoflavone 90 46.2 85.0 2.5
(n=30) Placebo 90 20, 0 55, 0 Õ7Õ <0, 001(n = 30) Placebo 90 20, 0 55, 0 Õ7Õ <0,001
(n=25) (n = 25)
Em uma comparação dos resultados mostrados na Tabela 3 para os Grupos Isoflavona e Grupo Placebo, nota-se que houve diferenças significativas já constatadas no Ti e T2 no grupo que utilizou isoflavonas por via vaginal, o mesmo não ocorrendo quando o produto utilizado foi o placebo. In a comparison of the results shown in Table 3 for the Isoflavone and Placebo Groups, it is noted that there were significant differences already observed in Ti and T 2 in the group that used isoflavones vaginally, the same not occurring when the product was used. placebo.
Mais especificamente, é possível notar que os resultados obtidos relativos à ação vaginal do produto confirmam o fato da ação local do medicamento. Logo no inicio do tratamento, isto é, com 30 dias de uso do gel vaginal, observa-se a ação do produto no epitélio vaginal. Esse dado é importante, quando nos referimos às mulheres que apresentam alguma contraindicação ao uso de terapia hormonal e que não podem utilizar qualquer produto que apresente absorção.  More specifically, it can be noted that the results obtained regarding the vaginal action of the product confirm the fact of the local action of the drug. At the beginning of treatment, that is, with 30 days of use of the vaginal gel, the action of the product on the vaginal epithelium is observed. This is important when referring to women who have some contraindication to the use of hormone therapy and who cannot use any product that presents absorption.
Em relação à frequência dos sintomas vaginais, foi observado que houve melhora nos itens secura, prurido, dor/ardor e dispareunia, conforme demonstrado na Tabela 4.  Regarding the frequency of vaginal symptoms, it was observed that there was an improvement in the items dryness, itching, pain / burning and dyspareunia, as shown in Table 4.
Tabela 4. Frequência de sintomas vaginais nos tempos 0 e 90 dias nos 2 grupos . Table 4. Frequency of vaginal symptoms at times 0 and 90 days in both groups.
Dias Sintomas n (%) n (% ) tratamento vaginais Grupo Grupo  Days Symptoms n (%) n (%) vaginal treatment Group Group
Isoflavona Placebo Isoflavone Placebo
Secura 0 Ausente 0 (0) 0 (0) Dryness 0 Missing 0 (0) 0 (0)
90 Ausente 12 (40) 5 (20) 90 Missing 12 (40) 5 (20)
Prurido 0 Ausente 8 (26,7) 0 (0) Itching 0 Missing 8 (26.7) 0 (0)
90 Ausente 29 (96,7) 5 (20) 90 Missing 29 (96.7) 5 (20)
Dor/ardor 0 Ausente 25 (83,3) 8 (32) Pain / burning 0 Absent 25 (83.3) 8 (32)
90 Ausente 30 (100) 21 (84) 90 Missing 30 (100) 21 (84)
Dispareunia 0 Ausente 0 (0) 0 (0) Dyspareunia 0 Missing 0 (0) 0 (0)
90 Ausente 12 (40) 1 (4) Entre as mulheres, que. inicialmente apresentavam queixa de secura vaginal ao final do tratamento, 40% não mais referiam esse sintoma no Grupo I, ou seja, o grupo de mulheres em que foi usado e aplicado o gel vaginal de isoflavona compreendendo genisteina (5%), e 20% no Grupo II. O prurido não estava mais presente em 96,7% das mulheres no Grupo I e somente 20% das mulheres no Grupo II não se apresentavam com este sintoma. Quanto à queixa de dor/ardor, 100% referiram melhora no Grupo I e 84% no Grupo II. Quanto à dispareunia, 40% das mulheres do Grupo I relataram ter se beneficiado com o tratamento com gel vaginal e apenas 4% no Grupo II - placebo. 90 Missing 12 (40) 1 (4) Among women, that. initially complained of vaginal dryness at the end of treatment, 40% no longer reported this symptom in Group I, ie, the group of women in which isoflavone vaginal gel comprising genistein (5%) was used and applied, and 20% in Group II. Pruritus was no longer present in 96.7% of women in Group I and only 20% of women in Group II did not present with this symptom. Regarding pain / burning complaints, 100% reported improvement in Group I and 84% in Group II. As for dyspareunia, 40% of women in Group I reported benefiting from vaginal gel treatment and only 4% in Group II - placebo.
Exemplo 7 : Seleção das mulheres a serem submetidas ao uso de isoflavona, placebo e estrogenio conjugado de equino: Example 7: Selection of women to undergo isoflavone, placebo and conjugated equine estrogen:
Realizou-se ensaio clinico, placebo-controlado, randomizado, por período de três meses, em um grupo de mulheres após a menopausa.  We conducted a randomized, placebo-controlled clinical trial over a period of three months in a group of postmenopausal women.
A seleção das mulheres para fazer parte do estudo clínico seguiu os mesmos critérios que os descritos nos exemplos acima.  The selection of women to be part of the clinical study followed the same criteria as those described in the examples above.
Exemplo 8 - Análise dos exames laboratoriais e distribuição das mulheres em dois grupos Example 8 - Analysis of laboratory tests and distribution of women into two groups
Os exames solicitados na primeira visita das mulheres ao ambulatório foram avaliados e aquelas que preencheram os critérios de inclusão, exames laboratoriais de imagens e citológicos normais, foram distribuídas aleatoriamente em três grupos para início do tratamento. Os grupos formados foram homogéneos quanto à idade das pacientes submetidas ao tratamento, tempo transcorrido após a menopausa e índice de massa corpórea. The exams requested at the first visit of the women to the outpatient clinic were evaluated and those that met the inclusion criteria, laboratory imaging and normal cytology tests were randomly assigned to three groups to begin treatment. The groups formed were homogeneous as to the age of the patients undergoing treatment, time after menopause and body mass index.
O Grupo 1 compreendeu as mulheres selecionadas para uso e aplicação do gel vaginal de isoflavona compreendendo genisteína (5%) . A aplicação foi local no epitélio vaginal, por meio de aplicadores vaginais de plástico, com marcador impresso de lg. A recomendação foi que a aplicação fosse realizada diariamente e preferencialmente na parte da noite.  Group 1 comprised women selected for use and application of isoflavone vaginal gel comprising genistein (5%). The application was local to the vaginal epithelium by means of plastic vaginal applicators with a lg printed marker. The recommendation was that the application should be performed daily and preferably in the evening.
0 Grupo 2 compreendeu as mulheres selecionadas para uso e aplicação do placebo, ou seja, o Grupo 2 serviu como grupo controle para a análise e acompanhamento dos resultados e efeitos obtidos com o tratamento. As mulheres do grupo controle fizeram uso e aplicação de um gel vaginal, o qual era isento do princípio ativo. A aplicação foi local no epitélio vaginal, por meio de aplicadores vaginais de plástico, com marcador impresso de lg. A recomendação foi que a aplicação fosse realizada diariamente e preferencialmente na parte da noite.  Group 2 comprised women selected for placebo use, ie Group 2 served as a control group for the analysis and follow-up of treatment outcomes and effects. The women in the control group used and applied a vaginal gel, which was exempt from the active ingredient. The application was local to the vaginal epithelium by means of plastic vaginal applicators with a lg printed marker. The recommendation was that the application should be performed daily and preferably in the evening.
O Grupo 3 compreendeu as mulheres selecionadas para uso e aplicação de estrogênios conjugados ou controle positivo. A aplicação de cerca de 0,3mg de creme vaginal de estrogênios conjugados foi local, no epitélio vaginal, por meio de aplicadores vaginais de plástico, com marcador impresso de lg. A recomendação foi que a aplicação fosse realizada diariamente e preferencialmente na parte da noite.  Group 3 comprised women selected for use and application of conjugated estrogens or positive control. Approximately 0.3 mg of conjugated estrogen vaginal cream was applied locally to the vaginal epithelium by means of plastic vaginal applicators with a lg marker. The recommendation was that the application should be performed daily and preferably in the evening.
As mulheres procederam com a aplicação diária do gel vaginal por períodos de 30 (trinta) dias, 90 (noventa) dias e 120 (cento e vinte) dias, conforme protocolo anterior descrito. Ao término de cada período as mulheres retornaram ao ambulatório para avaliação do uso do medicamento. The women proceeded with the daily application of vaginal gel for periods of 30 (thirty) days, 90 (ninety) days and 120 (one hundred and twenty) days, according to the previous protocol. described. At the end of each period, the women returned to the outpatient clinic to evaluate their medication use.
Os dados obtidos, como resultados durante todo o período de tratamento, foram tabulados em planilhas do Microsoft Excel® para arquivamento de informações e contagem de campos. Os dados foram submetidos a análises estatísticas realizadas por meio de um programa de computador usual àqueles com conhecimento na técnica. Para a presente invenção, o programa selecionado para uso foi o pacote estatístico SPSS para Windows.  The data obtained as results throughout the treatment period were tabulated in Microsoft Excel® spreadsheets for information archiving and field counting. The data were submitted to statistical analyzes performed by means of a computer program usual to those with knowledge in the art. For the present invention, the program selected for use was the SPSS statistical package for Windows.
Os resultados foram obtidos por meio do estudo isolado dos três Grupos e são mostrados nas Tabelas 5, 6, 7 e 8 e Figuras 1, 2 e 3. Em seguida foi ainda realizado um estudo comparativo entre os diferentes Grupos, conforme Tabelas 9, 10 e 11 e figura 4. Um estudo comparativo dos resultados de FSH é mostrado na Tabela 11 e o estudo eco endometrial é mostrado na tabela 13.  The results were obtained through the isolated study of the three groups and are shown in Tables 5, 6, 7 and 8 and Figures 1, 2 and 3. Then, a comparative study between the different groups was performed, as shown in Tables 9, 10 and 11 and figure 4. A comparative study of FSH results is shown in Table 11 and the endometrial echo study is shown in table 13.
Tabela 5. Distribuição de Idade (anos) nos 3 grupos. Table 5. Age distribution (years) in the 3 groups.
Grupo\idade Mediana V. máximo V. mínimo Kruskal- Wallis (p) Group \ Median age V. Maximum V. minimum Kruskal- Wallis (p)
Isoflavona 57 69 52 Isoflavone 57 69 52
(n=30)  (n = 30)
Placebo 57 69 51  Placebo 57 69 51
(n=25)  (n = 25)
EEC (n=20) 56 65 48 0,467  EEC (n = 20) 56 65 48 0.467
Pelos resultados mostrados na Tabela 5, observa-se que não foi encontrada diferença estatisticamente significante entre as medianas de idade nos 3 grupos (Kruskal-Wallis, p=0,467). O que demonstra que os Grupos foram pareados em relação à idade. Os resultados de índice Meisels, que avaliam a maturação do epitélio vaginal, ou seja, quanto maior o índice, melhor as condições tróficas do epitélio vaginal obtidos para o Grupo I, são mostrados na Tabela 6 e mostraram que houve diferenças estatisticamente significantes entre os três tempos (Friedman, p<0,001). 0 teste POST HOC de Dunn mostrou serem estatisticamente significantes as diferenças entre as medianas em todos os pares (0-30, 0-90 e 30-90) . From the results shown in Table 5, it is observed that no statistically significant difference was found between the median age in the 3 groups (Kruskal-Wallis, p = 0.467). This shows that the groups were matched for age. The Meisels index results, which assess the maturation of the vaginal epithelium, ie the higher the index, the better the trophic conditions of the vaginal epithelium obtained for Group I, are shown in Table 6 and showed that there were statistically significant differences between the three. times (Friedman, p <0.001). Dunn's POST HOC test showed that the differences between the medians in all pairs were statistically significant (0-30, 0-90 and 30-90).
Tabela 6. Valores de índice de Meisels nos tempos 0, 30 e 90 dias no grupo isoflavona (n=30) Table 6. Meisels index values at times 0, 30 and 90 days in the isoflavone group (n = 30)
Tempo Mediana Valor Valor Friedman Dunn Dunn Dunn Median Time Value Value Friedman Dunn Dunn Dunn
(dias ) máximo mínimo (P) (P) (P) (P) (days) minimum maximum ( P ) ( P ) ( P ) ( P )
0-30 0-90 30-90 0-30 0-90 30-90
0 3,7 20, 0 0,0 0 3.7 20, 0 0.0
30 27, 5 65, 0 0,0  30 27.565.0.0 0.0
90 46,2 85,0 2,5 <0, 001 <0, 001 <0, 001 <0, 05  90 46.2 85.0 2.5 <0.001 <0.001 <0.001 <0.05
Os resultados de índice de Meisels obtidos para o Grupo II são mostrados na Tabela 7 e mostraram diferença estatisticamente significante entre as medianas de índice Meisels no grupo placebo, nos 3 tempos (Friedman, p<0,001). O teste POST HOC de Dunn mostra que as diferenças entre os pares 0-30 e 0-90 são estatisticamente significantes. Cabe salientar que este resultado só tem valor quando comparado a outros Grupos estudados. The Meisels index results obtained for Group II are shown in Table 7 and showed a statistically significant difference between the Meisels index medians in the placebo group at 3 times (Friedman, p <0.001). Dunn's POST HOC test shows that the differences between pairs 0-30 and 0-90 are statistically significant. It should be noted that this result has value only when compared to other groups studied.
Tabela 7. Valores de índice de Meisels nos tempos 0, 30 e 90 dias no grupo placebo (n=25) Table 7. Meisels index values at 0, 30 and 90 days in the placebo group (n = 25)
Tempo Mediana Valor Valor Friedman Dunn Dunn Dunn Median Time Value Value Friedman Dunn Dunn Dunn
(dias ) máximo mínimo (p) (p) (P) (P) (days) minimum maximum ( p) ( p ) (P ) ( P)
0-30 0-90 30-90 0-30 0-90 30-90
0 0, 0 15, 0 0, 0 30 10,0 85,0 0,0 0 0, 0 15, 0 0, 0 30 10.0 85.0 0.0
90 20,0 55,0 0,0 <0,001 <0,010 <0,001 >0,05  90 20.0 55.0 0.0 <0.001 <0.010 <0.001> 0.05
Os resultados de índice de Meisels obtidos para o Grupo III são mostrados na Tabela 8 e também mostraram diferença estatisticamente significante entre as medianas de índice de Meisels, no grupo EEC, entre os tempos 3 tempos (Friedman, p<,001). 0 teste POST HOC de Dunn mostra serem estatisticamente significantes apenas as diferenças entre as medianas dos pares 0-30 e 0-90. The Meisels index results obtained for Group III are shown in Table 8 and also showed a statistically significant difference between the Meisels index medians in the EEC group between the 3-stroke times (Friedman, p <.001). Dunn's POST HOC test shows that only the differences between the medians of pairs 0-30 and 0-90 are statistically significant.
Tabela : 8. Valores de índice de Meisels nos tempos 0, 30 eTable: 8. Meisels index values at times 0, 30 and
90 dias no grupo EEC (n=20) 90 days in EEC group (n = 20)
Tempo Mediana Valor Valor Friedman Dunn Dunn Dunn Median Time Value Value Friedman Dunn Dunn Dunn
(dias ) máximo mínimo (P) (P) (P) (P) (days) minimum maximum ( P ) (P) ( P ) ( P )
0-30 0-90 30-90 0-30 0-90 30-90
0 0,0 10,0 0, 0 0 0.0 10.0 0, 0
30 30, 0 60, 0 2,5  30 30.0 60.0 2.5
90 50, 0 65, 0 15, 0' <0, 001 <0, 001 <0, 001 ' >0, 05 90 50.0 65.0 15.0 0 ' <0.001 <0.001 <0.001 ' > 0.05
Foi encontrada diferença estatisticamente significante entre as medianas de índice de Meisels no grupo EEC, entre os tempos 3 tempos (Friedman, p<,001). O teste POST HOC de Dunn mostra serem estatisticamente significantes apenas as diferenças entre as medianas dos pares 0-30 e 0-90. A statistically significant difference was found between the Meisels index medians in the EEC group, between times 3 times (Friedman, p <.001). Dunn's POST HOC test shows that only the differences between the medians of pairs 0-30 and 0-90 are statistically significant.
Estudos comparativos dos resultados para o índice Meisels também foram realizados.  Comparative studies of the results for the Meisels index were also performed.
Tabela 9 . Comparação dos valores de índice de Meisels no tempo 0, nos 3 grupos. Table 9 Comparison of Meisels index values at time 0 in the 3 groups.
Grupo\Meisels Mediana V. máximo V. mínimo Kruskal- Group \ Meisels Median V. Maximum V. Minimum Kruskal-
(0 dias) Wallis (p)(0 days) Wallis (p)
Isoflavona 3,7 20, 0 0,0 Isoflavone 3.7 20.0 0.0
Placebo 0,0 15, 0 0,0  Placebo 0.0 15, 0 0.0
EEC 0,0 10, 0 0, 0 0, 176 Tabela 10. Comparação dos valores de índice de Meisels no tempo 30 dias, nos 3 grup EEC 0.010.0.0.0.0166 Table 10. Comparison of Meisels index values at time 30 days in the 3 groups
Grupo\Meisels Mediana V. V. Kruskal- Dunn Dunn Dunn Group \ Meisels Median V. V. Kruskal- Dunn Dunn Dunn
(30 d) máximo mínimo Wallis Iso- Iso- Pla- pla EEC EEC(30 d) minimum maximum Wallis Iso-Iso-Plate EEC EEC
Isoflavona 27,5 65, 0 0, 0 Isoflavone 27.5 65, 0 0, 0
Placebo 10, 0 85, 0 0,0  Placebo 10.0 85.0 0.0
EEC 30, 0 60, 0 2,5 0, 003 <0, 0 >0, 05 <0, 01  EEC 30.0 60.0 2.50.003 <0.03> 0.05 <0.01
5  5th
Tabela 11. Comparação dos valores de índice de Meisels no tempo 90 dias, nos 3 grupos. Table 11. Comparison of Meisels index values at time 90 days in the 3 groups.
Grupo\Meiseis Mediana V. V. Kruskal- Dunn Dunn Dunn 90 d máximo mínimo Wallis Iso- Iso- Pla- pla EEC EEC Group \ Meiseis Median V. V. Kruskal- Dunn Dunn Dunn 90 d maximum minimum Wallis Iso-Iso-Plate EEC EEC
Isoflavona 46,2 85, 0 2,5 Isoflavone 46.2 85.0 2.5
Placebo 20,0 55, 0 0, 0  Placebo 20.0 55, 0 0, 0
EEC 50,0 65, 0 15,0 0, 000 <0, 0 >0, 05 <0,00  EEC 50.0 65.0 0 15.0 <0.000 <0.05 <0.05
01 1  01 1
Pelos resultados mostrados na Tabela 9, nota-se que não foram encontradas diferenças estatisticamente significantes entre as medianas de índice Meisels no tempo 0, entre os 3 grupos terapêuticos (Kruskal- allis, p=0,176) . Entretanto, o mesmo não ocorreu ao analisar os resultados da Tabela 10. Na análise comparativa da Tabela 10, identificou-se diferença estatisticamente significante entre as medianas de índice de Meisels aos 30 dias, entre os 3 grupos terapêuticos (Kruskal-Wallis, p=0,003) . O teste POST HOC de Dunn mostra serem estatisticamente significantes as diferenças entre as medianas dos grupos placebo e isoflavona e placebo-EEC. Não houve diferença significante entre os Grupos EEC e Isoflavona. O mesmo pode ser concluído pelos resultados da Tabela 11, onde houve diferença estatisticamente significante entre as medianas dos índices Meissels aos 90 dias, entre os 3 grupos terapêuticos (Kruskal-Wallis, p=0,000). O teste POST HOC de Dunn mostra que as diferenças estatisticamente significantes ocorrem entre as medianas dos grupos Isoflavona-placebo e placebo-EEC. Não houve diferença significante entre os Grupos EEC e Isoflavona. From the results shown in Table 9, it is noted that no statistically significant differences were found between the Meisels index medians at time 0, among the 3 therapeutic groups (Kruskal-allis, p = 0.176). However, the same did not occur when analyzing the results of Table 10. In the comparative analysis of Table 10, we identified a statistically significant difference between the Meisels index medians at 30 days, between the 3 therapeutic groups (Kruskal-Wallis, p = 0.003). Dunn's POST HOC test shows that the differences between the medians of the placebo and isoflavone and placebo-EEC groups are statistically significant. There was no significant difference between the EEC and Isoflavone Groups. The same can be concluded by the results of Table 11, where there was a statistically significant difference between the Meissels index medians at 90 days, between the 3 groups. therapeutic (Kruskal-Wallis, p = 0.000). Dunn's POST HOC test shows that statistically significant differences occur between the medians of the Isoflavone-placebo and placebo-EEC groups. There was no significant difference between the EEC and Isoflavone Groups.
0 estudo comparativo para os resultados de FSH mostra que não foram encontradas diferenças estatisticamente significantes entre as medianas de concentração de FSH inicial e aos 90 dias entre os 3 grupos terapêuticos (Kruskal-Wallis, p=0,176 e 0,188 respectivamente), conforme mostra a Tabela 12.  The comparative study for FSH results shows that no statistically significant differences were found between median baseline and 90-day FSH concentration between the 3 therapeutic groups (Kruskal-Wallis, p = 0.176 and 0.188 respectively), as shown in Table 12
Tabela.12. Comparação das concentrações de FSH (mUI/mL) nos tempos 0 e 90 dias, nos 3 grupos Table.12. Comparison of FSH concentrations (mIU / mL) at times 0 and 90 days in the 3 groups
Grupo\FSH Tempo Mediana V. máximo V. mínimo Kruskal- Group \ FSH Median Time V. Maximum V. Minimum Kruskal-
(dias ) Wallis (p)(days) Wallis (p)
Isoflavona 0 60,5 80,0 48,0 Isoflavone 0 60.5 80.0 48.0
Placebo 0 57,0 70,0 48,0  Placebo 0 57.0 70.0 48.0
EEC 0 59, 0 70,0 48,0 0, 176 EEC 0 59.0 70.0 48.0 0.176
Isoflavona 90 52,5 75,0 42, 0 Isoflavone 90 52.5 75.0 42.0
Placebo 90 52,0 66,0 40,0  Placebo 90 52.0 66.0 40.0
EEC 90 55,0 68,0 47,0 0, 188  EEC 90 55.0 68.0 47.0 0.188
Comparativamente, também não foram encontradas diferenças estatisticamente significantes entre as medianas de Eco endometrial nos tempos 0 e 90 dias, entre os 3 grupos terapêuticos (Kruskal-Wallis, p=0,652 e 0,497 respectivamente), conforme mostra a Tabela 13. Comparatively, no statistically significant differences were also found between endometrial echo medians at time 0 and 90 days, between the 3 therapeutic groups (Kruskal-Wallis, p = 0.652 and 0.497 respectively), as shown in Table 13.
Tabela 13. Comparação dos resultados de Eco endometrialTable 13. Comparison of Endometrial Echo Results
(mm) nos tempos 0 e 90 entre os 3 grupos (mm) at times 0 and 90 between the 3 groups
Grupo\Eco Tempo Mediana V. máximo V. mínimo Kruskal- Group \ Eco Median Time V. Maximum V. Minimum Kruskal-
(dias ) Wallis (p)(days) Wallis (p)
Isoflavona 0 3 5 1 Isoflavone 0 3 5 1
Placebo 0 2 4 1  Placebo 0 2 4 1
EEC 0 3 4 1 0, 652 EEC 0 3 4 1 0, 652
Isoflavona 90 2 3 1 Placebo 90 2 3 1 Isoflavone 90 2 3 1 Placebo 90 2 3 1
EEC 90 2 3 1 0, 497 EEC 90 2 3 1 0, 497
Uma vez mostrados e analisados os resultados comparativos do uso do gel de isoflavona com o uso de estrogênio conjugado de equino (ECC) , que é considerado o padrão ouro de tratamento, pode-se notar que o gel de isoflavona comporta-se de forma semelhante ao ECC, o que comprova a eficácia do gel de isoflavonas. Once the comparative results of the use of isoflavone gel with the use of equine conjugated estrogen (ECC), which is considered the gold standard of treatment, are shown and analyzed, it can be noted that the isoflavone gel behaves similarly. ECC, which proves the effectiveness of the isoflavone gel.
As manifestações atróficas vulvo-vaginais decorrentes do hipoestrogenismo de diferentes causas, especialmente após a menopausa, são prevalentes e constituem frequente motivo de consulta ginecológica. Os estrogênios utilizados por via vaginal são eficazes no tratamento, porém apresentam o inconveniente de absorção sistémica com efeitos muitas vezes indesejáveis.  Atrophic vulvo-vaginal manifestations resulting from hypoestrogenism of different causes, especially after menopause, are prevalent and constitute a frequent reason for gynecological consultation. Estrogens used vaginally are effective in treatment, but have the drawback of systemic absorption with often undesirable effects.
0 contingente de mulheres que rejeitam, por algum motivo, a terapia hormonal e optam por uma terapia alternativa atinge cada vez um maior número de pacientes, tendo em vista o aumento da expectativa de vida e, também, em virtude das novas estratégias utilizadas para o diagnóstico e tratamento de afecções, em que a terapia hormonal é contra-indicada, destacando-se mulheres portadoras de câncer hormônio-dependente .  The number of women who reject for some reason hormone therapy and opt for alternative therapy increasingly affects a larger number of patients, given the increase in life expectancy and also because of the new strategies used for the treatment. diagnosis and treatment of conditions, in which hormone therapy is contraindicated, especially women with hormone-dependent cancer.
As concretizações da presente invenção mostram-se uma alternativa eficaz e segura ao uso dos estrogênios no tratamento das afecções atróficas genitais.  Embodiments of the present invention are shown to be an effective and safe alternative to the use of estrogens in the treatment of genital atrophic disorders.
Os medicamentos ora propostos possuem uma ação exclusivamente local, evitando que haja absorção do produto pelo epitélio vaginal e causando uma ação indesejável em outros tecidos, podendo ser utilizado por periodo prolongado, sem levar a alterações sistémicas. The proposed drugs have an exclusively local action, preventing the absorption of the product by the vaginal epithelium and causing an undesirable action in other tissues and may be used for a prolonged period, without leading to systemic changes.

Claims

REIVINDICAÇÕES
1. Composição farmacêutica caracterizada por compreender: uma quantidade farmacologicamente ativa de uma substância disruptora endócrina e pelo menos um veiculo farmaceuticamente aceitável.  A pharmaceutical composition comprising: a pharmacologically active amount of an endocrine disrupting substance and at least one pharmaceutically acceptable carrier.
2. Composição farmacêutica, de acordo com a reivindicação 1, caracterizada por a referida substância ativa ser um fitoestrogênio selecionado a partir de compostos orgânicos naturais de origem vegetal.  Pharmaceutical composition according to Claim 1, characterized in that said active substance is a phytoestrogen selected from natural organic compounds of plant origin.
3. Composição farmacêutica, de acordo com a reivindicação 2, caracterizada por referido fitoestrôgenio ser extraído de espécies do grupo das leguminosas ( Fabaceae) .  Pharmaceutical composition according to claim 2, characterized in that said phytoestrogen is extracted from species of the legume group (Fabaceae).
4. Composição farmacêutica, de acordo com qualquer uma das reivindicações de 1 a 3, caracterizada por referido fitoestrôgenio ser do género Glycine.  Pharmaceutical composition according to any one of claims 1 to 3, characterized in that said phytoestrogen is of the genus Glycine.
5. Composição farmacêutica, de acordo com a reivindicação 4, caracterizada por as espécies vegetais do grupo do género Glycine serem selecionadas dentre Glycine albícans, Glycine aphyonota , Glycine arenaría , Glycine argyrea , Glycine canescens, Glycine clandestina , Glycine curva ta , Glycine cyrtoloba, Glycine falcata, Glycine gracei, Glycine hirticaulis, Glycine hirticaulís subsp. leptosa , Glycine lactovírens , Glycine latifolia , Glycine latrobeana , Glycine microphylla , Glycine montis-douglas, Glycine peratosa , Glycine pescadrensis, Glycine pindaníca , Glycine pullenii , Glycine rubiginosa , Glycine stenophita , Glycine syndetika , Glycine tabacina, Glycine tomentella e Glycine max. Pharmaceutical composition according to Claim 4, characterized in that the plant species of the genus Glycine are selected from Glycine albicans, Glycine aphyonota, Glycine arenaria, Glycine argyrea, Glycine clandestine, Glycine cyrtoloba, Glycine falcata, Glycine joke, Glycine hirticaulis, Glycine hirticaulís subsp. leptosa, Glycine lactovírens, Glycine latifolia, Glycine latrobeana, Glycine microphylla, Glycine montis-douglas, Glycine peratosa, Glycine pescadrensis, Glycine pindanica, Glycine pullenii, Glycine rubiginosa, Glycine latina, Glycine ruby
6. Composição farmacêutica, de acordo com a reivindicação 5, caracterizada por a espécie vegetal selecionada ser a espécie Glycine max Merr (isoflavona) . Pharmaceutical composition according to Claim 5, characterized in that the selected plant species is Glycine max Merr (isoflavone).
7. Composição farmacêutica, de acordo com qualquer uma das reivindicações de 1 a 7, caracterizada por a isoflavona selecionada ser solúvel ou parcialmente solúvel em água e ainda, compreender tanto a forma glicosada quanto a forma aglicona .  Pharmaceutical composition according to any one of claims 1 to 7, characterized in that the selected isoflavone is soluble or partially soluble in water and further comprises both the glycoside form and the aglycone form.
8. Composição farmacêutica, de acordo com qualquer uma das reivindicações de 1 a 7, caracterizada por o extrato vegetal compreender entre 0,5% a 80% de isoflavonas totais (genisteina, dadzeina e gliciteina) .  Pharmaceutical composition according to any one of claims 1 to 7, characterized in that the plant extract comprises from 0.5% to 80% of total isoflavones (genistein, dadzein and glycitein).
9. Composição farmacêutica, de acordo com a reivindicação 8, caracterizada por o referido extrato vegetal compreender cerca de 40% de isoflavonas totais.  Pharmaceutical composition according to Claim 8, characterized in that said plant extract comprises about 40% of total isoflavones.
10. Composição farmacêutica, de acordo com as reivindicações 8 ou 9, caracterizada por o referido extrato vegetal compreender cerca de 10% de isoflavonas totais.  Pharmaceutical composition according to claim 8 or 9, characterized in that said plant extract comprises about 10% of total isoflavones.
11. Composição farmacêutica, de acordo com a reivindicação 7, caracterizada por o extrato de isoflavona possuir uma solubilidade parcial em água.  Pharmaceutical composition according to Claim 7, characterized in that the isoflavone extract has partial solubility in water.
12. Composição farmacêutica, caracterizada por compreender: uma quantidade farmacologicamente ativa de genisteina total isolada do extrato bruto de isoflavona e pelo menos um veiculo farmaceuticamente aceitável.  Pharmaceutical composition, characterized in that it comprises: a pharmacologically active amount of total genistein isolated from the crude isoflavone extract and at least one pharmaceutically acceptable carrier.
13. Composição farmacêutica, de acordo com a reivindicação 12, caracterizada por a concentração de genisteina total (aglicona e glicona) variar entre 0,1 e 100%. Pharmaceutical composition according to Claim 12, characterized in that the concentration of total genistein (aglycone and glycone) ranges from 0.1 to 100%.
14. Composição farmacêutica, de acordo com a reivindicação 13, caracterizada por a concentração de genisteina total (aglicona e glicona) no referido extrato ser em torno de 60% a 70%. Pharmaceutical composition according to Claim 13, characterized in that the concentration of total genistein (aglycone and glycone) in said extract is about 60% to 70%.
15. Composição farmacêutica, de acordo com qualquer uma das reivindicações de 12 a 14, caracterizada por a concentração de genisteina na forma de glicona variar entre 40 a 80%.  Pharmaceutical composition according to any one of claims 12 to 14, characterized in that the concentration of genistein in the glycol form ranges from 40 to 80%.
16. Composição farmacêutica, de acordo com a reivindicação 15, caracterizada por a concentração de genisteina na forma de glicona variar entre 55 e 65%.  Pharmaceutical composition according to claim 15, characterized in that the concentration of genistein in the glycone form ranges from 55 to 65%.
17. Composição farmacêutica, de acordo com as reivindicações 15 ou 16, caracterizada por a concentração de genisteina na forma de glicona ser em torno de 60%.  Pharmaceutical composition according to claim 15 or 16, characterized in that the concentration of genistein in glycone form is around 60%.
18. Composição farmacêutica, de acordo com a reivindicação 12, caracterizada por a concentração de genisteina na forma de aglicona variar entre 0,1 e 10,0%.  Pharmaceutical composition according to Claim 12, characterized in that the concentration of genistein in the aglycone form ranges from 0.1 to 10.0%.
19. Composição farmacêutica, de acordo com a reivindicação 18, caracterizada por a concentração de genisteina na forma de aglicona ser em torno de 1,0%.  Pharmaceutical composition according to Claim 18, characterized in that the concentration of genistein in the aglycone form is around 1.0%.
20. Composição farmacêutica, caracterizada por compreender: uma quantidade farmacologicamente ativa de genisteina aglicona e pelo menos um veiculo farmaceuticamente aceitável.  A pharmaceutical composition comprising: a pharmacologically active amount of aglycone genistein and at least one pharmaceutically acceptable carrier.
21. Composição farmacêutica, de acordo com a reivindicação 20, caracterizada por a concentração de genisteina aglicona variar entre 0,1 e 10,0%, mas preferencialmente entre 05, e 1,5%. Pharmaceutical composition according to claim 20, characterized in that the concentration of aglycone genistein ranges from 0.1 to 10.0%, but preferably from 05 to 1.5%.
22. Composição farmacêutica, de acordo com a reivindicação 21, caracterizada por a concentração de genisteina na forma aglicona ser em torno de 1,0%. Pharmaceutical composition according to Claim 21, characterized in that the concentration of genistein in aglycone form is around 1.0%.
23. Composição farmacêutica, de acordo com qualquer uma das reivindicações de 1 a 22, caracterizada por serem utilizadas no tratamento e/ou prevenção das doenças decorrentes do hipoestrogenismo no trato genital inferior feminino, como produto para higiene pessoal feminina e como cosmético para firmeza e rejuvenescimento da pele.  Pharmaceutical composition according to any one of claims 1 to 22, characterized in that they are used for the treatment and / or prevention of diseases resulting from hypoestrogenism in the female lower genital tract, as a feminine hygiene product and as a cosmetic for firmness and skin rejuvenation.
24. Uso das composições farmacêuticas, conforme reivindicada de 1 a 22, caracterizado por ser na preparação de um medicamento para o tratamento e/ou prevenção das doenças decorrentes do hipoestrogenismo no trato genital inferior feminino.  Use of the pharmaceutical compositions as claimed in 1 to 22, characterized in that they are in the preparation of a medicament for the treatment and / or prevention of diseases resulting from hypoestrogenism in the female lower genital tract.
25. Uso, de acordo com a reivindicação 24, caracterizado por referido medicamento ser utilizado como um produto para a higiene pessoal da mulher.  Use according to claim 24, characterized in that said medicament is used as a personal hygiene product for women.
26. Uso, de acordo com a reivindicação 24, caracterizado por as formas farmacêuticas preferenciais do referido medicamento serem a pastosa e a liquida.  Use according to claim 24, characterized in that the preferred pharmaceutical forms of said medicament are pasty and liquid.
27. Uso, de acordo com qualquer úma das reivindicações de 24 a 26, caracterizado por o referido medicamento estar sob a forma pastosa.  Use according to any one of claims 24 to 26, characterized in that said medicament is in pasty form.
28. Uso, de acordo com a reivindicação 27, caracterizado por referido medicamento estar na forma de pomada, creme, pasta, gel, loção, uguentos, supositórios, emulsões, adesivos, comprimidos ou anel vaginal.  Use according to claim 27, characterized in that said medicament is in the form of ointment, cream, paste, gel, lotion, ointments, suppositories, emulsions, adhesives, tablets or vaginal ring.
29. Uso, de acordo com as reivindicações 27 e 28, caracterizado por referido medicamento estar na forma de um gel . Use according to claims 27 and 28, characterized in that said medicament is in the form of a gel.
30. Uso, de acordo com qualquer uma das reivindicações de 24 a 29, caracterizado por a via de administração do medicamento ser tópica. Use according to any one of claims 24 to 29, characterized in that the route of administration of the medicament is topical.
31. Uso, de acordo com qualquer uma das reivindicações de 24 a 30, caracterizado por cerca de 5,0mL do fármaco na forma de gel ser aplicado à mulher, preferencialmente 1 (uma) vez ao dia.  Use according to any one of claims 24 to 30, characterized in that about 5.0 ml of the drug in gel form is applied to the woman, preferably 1 (one) time per day.
32. Uso, de acordo com qualquer uma das reivindicações de 24 a 31, caracterizado pela dose diária da composição farmacêutica à base de isoflavonas totais ser de cerca de 40 , Omg .  Use according to any one of claims 24 to 31, characterized in that the daily dose of the total isoflavone-based pharmaceutical composition is about 40 µg.
PCT/BR2012/000101 2011-04-29 2012-04-10 Pharmaceutical compositions and uses thereof for the treatment and/or prevention of diseases caused by hypoestrogenism in the lower genital tract of women WO2012145809A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1038531A2 (en) * 1999-03-18 2000-09-27 Ajinomoto Co., Inc. A composition comprising soybean isoflavones and a method for the production thereof
EP1348439B1 (en) * 2002-03-29 2005-08-10 MARFARMA HOLDING S.p.A. Compositions for vaginal use
WO2007000193A1 (en) * 2005-06-29 2007-01-04 Dsm Ip Assets B.V. Isoflavone nanoparticles and use thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1038531A2 (en) * 1999-03-18 2000-09-27 Ajinomoto Co., Inc. A composition comprising soybean isoflavones and a method for the production thereof
EP1348439B1 (en) * 2002-03-29 2005-08-10 MARFARMA HOLDING S.p.A. Compositions for vaginal use
WO2007000193A1 (en) * 2005-06-29 2007-01-04 Dsm Ip Assets B.V. Isoflavone nanoparticles and use thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CARRAO-PANIZZI M.C. ET AL.: "Efeitos de genotipos, ambientes e de tratamentos hidrotermicos na concentracao de isoflavonas agliconas em graos de soja", PESQUISA AGROPECUARIA BRASILEIRA, vol. 38, no. 8, 2003, pages 897 - 902 *
LE DONNE, M. ET AL.: "The effect of vaginally administered genistein in comparison with hyaluronic acid on atrophic epitelium in postmenopause", ARCHIVES OF GYNECOLOGY AND OBSTETRICS, vol. 283, no. 6, 2011, pages 1319 - 1323, XP019901597, DOI: doi:10.1007/s00404-010-1545-7 *
MORGANTE, G. ET AL.: "Valutazione della somministrazione di isoflavoni di soia per via vaginale nel trattamento dei disturbi vulvovaginali in postmenopausa", GAZZETA MEDICA ITALIANA- ARCHIVIO PER LE SCIEHZE MEDICHE, vol. 162, no. 5, 2003, pages 117 - 120 *
TEDESCHI, C ET AL.: "Comparison of vaginal gel isoflavones versus no topical treatment in vaginal dystrophy: results of a preliminary prospective study", GYNECOLOGICAL ENDOCRINOLOGY, 9 February 2012 (2012-02-09), pages 1 - 3 *

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