RU2203060C2 - Method for prophylaxis of mammary cancer - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: method deals with constant injecting for, at least, one year the compound of formula

Description

 Carcinoma or breast cancer is a major medical problem for women, starting from the third decade of life, and exists throughout physiological aging. It has now been found that in the United States, one out of eight women has the disease throughout their lives (by the age of eighty), while one in twenty-nine women has a risk of dying from breast cancer (Harris et al., Ed. Diseases of the Breast, 1996; pp. 159-168). Breast carcinoma is the third most common cancer and the most common cancer in women. It is the main cause of death in women, as well as the cause of disability, mental trauma and economic damage. Breast carcinoma is the second most common cause of cancer death for women in the United States and the leading cause of cancer-related death for women aged 15 to 54 (Forbes, Seminars in Oncology, vol. 24 (1), Suppl 1, 1997 ; pp. S1-20-S1-35). The indirect effect of this disease also contributes to mortality from breast cancer, including the effects of a progressive disease, such as bone or brain metastases. Complications arising from suppression of bone marrow, radiation fibrosis and neutropen sepsis, collateral effects due to therapeutic effects such as surgery, radiation, chemotherapy or bone marrow transplantation also contribute to the prevalence and mortality of the disease.

 The epidemiology of this disease, although it is the subject of intensive research, is still not well understood. Apparently, there is an important genetic component that gives some women a predisposition to the appearance of this disease in them. It is not yet clear whether this genetic component is causative or permissive for this disease or only determines the course of the disease. Although it has been known for a long time that breast carcinoma tends to occur frequently in some families, such an analysis does not always predict the disease in other family members and is of little importance for predicting its spread in the entire population. It has now been found that only 5% of all breast cancers are the result of a genetic predisposition (Harris et al., Ed. Disease of the Breast, 1996: pp. 159-168).

 An extensive clinical and pharmacological study was conducted to explain the relationship between the hormone estrogen and the cause and course of development of breast carcinoma. Risk factors for this disease relate mainly to the duration of the cumulative effect of estrogen on a woman and include: age during menarche, history of childbirth, age during first full-term pregnancy, and age during menopause. Despite the fact that much is known about the participation of estrogen during the development of this disease and the importance of estrogen dependence for hormone therapy of this disease, there is a discussion about the role of estrogen in the pathogenesis of this disease, i.e., whether estrogen is a causative agent (initiator) or obligatory cofactor (activator) in the process of carcinogenesis.

 Estrogen, which includes 17-β-estradiol, estrone, and other active metabolites, is the main sex-related hormone in the body of a woman, but additionally, it seems to be an important hemostatic hormone for both men and women throughout their adulthood.

 All people have some level of endogenous estrogen. However, in the vast majority of the population, breast carcinoma is not detected, this fact supports the position that estrogen alone is not the initiator of carcinogenesis, as is the case with chemical carcinogen or environmental carcinogen. In addition, in women, when they have menopause followed by a loss in the production of endogenous ovarian estrogen, there is no proportional decrease in the risk of developing the disease. In fact, regardless of the personal history of breast cancer, age is the only, most powerful risk factor for the development of this disease. Breast cancer is rare in women under the age of 20, but this risk quickly increases with age. Compared with the risk of developing breast cancer in 20-year-old women, the risk in a woman aged 40 to 49 years increases by 40 times, in a woman aged 50 to 59 years, the risk increases by 60 times and women over 60 have a risk 90 times higher than that of younger women (Forbes, Seminars in Oncology, vol. 24 (1), Suppl 1, 1997: pp. S1-20-S1-35).

 Hormone replacement therapy (HRT) is often recommended for women in postmenopausal and near-climacteric periods to alleviate menopausal symptoms and reduce the risk of cardiovascular disease, osteoporosis and other serious consequences of prolonged estrogen deficiency. However, due to sufficiently recognized data on the direct effect of the cumulative effects of estrogen during life and the risk of breast cancer, there is controversy regarding the potential for hormonal replacement in increasing the risk of a woman developing breast carcinoma. While short-term HRT (less than 5 years) is associated with minimal risk or with no increased risk, epidemiological studies and meta-analyzes of the use of long-term HRT (between five and seven years) show an increase in the risk of developing breast cancer from 35 to 75% ( Grady et al., Hormone Therapy to Prevent Disease and Prolong Life in Postmenopausal Women., Ann. Intern Med, 117: pp. 1016-1037, 1992).

 Theories and evidence regarding the role of estrogen in the pathogenesis of this disease are complex. Experimental models of breast carcinoma in rats require the introduction of a carcinogen to induce a tumor (oncogenesis), while estrogen behaves as an activator (and not an initiator) of this process. Ovariectomy in these animal models will interfere with this chemically induced oncogenesis process. In humans, however, the timing of a carcinogenic event is unknown. Women who experience early menopause or medical or surgical oophorectomy before age 40 are known to have an approximately 50% reduction in breast cancer risk compared to women who have normal menopause at age 50 (Harris, et al., Ed. Diseases of the Breast, 1996; pp. 159-168). It is logical, therefore, that approaches to the prevention of breast cancer should be aimed at reducing the effects of estrogen throughout life. This can be achieved by pharmacologically induced estrogen deprivation through the administration of an agent that will block the production and / or action of estrogen everywhere in the hypothalamus-pituitary gland system. However, it is problematic to extrapolate the likely success of de novo breast carcinoma prophylaxis with agents of this nature.

 In contrast to the complex role of estrogen in the pathogenesis of this disease and despite the constantly evolving mass of data on this, significant success has been achieved in understanding the effects of estrogen in conditions of established breast carcinoma. Estrogen is a growth factor for most breast carcinoma cells in the early stages of the disease. Rapidly dividing cells are sensitive to its action through the estrogen receptor. It was also found, although it is not entirely clear, that at some point in the process of this disease, degenerate (cancerous) cells often lose their sensitivity to the promoting effect of estrogen. In the end, the majority of carcinoma cells become estrogen-independent in relation to growth and lose their susceptibility to hormone-based therapy, which broadly includes: GNRH antagonists, "antiestrogens", progestins and androgens.

 Great successes in the treatment of breast cancer have been achieved with the advent and widespread use of therapeutic effects on a hormonal basis. The most extensively used in endocrine therapy is tamoxifen. With this therapy, the five-year survival rate for women with breast carcinoma was significantly increased, however, no additional benefit or advantage is achieved by continuous therapy for more than five years. In fact, the data show a decrease in disease-free survival as well as overall survival when using tamoxifen for more than five years (NSABP B-14 Trial; Fisher et al. Five Versus More Than Five Years of Tamoxifen Therapy for Breast Cancer Patients With Negative Lymph Nodes and Estrogen Receptor-Positiv Tumors. Natl Cane Jnst, vol. 88 (21); pp. 1529-1542, 1996). Unfortunately, tamoxifen is also associated with significant side effects, such as a significantly increased frequency of venous thromboembolism, a significantly increased frequency of vasoconstrictive symptoms and paroxysmal sensation of heat (in the range of 16-67%), cataract formation and the formation of a DNA adduct, which, despite which is not clinically confirmed, nevertheless causes considerable concern regarding its potential for hepatocellular carcinoma (observed experimentally in animal models). However, the most serious fact is the estrogenic effect of tamoxifen in the uterus, which causes intrauterine hyperplasia and a significant increase in the number of cases of intrauterine carcinomas (the risk is three to four times after five years of tamoxifen administration) (Goldhirsch et. Al. Endocrine Therapies of Breast Cancer, Sem in Onc, vol. 23 (4), pp. 494-505, 1966). For this reason, and due to the lack of increased survival with long-term use of tamoxifen, therapy with tamoxifen for more than five years is now contraindicated.

 Evidence suggests that with long-term exposure to tamoxifen, breast tumor cells experience changes that cause them to develop resistance to its antiestrogenic effect, and vice versa, susceptibility to its estrogenic properties (Santen, Editorial: Long Term Tamoxifen Therapy: Can an Antagonist become an Agonist ?, J Clin Endo and Metab, vol. 81 (6), pp. 2027-2029, 1996). Changes at any stage in the estrogen receptor signaling pathway may be responsible for the mechanism of development of resistance to tamoxifen therapy, some of them do not cause cross-resistance to other hormone therapies, and some of them do lead to complete tolerance to endocrine therapy of any kind. One tamoxifen resistance mechanism is attributed to the gradual evolution of carcinoma cells from estrogen-dependent to estrogen-independent (cells having an estrogen receptor become cells that do not have an estrogen receptor). Thus, even in the case of the most successful combinations of treatment methods available (surgery, radiation and / or chemotherapy), the long-term prognosis for patients is poor, especially when there is a metastatic tumor. Clearly, there is a great need for improved treatments and, perhaps most importantly, a critical need for disease prevention at the outset (de novo, or primary prevention).

 Despite the fact that tamoxifen was extensively studied and proved effective in the conditions of an established disease, there were no completed, large-scale, placebo-controlled clinical trials designed for the potential use of this compound for primary prevention of breast cancer. Indeed, there are studies showing that women with a history of a carcinoma in one breast and treated with tamoxifen have a reduced number of cases of tumors in the contralateral mammary gland. Although this could be interpreted as a type of prophylaxis for this disease, it is not clear whether this is an antimetastatic effect or primary (de novo) inhibition of a given disease. Understanding this difference in the biological mechanism is very important for trying to prevent the disease in healthy women without a specific medical history with breast carcinoma or a risk factor for breast carcinoma.

 Over the past decade, it has been proven that “anti-estrogen” therapy, especially with tamoxifen, should be investigated to determine its potential for the prevention of de novo breast carcinoma. However, in part due to the lack of evidence of the usefulness of such a study and the known and potential toxicity of tamoxifen, no studies on the expected prevention in healthy women have been conducted. Two such prevention studies have recently been proposed, and each study has been the subject of considerable discussion. As a result of this discussion, it was concluded that the study, which was to be conducted in the UK, had an unfavorable relationship between risk and benefit, and it was not undertaken. Similarly, in Italy, due to safety concerns related to the case of intrauterine cancer, prevention studies using tamoxifen were prescribed only for women who underwent a hysterectomy. However, in the United States, such a study was undertaken with the assistance of the National Cancer Institute. Based on an understanding of the controversial analysis of such studies and the need for, otherwise, a huge number of samples, the study in the United States was limited only to women who had a high risk of developing this disease, and women were included in the study both in the pre- and postmenopausal periods ( young women, in order to be selected for the study, had to have a risk assessment equivalent to the risk assessment of a 60-year-old woman). The results of this study will not be available for at least three years. (For further information on the discussion of the potential use of tamoxifen as a chemotherapeutic agent for breast carcinoma, clinical plans and high-risk potential, see: ("Breast Cancer Prevention Study: Are Healthy Women Put at Risk by Federally Funded Research?" Transcript of the Hearing Before the Human Resources and Jntergovermental Relations Subcommittee of the Committee on Governmental Operations, House of Representatives of the One Hundred Second Congress, Second Session, October 22, 1992 [ISDN 0-16.044316-4] and the references cited in this publication and evidence.) Since the goal of disease prevention is to protect wives Other than a carcinogenic event (or a case of precancerous pathological changes) and subsequent activation or development of an invasive disease (cancer), prolonged use of a prophylactic therapeutic agent (Kelloff et al. Approaches to the Development and Marketing Approval of Drugs that Prevent Cancer, Cancer Epidemiology, Biomarkers and Prevention, vol 4, pp. 1-10, 1995). Therefore, it is necessary that therapy be extremely tolerant, with indicators of exceptional safety and minimal negative effects. Raloxifene has been studied in more than 12,000 subjects. Extensive integrated data from clinical trials of phase III with raloxifene for the prevention or treatment of osteoporosis in women in the postmenopausal period were analyzed for safety. When all doses of raloxifene were integrated, this analysis included more than 12,850 person-years of exposure to raloxifene. It has been proven that raloxifene is highly tolerant, has a broad therapeutic index and has minimal evidence of acute or chronic toxicity, these indicators are based on almost 3 years of clinical experience. In comparison, the side effect associated with the long-term use of tamoxifen is worrying about its suitability for use as a chemotherapeutic agent (Grainger et al. Tamoxifen: Teaching an Old Drug New Tricks, Nat Med. Vol. 2 (4), pp. 381-385, 1996).

 To date, there is no proven, effective prophylactic therapy for de nova breast carcinoma. In addition, there are no studies to improve or study the prevention of breast carcinoma in women who do not have a certain increased risk of developing breast cancer. Obviously, there is a great need for prophylactic therapy for breast cancer suitable for the entire population, including individuals at high risk, as well as individuals without a specific increased risk, including both men and women.

 The present invention provides methods for the prevention of breast cancer, including de novo breast cancer.

или его фармацевтически приемлемой соли или сольвата
Кроме того, изобретение относится к изделиям, которые содержат упаковочный материал и фармацевтическое средство, содержащееся в этом упаковочном материале, где упаковочный материал включает этикетку, которая указывает, что это фармацевтическое средство можно вводить для профилактики рака молочной железы, где фармацевтическим средством является соединение формулы 1 или его фармацевтически приемлемая соль или сольват.This invention relates to a method for the prevention of breast cancer in humans, which consists in administering to this person an effective dose of a compound of the formula for a sufficient period of time

or a pharmaceutically acceptable salt or solvate thereof
The invention further relates to articles that contain packaging material and a pharmaceutical agent contained in this packaging material, where the packaging material includes a label that indicates that this pharmaceutical agent can be administered for the prevention of breast cancer, where the pharmaceutical agent is a compound of formula 1 or a pharmaceutically acceptable salt or solvate thereof.

 The drawing shows the number of cases in percentage of breast cancer in patients who were treated with placebo and patients who were treated with raloxifene hydrochloride in placebo-controlled studies.

 The present invention relates to the discovery that the compounds of formula 1 are suitable for the prevention of breast cancer. The methods proposed by this invention are used to administer to a person in need thereof, for a sufficient period of time, a dose of raloxifene or its pharmaceutically acceptable salt or solvate, which is effective for the prevention of breast cancer.

 The term "prophylaxis" when used in combination with breast cancer, includes reducing the likelihood of a person developing or developing breast cancer. The term does not include treating a patient with a diagnosed breast cancer.

 The term "de novo", as used in the present invention, means the absence of first degeneration or metamorphosis of normal breast cells into cancerous or malignant cells. Such degeneration can proceed through stages in the same or daughter cells through an evolutionary process, or it can take place in the form of one main event. This de novo process is a process different from the process of metastasis, division and colony formation by tumor cells introduced into another organ, or the spread of already degenerated or malignant cells from the primary localization of the tumor to new localizations. The term "de novo" is associated with primary prevention. The invention also relates to the administration of a compound of formula 1 to a patient who has an increased risk of developing breast cancer, de novo or otherwise.

 A person who does not have a particular risk of developing breast cancer is a person who may develop de novo breast cancer, who has no evidence or suspicion that the risk potential of the disease is above normal, and who has never been diagnosed with this disease. The greatest risk factor contributing to the development of breast carcinoma is the medical history of a person with breast cancer, even when there is no evidence of residual disease, when 5 years or more after treatment of a human disease, and this person is considered “survivor of breast cancer” glands. " Another recognized risk factor is a family history of cancer.

 It was shown that raloxifene, which is the hydrochloride salt of the compound of formula 1, binds to the estrogen receptor, and it was initially believed that it is a molecule whose function and pharmacology was the function and pharmacology of the “antiestrogen”. In fact, raloxifene does indeed block the effects of estrogen in some tissues; however, in others, raloxifene activates the same genes as estrogen, exhibits similar pharmacology, and behaves as an estrogen agonist, for example, in the skeleton and on serum lipids.

 It is now believed that the unusual profile that raloxifene exhibits and which differs from the profile of estrogen and other "anti-estrogens" is the result of the unusual activation and / or suppression of various gene functions by the raloxifene-estrogen receptor complex as opposed to the activation and / or suppression of genes by the estrogen-receptor complex estrogen. Therefore, despite the fact that raloxifene and estrogen use the same receptor and compete for it, the pharmacological result of the gene regulation of these two agents is not easy to predict, and it is unique for each of them.

 Typically, this compound is formulated with conventional excipients, diluents or carriers, and compressed into tablets or formulated as elixirs or solutions for convenient oral administration or administered intramuscularly or intravenously. Compounds can be administered percutaneously or intravaginally, they can be made in the form of dosage forms with action, parenteral forms, depot forms and the like.

 The compounds used in the methods of the present invention can be obtained in accordance with accepted methods, described in detail in US patents 4133814, 4418068, 4380635, 5629425, application for UK patent 2293602, published March 3, 1966, and European patent application 95301291, filed February 28 1995, published on September 6, 1995. Typically, synthesis begins with benzo [b] thiophene having a 6-hydroxyl group and a 2- (4-hydroxyphenyl) group. The hydroxyl groups of the starting compound are protected, the free position is acylated, and the product is freed from the protective groups to form compounds of formula 1. Examples of the preparation of such compounds are presented in US patents and the British patent application discussed above.

 The compounds used in the methods of this invention form pharmaceutically acceptable acid and base addition salts with a large number of organic and inorganic acids and bases and include physiologically acceptable salts, which are often used in pharmaceutical chemistry. Such salts are also part of this invention. Inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric and the like. Salts derived from organic acids such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkanediolic acids, aromatic acids, aliphatic and aromatic sulfonic acids can also be used. Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, isobutyrate , butyn-1,4-dioate, hexin-1,4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroxy maleate, malonate, mandelate, mesylate , nicotinate, isonicotinate, nitrate, oxalate, phthalate, secondary acid phosphate, primary acid phosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, superate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzene sulfonate, p-bromobenzene sulfonate, sulfonated, sulfonated, , methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylene sulfonate, tartrate and the like. A preferred salt is the hydrochloride salt.

 Pharmaceutically acceptable acid addition salts are usually prepared by reacting a compound of formula 1 with an equimolar or excess acid. The reagents are usually mixed in a common solvent, such as diethyl ether or benzene. Salt is usually precipitated from the solution over a period of about one hour to 10 days, it can be isolated by filtration, or the solvent can be distilled off in the usual way.

 The bases commonly used for salt formation include ammonium hydroxide and hydroxides, alkali and alkaline earth metal carbonates, as well as aliphatic and primary, secondary and tertiary amines, aliphatic diamines. Bases particularly suitable for the preparation of addition salts include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, methylamine, diethylamine, ethylenediamine and cyclohexylamine.

 Pharmaceutically acceptable salts typically have enhanced solubility characteristics compared to the compound from which they are prepared, and thus are often more suitable for preparing a formulation in the form of liquids or emulsions.

 Pharmaceutical formulations can be prepared by methods known in the art. For example, the compounds can be formulated with conventional excipients, diluents or carriers and form tablets, capsules, suspensions, powders and the like. Examples of fillers, diluents and carriers suitable for such formulations include the following: fillers and diluents such as starch, sugars, mannitol and silicon derivatives; binders such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone; moisturizing agents such as glycerin; disintegrating agents such as calcium carbonate and sodium bicarbonate; dissolution inhibitors such as paraffin; absorption accelerators such as quaternary ammonium compounds; surfactants such as cetyl alcohol, glycerol monostearate; adsorbent carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate and solid polyethylene glycols.

 The compounds can also be formulated as elixirs or solutions for routine oral administration, or as solutions suitable for parenteral administration, for example, by intramuscular, subcutaneous or intravenous routes. In addition, these compounds are suitable for the preparation of formulations in the form of delayed-release dosage forms. Formulations can be formulated so that they release the active ingredient only or preferably in a certain part of the intestinal tract, possibly over a period of time. Coatings, shells and protective matrices can be made, for example, from polymeric substances or waxes.

 The specific effective and sufficient duration of administration and dose of the compound of formula 1 required for the prevention of breast cancer in accordance with this invention will depend on the physical characteristics of the patient, route of administration and related factors that can be evaluated by the attending physician. The preferred duration of administration is at least six months, more preferably at least one year, and most preferably at least two years, or the compound is administered continuously. Usually acceptable and effective daily doses will be from about 0.1 to about 1000 mg / day, preferably from about 30 to about 200 mg / day, and more preferably from about 50 to about 150 mg / day. The most preferred dose range is from about 60 to about 120 mg / day, with a particularly preferred dose of 60 mg / day.

 The dosage ranges described are not intended to limit the invention. Rather, these dose ranges clarify the invention, and the invention includes those ranges that are functionally equivalent by providing the detected chemo-prophylactic characteristics of the compound. Therefore, although some methods of administration may allow the use of a literally different dose range of the compounds of formula 1 for effective use in this invention, such a different dose range, if functionally equivalent to the specified range, is also included in the scope of this invention.

 In addition, the described dose ranges are based on the hydrochloride salt of a compound of formula 1. Therefore, a dose of 60 mg is equivalent to 55.71 mg of the free base. One skilled in the art will be able to calculate the free base equivalent of any salt of a compound of formula 1 that is pharmaceutically acceptable. For example, a dose of “about 60 mg” will contain from 55 to 65 mg of raloxifene hydrochloride with a content of 51.73 to 60.35 mg of the free base.

 It is also preferred that the compound be administered orally. The following oral dosage forms are suitable for such purposes.

Finished formulations
Finished formulation 1: gelatin capsules
Hard gelatine capsules are prepared using the following ingredients:
Ingredient - Amount (mg / capsule)
Raloxifene Hcl - 30-200
Starch, NF - 0-650
Loose starch powder - 0-650
Silicone fluid, 350 cSt - 0-15
The ingredients are mixed, passed through a 45 mesh US sieve and filled into hard gelatin capsules.

Examples of capsule formulations include the forms shown below:
Finished formulation 2: raloxifene capsule
Ingredient - Amount (mg / capsule)
Raloxifene Hcl - 30-200
Starch, NF - 112
Loose starch powder - 225.3
Silicone fluid, 350 cSt - 1.7
Finished formulation 3: raloxifene capsule
Ingredient - Amount (mg / capsule)
Raloxifene Hcl - 30-200
Starch, NF - 108
Loose starch powder - 225.3
Silicone fluid, 350 cSt - 1.7
Formulation 4: raloxifene capsule
Ingredient - Amount (mg / capsule)
Raloxifene Hcl - 30-200
Starch, NF - 103
Loose starch powder - 225.3
Silicone fluid, 350 cSt - 1.7
Formulation 5: raloxifene capsule
Ingredient - Amount (mg / capsule)
Raloxifene Hcl - 30-200
Starch, NF - 150
Loose Starch Powder - 397
Silicone fluid, 350 cSt - 3.0
The above specific formulations can be modified in accordance with the acceptable options provided.

A tablet formulation is prepared using the following ingredients:
Finished formulation 6: tablets
Ingredient - Amount (mg / tablet)
Raloxifene Hcl - 30-200
Cellulose, microcrystalline - 0-650
Colloidal Silica - 0-650
Stearic acid - 0-15
The components are mixed and compressed to form tablets.

In accordance with another option, tablets, each of which contains 0.1-1000 mg of active ingredient, is prepared as follows:
Finished formulation 7: tablets
Ingredient - Amount (mg / tablet)
Raloxifene Hcl - 30-200
Starch - 45
Cellulose, microcrystalline - 35
Polyvinylpyrrolidone (as a 10% solution in water) - 4
Sodium carboxymethyl cellulose - 4.5
Magnesium Stearate - 0.5
Talc - 1
The active ingredient, starch and cellulose are passed through a 45 mesh US sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resulting powder, which is then passed through a 14 mesh USA sieve. The granules thus obtained are dried at 50-60 ^{° C.} and passed through an 18 US mesh sieve. Sodium carboxymethyl cellulose, magnesium stearate and talc, previously passed through a 60 mesh US sieve, are then added to the granules, which are compressed to form tablets after mixing to form tablets.

Suspensions, each of which contains 0.1-1000 mg of the drug per 5 ml dose, are prepared as follows:
Finished formulation 8: suspensions
Ingredient - Amount (mg / 5 ml)
Raloxifene Hcl - 30-200
Sodium Carboxymethyl Cellulose - 50 mg
Syrup - 1.25 mg
A solution of benzoic acid - 0.10 ml
Fragrance - How much is required
Dye - How much is required
Purified water up to - 5 ml
The drug is passed through a 45 mesh US sieve and mixed with sodium carboxymethyl cellulose and syrup to form a uniform paste. The benzoic acid solution, flavor and color are diluted with some water and added with stirring. A sufficient amount of water is then added to obtain the desired volume of suspension.

 Preferred tablet formulations include two forms (see Table A).

TEST METHOD
As evidence of the usefulness of this invention, the results of temporary safety obtained in clinical trials of phase III using raloxifene are presented below.

 Most cases of breast carcinoma have taken place in a large, long-term study on the treatment of osteoporosis in 7704 postmenopausal women with established osteoporosis. However, additional cases were noted in smaller studies of postmenopausal women with a risk of osteoporosis. The studies indicated here used the double blind method with placebo as a control; most studies lasted approximately three years and were designed to determine the effectiveness of raloxifene for the prevention or treatment of osteoporosis in women in the postmenopausal period. In addition, studies provide health information regarding the cardiovascular system and other underlying medical conditions (including the incidence of breast carcinoma). Patients were randomly assigned to different groups to receive either placebo or 30, 60, 120 or 150 mg of the drug per day orally. To prescribe the investigational medicinal product, all patients and researchers were distributed blindly (double-blind). All patients in all groups received approximately 500 mg / day of calcium supplements. In addition, patients in a large study treating 7704 patients received supplements with vitamin D, 400-600 IU / day.

 The subjects selected for these studies were women in the postmenopausal period (at least 2 years from the last menstrual cycle) at the age of approximately forty-five to eighty years.

Typical criteria for exclusion from participation in these studies included: 1) the presence of a serious systemic disease;
2) acute or chronic liver disease, 3) significantly impaired renal function, 4) subjects who, according to the researcher, had poor medical or mental risk factors for inclusion in the clinical trial, for example, abuse of drugs or alcohol, etc., 5) subjects with any cancer within 5 years prior to being included in the research lists, except for shallow lesions, such as basal cell carcinoma of the skin; 6) the presence of abnormal uterine bleeding. The most important exclusion criterion was the exclusion of women with breast cancer or other estrogen-dependent neoplasia at this time or in the past. These exclusion criteria created a population of subjects that reflected the general population regarding the risk of developing breast carcinoma, or in other words, these subjects did not have a specific increased risk of developing breast cancer.

 Potential subjects were selected prior to registration to participate in the study. Subjects were required to present their medical history and report on their current medical condition. All potential patients were required to either have a background mammogram or an ultrasound evaluation of the mammary gland, or undergo one of these tests during the 12-month period preceding the listing for the study. Most studies required a mammogram after two years, however, annual mammograms were recommended. All subjects with diagnosed and reported cases of breast carcinoma should immediately cease participation in the study and were referred by the local investigator for appropriate oncological examination and observation.

 In all placebo-controlled studies lasting at least 6 months and among all subjects receiving treatment with the study drug for more than 1 month, a total of 42 cases of breast cancer were identified: 24 cases were observed in the placebo group compared to 18 cases in the treatment groups raloxifene. The overall ratio of treatment prescriptions for randomized patients (raloxifene group to placebo group) was approximately 2: 1.

 The results shown in Tables 1-4 relate to subjects with histopathological diagnoses of breast carcinoma. These data include the results of patients with optional mammograms over the next one year, as well as the required background mammogram and the required mammogram over the next two years. After a breast cancer diagnosis was made, these subjects stopped participating in the study and their status was disclosed to show the therapy (shoulder) to which they were assigned (i.e. what study drug they were receiving).

 For the studies of this invention, the number of patients randomly assigned to the placebo group was approximately 3195. The number of patients randomly assigned to the raloxifene groups (combined with all doses) was approximately 6681. In a large treatment study 7704 patients to patients who remained included in the study did not disclose the therapy code. Therefore, the number of patients assigned to each treatment group is approximate.

 The results shown below are presented for patients who were diagnosed as having breast carcinoma at any time during the study, but at least one month after they were randomly assigned to a drug therapy study (placebo or raloxifene). In the table. 1 presents the results of all placebo-controlled studies with data for all combined doses of raloxifene. In the table. 2 presents a subgroup of cases presented in table. 1, specifically patients enrolled in a large study treating 7,704 patients, in which the majority of cases of breast cancer occurred. The two doses of raloxifene in this study were 60 mg / day and 120 mg / day. As the number of cases of breast cancer increased with age, it was assumed that the study would have a higher number of cases of breast cancer [mean age of patients 67 years at the start of the study]. The tables show the number of cases of breast cancer (n) for each treatment group, the total number of patients prescribed for such treatment (N), an estimate of the relative risk of developing breast cancer, and a 95% confidence interval for the relative risk of developing breast cancer. It should be noted that if the upper limit of the 95% confidence interval is less than 1.0, then there is statistically significant evidence (at 5%) that the number of cases of breast cancer treated with raloxifene is less than the number of cases of breast cancer in the placebo group .

 In these placebo-controlled studies, the data clearly indicate that patients randomly assigned to the raloxifene group have a reduced incidence of breast cancer compared to patients randomly assigned to the placebo group. An assessment of the gross relative risk for all patients diagnosed at least one month after the random administration of the study drug gives a value of 0.36 with a 95% confidence interval (0.20, 0.64), showing a 64% decrease in the number of cases of cancer the mammary gland. When considering only a large treatment study, a gross relative risk assessment yields a value of 0.29 with a 95% confidence interval (0.15, 0.55), showing a 71% decrease in the incidence of breast cancer. These results are very statistically significant.

 Due to the fact that cancers diagnosed at least 1 year after randomization are most likely to represent cancers that have not previously been clinically available, we also analyzed these data, considering only cases that occurred at least 12 months after randomization for treatment with the studied drug. For all placebo-controlled studies, the coarse relative risk score is 0.23 with a 95% confidence interval (0.11, 0.45), corresponding to a 77% reduction in breast cancer. For a large treatment study, an assessment of the gross relative risk gives a value of 0.14 with a 95% confidence interval (0.06, 0.32), corresponding to an 86% reduction in the incidence of breast carcinoma.

 For further analysis of the appearance of tumors, depending on the length of time in the study in the table. Figures 3 and 4 present relative risk data, which are divided into three time periods: 1) cases diagnosed by background mammograms, i.e. all cases diagnosed between 1 and 6 months after the appointment for the study of a medicinal product; 2) cases diagnosed by mammograms after 1 year, i.e. all cases diagnosed between 6 and 18 months after the appointment for the study of the medicinal product, and 3) cases diagnosed by mammograms after two years, i.e. all cases diagnosed between 18 and 30 months after the appointment for the study of the medicinal product.

 In the table. Figure 3 shows the relative risk of breast cancer for each time period for all combined placebo-controlled studies. In the table. 4 presents information for a subgroup of patients listed in table. 3, namely, patients in a large treatment study of 7704 patients. From both tables it is obvious that the relative risk of developing breast carcinoma decreases with each subsequent period of time. The relative risk for both populations reaches statistical significance at the time point after the next two years.

 As a final conclusion, the figure graphically shows the number of cases of breast cancer in all placebo-controlled studies. (One patient who had breast cancer diagnosed after 30 months is excluded from this schedule, so the schedule represents approximately the same subsequent period in both treatment groups). The two curves (for placebo and raloxifene) are almost indistinguishable until the time point 1 year after which they diverge, and the number of cases of breast cancer in the placebo group rises at a faster rate than in the raloxifene group.

Claims (5)

1. A method of reducing the likelihood of breast cancer in a person in need thereof, characterized in that it includes the continuous introduction to the specified person for a sufficient period of time of at least one year, the compounds of formula (1)

or a pharmaceutically acceptable salt or solvate thereof, in a dose of 60 to 120 mg / day.  2. The method according to claim 1, characterized in that the dose is 60 mg / day.  3. The method according to claim 1, characterized in that said period of time is at least two years.  4. The method according to claim 1, characterized in that the compound is its hydrochloride salt.  5. The method according to p. 1, characterized in that the man is a woman in the postmenopausal period.

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