KR100522646B1 - Methods of Preventing Breast Cancer - Google Patents

Abstract

A method of preventing breast cancer comprising administering to a person in need thereof an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof.

<Formula 1>

Description

{Methods of Preventing Breast Cancer}

Breast carcinoma or cancer is a major medical problem that begins in the thirties of female life and persists through old age. In the United States, it is estimated that one in eight people can develop the disease during their lifetime (up to 80 years), and one in 28 women are at 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 first common cancer in women. This is not only a major cause of mortality in women, but also a cause of disability, psychological shock, and economic loss. Breast carcinoma is the second leading cause of cancer death in women in the United States and the leading cause of cancer-related death in women aged 15 to 54 years (Forbes, Seminars in Oncology, vol. 24 (1), Suppl 1, 1997: pp. S1-20-S1-35). In addition, the indirect effects of this disease, including advanced outcomes of breast cancer, such as metastasis to bone or brain, also contribute to mortality from breast cancer. Concomitant effects from complications resulting from bone marrow suppression, radiation fibrosis and neutropenia sepsis, surgery, radiation, chemotherapy or bone marrow transplantation contribute to the morbidity and mortality of the disease.

The epidemiology of the disease is a subject that is studied in depth, but little is understood. Some women appear to have a substantial genetic component that makes them more susceptible to the disease. However, it is not clear whether this genetic component causes or permits the disease or is only a precursor to disease progression. While breast carcinoma has long been known to tend to occur more frequently in some families, this analysis is not always a precursor to disease outbreaks in other household members and has little value as a measure of spread in the general population. It is currently estimated that only 5% of all breast cancers originate from genetic trends (Harris et. Al., Ed. Disease of the Breast, 1996: pp. 159-168).

Extensive medical and pharmaceutical research has been conducted in an attempt to elucidate the relationship between the hormonal estrogen and the cause and duration of breast carcinoma. Risk factors for breast cancer are primarily related to the duration of accumulated estrogen exposure in women and include menarche age, birth history, age at first birth, and menopause. Although much is known about the relationship between estrogens in the continuation of the disease and the importance of estrogen dependence on the endocrine treatment of the disease, the role of estrogens in the pathogenesis of the disease, ie whether estrogen is a causative agent (initiator) in the process of carcinogenesis or is essential. It is controversial whether it is a cofactor (promoter).

Estrogens, including 17-β-estradiol, estrone, and their active metabolites, are the major sex-related hormones in women, but in addition, estrogens are thought to be important homeostatic hormones throughout adult life in men or women. Everyone has some degree of regenerative estrogen. Most people do not develop breast carcinoma, which supports the view that estrogen itself is not a carcinogenic initiator as in the case of chemical or environmental carcinogenic substances. In addition, the risk of developing the disease seen in postmenopausal women, resulting in a loss of estrogen production in endogenous ovaries, is not reduced. In fact, apart from the history of breast cancer, age is one of the biggest risk factors for developing the disease. Breast cancer is rare in women under 20 years of age, but the risk of breast cancer increases rapidly with age. When comparing the risk of developing breast cancer with a 20-year-old woman, women 40 to 49 years of age have a 40-fold higher risk, 60-fold increase in women 50-59 years, and 90-fold higher than young controls in women over 60 years old. High (Forbes, Seminars in Oncology, vol. 24 (1), Suppl 1, 1997: pp. S1-20-S1-35).

Hormone replacement therapy (HRT) is often recommended for premenopausal and near postmenopausal women to reduce menopause syndrome and reduce the risk of cardiovascular disease, osteoporosis and other serious sequelae caused by long-term estrogen deficiency. However, due to well-accepted data on the direct effects of lifetime estrogen exposure and breast cancer risk, there is a lively discussion of the potential for hormone replacement that increases the risk of developing breast carcinoma in women. Short-term (less than 5 years) HRTs have minimal or no increased risk, but epidemiological studies and post-analysis with long-term (5-7 years) HRTs report a 35% to 75% increased risk of developing breast cancer. (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 on the role of estrogen in the pathogenesis of breast cancer are complex. Although experimental models of breast carcinoma in rats require the administration of carcinogenic agents for tumor induction (tumor development), estrogens act as promoters (rather than initiators) in this process. Ovariectomy in this animal model will prevent this process of chemically-induced carcinogenesis. However, the timing of carcinogenesis in humans is unknown. It is known that women who have had early menopause or had undergone medical or surgical ovarian resection before 40 years of age have a 50% reduction in breast cancer risk compared to women who have had natural menopause at age 50 (Harris et. Al., Ed. Disease of the Breast, 1996: pp. 159-168). Thus, an approach for the prevention of breast cancer is logically aimed at reducing estrogen exposure throughout life. This can be accomplished by inducing estrogen depletion pharmaceutically through administration of an agent that blocks the production and / or action of estrogen at any location along the hypothalamic-pituitary-gonadal axis. Nevertheless, it is problematic to estimate the likelihood of success for the prevention of de novo or other breast carcinomas using agents of this nature.

Contrary to the combined role of estrogens in the pathogenesis of the disease, and despite continually improving body data, there has been a significant increase in the understanding of the effects of estrogens on the initiation of established breast cancer carcinomas. Estrogen is a growth factor for most breast carcinoma cells in the early stages of the disease. Rapidly dividing cells are sensitive to the effects of estrogen through estrogen receptors. In addition, although not well understood, it has also been found that modified (cancer) cells at some point during the course of this disease often lose susceptibility to the promoting effects of estrogen. As a result, most of the carcinoma cells lose their response to estrogens and lose responsiveness to hormone-based therapies, which include a wide range of GNRH agonists, "anti-estrogen" progestins and androgens.

A great advantage in the treatment of breast cancer has been achieved with the advent and widespread use of hormone-based therapeutic interventions. The most used endocrine therapy is tamoxyphene. The 5-year survival rate for women with breast carcinoma has improved dramatically with this treatment; However, there was no additional benefit or survival benefit from more than 5 years of continuous treatment. In fact, data using tamoxyphene for more than five years indicate that disease-free survival and overall survival have decreased (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-Positive Tumors, J Natl Canc Inst, vol. 88) (21): pp. 1529-1542, 1996). Unfortunately tamoxyphene is also associated with significant adverse effects, such as the development of significantly increased venous thromboembolism, the symptoms of increased vasomotor movement or the occurrence of hot flashes (in the range of 16 to 67%), cataract formation, and clinical Although not confirmed by DNA, DNA-adduct formation still increases the interest in the potential of hepatocellular carcinoma (experimentally observed in animal models). However, the most serious is that the estrogenic effect of tamoxyphene causes endometrial hyperplasia in the uterus and substantially increases the incidence of endometrial carcinoma (risk is increased three to four times after five years of tamoxyphene administration). (Goldhirsch et.al., Endocrine Therapies of Breast Cancer, Sem in Onc, vol. 23 (4), pp. 494-505, 1996). Because of this and the lack of improvement in survival benefits with long-term tamoxyphene treatment, tamoxyphene therapy for more than five years is currently prohibited.

The data suggest that prolonged tamoxyphene exposure alters breast tumor cells to develop resistance to the anti-estrogenic effects of tamoxyphene and counteract its estrogenic properties (Santen, Editorial: Long Term). Tamoxifen Therapy: Can an Antagonist become an Agonist ?, J Clin Endo & Metab, vol. 81 (6), pp. 2027-2029, 1996). Changes at any stage of the estrogen receptor signal transduction pathway may be responsible for the developmental mechanism of resistance to tamoxyphene therapies, some of which do not cause cross-tolerance to other hormonal therapies, and some of Results in complete non-responsiveness to endocrine therapy. One mechanism for tamoxyphene resistance was due to the gradual transformation of carcinoma cells from estrogen dependent to estrogen independent (estrogen receptor positive cells become estrogen receptor negative). Thus, even with the most advanced and available combinations of treatment modalities (surgery, radiation, and / or chemotherapy), long-term prognosis of the patient is difficult, especially in the presence of metastatic disease. Certainly, there is a great need for improved therapies and in the first case there is a medical need (which may be most important) to prevent this disease (new or primary prevention).

Although tamoxyphene has been widely studied and proven effective in the treatment of established diseases, no large-scale, prospective placebo-control clinical trials addressing the potential use of this compound for the primary prevention of breast cancer have been completed. Studies have shown that there is a history of carcinoma in one breast and the tumor incidence is reduced in the opposite breast of a woman treated with tamoxyphene. This can be interpreted as a form of prevention of the disease, but it is not clear whether this is a metastatic inhibitory effect or angiogenesis suppression of the disease. Understanding these differences in biological mechanisms is very important in attempts to prevent the onset of new disease in healthy women who do not have a special history or risk factors for breast carcinoma.

In the last decade, anti-estrogen therapy, especially with tamoxyphene, should have been explored for its potential to prevent neoplastic breast carcinoma. However, in part due to the lack of evidence of advantage and the known and potential toxicity of tamoxyphene, promising prophylactic attempts have not been performed in healthy women. Recently, two such preventive attempts have been proposed and each has been the subject of substantial debate. As a result, attempts made in the UK were not conducted because the risk-to-benefit ratio was deemed disadvantageous. Similarly, in Italy, due to safety concerns associated with the development of uterine cancer, the tamoxyphene prevention study specified that only women with hysterectomy should be performed. However, in the United States, this attempt was made with the help of the National Cancer Institute. In the controversial analysis of these trials and the recognition that samples of varying sizes are needed, attempts in the United States have been limited to women at high risk of disease and include premenopausal and postmenopausal women (young women are 60 years old for eligibility for research) Should be the same as the risk assessed in The results of this attempt will not be available for at least three years. (For further information on the debate on the potential use of tamoxyphene as a chemopreventive agent in breast carcinoma, the definition of clinical design and high risk potential is described in "Breast Cancer Prevention Study: Are Healthy Women Put at Risk by Federally Funded." Research? ", Transcript of the Hearing Before the Human Resources and Intergovernmental Relations Subcommittee of the Committee on Governmental Operations, House of Representatives of the One Hundred Second Congress, Second Session, October 22, 1992] [ISBN 0-16-044316-4 And references and references cited here).

Because the purpose of disease prevention is to protect women from carcinogenic events (or the development of precancerous lesions) and subsequent promotion or progression to invasive diseases (cancer), there is a need to extend the use of prophylactic agents (Kelloff et. .al.Appoachs to the Developement and Marketing Approval of Drugs that Prevent Cancer, Cancer Epidemiology, Biomarkers & Prevention, vol 4, pp. 1-10, 1995). This requires very well-accepted treatment, with an exceptional safety profile and minimal side effects. Raloxifene has been studied in more than 12,000 patients. The vastly accumulated data from the Phase III clinical trial of raloxyphene for the prevention or treatment of osteoporosis in postmenopausal women was analyzed for safety. When all doses of raloxifene were accumulated, this analysis included over 12,850 patients who were exposed to raloxifene. Based on almost three years of clinical experience, raloxifene has proved to be very well tolerated, has a broad therapeutic index, and minimal acute or chronic toxicity. In contrast, the adverse effects of long-term tamoxyphene use have raised important concerns regarding their suitability for use as chemopreventive agents (Grainger et.al. Tamoxifen: Teaching an Old Drug New Tricks, Nat Med, vol. 2 (4), pp. 381-385, 1996).

To date, no effective prophylaxis against neonatal breast carcinoma has been demonstrated. In addition, no studies are ongoing or under consideration to prevent breast carcinoma in the general population of women, unless the risk of developing breast cancer is particularly increased. Clearly, there is a high demand for breast cancer prevention therapies that are useful not only for high-risk people, but also for the entire population, including both men and women, and especially those without increased risk.

The present invention provides a method for preventing breast cancer, including neonatal breast cancer.

The present invention relates to a method for preventing breast cancer in a human comprising administering to the human an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof.

<Formula 1>

The invention also relates to a product comprising a packaging substance and a pharmaceutical formulation contained within the packaging substance, wherein the packaging substance comprises a label indicating that the pharmaceutical formulation can be administered for the prevention of breast cancer, the pharmaceutical formulation Is a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof.

The present invention relates to the discovery that the compounds of formula (1) are useful for the prevention of breast cancer. The method provided by the present invention provides a dosage of raloxyphene or a pharmaceutically acceptable salt or solvate thereof effective for the prevention of breast cancer for a sufficient period of time administration of raloxyphene or a pharmaceutically acceptable salt or solvate thereof that is effective for the prevention of breast cancer. It is carried out by administering to a person who needs to administer the amount.

The term "prevent" when used in connection with breast cancer includes reducing the likelihood of developing or developing breast cancer in a human. The term does not include treating a patient diagnosed with breast cancer.

As used herein, the term “negative” means that the normal breast cells are not initially modified or transformed into cancer or malignant cells. Such modifications may occur at the same or daughter cell stage through the evolutionary process or may occur at central events alone. This neoplastic process is distinguished from the propagation, metastasis or colonization of cells that have already been transformed or maligned at the primary tumor site into new locations. The term "neonatal" relates to primary prevention. The invention also relates to administering a compound of formula (1) to a patient at an increased risk of developing neonatal or other breast cancer.

Persons who are not at particular risk of developing breast cancer are those who can develop new breast cancer, have no evidence or doubt that the likelihood of the disease is higher than normal risk, and have never been diagnosed with the disease. The biggest risk factor attributable to the development of breast carcinoma is the personal history of breast cancer, even when there is no evidence of the disease, a person who has been treated for five years or more is considered a "breast cancer survivor." Another well-accepted risk factor is the family history of the disease.

Raloxyphene, the hydrochloride of the compound of formula (1), was shown to bind to the estrogen receptor and was initially thought to be a molecule having the function and pharmacological activity of "anti-estrogen". Indeed, raloxifene blocks the action of estrogens in some tissues, but in other types of cells, raloxifene activates the same genes as the genes that estrogen activates, thereby activating the same pharmacological activity, e. Acts as an estrogen antagonist. Currently, the unique profile exhibited by raloxifene, which is different from the profile of estrogen, is unique to the various gene functions by the raloxyphene-estrogen receptor complex as opposed to the activation and / or inhibition of genes by the estrogen-estrogen receptor complex. By activation and / or inhibition. Thus, while raloxyphene and estrogens compete using the same receptors, the pharmacological consequences resulting from gene regulation by both are not easily predicted, each unique.

In general, the compounds are formulated with conventional excipients, diluents or carriers, compressed into tablets, formulated with elixirs or solutions for convenient oral administration, or administered by the intramuscular or intravenous route. The compounds can be administered transdermally or vaginally, and can be formulated in sustained release dosage forms, parenteral dosage forms, depo dosage forms, and the like.

The compounds used in the methods of the present invention are all US Pat. Nos. 4,133,814, 4,418,068, 4,380,635, 5,629,425, and GB 2,293,602, published March 3, 1996, all of which are incorporated herein by reference. And European Patent Application No. 95301291 (filed Feb. 28, 1995, published Sep. 6, 1995). In general, this method starts with benzo [b] thiophene having 6-hydroxyl groups and 2- (4-hydroxyphenyl) groups. The hydroxyl group of the starting compound is protected, the 3 position is acylated and the deprotected product forms a compound of formula (1). Preparations of such compounds are provided in the US patents and UK application literature discussed above.

The compounds used in the process of the present invention form pharmaceutically acceptable acid and base addition salts with a wide variety of organic and inorganic acids and bases, and include physiologically acceptable salts often used in pharmaceutical chemistry. Such salts also form part of the present invention. Typical inorganic acids used to form such salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, hypophosphorous acid, and the like. Salts derived from organic acids such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic acids and hydroxyalkanedionic acids, aromatic acids, aliphatic and aromatic sulfonic acids can also be used. Thus, such pharmaceutically acceptable salts include acetates, phenylacetates, trifluoroacetates, acrylates, ascorbates, benzoates, chlorobenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, methyl Benzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, β-hydroxybutyrate, butyne-1,4-dioate, hexin-1,4-dioate, cape Latex, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hiprate, lactate, maleate, maleate, hydroxymaleate, malonate, mandelate, Mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrate Genphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suverate, sulfate, bisulfate, pyosulfate, Sulfite, bisulfite, sulfonate, benzene-sulfonate, p-bromobenzenesulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, Naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate and the like. Preferred salts are hydrochlorides.

Pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of formula (1) with an equimolar or excess acid. The reactants are generally mixed in a common solvent such as diethyl ether or benzene. Salts generally precipitate out of solution within about 1 hour to 10 days and can be isolated by filtration or strip the solvent by conventional methods.

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

Pharmaceutically acceptable salts generally have better solubility compared to the compounds from which they are derived, and therefore are often easier to formulate as solutions or emulsions.

Pharmaceutical formulations may be prepared by procedures known in the art. For example, the compound may be formulated with conventional excipients, diluents or carriers to form tablets, capsules, suspensions, powders, and the like. Examples of suitable excipients, diluents and carriers for such formulations include fillers and extenders such as starch, sugars, mannitol and silicic acid derivatives; Binders such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin and polyvinyl pyrrolidone; Humectants, such as glycerol; Disintegrants such as calcium carbonate and sodium bicarbonate; Dissolution retardants such as paraffin; Resorption accelerators such as quaternary ammonium compounds; Surfactants such as cetyl alcohol and glycerol monostearate; Adsorptive carriers such as kaolin and bentonite; And lubricants such as talc, calcium and magnesium stearate, and solid polyethyl glycol.

The compound may also be formulated as a convenient oral elixir or solution, or in a solution suitable for parenteral administration (eg, intramuscular, subcutaneous or intravenous route). In addition, the compounds are well suited for formulation into sustained release dosage forms and the like. The formulations may be configured to release only the active ingredient, or preferably to release over time, preferably at specific sites of the intestinal tract. For example, coatings, envelopes and protective matrices can be prepared from polymeric materials or waxes.

The particular effective and sufficient duration and dosage of the compound of formula (1) necessary for inhibiting breast cancer according to the present invention will depend on the patient's physical characteristics, route of administration and related factors and will be determined by the attending physician. The preferred period of administration is at least 6 months, more preferably at least 1 year, most preferably at least 2 years or chronic. Generally, an acceptable and effective daily dose will be about 0.1 to about 1000 mg / day, preferably about 30 to about 200 mg / day, more preferably about 50 to about 150 mg / day. The most preferred dosage range is about 60 to about 120 mg / day, with 60 mg / day being particularly preferred.

The dosage ranges described are not meant to limit the invention. Rather, the scope illustrates the invention and the invention encompasses functionally equivalent ranges by providing the discovered chemo-preventive properties of the compound. Thus, while certain modes of administration allow for numerically different dosage ranges of the compounds of Formula 1 effectively used for the present invention, such numerically different dosage ranges are intended to be functionally equivalent to the ranges expressed by the present invention. Included.

In addition, the dosage ranges described are based on the hydrochloride salt of the compound of formula (1). Thus, a 60 mg dose is equivalent to 55.71 mg of free base. Those skilled in the art will be able to calculate the free base equivalents of any salts of the pharmaceutically acceptable compounds of formula (1). For example, "about 60 mg" includes 51.73 to 60.35 mg of organic base, while 55 to 65 mg of raloxyphene hydrochloride.

It is also advantageous to administer the compound by oral route. For that purpose, the following oral dosage forms are available.

Formulation

Formulation 1: Gelatin Capsule

Hard gelatin capsules were prepared as follows:

ingredient Amount (mg / capsules) Raloxyphene HCL 30-200 Starch, NF 0-650 Starch flow powder 0-650 Silicone Latex 350 Centistox 0-15

The components are blended and the 45th mesh U.S. Pass through the sieves and fill hard gelatine capsules.

Examples of capsule formulations include those shown below:

Formulation 2: raloxyphene capsule

ingredient Amount (mg / capsules) Raloxyphene HCL 30-200 Starch, NF 112 Starch flow powder 225.3 Silicone Latex 350 Centistox 1.7

Formulation 3: raloxyphene capsule

ingredient Amount (mg / capsules) Raloxyphene HCL 30-200 Starch, NF 108 Starch flow powder 225.3 Silicone Latex 350 Centistox 1.7

Formulation 4: raloxyphene capsule

ingredient Amount (mg / capsules) Raloxyphene HCL 30-200 Starch, NF 103 Starch flow powder 225.3 Silicone Latex 350 Centistox 1.7

Formulation 5: Raloxyphene Capsule

ingredient Amount (mg / capsules) Raloxyphene HCL 30-200 Starch, NF 150 Starch flow powder 397 Silicone Latex 350 Centistox 3.0

Such particular formulations may vary depending upon the reasonable parameters provided.

Tablets were prepared using the following ingredients:

Formulation 6: Tablet

ingredient Amount (mg / tablet) Raloxyphene HCL 30-200 Cellulose, Microcrystalline 0-650 Silicon dioxide, fumed 0-650 Stearate 0-15

The components were blended and compressed to form tablets.

Alternatively, tablets containing 0.1 to 1000 mg of active ingredient each were prepared as follows:

Formulation 7: Tablet

ingredient Amount (mg / tablet) Raloxyphene HCL 30-200 Starch 45 Cellulose, Microcrystalline 35 Polyvinylpyrrolidone (10% solution in water) 4 Sodium carboxymethyl cellulose 4.5 Magnesium stearate 0.5 Talc One

The active ingredient, starch and cellulose were extracted from the 45th mesh U.S. Pass through the sieve and mix thoroughly. A solution of polyvinylpyrrolidone was mixed with the resulting powder, which was then subjected to 14th mesh U.S. Passed through the sieve. The granules so produced are dried at 50-60 ° C. and the 18 th mesh U.S. Passed through the sieve. Sodium Carboxymethyl Starch, Magnesium Stearate and Talc were prepared in advance on 60th Mesh U.S. Pass through the sieve, then add to the granules, mix and compress on a tableting machine to obtain tablets.

Suspensions each containing 0.1 to 1000 mg of medicament per 5 ml dose were prepared as follows:

Formulation 8: Suspension

ingredient Volume (mg / 5ml) Raloxyphene HCL 30-200 Sodium carboxymethyl cellulose 50 mg syrup 1.25mg Benzoic acid solution 0.10 ml Spice Enough coloring agent Enough Purified water  5 ml

Medications 45 mesh U.S. Pass through the sieve and mix with sodium carboxymethyl cellulose and syrup to form a soft paste. The benzoic acid solution, flavor and colorant were diluted with a portion of water and added with stirring. Subsequently, a sufficient amount of water was added to fill the required volume.

Preferred tablet formulations include the following two.

Formulation 9:

ingredient Amount (mg) function Raloxyphene HCL 60.0 activation Spray dried lactose 30.0 Soluble Diluent Anhydrous lactose 12.0 Soluble Diluent Povidone 12.0 Binder Polysorbate 80 2.4 Humectant Crospovidone 14.4 Disintegrant Magnesium Stearate (Core Tablet Weight) 1.2 (240) slush Film coating Color mixture white 12.0 coloring agent Talc a very small amount Polishing aids Carnova wax - Polishing aids

Formulation 10:

ingredient Amount (mg) function Raloxyphene HCL 60.0 activation Spray dried lactose 29.4 Soluble Diluent Anhydrous lactose 120.0 Soluble Diluent Povidone 12.0 Binder Polysorbate 80 2.4 Humectant Crospovidone 14.4 Disintegrant Magnesium Stearate (Core Tablet Weight) 1.2 (240) slush Film coating Color mixture white 12.0 coloring agent Talc - Polishing aids Carnova wax a very small amount Polishing aids

Examination process

As a basis for the utility of the present invention, the interim safety results of the Phase III clinical trial with raloxifene are shown below.

Most cases of breast carcinoma occurred in the ongoing osteoporosis treatment study of a number of postmenopausal women of 7740 who were found to be osteoporosis. However, few cases have been reported in postmenopausal women at risk for osteoporosis. We report double-blind and placebo-control studies here; Most are designed to measure the effect of preventing or treating osteoporosis by raloxifene in postmenopausal women over a period of about three years. The study also provides information on cardiovascular health and other major medical conditions, including the development of breast carcinoma. Patients were orally administered with placebo, 30 mg, 60 mg, 120 mg or 150 mg of drug daily. All patients and researchers were blinded to drug assignment (double-blind design). All patients in all groups were prescribed about 500 mg / day calcium supplement daily. In addition, in many 7704-patient treatment studies, patients were prescribed 400 to 600 IU / day of vitamin D supplement.

The subjects selected for this study were postmenopausal women ranging from about 45 to 80 years old (women who have been more than two years from the last menstrual period).

Typical exclusion criteria from participation in these studies include: 1) presence of serious systemic disease, 2) acute or chronic liver disease, 3) significantly impaired kidney function, and 4) in the opinion of the investigator, for example, medical or drug addiction. 5) Subjects with poor medical or psychological risk factors, including trials; Include. Most important in the exclusion criteria was the exclusion of women with current or past personal history of breast cancer or other estrogen-dependent neoplasia. These exclusion criteria reflect a general group of risks of developing breast carcinoma, or in other words, a group of people whose risk of developing breast cancer is not particularly increased.

Potential subjects were screened before they entered the study. The test subject needed to reveal his medical history and current medical condition. All potential patients needed to have a basal mammogram or an ultrasound evaluation of the breast, or needed to perform one of these procedures within 12 months before the study. In most studies, a two year follow-up mammogram is required; However, annual mammograms are recommended. All subjects diagnosed and reported with breast carcinoma need to stop participating in the study immediately and are left to expert researchers for proper cancer evaluation and treatment.

In all subjects who received more than 1 month of all placebo-controlled trials and study medication over a period of 6 months or more, a total of 42 breast cancers were reported: 18 in the raloxifene group compared to 24 in the placebo group. The total ratio of treatment assignments (raloxyphene to placebo) for randomized patients was about 2: 1.

The results shown in Tables 1 to 4 relate to subjects who have undergone histopathological diagnosis of breast carcinoma. The data includes optional 1 year mammograms and the results from the required baseline and 2 year tracking mammograms. Once breast cancer is diagnosed, these subjects are taken out of the study and indicate their status by indicating the designated treatment (arm) (ie, the study drug that they assigned to them).

For the study reported herein, the number of patients randomly assigned to receive a placebo was about 3195. The number of patients randomly assigned to receive raloxyphene is about 6681 (total for all doses combined). (In a large 7704-patient treatment study, treatment codes were not presented to patients participating in the study. Thus, the number of patients assigned to each treatment group is an estimate.)

The results shown below are for patients diagnosed with breast carcinoma at any point in the study period (but at least one month after being randomly assigned to study medication (placebo or raloxyphene)). Table 1 shows all doses of raloxyphene treated data and the results of all placebo-control studies. Table 2 presents a subset of the events shown in Table 1, particularly for patients who participated in a number of 7704-patient treatment studies in which most breast cancer events occurred. The two doses of raloxifene in this treatment study are 60 mg / day and 120 mg / day. Since the incidence of breast cancer increases with age, it is speculated that treatment studies will have a higher incidence of breast cancer (mean age 67 years old at study entry). The table shows the number of breast cancer events (n) in each treatment group, the total number of patients assigned to treatment (N), an estimate of the relative risk of developing breast cancer, and a 95% confidence interval of the relative risk of developing breast cancer. If the upper limit of the 95% confidence interval is less than 1.0, there is statistically significant evidence (at 5% level) that breast cancer incidence with raloxyphene treatment is lower than breast cancer incidence with placebo treatment.

Analysis of relative risk of breast cancer, combining all combined placebo-control studies Time from treatment assignment to diagnosis N / N (%) for placebo N / N (%) for raloxyphene Relative risk (raloxyphene versus placebo) 95% confidence interval for relative risk More than 1 month 24/3195 18/6681 0.36 (0.20, 0.64) More than 12 months 21/3195 10/6681 0.23 (0.11, 0.45)

Analysis of relative risk of breast cancer in a number of (7704-patient) treatment studies in postmenopausal women diagnosed with osteoporosis Time from treatment assignment to diagnosis N / N (%) for placebo N / N (%) for raloxyphene Relative risk (raloxyphene versus placebo) 95% confidence interval for relative risk More than 1 month 21/2659 12/5317 0.29 (0.15, 0.55) More than 12 months 18/2659 5/5317 0.14 (0.06, 0.32)

In this placebo-control study, the data clearly indicate that patients with randomly assigned raloxifene had a lower incidence of breast cancer than patients who were randomly assigned to placebo. Estimates of the approximate relative risks of all patients diagnosed after 1 month or more of randomization of study medication were 0.36, 95% confidence intervals (0.20, 0.64), indicating a 64% reduction in breast cancer rates. Considering only one treatment study, the approximate estimate of relative risk is 0.29, 95% confidence intervals (0.15, 0.55), indicating a 71% reduction in breast cancer rates. These results are statistically significant.

Since cancer diagnosed after more than one year of randomization is not medically pre-existing, we also analyzed data considering only cases that occurred more than 12 months after randomizing study drugs. Combining all the placebo-control studies, the approximate relative risk estimates are 0.23, 95% confidence intervals (0.11, 0.45), corresponding to a 77% reduction in breast cancer incidence. For many therapeutic studies, the approximate estimate of relative risk is 0.14, 95% confidence intervals (0.06, 0.32), corresponding to a 86% reduction in the incidence of breast cancer.

To further analyze the appearance of tumors over time in the study, Tables 3 and 4 show relative risk data divided by three time periods: 1) events diagnosed from follow-up of baseline mammograms, i. All events diagnosed between 6 months; 2) events diagnosed from follow-up of 1-year mammogram, ie all events diagnosed between 6 and 18 months after study drug assignment; And 3) events diagnosed from follow-up of 2-year mammogram, ie all events diagnosed between 18 and 30 months after study drug assignment.

Table 3 shows the relative risk of breast cancer by adding all placebo-controls over each period. Table 4 presents information about subsets of patients reported in Table 3, ie, information on patients in multiple 7704-patient treatment studies. In both tables, it is clear that the relative risk of developing breast carcinoma decreases with each successive follow-up time. The relative risks of the two groups are statistically significant at the 2 year follow-up.

Annual relative risk of breast cancer, combined with all placebo-control studies ^a Mammogram ^b In the case of placebo In the case of raloxyphene Relative risk 95% confidence interval for relative risk Baseline (1-6 months) 2 5 1.20 (0.23, 6.15) 1-year tracking (6-18 months) 6 7 0.56 (0.19, 1.63) 2-year tracking (18-30 months) 16 5 0.15 (0.06, 0.36) ^a randomized-raloxyphene: placebo is 2.1: 1. ^b A patient diagnosed with breast cancer after 30 months is excluded from this analysis by period classification

Yearly Relative Risk of Breast Cancer, a Multiple (7704-Patient) Therapeutic Study of Postmenopausal Women Diagnosed with Osteoporosis ^a Mammogram ^b In the case of placebo In the case of raloxyphene Relative risk 95% confidence interval for relative risk Baseline (1-6 months) 2 5 1.25 (0.24, 6.42) 1-year tracking (6-18 months) 6 4 0.33 (0.10, 1.11) 2-year tracking (18-30 months) 13 3 0.12 (0.04, 0.33) a randomized-raloxyphene: placebo 2.1: 1.

As a final summary, FIG. 1 graphically shows the incidence of breast cancer in all placebo-control studies. (Since one patient diagnosed with breast carcinoma after 30 months was excluded from this graph, the graph shows approximately the same follow-up period in both treatment groups.) The two curves (placebo and raloxyphene) until 1-year time points. Almost indistinguishable, as the two curves separate, breast cancer incidence in the placebo group increases over the rate in raloxyphene.

Pharmaceutical formulations comprising a compound of formula (1) according to the present invention are useful for the prevention of breast cancer and administer an effective amount of raloxyphene or a pharmaceutically acceptable salt or solvate thereof to a person in need thereof for a sufficient period of time. The method provided by the invention is useful as a method of preventing breast cancer.

1 shows the incidence (%) of breast cancer in patients treated with placebo and raloxyphen hydrochloride in a placebo-control study.

Claims (6)

A pharmaceutical formulation comprising about 60 mg of the hydrochloride of the compound of formula (1) as an active ingredient for preventing de novo breasts in postmenopausal women by oral administration once daily to postmenopausal women: <Formula 1>

. The pharmaceutical formulation of claim 1, wherein the daily administration is performed for at least 6 months. The pharmaceutical formulation of claim 1, wherein said daily administration is performed for at least one year. The pharmaceutical formulation of claim 1, wherein said daily administration is carried out for at least two years. The pharmaceutical formulation of claim 1, wherein said daily administration is performed chronically. The pharmaceutical formulation of claim 1, wherein the postmenopausal woman is a woman who is not at particular risk of developing breast cancer.

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