TW201031400A - Trans-clomiphene for metabolic syndrome and diabetes mellitus type 2 - Google Patents

Abstract

The present invention relates to the administration of compositions comprising an antiestrogen, preferably trans-clomiphene, for treating metabolic syndrome in a subject. The invention is also directed to methods for reducing fasting glucose levels in a subject by administering a composition comprising an antiestrogen, preferably trans-clomiphene. The invention is also directed to methods for the prevention and treatment of diabetes mellitus type 2.

Description

201031400 - VI. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a composition and method for treating metabolic syndrome and a condition associated therewith with 9. More particularly, the present invention relates to the use of a composition comprising a sulphate-rich clofiphene, which is useful for treating metabolic syndrome in individuals with low or low normal testosterone and The condition associated with it. The invention also relates to the use of a composition comprising mifefen rich in trans-clomiphene for the treatment of type 2 diabetes. ❹ [Prior Art] Metabolic syndrome is characterized by a group of metabolic risk factors in an individual, including abdominal obesity, insulin resistance or glucose intolerance, atherogenic dyslipidemia, prothrombotic state, pre-inflammatory state (proinflammatory state) and high blood pressure. The adult treatment group defines metabolic syndrome in which the patient exhibits at least three of the following symptoms: the measured waist circumference of the male is at least 40 吋, the female waist circumference is at least 35 吋, and the serum triglyceride level is at least 150 mg/dl; HDL cholesterol levels are less than 40 mg/m in men (H's women are less than 50 mg/dl; blood pressure is at least 135/8〇mm Hg and blood glucose (jk clear glucose) is at least 110 mg/di. Up to 25% in the United States) The population suffers from metabolic syndrome. The underlying cause of the salty metabolic syndrome is the resistance to tamsin, in which the ability of the membrane to absorb glucose from the blood and fluid is weakened. This leads to an increase in glucose levels after eating, and the pancreas responds to secrete insulin. If left untreated, metabolic syndrome significantly increases the risk of developing type 2 diabetes, cardiovascular disease, and other diseases associated with plaque formation in the arterial wall. 3 201031400 Fasting pancreatic islet I u τ island level and serum testosterone in men The inverse correlation between the two has been confirmed by several studies. In addition, there are metabolic syndrome and other insulin-resistant conditions compared to the control group ( For example, obesity and sputum type 2 diabetes, men's steep blood/month stagnation _ is significantly lower. However, the mechanism for interpreting these observations is not clear. A recent study suggests that the relationship between _ and Tengdaosu may be It is regulated by changes in body mass index (BMI), which causes obesity and fatty acid metabolism to be poorly regulated by π 代谢 metabolism, which in turn promotes insulin resistance. In contrast to Bigu, the researcher No significant relationship was found between estrogen levels and insulin sensitivity. Another recent study evaluated the male hypothalamic-pituitary-gonadal axis with a wide range of 姨 sensitivity. In this study, insulin was observed. Positive correlation between sensitivity and testosterone' However, no relationship between sensitization sensitivity and luteinizing hormone (LH) secretion parameters was observed, indicating low tamping associated with resistance to tamsin _ Caused by defects in the hypothalamus or pituitary, but caused by changes in the function of Leyk cells (LevHk « η, , , Leydig cell ). In this respect, it has been recognized that at least 4 m _ Bulei cells in vitro Alcohol production is not only regulated by pulsatile secretion of LH but also by hormones, growth factors, cytokines, and lyme. There is a contradiction in the data on the effects of androgen supplementation on male insulin sensitivity. Among them, men with type 2 diabetes showed that glycemic control was not changed by codone supplementation,4 and a larger study showed a significant reduction in glycosylated hemoglobin. Majorosterone is the major male androgen in men's overall health. It plays an important role in the development and maintenance of specific reproductive tissues (test pills, prostate, epididymis, storage 201031400 seminal vesicles and penis) and male secondary sexual characteristics. It plays an important role in sexual and erectile function and is the beginning and maintenance Required for sperm production. Steroidal secretion is the final product of the -hormone process. The gonadotropin (GnRH) secreted by the hypothalamus (lh) and the pulsatile secretion of eLH secreted by the anterior pituitary (FSH) regulate the production of sputum And secretion, (d) FSH helps induce spermatogenesis.

Tamping _ deficiency may be caused by a underlying disease or genetic disorder and is often a complication of aging. For example, 'primary gonadal dysfunction is caused by primary testicular failure. Under this condition, sputum sputum levels are lower and pituitary gonadotropin levels (LH and FSH) are elevated. Secondary gonadal dystrophy or gonadotropin Hypogonadism (hyp〇g0nad〇tr〇phiC hyp〇g〇nadism) is due to insufficient secretion of pituitary gonadotropin. In addition to low levels of testosterone, lh and FSH levels were also low or low. Some sequelae of adult steroid deficiency include a variety of symptoms including: loss of libido, erectile dysfunction, decreased sperm or sperm, no secondary or secondary sexual deterioration, progressive muscle mass reduction, fatigue, depression And the risk of osteoporosis increases. Many of these conditions are generally referred to as male menopause. The anti-estrogen amifen (Fig. 2) associated with tamoxifen has also been used to treat men with low levels of testosterone. Gas fenfen blocks normal estrogen feedback on the hypothalamus and subsequent negative feedback on the pituitary. This leads to an increase in luteinizing hormone (LH) and follicle stimulating hormone (FSH). For males, these levels of increased gonadotropin stimulate the Leydig cells of the testis and produce higher levels of sputum. 5 201031400

Tenover et al, J. Clin. Endocrinol. Metab. <54:1103, (1987) and Tenover et al, j. Clin. Endocrinol. Metab. (54:1118 (1987) found young males treated with clomiphene Both fsh and LH were increased in older men. It was also found that both male free steroids and total steroids increased, with young males showing a significant increase.

Ernst et al., J. Pharmaceut. Sci. <55: 148 (1976) shows that simipen is called cis, - Ζ-, amifen (cis- amifen or zuclomiphene) A mixture of two geometric isomers with trans, -Ε-, amififen (trans-mifefen or enclomiphene). According to Ernst et al., the trans-mumefen hydrochloride has 149. (: melting point to 150.5 ° C ' and cis-mumefen hydrochloride has a melting point of 1 56.5 ° C to 158 ° C Ernst et al. also noted that (trans isomer) is antiestrogenic ( AE) while the cis isomer is in a more potent and more estrogen-like form and has also been reported to have antiestrogenic activity. The authors attribute the effect of the drug on ovulation activity to two forms 'illustrating the mixture ratio The trans-mimifen alone is more effective. The trans-isomer helps ovulation at the level of the hypothalamus. The androgen isomer cis- amifen helps to improve the typography beyond the physiological pathway leading to ovulation. These isomers have different in vivo half-lives. In addition, cis has been reported to maintain residual blood levels for more than one month after early doses. Currently approved gas fenfen is a mixture of cis isomer and trans isomer. The cis isomer is present in an amount of about 30% to 50% (Merck Handbook) for increasing the fertility of patients without ovulation. The gonadotropin is triggered by a series of endocrine events. And the subsequent end of follicular rupture to improve ovulation. Each dose of up to 100 mg of the drug is administered for 5 days. The imipenem is also associated with many side effects, including: blurred vision, abdomen 201031400 邛 discomfort, men's breast disease, testicular tumor, vasodilatation, red heart In addition, other studies have shown that glutamate has genotoxicity and enhancement of the membranous tumor. The net result of these observations is that the current form of micufen (with the cis isomer between the jasmine and the view) is cured in treatment. SUMMARY OF THE INVENTION The present invention relates to a method of treating metabolic syndrome comprising administering to an individual in need thereof an effective amount of an antiestrogens or a pharmaceutically acceptable amount thereof. The composition of the salt. The individual may be male or female. The individual may also have idiopathic or secondary gonadotropin hypogonadism. The present invention also relates to a method of treating metabolic syndrome in an individual, comprising An individual in need thereof is administered an effective amount of (cis, -Z-, trans-clomiphene) (hereinafter referred to as "cis-clomiphene") and 100% by weight. % to 71% W/W (trans, E_, cis-mifefen) (hereinafter referred to as "trans-muffin") or a composition of a pharmaceutically acceptable salt thereof. The composition may consist essentially of a composition of simivir or a salt thereof. The composition may also be composed of trans-mifefen or an analogue thereof. The individual may be male or female. The individual may also have idiopathic or secondary gonadotropin The present invention also relates to a method of treating one or more symptoms of a metabolic syndrome comprising administering to an individual in need thereof a composition comprising an effective amount of an antiestrogens or a pharmaceutically acceptable salt thereof. The individual may be male or female. The individual may also have idiopathic or secondary gonadotropin hypogonadism. The present invention also relates to a method of treating impaired glucose abnormality (impaired 201031400 fasting glucose) in an individual comprising The individual is administered a composition comprising an effective amount of an antiestrogens or a pharmaceutically acceptable salt thereof. The individual can be male or female. The individual can be a male or female who desires or needs to reduce fasting glucose levels. The individual may also have idiopathic or secondary gonadotropin hypogonadism. The invention also relates to a method for treating an abnormality in fasting glucose in an individual comprising administering to the individual 0% to 29% w/w (cis, · Z_, trans-mifefen) (hereinafter referred to as "cis" "Mimifen" and ... (^/. to 71〇/.w/w (trans, E-, cis-clomiphene) (hereinafter referred to as "trans-methine") or 医药 its medicine Composition of a salt of acceptable culture "The composition may consist essentially of trans-clomiphene or a salt thereof. The composition may also consist of trans-mifefen or an analogue thereof. The individual may be desired or needed A male or female that reduces serum glucose levels. The individual may also have idiopathic or secondary gonadotropin hypogonadism. The invention also relates to a method of treating type 2 diabetes in an individual comprising administering to the individual Containing from 〇% to 29% by weight/weight (cis, -Z-, trans-miffen) (hereinafter referred to as "cis-methine") and from 1% to 7% w/w ◎ (trans, Ε-, cis-miffen) (hereinafter referred to as "trans-muffin") or a composition of a pharmaceutically acceptable salt thereof. The composition may consist essentially of trans-mifefen or a salt thereof. The composition may also consist of trans-clomiphene or an analogue thereof. The individual may be a male or female who desires or desires to reduce serum glucose levels. May have idiopathic or secondary gonadotropin hypogonadism 实施 [Embodiment] 8 201031400 The present invention provides a method for treating metabolic syndrome and a condition associated therewith. The present invention also provides for the treatment of the second Method of Type 2 Diabetes. The present invention is based, in part, on the discovery of the following convulsions: the administration of a composition comprising trans-mifefen to an individual having low total steroids, such that the fasting serum glucose levels of the Wei are reduced At the same time, the level of tamping _ increased and the levels of cholesterol and triglyceride s曰 decreased. Because & 'the composition containing trans-mifefen is appreciatively applicable to the treatment of metabolic syndrome. ❹ , , , 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本There is a lack of correlation between susceptibility; and (3) the effect of low sputum on insulin sensitivity, if present, is regulated by changes in body mass index. It should be understood that the composition comprising trans-clomiphene is used in accordance with the present invention. Type 2 diabetes is not limited to male individuals or individuals with low testosterone. In one embodiment of the invention, a composition comprising an effective amount of an antiestrogens is administered to treat an individual in need of such treatment Metabolic syndrome. The individual can be male or female. The individual may also have idiopathic or secondary gonadotropin hypogonadism. In a preferred embodiment of the invention, an effective amount is included. A composition of a trans-mifefen or a predetermined blend of simipenyl isomers (which differs from the normally produced mixture) as described below to treat metabolic syndrome in a male or female individual. It should be understood that the term "metabolic syndrome" as used herein relates to metabolic syndrome as defined by the adult treatment group or any other recognized definition of this syndrome. Synonyms for "metabolic syndrome" used in this technique include Raven 9 201031400 syndrome (Reaven, s Syndr〇me), insulin resistance syndrome, and syndrome X. It should be understood that the term "metabolic syndrome" as used herein also refers to Riewen's syndrome, Tenguin resistance syndrome, and syndrome. In another embodiment of the invention, a composition comprising an effective amount of an anti-estrogen (preferably trans-mifefen) is administered to treat the symptoms of metabolic syndrome in an individual in need of such treatment. Symptoms of metabolic syndrome may include, but are not limited to, ascending glucose levels, elevated triglyceride levels, rising cholesterol levels, insulin resistance, hypertension, abdominal obesity, blood tests, state of the state, inflammation , or any combination of two or more symptoms. The individual can be male or female. The individual may also have idiopathic or secondary gonadotropin hypogonadism. In another embodiment of the invention, administration of an agent comprising an effective amount of an anti-androgen (preferably trans-clomiphene) to a subject having metabolic syndrome may be combined with any known therapeutic regimen. Known therapeutic regimens for metabolic syndrome include, but are not limited to, exercise regimen, weight loss, i-pressure drugs (such as ACE inhibitors), cholesterol-lowering drugs, and metfinchin. The compositions of the present invention may be administered simultaneously, separately or sequentially with any of the above known therapeutic regimens. " In addition to the specific - actual shot, the administration of an effective amount of anti-androgen, and the adult system is used to treat a fasting glucose abnormality of Zhao. The individual can be male or female. The individual may have idiopathic gonadal dysfunction. W-induced gonad hypoplasia (4) * This article is based on the fasting glucose tolerance test. In this test, the individual's blood glucose was measured 8 to 12 hours after the - - - % work stock. Individuals with normal fasting glucose have a fasting blood glucose level of 11〇 201031400 • mg/dl or less. Individuals with impaired glucose fasting have a fasting blood glucose level between 110 mg/dl and 125 mg/dl. Fasting glucose levels above 125 mg/dl indicate diabetes. Thus, the composition of the present invention can be administered to an individual having a blood glucose level between 110 mg/dl and 125 mg/dl. For example, the individual can have a fasting blood glucose level of 11 〇, U1, n2, lu, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, or 125 mg/dl. Administration of the compositions of the invention reduces fasting blood glucose levels to below 125, © 124, 123, 122, 12, 120, 119, 118, 117, 116, 115, 114, 113, 112, 111 and preferably less than 丨i 〇mg/dl. Patients with abnormal fasting glucose have a major risk of developing diabetes. Accordingly, the present invention provides a method for preventing an individual from transitioning from a fasting glucose abnormality to type 2 diabetes, comprising administering to the individual a composition comprising an effective amount of an anti-estrogen (preferably trans-clomiphene). The individual can be male or female. The sputum may also have idiopathic or secondary gonadal hypogonadism (hypogonadal hypogonadism). In another embodiment of the invention, an effective amount of an anti-estrogen is administered to a patient having idiopathic or secondary gonadotropinic hypogonadism requiring or wishing to reduce fasting blood glucose levels (better anti-estrogen) The composition of the gas sulphur. Gonadal low energy patients may have any fasting glucose level, but preferably have greater than about 1 〇〇, 101, 102, 103, 104, 105, 106, 107, 108, 1 〇 9, 11 〇, in, 112, 113, 114 , 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 11 201031400 150 , 151 , 152 , 153 , 154 , 155 , 160 , 165 , 170 ' 175 , 180 , 185 , 190 , 195 Or a fasting glucose level of 200 mg/dl. For example, patients with hypogonadism can have fasting glucose levels between 125 mg/dl and 140 mg/dl. The composition may contain an amount of anti-estrogen (preferably trans-mifefen) to reduce the fasting glucose level of the hypogonadal patient to below 200, 195, 190, 185, 180, 175, 170, 165, 160, 155, 154, 153, 152, 151, 150, 149, 148 '147, 148, 147, 146, 145, 144, 143, 142, 141, 140, 139,

138, 137, 136, 135, 134, 133, 132, 131, 130, 129, 128, 127, 126, 125, 124, 123, 122, m, 120, 119, 118, 117, 110, 115' 114' 113, 112, 111 mg/dl or preferably less than 1 丄〇mg/dl ° When the patient's glucose level exceeds about 125 mg/dl, the patient may also be diagnosed with type 2 diabetes. Accordingly, the present invention also provides a method for treating Type 2 diabetes comprising administering to a subject in need thereof a composition comprising an effective amount of an antiestrogens. In a preferred embodiment, the antiestrogens are trans-mifefen or a pharmaceutically acceptable salt thereof. The individual can be male or female. The individual may have idiopathic or secondary gonadotropin hypogonadism. In this regard, the composition of the present invention may be used for the second

Any known combination of therapeutic regimens for type 2 diabetes. Therapeutic regimens known for type 2 diabetes include, but are not limited to, exercise regimen; weight loss regimen 'injecting drugs' such as angiotensin converting enzyme (ace) inhibitors (eg, ramipril ( Ramipril)); dimethyl double vein; sigh sputum _ (TZD); 1 glucose (four) inhibitors, such as St. (aearbose) and miglitol (migHtGl); Meg (4) (meglitinide), such as Nag Lina 12 201031400 '(nateglinide), repaglinide; peptide analogs such as dipeptidyl-based enzyme-4 (DPP-4) inhibitors and amyloid agonist analogs; and insulin. The compositions of the present invention may be administered simultaneously, separately or sequentially with any of the above known therapeutic regimens. Individuals in need of treatment by any of the methods of the invention may have low or low normal total sputum. For example, a male individual in need of treatment can have less than about 320, 310, 300, 295, 290, 285, 280, 275, 270, 265, 260, 255, 250, 245, 240, 235, 230, 225 , 220 , 215 , © 210 , 205 , 20 〇 , 195 , 190 , 185 , 180 , 175 , 170 , 165 , 160 , 155 , 150 , 145 , 140 , 135 , 130 , 125 , 120 , 115 , 105 , 100 Total lactosterone levels of 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35 ' 30 ' 25, 20, 15, 10 or 5 ng/dl. Male individuals with a total sputum of less than about 300 ng/dl are defined as hypogonads. In a related aspect, the present invention provides a method for treating an adult onset of dysentery dystrophic hypogonadism (AIHH) or a condition associated therewith, which comprises The individual in need is administered an effective amount of a composition comprising an anti-estrogen (preferably trans-mifefen) or a salt thereof. Males with sputum are characterized by low steroids and luteinizing hormone ([η), usually accompanied by obesity and hyperglycemia. The compositions of the invention are useful in the treatment of any of these conditions. In a preferred embodiment of the invention, a dose or an effective amount of a composition is administered to a patient who has developed metabolic syndrome and has idiopathic or secondary gonadotropin hypogonadism (the composition) Contains trans-mifefen at a dose between 1 mg and about 200 mg (although the optimal dose is indeed 13 201031400)

In the case of trans, in order to treat metabolic syndrome or to apply it to the practice of the present invention.

At 71/29. The trans isomerization of simiflufen as described by Ernst et al., as described above, is also administered as a part of the drug delivery method, preferably also during the withdrawal period, the normal secreted total serum testosterone 1 ' described in serum steroids can be formulated. The form of the substance is administered to a peak serum testosterone level of about 8 am. Such pharmaceutical formulations may be, for example, in the form of sustained release formulations prepared as described below: U.S. Patent No. 6,221,399, Japanese Patent No. 4-312,522, Meshali et al., Int. j. Phar 89:177_181 (1993) ),

Kharenko et al., intern. Symp. Control 22: 232-233 (1995), WO 95/35093, Da *〇l Rel. Bioact. Mater. Dangprasit et al., Drug.

U.S. Patent 2,143,353, 6,190,591, ίο%. No. 6,129,933, 6, 126, 969, 6, 248, 363, and other forms of sustained release formulations well known in the art. The dosage of trans-mifefen may range from 5 mg to 100 mg. The dose of simiflufen may also be from 12 5 mg to 5 mg. The dose of trans-clomiphene may also be 12.5 mg, 25 mg or 50 mg. The procedure used in this application § "treatment" means treatment Sexual treatment and preventive measures, wherein the purpose is to prevent or slow down (mitigate) the development of undesirable physiological or psychological changes or conditions, such as type 2 diabetes. For the purposes of the present invention, advantageous or desirable clinical outcomes include, but are not limited to, 201031400 'reducing symptoms, attenuating disease levels, stabilizing (ie, not deteriorating) disease delays or slowing disease progression, improving or mitigating disease diseases Moreover, no matter which part or all of it, whether it is detectable or undetectable. "Treatment: mat" can also mean prolonging survival compared to expected survival without treatment. The individual in need of treatment includes an individual who already has a condition or disorder and an individual who tends to develop a diseased bite or an individual to be prevented from developing a condition or disorder. As used in this application, the term "modulation" refers to therapeutic treatment and prophylactic measures in which the purpose is to prevent or slow down (mitigate) undesired Pro-bed parameters. For the purposes of the present invention, advantageous or desirable clinical outcomes include, but are not limited to, modifying clinical parameters, attenuating the extent of clinical parameters, stabilizing (i.e., not worsening) clinical parameters, delaying or slowing down clinical parameters. "Anti-estrogen" means a compound that prevents estrogen from exhibiting its effects on estrogen-dependent target tissues, thereby antagonizing various estrogen-dependent processes. Based on the surprising discovery that the anti-estrogen trans-mfmf isomer is effective in reducing the level of glucose in the hypogonads, any compound having anti-estrogen activity will be suitable for use in the present invention. In all cases, the antiestrogens suitable for the practice of the present invention are antiestrogens which are capable of blocking the action of estrogen. Antiestrogens suitable for use in the practice of the present invention may be purely antiestrogens or may have partial estrogenic effects, such as selective estrogens which exhibit antiestrogen properties in some tissues and estrogenic properties in other tissues. In the case of a body conditioner (SERM). The pure antiestrogens of the present invention include, but are not limited to, RU 58, 688, pp. 13_ 曱基_7_[9_(4,4,5,5,5- 15 201031400 pentafluoropentylsulfinyl) fluorenyl]-7,8,9,11,12,13,14'15 ,16,17-decahydro,-6H-cyclopenta[a]-phenanthrene-3,17-diol (ICI 182,780/fulvestrant) and other compounds; Wakeling and Bowler, J.

Endocrin., 112: N-butyl-11-[(7R, 88,93,13 8,148,178)-3,17-dihydroxy-13-methyl- as described in R7-R110 (1987) 6,7,8,9,11,12,14, 15,16,17-decahydrocyclopenta[a]phenanthrene-7-yl]-N-methyl-undecylamine (Ια 164,384) ; (#)-7-Pentyloxy-3-(4,pentyloxyphenyl)-4-mercapto-2-(4"-(2" Piper as described in WO 96/26201 Pyridylethoxy)phenyl)-2H- benzopyran (EM-800/SCH 57050) and other compounds; (2S)-3-(4-|f Q phenyl)-4-methyl-2 -[4-[2-(l-Piperidinyl)ethoxy]phenyl]-2H-0 keto-7-ol (EM-652/SCH 5 7068) and its analogs. The SERMs of the present invention include, but are not limited to, triphenyl olefins, such as triphenylethylene, which include 2-[4-" as described in U.S. Patent No. 4,536,516, incorporated herein by reference. (1,2-diphenylbutan-1-yl) oxy]-N,N-dimethyl-ethylamine (tamoxifen) and other compounds; U.S. Patent No. 4,623,660 (which is incorporated by reference) The method is as described in the above), trans-4-(1-(4-(2-dimethylamino)ethoxy)phenyl)_2-phenyl-indole-butyl) (4-hydroxytamoxifen) and other compounds; 1 [4,-monomethylaminoethoxy)benzene as described in U.S. Patent No. 5, the disclosure of which is incorporated herein by reference. -1(3'-hydroxyphenyl)_2_phenylbuty- ene (droloxifene) and other compounds; U.S. Patent Nos. 4,696,949, 5,491,173 and 2_[p-seven z)_4 gas phenyl butyl succinyl] phenoxy]-N,N-dimethylethylamine described in No. 4,996,225, each of which is incorporated herein by reference. (toremifene) and other compounds; US patent (7) (1)(1-(4-(ΐ·(4_^_本基基)-2-phenyl), as described in No. 55 (which is incorporated herein by reference) • butyl _ _ _ _ _ _ phenoxy) _ ethyl piroxime (idoxifene) and other compounds; simifen and its two isomers; and US Patent No. 4,696,949 And the compounds described in U.S. Patent Nos. 5,491,173 and 6,576,645, each of which are incorporated herein by reference in its entirety. the SERM of the present invention also includes, but is not limited to, phenothiophene derivatives, such as [6-Hydroxy-2-(4-phenyl)-benzothiophene as described in U.S. Patent Nos. 4,418,068 and 5,393,763, both of which are incorporated herein by reference. 3_yl]_[4_[2-(1-piperidinyl)ethoxy]phenyl]-methylamine (raloxifene) and other compounds W〇98/45286, WO 98/ LY353381 and LY335563 and other compounds described in 45287 and WO 98/45288; benzopyran derivatives such as those described in w〇96/26201 _7_t-pentyloxy_3_(4 Pentyloxybenzene

4-mercapto-2-(4"-(2"piperidinylethoxy)phenyl)-2H-benzopiperine South (em 800/SCH 57050) and other compounds; (2S)- 3-(4-Hydroxyphenyl)_4_methyl® 々-['IX1-piperidinyl)ethoxy]phenyl]-2Η-α ketene-7-ol (eM 652); naphthalene derivative, Cis-6-phenyl-5-[4-(2-indolyl-1-yl-ethoxy)-phenyl]-5,6,7, as described in U.S. Patent No. 5,552,412. 8_tetrahydronaphthalene-2-alcohol (lasofoxifene / CP 336, 156) and other compounds; 3, 4 as described in U.S. Patent No. 4,230,862, incorporated herein by reference. -dihydro-2-(p-methoxyphenyl)_}•naphthyl-p-[2-(1-»birtyridyl)ethoxy]phenyl ketone (rwoxifen (ui〇) Xifene) / LY 133 314) and other compounds; and ι_(4_substituted alkoxy)benzyl) naphthalene compounds, such as those described in U.S. Patent No. 6,509,356, incorporated herein by reference herein Alkane, such as 3,4-trans-2,2-dimethyl-3-phenyl-4-[[4] described in WO 97/25034, WO 97/25035, WO 97/25037 and WO 97/25038 4-(2-(2-(°-r-pyridin-1-yl)) Oxy)phenyl)-7-decyloxy keke (left meloxime) and other compounds; and in U.S. Patent No. 3,822,287, incorporated herein by reference. 1-(2-((4-(-methoxy-2,2,-didecyl-3-phenyl-oxo-4-yl)-phenoxy)-ethyl)-pyrrole Acridine (centchr〇jnan) and other compounds. Other SERMs of the invention include, but are not limited to, U.S. Patent Nos. 6,3,87,920, 6,743,815, 6,750,213, 6,869,969. And the compounds described in U.S. Patent Nos. 6,927,224, 7,045,540, 7, 138, 426, 7, 151, 196, and 7, 157, 604, each of each of each of each of each Other non-limiting antiestrogens of the invention include: 6 〇; _ chloro _ 16 ~ methyl gestation -4- sulphur - 3, 20-a genus (ci〇nletherone); 6-gas - 17_ 基基甾甾-1,4,6-triene_3,2〇-dione (delmadinone); 1-[2-[4-[1-(4-methoxybenzene) 2) nitro-2-phenylindoleyl]phenoxy]ethyl]-indolyl (nifefen) Itr〇mifene ) /CN-55,945-27); and l-[2-[p-(3,4-dihydro-6-methoxy-2-phenyl-1_naphthyl)phenoxy]ethyl ]»Byridine (naf〇xidene). Other non-limiting antiestrogens of the invention include hydrazine, such as j. Med

Chem., 33: 2635-2640 (1990), j. Med. Chem., 30: 131-136 (1987), WO 93/10741, WO 95/17383 'WO 93/23374 and U.S. Patent No. 6,503,938 and 6, the disclosure of which is incorporated herein by reference. 18 201031400 Other non-limiting antiestrogens of the invention include 2-[3-(1-cyano-ι-methyl-ethyl)·5·(ιη-1,2,4- described in EP 0296749 Triazol-1-ylmethyl)phenyl]_2-mercapto-propionitrile (anastrozole) and other compounds; described in U.S. Patent No. 4,808,616, incorporated herein by reference. 6-Methylene male oxime, i, 4-diene-3,17-dione (exemestane) and other compounds; U.S. Patent No. 5,473,078, incorporated herein by reference. 4_[(4-Cyanophenyl)-(1,2,4-diindole-yl)indenyl]benzonitrile (来tr唾z〇ie) and ❹ other a compound of the formula 1-[4,-didecylaminoethoxy]phenyl]hydroxyphenyl)-2-phenylbutene as described in U.S. Patent No. 5,047,431, incorporated herein by reference. 1-ene (dlooxifene) and other compounds; 2% 3~cyclothio- 5α-androstene-17-alcohol (epiti〇stanol; 2α, 3α-cyclothio- 5α-androstane-17/3-yl-1-decyloxycyclopentyloxy (mepitiostane); U.S. Patent No. 2,464,203 4-[(2Z,4Z)-4-(4-Hydroxyphenyl)hexa-2,4-diene as described in No. 2,465,505, the disclosure of which is incorporated herein by reference. -3-yl]phenol (cycladiene) and other compounds; Unlisted Drugs, 28(10): 169(0) (1976) CI-680; Unlisted Drugs, 26(7): 106 (1) CI-628 as described in (1974); 13-ethyl-17α-acetylene-17/3-hydroxyadenine-4,9,1-dicarben-3-one (R2323); Geynet, et al. Man, Gynecol. Invest. 3(1): 2-29 (1972) for diphenol hydrogenation and red-MEA; Merck Index, 10th edition, sheet 2 149 described in ΐ_[ι·气_2,2-bis(4-methoxyphenyl)vinyl]-4-decyloxy-benzene (chl〇rotrianisene); Merck Index, 10th edition, #3668 1-[4-(2·Diethylaminoethoxy)phenyl]-1-phenyl-2-(p-methoxybenzyl)ethanol (ethylamine oxytriphenyl alcohol 19 201031400 (ethamoxytriphetol)); 2_p-Oxophenyl_丨_[p-(2-diethylaminoethoxy)phenyl]-^ pair as described in U.S. Patent No. 2,914,562, the disclosure of which is incorporated herein by reference. -tolueneethanol (tricapalol (triparan) Ol)) and other compounds. Other antiestrogens in the present invention include, but are not limited to, Wilson et al 'Endocrinology, 138(9): 3901-3911 (1997) and (2e)-3-(4- described in WO 95/10513 ((le)-l,2-diphenylbut-1-enyl)phenyl)acrylic acid (GW5638), GW7604 and other compounds; ^[4-(2-diethylaminoethoxy)phenyl] -2-(4-decyloxyphenyl)_ι-phenyl-ethanol (MER-25), N,N-indole diethyl-2-[4-(5-methoxy-2-phenyl- 3H-Indol-1-yl)phenoxy]ethylamine hydrochloride (U-11, 555A), 1-[2-[4-(6-decyloxy-2-phenyl-3,4-di Hydronaphthalen-1-yl)phenoxy]ethyl]0-pyridyl hydrochloride (U-ll, 100A), ICI-46,669, 2-[4-[(Ζ)-1,2-diphenyl Butyl alkenyl]phenoxy]_NN_dimethyl_B

2-Hydroxypropane-1,2,3-tricarboxylic acid (ici-46,474) and other compounds described in the '' Terenius et al., Gynec. Invest., 3: 96-107 (1972); Alkyl-6-naphthoic acid (aiien〇ncacid); [4-[(4-acetoxyphenyl)-cyclohexylene-indenyl]phenyl]acetate (cyclopropene) Cyclofenyl Q /ICI-48213 ); [6-hydroxy-2-(4-hydroxyphenyl)benzothiophenyl]-[4-[2-(1_ 咬 )))) Hyperthyroid (keoxifene); 4-[(Ζ)-1-[4-(2-dimethylaminoethoxy)phenyl]-2-(4-propan-2-ylbenzene) Butyl-1-alkenyl]phenol (DP-TAT-59/miproxifene); (lRS, 2RS)-4,4'-diethoxycarbonyl-5,5,-difluoro -(1-ethyl-2-methylene)di-m-phenylenediacetate (acefluranol); 6-carbyl-2-(p-phenyl)-benzo(b) °Septen-3-yl [2-(1-heptidyl)-ethinylphenyl] ketone (LY-117018); and [6-hydroxy-2-(4-hydroxy-stupyl) stupid And (b) thiophene _3. 20 201031400 Η 4-(2-(ΐ·娘啶基)·ethoxy)phenyl]methanone (five) seven coffee). Other antiestrogens of the invention include, but are not limited to, non-steroidal hormone receptor ligands such as U.S. Patent No. 5, (8), No. 835, No. 5, m 219 == 716, No. and No. Μ99, _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ; 7α_η_Amino-androst-tris, as described in Qing 98/07740; u_心素素_7〇; substituted estriene, such as those described in Touching Huanghuang 55; 17 (four)-based oxygen transport Alkaloids, such as U.S. Patent Application Serial No. 1/305,418, the disclosure of which is incorporated herein by reference in its entirety in its entirety in A singularity, such as that described in U.S. Patent No. 7.132,417 (which is incorporated herein by reference); 4_m2h_benzo (4), such as the United States (4) 6,844 coffee said (by way of introduction) And the U.S. Patent No. 4,133,814 (which is hereby incorporated by reference herein in its entirety by reference) [ 221]heptyl 2 —yl)-ethoxylated)-phenylindole 6-carbyl-2-(4-yl-phenyl-phenyl)-benzo-indole _3_yl)-substitupy and statin Phenomenon; 2-phenyl-o-(2-aminoethoxy oxime b) (IV), such as U.S. Patent No. 5,998, the disclosure of which is incorporated herein by reference. 3·[4_(2_phenyl"pyridinylmethyl)phenyl]-propene oxime and other compounds described in No. 5,985,91G (which is incorporated by reference) 2 phenyl-H4-(amino-b-based-fast) as described in Nos. 5, 78, 497 and 5, 88 〇, m (both of which are incorporated herein by reference) Base)························ Each of these patents is incorporated herein by reference in its entirety; bis ( 3 ' hydroxy phenyl ) alkane compound ' such as U.S. Patent No. 4, 〇 94,994, incorporated herein by reference. Said; benzene derivatives, such as US Patent No. 4, 75 i, 24 No., which is incorporated herein by reference; 2,3-diaryl-2H-1-benzopyran analog, such as 8 deduction " et al, j chem, 33:3210- 3216 (1990) and Shama et al.;; Fu Ch. 33:3216-3229 (1990); and benzotrim and triaryl odor analogs, such as Durani et al., J. Med. Chem., 32: 1700-1707 (1989). In one embodiment, the compositions of the present invention comprise one or more antiestrogens or (4) a scientifically acceptable salt thereof. The salt compound obtained may be in a neutral form or a salt form depending on the treatment conditions. Salt forms include hydrates and other/combination compounds as well as crystalline polytypes. According to the present invention, free tests and salts of such final products can be used. The acid addition salt can be used with an alkaline reagent such as a base (alkaH) or by

The subexchange is converted to the free base in a manner known per se. The free base obtained may also form a salt with an organic or inorganic acid. In the preparation of acid addition salts, it is preferred to use an acid which will form a suitably pharmaceutically acceptable salt. Examples of such acids are hydrochloric acid, sulfuric acid, phosphoric acid, acid, aliphatic acid, alicyclic carboxylic acid or sulfonic acid, such as citric acid, acetic acid, butyl succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, lemon Acid, anti-acid acid, glucuronic acid, fumaric acid, maleic acid, hydroxy succinic acid, pyruvic acid, aspartic acid, glutamic acid, p-hydroxybenzoic acid, subunit bishydroxy Navonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, benzene 22 201031400 Acid: mandelic acid, aI 〇genbensenesulf〇nic acid, f phthalic acid, galactose diacid, galactose acid or naphthoic acid. According to the present invention, all of the crystalline polytypes can be used. Base addition salts can also be used in accordance with the present invention and can be prepared in a conventional manner by bringing the free acid form into contact with a sufficient amount of the desired salt. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free & Pharmaceutically acceptable test addition salts are formed with metals or amines such as metals and soil metals or organic amines. Examples of metals used as cations are sodium, unloading, mom, town and the like. Examples of suitable amines are amino acids (such as lysine), choline, diethanolamine, ethylenediamine, N-f-glucosamine, and the like. The compositions of the present invention can be prepared in the form of dosage units suitable for oral, parenteral, transdermal, transrectal, transmucosal or topical administration. Parenteral administration includes, but is not limited to, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intralesional, and intraarticular administration. The term "oral administration" or "oral delivery" as used herein includes any form of delivery of a therapeutic agent or composition thereof to an individual, wherein the therapeutic agent or composition is placed in the mouth of the individual, whether the therapeutic agent or Whether the composition is swallowed. Therefore, "oral administration" includes oral and sublingual administration as well as transesophageal (e.g., inhalation). In another embodiment, the compositions of the present invention are formulated as rectal suppositories which may contain suppository bases including, but not limited to, cocoa butter or glycerides. The compositions of the present invention may also be formulated for inhalation, which may be in the form of, but not limited to, a solution, suspension or emulsion, which may be used as a dry 23 201031400 powder form or using a dihalofluoromethane machine or two. A form of aerosol of fluoromethane is administered. The composition of the invention may also be used for transdermal delivery, for example, as a ι#ι cream, ointment, lotion, paste, gel, medicated plaster, paste Tablets or membranes. The compositions /), x* are disclosed to comprise any suitable excipient penetration enhancer and analogs thereof. The compositions of the present invention may also be formulated for parenteral administration, including, but not limited to, parenteral administration by injection or continuous blistering. For injection

The formulation may be in the form of a suspension, solution or emulsion in an oily or aqueous vehicle. Such compositions may also be provided in powder form for reconstitution with a suitable vehicle, including, but not limited to, sterile water, pyrogen-free water, water for injection (Wn), and the like. The compositions of the present invention may also be formulated as a pharmaceutical reservoir formulation (depw preparathnO, which may be administered by implantation or intramuscular injection. Suitable polymeric or hydrophobic materials may be employed (e.g., as an acceptable oil) milk

Liquid, an ion exchange resin to formulate the compositions or formulated as a sparingly soluble derivative (e.g., as a sparingly soluble salt). The compositions of the invention may also be formulated as liposomal formulations. The liposomal formulation can comprise a liposome that penetrates the cell or stratum corneum of interest and fuses with the cell membrane, allowing the contents of the plastid to be delivered into the cell. For example, a liposome as described in U.S. Patent No. 4, 508, 023 to Redziniak et al., or U.S. Patent No. 4,508,703 to Redziniak et al. The compositions of the present invention may be in the form of solid dosage units such as lozenges (e.g., suspension tablets, bite suspension tablets, 24 201031400 - fast dispersing lozenges, chewable lozenges, foamed ingots ( Effervescent tablet ), double-layer tablets, etc., caplets, capsules (such as soft or hard gelatin capsules), powders (such as encapsulated powders, dispersible powders or foaming powders), ingots, sachets, flat gels, Sugar-coated tablets, pellets, granules, microparticles, encapsulated microparticles, powder aerosol formulations or any other solid dosage form suitable for administration. Tablets can be prepared according to any of a number of related and well known pharmaceutics techniques. In one embodiment, a tablet or other solid dosage form can be prepared by a process using one of the following methods or methods, including (but not limited to dry mixing, (2) direct compression, (3) Grinding method, (4) dry or non-aqueous granulation method '(5) wet granulation method, or (6) fusion method. The individual steps of the wet granulation method for tablet preparation typically include grinding and component screening, Dry powder mixing, wet lumping, granulation and final grinding. Dry granulation involves pressing the powdered mixture into a crude lozenge or "crushing" on a heavy-duty rotary tablet machine, followed by a grinding operation (usually by Oscillating granulators) Decompose slugs into granules. Individual steps include mixing powder, pressing (crushing) and grinding (reducing lumps or granulation). Typically, no wet step is involved in any step. Adhesive or Moisture. In another embodiment, a solid dosage form can be prepared by mixing an antiestrogens with one or more pharmaceutical excipients to form a substantially homogeneous pre-blended blend. The pre-blended blend can then be prepared. Subdivided and viewed Further treatment (eg, compression, encapsulation, encapsulation, dispersion, etc.) into any desired dosage form. The compressed lozenge can be prepared by compacting the powder or granule composition of the present invention. A common, non-coated scent suitable for oral ingestion' is prepared by a single compression or by a pre-compaction UPping followed by a final compression. The present invention 25 201031400 (4) Covering the coating to read the advantages of the improved or storage characteristics of the refreshing agent; in a specific example, the selected one. '" 匕 ^ makes the invention substantially delayed after the administration of the drug The beginning of the effect of the substance/alpha therapy. As used herein, the term "suspended tablet" refers to a compressed tablet which is rapidly disintegrated after being placed in water." Suitable liquid dosage forms for the compositions of the present invention include solutions, aqueous or oily suspensions. Liquid, brewing agent, syrup, emulsion, liquid aerosol formulation, gel,

Cream, ointment, etc. The compositions may also be formulated as a dry product for reconstitution with water or other suitable vehicle prior to use. In a specific embodiment, when the liquid or semi-solid composition is stored in a closed container maintained at room temperature, refrigerated (e.g., about 5 to 10 ° C) or frozen, the time is about 2, 3...^..., ^ 10. At or 12 months, an initial anti-estrogen compound is present which is present in at least about 9%, at least about 92%, to about 95%, or at least about 97.5%.

If desired, the compositions of the present invention may include one or more pharmaceutically acceptable excipients. The term "excipient" as used herein means that it is not itself a therapeutic agent but is used as a carrier or vehicle for delivering a therapeutic agent to an individual, or to a pharmaceutical composition to improve its handling properties or storage properties or to permit or promote a composition. Form a unit dose of any substance. For the purpose of illustration and not limitation, excipients include diluents, remedies, binders, adhesives, wetting agents, lubricants, slip agents, surface modifiers or surfactants, fragrances, suspensions Agents \ Emulsifiers, non-aqueous vehicles, preservatives, antioxidants, adhesives, agents that adjust pH and volume osmolality (eg buffers), preservatives, thickeners, sweeteners, flavoring agents, taste masking A agent, a colorant or dye, a penetration enhancer, and a substance added to improve the appearance of the composition. 26 201031400 The excipients used in the present invention as the case may be solid, semi-solid, liquid or a combination thereof, as appropriate. Compositions of the invention containing excipients can be prepared by any of the known pharmacy techniques' including mixing excipients with drugs or therapeutic agents. image

G The compositions of the present invention optionally comprise one or more pharmaceutically acceptable diluents as excipients. Suitable exemplary diluents include the following individual or combined agents. Lactose, including anhydrous lactose and lactose monohydrate; powders, including directly compressible powders and hydrolyzed starches (eg Cei_bTM and

EmdexTM); mannitol; sorbitol; xylitol; dextrose (eg Cerel® SeTM 2000) and dextrose monohydrate; dicalcium phosphate dihydrate; sucrose-based diluent; C〇nfecti〇ner, broad-salt basic calcium sulphate monohydrate; calcium sulphate dihydrate; granular calcium lactate trihydrate; dextrates; inositol; hydrolyzed sputum solid, · amylose; "Cellulose" includes microcrystalline cellulose, cellulose of food grade origin and amorphous cellulose (such as RexcelTM) and powdered cellulose; calcium carbonate; glycine; bentonite; polyvinylpyrrolidone; If present, the total amount will comprise from about 5% to about 99%, from about 10% to about 85%, or from about 2% to about 8% by weight based on the total weight of the composition. Any diluent selected. It preferably exhibits suitable fluidity and exhibits compressibility when a tablet is desired. Use of extragranular microcrystalline cellulose (i.e., microcrystalline cellulose added to the wet particulate composition after the drying step) is available To improve hardness (for tablets) and / or disintegration time. The composition optionally comprises one or more pharmaceutically acceptable disintegrants as excipients, particularly for lozenges, capsules or other solid formulations 27 201031400 & suitable detoxifying agents include the following individual or combination Reagents: starch, including glycolic acid powder (such as PenWest's Εχρΐ〇_ΤΜ) and pre-kneeized corn starch (such as Nati〇nalTM 1551, NationalTM 155〇 and

ColocornTM 1500), 上上丄,,,,r Τλ (ΙClay (eg Veegum M HV), cellulose, such as pure cellulose, proud a Yue; Shiwei cellulose, methyl cellulose, carboxymethyl Cellulose and sodium methicone, cross-linked methine cellulose (eg, De-Sg1TM), alginate, cross-linked poly-remaining, and tree mites, such as lycopene Gum-sin, locust bean gum, karaya gum, pectin and tragacanth. ' ' Disintegrant can be added in any suitable step during the damaging process, especially before the granulation step or before (4) During the lubricating step, if such disintegrants are present, they collectively constitute from about 2% to about 3%, from about 0.2% to about 1%, or from about 2% to about 5% of the total weight of the composition. ❹ The composition of the present invention optionally comprises one or more pharmaceutically acceptable binders or adhesives as excipients, particularly for lozenge formulations. The binders and adhesives are preferably used in the preparation of ingots. The powder imparts sufficient cohesion to allow normal processing operations such as sizing, lubrication, tanning and encapsulation, while the blue still allows (four) agents Appropriate disintegration and absorption of the composition. Suitable agents and adhesives include the following (four) or combination of reagents: gum arabic; gutta percha; recommended sugar; gelatin; glucose; temple powder, such as (but not limited to) = Sheng Ning (4) (eg NatiQnalTM 15u and Nat_alTM 1500); = vitamins such as (but not limited to) methylcellulose and sulfhydryl cellulose (eg W(10)); alginic acid and alginate; : ergic; polyacid; bentonite; vesicular, such as valvidin K_15, K-3 oxime and polymethacrylic acid vinegar; HPMC; propyl cellulose (Example 28 201031400 such as KlucelTM); and ethyl cellulose (e.g., Eth〇celTM). If present, the binder and/or the adhesive' totals from about 0.5°/❶ to about 25°/〇, from about 0.75% to about 15%, or about the total weight of the composition. 1% to about 1〇〇/0.

The compositions of the present invention optionally comprise one or more pharmaceutically acceptable wetting agents as excipients. Non-limiting examples of surfactants useful as wetting agents in the compositions of the present invention include quaternary ammonium compounds such as benzalkonium chloride, benzathine, and cetylpyridinium; sulfobutane Sodium dioctyl sulphate; polyoxyethylene succinyl ether, such as nonoxynol 9, nonoxynol, and octyl benzene; 9; poloxamer (p〇1〇xamer) (polyoxyethylene) a block copolymer with polyoxypropylene); a polyoxyethylene fatty acid glyceride and an oil such as polyoxyethylene (8) caprylic/capric acid monoglycerol s and diglycerin (for example

LabraS〇lTM), polyoxyethylene (h) castor oil and polyoxyethylene (40) hydrogenated lotus oil, polyoxyethylene alkyl ether, such as polyoxyethylene (2〇) hexadecyl octadecyl ether; polyoxyethylene Fatty acid esters, such as polyoxyethylene (4〇) stearate; polyoxyethylene sorbitan esters, such as polysorbate 2〇 and polysorbate 8〇 (eg 1 to TweenTM 8〇); propylene glycol Fatty acid vinegar, such as propylene glycol lauric acid (such as Gattefossk LauroglycolTM); sodium lauryl sulfate; fatty acids and their salts such as oleic acid, sodium oleate and triethanolamine oleate; fatty acid glycerin, such as glyceryl monostearate; Sorbitol vinegar, such as sorbitan monolaurate _, sorbitan monooleate cool, sorbitan monopalmitate and sorbitan monostearate taloxapol (coffee _) , and mixtures thereof. If such wetting agents are present, they together constitute from about 0.25% to about 15%, from about 4% to about 10%, or from about 0.5% to about 5%, by total weight of the composition. The compositions of the present invention optionally comprise - or a plurality of pharmaceutically acceptable 29 201031400 lubricants (including anti-adherents and/or slip agents) as excipients. Suitable lubricants include the following individual or combined agents: glyceryl behapate (eg CompritolTM 888); stearic acid and its salts, including stearic acid, calcium stearate and sodium stearate; Hydrogenated vegetable oil (eg Ster〇texTM); colloidal ceria; talc; wax; boric acid; sodium benzoate; sodium acetate 'sodium fumarate; sodium vaporized; DL-leucine;

CarbowaxTM 4000 and CarbowaxTM 6000); sodium oleate; sodium lauryl sulfate; and lauryl magnesium sulfate. If such lubricants are present, they collectively comprise from about 0.1% to about 10%, from about 2% to about 8%, or from about 0.25% to about 5%, by total weight of the composition. Suitable anti-sticking agents include talc, corn starch, Dl leucine, sodium lauryl sulfate and stearic acid metal salts. Talc is an anti-adhesive or slip agent used, for example, to reduce the adhesion of the formulation to the surface of the device and to reduce static in the blend. If one or more anti-sticking agents are present, they comprise from about 0.1% to about 10%, from about 25% to about 5%, or from about 5% to about 2%, by total weight of the composition. A slip agent can be used to promote powder flow of the solid formulation. Suitable slip agents include colloidal oxidized hair, starch, talc, sour sauce, powdered sputum, and magnesium disilicate. Colloidal cerium oxide is particularly preferred. The compositions of the present invention may comprise one or more antifoaming agents. Polydimethyloxane is an exemplary defoamer. If present, the antifoaming agent will comprise from about 0.001 / angstrom to about 5%, from about 1% to about 5%, or from about 5% to about 1% by weight of the total weight of the composition. Exemplary antioxidants for use in the present invention include, but are not limited to, dibutylhydroxymethyl hydroxy methoxy methoxybenzene, potassium meta sulfite, and the like. If necessary or as a plurality of antioxidants, typically from about 0.0 to about 30 201031400 2.5%' by weight, for example about 1%, about 5%, about %1%, about 5%, about 1.5%, about 1.5%, An amount of about 175%, about 2%, about 225%, or about 25% is present in the compositions of the present invention. In various embodiments, the compositions of the present invention may comprise a preservative. Suitable preservatives include, but are not limited to, benzalkonium chloride, methylparaben, ethyl p-hydroxybenzoate, propylparaben or butyl hydroxybenzoate, benzyl alcohol, benzene. Ethanol, benzeth〇nium, p-paraben or methylparaben and sorbic acid or a combination thereof. Typically, the optional preservative is present in an amount of from about 0.01 to about 0.5% or from about 0.01% to about 2.5% by weight. In a specific example, the composition of the present invention optionally contains a buffer. Buffers include agents that reduce pH changes. Illustrative classes of buffers useful in various embodiments of the invention include salts of Group IA metals, including, for example, Group IA metal bicarbonates, Group IA metal carbonates; alkali metal buffers or alkaline earth metals Buffer, aluminum buffer, calcium buffer, sodium ◎ buffer or magnesium buffer. Suitable buffering agents include any of the carbonates, phosphates, bicarbonates, citrates, borates, acetates, phthalates, tartrates, succinates, such as sodium or Potassium phosphate, citrate, borate, acetate, bicarbonate and carbonate. Non-limiting examples of suitable buffering agents include aluminum hydroxide, hydrazine hydroxide, aluminum glycinate, calcium acetate, calcium hydrogencarbonate, calcium borate, carbonate, calcium citrate, calcium gluconate, calcium glycinate, Hydrogen telluride calcium, calcium lactate, calcium phthalate, calcium phosphate, calcium succinate, calcium tartrate, dibasic sodium phosphate, dihydrogen phosphate, dipotassium phosphate, phosphoric acid Disodium hydr〇gen 31 201031400 phosphate, di-succinic acid succinate, anhydrous A-oxidized IS gel, acetic acid, magnesium citrate, magnesium borate, magnesium hydrogencarbonate, magnesium carbonate, magnesium citrate, Portuguese Magnesium gluconate, magnesium hydroxide, magnesium lactate, aluminate, magnesium citrate, magnesium oxide, magnesium phthalate, magnesium phosphate, magnesium citrate, magnesium succinate, magnesium tartrate, potassium acetate, potassium carbonate, hydrogen carbonate Potassium, potassium borate, potassium citrate, potassium metaphosphate, potassium phthalate, potassium phosphate, potassium polyphosphate, potassium pyrophosphate, potassium succinate, potassium tartrate, sodium acetate, sodium hydrogencarbonate, sodium borate, sodium carbonate , sodium citrate, sodium gluconate, dihydrogen hydride Sodium hydrogen phosphate, sodium hydroxide, sodium lactate, sodium phthalate, sodium phosphate, sodium polyphosphate, sodium pyrophosphate, sodium tricarbonate, sodium succinate, sodium tartrate, sodium tripolyphosphate, synthesis Hydrotalcite, tetrapotassium pyrophosphate, tetrasodium pyrophosphate, tripotassium phosphate, diammonium phosphate and trometarnol. (Partially based on the catalogue provided in The Merck Index, Merck & Co. Rahway, N.J. (2001)). Further, any combination or mixture of two or more of the above buffers can be used in the pharmaceutical compositions described herein. If necessary, one or more buffering agents are present in the compositions of the invention in an amount of from about 0.01% to about 5% or from about 0.01% to about 3% by weight. ❹ In various embodiments, the compositions of the present invention may include one or more agents that increase viscosity. Exemplary agents that increase viscosity include, but are not limited to, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, carrageenan, polyacrylic acid, and/or combinations thereof. One or more viscosity increasing agents are typically present in the compositions of the invention in an amount of from about 0.1% to about 10%, or from about 0.1% to about 5%, by weight, if desired. In various embodiments, the compositions of the present invention comprise an "organoleptic agent" to improve the functional properties of the composition. 32 201031400 "Functional agent" means any excipient which improves the flavor or odor of the compositions of the present invention, or which aids in masking the unpleasant flavor or odor of the compositions of the present invention. Such agents include sweetening, flavoring, and/or taste masking agents. Suitable sweeteners and/or flavoring agents include sweetening or medicinating the pharmaceutical composition

Any agent that provides flavor to the composition. Optionally, optionally, the functional agent is typically present in an amount from about 0.1 mg/mL to about 1 mg/mL, from about 5 mg/mL to 5 mg/mL, or about 1 mg/mL. It is present in the composition of the present invention. Exemplary sweeteners or flavoring agents include, but are not limited to, gum arabic syrup, big back fragrant brain, anise oil, aromatic elixirs, benzaldehyde, benzofurald oxime, cyclodextrin, caraway , caraway oil, cardamom oil, cardamom seeds, cardamom, cardamom, cherry juice, cherry syrup, cinnamon, cinnamon oil, cinnamon water, citric acid, citric acid syrup, clove oil, cocoa powder, cocoa Powder syrup, eucalyptus oil, dextrose, hairy grass, hairy grass extract, hairy grass syrup, aromatics, ethyl acetate, ethyl vanillin, cumin oil, ginger, ginger , ginger oleoresin, dextrose, glucose, sugar, maltodextrin, glycerin, licorice, licorice tincture, licorice extract, pure licorice extract, licorice sorghum extract, licorice sugar, honey, and other alcohol Agent (is〇_aiec)h()lie elixi〇, lavender oil, lemon oil, lemon syrup, mannitol, salicylic acid A, meat bursa oil, bitter orange ugly agent, bitter oil, orange Flower oil, scented water, oil, bitter orange nail, sweet orange nail: orange peel, orange peel, peppermint oil, Peppermint, mint water, phenylethyl alcohol, tree juice, tree poison, sugar, sesame oil, rose oil, rose water (concentrate), saccharin, saccharin calcium, saccharin sodium, sarsapaHna syrup, Salsa , sorbitol solution, spearmint, spearmint oil, sugar, vegetable glycogen, sugar, thyme oil, toluene gum d), toluoli gum syrup, vanilla, vanilla nail, vanilla extract, wild cherry Sugar 33 201031400 pulp or a combination thereof. Exemplary taste masking agents include, but are not limited to, cyclodextrins, cyclodextrin emulsions, cyclodextrin particles, cyclodextrin complexes, or combinations thereof. Examples of non-suspensing agents include, but are not limited to: sorbitol syrup, thioglycolic cellulose, glucose/sugar polymerization, gelatin, ethylcellulose, m-methylcellulose, stearic acid gel and hydrogenated edible fat. , . Examples include, but are not limited to, lecithin, sorbitan monooleate, and gum arabic. Non-aqueous agents include, but are not limited to, edible oil almonds/yield, fractionated coconut oil, oily esters. (〇iiy ester), propylene glycol and hydrazine ethanol. The excipients described above may have various effects known in the art. For example, starch may be used as a filler and a disintegrant. The classification should not be construed as limiting in any way. The compositions of the invention may be administered in any manner, including but not limited to, orally, parenterally, sublingually, transdermally, transrectally, transmucosally, topically, via Inhalation, administration via the oral cavity, or a combination thereof. Parenteral administration includes, but is not limited to, administration via intravenous, intraarterial, intra-abdominal, intradermal, intramuscular, intrathecal, intra-articular, intracisternal, and intraventricular. The therapeutically effective amount of the composition required for use in therapy varies with the length of time required for the activity, and the age and condition of the patient to be treated, along with other factors, and is ultimately determined by the attending physician. Generally, the dosage for human treatment is typically in the range of from about 1 mg/kg to about 5 mg/kg per guanidine, for example from about 1 mg/kg to about i mg/kg per guanidine or For each large mammal, the total dose is about 1 mg to 100 mg, preferably about 2 mg to 8 mg. Adjustable 34 201031400 doses are administered. The method is to provide an optimal therapeutic response. The desired dose is preferably administered in a single dose or in multiple doses at appropriate intervals, for example, 2, 3, 4 or more sub-doses per sputum. Optionally, the composition of the invention can be administered to an individual to provide the individual with an antiestrogens in an amount of from about 1 jitg/kg to about 1 mg/kg body weight, for example about 1 Mg/kg, 'about 25 /ig/kg , about 50 jiig/kg, about 75 / xg / kg, about 100 / xg / kg, about 125 / ig / kg, about 150 Hong Lu / 1 "; Lu, about 175 / xg / kg, about 200 / ig /kg, about 225 /xg / kg, about 250 jug / kg, about 275 gg / kg, about 300 / ig / kg, about 325 / xg / kg, about 350 jiig / kg, about 375 / xg / kg, about 400 jtig/kg, about 425 /ig/kg, about 450 ^g/kg, about 475 jwg/kg, about 500 /ig/kg About 525 jiig/kg, about 550 jixg/kg, about 575/xg/kg, about 600 jiig/kg, about 625/xg/kg, about 650 pg/kg, about 675 />ig/kg, about 700 pg /kg, about 725 ^g/kg, about 750 /ig/kg, about 775 pg/kg, about 800 /ig/kg, about 825 /ig/kg, about 850 /ig/kg, about 875 /ig/kg , about 900 /Ag / kg, about 925 pg / kg, about 950 / ig / kg, about 975 / ig / kg or about 1 mg / kg body weight. In a preferred embodiment, the compositions of the present invention comprise trans-mifefen at a dose between 1 mg and about 200 mg (although the optimum amount of spike is determined to be within the skill of the average). The composition may comprise doses of about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg , 1 80 mg, 1 90 mg, 200 mg or a trans-mifefen between them. The composition may also comprise ratios of about 71/29, 72/28, 73/27, 74/26, 35 201031400 75/25, 76/24, 77/23, 78/22, 79/21, 80/20. , 81/19, 82/18, 83/17, 84/16, 85/15, 86/14, 87/13, 88/12, 89/11, 90/10, 91/9, 92/8, 93 /7, 94/6, 95/5, 96/4, 97/3, 98/2, 99/1, 99.5/0.5 or between trans-miffen and cis-miffin. The trans isomers of cismifen and analogs of cis isomers (such as described by Ernst et al. above) are also suitable for use in the practice of the present invention. The composition of the present invention can also be administered for a long period of time. In this aspect, the compositions can be administered at least 1, 2, 3' 4, 5, 6, 7, 8, 9, 1 , 11, 12, 13,

14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or more days. The compositions may also be administered for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 1 , u, 12 months or more. The compositions may also be administered for at least 2, 3 4 5 6 , 7 8 , 9 , 10 or more years of administration. The composition may be administered daily or during the administration (such as every other day, and the like) during administration. The composition of the present invention can also be administered intermittently. For example, such groups

The time of administration may be 2, 3, 4, 5 weeks or more, with the stop-stage period, followed by the time of 2, 3, 4, 5 weeks or more, and so on. All references cited herein are hereby incorporated by reference in their entirety. The following examples are intended to illustrate the invention and are not intended to limit the scope of the invention as set forth in the appended claims. Example 1 Effect of sulphide and its isomers on serum sputum and gallbladder 36 201031400 of male cockroaches 1.5 mg/kg clomiphene (citric acid micufene), encrometa Adult male cockroaches were given for 12 consecutive days (trans-muffin) or clopidogrel (cis-miffin). The samples analyzed were serum collected after the first treatment (days), 12 days after treatment (days), and 7 days (end or removal) after the last treatment. 1. Effects on body weight and serum LH, FSH, PRL and testosterone Total serum testosterone was significantly increased in the group receiving encromet. See Table 1. There was no difference between the baseline or day 0 groups. There was no difference between the two groups 7 days after the treatment (the elimination period). However, on day 6 compared with clomiphene and beclozedil (P = 0.03 and p = 0.00002, respectively), and on day 12 compared with beclomid (p = 0.047), Enkromid produces a relatively high level of testosterone. The clopidogrel apparently did not increase the total blood and clear ketones to any degree. Compared with the animals receiving the Encromet, the animals of the sensation of Crome had a greater change in the total Q-cumamine level after the 6th and 6th days, as judged by their coefficient of variation. When considering the course of the action (Fig. 3), compared with the baseline or the value of the third day, we determined that only Encrometi showed a significant increase in the total serum testosterone on day 6 and the 12th angel. The cessation of enkelotide treatment resulted in a significant decrease in total serum testosterone levels between day 12 and day 18 (clearance). This indicates that Enkromide is easily removed from the circulation, consistent with the metabolic clearance observed in humans in Encromet. Encrometi is clearly better and more consistent than Cromidy itself, while Zhukeromiti is ineffective. 37 201031400 Table 1 - Serum testosterone levels (ng/dl) Group ID Baseline 12/3/01 Day 0 12/7/01 Day 6 12/13/01 Day 12 12/20/01 Clear 12/26/ 01 7500 79.01 76.15 940.97 891.5 150.9 Cromite 9012 97.55 305.24 585.92 555.6 316.3 9097 158.06 102.94 151.12 318.9 143.6 Average 111.5 161.4 559.3 588.7 203.6 Standard deviation 41.3 125.2 395.6 287.7 97.7 7223 64.57 74.96 1223.8 633.6 307.2 Encrometi 8021 166.86 133.59 1128.2 1466 399.2 8369 170.45 106.47 1081.1 1166 271 Average 134.0 105.0 1144.4 1088.5 325.8 Standard deviation 60.1 29.3 72.7 421.6 66.1 7438 124.84 210.4 137.51 314.5 359.7 克罗罗米地8292 104.66 67.37 169.98 406.1 860.5 10098 282.29 904.82 227.95 353.0 274.1 Average 170.6 394.2 178.5 357.9 498.1 Standard deviation 97.3 448.0 45.8 46.0 316.8 ANOVA p = 0.61 p = 0.43 p = 0.007 p = 0.57 p = 0.256 KW p = 0.56 p = 0.84 p = 0.051 p = 0.079 p = 0.252 jk clear LH or FSH no change . The ratio of total serum testosterone to LH followed the same pattern as total serum testosterone, indicating a lack of dependence (data not shown). There was no change in body weight during the 12-day study period. In the course of the study of the group receiving Encromet, serum prolactin (PRL) decreased, indicating the role of antiestrogens, which has been partially described (Ben-Jonathan and Hnasko, 2001) and based on The increase in male age, the decline in testosterone and the promotion of the fact that lactogen is increased (Feldman et al., 2002). 2. Effect on the level of bile fermentation The treatment with encrometa tends to reduce serum cholesterol and the clopidogrel tends to increase the same parameters. Preliminary analysis indicated that changes in cholesterol levels were not statistically significant and the changes were within the normal range. Since the observed trends for the two isomers show a reverse effect on cholesterol levels in the short term 38 201031400 响'. Further analysis of this beta detailed analysis indicated that enkromide resulted in a 8% reduction in serum cholesterol levels. Conversely, treatment with clopidogrel resulted in a 22% increase in serum steroid levels. Treatment with clomiphene resulted in a slight increase in serum cholesterol levels. It is known that encrometa and beclomid have estrogen agonist activity or antagonist activity (alternatively), and thus the relative effects of these isomers on serum cholesterol levels are not unexpected. These results indicate that Enkromidyl can be used to treat patients with high cholesterol levels. These results also indicate that if long-term use to increase the level of sputum, then Enkromiti is more beneficial than chlorpyrifos. 3. The impact on the clinical chemistry parameters At the beginning of the study, for any test parameters, the average values of the parameters between the three groups did not differ, such as by analysis of the variance or by the Krasca-Walris test. (Kruskal_WalHs test) determined. All groups showed the normal values of each parameter except: (1) serum sodium; a related calculation of the ubiquitous parameter, the anion between the P, the value of the nine buds in the entire test towel were low; (?) serum glucose; and (3 BUN, which is higher on the third day for the group to be treated with encromet. On the 12th day of treatment and 7 days after treatment (clearing), there was no difference in any parameters between the groups, except for the anion gap, which showed that the clomiphene and the beclozedil group had lower than the Enkromiti group. value. The values of the ash and anion gaps appear to be anomalies associated with this group. ~, Clomimites and Physicians have a substantial effect on the red blood cell population and the clopidogrel has a substantial effect on the hematocrit. All compounds white reduced the mean cellular hemoglobin influx (anal) on day 1-3 or at the end point. There was no change in mean cellular hemoglobin (MCH) and the mean cell volume (MCV) 39 201031400 increased 'so it is predicted that MCHC will decrease. Although it is expected that tamping _ can increase the hematocrit of the hematocrit, it is only the difference between the treatment of cypresses (which does not increase the total ash stagnation _). It is obvious that the characteristics of the red blood cell population of men who have been clinically tested using clopidogrel should be monitored. It is expected that Enkrodi will have a smaller impact. The 12-day encromet treatment appeared to have a significant effect on platelets, although the values were still in the normal range. One thing to consider here is the platelet count of male sex between males and females (male versus male 348). This is most likely due to hormones. Because the encrometa group showed an increase in sputum ketones, the decrease in platelet count in this group compared with the change in testosterone was secondary. In addition, treatment with encrometide resulted in platelet counts reaching their normal male levels from day 0 to the upper end of the normal range for this group. Enkromid is not necessarily expected to have a detrimental effect on platelets. Clomiphene citrate, enkelotide, and clopidogrel all have an effect on the white globule (WBC) population, most notably the increase in lymphoid size and the count of eosinophils in encrometa. These effects are not as simple as they seem. Encrometi appears to have a strong effect on reducing the percentage of granulocytes in the blood. These effects are still very strong after the 7-day washout period, when the value is reduced below the normal range. (This procedure reflects the relative length of time required to influence changes in the white blood cell population.) There are only a few bisexual forms in the white blood cell population of sputum. The effect is likely to be due to changes in the compound itself rather than steroids. However, when considering the use of white blood cell counts to calculate granulocyte counts, we found that granulocyte counts were not different for any compound. Accompanying it's most interesting is the report of lymphocytes. Treatment with encrometa increased lymphocyte counts and percentages in the population by 40 201031400 ❹ plus. While the average percentage of lymphocytes remained in the normal range, the net effect was an increase in white blood cell count, and the net effect was an increase in the number of cells after the use of enkromide. The results of eosinophils are similar. It is clearly suggested that men with low lymphocytes (such as men with HIV anodes) can be treated. Because it is impossible to reduce lymphocytes based on this result, it can be justified to use it in a male population with AIDS. Due to the consumptive effects of the disease, these individuals are often treated with a drug intended to enhance tamping. Low liver nephrotoxicity and its beneficial effects on cholesterol and lipids are also highly preferred properties of any drug intended for use in HIV anodes that have been compromised by disease. The increase in glucose production by chlorpyrifos or clopidogrel is within the normal range. In the case where the average serum glucose value is higher on the qth day, the treatment does not increase the average serum (tetra) sugar value. There is no evidence that Encromet has a detrimental effect on sugar. According to the enzyme AST and ALT, it is clear that there is no significant side effect on liver function. The trend of this = value decreases with treatment. The increase in the level of enzyme in the clearing indicates that the liver is bad. At the end of the study of the Cromiform group, alt/sgpt was below the allowable but the difference in the treatment period was not statistically significant. The changes caused by Encrometi and Beclozed are within the normal range. When ast is pregnant, estrogen agonists (such as clopidogrel) reduce the edge: the role of the level can be explained. Qualitative phosphatase (A = can be found and raised in various diseases) ^ ALp ^ = liver is not damaged. Magical albumin (also liver production) no change. Strong inhibition during the period of steroid prolongation can promote human self" Qing, as a level, but sex hormone binding globulin plays a more important role as the bottom line, based on the parameters determined, no compound can be associated with liver damage phase 201031400. Osteoblast activity and bone disease are accompanied by high serum alp values. ALP did not increase after treatment with clopidogrel, but decreased after treatment with encromet. The use of encrometa was expected to be more favorable than using clopidogrel. There were changes in BUN and BUN/creatinine during the study of the clomimites and encrometa groups, but no confirmed changes in creatinine demonstrated no renal dysfunction. Loss of glomerular filtration capacity will result in an increase in BUN. Reduced BUN due to malnutrition (impossible in controlled settings) or high fluid intake (possibly accompanied by edema). In addition, although total serum testosterone was used on Day 0 and Day 12 of Enkromide There was no increase in days, but there was no difference in serum creatinine values, indicating no increase in muscle mass during this short interval. All animals had serum sodium levels lower than the reference value throughout the study. For Cromi In the group, the serum sulphate was compared with the reference value on day 12. The serum anion gap was low in all animals throughout the study, similar to the sodium result. Enkromidide made this parameter It increases in the direction of normal sputum. The electrolyte imbalance detected in the test animals throughout all treatment periods remains confusing, but may be part of the same fluid disorder as indicated by the BUN results. Encrometa is more effective in improving total serum steroids than in clopidogrel or in clopidogrel. It is clear that clopidogrel is not effective' and this shortcoming limits the use of clomiphene for any use of gonadal dysfunction , especially since it considers that the composition of the Crome has a longer half-life, so it will prevail in the cycle over time. 42 201031400 When with the clopidogrel and Often 5 ancient, when Dad to Cromidy, Enkro only seems to be relatively beneficial in all aspects of white. When considering the trend of lowering cholesterol and liver enzymes in Enkromide (such as with the clopidogrel) This is especially true when the trend of increasing the same parameters is reversed. If the CD4 + subpopulation of the lymphocytes in the right sputum is not reduced or raised, the enclave half & u brother Wei Mudi increases the lymphocyte count. The trend may be useful for men with AIDS. Example 2 Treatment of fasting glucose abnormalities by administering a mixture of trans-mufffen and trans-gas fenflurazine cis-mifefen at a ratio greater than 71/29 Methods Individuals continued overnight for 8 to 12 hours on an empty stomach, after which ▲ liquid samples were taken and fasting glucose levels were measured. Individuals with fasting blood glucose levels between 110 mg/dl and 125 mg/dl were given 1.5 mg/kg chloramine. The ratio of trans-mifefen to cis-miffin is greater than 71/29. Fasting blood glucose levels are monitored at regular intervals to adjust the dose and dose frequency to achieve therapeutic fasting blood glucose levels in the individual.

Example 3 A method for treating the resistance of methadone by administering a mixture of trans-mifen and a ratio of trans-clomiphene and cis-mifefen having a ratio of greater than 71/29, such as Defronzo et al., Am. J. Physiol. 237: E214-E223 (1979) _ described using, for example, high insulin blood-normal glycoplasty, and/or as described by Matthews et al., Diabetologia. 28:412-419 (1985) The Balanced Insulin Resistance Assessment Model (HOMA-IR) assesses the insulin sensitivity of an individual. Individuals with insulin resistance were given a dose of 1.5 mg/kg of sulphate per genus 43 201031400, with a ratio of trans-miffen to cis-clomiphene greater than 71/29. Insulin sensitivity is monitored at regular intervals to adjust the dose and dose frequency to achieve a therapeutic increase in insulin sensitivity in the individual. Example 4 A method for treating type 2 diabetes by administering a mixture of trans-mufffen and a trans-mifefen cis-mifefen having a ratio of greater than 71/29 to diagnose an individual having type 2 diabetes A daily dose of i 5 mg/kg of imipenem was administered, wherein the ratio of trans-miffen to cis-miffin was greater than 71/29. The distance between the mother and the sputum is monitored by the sugar ash, the valerian blood and optionally ◎ the plasma triglyceride level to adjust the dose and the dose frequency to achieve the therapeutic benefit of the insulin response and/or the jk sugar level. Example 5 Comparison AndroxalTM 舆 Androgel® Advanced Biological in Hackensack, New Jersey

The Research (ABR) Clinical Research Center conducted a placebo-controlled challenge study to compare Andr〇xalTM (trans-clomiphene) with Androgel® in men with hypogonadism. Androgel® (Solvay Pharmaceuticals, ❹) consists of a cream administered to exogenous steroids in the percutaneous matrix. The study enrolled 62 gonadal low-energy men with a testosterone level of less than 300 ng/dl (normal value 298-1034 ng/dl), randomized into 6 different groups (arm), three doses of AndroxalTM (12.5 mg, 25 mg) And 50 rag ), placebo, and two high doses and low doses of Androgel®. One and a half males in each of the AndroxalTM and placebo groups were randomized into groups that experienced clinical time on Days 1 and 14 to determine the pharmacokinetic parameters of AndroxalTM and the periodic changes in tamping. Placebo and 44 201031400 ' AndroxalTM dose is administered in a double-blind manner. Androgel® cream is administered by open-labeling. Half of Androgel® patients experienced clinical time similar to other patients in the study. After two weeks of drug exposure, the patient was followed for another 7 to 1 day to determine the condition of the tamping level. Unlike placebo, no side effects were recorded in the AndroxalTM or Androgel® group. 1. Effect on sputum-fixing levels All doses of AndroxalTM or Androgel® produced statistically significant changes in testosterone compared to baseline sputum ketone levels (Figure 5 Low, medium and high doses of AndroxalTM* reached 169 ng/dl , an average increase of 247 ng/dl and 294 ng/dl, while the dose of Andr〇gei® 5G (minimum approved dose) and the dose of Androgel® 10G (highest approved dose) produced 212 ng/dl and 363 compared to baseline. Changes in ng/dl. These values are statistically indistinguishable from those achieved by AndroxalTM. This does not show the difference between AndroxalTM and Androgel® that appears to be the result of the highly variable results obtained with Androgel®. For example, the ® 50 mg dose of AndroxalTM increased mean total steroids to 5 89 ± 172 ng/dl after 15 days, with a coefficient of variation (CV) of 29% and was similar to the placebo group (36%). On the one hand, Androgel® 5G and 10G obtained an average total ketamine value of 473±289 ng/dl and 608±323 ng/dl, respectively, with CV of 61% and 53%.

After 14 days of AndroxalTM therapy, all doses were associated with a total tamping_曰 week pattern (similar to the placebo group), which was the peak at morning, the lowest at noon, and increased overnight. Without wishing to be bound by theory, this mode can be attributed to the mode of action of AndroxalTM, which appears to be mediated through the effect of the hypothalamic-pituitary axis shown below. The use of Androgel® men's 曰 模 45 45 201031400 is almost flat. However, spikes in total steroids of Androgel® are drug-related and often exceed the normal high levels of 1, 〇34 ng/dl. Some individuals using Androgel® i〇G can achieve a total tamping_peak level greater than 2500 ng/dl. Interestingly, the level of serum total steroids unexpectedly continued to be high during the follow-up period after treatment with AndroxalTM (i.e., after 7 to 10 days of cessation of oral therapy). In addition, serum total ketamine levels were significantly higher at the highest dose of AndroxalTM compared to high dose AndroGel® 1% (p = 0.017, t-test). ❿ 2. Effects on LH and FSH levels In the low-energy male gonads, treatment with AndroxalTM produced a statistically significant increase in the level of LH clearance (Figure 6). As in the case of total serum testosterone, there was an unexpected continuation of the serum lh level during the high level of tracking for the three doses of AndroxalTM (i.e., after 7 to 1 day after each oral treatment was stopped). In comparison, treatment with AndroGel® initially reduced LH and rebounded significantly to the level before treatment.

Treatment with AndroxalTM in the hypogonadal male subjects also produced a statistically significant increase in FSH© serum levels (Figure 7). The pattern of FSH increase is similar to what is seen in the condition of 'all', AndroxalTM promotes blood/month FSH, which continues to be high during the follow-up period and AndroGel® inhibits the level of serum FSH and stops treatment, making serum FSH more similar to concentration. The level of rebound before treatment. 3. Effects on chemical parameters of other roadbeds The effect of serum-based steroids (DHT) levels was also measured. DHT in men using Andr〇xalTM favorably changes to total steroids. For example, 46 201031400 • The ratio of male DHT/TT using a 50 mg dose of AndroxalTM was 0.83, compared to a ratio of 1〇7 in the placebo group. Conversely, the DHT/TT ratio for any of the Androgel® groups was >h5e. These results indicate that men using Androgel® get DHT faster than total steroids. As a result, the normal level of dht is disturbed relative to men who use Androgel® therapy. The results of the clinical chemistry parameters also unexpectedly indicate a non-dose-dependent reduction in male triglycerides using Andr〇xalTM. The reduction in triglyceride decyl ester decreased by an average of 19.1% after two weeks of therapy. This is compared to the 5.9% reduction in the placebo group, and for the eight 11 (11*〇§61@5(} and 1〇(} increase by 〇3% and 22% respectively. 4. Discussion Based on this study, we infer AndroxalTM There are many potential advantages as a potential therapy. ^Andr〇xalTM appears to lift total steroids to a normal range in a highly consistent manner without abnormally high levels of serum steroids. ◎ Peak In addition, trans-clomiphene is used to treat secondary infections. Men with gonadal dysfunction provide a novel approach that may counteract one of the major side effects of exogenous therapy such as Andr〇gei. Exogenous therapy provides negative feedback to stop FSH and LH from producing eFSH as a necessary reproductive hormone and Stimulation of sperm production in men. Due to its effect on FSH, 'long-term exposure to exogenous steroids can lead to reduced sperm synthesis, resulting in temporary infertility due to low sperm count, thus causing Huamao contraction, because Huamao volume and The level of spermatogenesis in the Seminiferus tubule is also increased. The increase in fsh levels also indicates that Α-μ can be used to treat men (including hypogonads). In addition, Andr〇xalTM has an effect on the prolongation of serum steroids, μη and 47 201031400 to levels. # Andr〇xalTM can be administered at varying doses or on time μ. Perhaps even non-daily treatment or staged treatment. Example 5 Effect of transclofibrate on fasting glucose levels A placebo-controlled study was performed to determine the effect of oral administration of Andr〇xalTM (trans-muffin) and Androgel® on blood glucose levels. Andr〇gel8 (Solvay Pharmaceuticals) The company consists of a cream administered to exogenous steroids in the percutaneous matrix. The glandular low-energy males recruited by the Institute (睪固嗣 less than 3 〇〇ng/dl) ◎ have a wide range of body mass index (BMI patients randomized) Three different groups of '50 mg doses of AndroxalTM, placebo, and high doses of Androgel® were administered. Placebo and Androxal TN1 doses were administered in a double-blind manner. Androgel 8 cream was administered as an open label. (Baseline) and fasting glucose levels were monitored at regular intervals during the study. Unlike placebo, the study's AndroxalT No side effects were recorded in the M or Androgel® group. Figure 8 depicts baseline blood glucose levels for each treatment group. The patients in each treatment group were differentiated according to bmi 。. The dark bar graph depicts BMI in each treatment group 26 (EP300) Baseline blood glucose of the patient. Light bar graph depicting baseline blood glucose in patients with BMI <27 in each treatment group. As can be seen from Figure 8, baseline BMI in patients with BMI > 26 in all treatment groups versus BMI < A significant increase in baseline blood glucose was observed in 27 patients. Figure 9 depicts the change in glucose from baseline in the Androxal treatment group. Patients are differentiated according to BMI on the chart. The dark bar graph depicts changes in serum glucose from patients with BMI > 26 (EP300) compared to baseline. Light strips 48 201031400 • The shape, depicting changes in serum glucose in patients with BMI < 27 compared to baseline. As can be seen from Figure 9, treatment with Androxal for patients with BMI > 26 effectively reduced serum glucose levels throughout the treatment period, with a decrease of approximately 24 mg/dl observed during the 3rd month and 4.5 months. Figure 10 depicts the change in serum glucose from baseline in patients with BMI > 26 (EP300) in the Andr〇gel8 and placebo treatment groups. The dark bar plot depicts changes in serum glucose from patients in the placebo group compared to baseline. The light bar graph depicts changes in serum glucose versus 〇 baseline in patients in the Androgel® treatment group. As can be seen from Figure 1, there was no significant difference in serum glucose between the BMI > 26 patients in the Androgel® or placebo treatment groups compared to baseline. These data indicate that Aiidr〇xalTM is surprisingly effective in reducing fasting glucose levels (and accompanying insulin resistance) in patients with developed metabolic syndrome and having low or normal lower tonicosterone, and shows that AndroxafM is in the treatment of metabolic syndrome and Efficacy in relation to the condition (such as high glucocorticol level, high triglyceride S level, high cholesterol level, islet sex, high gold pressure and obesity). In contrast, administration of exogenous piccodone is ineffective in reducing glucose levels in patients with developed metabolic syndrome and having low or normal less than the same. Based on these data, Ancir·^ is also effective in treating type 2 diabetes in both male and female individuals. [Simplified illustration] Total normal secretion in Figure 1 is a representative graph of serum testosterone characteristics in healthy males (young and older males). Figure 2 shows the chemical structure of citric acid micufene. 49 201031400 Figure 3 shows Clomid, Clonum, Enclomid, and 2uci〇mjd, cis-type rice Fin) is a graphical representation of the time course of clearing the level of solidarity. Figure 4 is a graph showing the cholesterol levels of male cockroaches treated with clomipramine (citric acid micufene), enclommomisate (trans-mifene), and clopidogrel (cis-mifefen). An illustration of the time course. Figure 5 shows the effect of Andr〇xalTM or Andr〇gel8 on the tamping_level. Figure 6 shows the effect of AndroxalTM or Androgel® on LH levels. Figure 7 shows the effect of AndroxalTM or Androgel® on FSH levels. Figure 8 shows baseline blood glucose in the AndroxalTM, Andr〇gel (g), and placebo treatment groups. Figure 9 shows the effect of AndroxalTM on blood glucose levels. Figure_ shows the effect of Androgel® on blood glucose levels. [Main component symbol description] None

Claims (1)

201031400 VII. Patent application scope: 1. An anti-estrogen use for the manufacture of a medicine for preventing or treating type 2 diabetes in an individual. 2. The use of claim 1 in the scope of the patent, wherein the pharmaceutical product comprises from 0% to about 29% w/w of cis- amifen (cb_cl〇miphene) and from about ι〇〇0/〇 to about 71Χ» Trans-clomiphene (iraw^_ci〇iniphene) or an analogue thereof. 3. The use of claim 2, wherein the pharmaceutical product consists essentially of trans-mifefen or an analogue thereof. 4. The use of the third aspect of the patent application, wherein the trans-clomiphene dosage is from about 12.5 mg to about 50 mg. 5. The use of the fourth application of the patent scope, wherein the dose is 12.5 mg, 25 mg or 50 mg. 6. The use of claim 2, wherein the individual has a fasting glucose level of greater than 140 mg/dl after the administration. 7. For the purposes of claim 2, where the individual is a male. 8. For the use of item 7 of the patent application, wherein the individual has a testosterone level of less than 300 ng/dl. 9. For the purposes of claim 2, where the individual is a woman. 10. The use of claim 2, wherein the pharmaceutical product increases the insulin sensitivity of the individual. 11. The use of claim 2, wherein the pharmaceutical product reduces the fasting glucose level of the individual. 12. The use of claim 2, wherein the pharmaceutical product lowers the serum glucose concentration of the individual. 1 3. The use of claim 2, wherein the pharmaceutical product reduces the serum triglyceride concentration of the individual by 51 9 201031400. A pharmaceutical composition for preventing or treating type 2 diabetes in an individual, which comprises an effective amount of an antiestrogens. 15. The pharmaceutical composition of claim 14 wherein the composition comprises from 0% to about 29% w/w of cis gas, rice fen and about 1% to about 71% trans-gas. Fen or its analogs. 16. The pharmaceutical composition of claim 15 wherein the composition consists essentially of trans-mifefen or an analogue thereof. 17. The pharmaceutical composition of claim 16, wherein the trans-clomid is administered at a dose of from about 12.5 mg to about 50 mg. 18. The pharmaceutical composition of claim 17 wherein the dose is 12.5 mg, 25 mg or 50 mg. 19. The pharmaceutical composition of claim 15 wherein the individual has a fasting glucose level of greater than 14 mg/dl prior to administration. 20. The pharmaceutical composition of claim 15 wherein the individual is a male. 21. The pharmaceutical composition of claim 20, wherein the individual Q has a testosterone level of less than 3 ng/dl. U. For example, the pharmaceutical composition of claim 15 wherein the individual is a female. The pharmaceutical composition of claim 15 wherein the composition increases the insulin sensitivity of the individual. A pharmaceutical composition as claimed in claim 15 wherein the composition reduces the fasting glucose level of the individual. The pharmaceutical composition of claim 15, wherein the composition 52 201031400 reduces the serum glucose concentration of the individual. 26. The pharmaceutical composition of claim 15 wherein the composition reduces the individual Serum triglyceride concentration. Eight, schema: (such as the next page) 53