TW586942B - A pharmaceutical composition for use in preventing breast cancer - Google Patents

Abstract

A pharmaceutical composition for use in preventing breast cancer comprising an effective amount of a compound having the formula and pharmaceutically acceptable salt sand solvates thereof to a human in need for a sufficient term.

Description

586942 A7 B7 5 Invention Description (Printing breast cancer or breast cancer is a major medical problem in a woman's life from 30 years of age to the entire aging period. Recently it has been estimated that in the life of American women ( Before age 80) One in eight chances of developing the disease, and one in 28 women are at risk of dying from breast cancer in their lifetime (Harris et al., Ed. Breast Disease, 1996; pp. 159- (P. 168). Breast cancer is the third most common type of cancer and the most common cancer among women. Breast cancer is the main cause of lethality in women and the cause of disability, psychological trauma, and economic loss. Breast cancer is the cause of cancer in American women. The second most common cause of death, and is the main cause of cancer-related deaths for women aged 15 and 54 years (Forbes, Oncology, Volume 2 ^ (1), Suppl 1, 1997 ·· Pages S 1-2 0-S 1-35). The indirect effects of the disease can also be the cause of death from breast cancer, including the result of worsening of the disease, such as metastasis to bone or brain. Inhibition by the spinal cord, radiation fibrosis The complications of neutrophilic septicemia from side effects of treatments, such as surgery, radiation therapy, chemotherapy, or bone marrow transplantation-are also the causes of this disease or death. Although the disease is pathologically dense, Research, but still not much knowledge. It seems that there are many genetic components that make some women vulnerable to the disease. However, it is not clear whether this genetic component is the cause or the disease of the disease, or it is only a precursor to the disease process. Although some are already known Races are prone to cancerous tumors, but this analysis does not necessarily predict the incidence of this disease in other race members, so the prediction of the penetration rate of the general ethnic group is very small. At present it is estimated that only * 5% of all breast cancers are due to heredity And those who are prone to rheumatism (Harris et al., Ed. Breast Disease, 1996; pages 159_168). Intensive clinical and pharmacological studies have begun to try to explain hormone estrus

(Please read the precautions on the back before reloading. 1T 586942 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, a description of the invention (2 The relationship between the cause of hormones and breast cancer and subsequent development. The risk factors for diseases are mainly related to women Cumulative estrogens are related to exposure, and include: menarche age, number of births, age at first term of pregnancy, and menopause. Although regarding endocrine therapy for diseases, the importance of estrogen hormones for the continuation of the disease and estrogen dependence A lot has been known about the relationship, but the role of estrogens in this disease pathogen, such as whether estrogens are a causative agent (initiator) or necessary cofactor (promoter) in the carcinogenesis process, is still There is considerable controversy. The estrogen hormone 'including 1 7 _ Lu-strong courtship hormone, estrone and its active metabolites, is a female hormone that mainly has sex with IT, but it also seems to be important in the lifetime of men and women adults The body's constant hormones. All people have some endogenous estrogens. But most people Breast cancer can occur, thus supporting the statement that estrogens are not in principle the initiator of carcinogenesis, but rather chemical or environmental carcinogens. In addition, when women experience menopause and subsequently lose the production of endogenous ovarian estrogens, and It will not relatively reduce the risk of developing this disease. In fact, 'except for a personal history of breast cancer' age is the single largest risk factor for this disease. Breast cancer is rare in women under 20 years of age, but it increases with age Risk surges. When compared with the risk of breast cancer in women aged 20, women aged between 0 and 40 years are 40 times more likely to be at risk, women between 50 and 59 years old are increased 60 times, and women over 60 years old are similar but more likely than 90 times higher in young people (1; «〇1 ^^, Oncology Discussion, Book 24 (1), Suppl 1, 1997: pages S1-20-S1.35). Postmenopausal and premenopausal are generally recommended Women receive hormonal replacement therapy 5 paper sizes are applicable to the Chinese National Standard (CNS) Λ4 size (210X297 cm) (Please read the precautions on the back before loading.

586942 A7 _______ B7 V. Description of the invention (3) Printed by the Shellfish Consumer Cooperative (HRT) of the Central Standards Bureau of the Ministry of Economic Affairs to alleviate postmenopausal symptoms and reduce cardiovascular disease, osteoporosis and other serious sequelae due to chronic estrus hormone deficiency Dangerous. However, as the data have fully accepted the direct impact of cumulative lifetime estrogenic hormone exposure and the risk of breast cancer, there is a fierce debate over the risk of hormonal replacement increasing the risk of breast cancer in women. When the short-term period is below) associated with minimal or no increase in risk, epidemiological studies and long-term use of HRT analysis (between 5 and 7 years) announce that the risk of breast cancer is increased by 3 5 /. To 75% (Grady et al., Preventing disease and prolonging life in postmenopausal women. Seromonal therapy, Ann Intern Med, 117: pp. 1016_103, 1992) ° '^ Regarding estrogens in this disease The theory and evidence of the role of the disease principle is complex. The experimental model of mouse breast cancer requires the administration of a carcinogen to induce tumors (tumor development). In fact, the estrogens act as a process promoter (rather than an initiator). Ovariectomy interferes with this chemically induced carcinogenesis in these animal models. However, for humans, the timing of carcinogenesis is unknown. It is only known that women who have premature menopause or undergoing medical or surgical ovarian removal before the age of 40 years have a 'reduction in breast cancer risk of approximately 50% compared to women who naturally stop menstruating at the age of 50 years (Harris et al., Ed. Disease, a%; pp. 159-168). Therefore, it is inevitable to reduce breast cancer exposure in order to reduce the amount of vivid hormone exposure. Blocking the production and / or action of estrogens by administering a formulation along the pterosexual gonad axis can lead to the loss of estrogens through pharmacological defamation. Nonetheless, it is expected that it will be difficult to re-prevent the possible success rate of preventing breast cancer by other methods using a preparation of this nature. c Please read the precautions on the back before I— m «nn _ I installed—, ι-α This paper is suitable for financial purposes 586942 A7 B7 V. Description of the invention (4 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs and estrus hormones The complex role of this disease is different in the principle, and although physical data has been continuously developed, we have made considerable progress in understanding the effects of estrogen hormones on the impact of what has been identified as breast cancer. A growth factor in the early stages of breast cancer cell disease. Fast-dividing cells are sensitive to their effects through estrus hormone receptors. Although the process of this disease is not fully understood, it is certain that at some point in its course Deformed (cancer) cells often lose their sensitivity to the effects of estrogens. Finally, most cancerous cells grow irrelevant to estrogens and lose their responsiveness to hormone-based therapies, These include: GNRH stimulants, "anti-estrous hormones", progesterone and androgens. Since hormones are the main treatment method, It is now widely used and has been used to treat breast cancer. The most widely used endocrine therapy is tamoxifen. The 5-year survival rate of women with breast cancer has been obtained by this therapy. Greatly improved; however, continuous treatment for more than 5 years can not get more benefits or survival advantages. In fact, data show that treatment with tamoxifen for more than 5 years, the recovery survival rate and overall survival rate are relatively reduced (NSABP B14 Trial: Fisher et al. Comparison of 5 years and more with breast cancer patients with negative lymph nodes and estrogens receptor-positive tumors treated with tamoxifen, j Natl Cane Inst, Vol. 88) (21): No. 1529-1542 '1996). Unfortunately, tamoxifen is also associated with some obvious side effects, such as a significant increase in the incidence of venous thromboembolism, a significantly increased incidence of vasomotor symptoms or heat flashes (16-67〇 / 〇 Within the scope) 'cataract formation and DNA-introduction formation, although not clinically confirmed (please read the precautions on the back before loading. ， 1Τ 线 -7- wood paper scale applies the Zhongguanjia Standard (CNS) A4 specification (2 resembling 297 Gongchu) 586942 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (5) & 'But still cause concern that may be related to hepatocellular carcinoma (observed in animal experimental mode However, the most serious thing is that the estrogens of tamoxifen can cause endometrial hyperplasia and the incidence of endometrial cancer in the uterus. (After 5 years of tamoxifen administration, it is dangerous (3- to 4-fold increase in sexuality) (Goldhirsch et al., Endocrine Therapy for Breast Cancer, Discussion of Oncology, Vol. 23 (4), pp. 494-505, 1996). For this reason and long-term use of tamoxifen cannot be improved Survival benefits, so currently banned More long-term tamoxifen treatment for more than 5 years. Data show that with long-term exposure to tamoxiphene, breast tumor cells will undergo changes, thus making their cells resistant to anti-estrous hormone effects, and Instead, it responds to its estrogen hormone properties (Santen, editorial: long-term tamoxifen therapy: can antagonists become stimulants?), J CHn End〇 & Metab, Vol. 81 (6), No. 2027_2029 (1996, 1996). Changes in any step in the signal pathway of the estrus hormone carcass respond to the mechanism of resistance to tamoxifen therapy, some of which do not cause the 夂% resistance of other hormone therapies. Some are completely unresponsive to any kind of endocrine therapy. One of the mechanisms of tamoxifen resistance has become the cause of cancerous cells gradually changing from estrogen-dependent to non-dependent (estrogen receptor-positive cells become (Estrous hormone receptor negative). Therefore, even with the most advanced combination of treatment regimens (surgery, radiation therapy, and / or chemotherapy), the patient's long-term prognosis is poor, especially When metastatic disease appeared, people were in great need of improved therapy, and perhaps the most important thing was urgently needed-prevention of this disease at the beginning (re-doing 0 "or preliminary prevention). This paper standard applies to China Standards (Please read the precautions on the back before you install-π line A7 ~ ^ s _ B7 V. Description of invention (6) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs The efficacy of phene in confirming the disease, but no complete, large-scale, predictable placebo-controlled clinical trials have shown the possible use of this compound for the primary prevention of breast cancer. Studies have indeed shown 7F to treat a breast with cancer with tamoxifen Women with a history of neoplasia have reduced the incidence of tumors on the other side of the breast. Although this may be interpreted as a preventive form of the disease, it is not clear whether it is an anti-metastatic effect or reinhibition of the disease. Understanding the differences in this biological mechanism is important for healthy women who are trying to prevent recurrence of the disease in healthy women who have no special history of breast cancer or risk factors. Regarding the use of anti-sex hormone therapy, particularly tamoxifen, which has been debated in the last decade, the possibility of preventing breast cancer recurrence should be studied. However, Shao Fen's lack of proof of the benefits of tamoxifen and its known and probable toxicological and anticipatory prophylaxis was performed in healthy women. Recently, two prevention trials have been proposed, each of which is a fairly controversial subject. As a result, the risk-benefit ratio in the trials conducted in the United Kingdom was considered unsatisfactory and was not adopted. Similarly, in Italy, due to safety considerations for the development of endometrial cancer, tamoxifen prevention studies are required only in women after hysterectomy. However, the United States conducts such tests under the auspices of the National Cancer Institute. Knowing the controversial analysis of this trial, and many other sample sizes required, the 'U.S. trial is limited to women at high risk of developing the disease' and to women before and after menopause (risk of young women * sex The assessment needs to be equivalent to a risk assessment for a 60-year-old woman before it can be used in the study). The results of this test are not feasible for at least three years. (Controversy, clinical design and possible use of tamoxifen as a chemopreventive agent in breast cancer. (Please read the precautions on the back before loading. Binding line The paper size applies the Chinese National Standard (CNS) A4 specification. (210X297 mm) A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (7) ~ Definition of high risk and more information, see "Breast Cancer Prevention Research: Federal grant research puts healthy women in Is it dangerous? ", Copy of the public hearing of the Public Relations Subcommittee of the Human Resources and Government Operations Committee, Session 102 of the 102nd House of Representatives, October 22, 1992 [ISBN 0-16- 044316-4] and references and testimonies cited herein. Because the goal of preventing this disease is to keep women away from carcinogens (or the occurrence of pre-cancerous damage) and subsequent acceleration or becoming an invasive disease (cancer), it is necessary A long-acting preventive therapeutic agent (Kelloff et al., Marketing authorization method for the development of cancer prevention drugs, cancer epidemiology, biomarkers and prevention, Book 4, Page 10, Γ only 5 years). This therapy requires excellent tolerability and a particularly safe appearance with minimal side effects. Raloxifene has been tested for 2,000,000. This study has been performed on each patient. For safety, phase 111 clinical trials from La Roxophe have also been analyzed for densely integrated data on the prevention or treatment of osteoporosis in postmenopausal women. This analysis has included exposure to more than 12,850 people per year in laroxine. Based on the most recent 3 years of clinical experience, laroxine has proven to be very well tolerated and has a universal therapeutic index with minimal evidence of acute or chronic poisoning. Compared with the long-term side effects associated with the use of tamoxifen, its applicability as a chemopreventive agent has attracted significant attention (Graingei < Tam's moxifen: a guide to new uses of old drugs, Nat Med, p. Volume 2 (4), p. 381, 385, 1996). To date, it has not been proven effective in preventing the recurrence of breast cancer. In addition, prevention of breast cancer in women who do not particularly increase the risk of breast cancer among the general population There is no progress or long-term research. Obviously, all the people are very ________ -10- — This paper size applies to the Chinese National Standard (CNS) A4 specification (2ιχχ297 mm) (Please read the note on the back first Matters then mrl · • pack. Line 586942 A7 B7 V. Description of the invention (8 Need useful breast cancer prevention therapy, including high-risk groups and people who do not particularly increase risk, and include men and women. R The present invention provides prevention Breast cancer, including a method for re-emerging breast cancer. The present invention is directed to a method for preventing breast cancer in humans, which comprises administering an effective dose of a compound of formula

(Please read the notes on the back first

* 1 雪 -1 _____ ...... I Equipment 丨 · Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs or a pharmaceutically acceptable salt or solvate thereof. The invention also relates to a kind of packaging material, and the packaging material: a manufacturing product of a medical preparation, wherein the packaging material includes a sign that the medical preparation can be administered to prevent breast cancer, and the medical preparation Or a pharmaceutically acceptable salt or solvate thereof. In a liniment-controlled study, the percentage of breast cancers that occurred after treating patients with facials and raloxifene chloride. The present invention relates to the discovery that magic compounds can be used to prevent breast cancer. According to the present invention, the method is to administer a pre-phene or a pharmaceutically acceptable salt or something thereof to a person in need within a sufficient period of time, so that when "preventive words are used in breast cancer, Including lowering human lo ^

Ordering line • I 1 m · 586942 Α7 Β7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (9) The possibility of breast cancer. The term does not include the treatment of patients who have been diagnosed with breast cancer. The term "de novo" as used in the present invention means that at the beginning normal breast cells have not deformed or degenerated into cancerous or malignant cells. Such deformation can occur at the same or daughter-cell stage through evolutionary processes, or on a single major occasion. This process is different from the process of metastasis, transplantation, or dissemination of malignant cells that have been deformed or moved from the original tumor site to the new area. The term “renewal” is related to the initial prevention. The present invention also relates to the re-development or other human administration of compounds of formula I that increase the risk of breast cancer. Patients who have no evidence or cannot suspect that they may have new breast cancer but are not particularly at risk of developing breast cancer will have a high normal risk of a normal disease that has not been diagnosed with this disease. The greatest risk factor for breast cancer is a person's history of breast cancer. A person is considered a “breast cancer survivor” 5 years or more before the disease is treated, even when there is no evidence of residual disease. Another fully accepted risk factor is a family history of the disease. 2 Luoxifen, which is the hydrochloride of the formula compound, has been shown to be combined with the estrus hormone, and was originally thought to be an anti-estrous molecule with functional and pharmacological properties. — In some tissues, the effect of estrus stimulation is blocked; however, in other tissues, Laloxifene will act as an estrogen hormone, Sanjuli and act as an estrus, such as in bones and in serum / households.妯 &-β β ^ _ The appearance of Lochphen in Beshang differs from the appearance of estrogens, and the other "anti-stress" is due to the specificity of the compound Activation and / or inhibition of various gene functions rather than

(Please read the precautions on the back before installing. 586942 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (1) The compound or inhibitory effect of estrogen and estrogen receptors. The activation of mu and the same receptor, but it is not easy; ^ = # 和 = cyanosteroids use and compete with each other, and they are unique-unique #_ 基 _ 节 的 Pharmacological connection: It is common with It is formulated with excipients, diluents or carriers, and is formulated as a tincture or solution for oral administration or administration by intramuscular or intravenous routes. The compound can be administered through the skin or intravaginally. It can be administered and can be formulated into a sustained-release dosage form, parenteral form, long-acting form and the like. 4 38〇635, 5 629 425, UK Patent Application gb 2,293,602 published on March 3, 996, and filed on February 28, 1995, European published on September 6, 1995 Established steps detailed in Patent Application No. 95301921 Made, all of which are incorporated by reference in their entirety. Generally, the process begins with a phenylhydrazone [b] p-phenene bearing a 6-hydroxyl group and a 2- (4- unmethylfluorenyl) group. The chemical radical of the compound is protected, and three positions are tritiated, and the product is deprotected to form a compound of formula I. As mentioned above, the US patent and the British patent application provide examples of preparing such compounds. Methods of the Invention The compounds used form pharmaceutically acceptable acids and addition salts with many organic and inorganic acids and bases, including the physiologically acceptable salts often used in medicinal chemistry. These salts are also part of the present invention. Typical inorganic acids that form such salts include hydrogen acid, hydrobromic acid, hydrogen-for-acid, nitric acid, sulfuric acid, phosphoric acid, low phosphoric acid, and the like. Derivatives can also be used (please read the precautions on the back first and then 1-- In · .Assemble · Thread _ 13- This paper size is applicable to Chinese National Standard (CMS) A4 (2 丨 0X297mm) 586942 Printed by A7 B7 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention (11) Organic Acid salt, Such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, # -based chain dicarboxylic acids, and di-chain chain dicarboxylic acids, aromatic acids, aliphatic and aromatic sulfonic acids. These are pharmaceutically acceptable Salts therefore include acetate, phenylacetate, trifluoroacetate, propionate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, formate Oxybenzoate, Methylbenzoate, Ortho-Ethoxybenzoate, A-2-benzoate, Bromide, Isobutyrate, Phenylbutyrate, Lu -Hydroxybutyrate, butyne-1,4-diacid, hexyne-1,4.diacid, caprate, caprylate, gas, cinnamate, citrate 'formate, Fumarate, glycolate, heptanoate, hippurate = lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate Salt, nicotine salt, isonic nicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphonate, Pyrophosphate Propionate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, sulfite Bisulfate, sulfonate, benzenesulfonate, p-bromobenzenesulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, pinanesulfonate, stubble -1 -sulfonate, moss-2 -sulfonate, p-toluenesulfonate, tosylate, tartrate and the like. The preferred salt is the hydrochloride. Pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of formula I with an equimolar or excess acid. The reactants are usually mixed with a mutual solvent such as diethyl ether or benzene. Under normal circumstances, the salt will precipitate from the solution in about 1 hour to 10 days, and can be separated by filtration or washed by traditional methods. _-14-_ This paper size applies Chinese National Standard (CNS) Λ4 specifications (210X297 mm) (Please read the precautions on the back before loading, 1T

586942 A7 B7 V. Description of Invention (12 Solvents are printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. They are commonly used to form salts of ammonium hydroxide and test metal hydroxides, carbonates, and aliphatics. And the first, second, and third amines, and aliphatic diamines. Tests that are particularly useful in the preparation of addition salts include hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, methylamine, diethylamine, and u- Ethylenediamine and cyclohexylamine. Pharmaceutically acceptable salts generally have properties that are more soluble than the compounds from which they are derived, so they are often easier to formulate into liquids or emulsions. They can be prepared by sufficient steps known in the art. Pharmaceutical formulations. For example, the compound can be formulated with common excipients, diluents or carriers, into tablets, sacs, floating fluids, powders, and the like. Excipients, dilutions suitable for such formulations Examples of agents and carriers include the following: fillers and supplements such as starch, sugar, sorbitol and silicic acid derivatives; binders such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin Polyene Pyrrolidone; Wetting agents, such as glycerol; Disintegrating agents, such as calcium carbonate and bicarbonate, preparations that hinder decomposition, such as paraffin; Resorption accelerators, such as quaternary ammonium compounds; Surfactants, such as whale wax Alcohols, glycerol monostearate; adsorbent carriers' * clay and bentonite; and lubricants such as talc, stearic acid and magnesium and solid polyethylene glycols. Chemicals can also be formulated as tinctures Or solution for traditional oral administration or a solution suitable for parenteral administration, for example by intramuscular, subcutaneous or intravenous routes. &Amp; The compound is also well-suited for formulation into sustained release dosage forms and the like The formulated product may release the active ingredient only or preferably in special parts of the intestine for more than a period of time. It can be made of polymer or paper tape, for example (please read the precautions on the back before loading.

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-15- ^ 00 ^ 42 V. Description of the invention (13 Wax is made of coating, film and protective matrix. The special efficacy and sufficient period and dosage of the compound of formula (I) required for the prevention of breast cancer, according to the present invention, are by the physician according to the patient's body Characteristics, route of administration, and related factors. The preferred period of administration is at least six months, more preferably at least one year, and most preferably at least two years or longer. Generally, a daily dose that is accepted and effective is about 0 to about 1000 mg / day, and preferably about 30 to about 2000 € g / day, but more preferably about 50 to about 150 mg / day. The optimal dosage range is between about Between 60 and about 120 mg / day, 60 mg / day is particularly preferred. _ The full dosage range is not meant to be affected by the present invention. In addition to revealing the < range, the present invention also includes chemistry by providing a display compound The preventive properties are functionally equivalent to these ranges. Therefore, when certain modes of administration allow the effective use of each of the compounds of the formulae literally different dose ranges, these different dose ranges on When the function is equivalent to the scope of the reveal It is included in the present invention. In addition, the dosage range described is mainly the hydrochloride salt of the compound of Formula 1. Therefore, a 60 mg dose is equivalent to 55.71 mg of free base. It is a common skill in the art to calculate A free base equivalent to any salt of a pharmaceutically acceptable compound of the formula. For example, "about 60 mg" contains 55 to 65 grams of laloxine hydrochloride, but on the other hand contains 51 73 to 6035 mg of free base. It is also beneficial to administer the compound via the oral route. The following oral dosage forms can be used to achieve this. Formulations (please read the precautions on the back before loading.)

Printed by the Consumers 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs-16 586942 A7 B7 V. Description of the Invention (14) Preparations printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 1: Gelatin capsules The following substances are used to prepare hard gelatin capsules: Quantity (mg) / Capsules) Laloxine HC1 30-200 Starch, NF 0-650 Flowable starch powder 0-650 Silicone liquid 350 centimeters (M5 After mixing the ingredients, pass through the No. 4 and No. 5 sieve openings of the US sieve, then Fill in hard gelatin capsules. — Examples of capsule formulations include the following: Formulation 2: Laloxine Capsules (mg / capsule) Laloxine HC1 30-200 Starch, NF 112 Flowable starch powder 225.3 Siloxane 350 histories 1.7 Formulation 3: Laloxine capsule amount (mg / capsule) Laloxine HC1 λ 30-200 starch, NF 108 Flowable starch powder 225.3 Siloxane liquid 350 centimeter history 1.7 (Please read the precautions on the back before -17- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 586942 B7 V. Description of the invention (15) Formulation 4: Number of Laloxifene Capsules (mg / capsule) Laloxifine HC1 30-200 Starch, NF 103 Flowable starch powder 225.3 Silane solution 350% History 1.7 Please read the precautions on the back first ΐϋ'-ϋΐ -Packing · Ministry of Economic Affairs ^ Standards Bureau Consumer Consumption Cooperative Association Printing $-Formulation 5: Laloxifine Capsule Ingredients (mg / capsule) Laloxifine HC1 ~ 30-200 Starch, NF 150 Flowable Starch powder 397 Silane solution 350 centimeters and above 3.0 Special formulations can be changed within reasonable variations as needed. Use the following ingredients to prepare tablet formulations: Formulation 6: Number of tablet ingredients (mg / tablet) Laloxphen HC1 30-200 cellulose, microcrystalline 0-650 silicon dioxide, fumes. 0-650 stearic acid 0-15 After mixing the ingredients and compressing them into tablets. -18- This paper size applies to Chinese national standards (CNS ) Specification of Λ4 (210X297 mm) Binding V. Description of the invention (16 In addition, each tablet contains 0-1000 milligrams of active ingredient, which is prepared as follows: Formulation 7: Number of tablet ingredients (mg / tablet) Pull Roche HC1 Starch cellulose, microcrystalline polyvinylpyrrolidone (dissolved in water as a 100 / 〇 solution) Carboxyfluorenyl cellulose sodium stearate ~ talc 30-200 45 35 4 4.5 0.5 1 Please read the back first Note-Caution: Mix active ingredients, starch and cellulose after passing through a No. 45 sieve of US sieve. The polyvinylpyrrolidone solution was mixed with the resulting powder. It then passed through a No. 14 sieve in the United States. The granules thus produced are at 50. It was dried at 60 ° C. and passed through a No. 8 sieve of an American sieve. Next, sodium carboxymethylcellulose, starch, magnesium stearate, and talc that had previously passed through a sieve of No. 60 US sieve were added to the granules, and after mixing, they were compressed on a tablet machine to produce tablets. Each suspension contains from 0.1 to 100 g of medicament per 5 ml dose and is prepared as follows: Formulation i: suspension

Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economics-1Q-Taiji Paper Standard is applicable to China's National Dejin "ΓΝ.ς, Strain 7 586942 A7 B7 V. Description of Invention (17) Printed by the Central Standards Bureau of the Ministry of Economic Affairs Quantity (mg / 5ml) Laloxine HC1 30-200 Sodium Carboxymethyl Cellulose 50mg Syrup 1.25mg Benzoic Acid Solution 0.10ml Fragrance Moderate Colorant Moderate Add Pure Water to 5ml Pharmacy Pass No. 45 If US After pores, it is mixed with sodium carboxymethyl cellulose and syrup to form a smooth paste. Then add some benzoic acid solution diluted in water, perfume and colorant while stirring. Then add enough water to make the required amount. The preferred tablet formulations include the following two: Formulation 9: Ingredients (mg) Function Laloxine HC1 60.0 Active Spray-Dried Lactose 30.0 Soluble Diluent Anhydrous Lactose 12.0 Soluble Diluent Polyethylene Sagapotone 12.0 Adhesive polyethoxy ether 80, 2.4 Wetting agent Cross-linked polyethylene acetophenone 14.4 Disintegrator Magnesium stearate 1.2 Lubricant (center tablet weight 240.0) (Please read the back Precautions Re-installed

、 1T line-=-20 = — This paper size applies Chinese National Standard (CNS) A4 specification (210X297mm) 586942 A7 B7 V. Description of the invention (18) Thin film coating white coloring material 12.0 Colorant talc polishing Auxiliary Carnauba — Polishing Auxiliary Formulation 10: Ingredients (mg) Function Laloxifine HC1 60.0 Active Spray-Dried Lactose 29.4 Soluble Diluent Anhydrous'-120.0, Soluble Diluent Polyvinylpyrrolidone 12.0 Adhesive polyethoxy ether 80 2.4 Wetting agent Cross-linked polyethylene erogenol J with 14.4 Disintegrant Magnesium stearate 1.2 Lubricant (center tablet weight 240.0) · White pigmented film coating 12.0 Talc as a coloring agent — Polishing aid A small amount of polishing aid for Carnauba palm (Please read the precautions on the back before printing the test procedure by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. When you agree with the effectiveness of the present invention, use Laloxphen The safety results in the middle of conducting a phase III clinical trial are shown below. Most examples of breast cancers are high-volume, ongoing osteoporosis _-21 -_ The paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) 586942 Α7 Β7 V. Description of the invention (19) I 1 III 1-7704 patients printed and researched by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs There are post-menopausal women with established osteoporosis. However, there are examples of a smaller number of post-menopausal women studying the risk of osteoporotic foot. The study published in this article was unaware of both the patient and the investigator and was a placebo Most of them are about 3 years, and are designed to determine the effectiveness of laloxifen in the prevention or treatment of osteoporosis in postmenopausal women. In addition, the study provides cardiovascular health and other major medical conditions (including Breast cancer incidence). Randomly assigned patients received 30 mg, 60 mg, 120 mg, or 10.5 g of oral placebo daily. All patients and researchers—no knowledge of the designation of the study drug. (Both sides did not know the design.) All patients in group ^ received calcium supplements of about 500 mg / day per day. In addition, in 7704 patients In treatment studies, patients receiving vitamin D supplements at 400-600 IU / day were selected in these studies as postmenopausal women (at least 2 years from the last menstrual cycle). The age range was about 55 to 80 years. Criteria that typically cannot participate in these studies include: "Severe systemic disease, 2) Acute or chronic liver disease, 3) Impaired renal function, 4) Researcher's opinion that the patient's medical or mental illness is poor, etc. Risk factors, not suitable for clinical trials, such as drug or alcohol abuse, 5) patients with any medical history of cancer within 5 years of participation in the study, except for surface damage, such as basal cell carcinoma of the skin, 6) abnormal uterus Bleeding. The most important criterion for exclusion is to exclude women who have or have a personal history of breast cancer or other estrogen-dependent neoplasms. The patient populations generated by these exclusion criteria reflect the risk of developing breast cancer, or in other words, their risk of developing breast cancer is not particularly high. -22- This paper hates the ruler! Tongguo National Standard (CNS) M Specification ((Please read the notes on the back first s- ^ I ............ m .......... ·· 装 ·

1T ^ «6942 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of Inventions (20 Screen for possible patients before registering for participation in the study. Disease = Medical history and recent medical status. All possible patient regulations 嶋 photography or Ultrasound assessment of the breast, or these steps were performed in 12 rooms before participating in the study. In most studies, 2 years are required; 5V follow-up examination; 5V follow-up examination; however, it is recommended to perform breast photography every year. After diagnosis and All patients declared as breast cancer need to immediately suspend participation in the study and be instructed by the field investigator to perform appropriate cancer assessment and care. Guan A. All placebo-controlled trials for at least six months and all those receiving study medication for more than one month. In the disease, a total of ^ breast cancer cases were reported. Compared with 18 cases of Laoxifen treatment of Cai ~ group, 24 cases were observed in the placebo group. Randomized patients designated treatment (Lalo The total ratio of thiophene to placebo) is approximately 2: 1. The results shown in Tables 1-4 are for patients who have been diagnosed with a histopathological diagnosis of breast cancer. Data include breasts for any year And necessary basic and two-year follow-up results of mammography. Once breast cancer is diagnosed, these patients discontinue the study and explain their situation and reveal their assigned treatment (treatment group) (eg, what drugs the patient has received For the study published in the present invention, the number of patients randomly assigned to receive placebo was approximately 3195. The number of patients randomly assigned to receive laroxine (all doses added up) was approximately 6681. (7704 patient treatment studies The majority of treatments were not disclosed to patients who are still enrolled in the study. Therefore, the number of patients assigned to each treatment group is an estimate. The results below are for any time during the study period, but were randomly assigned to study medication (placebo or placebo or Laloxifen) was diagnosed with breast cancer at least one month later (please read the precautions on the back before-binding · ordering

-23- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 586942 A7 B7 V. Description of invention (21 people. Table 1 shows the results of all placebo-controlled studies and collects all Dose data. Table 2 shows the subpopulations of the examples shown in Table 1; especially the large number of groups registered in the treatment study of 7704 patients, most of which will develop breast cancer. Two Laroche in this treatment study The doses of phenone are 60 mg / day and 120 mg / day. As the incidence of breast cancer increases with age, the incidence of breast cancer in treatment studies is expected to be higher [average patient age at the beginning of the study is 67 years]. The table shows that each The number of cases of breast cancer in the treated population (η), the total number of patients designated for the treatment (N), the estimated relative risk of breast cancer, and the phase of breast cancer _ 95% reliable interval to risk. Note that if 95% When the number of reliable intervals is less than 1.0, it means that the incidence of breast cancer with laroxifen is lower than that with placebo, which is statistically evident (at a 5% level). Please read ik first Note -Note M Table 1. Analysis of the relative risk of breast cancer combined with all placebo-controlled studies. From the designated treatment to the placebo case Lalochphene case relative risk (95% of the time Lalotus relative risk diagnosis η / Ν (° / 〇) Child η / Ν (%) thiophene versus placebo) Reliable interval at least 1 month 24/3195 18/6681 0.36 (0.20, 0.64) At least 12 months 24/3195 10/6681 0.23 (0.11 , 0.45) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economics of Line I-24- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 586942 Α7 Β7 V. Description of the invention (22) Relative risk of breast cancer Analysis of a large number of 11704 patients with postmenopausal women who have been identified as osteoporosis) Treatment Study _ From the designated treatment to the placebo example Lalochphene relative risk (95% of Lalox relative risk time to diagnosis η / N (%) sub-η / Ν (0 / 〇) thiophene versus placebo) reliability interval at least 1 month 21/2659 12/5317 0.29 (0.15, 0.55) at least 12 months 18/2659 5/5317 0.14 ( 0.60, 0.32) (Please read the notes on the back first and install it in the center of the Ministry of Economy Printed by the Prospective Staff Consumer Cooperative in these placebo-controlled studies, it is clear that patients who were randomly assigned to use laroxine had lower breast cancer rates than patients who were randomly assigned to use placebo. After randomizing the study drug At least one month, the original relative risk of all patients diagnosed was estimated to be 0 36,95%. The reliability interval (0.20, 0.064) represents a 64% reduction in breast cancer risk. When considering only a large number of treatment studies, the original relative risk estimate was 0.29, 95% reliable interval (0.15, 0.55), representing a 71% reduction in breast cancer probability. These results are very important statistically. ’Because breast cancer diagnosed at least one year after random designation is most likely to represent a non-clinical pre-existing cancer, we also analyzed data considering only cases that occurred at least 12 months after random designation of the study drug. The estimate of the original relative risk for combining all placebo-controlled studies was 0.23, 9 5% reliable interval (0.1 1, 0.45), which corresponds to a 77% reduction in breast cancer rate. Regarding multiple treatments Research 5 ?: ’Estimation of the original relative risk 値 is 14.95% reliable interval (0.06, 0.3 2), which is equivalent to reducing the incidence of breast cancer by 86%. In order to further analyze the length of the study and the appearance of tumors, Tables 3 and 4 -25- This paper is suitable for financial standards (CNS) A4 specifications (2ΐϋ7mm I line 586942 A7 V. Description of the invention (23) Reveal the relative risk data , Which is divided into three periods: υ Examples of diagnosis after follow-up of basic mammography, such as all examples of diagnosis between 丨 6 months after the designation of study drugs; 2) Examples of diagnosis after 丨 year-old mammography follow-up All examples diagnosed between 6 and 18 months after study drug designation, and 3) Examples diagnosed after 2 years of mammography tracking, such as all diagnoses between 18 and 30 months after study drug designation example. Table 3 shows the relative risks of breast cancer for each time period combined with all placebo-controlled studies. Table 4 shows the data of the patient subgroups published in Table 3, that is, a large number of patients who died of treatment in 7704 patients (patients. In the two tables, the relative risk of breast cancer I in each successive pursuit period was significantly reduced. The relative risk of people of the two ethnic groups during the 2-year follow-up period is of statistical significance. Table 3 · The relative risk of breast cancer each year (please read the precautions on the back before-00 I.-equipment. Order Ministry of Economy Printed by the Central Bureau of Standards Consumer Cooperatives and combined with all placebo-controlled studies are a mammography placebo example Laroxifen example relative risk HCO / rsr σ quasi-risk (1-6 months) 2 5 1.20 95% acceptable interval (0.23, 6.15) 1-year follow-up (6-18 months) 6 7 0.56 (0.19, 1.63) 2-year follow-up (18-30 months) 16 5 0.15 (0.06, 0.36) a · Random designation -Laloxifine: placebo is 2 1. ^ B. Patients diagnosed with breast cancer 'tumor after 30 months are excluded from this analysis by time classification. This paper standard applies Chinese National Standard (CNS) A4 Specifications (210X29? Mm 586942 A7 B7 V. Description of the invention (24) Table 4. Annual milk Relative risk of cancer. Large number of postmenopausal women with identified osteoporosis (7704 patients). Treatment study. Mammography. Placebo example. Laloxifen. Relative risk. 95% reliable interval baseline. (1 -6 months) 2 5 1.25 (0.24, 6.42) 1 year follow-up (6-18 months) 6 4 0.33 (0.10, 1.11) 2 years follow-up (18_30 months) 13 3 0.12 (0.04, 0.33) a · random Designation-Laloxifine: Placebo is 2.1: 1 Please read the precautions on the back before loading-according to the final summary, Figure 1 shows the incidence of breast cancer in all placebo-controlled studies. (30 months later Patients diagnosed with breast cancer are excluded from this chart, so the chart shows approximately the same follow-up period for both treatment groups.) Until a 1-year time point, the incidence of breast cancer in the placebo group was higher than that of lalaxifen. When the incidence of breast cancer in ethnic groups is large, the two lines (placebo and laloxifine) can be almost distinguished after they are separated. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Online Economics -27 This paper applies the Chinese national standard ( CNS) A4 size (2H3X 297 PCT)

Claims (1)

Case No. 586942 (92, please apply for the benefit of this application I. The scope of the application is 15, the scope of the application is 2nd, the application is 116, and the application is 864. The BCD is applied. 1. The scope of the patent application 1. A pharmaceutical composition for preventing human breast cancer, which contains Compound of formula ^^^ och2ch 0H or a pharmaceutically acceptable salt or solvate thereof is used as an active ingredient by administering an effective dose of the compound to a postmenopausal woman for a sufficient period of time, the period being at least one year, and the limitation is that it is effective The dosage is not between 60 mg and 120 mg / day. 2. The pharmaceutical composition according to item 1 of the scope of patent application, wherein the effective dose is between 30 mg and 200 mg / day, and the limitation is that the effective dose is not between 60 mg and 120 mg / Day. 3. The pharmaceutical composition according to the scope of the patent application, wherein the effective dose is between 50 mg and 150 mg / day, and the limitation is that the effective dose is not between 60 mg and 120 mg / day. Between days. 4. The pharmaceutical composition according to item 1 of the scope of patent application, wherein the period is at least two years. 5. The pharmaceutical composition according to item 1 of the scope of patent application, wherein the period is a long period.疋 O: \ 49 \ 49948-92080U The paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 586942 A8 B8 C8 D8 2. Patent application scope 6 The pharmaceutical composition according to item 丨 of the patent application scope, wherein the compound is its hydrochloride. 7. The pharmaceutical composition according to item 丨 of the application, wherein the human is a post-menopausal woman who is not particularly at risk of developing breast cancer. 8. The pharmaceutical composition according to item 丨 of the patent application scope, wherein the breast cancer is heavy 9. A pharmaceutical composition for preventing human invasive breast cancer, comprising a compound of the formula Or a pharmaceutically acceptable salt or solvate thereof as an active ingredient by administering an effective dose of the compound to a postmenopausal woman over a sufficient period of time, the period being at least one year, and the limitation is its effective dose Not between 60 mg and 120 mg / day. 10. The pharmaceutical composition according to item 9 of the scope of patent application, wherein the effective dose is between 30 mg and 200 mg / day, and the limitation is that the effective dose is not between 60 mg and 120 mg / day. Between days. 11. The pharmaceutical composition according to item 9 of the scope of patent application, wherein the effective dose is based on the Chinese National Standard (CNS) A4 specification (210X297 mm) 586942 Its effectiveness is between 50 mg and 150 mg / day, and the limitation is that the dose is not between 60 mg and 120 mg / day. 12. The pharmaceutical composition according to item 9 of the scope of patent application, in which the period is two years less. " 疋 to 13. The pharmaceutical composition according to item 9 of the scope of patent application, wherein the period. 14. The pharmaceutical composition according to item 9 of the application, wherein the compound is its hydrochloride. 15. The pharmaceutical composition according to item 9 of the scope of patent application, wherein the human is a post-menopausal woman who is not particularly at risk of developing breast cancer. 16. The pharmaceutical composition according to item 9 of the scope of patent application, wherein the breast cancer is de novo. O: \ 49 \ 49948-92080I.DOC \ 5-β-This paper size applies to China National Standard (CNS) Α4 specification (210 × 297 mm)