Method for treating endometriosis

Abstract

The present invention relates to methods for treating endometriosis or preventing recurrence of endometriosis. In particular, the present invention relates to methods for treating endometriosis and recurrence thereof comprising administering to a female having endometriosis a pharmaceutical composition comprising an S-alkylisothiouronium derivative, specifically S-ethylisothiouronium diethylphosphate. The methods and pharmaceutical composition of the present invention preserve fertility and enable conception.

Description

[0001] METHOD FOR TREATING ENDOMETRIOSIS

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to methods for treating endometriosis. In particular, the present invention relates to methods for treating endometriosis or preventing recurrence of endometriosis comprising administering to women having endometriosis or suffering recurrence of endometriosis a pharmaceutical composition comprising an S- alkylisotiouronium derivative, specifically S-ethylisothiouronium diethylphosphate.

[0004] BACKGROUND OF THE INVENTION

[0005] Endometriosis is a common and debilitating disease of fertility aged women. It occurs in around 10% of menstruating women, in 20-50% of infertile women and in 50- 60% of women with chronic pelvic pain. It is characterized by the presence of functional ectopic endometrial or endometriotic tissue in areas outside the uterus. Similar to normal eutopic endometrial tissue, endometriosis lesions respond to estrogen stimulation that enables it to grow and differentiate in response to changes in hormonal levels during the menstrual cycle. There are three main subtypes of endometriosis which include superficial (peritoneal), deep and ovarian endometriosis. The lesions are usually confined to the pelvis and lower abdomen and are common in areas such as the ovaries, posterior broad ligament, posterior cul-de-sac, uterosacral ligaments, large bowel (rectosigma), ureters, bladder and upper vagina and cervix. Less commonly these lesions can be found outside the abdominal cavity including on the pleura, and pericardium and rarely in end organs such as the eyes, brain and fingers. Clinical manifestations of endometriosis comprise pelvic pain including menstrual and ovulation pain, pain during sexual intercourse as well as bowel and bladder symptoms. Subfertility can be found in 30-50% of endometriosis patients. 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 .

[0006] Current methods for treating endometriosis suffer from numerous drawbacks.

[0007] The mainstay of management of endometriosis symptoms since the late 1950s has been combined oral contraceptive pills. Although not curative, contraceptive pills are generally well tolerated and alleviate the main symptoms of pain by suppressing the menstrual cycle and down-regulating endometriosis lesions. For endometriosis patients it is recommended to use the pills in a continuous fashion. Common side effects include irregular vaginal bleeding, fluid retention, abdominal bloating, weight gain, increased appetite, nausea, headaches, breast tenderness and depression. A significant disadvantage is the contraceptive effect and therefore contraceptive pills are not suited for women who wish to preserve fertility.

[0008] Synthetic progesterone (e.g., progestin / progestogens) prevents ovulation and has been used successfully to treat endometriosis since the mid-1950s. This includes oral progestetives, intramuscular injections and hormonal intrauterine devices. Common side effects of synthetic progesterone include mood changes, bloating, irregular bleeding, breast tenderness, nausea, headaches, acne or oily skin, changes in libido, fatigue and weight gain.

[0009] Gonadotropin-releasing hormone (GnRH) agonists and GnRH antagonists induce an artificial menopausal state by blocking estrogen production. However, common side effects include hot flushes, vaginal dryness and low libido. Long term use, is associated with bone loss leading to osteoporosis and effects of cardiac function.

[0010] Surgical intervention can be done using minimal invasive surgery by laparoscopy. Surgery includes removal of the endometrial lesions, separation of adhesions, removal or ablation of endometriotic ovarian cysts, inspection and testing of the fallopian tube patency and more. In cases of deep endometriosis where bowel, bladder or ureters are involved sometimes extensive surgery is required. This bowel resection, removal of part of the bladder (partial cystectomy) and ureter reimplantation into the bladder or reanastomosis (reconnection) of the ureter ends

[0011] Following surgery symptom improvements are often achieved but lesions can reoccur over time in the same way they initially formed prior to the surgery. Therefore, hormonal treatment is often recommended to avoid recurrence of lesions.

[0012] U.S. Patent No. 7,148,208 to Barkan et al. discloses methods for treating headaches and migraines as well as nausea and vomiting comprising administering to a subject in need of such treatments a composition comprising an S-alkylisothiouronium derivative.

[0013] WO 2007 / 029255 to some of the inventors of the present invention discloses methods for preventing hypotension and stabilizing blood pressure in hemodialysis patients comprising administering to these patients a pharmaceutical composition comprising an S-alkylisothiouronium derivative. W02007 / 108004 to one of the inventors of the present invention discloses methods for treating inflammation comprising administering to a subject in need of such treatment a pharmaceutical composition comprising an S-alkylisothiouronium derivative.

[0014] W02009 / 060451 to one of the inventors of the present invention discloses methods for treating uterine hypercontractility disorders, specifically abnormal uterine bleeding and dysmenorrhea, comprising administering to women suffering from such disorders a pharmaceutical composition comprising an S-alkylisothiouronium derivative.

[0015] There remains a need for improved methods for treating endometriosis which enable preserving fertility and which have negligible side-effects as compared to the medications currently used for treating endometriosis.

[0016] SUMMARY OF THE INVENTION

[0017] The present invention provides methods for treating endometriosis comprising administering to a female in need thereof a pharmaceutical composition comprising an S- alkylisothiouronium derivative.

[0018] It is now disclosed for the first time that administration of a pharmaceutical composition comprising S-ethylisothiouronium diethylphosphate as the active agent to women suffering from endometriosis reduces the number and / or size of endometrial lesions. Advantageously the treatment of endometriosis with S-ethylisothiouronium diethylphosphate does not have adverse effects on the hormonal status of the patient and preserves fertility in the treated women.

[0019] It is further disclosed that women who have endometriosis and receive treatment of a pharmaceutical composition comprising S-ethylisothiouronium diethylphosphate immediately after keyhole laparoscopy to remove the endometrial tissue in the peritoneum, do not suffer from recurrence of endometriosis or have significant reduction of recurrence.

[0020] It is further disclosed that the pharmaceutical composition comprising S- ethylisothiouronium diethylphosphate preserves fertility, reduces the number and / or size of endometrial lesions, prevents lesion recurrence and exhibits negligible or no side effects as compared to known medicaments. Women treated with said pharmaceutical composition are able to conceive while on treatment. Also, said pharmaceutical composition does not induce symptoms of menopause. It is further disclosed that a clinical trial protocol is underway to test the use of S- ethylisothiouronium diethylphosphate in patients with confirmed endometriosis. It is disclosed herein for the first time that unexpectedly the treatment with S- ethylisothiouronium diethylphosphate not only relieves pain and improves the subjective wellbeing of the patients, but also reduces the recurrence of endometriosis. In other words, the proliferation, migration and / or infiltration of endometrial cells into extra-uterine sites in the peritoneum and pelvic organs as well as within the uterine wall (myometrium) is reduced or eliminated. Thus, the methods of the present invention are highly advantageous as compared to the methods and medicaments being used at present for treating endometriosis.

[0021] According to a first aspect, the present invention provides a method for treating endometriosis or preventing recurrence of endometriosis comprising administering to a female in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising as an active agent a compound of formula I:

[0022] (I) wherein

[0023] R is a straight or branched alkyl, optionally substituted by halogen; and

[0024] A (-) is an anion derived from a phosphorous containing acid, a phosphorous acid ester and a phosphorous acid amide.

[0025] According to some embodiments, the anion of the compound of formula I is derived from a mono or di- alkyl ester of a phosphate or phosphite.

[0026] According to additional embodiments, the compound is selected from the group consisting of:

[0027] S-methylisothiouronium methylphosphite;

[0028] S-methylisothiouronium dimethylphosphate;

[0029] S -ethy lisothiouronium metapho sphate ;

[0030] S -ethy lisothiouronium ethy Ipho sphite ;

[0031] S -ethy lisothiouronium diethylpho sphate ; S -propy lisothiouronium propy Ipho sphite ;

[0032] S-isopropylisothiouronium metaphosphate;

[0033] S-isopropylisothiouronium isopropylphosphite;

[0034] S-buty lisothiouronium dibutylphosphate; and

[0035] S-isobuty lisothiouronium isobutylphosphite.

[0036] According to a certain embodiment, the compound is S-ethy lisothiouronium diethylpho sphate .

[0037] According to some embodiments, endometriosis is selected from the group consisting of endometriosis externa, endometrioma, adenomyosis, endometriotic nodules of the uterosacral ligaments, and endometriotic nodules other than of the uterosacral ligaments.

[0038] According to further embodiments, administration of the pharmaceutical composition is performed by oral, vaginal, cervical, intrauterine, intraperitoneal, or intralesional administration route. According to certain embodiments, administration of the pharmaceutical composition is performed by oral administration route. According to an exemplary embodiment, administration of the pharmaceutical composition is performed by vaginal administration route.

[0039] According to certain embodiments, the composition is formulated in a form selected from the group consisting of tablets, capsules, powders, solutions, suspensions, emulsion, suppositories, implants or sustained-release formulations.

[0040] According to further embodiments, the pharmaceutical composition is formulated in a form selected from the group consisting of tablets, capsules, liquids, gels, syrups, slurries and suspensions.

[0041] According to yet further embodiments, the pharmaceutical composition is formulated in a form selected from the group consisting of a vaginal suppository, a vaginal tampon, a vaginal ring, a vaginal pessary, a vaginal sponge, a medicated intrauterine device (IUD), spray, cream, gel, ointment, a sustained-release formulation, a tablet, a capsule, a solution, a suspension, an emulsion, and a powder. According to certain embodiments, the pharmaceutical composition is formulated as a vaginal suppository or as a tablet.

[0042] According to further embodiments, the pharmaceutical composition is administered daily prior to menstruation, during menstruation, or both. The administration is performed for one, two, three, four, or five months, or as long as needed to treat endometriosis. According to certain embodiments, the pharmaceutical composition is administered continuously.

[0043] According to some embodiments, the pharmaceutical composition is administered 2 to 7 days prior to menstruation and during menstruation. According to a certain embodiment, the pharmaceutical composition is administered 2 days prior to menstruation and during menstruation.

[0044] According to some embodiments, the pharmaceutical composition is administered daily beginning on day 18 to 23 from the first day of menstruation for 11 to 17 days. According to an exemplary embodiment, the pharmaceutical composition is administered on day 21 of the menstrual cycle. According to another exemplary embodiment, the pharmaceutical composition is administered daily for 14 consecutive days.

[0045] According to certain embodiments, the pharmaceutical composition is administered once a day, once in two days, once in three days, once a week, once in two weeks, or once a month for a period beginning on day 18 to 23 from the first day of menstruation. Alternative regimens can be adapted according to the instructions of a physician treating a patient in need of 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 necessary.

[0046] According to yet further embodiments, the pharmaceutical composition is administered once a day, once in two days, once in three days, once a week, once in two weeks, or once a month after laparoscopy or endometriotic tissue removal, thereby preventing recurrence of endometriosis.

[0047] According to still further embodiments, the pharmaceutical composition is administered once a day, once in two days, once in three days, once a week, once in two weeks, or once a month after laparoscopy or endometriotic tissue removal for a period of at least one month, two months, three months, four months, five months, or at least six months, or so long as required to prevent recurrence of endometriosis.

[0048] According to some embodiments, the therapeutically effective amount of the compound of formula I ranges from 1 mg to about 400 mg, alternatively from 50 mg to about 200 mg, alternatively from 30 mg to about 150 mg. According to a certain embodiment, the therapeutically effective amount of S-ethylisothiouronium diethylphosphate is 100 mg per unit dose. Each possibility represents a separate embodiment of the invention. According to certain embodiments, administration of the pharmaceutical composition treats endometriosis. According to other embodiments, administration of the pharmaceutical composition prevents recurrence of endometriosis. According to further embodiments, administration of the pharmaceutical composition prevents the proliferation, migration and / or infiltration of endometrial cells into extra uterine sites. According to certain embodiments, administration of the pharmaceutical composition reduces the proliferation, migration and / or infiltration of endometrial cells into extra uterine sites in the peritoneum and pelvic organs. According to certain embodiments, administration of the pharmaceutical composition prevents the proliferation, migration and / or infiltration of endometrial cells within the uterine wall (myometrium). According to further embodiments, administration of the pharmaceutical composition reduces the proliferation, migration and / or infiltration of endometrial cells within the peritoneum and pelvic organs. According to further embodiments, the administration of the pharmaceutical composition reduces the size of endometrial lesions. According to some embodiments, the administration of the pharmaceutical composition shrinks endometrial lesions.

[0049] According to a further aspect, the present invention provides a pharmaceutical composition comprising as an active agent a compound of formula I:

[0050] (I) wherein

[0051] R is a straight or branched alkyl, optionally substituted by halogen; and

[0052] A (-) is an anion derived from a phosphorous containing acid, a phosphorous acid ester and a phosphorous acid amide, for use in treating endometriosis or preventing recurrence of endometriosis. According to another aspect, the present invention provides a method for treating a female suffering from endometriosis while preserving fertility by administering therapeutically effective amount of a pharmaceutical composition comprising as an active agent a compound of formula I:

[0053] (I) wherein

[0054] R is a straight or branched alkyl, optionally substituted by halogen; and

[0055] A (-) is an anion derived from a phosphorous containing acid, a phosphorous acid ester and a phosphorous acid amide, thereby enhancing probability of conception.

[0056] These and other embodiments of the present invention will be better understood in relation to the description, examples and claims that follow.

[0057] DETAILED DESCRIPTION OF THE INVENTION

[0058] The present invention provides methods for treating endometriosis and / or preventing recurrence of endometriosis and / or endometriotic lesions and / or preserving fertility in females suffering from endometriosis. The methods comprise administering to a female having endometriosis or at risk for recurrence of endometriosis a pharmaceutical composition comprising as an active agent an S-alkylisothiouronium derivative. Said methods and pharmaceutical composition preserve the fertility of women suffering from endometriosis, thereby enabling conception during or following treatment. of the invention

[0059] According to the present invention, S-alkylisothiouronium derivative is a compound of formula I:

[0060] (I) wherein R is a straight or branched alkyl, optionally substituted by halogen; and

[0061] A (-) is an anion derived from a phosphorous containing acid, a phosphorous acid ester and a phosphorous acid amide.

[0062] According to some embodiments, the anion is derived from a mono or di- alkyl ester of a phosphate or phosphite.

[0063] According to additional embodiments the compound is selected from the group consisting of:

[0064] S -methy lisothiouronium methy Ipho sphite ;

[0065] S-methylisothiouronium dimethylphosphate;

[0066] S -ethy lisothiouronium metapho sphate ;

[0067] S -ethy lisothiouronium ethy Ipho sphite ;

[0068] S -ethy lisothiouronium diethylpho sphate ;

[0069] S -propy lisothiouronium propy Ipho sphite ;

[0070] S-isopropylisothiouronium metaphosphate;

[0071] S-isopropylisothiouronium isopropylphosphite;

[0072] S-buty lisothiouronium dibutylphosphate; and

[0073] S-isobuty lisothiouronium isobutylphosphite.

[0074] According to a certain embodiment, the compound is S -ethy lisothiouronium diethylpho sphate .

[0075] Pharmaceutical

[0076] The pharmaceutical compositions of the present invention comprise an S- alkylisothiouronium derivative and a pharmaceutically acceptable carrier.

[0077] The term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U. S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents. Water, saline solutions, aqueous dextrose solutions, and glycerol solutions can be employed as liquid carriers, for example, for injection. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, propylene glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents such as acetates, citrates or phosphates. Antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; and agents for the adjustment of tonicity such as sodium chloride or dextrose are also envisioned.

[0078] The compositions can take the form of tablets, capsules, powders, solutions, suspensions, emulsion, suppositories, implants, sustained-release formulations and the like depending on the route of administration chosen.

[0079] Routes of administration that are appropriate in the practice of the present invention include oral, vaginal, intrauterine, intraperitoneal, and intralesional administration routes.

[0080] For oral administration, the pharmaceutical composition of the invention can be formulated as tablets, capsules, liquids, gels, syrups, slurries, suspensions, and the like. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose; and / or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. Such compositions will contain a therapeutically effective amount of an S-alkylisothiouronium derivative together with a suitable amount of a carrier so as to provide the form for proper administration to the subject.

[0081] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0082] For parenteral administration, the pharmaceutical composition of the invention can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank’s solution, Ringer’s solution, or physiological saline buffer. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds, to allow for the preparation of highly concentrated solutions. Parenteral formulations may optionally contain one or more additional ingredients among which may be mentioned preservatives (when the formulations are presented in multi-dose containers), buffers to provide a suitable pH value for the formulation, and sodium chloride, or glycerin, to render a formulation isotonic with the blood.

[0083] The pharmaceutical compositions of the present invention can be formulated in an extended release pharmaceutical dosage form as known in the art (see, for example, US Patent Nos. 6,605,303; 6,419,958; 6,245,357, the content of which is incorporated by reference as if fully set forth herein).

[0084] Thus, an extended release pharmaceutical dosage form of the S-alkylisothiouronium derivatives of the present invention comprise an S-alkylisothiouronium derivative, a polymer, and optionally one or more additional pharmaceutically acceptable excipient or carrier.

[0085] Polymers that can be used for the preparation of the extended release pharmaceutical dosage form of the present invention include hydrophilic polymers, hydrophobic polymers, and a combination thereof.

[0086] Suitable hydrophilic polymers are for instance hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethylhydroxy ethylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, polyethylene oxides, polyvinyl alcohols, tragacanth, and xanthan. These polymers can be used alone or in mixtures with each other.

[0087] Hydrophobic polymers are exemplified by for instance polyvinyl chloride, ethyl cellulose, polyvinyl acetate and acrylic acid copolymers, such as Eudragith™. The polymers can be used alone or as mixtures. Alternatively or additionally, hydrophobizing agents can be used for the hydrophobic matrix such as for instance cetanol, cetostearyl alcohol, cetyl palmitate, waxes lice carnauba wax, paraffin, magnesium stearate, sodium stearyl fumarate, and medium- or long-chain glycerol esters alone or in any mixtures.

[0088] The extended release pharmaceutical dosage forms of the invention can further comprises binders such as for instance sugars, polyvinyl pyrrolidine, starches and gelatin; surfactants such as non-ionic surfactants such as for instance polysorbate 80, or ionic surfactants such as for instance sodium lauryl sulfate; lubricants such as for instance magnesium stearate, sodium stearyl fumarate, or cetyl palmitate; fillers such as for instance sodium aluminum silicate, lactose, or calcium phosphate; glidants such as for instance talc and aerosol; and antioxidants.

[0089] Transmucosal administration can be accomplished using preparations in the form of ointments, emulsions, gels, lotions, solutions (e.g., douches), 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 alcohol ointments, vaseline, and paraffin, or mixtures thereof.

[0090] For transmucosal delivery of a gel, cream, or ointment formulation to the vaginal mucosa, bioadhesive polymer-based carrier compositions are particularly useful. Suitable bioadhesive polymers are, e.g., those that are described in U.S. Pat. No. 4,615,697, the content of which is incorporated herein by reference. Particularly useful polymers are cross-linked 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. Pat. No. 5,543,150 and U.S. Pat. No. 5,667,492. Other additives suitable for incorporation into a bioadhesive polymer formulation include one or more of a preservative, a humectant, a lubricating agent and / or moisturizing agent, a stabilizer, a pigment, a pH modifier (e.g., a base) and purified water. Depending on the formulation additives and the resulting viscosity, such formulations may be administered vaginally as a douche, with a plunger, or as a suppository.

[0091] Vaginal suppositories comprising an S-alkylisothiouronium derivative provide for release over an extended period of time and are particularly useful in treating or preventing endometriosis. Rectal suppositories may also be used to deliver an S-alkylisothiouronium derivative. Typical base carriers for vaginal or rectal suppositories include, for example, natural, synthetic or partially synthetic fats, waxes and derivatives thereof from animal, vegetable, or mineral origin. Specific examples include olive oil, corn oil, castor oil, hydrogenated oils, petrolatum, solid paraffin, liquid paraffin, carnuba wax, bees wax, lanolin, partially or totally synthetic esters of glycerol fatty acid, mono, di, or triglycerides of saturated or unsaturated fatty acids, and well known carriers in the art. Other additives suitable for incorporation into a suppository of the invention include preservatives, stabilizers, surfactants, pigments, pH modifiers and purified water as known in the art.

[0092] Devices suitable for vaginal or cervical implant include tampons, vaginal rings, vaginal cups, cervical cups, vaginal pessaries, vaginal sponges, and medicated intrauterine devices (IUDs). A tampon may be impregnated and / or coated with efficacious amount of S-alkylisothiouronium derivative for a period of time consonant with safe and hygienic tampon usage (typically one tampon every 4 to 8 hours). Examples of tampons impregnated or coated with therapeutic agents are found, e.g., in U.S. Pat. Nos. 3,995,636, 4,186,742, 4,340,055, 4,582,717, 5,201,326, and 5,417,224; the content of which is incorporated herein by reference. S-alkylisothiouronium derivative can be incorporated / impregnated into an over-wrap sheet of non-woven material which is permeable by body fluids and which is superimposed on a first sheet of absorbent material which forms the corpus of the tampon when the sheets are 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 corpus absorbent sheet and the permeable over- wrap sheet during manufacturing. Alternatively, S-alkylisothiouronium derivative can be incorporated into a tampon cover made from a hardened collagen or gelatin foam with a release retardant material such as triglycerides of higher fatty acids melting at body temperature, for application to an absorbent natural or synthetic tampon core.

[0093] Another mode of manufacturing an S-alkylisothiouronium derivative-impregnated tampon incorporates the S-alkylisothiouronium derivative into a suppository base formulation which is melted, syringe-impregnated into tampons, and allowed to cool. Alternatively, pre-formed tampons can be coated with the melted suppository formulation containing the active agent. In either case, the result is a tampon that releases S- alkylisothiouronium derivative gradually as the suppository base melts in the presence of body temperature. Useful suppository auxiliaries are those recited hereinbefore as well as those described in U.S. Pat. No. 4,582,717.

[0094] In vaginal and cervical devices such as vaginal rings, vaginal cups, cervical cups, vaginal pessaries, vaginal sponges, the compound is incorporated into these devices as a cream, lotion, foam, solution, paste, ointment, or gel.

[0095] IUDs include non-bio-erodible, partially bio-erodible, and completely bio-erodible IUDs. Typically, the IUD is made of a flexible polymeric non-eroding core and is over- coated with a bio-erodible coat material containing an S-alkylisothiouronium derivative. Alternatively, the IUD core can be a bio-erodible material containing the S- alkylisothiouronium derivative for sustained-release, and may or may not further comprise an active agent-releasing outer coat. The latter construction makes it unnecessary to remove the device after the entire medicament is released. For example, a medicated intrauterine device within the practice of the invention can consist of a non-bioerodible hydrophobic substrate of high mechanical resiliency, wherein the substrate comprises, within the volume thereof, inclusions of polymerized hydrophilic substances, grafted on the hydrophobic substrate and cross-linked, in which an S-alkylisothiouronium derivative has been stored and which will perfuse through the hydrophobic substrate when the latter is placed in an aqueous medium. Materials suitable for the hydrophobic substrate are polymerized thermoplastic products such as, e.g., vinyl acetate, polyethylene or a copolymer of vinyl acetate and polyethylene, or, more generally, an ethylene co-polymer, a polyether, a polyurethane or a polyacrylonitrile. Materials suitable for the hydrophilic substances include ethylene-glycol acrylate, ethylene-glycol methacrylate, acrylamide, methacrylamide, acrylamide methylol, acrylamide diacetone or an unsaturated acidic product such as malic acid, acrylic acid, methacrylic acid, fumaric acid, itaconic acid or propylene glycol acrylate or methacrylate. Also polypropylene, polyamides, polyesters such as ethylen-glycol, polyterephtalate, polyvinyl chloride, polyformaldehyde chloride, polycarbonates and olytetrafluoroethylene ("Teflon") may be used.

[0096] For a medicated intrauterine device that is at least partially bio-erodible, the materials must be non-toxic and non-irritating to the endometrium of the uterus, and the bioerosion end products of which must also be non-toxic and easily eliminated from the body. Exemplary bioerodible materials include both natural and synthetic materials such as (a) structural proteins and hydrocolloids of animal origin; (b) polysaccharides and other hydrocolloids of plant origin; and (c) synthetic polymers. Some of these matrix materials are suitable as in their native form but others, particularly hydrocolloids, require insolubilization either by chemical modification, or physical modification, such as orientation, radiation cross-linking, etc. Exemplary of the first category are: native and modified collagens, muscle proteins, elastin, keratin, resilin, fibrin, etc. Exemplary of polysaccharides and plant hydrocolloids are: a lignin, pectin, carrageenan, chitin, heparin, chondroitin sulfate, Agar-agar, Guar, locust bean gum, gum arabic, gum Karaya, tragacanth, gum Ghatti, starch, oxystarch, starch phosphate, carboxymethyl starch, sulfaethyl starch, aminoethyl starch, amido ethyl starch, starch esters such as starch maleate, succinate, benzoate and acetate, and mixtures of starch and gelatin; cellulose and its derivatives such as modified cellulose, such as partially hydroxyethylated cotton obtained by the treatment of cotton with ethylene oxide or partially carboxymethylated cotton obtained by the treatment of cotton with caustic and choroacetic acid. Examples of synthetic polymers are: poly(vinyl alcohol), poly(ethylene oxide), poly(acrylamide), poly(vinyl pyrrolidone), poly(ethyleneimine), poly(vinyl imidazole), poly(phosphate), synthetic polypeptides, polyvinyl alkyl ether, polyacryl-and polymethacrylamides, and copolymers of acrylamide and methacrylamide with up to 40% by weight of N-methylene bisacrylamide or N,N-dimethylol urea; polyalkyl aldehydes, water soluble hydrophilic polymers of uncross-linked hydroxyalkyl acrylates and methacrylates, polyalkylene carbonates, and the like. Any bioerodible material which is compatible with S- alkylisothiouronium derivative and non-toxic and which has the desired erosion and release rates can be used. Typically cross-linking agents (e.g., aldehydes, such as acetaldehyde, formaldehyde, acrolein, crotonaldehyde, glutaraldehyde, glyoxal, dimethylol urea, trimethylol melamine, tetra(methoxymethyl) urea, melamine, epichlorohydrin, and hexamethylene tetramine) and plasticizers (e.g., acetyl tri-n-butyl citrate, epoxidized soy bean oil, glycerol monoacetate, polyethylene glycol, propylene glycol dilaurate, decanol, dodecanol, 2-ethyl hexanol, 2,2-butoxyethoxyethanol and the like) are added to impart the desired rate of bioerosion and flexibility, respectively, to the IUD. Medicated intrauterine devices include, for example, pessaries, spirals or coils, such as the Mirena® coil.

[0097] Uses of S-alkylisothiouronium derivatives

[0098] The present invention provides effective and highly safe methods for treatment of endometriosis in females. The methods comprise administering to a female having endometriosis or at risk of recurrence of endometriosis a pharmaceutical composition comprising as an active agent an S-alkylisothiouronium derivative.

[0099] The term "endometriosis" as used herein refers to any nonmalignant disorder in which functioning endometrial tissue is present in a location in the body other than the endometrial cavity of the uterus. If endometrial tissue is present within the uterine wall (myometrium) this is termed "adenomyosis" of the uterus. Thus, the term "endometriosis" includes "endometriosis" as defined in The Merck Manual, where the endometrial tissue is present outside the uterine cavity, including uterosacral nodules, endometriomas, adnexal adhesions, and adenomyosis, where the endometrial tissue is present within the myometrium of the uterus.

[0100] Endometriosis therefore includes the conditions commonly referred to as peritoneal endometriosis, deep infiltrating endometriosis, ovarian endometriosis, endometriosis externa, endometrioma, uterine endometriosis (adenomyosis), any term that includes "endometriosis" such as scar endometriosis, and any nonmalignant disorder in which functioning endometrial tissue is present at a locus other than the endometrium.

[0101] As used herein, "endometriotic tissue" is endometrial tissue seen in endometriosis, that is, the endometrial tissue present in a location other than the endometrium of the uterus.

[0102] The terms "treatment" and “treating”, used interchangeably throughout the specification and claims, refer to the ability to effectively abate endometriosis. Thus, treatment of or treating endometriosis includes, for example, causing the regression or disappearance of endometriotic lesions. It is to be appreciated that the terms treatment and treating include prophylaxis. By "prophylaxis" it is meant the ability to prevent the recurrence of endometriosis.

[0103] The term "menstrual cycle" as used herein refers to the time from the first day of a woman's menstrual period (menstruation) until the first day of her next menstrual period.

[0104] Thus, according to the present invention, an S-alkylisothiouronium derivative of the present invention can reduce the number and / or size of lesions of endometriotic tissue. Preferably, an S-alkylisothiouronium derivative of the invention can prevent the recurrence of endometriosis. Specifically, according to the present invention, an S- alkylisothiouronium derivative of the present invention can reduce or eliminate the proliferation, migration and / or infiltration and invasion of endometrial or endometriotic cells into extra uterine sites as well as within the uterine wall (myometrium). An S- alkylisothiouronium derivative of the present invention can also reduce or eradicate symptoms associated with endometriosis, such as, for example, infertility. Thus, an S- alkylisothiouronium derivative of the present invention may improve fertility in women suffering from endometriosis. According to some embodiments, an S-alkylisothiouronium derivative of the invention can be administered for a period commencing one to seven days after removal of endometriotic tissue by laparoscopy or by surgery and ending at least one month thereafter. For preventing recurrence of endometriosis, an S- alkylisothiouronium derivative of the invention can be administered once a day, once in two days, once in three days, once a week, once in two weeks, or once a month. For preventing recurrence of endometriosis, an S -alkylisothiouronium derivative of the invention can be administered for one year or more as required. For preventing recurrence of endometriosis, an S -alkylisothiouronium derivative of the invention can be administered subsequently as required. Alternative regimens can be adapted according to the physician treating a patient in need of treatment.

[0105] The pharmaceutical compositions of the present invention can be administered by administration route selected from the group consisting of oral, vaginal, cervical, intrauterine, intraperitoneal, and intralesional administration routes.

[0106] As used herein, "intralesional administration" means administration into or within a pathological area. Administration is affected by injection into a lesion and / or by instillation into a pre-existing cavity, such as in endometrioma. Intralesional administration refers to treatment within endometriotic tissue or a cyst formed by such tissue, such as by injection into a cyst. "Intralesional administration" also includes administration into tissue in such close proximity to the endometriotic tissue such that the S -alkylisothiouronium derivative acts directly on the endometriotic tissue.

[0107] Administration of therapeutic doses of an S -alkylisothiouronium derivative with other therapeutically active agents useful in treating or alleviating endometriosis is also encompassed in the present invention. In methods of co-administering an S- alkylisothiouronium derivative with one or more additional therapeutically active agents, it is envisioned that all of the active agents can be administered either simultaneously or sequentially. Accordingly, the effective dose of an S -alkylisothiouronium can be coformulated with the additional active agent(s) in a single composition. Alternatively, where sequential co-administration is more appropriate or practical, then separate dosage forms for administration by the same or different route of administration, will be used.

[0108] Compounds suitable for "another therapeutically active agent" are those agents which are useful for abating or treating endometriosis. Representative therapeutic agents for treating endometriosis include hormones, such as combined contraceptives, androgens e.g., danazol, gonadotropin-releasing hormone (GnRH) analogs, and progestogens.

[0109] Pharmaceutical compositions suitable for use in context of the present invention include a therapeutically effective amount of the active agents to achieve the intended purpose. More specifically, “a therapeutically effective amount” means an amount of a compound effective to prevent, alleviate or treat endometriosis in the female being treated.

[0110] Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the disclosure provided herein.

[0111] Administration of the pharmaceutical composition of the invention can be performed prior to menses, during menses, or both. Alternatively, administration of the pharmaceutical composition can be performed during the luteal phase of the menstrual cycle.

[0112] The term "preserving fertility" as used herein, refers to the ability of a woman to become pregnant. The non-hormonal treatment for endometriosis provided in the present invention allows / enables female subjects receiving said treatment to conceive during or following treatment. The pharmaceutical composition of the present invention not only preserves women's fertility, but also enhances the probability of conception.

[0113] The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl, et al., 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p.l).

[0114] The amount of a composition to be administered will be dependent on the subject being treated, for example, weight, age, prior medical history, the severity of the disease, the route of administration, the judgment of the prescribing physician, etc.

[0115] EXAMPLE 1

[0116] Effect of S-ethylisothiouronium diethylphosphate on endometriosis in women

[0117] In order to evaluate the effect of S-ethylisothiouronium diethylphosphate on moderate to severe endometriotic lesions in women, forty women suffering from endometriosis at the age of 20-50 years are enrolled to the experiment. Twenty women are treated with tablets of 100 mg of S-ethylisothiouronium diethylphosphate. Twenty women are treated with placebo. Each woman is treated once a day, starting two days prior to menstruation and during five days of menstruation. The treatment is repeated for three cycles. The women undergo ultrasound examination to evaluate the size and number of endometrial lesions. Additional parameters, such as the volume of blood in each menstruation and the physical state of the women are evaluated. EXAMPLE 2

[0118] Effect of S-ethylisothiouronium diethylphosphate on endometriotic cells in women suffering from endometriosis

[0119] In order to evaluate the safety and efficacy of RAVISET® (S-ethylisothiouronium diethylphosphate) for treatment of pain, quality of life and endometriotic lesions in women suffering from endometriosis, a phase II prospective, randomized, double blind, placebo controlled, multicenter study is conducted. The study includes 74 premenopausal women between the ages of 18 and 49 years, who are diagnosed with endometriosis (surgically or clinically), and suffer moderate to severe pain. Women participating in this study must have regular menstrual cycles with an interval of 24-38 days and a bleeding period of 3-8 days. Women who are pregnant, breast feeding or planning a pregnancy within the next 8 months are excluded from this study. Women willing to participate in the clinical study are requested to sign an Informed Consent Form. Eligible women subjects providing informed consent and fulfilling the inclusion criteria go through a Screening visit (visit 1), at the end of which they are enrolled into the study and are allocated to receive the investigational product treatment or placebo. During visit 1, prior to enrolment, subjects' demographic data, general medical history for concomitant diseases and medications and specific endometriosis medical history, is recorded.

[0120] Study design includes 37 women treated with tablets of 100 mg of S- ethylisothiouronium diethylphosphate and 37 women treated with placebo, taken orally. All women undergo 3 months washout period and stop any hormonal therapy before treatment initiation. Treatment is initiated at the end of the washout period, after determination of the menstrual cycle length, on day 21 of the individual menstrual cycle of each month, for 14 consecutive days, for 3 consecutive cycles. The women undergo ultrasound examination to evaluate the size and number of endometrial lesions. As part of the protocol, women also undergo a physical examination including vital signs (heart rate (HR), blood pressure (BP), body temperature) recording and asked to provide pregnancy test results. Blood for routine laboratory tests include: complete blood count (CBC), clinical chemistry, coagulation functions. Vaginal pH and a urinalysis test are performed as well.

[0121] In order to evaluate the impact of study treatment on subjects' quality of life, women are required to complete the following questionnaires: • Patient Global Impression of Change questionnaire (PGIC)

[0122] • 30-item Endometriosis Health Profile (EHP-30), a self-administered questionnaire and

[0123] • Endometriosis Health Profile (EQ-5D-5L) questionnaire

[0124] All participating subjects receive at the end of the screening visit (Visit 1) an electronic diary and training how to report daily Endometriosis associated pain assessments, protocol- specified rescue analgesic use and uterine bleeding characteristics throughout the duration of the washout run in period and the study treatment period.

[0125] Through the “Run in washout period” subjects are asked to visit the clinic every 6 weeks and observed twice at 45 days (Visit 2) and 90 days (Visit 3) post enrollment. At each one of the “Run in washout period” visits, subjects undergo a physical examination including vital signs (HR, BP, Body temperature) recording, asked to provide pregnancy test results, and evaluated by transvaginal ultrasound. Composite Pelvic Signs and Symptoms Score (CPSSS) pain score is assessed by the physician that also reviews the personal daily endometriosis associated pain, rescue analgesic medication use and uterine bleeding subjects’ assessments. Subjects are asked to complete all study questionnaires and adverse events as well as change in concomitant medication. At the last “Run in washout period” visit (Visit 3) subjects are dispensed with the study investigational product Raviset® or placebo tablets and provided detailed instructions for its use.

[0126] Once the 3 months “Run in washout period” ends and the individual menstrual cycle length is determined, participants enter the study “treatment period”. During this period that lasts 3 months, they self-administer the study tablet, continue to maintain the daily e-diary recordings (as described above) and are asked to arrive at the clinic once monthly. During each one of the “treatment period” monthly visits (Visit 4 - Visit 6) subjects undergo a physical examination including vital signs (HR, BP, Body temperature) recording, asked to provide pregnancy test results, and evaluated by transvaginal ultrasound. CPSSS pain score are assessed by the physician that also reviews the personal daily endometriosis associated pain, rescue analgesic medication use and uterine bleeding subjects’ daily e-diary assessments. Subjects are asked to complete all study questionnaires and adverse events as well as change in concomitant medication. Subjects are instructed to return the used / unused tablets container on the consecutive treatment visit for drug compliance determination. The treatment period is accomplished by a safety Follow up (FU) telephone visit (Visit 7) 30 days post the end of treatment (EoT) visit. During the safety FU telephone visit, subjects are asked for any adverse events and any change in concomitant medication recorded. However, if any serious adverse event (SAE) was not resolved or abnormalities were observed during the EoT transvaginal ultrasound and / or lab tests, the subject is asked to arrive at the clinic for the safety Follow up (FU) visit.

[0127] Although the protocol was devised to confirm reduction of pain, unexpectedly, S- ethylisothiouronium diethylphosphate (RAVISET®) reduces the recurrence of endometriotic infiltration into peritoneal extrauterine sites. It will be appreciated by persons skilled in the art that the present invention is not limited by what has been particularly shown and described herein above. Rather the scope of the invention is defined by the claims that follow.

Claims

CLAIMS1. A method for treating endometriosis or preventing recurrence of endometriosis comprising administering to a female in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising as an active agent a compound of formula I:© H2N©A" / C - S - R"H2N(I) whereinR is a straight or branched alkyl, optionally substituted by halogen; andA (-) is an anion derived from a phosphorous containing acid, a phosphorous acid ester and a phosphorous acid amide.

2. The method according to claim 1, wherein A (-) is an anion derived from a mono or di- alkyl 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 methylphosphite; S-methylisothiouronium dimethylphosphate; S-ethylisothiouronium metaphosphate; S-ethylisothiouronium ethylphosphite; S-ethylisothiouronium diethylphosphate; S-propylisothiouronium propylphosphite; S-isopropylisothiouronium metaphosphate; S- isopropylisothiouronium isopropylphosphite; S-butylisothiouronium dibutylphosphate; and S-isobutylisothiouronium isobutylphosphite.

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

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

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

7. The method according to claim 6, wherein administering the pharmaceutical composition is performed by oral administration 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 a tablet, a capsule, a solution, a suspension, an emulsion, a powder, a liquid, gel, syrup, slurry, powder, a vaginal suppository, a vaginal ring, a vaginal pessary, a vaginal tampon, an implant, a medicated intrauterine device, spray, cream, gel, ointment, and a sustained-release formulation.

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

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

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

12. The method according to any one of claims 1 to 8, wherein the pharmaceutical composition is administered daily for a period beginning on day 18 to 23 of the menstrual cycle for 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 day 21 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 endometriotic tissue removal, thereby preventing 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 infiltration of endometrial cells into extra-uterine sites.

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 infiltration 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 ranges from 1 mg to 400 mg per day.

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

20. A pharmaceutical composition comprising as an active agent a compound of formula I:(I) whereinR is a straight or branched alkyl, optionally substituted by halogen; andA (-) is an anion derived from a phosphorous containing acid, a phosphorous acid ester and a phosphorous acid amide, for use in treating endometriosis or preventing recurrence of endometriosis.

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

22. The pharmaceutical composition of claim 20, wherein the compound is selected from the group consisting of S-methylisothiouronium methylphosphite; S- methylisothiouronium dimethylphosphate; S-ethylisothiouronium metaphosphate; S- ethylisothiouronium ethylphosphite; S-ethylisothiouronium diethylphosphate; S- propylisothiouronium propylphosphite; S-isopropylisothiouronium metaphosphate; S -isopropylisothiouronium isopropylphosphite; S -butylisothiouronium dibutylphosphate; and S-isobutylisothiouronium isobutylphosphite.

23. The pharmaceutical composition of claim 22, wherein the compound is S- ethy lisothiouronium diethylpho sphate .

24. The pharmaceutical composition of claim 20, wherein endometriosis is selected from the group consisting of endometriosis externa, endometrioma, adenomyosis, endometriotic nodules of the uterosacral ligaments, and endometriotic nodules other than of the uterosacral ligaments.

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

26. The pharmaceutical composition of claim 20, wherein the pharmaceutical composition is formulated in a form selected from the group consisting of a tablet, a capsule, a solution, a suspension, an emulsion, a powder, a liquid, gel, syrup, slurry, powder, a vaginal suppository, a vaginal ring, a vaginal pessary, a vaginal tampon, an implant, a medicated intrauterine device, spray, cream, gel, ointment, and a sustained-release formulation.

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

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

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

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

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

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

33. The pharmaceutical composition of any one of claims 20 to 26, wherein administration of the pharmaceutical composition prevents or reduces the proliferation, migration and / or infiltration of endometrial cells into extra uterine sites.

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

35. The pharmaceutical composition of claim 20, wherein the pharmaceutical composition is administered in a therapeutically effective amount to a female for treating or preventing recurrence of endometriosis.

36. The pharmaceutical composition of claim 35, wherein the therapeutically effective amount of the compound ranges from 1 mg to 400 mg per day.

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

38. A method of treating a female suffering from endometriosis while preserving fertility by administering therapeutically effective amount of a pharmaceutical composition comprising as an active agent a compound of formula I:© H2NA"XC - S - R" H2N(I) wherein R is a straight or branched alkyl, optionally substituted by halogen; andA (-) is an anion derived from a phosphorous containing acid, a phosphorous acid ester and a phosphorous acid amide, thereby enhancing probability of conception.

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