Methods for treating endometriosis

Abstract

The present invention relates to a method for treating endometriosis or preventing the recurrence of endometriosis. In particular, the present invention relates to a method for treating endometriosis and its recurrence, comprising administering to a woman having endometriosis a pharmaceutical composition comprising an S-alkylisothiouronium derivative, in particular S-ethylisothiouronium diethyl phosphate. The method and pharmaceutical composition of the present invention maintain fertility and enable conception.

Description

Technical Field

[0001] The present invention relates to a method for treating endometriosis. In particular, the present invention relates to a method for treating endometriosis or a method for preventing recurrence of endometriosis, comprising administering to a woman having endometriosis or suffering from recurrence of endometriosis a pharmaceutical composition comprising an S-alkylisothiuronium derivative, in particular S-ethylisothiuronium diethyl phosphate.

Background Art

[0002] Endometriosis is a debilitating disease common in women of reproductive age. It occurs in about 10% of menstruating women, 20 to 50% of infertile women, and 50 to 60% of women with chronic pelvic pain. It is characterized by the presence of functional ectopic endometrial tissue or endometriotic tissue in areas outside the uterus. Like normal orthotopic endometrial tissue, endometriotic lesions respond to estrogen stimulation, which allows them to grow and differentiate in response to changes in hormone levels during the menstrual cycle. There are three main subtypes of endometriosis, including superficial (peritoneal) endometriosis, deep endometriosis, and ovarian endometriosis. Lesions are usually restricted to the pelvis and lower abdomen, and are commonly found in areas such as the ovary, posterior broad ligament, posterior vaginal fornix, uterosacral ligament, large intestine (rectosigmoid colon), ureter, bladder, as well as upper vagina and cervix. These lesions are less commonly found outside the abdominal cavity, including the pleura and pericardium, but may rarely be found in distal organs such as the eyes, brain, and fingers. Clinical symptoms of endometriosis include pelvic pain including dysmenorrhea and ovulation pain, pain during sexual intercourse, and intestinal and bladder symptoms. Reduced fertility can be found in 30 to 50% of patients with endometriosis. Patients with endometriosis suffer from additional comorbidities such as irritable bowel syndrome (IBS), painful bladder syndrome, chronic fatigue, premenstrual syndrome (PMS), and emotional changes such as stress and depression.

[0003] Current methods for treating endometriosis suffer from many drawbacks.

[0004] Since the late 1950s, the mainstream management of endometriosis symptoms has been in combination with oral contraceptives. While not curative, contraceptives are generally well-tolerated and alleviate the main symptom, pain, by suppressing the menstrual cycle and downcontrolling endometriotic lesions. Continuous use of the pill is recommended for endometriosis patients. Common side effects include irregular vaginal bleeding, fluid retention, abdominal distension, weight gain, increased appetite, nausea, headache, breast tenderness, and depression. A significant drawback is its contraceptive effect; therefore, birth control pills are not suitable for women who wish to maintain their fertility.

[0005] Synthetic progesterone (e.g., progestin / progestogen) inhibits ovulation and has been successfully used to treat endometriosis since the mid-1950s. This includes oral progestin preparations, intramuscular injections, and hormonal intrauterine devices. Common side effects of synthetic progesterone include mood changes, bloating, irregular bleeding, breast tenderness, nausea, headache, sores or oily skin, changes in libido, fatigue, and weight gain.

[0006] Gonadotropin-releasing hormone (GnRH) agonists and antagonists induce an artificial menopausal state by blocking estrogen production. However, common side effects include hot flashes, vaginal dryness, and decreased libido. Long-term use is associated with bone loss leading to osteoporosis and effects on cardiac function.

[0007] Surgical intervention can be performed using minimally invasive laparoscopic surgery. Surgery may include removal of endometrial lesions, dissection of adhesions, removal or excision of endometriotic ovarian cysts, and confirmation and examination of fallopian tube patency. In cases of deep endometriosis involving the intestines, bladder, or ureters, extensive surgery may sometimes be required. This may involve bowel resection, partial cystectomy (removal of part of the bladder), and re-implantation of the ureters into the bladder or re-anastomosis (reconnection) of the ureteral terminals.

[0008] While symptom improvement is often achieved after surgery, lesions may recur over time, just as they were initially formed before surgery. Therefore, hormone therapy is often recommended to prevent recurrence of lesions.

[0009] Barkan et al., U.S. Patent No. 7,148,208, discloses a method for treating headaches and migraines, as well as nausea and vomiting, comprising administering a composition comprising an S-alkylisothiouronium derivative to a subject in need of such treatment.

[0010] International Publication No. WO2007 / 029255 by some of the inventors of the present invention discloses a method for preventing hypotension and stabilizing blood pressure in hemodialysis patients, the method comprising administering to these patients a pharmaceutical composition comprising an S-alkylisothiouronium derivative.

[0011] International Publication No. WO2007 / 108004 by one of the inventors of the present invention discloses a method for treating inflammation, comprising administering a pharmaceutical composition comprising an S-alkylisothiouronium derivative to a subject in need of such treatment.

[0012] International Publication No. WO2009 / 060451 by one of the inventors of the present invention discloses a method for treating uterine hypercontraction disorders, particularly abnormal uterine bleeding and dysmenorrhea, comprising administering a pharmaceutical composition comprising an S-alkylisothiouronium derivative to a woman suffering from such a disorder.

[0013] There is still a need for improved methods for treating endometriosis that can preserve fertility and have negligible side effects compared to the drug therapies currently used to treat endometriosis. [Overview of the project]

[0014] The present invention provides a method for treating endometriosis, comprising administering a pharmaceutical composition containing an S-alkylisothiouronium derivative to a woman in need of such treatment.

[0015] It is disclosed for the first time that administering a pharmaceutical composition containing S-ethylisothiouronium diethyl phosphate as an activator to women suffering from endometriosis reduces the number and / or size of endometrial lesions. Advantageously, treatment of endometriosis with S-ethylisothiouronium diethyl phosphate has no adverse effects on the patient's hormonal status and maintains fertility in treated women.

[0016] It is further disclosed that women with endometriosis who receive treatment with a pharmaceutical composition containing S-ethylisothiouronium diethyl phosphate immediately after keyhole laparoscopy to remove endometrial tissue from the peritoneum are free from or have a significant reduction in recurrence of endometriosis.

[0017] It is further disclosed that a pharmaceutical composition containing S-ethylisothiouronium diethyl phosphate maintains fertility, reduces the number and / or size of endometrial lesions, prevents lesion recurrence, and exhibits or does not exhibit negligible side effects compared to known pharmaceuticals. Women treated with the pharmaceutical composition can become pregnant even during treatment. Furthermore, the pharmaceutical composition does not induce menopausal symptoms.

[0018] Furthermore, it is disclosed that a clinical trial protocol is underway to test the use of S-ethylisothiouronium diethyl phosphate in patients with confirmed endometriosis. For the first time herein, it is disclosed that treatment with S-ethylisothiouronium diethyl phosphate unexpectedly reduces pain, improves the patient's subjective health status, and reduces the recurrence of endometriosis. In other words, the proliferation, migration, and / or invasion of endometrial cells into the extrauterine parts of the peritoneum and pelvic organs, as well as into the uterine wall (myometrium), is reduced or eliminated. Thus, the method of the present invention is highly advantageous compared to currently used methods and pharmaceuticals for treating endometriosis.

[0019] According to a first aspect, the present invention relates to a method for treating endometriosis or a method for preventing the recurrence of endometriosis, wherein a woman in need of such treatment is provided with a compound of formula I,

[0020] [ka] During the ceremony, R'' is a linear or branched alkyl group, optionally substituted with a halogen. The present invention provides a method comprising administering a therapeutically effective amount of a pharmaceutical composition containing a compound of formula I as an activator, wherein A''(-) is an anion derived from a phosphorus-containing acid, a phosphite ester, and a phosphite amide.

[0021] According to some embodiments, the anion of the compound of formula I is derived from a mono or dialkyl ester of a phosphate or phosphine.

[0022] According to an additional embodiment, the compound is selected from the group consisting of: S-methylisothiouronium methylphosphite, S-methylisothiouronium dimethyl phosphate, S-ethylisothiouronium metaphosphate, S-ethylisothiouronium ethyl phosphite, S-ethylisothiouronium diethyl phosphate, S-propylisothiouronium propyl phosphite, S-isopropylisothiouronium metaphosphate, S-isopropylisothiouronium isopropyl phosphite, S-butylisothiouronium dibutyl phosphate, and S-isobutylisothiouronium isobutyl phosphite.

[0023] According to a specific embodiment, the compound is S-ethylisothiouronium diethyl phosphate.

[0024] According to some embodiments, endometriosis is selected from the group consisting of external endometriosis, endometrioma, adenomyosis, endometriotic nodules of the uterosacral ligament, and endometriotic nodules other than those of the uterosacral ligament.

[0025] According to a further embodiment, administration of the pharmaceutical composition is performed via an oral, vaginal, cervical, intrauterine, intraperitoneal, or intralesional route of administration. According to a specific embodiment, administration of the pharmaceutical composition is performed via an oral route of administration. According to an exemplary embodiment, administration of the pharmaceutical composition is performed via a vaginal route of administration.

[0026] According to a specific embodiment, the composition is formulated in a form selected from the group consisting of tablets, capsules, powders, solutions, suspensions, emulsions, suppositories, implants, or sustained-release preparations.

[0027] According to a further embodiment, the pharmaceutical composition is formulated in a form selected from the group consisting of tablets, capsules, solutions, gels, syrups, slurries, and suspensions.

[0028] In further embodiments, the pharmaceutical composition may be formulated in a form selected from the group consisting of vaginal suppositories, vaginal tampons, vaginal rings, vaginal pessaries, vaginal sponges, drug-containing intrauterine devices (IUDs), sprays, creams, gels, ointments, sustained-release formulations, tablets, capsules, solutions, suspensions, emulsions, and powders. In a particular embodiment, the pharmaceutical composition may be formulated as a vaginal suppository or a tablet.

[0029] According to further embodiments, the pharmaceutical composition is administered daily before menstruation, during menstruation, or both. Administration is carried out for one, two, three, four, or five months, or for the duration necessary to treat endometriosis. According to certain embodiments, the pharmaceutical composition is administered continuously.

[0030] According to some embodiments, the pharmaceutical composition is administered 2 to 7 days before menstruation and during menstruation. According to a particular embodiment, the pharmaceutical composition is administered 2 days before menstruation and during menstruation.

[0031] According to some embodiments, the pharmaceutical composition is administered daily for 11 to 17 days, starting from the 18th to 23rd day of menstruation. According to an exemplary embodiment, the pharmaceutical composition is administered on the 21st day of the menstrual cycle. According to another exemplary embodiment, the pharmaceutical composition is administered daily for 14 consecutive days.

[0032] According to certain embodiments, the pharmaceutical composition is administered once daily, every other day, every three days, once a week, every two weeks, or once a month, starting from the 18th to 23rd day of menstruation. Alternative regimens can be adapted according to the instructions of the physician treating the patient requiring treatment. According to certain embodiments, the pharmaceutical composition is administered multiple times a day, for example, twice a day, three times a day, or as needed.

[0033] In further embodiments, the pharmaceutical composition is administered once a day, once every two days, once every three days, once a week, once every two weeks, or once a month after laparoscopy or removal of endometriotic tissue, thereby preventing the recurrence of endometriosis.

[0034] In further embodiments, the pharmaceutical composition is administered once daily, once every two days, once every three days, once a week, once every two weeks, or once a month after laparoscopy or removal of endometriotic tissue for a period of at least one, two, three, four, five, or six months, or for as long as necessary to prevent recurrence of endometriosis.

[0035] According to several embodiments, the therapeutically effective dose of the compound of formula I ranges from 1 mg to about 400 mg, alternatively from 50 mg to about 200 mg, and alternatively from 30 mg to about 150 mg. According to a particular embodiment, the therapeutically effective dose of S-ethylisothiouronium diethyl phosphate is 100 mg per unit dose. Each possibility represents a distinct embodiment of the present invention.

[0036] According to certain embodiments, administration of the pharmaceutical composition treats endometriosis. According to other embodiments, administration of the pharmaceutical composition prevents the recurrence of endometriosis. According to further embodiments, administration of the pharmaceutical composition prevents the proliferation, migration, and / or invasion of endometrial cells into the extrauterine region. According to certain embodiments, administration of the pharmaceutical composition reduces the proliferation, migration, and / or invasion of endometrial cells into the extrauterine region in the peritoneum and pelvic organs. According to certain embodiments, administration of the pharmaceutical composition prevents the proliferation, migration, and / or invasion of endometrial cells within the uterine wall (myometrium). According to further embodiments, administration of the pharmaceutical composition reduces the proliferation, migration, and / or invasion of endometrial cells within the peritoneum and pelvic organs. According to further embodiments, administration of the pharmaceutical composition reduces the size of endometrial lesions. According to some embodiments, administration of the pharmaceutical composition shrinks endometrial lesions.

[0037] In a further embodiment, the present invention relates to a compound of formula I for use in the treatment of endometriosis or the prevention of recurrence of endometriosis,

[0038] [ka] During the ceremony, R'' is a linear or branched alkyl group, optionally substituted with a halogen. The present invention provides a pharmaceutical composition comprising a compound of formula I as an activator, wherein A''(-) is an anion derived from a phosphorus-containing acid, a phosphite ester, and a phosphite amide. In another embodiment, the present invention provides a compound of formula I,

[0039] [ka] During the ceremony, R'' is a linear or branched alkyl group, optionally substituted with a halogen. A therapeutically effective amount of a pharmaceutical composition containing a compound of formula I as an activator, wherein A''(-) is an anion derived from phosphorus-containing acids, phosphite esters, and phosphite amides, is used to treat women suffering from endometriosis while maintaining fertility. This provides a method to increase the probability of conception.

[0040] These embodiments and other embodiments of the present invention will be better understood in connection with the following description, examples, and claims. [Modes for carrying out the invention]

[0041] The present invention provides a method for treating endometriosis, and / or a method for preventing the recurrence of endometriosis and / or endometriotic lesions, and / or a method for maintaining fertility in women with endometriosis. The method comprises administering a pharmaceutical composition containing an S-alkylisothiouronium derivative as an activator to a woman with endometriosis or a woman at risk of endometriosis recurrence. The method and pharmaceutical composition maintain fertility in women with endometriosis, thereby enabling conception during or after treatment.

[0042] The compound of the present invention According to the present invention, the S-alkylisothiouronium derivative is a compound of formula I,

[0043] [ka] During the ceremony, R'' is a linear or branched alkyl group, optionally substituted with a halogen. The compound is of formula I, where A''(-) is an anion derived from phosphorus-containing acids, phosphite esters, and phosphite amides.

[0044] According to some embodiments, the anion is derived from a mono or dialkyl ester of a phosphate or phosphine.

[0045] According to an additional embodiment, the compound is selected from the group consisting of: S-methylisothiouronium methylphosphite, S-methylisothiouronium dimethyl phosphate, S-ethylisothiouronium metaphosphate, S-ethylisothiouronium ethyl phosphite, S-ethylisothiouronium diethyl phosphate, S-propylisothiouronium propyl phosphite, S-isopropylisothiouronium metaphosphate, S-Isopropylisothiouronium isopropyl phosphite, S-butylisothiouronium dibutyl phosphate, and S-Isobutylisothiouronium isobutyl phosphite.

[0046] According to a particular embodiment, the compound is S-ethylisothiouronium diethyl phosphate.

[0047] Pharmaceutical composition The pharmaceutical composition of the present invention comprises an S-alkylisothiouronium derivative and a pharmaceutically acceptable carrier.

[0048] The term “pharmaceutically acceptable” means approved by a federal or state regulatory authority, or listed in the United States Pharmacopeia or other generally accepted pharmacopoeia for use in animals, more specifically, in humans. The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle administered with the therapeutic compound. Such pharmaceutical carriers may be sterile liquids such as water and oils, including petroleum, animal, plant, or synthetic sources such as peanut oil, soybean oil, mineral oil, sesame oil, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents. Water, saline, dextrose aqueous solutions, and glycerol solutions can be used, for example, as liquid carriers for injection. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, propylene glycol, water, and ethanol. The composition may, if desired, contain small amounts of wetting agents or emulsifiers, or pH buffers such as acetates, citrates, or phosphates. Antimicrobial agents such as benzyl alcohol or methylparaben, antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as ethylenediaminetetraacetic acid, and agents for adjusting tonicity such as sodium chloride or dextrose are also conceivable.

[0049] Depending on the selected route of administration, the composition may take the form of tablets, capsules, powders, solutions, suspensions, emulsions, suppositories, implants, sustained-release formulations, and other similar forms.

[0050] Suitable routes of administration for carrying out the present invention include oral, vaginal, intrauterine, intraperitoneal, and intrafocal administration routes.

[0051] For oral administration, the pharmaceutical compositions of the present invention can be formulated as tablets, capsules, liquids, gels, syrups, slurries, suspensions, etc. Suitable excipients include fillers such as sugars containing lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, etc.; and / or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). Optionally, disintegrants such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate, may be added. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. Such compositions would contain a therapeutically effective amount of the S-alkylisothiouronium derivative of the present invention together with a suitable amount of carrier to provide a form for appropriate administration to the subject.

[0052] For oral administration, the composition may take the form of tablets or lozenges formulated using conventional methods.

[0053] For parenteral administration, the pharmaceutical compositions of the present invention can be formulated in aqueous solutions, preferably Hanks' solution, Ringer's solution, or physiologically compatible buffers such as physiological saline buffer. Additionally, suspensions of the active compound can be prepared as suitable oily injectable suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate, triglycerides, or liposomes. The aqueous injectable suspension may also contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to enable the preparation of high-concentration solutions. Parenteral formulations may optionally contain one or more additional components, including preservatives (if the formulation is in a multi-dose container), buffers to provide a suitable pH value for the formulation, and sodium chloride or glycerin to make the formulation isotonic with blood.

[0054] The pharmaceutical compositions of the present invention can be formulated in sustained-release pharmaceutical dosage forms known in the art (see, for example, U.S. Patents 6,605,303, 6,419,958, and 6,245,357, which are incorporated herein by reference as being fully described herein).

[0055] Therefore, the sustained-release pharmaceutically acceptable dosage form of the S-alkylisothiouronium derivative of the present invention comprises the S-alkylisothiouronium derivative, a polymer, and optionally one or more additional pharmaceutically acceptable excipients or carriers.

[0056] Polymers that can be used in the preparation of the sustained-release pharmaceutical dosage form of the present invention include hydrophilic polymers, hydrophobic polymers, and combinations thereof.

[0057] Suitable hydrophilic polymers include, for example, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, polyethylene oxide, polyvinyl alcohol, tragacanth, and xanthanum. These polymers can be used individually or in combination with each other.

[0058] Hydrophobic polymers include, for example, polyvinyl chloride, ethylcellulose, polyvinyl acetate, and acrylic acid copolymers, e.g., Eudragith®. The polymers can be used alone or in mixtures. Alternatively or additionally, the hydrophobic matrix may contain hydrophobic agents, such as cetanol, cetostearyl alcohol, cetyl palmitate, waxes like carnauba wax, paraffin, magnesium stearate, sodium stearyl fumarate, and medium-chain or long-chain glycerol esters, either alone or in any mixture.

[0059] The sustained-release pharmaceutical dosage form of the present invention may further include, for example, binders such as sugars, polyvinylpyrrolidine, starch, and gelatin; surfactants such as nonionic surfactants (e.g., polysorbate 80, etc.) or ionic surfactants (e.g., sodium lauryl sulfate, etc.); lubricants such as magnesium stearate, sodium stearyl fumarate, or cetyl palmitate; fillers such as sodium aluminum silicate, lactose, or calcium phosphate; flow promoters such as talc and aerosols; and antioxidants.

[0060] Transmucosal administration can be achieved using preparations in the form of ointments, emulsions, gels, lotions, solutions (e.g., irrigation solutions), creams, or patches (in the case of transdermal delivery). Suitable pharmaceutical carriers for transmucosal administration include, for example, polyethylene glycol, propylene glycol, glycerin, isopropanol, ethanol, oleic acid, N-methylpyrrolidone, sesame oil, olive oil, wood extract ointment, petrolatum, and paraffin, or mixtures thereof.

[0061] For transmucosal delivery of gel, cream, or ointment formulations to the vaginal mucosa, bioadhesive polymer-based carrier compositions are particularly useful. Suitable bioadhesive polymers are described, for example, in U.S. Patent No. 4,615,697 (the contents of which are incorporated herein by reference). Particularly useful polymers are crosslinked polycarboxylic acid polymers having a sufficiently high degree of crosslinking to impart the desired level of bioadhesion to the target epithelial surface. Representative bioadhesive polymer formulations are described, for example, in U.S. Patents No. 5,543,150 and No. 5,667,492. Other additives suitable for incorporation into bioadhesive polymer formulations include one or more of preservatives, wetting agents, lubricants and / or humectants, stabilizers, pigments, pH adjusters (e.g., bases), and purified water. Depending on the additives in the formulation and the resulting viscosity, such formulations may be administered vaginally as an irrigation solution using a plunger or as suppositories.

[0062] Vaginal suppositories containing S-alkylisothiouronium derivatives provide long-lasting release and are particularly useful for the treatment or prevention of endometriosis. Rectal suppositories can also be used to deliver S-alkylisothiouronium derivatives. Typical base carriers for vaginal or rectal suppositories include, for example, natural, synthetic, or partially synthetic fats, waxes, and their derivatives of animal, plant, or mineral origin. Specific examples include olive oil, corn oil, castor oil, hydrogenated oil, petrolatum, solid paraffin, liquid paraffin, carnauba wax, beeswax, lanolin, partially or whole-synthesized esters of glycerol fatty acids, mono, di, or triglycerides of saturated or unsaturated fatty acids, and carriers well known in the art. Other additives suitable for incorporation into the suppositories of the present invention include preservatives, stabilizers, surfactants, dyes, pH adjusters, and purified water known in the art.

[0063] Suitable devices for vaginal or cervical implantation include tampons, vaginal rings, vaginal cups, cervical cups, vaginal pessaries, vaginal sponges, and drug-containing intrauterine devices (IUDs). Tampons may be impregnated and / or coated with an effective amount of S-alkylisothiouronium derivative for a period of time corresponding to safe and hygienic tampon use (typically one tampon every 4 to 8 hours). Examples of tampons impregnated or coated with therapeutic agents can be found, for example, in U.S. Patents 3,995,636, 4,186,742, 4,340,055, 4,582,717, 5,201,326, and 5,417,224 (these are incorporated herein by reference). S-alkylisothiouronium derivatives can be incorporated into / impregnated into over-wrap sheets of nonwoven material permeable to bodily fluids. The overlap sheet is superimposed on the first sheet of absorbent material that forms the body of the tampon when the sheet is rolled or formed into the desired tampon shape, with the S-alkylisothiouronium derivative-containing layer remaining on the outermost surface. Alternatively, the S-alkylisothiouronium derivative can be deposited between the absorbent sheet body and the permeable overlap sheet during manufacturing. Alternatively, the S-alkylisothiouronium derivative can be incorporated into a tampon cover made from hardened collagen or gelatin foam containing release-delaying materials such as higher fatty acid triglycerides that melt at body temperature, for application to an absorbent natural or synthetic tampon core.

[0064] Another method of manufacturing S-alkylisothiouronium derivative-impregnated tampons involves incorporating the S-alkylisothiouronium derivative into a suppository base formulation, melting it, impregnating the tampon with it using a syringe, and then cooling it. Alternatively, pre-formed tampons can be coated with a melted suppository formulation containing an activator. In either case, the result is a tampon that gradually releases the S-alkylisothiouronium derivative as the suppository base melts in the presence of body temperature. Useful suppository adjuvants are those listed above and those described in U.S. Patent No. 4,582,717.

[0065] In vaginal and cervical devices such as vaginal rings, vaginal cups, cervical cups, vaginal pessaries, and vaginal sponges, the compounds are incorporated into these devices as creams, lotions, foams, solutions, pastes, ointments, or gels.

[0066] IUDs include non-biologically invasive, partially bio-invasive, and fully bio-invasive IUDs. Typically, an IUD is made from a flexible polymer non-invasive core and coated with a bio-invasive coating material containing an S-alkylisothiouronium derivative. Alternatively, the IUD core may be a bio-invasive material containing an S-alkylisothiouronium derivative for sustained release and may or may not further include an activator-releasing outer coat. The latter structure eliminates the need to remove the device after the entire drug has been released. For example, a drug-containing intrauterine device in an embodiment of the present invention may consist of a highly mechanically elastic non-biologically invasive hydrophobic substrate, the substrate containing, within its volume, an inclusion of a polymerized hydrophilic material grafted onto the hydrophobic substrate and crosslinked, in which the S-alkylisothiouronium derivative is stored, and the S-alkylisothiouronium derivative perfuses through the hydrophobic substrate when the hydrophobic substrate is placed in an aqueous medium. Suitable materials for hydrophobic substrates include, for example, vinyl acetate, polyethylene, or copolymers of vinyl acetate and polyethylene, or more generally, polymerized thermoplastic products such as ethylene copolymers, polyethers, polyurethanes, or polyacrylonitriles. Suitable materials for hydrophilic substances include ethylene glycol acrylate, ethylene glycol methacrylate, acrylamide, methacrylamide, acrylamide methylol, acrylamide diacetone, or unsaturated acidic products such as malic acid, acrylic acid, methacrylic acid, fumaric acid, itaconic acid, or propylene glycol acrylate or methacrylate. Polypropylene, polyamide, polyester (e.g., ethylene glycol), polyterephthalate, polyvinyl chloride, polyformaldehyde chloride, polycarbonate, and polytetrafluoroethylene ("Teflon") may also be used.

[0067] For drug-containing intrauterine devices that are at least partially bioerosive, the materials must be non-toxic and non-irritating to the endometrium of the uterus, and the final products of bioerosion must also be non-toxic and easily eliminated from the body. Exemplary bioerosive materials include both natural and synthetic materials such as (a) structural proteins and hydrophilic colloids of animal origin, (b) polysaccharides and other hydrophilic colloids of plant origin, and (c) synthetic polymers. Some of these matrix materials are suitable in their natural forms, while others, particularly hydrophilic colloids, require insolubilization by either chemical modification or physical modification (e.g., orientation, radiation crosslinking). Examples of the first category include natural and modified collagen, muscle proteins, elastin, keratin, resilin, and fibrin. Examples of polysaccharides and plant hydrophilic colloids include lignin, pectin, carrageenan, chitin, heparin, chondroitin sulfate, agar, guar, locust bean gum, gum arabic, karaya gum, tragacanth, gatti gum, starch, oxystarch, starch phosphate, carboxymethyl starch, sulfaethyl starch, aminoethyl starch, amidoethyl starch, starch esters (e.g., maleic acid, succinic acid starch, benzoic acid starch, and acetate starch), and mixtures of starch and gelatin; cellulose and its derivatives, for example, modified cellulose (e.g., partially hydroxyethylated cotton obtained by treating cotton with ethylene oxide, or caustic alkali and chloroacetic acid). This is partially carboxymethylated cotton obtained by treating cotton with [a specific agent]. Examples of synthetic polymers include poly(vinyl alcohol), poly(ethylene oxide), poly(acrylamide), poly(vinylpyrrolidone), poly(ethyleneimine), poly(vinylimidazole), poly(phosphate), synthetic polypeptides, polyvinyl alkyl ethers, polyacrylamide and polymethacrylamide, as well as copolymers of acrylamide and methacrylamide with up to 40% by weight of N-methylenebisacrylamide or N,N-dimethylolurea; water-soluble hydrophilic polymers of polyalkylaldehydes, non-crosslinked hydroxyalkyl acrylates and methacrylates, polyalkylene carbonates, and the like.Any bio-erosive material compatible with S-alkylisothiouronium derivatives, non-toxic, and possessing the desired erosion and release rates can be used. Typically, crosslinking agents (e.g., aldehydes such as acetaldehyde, formaldehyde, acrolein, crotonaldehyde, glutaraldehyde, glyoxal, dimethylolurea, trimethylolmelamine, tetra(methoxymethyl)urea, melamine, epichlorohydrin, and hexamethylenetetramine) and plasticizers (e.g., tri-n-butyl acetylcitrate, epoxidized soybean oil, glycerol monoacetate, polyethylene glycol, propylene glycol dilaurate, decanol, dodecanol, 2-ethylhexanol, 2,2-butoxyethoxyethanol, etc.) are added to impart the desired rate of bio-erosion and flexibility to the IUD. Drug-containing intrauterine devices include, for example, pessaries, spirals, or coils (e.g., Mirena® coils).

[0068] Use of S-alkylisothiouronium derivatives The present invention provides an effective and highly safe method for the treatment of endometriosis in women. The method involves administering a pharmaceutical composition containing an S-alkylisothiouronium derivative as an activator to women with endometriosis or women at risk of endometriosis recurrence.

[0069] As used herein, the term “endometriosis” refers to any non-malignant disease in which functional endometrial tissue is present in any part of the body other than the endometrial cavity of the uterus. When the endometrial tissue is present within the uterine wall (myometrium), this is called “adenomyosis” of the uterus. Thus, the term “endometriosis” includes “endometriosis” as defined in The Merck Manual, in which endometrial tissue is present outside the uterine cavity, and also includes uterosacral tuberosities, endometriomas, adnexal adhesions, and adenomyosis in which endometrial tissue is present within the myometrium of the uterus.

[0070] Therefore, endometriosis includes conditions commonly referred to as peritoneal endometriosis, deep invasive endometriosis, ovarian endometriosis, extrauterine endometriosis, endometrioma, and uterine endometriosis (adenomyosis), as well as any other term including "endometriosis," such as scarred endometriosis, and any non-malignant disorder in which functional endometrial tissue is present in a location other than the endometrium.

[0071] As used herein, “endometriotic tissue” means endometrial tissue found in endometriosis, that is, endometrial tissue located outside the uterine lining of the uterus.

[0072] The terms “treatment” and “treating” as used interchangeably throughout this specification and the claims refer to the ability to effectively alleviate endometriosis. Therefore, treating or treating endometriosis includes, for example, causing regression or disappearance of endometriotic lesions. It should be understood that the terms treatment and treating include prevention. “Prevention” means the ability to prevent recurrence of endometriosis.

[0073] As used herein, the term “menstrual cycle” refers to the period from the first day of a woman’s menstrual period to the first day of the next menstrual period.

[0074] Therefore, according to the present invention, the S-alkylisothiouronium derivatives of the present invention can reduce the number and / or size of lesions in endometriotic tissue. Preferably, the S-alkylisothiouronium derivatives of the present invention can prevent the recurrence of endometriosis. Specifically, according to the present invention, the S-alkylisothiouronium derivatives of the present invention can reduce or eliminate the proliferation, migration, and / or invasion and invasion of endometrial cells or endometriotic cells into the extrauterine site and the uterine wall (myometrium). The S-alkylisothiouronium derivatives of the present invention can also alleviate or eliminate symptoms associated with endometriosis, such as infertility. Therefore, the S-alkylisothiouronium derivatives of the present invention can improve the fertility of women suffering from endometriosis. According to some embodiments, the S-alkylisothiouronium derivatives of the present invention can be administered starting 1 to 7 days after removal of endometriotic tissue by laparoscopy or surgery, and then discontinued for at least 1 month. To prevent the recurrence of endometriosis, the S-alkylisothiouronium derivative of the present invention can be administered once daily, once every two days, once every three days, once a week, once every two weeks, or once a month. To prevent the recurrence of endometriosis, the S-alkylisothiouronium derivative of the present invention can be administered for more than one year, if necessary. To prevent the recurrence of endometriosis, the S-alkylisothiouronium derivative of the present invention can be administered thereafter, if necessary. Alternative regimens can be adapted according to the physician treating the patient requiring treatment.

[0075] The pharmaceutical compositions of the present invention can be administered by a route of administration selected from the group consisting of oral, vaginal, cervical, intrauterine, intraperitoneal, and intralesional administration routes.

[0076] As used herein, “intrafocal administration” means administration to or within a pathological area. Administration is performed by injection into a lesion and / or by infusion into an existing cavity, such as an endometrioma. Intrafocal administration refers to treatment within endometriotic tissue or within cysts formed by such tissue (e.g., treatment by injection into a cyst). “Intrafocal administration” also includes administration to tissue very close to endometriotic tissue so that the S-alkylisothiouronium derivative acts directly on the endometriotic tissue.

[0077] The present invention also encompasses administering a therapeutic dose of an S-alkylisothiouronium derivative together with other therapeutic activators useful for treating or alleviating endometriosis. In a method of co-administering an S-alkylisothiouronium derivative with one or more additional therapeutic activators, it is assumed that all activators can be administered simultaneously or sequentially. Therefore, an effective dose of S-alkylisothiouronium can be co-formulated with additional activators in a single composition. Alternatively, separate dosage forms for administration via the same or different routes of administration may be used where sequential co-administration is more appropriate or practical.

[0078] Suitable compounds for "other therapeutic agents" are drugs useful for alleviating or treating endometriosis. Representative therapeutic agents for treating endometriosis include hormones, such as combination contraceptives; androgens, such as danazol; gonadotropin-releasing hormone (GnRH) analogs; and progestogens.

[0079] A pharmaceutically acceptable composition for use in the context of the present invention contains a therapeutically effective amount of an activator to achieve the intended purpose. More specifically, “therapeutically effective amount” means the amount of a compound that is effective in preventing, alleviating, or treating endometriosis in the woman being treated.

[0080] Determining the therapeutically effective dose is well within the capabilities of those skilled in the art, particularly in light of the disclosures provided herein.

[0081] The pharmaceutical composition of the present invention can be administered before menstruation, during menstruation, or both. Alternatively, the pharmaceutical composition can be administered during the luteal phase of the menstrual cycle.

[0082] As used herein, the term “maintain fertility” refers to a woman’s ability to conceive. The non-hormonal treatments for endometriosis provided in this invention allow / enable women undergoing such treatment to become pregnant during or after treatment. The pharmaceutical compositions of this invention not only maintain female fertility but also increase the probability of conception.

[0083] The exact prescription, route of administration, and dosage may be selected by individual physicians, taking into account the patient's condition. (See, for example, Fingl, et al. (1975), "The Pharmacological Basis of Therapeutics," Ch.1, p.1).

[0084] The amount of the composition administered will depend on the patient being treated, such as weight, age, medical history, severity of the disease, route of administration, and the judgment of the prescribing physician. [Examples]

[0085] Example 1 The effect of S-ethylisothiouronium diethyl phosphate on endometriosis in women To evaluate the efficacy of S-ethylisothiouronium diethyl phosphate for moderate to severe endometriotic lesions in women, 40 women aged 20–50 years with endometriosis will be enrolled in the study. Twenty women will be treated with 100 mg of S-ethylisothiouronium diethyl phosphate tablets. Twenty women will be treated with a placebo. Each woman will be treated once daily for five days during her menstrual period, starting two days before menstruation. This treatment will be repeated for three cycles. Women will undergo ultrasound examinations to assess the size and number of endometrial lesions. Additional parameters such as blood volume and the woman's physical condition will be evaluated during each menstrual period.

[0086] Example 2 The effect of S-ethylisothiouronium diethyl phosphate on endometriosis cells in women suffering from endometriosis. A prospective, randomized, double-blind, placebo-controlled, multicenter Phase II trial will be conducted to evaluate the safety and efficacy of RAVISET® (S-ethylisothiouronium diethyl phosphate) for the treatment of pain, quality of life, and endometriotic lesions in women with endometriosis. This trial will include 74 premenopausal women aged 18–49 years who have been diagnosed with endometriosis (surgically or clinically) and are experiencing moderate to severe pain. Women participating in this trial must have a regular menstrual cycle with intervals of 24–38 days and bleeding periods of 3–8 days. Pregnant, lactating, or women planning to become pregnant within the next 8 months will be excluded from this trial. Women wishing to participate in the clinical trial will be required to sign an informed consent form. Eligible women who provide informed consent and meet the inclusion criteria will undergo a screening visit (Visit 1), and upon completion of this visit, will be enrolled in the trial and assigned to receive either the investigational drug or a placebo. During the first visit, prior to registration, record the patient's demographic data, general medical history of comorbidities and drug therapies, and history of specific endometriosis conditions.

[0087] The study design includes 37 women treated with orally administered 100 mg S-ethylisothiouronium diethyl phosphate tablets and 37 women treated with a placebo. All women discontinue hormone therapy before the start of treatment, following a 3-month drug-free period. Treatment will begin on the 21st day of each individual menstrual cycle for 14 consecutive days over three consecutive cycles, after determining the length of the menstrual cycle at the end of the drug-free period. Women will undergo ultrasound examinations to assess the size and number of endometrial lesions. As part of the protocol, women will also undergo a physical examination, including recording vital signs (heart rate (HR), blood pressure (BP), and body temperature), and will be asked to provide pregnancy test results. Routine clinical blood tests will include complete blood count (CBC), clinical chemistry, and coagulation function. Vaginal pH and urinalysis will also be performed.

[0088] To assess the impact of the trial treatment on the quality of life of the subjects, women are required to complete the following questionnaire: • Patient Global Impression of Change (PGIC) Questionnaire • 30-item Endometriosis Health Profile (EHP-30), self-administered questionnaire, and ·Endometriosis Health Profile (EQ-5D-5L) Questionnaire

[0089] All participants will receive an electronic diary at the end of their screening visit (visit 1) and will be trained throughout the entire duration of the drug-free period and the trial treatment period to report on the daily assessment of endometriosis-related pain, the use of protocol-designated emergency analgesics, and the characteristics of uterine bleeding.

[0090] Throughout the "Run-in washout period," participants are required to visit the clinic every six weeks and will be observed twice, on day 45 (visit 2) and day 90 (visit 3) after registration. At each "Run-in washout period" visit, participants will undergo a physical examination including recording vital signs (HR, BP, temperature), provide pregnancy test results, and be evaluated by transvaginal ultrasound. The Composite Pelvic Signs and Symptoms Score (CPSSS) pain score will be assessed by the physician, who will also review the individual's daily endometriosis-related pain, emergency analgesic use, and uterine bleeding. Participants will be required to complete all study questionnaires and report any adverse events, as well as any changes in concomitant medications. At the final "Run-in washout period" visit (visit 3), participants will be given either the investigational drug Raviset® or a placebo tablet, along with detailed instructions for its use.

[0091] After the 3-month "drug-free period" is completed and the length of each individual's menstrual cycle is determined, participants enter the study's "treatment period." During this 3-month period, participants are required to self-administer the study tablets, maintain daily electronic diary records (as described above), and visit the clinic once a month. Between each monthly visit (visits 4-6) of the "treatment period," participants are required to undergo a physical examination including recording vital signs (HR, BP, temperature), provide pregnancy test results, and be assessed by transvaginal ultrasound. The CPSSS pain score is assessed by the physician, who also reviews the individual's daily endometriosis-related pain, emergency analgesic use, and daily electronic diary assessments for uterine bleeding. Participants are required to complete all study questionnaires and report any adverse events, as well as any changes in concomitant medications. Participants are instructed to return used / unused tablet containers at their next treatment visit for drug compliance determination. The treatment period is completed by a safety follow-up (FU) telephone visit (visit 7) 30 days after the end of treatment (EoT) visit. During the safety FU telephone visit, the patient will be questioned about any recorded adverse events and any changes in concomitant medications. However, if any serious adverse event (SAE) is not resolved, or if any abnormalities are observed during EoT transvaginal ultrasound and / or clinical examinations, the patient will be asked to come to the clinic for a safety follow-up (FU) visit.

[0092] This protocol was designed to confirm pain reduction, but unexpectedly, S-ethylisothiouronium diethyl phosphate (RAVISET®) reduces the recurrence of endometriotic invasion into the extraperitoneal uterine site.

[0093] Those skilled in the art will understand that the present invention is not limited to what has been specifically shown and described above. Rather, the scope of the present invention is defined by the following claims.

Claims

1. A method for treating endometriosis or preventing the recurrence of endometriosis, wherein a compound of formula I is used for women in need of such treatment. 【Chemistry 1】 During the ceremony, R'' is a linear or branched alkyl group, optionally substituted with a halogen. A method comprising administering a therapeutically effective amount of a pharmaceutical composition containing a compound of formula I as an activator, wherein A''(-) is an anion derived from a phosphorus-containing acid, a phosphite ester, and a phosphite amide.

2. A ” The method according to claim 1, wherein (-) is an anion derived from a mono or dialkyl ester of a phosphate or phosphite.

3. The method according to claim 1, wherein the compound is selected from the group consisting of S-methylisothiouronium methyl phosphite, S-methylisothiouronium dimethyl phosphite, S-ethylisothiouronium metaphosphate, S-ethylisothiouronium ethyl phosphite, S-ethylisothiouronium diethyl phosphite, S-propylisothiouronium propyl phosphite, S-isopropylisothiouronium metaphosphate, S-isopropylisothiouronium isopropyl phosphite, S-butylisothiouronium dibutyl phosphate, and S-isobutylisothiouronium isobutyl phosphite.

4. The method according to claim 3, wherein the compound is S-ethylisothiouronium diethyl phosphate.

5. The method according to any one of claims 1 to 4, wherein the endometriosis is selected from the group consisting of external endometriosis, endometrioma, adenomyosis, endometriotic nodules of the uterosacral ligament, and endometriotic nodules other than those of the uterosacral ligament.

6. The method according to any one of claims 1 to 5, wherein the pharmaceutical composition is administered via a route of administration selected from the group consisting of oral, vaginal, cervical, intrauterine, intraperitoneal, and intralesional administration routes.

7. The method according to claim 6, wherein the pharmaceutical composition is administered by an oral route.

8. The method according to any one of claims 1 to 7, wherein the pharmaceutical composition is formulated in a form selected from the group consisting of tablets, capsules, solutions, suspensions, emulsions, powders, liquids, gels, syrups, slurries, powders, vaginal suppositories, vaginal rings, vaginal pessaries, vaginal tampons, implants, drug-containing intrauterine devices, sprays, creams, gels, ointments, and sustained-release formulations.

9. The method according to any one of claims 1 to 8, wherein the pharmaceutical composition is administered daily before menstruation, during menstruation, or both.

10. The method according to claim 9, wherein the pharmaceutical composition is administered daily two to seven days before menstruation and during menstruation.

11. The method according to claim 9, wherein the pharmaceutical composition is administered daily two days before menstruation and during menstruation.

12. The method according to any one of claims 1 to 8, wherein the pharmaceutical composition is administered daily, starting on the 18th to 23rd day of the menstrual cycle, for a period of 11 to 17 consecutive days.

13. The method according to any one of claims 1 to 8, wherein the pharmaceutical composition is administered daily from the 21st day of the menstrual cycle and during menstruation.

14. The method according to any one of claims 1 to 8, wherein the pharmaceutical composition is administered daily for 14 consecutive days.

15. The method according to any one of claims 1 to 8, wherein the pharmaceutical composition is administered daily after laparoscopy or removal of endometriotic tissue, thereby preventing the recurrence of endometriosis.

16. The method according to any one of claims 1 to 8, wherein administration of the pharmaceutical composition prevents or reduces the proliferation, migration, and / or invasion of endometrial cells into the extrauterine region.

17. The method according to any one of claims 1 to 8, wherein administration of the pharmaceutical composition prevents or reduces the proliferation, migration, and / or invasion of endometrial cells within the uterine wall (myometrium).

18. The method according to any one of claims 1 to 17, wherein the therapeutically effective amount of the compound is in the range of 1 mg to 400 mg per day.

19. The method according to claim 18, wherein the therapeutically effective dose is 50 mg to 100 mg per day.

20. A compound of formula I for use in the treatment of endometriosis or the prevention of recurrence of endometriosis, 【Chemistry 2】 During the ceremony, R'' is a linear or branched alkyl group, optionally substituted with a halogen. A pharmaceutical composition comprising a compound of formula I as an activator, wherein A''(-) is an anion derived from a phosphorus-containing acid, a phosphite ester, and a phosphite amide.

21. The pharmaceutical composition according to claim 20, wherein the anion of the compound of formula I is derived from a mono or dialkyl ester of a phosphate or phosphite.

22. The pharmaceutical composition according to claim 20, wherein the compound is selected from the group consisting of S-methylisothiouronium methyl phosphite, S-methylisothiouronium dimethyl phosphite, S-ethylisothiouronium metaphosphate, S-ethylisothiouronium ethyl phosphite, S-ethylisothiouronium diethyl phosphite, S-propylisothiouronium propyl phosphite, S-isopropylisothiouronium metaphosphate, S-isopropylisothiouronium isopropyl phosphite, S-butylisothiouronium dibutyl phosphite, and S-isobutylisothiouronium isobutyl phosphite.

23. The pharmaceutical composition according to claim 22, wherein the compound is S-ethylisothiouronium diethyl phosphate.

24. The pharmaceutical composition according to claim 20, wherein the endometriosis is selected from the group consisting of external endometriosis, endometrioma, adenomyosis, endometriotic nodules of the uterosacral ligament, and endometriotic nodules other than those of the uterosacral ligament.

25. The pharmaceutical composition according to claim 20, wherein the administration of the pharmaceutical composition is carried out by oral, vaginal, cervical, intrauterine, intraperitoneal, or intralesional administration route.

26. The pharmaceutical composition according to claim 20, wherein the pharmaceutical composition is formulated in a form selected from the group consisting of tablets, capsules, solutions, suspensions, emulsions, powders, liquids, gels, syrups, slurries, powders, vaginal suppositories, vaginal rings, vaginal pessaries, vaginal tampons, implants, drug-containing intrauterine devices, sprays, creams, gels, ointments, and sustained-release formulations.

27. The pharmaceutical composition according to claim 20, wherein the pharmaceutical composition is administered daily before menstruation, during menstruation, or both.

28. The pharmaceutical composition according to claim 27, wherein the pharmaceutical composition is administered daily two to seven days before menstruation and during menstruation.

29. The pharmaceutical composition according to any one of claims 20 to 26, wherein the pharmaceutical composition is administered daily, starting on the 18th to 23rd day of the menstrual cycle, for a period of 11 to 17 consecutive days.

30. The pharmaceutical composition according to any one of claims 20 to 26, wherein the pharmaceutical composition is administered daily from the 21st day of the menstrual cycle and during menstruation.

31. The pharmaceutical composition according to any one of claims 20 to 26, wherein the pharmaceutical composition is administered daily for 14 consecutive days.

32. The pharmaceutical composition according to any one of claims 20 to 26, wherein the pharmaceutical composition is administered daily after laparoscopy or removal of endometriotic tissue, thereby preventing the recurrence of endometriosis.

33. The pharmaceutical composition according to any one of claims 20 to 26, wherein administration of the pharmaceutical composition prevents or reduces the proliferation, migration, and / or invasion of endometrial cells into the extrauterine region.

34. The pharmaceutical composition according to any one of claims 20 to 26, wherein administration of the pharmaceutical composition prevents or reduces the proliferation, migration, and / or invasion of endometrial cells within the uterine wall (myometrium).

35. The pharmaceutical composition according to claim 20, wherein the pharmaceutical composition is administered to a woman in a therapeutically effective amount for the treatment of endometriosis or the prevention of its recurrence.

36. The pharmaceutical composition according to claim 35, wherein the therapeutically effective amount of the compound is in the range of 1 mg to 400 mg per day.

37. The pharmaceutical composition according to claim 35, wherein the therapeutically effective dose is 50 mg to 100 mg per day.

38. A method for treating women suffering from endometriosis while maintaining their reproductive capacity, comprising a compound of formula I, 【Transformation 3】 During the ceremony, R'' is a linear or branched alkyl group, optionally substituted with a halogen. A therapeutically effective amount of a pharmaceutical composition containing a compound of formula I as an activator, wherein A''(-) is an anion derived from a phosphorus-containing acid, a phosphite ester, and a phosphite amide, is administered. A method that increases the chances of conception.

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