LT4634B - Articles of manufacture for preventing breast cancer - Google Patents

Description

Field of the Invention

The present invention provides an article comprising a packaging material and a pharmaceutical agent contained within the packaging material for the prophylaxis of breast cancer.

Preconditions of the invention

Breast carcinoma or cancer is a major health problem for women between the age of thirty and old. It is now estimated that in the United States, the likelihood that women will have the disease (under 80) is one in eight, while the likelihood of death from breast cancer in women is one in twenty (Harris et al., Eds. Diseases of the Breast , 1996: pp. 159-168). Breast cancer is the third most common type of cancer and the most common cancer among women. It is the leading cause of female mortality, as well as incapacity, psychological trauma and economic loss. Breast cancer is the second leading cause of cancer death in women in the US, and is the leading cause of cancer-related death among women aged 15 to 54 (Forbes, Seminars in Oncology, Vol. 24 (1), Suppl 1, 1997: p. S1-20-S1-35 Indirect effects of the disease, including advanced disease outcomes such as bone or brain metastases, also contribute to mortality in breast cancer Complications due to bone marrow depression, radiation fibrosis and neutropenic sepsis, therapeutic interventions surgical intervention, radiation, chemotherapy or bone marrow transplantation, side effects also contribute to the morbidity and mortality of this disease.

Although the disease is under intensive research, its epidemiology is still not understood. It is believed that there is an essential genetic component that predisposes some women to the disease. But it is still unclear whether this genetic component is causal, non-essential or merely predictive of the disease. Although it has long been known in some families that breast cancer tends to occur more frequently, such analysis does not always correctly predict the onset of the disease in other family members, and is of little value in predicting the prevalence of the disease in the general population. Currently, only 5% of all breast cancers are estimated to be due to genetic predisposition (Harris et al., Ed. Disease of the Breast, 1966: p.159-168).

Extensive clinical and pharmacological studies have been conducted to determine the relationship between the causes and course of estrogen and breast cancer. The risk factors for developing the disease are, in principle, related to the increasing duration of estrogen in a woman and include: age at first menstruation, presence of pregnancy, age at first full pregnancy and menopause. Although much is known about the dependence of estrogen on the course of the disease and the role of estrogen in endocrine therapy, there are significant contradictions regarding the role of estrogen in the pathogenesis of this disease, i.e., whether estrogen is a causative agent or a necessary cofactor.

Estrogen, which includes 17-β-estradiol, estrone and their active metabolites, is a major female sex hormone, but is also an important homeostatic hormone for both men and women throughout the life of a mature organism. All people have a certain amount of endogenous estrogen. However, the vast majority of people do not have breast cancer, which suggests that estrogen per se is not a initiator of carcinogenesis as it is with chemical or environmental carcinogens. In addition, postmenopausal women and consequent decreased ovarian estrogen production do not show a corresponding reduction in risk of developing this disease. In fact, age is the only higher risk factor for developing this disease. Breast cancer is rare in women under the age of 20, but the risk increases dramatically with age. Compared to women aged 20, the risk of developing the disease is 40 times higher for women between 40 and 49 years, 60 times for women between 50 and 59 years, and 90 times for women over 60 (Forbes, Seminars in Oncology, vol. 24 (1), Suppl 1, 1997: pp.S1-20-S135).

Hormone replacement therapy (HRT) is often recommended for post- and perimenopausal women to relieve menopausal symptoms and reduce the risk of cardiovascular disease, osteoporosis and other long-term effects of estrogen deficiency. However, due to the generally accepted data on the direct influence of increasing estrogen levels on the occurrence of breast cancer, there is intense debate about the potential of hormone replacement therapy to increase the risk of breast cancer in women. While short-term HRT (less than 5 years) is associated with minimal or no risk of disease, epidemiological studies and long-term HRT (between 5 and 7 years) show an increase in the risk of 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).

The theory and evidence for the role of estrogen in the pathogenesis of this disease are complex. Experimental modeling of mammalian carcinoma in rats requires the use of carcinogen for tumor induction, whereas estrogen acts as a promoter rather than an initiator in this process. In these animal models, ovariectomy interferes with the process of chemically induced carcinogenesis. However, in humans, the time of occurrence of the carcinogenic event is unknown. Women who have undergone premature menopause or have undergone medical or surgical removal of their ovaries before the age of 40 are known to have a 50% lower risk of developing breast cancer compared to women who have undergone normal menopause at 50 (Harris et al., Ed. .Diseases of the Breast, 1996: pp.159-168). Therefore, it is logical that efforts to prevent breast carcinoma should be directed towards reducing the duration of estrogen presence. This may be accomplished by pharmacologically inducing estrogen deprivation by administering to the patient an agent that blocks estrogen production and / or function anywhere on the hypothalamic-pituitary gland axis. However, predicting the potential success of breast cancer prophylaxis in this type of agent is problematic.

Despite the complex role of estrogen in the pathogenesis of this disease and the ever-increasing amount of data, significant progress has been made in understanding the influence of etrogen on breast carcinoma. In the early stages of the disease, estrogen is a growth factor in most breast cancer cells. Rapidly dividing cells are sensitive to its influence on estrogen receptors. It is also established, though not fully understood, that some of this disease course

Iv-transformed (cancerous) cells often lose their sensitivity to the stimulatory effects of estrogen. Eventually, the vast majority of cancer cells cease to be estrogen-dependent as growth factor and lose their reactivity to hormone-based therapies, which generally include GNRH agonists, "anti-estrogens", progestins and androgens.

Much progress has been made in the treatment of breast cancer with the advent and widespread use of hormone-based therapies. The most widely used endocrine treatment is tamoxifen. This treatment significantly improved survival time in five-year-old women, but did not provide any additional benefit or prolongation of survival beyond 5 years. In fact, with tamoxifen used for more than five years, the data show a reduction in both overall survival and disease-independent survival (NSABP Study B-14: Fisher et al., Five Versus More Than Five Years of Tamoxifen Cancer Patients With Negative Lymph Nodes and Estrogen ReceptorPositive Tumore, J. Nat / FCanc Inst, Vol 88 (21): pp. 1529-1542, 1996). Unfortunately, tamoxifen is also associated with significant adverse effects, such as a significantly increased incidence of venous thromboembolism, vasomotor symptoms or hot flashes (16-67%), cataract formation, and DNA adduct formation, which, although not clinically confirmed, is suspected as potential. hepatocellular carcinoma agent (experimentally observed in animal models). However, the most potent effect is the uterine estrogenic effect of tamoxifen, which results in endometrial hyperplasia and an increased incidence of endometrial carcinoma (a 3-4 fold increase in the risk of tamoxifen administration after 5 years) (Goldhirsh et al., Endocrine Therapies of Breast Cancer, Sem. , vol.23 (4), pp. 494-505, 1996). For these reasons and because long-term use of tamoxifen does not prolong survival, tamoxifen treatment for more than 5 years is now considered contraindicated.

The data suggest that long-term administration of tamoxifen undergoes changes in breast tumor cells that result in the development of resistance to anti-estrogenic action (Santen, Editorial: Can an Antagonist Become an Agonist? J. Din. Endo. & Metab., Vol. . 81 (6), pp. 2027-2029, 1996). Alterations at any of the estrogen receptor signaling sites may be responsible for the mechanism of tamoxifen resistance development, with some moments not inducing cross-resistance to other hormones and some giving complete insensitivity to any endocrine therapy. According to one mechanism of tamoxifen resistance, cancer cells from estrogen-dependent cells gradually become estrogen-independent (estrogen-positive cells become estrogen-negative). Thus, even with the most advanced combinations of currently available therapies (surgery, irradiation and / or chemotherapy), the long-term prognosis of the patient is poor, especially when metastases are present. It is clear that there is a huge need for better therapy and, perhaps most importantly, the need to prevent the disease at an early stage (de noi / oarba primary prevention).

Although tamoxifen has been extensively studied and has proven efficacious in the treatment of established disease, full-scale, placebo-controlled, clinical trials have not been conducted to investigate the potential use of this compound for the prevention of breast cancer. Studies have shown that women who have had breast cancer in one breast and have been treated with tamoxifen have a lower incidence of cancer in the other breast. Although this fact may be interpreted as a kind of prophylaxis, it is unclear whether it is an antimetastatic effect or a de novo inhibition of the disease. Understanding such differences in the biological mechanism is crucial in preventing de novo disease initiation in healthy women who did not have a specific fact or risk factor for breast cancer.

Over the past decade, consideration has been given to whether “anti-estrogenic” therapy, especially tamoxifen, should be investigated for de novo breast cancer prevention. However, partly due to the lack of evidence of utility, and due to the known and potential toxicity of tamoxifen, no prophylactic studies have been conducted in healthy women. Two such prophylactic studies have recently been proposed and both have been contradictory. As a result, a study that should have been conducted in the United Kingdom was found to have a useless risk-benefit balance and was abandoned. Similarly, in Italy, for safety reasons, only women undergoing hysterectomy were allowed to undergo tamoxifen prophylaxis with regard to the occurrence of endometrial cancer. However, in the United States, such tests were conducted under the auspices of the National Cancer Institute. Recognizing the contradiction in the analysis of such studies and the need for a large number of samples, the US study was limited to high-risk women and included both pre- and post-menopausal women (for research integrity, young women should have a the degree of risk in the metropolitan area). The results of this study will not be available for at least another three years. (For more information on the potential use of tamoxifen as a chemoprophylactic agent against breast cancer, clinical trials and risk assessment, see Breast Cancer Prevention Study: Are Healthy Women Put at Risk by Federally Funded Research?) Intergovernmental Operations, House of Representatives of the One Hundred Second Congress, Second Session, October 22, 1992 [ISBN 0-16-044316-4] and references therein and quotes).

Because the purpose of disease prevention is to protect a woman from the carcinogenic fact (or from the formation of anticancer derivatives) and subsequent development into an invasive disease (cancer), long use of a prophylactic therapeutic agent (Kelloff et al., Approaches to the Development and Marketing Approval of Drugs that Prevent Cancer, Cancer Epidemio / ogy, Biomarkers & Prevention, vol. 4, pp. 1-10, 1995). This requires therapy to be particularly well tolerated, with extreme safety and minimal side effects. Raloxifene has been studied in over 12,000 subjects. From a safety point of view, extensive pooled data from raloxifene Phase III clinical trials in the treatment or prevention of osteoporosis in postmenopausal women have been analyzed. Combining data on total doses of raloxifene, this analysis included raloxifene use in more than 12,850 patient years. Based on clinical practice for approximately 3 years, raloxifene has been shown to be extremely well tolerated, with a wide range of therapeutic effects and minimal acute or chronic toxicity. The adverse effects associated with the long life of tamoxifen give rise to serious doubts as to its suitability as a chemoprophylaxis agent (Grainger et al. Tamoxifen: Teaching an Old Drug New Tricks, Nat Med., Vol. 2 (4), p. 381,385, 1996). ).

To date, there is no effective preventive treatment of de novo breast cancer. In addition, there have been no studies on the prevention of breast cancer in women who do not have any higher risk factor for developing breast cancer. It is clear that there is a huge need for breast cancer prevention therapy for the benefit of the general population, including those at high risk, as well as individuals without any specific risk factor, including both men and women.

The present invention provides methods of preventing breast cancer, including de novo breast cancer.

Summary of the Invention

The present invention is directed to a method of prophylaxis of human breast cancer comprising administering to a human subject an effective amount of a compound of Formula I for a period of time.

or a pharmaceutically acceptable salt or solvate thereof.

The invention further relates to an article of manufacture comprising a packaging material and a pharmaceutical agent contained within the packaging material, wherein the packaging material has a label indicating that the pharmaceutical agent may be administered for the prophylaxis of breast cancer, wherein the pharmaceutical agent is an acceptable salt or solvate.

Brief description of the drawing

Fig. 1 depicts breast cancer incidence as a percentage of placebo and raloxifene hydrochloride treated patients in placebo-controlled studies.

Detailed Description of the Invention

The present invention relates to the discovery that compounds of formula I are useful in the prophylaxis of breast cancer. The methods of the present invention are embodied in administering to a human subject, when needed, a sufficient dose of raloxifene or a pharmaceutically acceptable salt or solvate thereof which is effective in preventing breast cancer.

The term "prophylaxis", when used in breast cancer, includes a reduction in the likelihood of the human being developing or developing breast cancer. This term does not include the treatment of a patient diagnosed with breast cancer.

The term "de novd" as used in the present invention primarily refers to the absence of normal breast cell alteration or conversion to cancerous or malignant cells. Such changes can occur within the cell itself or in the daughter, during development, or may occur in one major case. This de novo process is distinct from the process of metastasis, colonization, or migration of already transformed or malignant cells from the original site of the cancer to other sites. The term 'de novo' relates to primary prevention. The present invention also relates to administering a compound of Formula I to a patient at increased risk of developing breast cancer, de novo or otherwise.

A person who has no specific risk factor for developing breast cancer is one who may develop de novo breast cancer for whom there is no evidence or suspicion of developing the disease and who has never been diagnosed with the disease. The greatest risk factor for developing breast cancer is the personal history of breast cancer, even when there is no residual disease and more than 5 years after the end of treatment, and the individual is considered to have survived the breast cancer. Another widely recognized risk factor is breast cancer in the family.

Raloxifene, which is the hydrochoride salt of a compound of formula I, has been shown to bind to estrogen receptors and was initially thought to function as "anti-estrogen". In fact, raloxifene blocks estrogen action in some tissues; however, at other sites, such as the skeleton and serum lipids, raloxifene activates the estrogen gene itself, displays / similar pharmacology, and acts as an estrogen agonist. The specific profile by which raloxifene is expressed and differs from estrogen and other "anti-estrogens" is believed to be due to the unique activation and / or inhibition of various gene functions by the raloxifene-estrogen receptor complex as opposed to gene activation and / or inhibition by the estrogen-estrogen receptor complex. Therefore, although raloxifene and estrogen both use and compete for the same receptors, the pharmacological result of gene regulation by them is not easily predictable and unique for each of them.

Typically, the compound is incorporated into a formulation with conventional excipients, diluents or carriers, and compressed into tablets, either to form elixirs or solutions for routine oral administration, or to be administered intramuscularly or intravenously. The compounds may be administered transdermally or intravaginally, and may be formulated in a sustained release dosage form, parenteral form, depot form, and the like.

The compounds used in the methods of the present invention may be prepared according to known procedures such as those described in U.S. Pat. 4133814, 4418068,

No. 4,380,635, 5,629,425, United Kingdom Patent Application GB 2293602, published June 1996; European Patent Application 95301291, filed March 3, 1995 28 February 1995. filed September 6, 1997, PCT Application PCT / US97 / 04259. March 20, 1997, September 26; all of which are incorporated herein by reference. Generally, benzo [b] thiophene having a 6-hydroxyl group and a 2- (4-hydroxyphenyl) group is obtained. The hydroxyl groups of the starting compound are blocked, the third position is acylated, and the product is deprotected to form compounds of formula I. Examples of the preparation of such compounds are given in the aforementioned U.S. Patents and UK Patent Application.

The compounds used in the methods of the present invention form pharmaceutically acceptable salts with a variety of organic and inorganic acids and bases, and include physiologically acceptable salts which are frequently prepared in pharmaceutical chemistry. Such salts are also part of the present invention. Typical inorganic acids used to form salts include hydrochloric, hydrobromic, hydroiodic, nitrate, sulfate, fostate, hydrophosphate and the like. Salts formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanecarboxylic acids, hydroxyalkanoic and hydroxyalkandicarboxylic acids, aromatic acids, aliphatic and aromatic sulfonic acids may also be used. Thus, such pharmaceutically acceptable salts include acetates, phenylacetates, trifluoroacetates, acrylates, ascorbates, benzoates, chlorobenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, methylbenzoates, o -acetoxybenzoates, naphthalene-2-benzoates, bromides, isobutyrates, bromides, isobutyrates 4dioates, hexin-1,4-dioates, caprates, caprylates, chlorides, cinamates, citrates, formates, fumarates, glycolates, heptanoates, hippurates, lactates, malates, maleate, hydroxy maleate, malonate, almond acid salts, mesicates, nicotinates, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberatus, sulfate, bisulfate, red sulfate, sulfonate, bisulfite, bisulfite, bromobenzenesulfonates, chlorobenzenesulfonates, ethanesulfonates, 2-hydroxyethanesulfonates, methanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, p-toluenesulfonates, xylenesulfonates, tartrates and the like. The hydrochloride salt is preferred.

Pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of formula I with an equimolar or excess amount of acid. Reagents are usually mixed in a solvent such as diethyl ether or benzene. The salt usually falls out of solution within 1 hour to 10 days and can be isolated by filtration or by suction removal of the solvent by conventional means.

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

Pharmaceutically acceptable salts generally have a higher solubility as compared to the parent compound from which they are made, and are thus more readily prepared in the form of a liquid or emulsion.

Pharmaceutical compositions may be prepared by methods well known in the art. For example, the compounds may be formulated with conventional excipients, diluents or carriers to form tablets, capsules, suspensions, powders, and the like. Examples of fillers, diluents and carriers suitable for this purpose include: fillers such as starches, sugars, mannitol, and silicate derivatives; binders such as carboxymethylcellulose and other cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone; wetting agents such as calcium carbonate and sodium bicarbonate; dissolution retardants such as paraffin; resorption 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 stearates, and solid polyethyl glycols.

The compounds may also be formulated as elixirs or solutions for conventional oral administration or as solutions suitable for parenteral administration, for example, intramuscularly, subcutaneously, or intravenously. In addition, the compounds are well suited for sustained release formulation and the like. The dosage form may be formulated so as to release the active ingredient only, or by preference, at a particular location in the gastrointestinal tract, possibly over a period of time. Coatings, coatings and protective layers may be made of, for example, polymeric materials or resins.

In the particular case, the effective and sufficient time for administration of the compound of formula I and the dosage required for the prophylaxis of breast cancer will depend upon the patient's physical characteristics, the route of administration, and related factors as assessed by the attending physician. Preferably, the duration of administration is at least six months, more preferably at least one year, preferably at least two years, or continuously. Generally, acceptable and effective doses are from about 0.1 to about 1000 mg / day, preferably from about 30 to about 200 mg / day, more preferably from about 50 to about 150 mg / day. The preferred dosage range is between about 60 and about 120 mg / day, with 60 mg / day being particularly preferred.

The dose ranges described are not to be construed as limiting the invention. In contrast, the ranges illustrate the invention, and the invention encompasses those ranges that are functionally suitable for disclosing the chemoprophylactic properties of the compound. Therefore, some modes of administration may require a directly different dosage range of the compound of Formula I to be used effectively in accordance with the present invention, and the invention also encompasses such different dosage ranges and their functionally equivalent equivalents.

In addition, dose ranges are expressed relative to the hydrochloride salt of the compound of formula I. Therefore, the 60 mg dose is equivalent to 55.71 mg of free base. The average person skilled in the art will be able to calculate the amount of free base that is pharmaceutically acceptable equivalent to any salt of a compound of formula I. For example, "about 60 mg" includes 55 to 65 mg of raloxifene hydrochloride, while it includes 51.73 to 60.35 mg of free base.

It is useful to administer the compound orally. For this purpose, there are oral dosage forms.

Composition Composition: Gelatin Capsule.

Hard gelatin capsule made from:

The Ingredient Amount (mg / capsule) raloxifene · HCl 30-200 starch, NF 0 -650 starch flowing powder 0 -650 silicone oil, 350 centistokes viscosity 0-15

The ingredients are mixed through a 45 mesh sieve and filled into a hard gelatin capsule.

Examples of capsule compositions include the following:

composition: raloxifene capsule.

The Ingredient Amount (mg / capsule) raloxifene · HCl 30-200 starch, NF 112 starch flowing powder 225.3 silicone oil, 350 centistokes viscosity 1.7

Composition 3: Raloxifene capsule.

The Ingredient Amount (mg / capsule) raloxifene · HCl 30-200 starch, NF 108 starch flowing powder 225.3 silicone oil, 350 centistokes viscosity 1.7

composition: raloxifene capsule.

The Ingredient Amount (mg / capsule) raloxifene · HCl 30-200 starch, NF 103 starch flowing powder 225.3 silicone oil, 350 centistokes viscosity 1.7

composition: raloxifene capsule.

The Ingredient Amount (mg / capsule) raloxifene · HCl 30-200 starch, NF 150 starch flowing powder 397 silicone oil, 350 centistokes viscosity 3.0

The specific compositions above may be modified in accordance with the acceptable variations described.

The tablet formulation is prepared using the following ingredients:

Composition 6: Tablets.

The Ingredient Amount (mg / tablet) raloxifene · HCl 30-200 microcrystalline cellulose 0 -650 silica, 0 -650 stearic acid 0-15

The components are mixed and compressed into a tablet.

Alternatively, a tablet containing 0.1-1000 mg of active ingredient is prepared from the following materials:

composition: tablets.

The Ingredient Amount (mg / tablet) raloxifene · HCl 30-200 starch 45 microcrystalline cellulose 35 polyvinylpyrrolidone (10% solution in water) 4 sodium carboxymethylcellulose 4.5 magnesium stearate 0.5 talc 1

Pass the active ingredient, starch and cellulose through a 45 mesh sieve and mix thoroughly. The resulting powder is mixed with a polyvinylpyrrolidone solution and then passed through a 14 mesh sieve. The pellets thus obtained are dried at 50-60 ° C and passed through a sieve of 18 mesh. Sodium carboxymethylcellulose, magnesium stearate and talc are then added, passing through a 60 mesh sieve, and, after mixing, compressed into tablets in a tablet making machine.

Suspensions containing 0.1 to 1000 mg of drug per dose of 5 ml are prepared as follows:

composition: suspensions.

The Ingredient Amount (mg / 5 ml) raloxifene · HCl 30-200 sodium carboxymethylcellulose 50 mg syrup 1.25 mg benzoic acid solution 0.10 ml scents q.v. paint q.v. purified water up to 5 ml

The drug is passed through a 45 mesh sieve and mixed with sodium carboxymethyl cellulose and syrup to form a homogeneous paste. The benzoic acid solution, odors and paints are diluted with a small amount of water and added by mixing. A sufficient quantity of water is then added to obtain the required volume.

Preferred tablet formulations include the following two:

composition:

The Ingredient Amount (mg) Function Raloxifene · HCl 60.0 active lactose, spray-dried 30.0 soluble diluent lactose, anhydrous 12.0 soluble diluent povidone 12.0 binder polysorbate 80 2.4 moisturizing agent crospovidone 14.4 disintegrator magnesium stearate 1.2 lubricant (Tablet core mass 240) Denqianti film white paint mixture 12.0 coloring agent talc traces polishing additive carnauba wax - polishing additive

composition:

The Ingredient Amount (mg) Function Raloxifene · HCl 60.0 active lactose, spray-dried 29.4 soluble diluent lactose, anhydrous 120.0 soluble diluent povidone 12.0 binder polysorbate 80 2.4 moisturizing agent crospovidone 14.4 disintegrator magnesium stearate 1.2 lubricant (Tablet core mass 240) Denqianti film white paint mixture 12.0 coloring agent talc - polishing additive carnauba wax traces polishing additive

Research methodology

As a demonstration of the use of the present invention, the preliminary results of raloxifene Phase III clinical trials are presented below.

The vast majority of breast cancers have been identified in a large group of 7,704 postmenopausal women diagnosed with osteoporosis and still undergoing treatment for osteoporosis. However, cases have also been identified in smaller studies of postmenopausal women with a risk factor for osteoporosis. The studies presented here are double blind and compared with placebo; most of them lasted about three years and were designed to determine the effectiveness of raloxifene in treating or preventing osteoporosis in postmenopausal women. In addition, studies provide information on the condition of the cardiovascular and other major systems (including the occurrence of breast cancer). Patients were randomized to receive either placebo or 30 mg, 60 mg, 120 mg or 150 mg daily. All patients and investigators were unaware of the administration of the drug (double blind technique). Approximately 500 mg / day of calcium supplement was administered to all patient groups. In addition, a large group of 7,704 patients received vitamin D supplementation, 400–600 IU / day.

The subjects selected for these studies are postmenopausal women (at least 2 years from the last menstrual period), ranging in age from about forty-five to eighty years.

Typical elimination criteria from these studies include: (1) presence of serious systemic disease: (2) acute or chronic liver disease; 3) significantly impaired renal function; 4) persons who, in the opinion of the investigators, have poor medical or psychiatric characteristics in the context of clinical trials, such as drug or alcohol addiction, etc .; (5) persons with cancer other than superficial lesions, such as basal skin, for a period of five years from the start of the study; 6) pathological uterine bleeding. The primary exclusion criterion was the presence or absence of breast cancer or other estrogen-dependent tumors. These elimination criteria allow the generation of a population that reflects the general population in terms of risk of developing breast cancer, or in other words, individuals who do not have any particular increased risk of developing breast cancer.

Persons selected for the study in advance. Data was required on their health history and current status. Prospective patients were required to have a baseline mammogram or an ultrasound scan of the breast or to have had these examinations within the last 12 months prior to commencement of the study. Most studies have required mammographic examination once every two years, but are recommended once a year. Any person diagnosed with breast cancer shall be immediately excluded from the examination and given appropriate oncological treatment.

Of all placebo-controlled studies of at least 6 months duration and over 1 month in all subjects treated with the study drug, there were 42 cases of breast cancer: 24 in the placebo group and 18 in the raloxifene group. The overall ratio of patients selected for treatment (raloxifene to placebo) is approximately 2: 1.

Tables 1-4 present the results for individuals with a histopathologic diagnosis of breast cancer. The data include one-year mammogram results, as well as mandatory baseline mammograms and mammograms over two-year studies. After being diagnosed with breast cancer, individuals are excluded from further investigations and their data decoded to reveal which drug they were receiving.

The number of patients randomized to receive placebo in the studies of the present invention is approximately 3195. The number of patients randomized to receive raloxifene is approximately 6681. .)

The results are presented below for patients diagnosed with breast cancer at any point in the study but at least one month after randomized treatment selection (placebo or raloxifene). Table 1 shows the results of all studies comparing placebo with pooled data for all doses of raloxifene. Table 2 presents a portion of the cases in Table 1, specifically patients from a large cohort of 7,704 patients with the highest incidence of breast cancer. Two doses of raloxifene 60 mg / day and 120 mg / day were used in this study. Because breast cancer incidence increases with age, this study is expected to have a higher incidence of breast cancer (mean age at start of study 67 years). The tables present the number of breast cancers in each group, n, the total number of patients in that group, the relative risk of developing breast cancer, and the 95% confidence interval for the relative risk of developing breast cancer. Notably, if the upper 95% confidence limit is below 1.0, we have statistically significant evidence (at the 5% level) that the incidence of breast cancer with raloxifene is lower than with placebo.

table. Analysis of relative risk of developing breast cancer from pooled comparative studies with piacebo

Time from healing Placebo Raloxifene Relative 95% reliable- mo start to cases cases risk mo interval diagnoses w / w (%) w / w (%) (raloxifene with piacebo) for relative risks for at least 1 year. 24/3195 18/6681 0.36 (0.20, 0.64) at least 12 months 21/3195 10/6681 0.23 (0.11, 0.45)

table. Analysis of the relative risk of developing breast cancer in a large group of postmenopausal women with osteoporosis (7704 patients)

Time from healing Placebo Raloxifene Relative 95% reliable- mo start to cases cases risk mo interval diagnoses w / w (%) w / w (%) (raloxifene with placebo) for relative risks at least 1 month 21/2659 12/5317 0.29 (0.15, 0.55) at least 12 months 18/2659 5/5317 0.14 (0.06, 0.32)

The data from these placebo-controlled studies clearly show that breast cancer patients randomized to raloxifene had a significantly lower incidence of breast cancer compared to placebo. Net relative risk at 1 month from the start of study drug, the estimate is 0.36 with a 95% confidence interval (0.20, 0.64), showing a 64% reduction in breast cancer cases. When large studies are taken individually, the net relative risk score is 0.29 with a 95% confidence interval (0.15, 0.55) indicating a 71% reduction in breast cancer cases. The results are characterized by high statistical reliability.

Because cancers diagnosed after at least 1 year from the start of follow-up probably reflect those cancers that did not exist clinically until then, we also analyzed data that included only those occurring at least 1 year after the start of screening. From all pooled placebo-controlled studies, the relative risk score is 0.23 with a 95% confidence interval (0.11, 0.45), corresponding to a 77% reduction in breast cancer cases. In large-scale studies, the estimated net relative risk is 0.14 with a 95% confidence interval (0.06, 0.32), corresponding to a 86% reduction in breast cancer cases.

For further analysis of the onset of cancer depending on the duration of the tests, Tables 3 and 4 present relative risk factor data broken down into three time periods: 1) cases diagnosed with follow-up after baseline mamogam, ie all cases diagnosed between 1 and 6 start of introduction; 2) cases diagnosed after 1 year of mammograms, i.e., all cases diagnosed between 6 and 18 months after commencement of study drug administration; and 3) cases diagnosed after a 2-year mammogram, i.e., all cases diagnosed between 18 and 24 months after initiation of study drug.

The table below provides an estimate of the relative risk of breast cancer for each time period combined across all placebo-controlled studies. Table 4 presents data from a subset of patients evaluated in Table 3, namely, patients from a large 7704 member study group. The data in both tables clearly show that the relative risk of breast cancer decreases with each subsequent step of the study. The relative risk in both populations becomes statistically significant at the two-year study point.

table. Analysis of Relative Annual Risk of Breast Cancer from Pooled Comparison Study Data ^a

Mammograms ^b Placebo cases Raloxifene cases Relative risk 95% confidence interval for relative risk Basic (1-6 months) 2 5 1.20 (0.23, 6.15) After 1 year of research (6-18 months) 6th 7th 0.56 (0.19, 1.63) After 2 years of research (18-30 months) 16th 5 0.15 (0.06, 0.36) ^a Selection ra oxifen.-placebo is 2.1: 1.

^b One patient was diagnosed with breast cancer after 30 months and was not included in this analysis at intervals.

table. Analysis of the Relative Annual Risk of Breast Cancer in a Large (7704 Patients) Postmenopausal Women diagnosed with Osteoporosis ^a

Mammograms Placebo cases Raloxifene cases Relative risk 95% confidence interval for relative risk Basic (1-6 months) 2 5 1.25 (0.24, 6.42) After 1 year of research (6-18 months) 6th 4 0.33 (0.10, 1.11) After 2 years of research (18-30 months) 13th 3 0.12 (0.04, 0.33) ^a Selection ra oxifen: placebo is 2.1: 1.

In conclusion, Fig. 1 depicts breast cancer in all placebo-comparative studies. (One patient diagnosed with breast cancer after 30 months is not included in this graph, so the graph represents approximately the same time interval in both study groups.) The two curves (placebo and raloxifene) are almost indistinguishable to a point of breast cancer rates were higher in the placebo group than in the raloxifene group.

Claims (65)

DEFINITION OF INVENTION An article comprising a packaging material and a pharmaceutical agent contained within said packaging material, wherein said packaging material is provided with a label stating how said pharmaceutical agent should be administered in an effective amount for the prophylaxis of invasive human breast cancer, and wherein said pharmaceutical agent is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. 2. The article of manufacture of claim 1 wherein the effective dose of a compound of formula I is from 30 mg to 200 mg per day. The article of manufacture of claim i *, wherein the effective dose of the compound is 150 mg per day. The article of manufacture of claim 1, wherein the effective dose of the compound is 120 mg per day. wherein the dose of said Formula I is from 50 mg to that of said Formula I is from 60 mg to 5. The article of manufacture of claim 1 wherein the effective dose of a compound of Formula I is 60 mg per day. 6. The article of claim 1, wherein said administration period is at least six months. 7. The article of claim 1, wherein said administration period is at least one year. 8. The article of claim 1, wherein said label has an introduction time of at least two years. 9. The article of claim 1, wherein the time of introduction indicated on said label is continuous. 10. The article of Claim 1 wherein said compound is its hydrochloride salt. 11. The article of claim 1, wherein said man is a postmenopausal woman without any particular risk factor for breast cancer. 12. The article of claim 1, wherein said breast cancer is de novo. 13. The bud of claim 1, wherein said man is a postmenopausal woman. 14. An article comprising a packaging material and a pharmaceutical agent within said packaging material, wherein said packaging material has a label indicating how said pharmaceutical agent should be administered in an effective amount for the prophylaxis of breast cancer in the postmenopausal age. a female, wherein said pharmaceutical agent is a compound of formula I OH (l) or a pharmaceutically acceptable salt or solvate thereof. 15. The article of manufacture of claim 14, wherein the effective dose of a compound of Formula I is from 30 mg to 200 mg per day. 16. The article of manufacture of claim 14, wherein said label indicates an effective dose of a compound of Formula I in the range of 50 mg to 150 mg per day. 17. The article of manufacture of claim 4 wherein said label provides an effective dosage of a compound of Formula I in the range of 60 mg to 120 mg per day. 18. The article of manufacture of claim 14, wherein the effective dose of a compound of Formula I indicated on the label is 60 mg per day. 19. The article of claim 14, wherein said administration period is at least six months. 20. The article of claim 14, wherein said administration period is at least one year. 21. The article of claim 14, wherein said labeled administration period is at least two years. 22. The article of claim 14, wherein the time of introduction indicated on said label is continuous. 23. The article of Claim 14 wherein said compound is its hydrochloride salt. 24. The article of manufacture of claim 14, wherein said man is a postmenopausal woman without any particular risk factor for breast cancer. 25. The article of Claim 14 wherein said breast cancer is de novo. 26. An article comprising a packaging material and a pharmaceutical agent within said packaging material, wherein said packaging material has a label indicating how said pharmaceutical agent should be administered in an effective amount for the prophylaxis of breast cancer in a human subject having no a specific risk factor for breast cancer, and wherein said pharmaceutical agent is a compound of formula I (D or a pharmaceutically acceptable salt or solvate thereof). 27. The article of manufacture of claim 26, wherein said label indicates an effective dose of a compound of Formula I in the range of 30 mg to 200 mg per day. 28. The article of manufacture of claim 26, wherein said label indicates an effective dosage of a compound of Formula I in the range of 50 mg to 150 mg per day. 29. The article of manufacture of claim 26, wherein said label indicates an effective dosage of a compound of Formula I in the range of 60 mg to 120 mg per day. 30. The article of manufacture of claim 26, wherein the effective dose of a compound of Formula I indicated on the label is 60 mg per day. 31. The article of claim 26, wherein said labeled administration period is at least six months. 32. The article of manufacture of claim 26, wherein said administration period is at least one year. 33. The article of claim 26, wherein said label has an introduction time of at least two years. 34. The article of claim 26, wherein the time of introduction indicated on said label is continuous. 35. The article of Claim 26 wherein said compound is its hydrochloride salt. 36. The article of manufacture of claim 26, wherein said man is a postmenopausal woman. 37. An article comprising a packaging material and a pharmaceutical agent within said packaging material, wherein said packaging material is provided with a label specifying how said pharmaceutical agent should be administered over a sufficient period of time at an effective dose when said period is at least for one year, for the prevention of human breast cancer, wherein said pharmaceutical agent is a compound of formula I O), or a pharmaceutically acceptable salt or solvate thereof. 38. The article of manufacture of claim 37, wherein the effective dose of a compound of Formula I is from 30 mg to 200 mg per day. 39. The article of manufacture of claim 37, wherein said label provides an effective dosage of a compound of Formula I in the range of 50 mg to 150 mg per day. 40. The article of manufacture of claim 37, wherein said label provides an effective dosage of a compound of Formula I in the range of 60 mg to 120 mg per day. 41. The article of manufacture of claim 37, wherein the effective dose of a compound of Formula I indicated on the label is 60 mg per day. 42. The article of claim 37, wherein said administration period is at least two years. 43. An article of manufacture of claim 37, wherein the time of introduction indicated on said label is continuous. 44. The article of Claim 37 wherein said compound is its hydrochloride salt. 45. The article of manufacture of claim 37, wherein said man is a postmenopausal woman without any particular risk factor for breast cancer. 46. The article of manufacture of claim 37, wherein said breast cancer is de novo. M. The article of claim 37, wherein said man is a postmenopausal woman. 48. An article comprising a packaging material and a pharmaceutical agent within said packaging material, wherein said packaging material has a label indicating how said pharmaceutical agent should be administered for a sufficient period of time at an effective dose when said period is at least for one year, for the prophylaxis of breast cancer in a post-menopausal woman, wherein said pharmaceutical agent is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. 49. The article of manufacture of claim 48, wherein said label indicates an effective dosage of a compound of formula I in the range of 30 mg to 200 mg per day. 50. The article of manufacture of claim 48, wherein said label provides an effective dose of a compound of formula I in an amount of 50 mg to 150 mg per day. 51. The article of manufacture of claim 48, wherein said label provides an effective dosage of a compound of Formula I in the range of 60 mg to 120 mg per day. 52. The article of manufacture of claim 48, wherein said label indicates an effective dose of a compound of Formula I at 60 mg per day. 53. The article of Claim 48 wherein said label has an introduction time of at least two years. 54. The article of claim 48, wherein the time of introduction indicated on said label is continuous. 55. The article of claim 48, wherein said compound is its hydrochloride salt. 56. The article of claim 48, wherein said man is a postmenopausal woman without any particular risk factor for developing breast cancer. 57. The article of claim 48, wherein said breast cancer is de novo. 58. An article comprising a packaging material and a pharmaceutical agent within said packaging material, wherein said packaging material is provided with a label stating how said pharmaceutical agent should be administered in an effective amount over a period of time at least for one year, for the prophylaxis of breast cancer in a person without any particular risk factor for breast cancer, wherein said pharmaceutical agent is a compound of formula I (l) or a pharmaceutically acceptable salt or solvate thereof. 59. The article of manufacture of claim 58, wherein said label indicates an effective dosage of a compound of Formula I in the range of 30 mg to 200 mg per day. 60. The article of manufacture of claim 58, wherein said label provides an effective dosage of a compound of Formula I in the range of 50 mg to 150 mg per day. 61. The article of manufacture of claim 58, wherein said label provides an effective dosage of a compound of Formula I in the range of 60 mg to 120 mg per day. 62. The article of manufacture of claim 58, wherein said label indicates an effective dose of a compound of Formula I is 60 mg per day. 63. The article of claim 58, wherein said label has an introduction time of at least two years. 64. The article of claim 58, wherein the entry time indicated on said label is continuous. 65. The article of Claim 58 wherein said compound is its hydrochloride salt. 66. The article of claim 58, wherein said man is a postmenopausal woman.