KR19980033284A - Improved Breast Cancer Prevention - Google Patents

Abstract

The present invention relates to the prevention of breast cancer in postmenopausal women, in which the woman is administered raloxyphene, or a pharmaceutically-acceptable salt thereof, in an amount from about 30 mg to about 150 mg / day.

Description

Improved Breast Cancer Prevention

The present invention relates to a method for preventing female breast cancer.

Breast adenocarcinoma or cancer is a major medical problem, especially for women over 35 years of age. In the United States, it is estimated that one in eight people can develop the disease during their lifetime. Breast carcinoma is not only a major cause of mortality in women, but also a cause of disability, psychological shock, and economic loss. Many women with this disease eventually die from their direct or indirect complications.

Raloxyphene has the structure of formula (1), in particular its pharmaceutically acceptable salts are described for the first time in US Pat. No. 4,418,068.

US Pat. No. 4,418,068 teaches that raloxyphene is useful for the treatment of breast tumors and for the prevention of recurrence of benign breast fibrotic disease. Unfortunately, raloxyphene's clinical trials for the treatment of breast cancer did not support human efficacy. Such negative results have lowered the further evaluation of raloxyphene as a treatment for breast cancer in humans.

Surprisingly, accidental findings have now established that raloxifene is very effective in the prevention of breast cancer. More surprisingly, it has been found that this prophylactic effect manifests itself particularly strongly in a narrow dosage range.

Thus, according to one aspect of the invention, the development of breast cancer in postmenopausal women comprising administering to the woman raloxyphene, or a pharmaceutically-acceptable salt thereof in an amount of about 30 to about 150 mg / day It provides a way to suppress.

In a second aspect of the invention, a medicament adapted to administer about 30 to about 150 mg / day of raloxyphene, or a pharmaceutically-acceptable salt thereof, to postmenopausal women to inhibit the onset of breast cancer in postmenopausal women. In the preparation, there is provided the use of raloxyphene, or a pharmaceutically acceptable salt thereof.

In a third aspect of the invention, the composition is sufficient to provide about 30 to about 150 mg / day of raloxyphene, or a pharmaceutically-acceptable salt of raloxyphene, or a pharmaceutically-acceptable salt thereof. Pharmaceutical compositions are provided for inhibiting the development of breast cancer in postmenopausal women, comprising salts.

In a fourth aspect of the invention, a packaging material and a raloxyphene, or a pharmaceutically-acceptable salt thereof, included in the packaging material, wherein the packaging material is a raloxyphene or a salt of a pharmaceutically-acceptable raloxyphene A product is provided that includes labeling instructions indicating that this postmenopausal woman is to be administered in an amount of about 30 mg to about 150 mg / day to inhibit the development of breast cancer.

Preferably, raloxyphene, or a pharmaceutically-acceptable salt thereof, should not be administered in an amount greater than 120 mg / day, more preferably less than 100 mg / day. The preferred lower level of administration is about 40 mg / day, more preferably about 50 mg / day. The most preferred range for prophylactic efficacy is 50 to 80 mg / day, and a characteristic protective effect is observed at about 60 mg / day, for example 50 to 70 mg / day.

As used herein, the term prophylaxis of the development of breast cancer is mainly referred to in situations where de novo modification from normal breast cells to cancer or malignant cells is inhibited. However, there may be women with medically non-detected cancer cells in the breast, and inhibition of this onset, however, may also form medically insignificant cancers as part of the present invention. Not falling within the scope of the present invention is the treatment of present, medically-detectable breast cancer.

Raloxyphene, and pharmaceutically-acceptable salts thereof, which may be prepared according to established processes are described in US Pat. Nos. 4,133,814, 4,418,068, 4,380,635 and British Patent Application 2,293,602. Preferred crystalline forms are described in British Patent Application No. 2,293,382, all of which are incorporated herein by reference. In general, the synthesis starts with benzo [b] thiophene with 6-hydroxyl groups and 2- (4-hydroxyphenyl) groups. The hydroxyl group of the starting compound is protected, the 3 position is acylated, and the product is protected to form the desired compound.

Raloxyphene forms pharmaceutically acceptable acid and base addition salts with bases including a wide variety of organic and inorganic acids and 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, phosphoric 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, benzenesulfonate, p-bromobenzenesulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene 2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate and the like. Preferred salts for use in the present invention are hydrochlorides.

Pharmaceutically acceptable salts are generally easier to formulate as liquids or emulsions because they are more soluble than the compounds from which they are derived.

Pharmaceutical formulations may be prepared by procedures known in the art. For example, the compound may be formulated with common excipients, diluents or carriers and formed into 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 glycols.

The compounds may also be formulated as elixirs or solutions for convenient oral administration. Parenteral administration (eg intramuscular, subcutaneous or intravenous routes) is also possible, but for prevention is certainly less preferred than oral administration. In addition, the compounds are well suited for formulation into sustained release dosage forms and the like. The formulation may be formulated to release only the active ingredient or preferably at specific sites of the intestine, possibly over a prolonged period. For example, coatings, envelopes and protective matrices can be prepared from polymeric materials or waxes.

The daily dose of raloxyphene, or pharmaceutically-acceptable salt, is about 30 to about 150 mg / day. Such dosage will be consumed by the subject once to possibly three times a day. Preferred dosages range from about 60 to about 120, or 150, mg / day, particularly preferably 60 mg / day.

Although it can be expected that the prolaclactic effect provided by the present invention is direct and statistically significant data compared to the general population, the administration period is most preferably at least 6 months, preferably at least 1 year, most preferably at least 2 years. It is obvious. Clearly, prevention of breast cancer is a significant improvement in the quality of life of women, with very long and even long life and treatment being advantageous.

As mentioned above, the preferred route of administration is the oral route. For that purpose, the following oral dosage forms are available.

Formulation

Formulation 1: Raloxyphene Capsule

ingredient Amount (mg / capsules) Raloxyphene HCl 60 Starch, NF 112 Starch flow powder 225.3 Silicone Latex 350 Centistox 1.7

Examples of preferred tablet formulations include those shown below:

Formulation 2:

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 (240.0) slush Film coating Color mixture white 12.0 coloring agent Talc a very small amount Polishing aids Carnova wax - Polishing aids

Formulation 3:

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

The results of medical studies in raloxyphene (in the form of hydrochloride) are shown to demonstrate the protective effect of the present invention.

The main design is double-blind randomization, and placebo-control in about 7500 postmenopausal women. Studies generally have three groups (arms), randomly assigned the same number per group via the oral route to placebo, drug 60 mg / day, or drug 120 mg / day.

Patients selected for this study are postmenopausal women between about 50 and 80 years old (more than two years since the last menstrual period). In addition, these women generally had good health appropriate for their age.

Exclusion criteria from participation in this study include past or present cancer. In particular, it does not allow the participation of a person currently or suspected of having a history of breast carcinoma or other estrogen-dependent neoplasia. This exclusion criterion generates a population of patients that reflects the potential of the general population regarding the potential to develop breast cancer.

Potential patients are screened before participation in the study. The patient is required to identify the current medical condition and medical history. All potential patients are required to have a basal mammogram or breast ultrasound assessment (to screen for the presence of breast cancer). If the patient has any reason to discontinue the study, it may or may be breast cancer, so the patient is evaluated for breast cancer. Diagnosis of breast cancer is made pathologically from biopsy or surgical specimens.

The results shown in Table 1 are patients found through various diagnostic methods, including one year mammogram results, with breast adenocarcinoma or cancer. These patients are immediately discontinued from the study participation and reveal their blinded condition to reveal their randomized treatment (arm).

The number of patients in each arm of the study was 5078 at two dose levels of raloxifene and 2539 at placebo.

Patient number Treatment group Months 4053 Placebo 5 3057 Placebo 12 6637 Placebo 12 2233 Placebo One 2652 Placebo 4 7666 Placebo 3.5 3994 Placebo 2 4678 Placebo 6 6018 Placebo 15 3817 Placebo 13 1858 Placebo 13 238 Placebo 3 3930 60 mg raloxyphene 11 2693 120 mg raloxyfen 4 5801 120 mg raloxyfen 4 393 120 mg raloxyfen 4 32 120 mg raloxyfen 12

The results of the data indicate that the relative risks of patients in this study were diagnosed as having breast cancer when compared to placebo, with 1.0 (definition) and raloxifene dosage (data for both 60 mg and 120 mg doses) in placebo The ruler was 0.21 (95% confidence interval, 0.07 vs 0.59). The 60 mg dose is very useful and therefore a preferred aspect of the present invention.

Combined all relevant studies with raloxyphene, breast cancer occurred in a total of 14 placebo-arm patients and breast cancer in a total of 9 raloxyphene patients. The total number of placebo patients was 3087 and the total number of raloxifene patients was 6584.

Table 2 below shows some additional results from the study with different raloxyphene dosage levels.

Patient number Treatment group Months 888 Placebo 22 3601 Placebo 21 2889 Raloxyphene 150 mg 20 3857 Raloxyphene 30 mg 13 3622 Raloxyphene 30 mg 8 5415 Raloxyfen 60 mg 13

In all studies, the crude relative risk estimate (RR) of the development of breast carcinoma of raloxyphene versus placebo was 0.31 (95% confidence interval, 0.13 to 0.71). This reported difference in treatment group probability at incidence is due to the random probability being about 0.6%. Approximate incidences of cancer were: placebo = 4.23, raloxifene 30 mg = 4.0, raloxifene 60 mg = 0.6, raloxifene 120 mg = 1.6, raloxifene 150 mg = 2.6 Rate is expressed as the number of reported cases per 1,000 patient-years of exposure to the drug.

Claims (2)

Wherein the composition provides about 30 to about 150 mg / day of raloxyphene, or a pharmaceutically-acceptable salt of raloxyphene, including a sufficient raloxyphene, or a sufficient pharmaceutically-acceptable salt thereof , Pharmaceutical compositions for inhibiting the development of breast cancer in postmenopausal women. The pharmaceutical composition of claim 1, comprising about 60 mg of raloxyphene hydrogen chloride.