WO2012145809A1 - Compositions pharmaceutiques et leurs utilisations pour le traitement et/ou la prévention de maladies liées à l'hypoestrogénie dans le tractus génital inférieur de la femme - Google Patents

Compositions pharmaceutiques et leurs utilisations pour le traitement et/ou la prévention de maladies liées à l'hypoestrogénie dans le tractus génital inférieur de la femme Download PDF

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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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glycine
pharmaceutical composition
composition according
genistein
isoflavone
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Portuguese (pt)
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Sônia Maria Rolim Rosa . Lima
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Hebron Farmaceutica Pesquisa Desenvolvimento e Inovacao Tecnologica Ltda
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Hebron Farmaceutica Pesquisa Desenvolvimento e Inovacao Tecnologica Ltda
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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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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne l'obtention de compositions pharmaceutiques comprenant une substance d'origine végétale choisie dans le groupe de substances appelées perturbateurs endocriniens, et au moins un véhicule pharmaceutiquement acceptable. Plus particulièrement, ladite substance active est un phytoestrogène choisi parmi des composés organiques naturels d'origine végétale. Les compositions pharmaceutiques de la présente invention peuvent être utilisées dans le traitement et/ou la prévention des maladies liées à l'hypoestrogénie dans le tractus génital inférieur féminin, ainsi que dans la préparation de médicaments pour administration vaginale.
PCT/BR2012/000101 2011-04-29 2012-04-10 Compositions pharmaceutiques et leurs utilisations pour le traitement et/ou la prévention de maladies liées à l'hypoestrogénie dans le tractus génital inférieur de la femme Ceased WO2012145809A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
BRPI1101820-8 2011-04-29
BRPI1101820-8A BRPI1101820A2 (pt) 2011-04-29 2011-04-29 composiÇÕes farmacÊuticas e seus usos para tratamento e/ou prevenÇço de doenÇas decorrentes do hipoestrogenismo no trato genital inferior feminino

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WO2012145809A1 true WO2012145809A1 (fr) 2012-11-01

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PCT/BR2012/000101 Ceased WO2012145809A1 (fr) 2011-04-29 2012-04-10 Compositions pharmaceutiques et leurs utilisations pour le traitement et/ou la prévention de maladies liées à l'hypoestrogénie dans le tractus génital inférieur de la femme

Country Status (2)

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BR (1) BRPI1101820A2 (fr)
WO (1) WO2012145809A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1038531A2 (fr) * 1999-03-18 2000-09-27 Ajinomoto Co., Inc. Composition contenant des isoflavones de soja et son procede de production
EP1348439B1 (fr) * 2002-03-29 2005-08-10 MARFARMA HOLDING S.p.A. Compositions pour utilisation vaginale
WO2007000193A1 (fr) * 2005-06-29 2007-01-04 Dsm Ip Assets B.V. Nanoparticules d’isoflavone et utilisation correspondante

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1038531A2 (fr) * 1999-03-18 2000-09-27 Ajinomoto Co., Inc. Composition contenant des isoflavones de soja et son procede de production
EP1348439B1 (fr) * 2002-03-29 2005-08-10 MARFARMA HOLDING S.p.A. Compositions pour utilisation vaginale
WO2007000193A1 (fr) * 2005-06-29 2007-01-04 Dsm Ip Assets B.V. Nanoparticules d’isoflavone et utilisation correspondante

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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