TWI458478B - Trans-clomiphene for metabolic syndrome and diabetes mellitus type 2 - Google Patents

Description

Trans-clomiphene for metabolic syndrome and type 2 diabetes

The present invention relates to compositions and methods for treating metabolic syndrome and conditions associated therewith. More specifically speaking, the present invention is based on the use of composition comprising trans-clomiphene enriched (trans -clomiphene) of the clomiphene things, for treating an individual having a low or low-normal testosterone of metabolic syndrome and its related The condition. The invention also relates to the use of a composition comprising clomiphene-enriched clomiphene for the treatment of type 2 diabetes.

Metabolic syndrome is characterized by a population of metabolic risk factors in an individual, including abdominal obesity, insulin resistance or glucose intolerance, atherogenic dyslipidemia, prothrombotic state, proinflammatory state, and hypertension. The adult treatment group defines metabolic syndrome in which the patient exhibits at least three of the following symptoms: a male waist circumference of at least 40 吋, a female waist circumference of at least 35 吋, and a serum triglyceride level of at least 150 mg/dl; HDL cholesterol Level males are less than 40 mg/dl, women are less than 50 mg/dl; blood pressure is at least 135/80 mm Hg and blood glucose (serum glucose) is at least 110 mg/dl. It is estimated that as many as 25% of the population in the United States suffer from metabolic syndrome.

The underlying cause of the metabolic syndrome is insulin resistance, in which insulin's ability to absorb glucose from the blood is diminished. This results in an increase in glucose levels after eating, which the pancreas secretes in response to it. Without treatment, metabolic syndrome significantly increases the risk of type 2 diabetes, cardiovascular disease, and other diseases associated with plaque formation in the arterial wall.

The inverse correlation between fasting insulin levels in men and serum testosterone has been confirmed by several studies. In addition, serum steroids were significantly lower in men with metabolic syndrome and other insulin-resistant conditions, such as obesity and type 2 diabetes, compared to the control group. However, the mechanism for interpreting these observations has not been elucidated.

A recent study suggests that the relationship between testosterone and insulin can be regulated by changes in body mass index (BMI), which causes obesity and poor regulation of fatty acid metabolism, which in turn contributes to insulin resistance. In contrast to testosterone, no significant relationship between estrogen levels and insulin sensitivity was found in this study.

Another recent study evaluated the hypothalamic-pituitary-gonadal axis of men with a wide range of insulin sensitivity. In this study, a positive correlation between insulin sensitivity and testosterone was observed, however, no relationship between insulin sensitivity and luteinizing hormone (LH) secretion parameters was observed, indicating low steroids associated with insulin resistance. Not caused by defects in the hypothalamus or pituitary, but by changes in the function of the Leydig cell. In this regard, it has been recognized that at least in vitro Leydig cell steroid production is regulated not only by pulsatile secretion of LH but also by hormones, growth factors, cytokines, and insulin.

There is a contradiction between the data on the effects of androgen supplementation on male insulin sensitivity. In one study, men with type 2 diabetes showed that glycemic control was not improved by steroidal supplementation, and a larger study showed a significant reduction in glycosylated hemoglobin.

Steroids are the major male androgen and play an important role in the overall health of men. Steroids are essential for the development and maintenance of specific reproductive tissues (test pills, prostate, epididymis, seminal vesicles and penis) and male secondary sexual characteristics. It plays an important role in libido and erectile function and is necessary to initiate and maintain spermatogenesis.

Steroid secretion is the end product of a series of hormonal processes. The gonadotropin (GnRH) secreted in the hypothalamus controls the pulsatile secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) secreted by the anterior pituitary. LH also regulates the production and secretion of testosterone in the pellets of the testis, while FSH helps induce spermatogenesis.

The lack of testosterone may be caused by underlying disease or genetic conditions and is often a complication of aging. For example, primary gonadal dysfunction is caused by primary testicular failure. Under this condition, the level of testosterone is low and the pituitary gonadotropin levels (LH and FSH) are elevated. Secondary gonadal dysfunction or hypogonadotrophic hypogonadism is attributed to insufficient secretion of pituitary gonadotropin. In addition to low levels of testosterone, LH and FSH levels are 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 clomiphene associated with tamoxifen (Figure 2) has also been used to treat men with low levels of testosterone. Clomiphene blocks normal estrogen feedback on the hypothalamus and subsequent negative feedback on the pituitary. This results in an increase in luteinizing hormone (LH) and follicle stimulating hormone (FSH). For men, these levels of increased gonadotropin stimulate the Leydig cells of the testis and produce higher levels of testosterone.

Tenover et al, J. Clin. Endocrinol. Metab. 64 :1103, (1987) and Tenover et al, J. Clin. Endocrinol. Metab. 64 :1118 (1987) found young males and elderly after treatment with clomiphene Both male FSH and LH increased. It also found that both male free steroids and total steroids increased, with young males showing a significant increase.

Ernst et al, J. Pharmaceut. Sci. 65 : 148 (1976) shows that clomiphene is called cis, -Z-, clomiphene (cis-clomiphene or zuclomiphene) and A mixture of two geometric isomers of the formula, -E-, clomiphene (trans-clomiphene or enclomiphene). According to Ernst et al., trans-clomiphene hydrochloride has a melting point of 149 ° C to 150.5 ° C, while cis-clomiphene hydrochloride has a melting point of 156.5 ° C to 158 ° C. Ernst et al. have also noted that (trans isomers) are antiestrogenic (AE) and cis isomers are more effective and more estrogenic in form and have been reported to have antiestrogenic activity. These authors attributed the effect of the drug on ovulation activity to two forms, indicating that the mixture is more effective than trans-clomiphene alone. The trans isomer helps ovulation at the level of the hypothalamus. The estrogen isomer, cis-clomiphene, helps to increase ovulation beyond the physiological pathway leading to ovulation. It is also reported that 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 a single dose.

Currently approved clomiphene is a mixture of cis isomer and trans isomer, and cis isomer is present in an amount of about 30% to 50% (Merck Handbook) for increasing fertility in patients without ovulation . Clomiphene improves ovulation by triggering a series of endocrine events that pre-ovulation gonadotropin surges and subsequent follicular rupture. It is recommended to administer up to 100 mg of the drug daily for 5 days. Clomiphene is also associated with a number of side effects including: blurred vision, abdominal discomfort, men's breast disease, testicular tumors, vasodilatation, nausea, and headache. In addition, other studies have shown that clomiphene has genotoxic and tumor enhancing effects. The net result of these observations is that the current form of clomiphene (having between 30% and 50% of the cis isomer) is unacceptable in chronic therapy for men who are suffering from testosterone deficiency.

The present invention relates to a method of treating 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 can be male or female. The individual may also have idiopathic or secondary gonadotropin hypogonadism.

The invention also relates to a method of treating metabolic syndrome in an individual comprising administering to an individual in need thereof an effective amount comprising from 0% to 29% w/w (cis, -Z-, trans-clomiphene) (bottom) (referred to as "cis-clomiphene") and 100% to 71% w/w (trans, E-, cis-clomiphene) (hereinafter referred to as "trans-clomiphene") or its medicine A composition of a salt that is acceptable for learning. The composition may consist essentially of trans-clomiphene or a salt thereof. The composition may also consist of trans-clomiphene or an analogue thereof. The individual can be male or female. The individual may also have idiopathic or secondary gonadotropin hypogonadism.

The invention also relates to a method of treating one or more symptoms of 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 can be male or female. The individual may also have idiopathic or secondary gonadotropin hypogonadism.

The invention also relates to a method of treating impaired fasting glucose in an individual comprising administering to the individual 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 wishes or needs to reduce fasting glucose levels. The individual may also have idiopathic or secondary gonadotropin hypogonadism.

The invention also relates to a method of treating an abnormality in fasting glucose in an individual comprising administering to the individual from 0% to 29% w/w (cis, -Z-, trans-clomiphene) (hereinafter referred to as "shun" "clomiphene" and 100% to 71% w/w (trans, E-, cis-clomiphene) (hereinafter referred to as "trans-clomiphene") or its pharmaceutically acceptable The composition of the salt. The composition may consist essentially of trans-clomiphene or a salt thereof. The composition may also consist of trans-clomiphene or an analogue thereof. The individual can be a male or female who desires or needs to reduce 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 0% to 29% w/w (cis, -Z-, trans-clomiphene) (hereinafter referred to as " (cis-clomiphene) and 100% to 71% w/w (trans, E-, cis-clomiphene) (hereinafter referred to as "trans-clomiphene") or pharmaceutically acceptable The composition of the salt. The composition may consist essentially of trans-clomiphene or a salt thereof. The composition may also consist of trans-clomiphene or an analogue thereof. The individual can be a male or female who desires or needs to reduce serum glucose levels. The individual may also have idiopathic or secondary gonadotropin hypogonadism.

The present invention provides methods for treating metabolic syndrome and conditions associated therewith. The invention also provides methods for treating type 2 diabetes. The present invention is based, in part, on the surprising discovery that a composition comprising trans-clomiphene is administered to an individual having low total steroids, such that the individual's fasting serum glucose levels are reduced while the testosterone levels are increased and cholesterol and triacids are present. The level of glycerides is reduced. Therefore, the composition comprising trans-clomiphene is surprisingly suitable for the treatment of metabolic syndrome. This finding is unexpected in light of the following findings from recent studies: (1) insulin resistance associated with low steroids is not caused by defects in the hypothalamus or pituitary; (2) in estrogen and insulin There is a lack of correlation between susceptibility; and (3) the effect of low steroids on insulin sensitivity, if present, is regulated by changes in body mass index (BMI). It will be appreciated that the use of a composition comprising trans-clomiphene to treat Type 2 diabetes in accordance with the present invention 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 anti-estrogen is administered to treat a metabolic syndrome in an individual in need of such treatment. The individual can be male or female. The individual may also have idiopathic or secondary gonadotropin hypogonadism.

In a preferred embodiment of the invention, a male is treated with a composition comprising an effective amount of trans-clomiphene or a predetermined blend of clomiphene isomers as described below, which differs from the normally produced mixture. Or a metabolic syndrome in a 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 of "metabolic syndrome" used in this technology include Reaven's Syndrome, insulin resistance syndrome, and syndrome X. It should be understood that the term "metabolic syndrome" as used herein also refers to Ravine's syndrome, insulin resistance syndrome, and syndrome X.

In another embodiment of the invention, a composition comprising an effective amount of an anti-estrogen (preferably trans-clomiphene) 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, elevated glucose levels, elevated triglyceride levels, elevated cholesterol levels, insulin resistance, hypertension, abdominal obesity, prethrombotic state, pre-inflammatory status , 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 composition comprising an effective amount of an anti-estrogen (preferably trans-clomiphene) to an individual having metabolic syndrome may be combined with any known therapeutic regimen. Known therapeutic regimens for metabolic syndrome include, but are not limited to, exercise regimens, weight loss regimens, blood pressure medications (such as ACE inhibitors), cholesterol reduction medications, and metformin. The compositions of the present invention may be administered simultaneously, separately or sequentially with any of the above known therapeutic regimens.

In another embodiment of the invention, a composition comprising an effective amount of an anti-estrogen is administered to treat an impaired glucose abnormality in an individual. The individual can be male or female. The individual may have idiopathic or secondary gonadotropin hypogonadism.

It should be understood that "fasting glucose abnormality" as used herein is defined in relation to the fasting glucose tolerance test. In this test, the individual's blood glucose was measured 8 to 12 hours after fasting. Individuals with normal fasting glucose have a fasting blood glucose level of 110 mg/dl or less. Individuals with fasting glucose abnormalities have fasting blood glucose levels between 110 mg/dl and 125 mg/dl. Fasting glucose levels above 125 mg/dl indicate diabetes. Thus, the compositions of the invention can be administered to an individual having a fasting blood glucose level between 110 mg/dl and 125 mg/dl. For example, the individual can have a fasting blood glucose level of 110, 111, 112, 113, 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, 121, 120, 119, 118, 117, 116, 115, 114, 113, 112, 111 and preferably less than 110 mg/ Dl.

Patients with abnormal fasting glucose have a significant 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 individual 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 clomiphene. A gonadal low energy patient may have any fasting glucose level, but preferably has greater than about 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 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, Fasting glucose of 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 160, 165, 170, 175, 180, 185, 190, 195 or 200 mg/dl Level. For example, a hypogonadal patient can have a fasting glucose level between 125 mg/dl and 140 mg/dl. The composition may comprise an amount of anti-estrogen (preferably trans-clomiphene) 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, 121, 120, 119, 118, 117, 116, 115, 114, 113, 112, 111 mg/dl or preferably lower 110mg/dl.

When the patient's glucose level exceeds about 125 mg/dl, the patient can also be diagnosed with type 2 diabetes. Accordingly, the present invention also provides a method for treating Type 2 diabetes comprising administering to an individual in need thereof a composition comprising an effective amount of an antiestrogens. In a preferred embodiment, the antiestrogens are transclofibrate 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 compositions of the invention may be combined with any known therapeutic regimen for Type 2 diabetes. Therapeutic regimens known for type 2 diabetes include, but are not limited to, exercise regimen; weight loss regimen; blood pressure medications such as angiotensin converting enzyme (ACE) inhibitors (eg, Ramipril) ;); metformin; thiazolidinedione (TZD); alpha-glucosidase inhibitors, such as acarbose and miglitol; meglitinide, such as nateglinide Nateglinide), repaglinide; peptide analogs such as dipeptidyl peptidase-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 steroids. 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, 200, 195, 190, 185, 180, 175, 170, 165, 160, 155, 150, 145, 140, 135, 130, 125, 120, 115, 105, 100, 95, Total ketol levels of 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 testosterone of less than about 300 ng/dl are defined as hypogonads.

In a related aspect, the present invention provides a method for treating adult onset idiopathic hypogonadotrophic hypogonadism (AIHH) or a condition associated therewith, comprising The individual is administered an effective amount of a composition comprising an anti-estrogen (preferably trans-clomiphene) or a salt thereof. Men with AIHH are characterized by low steroids and luteinizing hormone (LH), usually accompanied by obesity and hyperglycemia. The compositions of the invention may be adapted to treat any of these conditions.

In a preferred embodiment of the invention, one or more doses of an effective amount of the composition are administered to a patient who has developed metabolic syndrome and has idiopathic or secondary gonadotropinic hypogonadism (the composition) The dose comprises transfluromfen at a dose between 1 mg and about 200 mg (although the optimal dosage is determined to be within the level of the average)) in order to treat metabolic syndrome or a condition associated therewith. The cis-clomiphene may also be present in the composition as long as the ratio of trans-clomiphene to cis-clomiphene is greater than 71/29. The trans isomers of clomiphene 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 dosage is preferably, but not necessarily, administered as a portion of the administration regimen, which is designed to mimic serum tocodone levels during administration and preferably also during withdrawal, or to correspond to the normal secreted total serum described in Figure 1. Steroid characteristics. For example, according to Figure 1, a preferred composition can be administered in the form of a pharmaceutical formulation that will produce a peak serum testosterone level of about 8 a.m. 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 Rel. Bioact. Mater. 22: 232-233 (1995), WO 95/35093, Dangprasit et al., Drug. Devel. and Incl. Pharm. 21 (20) : 2323-2337 (1995); U.S. Patent Nos. 6, 143, 353, 6, 190, 591, 6, 096, 338, 6, 129, 933, 6, 126, 969, 6, 248, 363, and other forms of sustained release formulations well known in the art. The dose of trans-clomiphene may range from 5 mg to 100 mg. The dose of trans-clomiphene may also be from 12.5 mg to 50 mg. The dose of trans-clomiphene may also be 12.5 mg, 25 mg or 50 mg.

The term "treatment" as used in this application refers to therapeutic treatment and prophylactic measures, wherein the purpose is to prevent or slow down (mitigate) undesirable physiological or psychological changes or conditions, such as the development of type 2 diabetes. For the purposes of the present invention, advantageous or desirable clinical outcomes include, but are not limited to, alleviating symptoms, attenuating disease levels, stabilizing (ie, not deteriorating) disease conditions, delaying or slowing disease progression, ameliorating or mitigating disease conditions and Mitigation (whether part or all), whether detectable or undetectable. "Treatment" can also mean prolonging survival as 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 is prone to develop a condition or disorder or an individual to be prevented from developing a condition or disorder.

The term "modulate" as used in this application refers to therapeutic treatment and prophylactic measures, wherein the purpose is to prevent or slow (reduce) undesired clinical 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 unexpected discovery that the anti-estrogen trans-clomifen isomer is effective in reducing serum glucose levels in hypogonads, it is expected that any compound having antiestrogenic 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 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-Methyl-7-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)indolyl]-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,8S,9S,13S,14S,17S)-3,17-dihydroxy-13-methyl-6 as described in R7-R110 (1987) , 7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-7-yl]-N-methyl-undecylamine (ICI 164,384); (#)-7-pentyloxy-3-(4'-p-pentyloxyphenyl)-4-methyl-2-(4"-(2" piperidine as described in WO 96/26201 Ethyloxy)phenyl)-2H-benzopyran (EM-800/SCH 57050) and other compounds; (2S)-3-(4-hydroxyphenyl)-4-methyl-2-[4 -[2-(1-piperidinyl)ethoxy]phenyl]-2H- Alkene-7-ol (EM-652/SCH 57068) 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-diphenylbut-1-enyl)phenoxy]-N,N-dimethyl-ethylamine (tamoxifen) and other compounds; U.S. Patent No. 4,623,660 (which is incorporated by reference) In a manner of incorporation of trans-4-(1-(4-(2-dimethylamino)ethoxy)phenyl)-2-phenyl-1-butenyl)phenol (described herein) 4-Hydroxy Tamoxifen) and other compounds; 1-[4'-dimethylaminoethoxy)phenyl]- described in U.S. Patent No. 5,047,431, incorporated herein by reference. 1-(3'-hydroxyphenyl)-2-phenylbut-1-ene (droloxifene) and other compounds; U.S. Patent Nos. 4,696,949, 5,491,173 and 4,996,225 (these patents) 2-[p-[(Z)-4-chloro-1,2-diphenyl-1-butenyl]phenoxy]-N, as described herein, in the context of N-dimethylethylamine (toremifene) and other compounds; (E)-1-(2-(), as described in U.S. Patent No. 4,839,155, incorporated herein by reference. 4- (1-(4-Iodo-phenyl)-2-phenyl-but-1-enyl)-phenoxy)-ethyl)-pyrrolidone (idoxifene) and other compounds; And a mixture of the two isomers; and the compounds described in U.S. Patent Nos. 4,696,949 and 5,491,173 and 6,576,645 each incorporated herein by reference.

The SERMs of the present invention also include, but are not limited to, benzothiophene derivatives such as those described in U.S. Patent Nos. 4,418,068 and 5,393,763, both incorporated herein by reference. Hydroxy-2-(4-hydroxyphenyl)-benzothiophen-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl]-methanone (raloxifene) Raloxifene)) and other compounds; LY353381 as described in WO 98/45286, WO 98/45287 and WO 98/45288; and LY335563 and other compounds; benzopyran derivatives, such as described in WO 96/26201 (#)-7-Pentyloxy-3-(4'-p-pentyloxyphenyl)-4-methyl-2-(4"-(2"piperidinylethoxy)phenyl) -2H-benzopyran (EM 800/SCH 57050) and other compounds; (2S)-3-(4-hydroxyphenyl)-4-methyl-2-[4-[2-(1-piperidine) Ethyl]phenyl]-2H- Alkene-7-ol (EM 652); a naphthalene derivative such as cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy) as described in U.S. Patent No. 5,552,412 -Phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol (lasofoxifene/CP 336,156) and other compounds; U.S. Patent No. 4,230,862 (which is incorporated by reference) 3,4-Dihydro-2-(p-methoxyphenyl)-1-naphthyl-p-[2-(1-pyrrolyl)ethoxy]phenyl as described herein) Ketones (trioxifene/LY133314) and other compounds; and 1-(4-substituted alkoxy)benzyl)naphthalene compounds, such as U.S. Patent No. 6,509,356, incorporated herein by reference. Said in the; Alkane, such as 3,4-trans-2,2-dimethyl-3-phenyl-4-[4, as described in WO 97/25034, WO 97/25035, WO 97/25037, and WO 97/25038 -(2-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-7-methoxy Alkane (levolmeloxifene) and other compounds; and 1-(2-((4-(-methoxy))), and U.S. Patent No. 3,822,287, incorporated herein by reference. -2,2,-dimethyl-3-phenyl- Alkyl-4-yl)-phenoxy)-ethyl)-pyrrolidine (centchroman) and other compounds.

Other SERMs of the present invention include, but are not limited to, U.S. Patent Nos. 6,387,920, 6,743,815, 6,750,213, 6,869,969, 6,927,224, 7,045,540, 7,138,426, 7,151,196, and 7,157,604. The compounds described in each of these patents are incorporated herein by reference.

Other non-limiting antiestrogens of the invention include: 6α-chloro-16α-methyl-pregn-4-ene-3,20-dione (clometherone); 6-chloro-17- Hydroxypregna-1,4,6-triene-3,20-dione (delmadinone); 1-[2-[4-[1-(4-methoxyphenyl)- 2-nitro-2-phenylvinyl]phenoxy]ethyl]-pyrrolidine (nitromifene/CN-55, 945-27); and 1-[2-[p--3,4 -Dihydro-6-methoxy-2-phenyl-1-naphthyl)phenoxy]ethyl]pyrrolidine (nafoxidene).

Other non-limiting antiestrogens of the invention include hydrazines, such as J. Med. Chem., 33: 2635-2640 (1990), J. Med. Chem., 30: 131-136 (1987), WO 93/ U.S. Patent No. 6,741, the disclosure of which is incorporated herein by reference.

Other non-limiting antiestrogens of the invention include 2-[3-(1-cyano-1-methyl-ethyl)-5-(1H-1,2,4-triazole) as described in EP 0296749 -1-ylmethyl)phenyl]-2-methyl-propionitrile (anastrozole) and other compounds; described in U.S. Patent No. 4,808,616, incorporated herein by reference. 6-Methylene-androst-1,4-diene-3,17-dione (exemestane) and other compounds; U.S. Patent No. 5,473,078 (which is incorporated herein by reference) 4-[(4-Cyanophenyl)-(1,2,4-triazol-1-yl)methyl]benzonitrile (letrozole) and other compounds described in the above; US patent 1-[4'-Dimethylaminoethoxy]phenyl]-1-(3'-hydroxyphenyl)-2-benzene as described in No. 5, 047, 431, which is incorporated herein by reference. Butyl-1-ene (dlooxifene) and other compounds; 2α, 3α-cyclothio-5α-androstane-17β-ol (epitiostanol; 2α, 3α-cyclothio- 5α-androstane-17β-yl-1-methoxycyclopentyloxy (mepitiostane); U.S. Patent Nos. 2,464,203 and 2,465,505 both incorporated herein by reference. 4-) [(2Z,4Z)-4-(4-Hydroxyphenyl)hex-2,4-dien-3-yl]phenol (cycladiene) and other compounds; Unlisted Drugs, 28(10): CI-680, described in 169(O) (1976); Unlisted Drugs, 26(7): 106(1) (1974); CI-628; 13-ethyl-17α-acetylene-17β-hydroxyl Adenine-4,9,1-trien-3-one (R2323); Geynet, et al., Gynecol. Invest. 3(1): 2-29 (1972). -MEA; Merck Index, 10th Edition, #2149, 1-[1-chloro-2,2-bis(4-methoxyphenyl)vinyl]-4-methoxy-benzene (chlorine) Chlorotrianisene; Merck Index, 10th Edition, #3668, 1-[4-(2-diethylaminoethoxy)phenyl]-1-phenyl-2-(pair) Methoxybenzyl)ethanol (ethamoxytripheto); and 2-p-chlorophenyl-1-[2] described in U.S. Patent No. 2,914,562, the disclosure of which is incorporated herein by reference. P-(2-Diethylaminoethoxy)phenyl]-1-p-tolylethanol (triparanol) and other compounds.

Other antiestrogens in the present invention include, but are not limited to, (2e)-3-(4-) as described in Wilson et al, Endocrinology, 138(9): 3901-3911 (1997) and WO 95/10513. ((1e)-1,2-diphenylbut-1-enyl)phenyl)acrylic acid (GW5638), GW7604 and other compounds; 1-[4-(2-diethylaminoethoxy)phenyl ]-2-(4-methoxyphenyl)-1-phenyl-ethanol (MER-25), N,N-diethyl-2-[4-(5-methoxy-2-phenyl) -3H-indol-1-yl)phenoxy]ethylamine hydrochloride (U-11, 555A), 1-[2-[4-(6-methoxy-2-phenyl-3,4-di Hydronaphthalen-1-yl)phenoxy]ethyl]pyrrolidine hydrochloride (U-11,100A), ICI-46,669,2-[4-[(Z)-1,2-diphenylbutan-1 -alkenyl]phenoxy]-N,N-dimethyl-ethylamine; 2-hydroxypropane-1,2 as described in Terenius et al., Gynec. Invest., 3: 96-107 (1972), 3-tricarboxylic acid (ICI-46, 474) and other compounds; 2-hydroxy-6-naphthoic acid (allenolic acid); [4-[(4-acetoxyphenyl)-cyclo ring Hexyl-methyl]phenyl]acetate (cyclofenyl/ICI-48213); [6-hydroxy-2-(4-hydroxyphenyl)benzothiophen-3-yl]-[4- [2-(1-piperidinyl)ethoxy]phenyl]methanone (keoxifene); 4-[(Z)-1-[4-(2-dimethyl Ethyloxy)phenyl]-2-(4-propan-2-ylphenyl)but-1-enyl]phenol (DP-TAT-59/miproxifene); (1RS, 2RS -4,4'-diethoxycarbonyl-5,5'-difluoro-(1-ethyl-2-methylene)di-isophthalate (acefluranol) 6-hydroxy-2-(p-hydroxyphenyl)-benzo(b)thiophen-3-yl[2-(1-pyrrolidinyl)-ethoxyphenyl]one (LY-117018); [6-Hydroxy-2-(4-hydroxy-phenyl)benzo(b)thiophen-3-yl]-[4-(2-(1-piperidinyl)-ethoxy)phenyl]methanone (LY-156758).

Other antiestrogens of the invention include, but are not limited to, non-steroidal estrogen receptor ligands such as U.S. Patent Nos. 5,681,835, 5,877,219, 6,207,716, 6,340,774 and 6,599,921 (the patents) Each of which is incorporated herein by reference; a steroid derivative, such as described in U.S. Patent No. 4,659,516, incorporated herein by reference herein; Estriene, such as described in WO 98/07740; 11-β-halogen-7α-substituted estratriene, such as described in WO 99/33855; 17α-alkyl-17β-oxy-estratriene , such as described in U.S. Patent Application Serial No. 10/305,418, the disclosure of which is incorporated herein in - 吲哚, such as described in U.S. Patent No. 7.132, 417, which is incorporated herein by reference, which is incorporated herein by reference in its entirety, in its entirety, in its entirety, in its entirety, in the U.S. Patent No. 6,844,336. </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; double [2.2.1]Hept-2-yl)-ethoxy)-phenyl)-(6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl)- Ketones and other benzothiophenes; 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indole, such as U.S. Patent No. 5,998,402, incorporated herein by reference. The 3-[4-(2-phenyl-indol-1-ylmethyl)phenyl]- described in U.S. Patent No. 5,985,910, the disclosure of which is incorporated herein by reference. Acrylamide and other compounds; 2-phenyl-1-[4-(amino-1) as described in U.S. Patent Nos. 5,780,497 and 5,880,137, both incorporated herein by reference. -yl-yn-1-yl)-benzyl]-1H-indol-5-ol and other compounds; steroids such as U.S. Patent Nos. 6,455,517, 6,548,491, 6,747,018 and 7,041,839 (the patents , each of which is incorporated herein by reference; bis-(3'-hydroxyphenyl)-alkane compound, such as described in U.S. Patent No. 4,094,994, incorporated herein by reference. a phenol derivative, such as described in U.S. Patent No. 4,751,240, the disclosure of which is incorporated herein by reference. -Diaryl-2H-1-benzopyran analogs, such as Saeed et al, J. Med. Chem., 33:3210-3216 (1990) and Sharma et al, J. Med. Chem. 33:3216 -3229 (1990); and benzofuran and triaryl furan analogs, such as those described in 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 pharmaceutically acceptable salts 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 solvates as well as crystalline polytypes. According to the invention, the free bases and salts of such final products can be used.

The acid addition salts can be converted to the free base in a manner known per se using an alkaline reagent such as an alkali or by ion exchange. 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, nitric acid, aliphatic acids, alicyclic carboxylic acids or sulfonic acids such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, lemon Acid, ascorbic acid, glucuronic acid, fumaric acid, maleic acid, hydroxy maleic acid, pyruvic acid, aspartic acid, glutamic acid, p-hydroxybenzoic acid, methylene bishydroxy Illustranic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, phenylacetic acid, mandelic acid, algogenbensenesulfonic acid, toluenesulfonic acid, galactonic acid, galacturonic acid or naphthalenesulfonic acid. According to the invention, all crystalline polymorphs 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 contacting the free acid form with a sufficient amount of the desired base to produce the salt. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. Pharmaceutically acceptable base addition salts are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines. Examples of the metal used as the cation are sodium, potassium, calcium, magnesium and the like. Examples of suitable amines are amino acids (such as lysine), choline, diethanolamine, ethylenediamine, N-methylglucamine, 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, intrathecal, 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 (eg 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, solutions, suspensions or emulsions which may be used as a dry powder or as a propellant such as dichlorofluoromethane or trichlorofluoromethane. The agent is administered in the form of an aerosol.

The compositions of the invention may also be formulated for transdermal delivery, for example as a cream, ointment, lotion, paste, gel, medicated plaster, patch or patch. The compositions may comprise any suitable excipients such as penetration enhancers and the like.

The compositions of the invention may also be formulated for parenteral administration, including, but not limited to, parenteral administration by injection or continuous infusion. Formulations for injection may be in the form of a suspension, solution or emulsion in an oily or aqueous vehicle. The 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 (WFI), and the like.

The compositions of the invention may also be formulated as a drug depot preparation which may be administered by implantation or intramuscular injection. The compositions may be formulated with a suitable polymeric or hydrophobic material (e.g., as an emulsion in an acceptable oil), an ion exchange resin, 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. Liposomal formulations can comprise liposomes that penetrate the cell or stratum corneum of interest and fuse with the cell membrane to allow the contents of the liposome to be delivered into the cell. For example, liposomes as described in U.S. Patent No. 5, 077, 211 to Yarosh, U.S. Patent No. 4,621, 023 to Redziniak et al., or U.S. Patent No. 4,508,703 to Redziniak et al.

The composition of the present invention may be in the form of a solid dosage unit such as a tablet (e.g., a suspension tablet, a bite suspension tablet, a fast dispersing tablet, a chewable tablet, an 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), mouth-containing tablets, sachets, flat gels, sugar-coated tablets, pills Granules, 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 lozenge or other solid dosage form can be prepared by a process using one of the following methods or methods, including but not limited to: (1) 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 process for tablet preparation typically include milling and component screening, dry powder mixing, wet lumping, granulation, and final milling. Dry granulation involves pressing a powdered mixture into a crude lozenge or "crushing" on a heavy duty rotary tablet machine. The slug is then broken down into granules by a grinding operation (usually by means of an oscillating granulator). Individual steps include mixing the powder, pressing (pressing) and grinding (reducing the mass or granulating). Typically, no wet adhesive or moisture is involved in any of the steps.

In another embodiment, the solid dosage form can be prepared by mixing the antiestrogens with one or more pharmaceutical excipients to form a substantially uniform pre-blended blend. The pre-blended blend can then be subdivided and further processed (eg, pressed, encapsulated, encapsulated, dispersed, etc.) into any desired dosage form as appropriate.

The compressed tablet can be prepared by compacting the powder or granule composition of the present invention. The term "pressed tablet" generally refers to a conventional, uncoated lozenge suitable for oral ingestion, which is prepared by a single compression or by pre-compaction tapping followed by a final compression. The lozenges of the present invention may be coated or mixed to provide a dosage form having the advantages of improved handling characteristics or storage characteristics. In one embodiment, any such coating selected does not substantially delay the onset of the therapeutic effect of the compositions of the invention upon administration to the individual. The term "suspended tablet" as used herein refers to a compressed tablet that rapidly disintegrates after being placed in water.

Suitable liquid dosage forms for the compositions of the present invention include solutions, aqueous or oily suspensions, elixirs, syrups, emulsions, liquid aerosol formulations, gels, creams, ointments and the like. The compositions may also be formulated as a dry product for reconstitution with water or other suitable vehicle prior to use.

In one embodiment, the liquid or semi-solid composition is stored in a closed container maintained at room temperature, refrigerated (eg, about 5 to 10 ° C) or frozen at a temperature of about 1, 2, 3, 4, 5, At 6, 7, 8, 9, 10, 11 or 12 months, at least about 90%, at least about 92.5%, at least about 95% or at least about 97.5% of the initial anti-estrogen compound is present.

If desired, the compositions of the present invention may include one or more pharmaceutically acceptable excipients. The term "excipient" as used herein means a carrier or vehicle that is not itself a therapeutic agent but is used to deliver a therapeutic agent to an individual, or is added to a pharmaceutical composition to improve its handling properties or storage properties or to permit or facilitate the composition. Form a unit dose of any substance. For the purpose of illustration and not limitation, excipients include diluents, disintegrating agents, binders, adhesives, wetting agents, lubricants, slip agents, surface modifiers or surfactants, fragrances, suspending agents, Emulsifiers, non-aqueous vehicles, preservatives, antioxidants, adhesives, agents for adjusting pH and volumetric osmolality (eg buffers), preservatives, thickeners, sweeteners, flavoring agents, taste masking agents, A colorant or dye, a penetration enhancer, and a substance added to improve the appearance of the composition.

The excipients used in the compositions of the invention may optionally be solids, semi-solids, liquids or combinations thereof. Compositions of the invention containing excipients can be prepared by any of the known pharmacy techniques, including mixing the excipient with a pharmaceutical or therapeutic agent.

The compositions of the present invention optionally comprise one or more pharmaceutically acceptable diluents as excipients. Exemplary of suitable diluents include the following individually or in combination of agents: lactose, including anhydrous lactose and lactose monohydrate; starches, including directly compressible starch and hydrolyzed starches of (e.g. Celutab ^TM and Emdex ^TM); mannitol; sorbitol Sugar alcohol; xylitol; dextrose (such as Cerelose ^TM 2000) and dextrose monohydrate; dicalcium phosphate dihydrate; sucrose-based diluent; confectioner's sugar; monobasic calcium sulfate Monohydrate; calcium sulfate dihydrate; granular calcium lactate trihydrate; dextrates; inositol; hydrolyzed cereal solids; amylose; cellulose, including microcrystalline cellulose, food grade source - no crystalline cellulose, and cellulose (e.g., Rexcel ^(TM)) and powdered cellulose; calcium carbonate; glycine; bentonite; polyvinylpyrrolidone foot-one; and the like. If such diluents are present, they together constitute from about 5% to about 99%, from about 10% to about 85%, or from about 20% to about 80%, by total weight of the composition. Any diluent selected preferably exhibits suitable fluidity and exhibits compressibility when a tablet is desired.

The use of extragranular microcrystalline cellulose (i.e., microcrystalline cellulose added to the wet particulate composition after the drying step) can be used to improve hardness (for tablets) and/or disintegration time.

The compositions of the present invention optionally comprise one or more pharmaceutically acceptable disintegrants as excipients, particularly for lozenges, capsules or other solid formulations. Of suitable disintegrating agents include agents individually or in combination of the following: starches, including sodium starch glycolate (e.g. PenWest of Explotab ^TM) and pregelatinized corn starches (e.g., National ^TM 1551, National ^TM 1550 and Colocorn ^TM 1500), clay (e.g. Veegum ^TM HV), celluloses, pure cellulose, microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose and sodium carboxymethylcellulose, croscarmellose sodium (e.g., such as cellulose of FMC Ac-Di-Sol ^TM), alginic acid, cross-linked povidone, and gums such as agar, guar gum, xanthan gum, locust bean gum, karaya, pectin and tragacanth.

The disintegrant can be added in any suitable step during the preparation of the composition, particularly prior to the granulation step or during the lubrication step prior to pressing. If such disintegrants are present, they collectively comprise from about 0.2% to about 30%, from about 0.2% to about 10%, or from about 0.2% to about 5% by weight of the total composition.

The compositions of the present invention optionally comprise one or more pharmaceutically acceptable binders or adhesives as excipients, particularly for lozenge formulations. Preferably, the binders and adhesives impart sufficient cohesion to the powder of the ingot to allow for normal processing operations such as sizing, lubrication, compression and encapsulation, but still allow the tablet to disintegrate upon ingestion and the composition absorb. The suitable adhesives and adhesive agents include the following individually or in combination of: gum arabic; tragacanth; sucrose; gelatin; glucose; starches, such as (but not limited to) pregelatinized starch (e.g., National ^TM 1511 and National ^TM 1500 ); cellulose, such as (but not limited to) methyl cellulose, and sodium carboxymethylcellulose (e.g., Tylose ^TM); alginic acid and alginates; magnesium aluminum silicate; PEG; guar gum; polysaccharide acids; bentonites ; povidone, for example povidone K-15, K-30 and K-29/32; polymethacrylates; HPMC; hydroxypropyl cellulose (e.g. Klucel ^TM); and ethylcellulose (e.g., Ethocel ^TM ). If such binders and/or binders are present, they collectively comprise from about 0.5% to about 25%, from about 0.75% to about 15%, or from about 1% to about 10%, by total weight of the composition.

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, benzethonium chloride and cetylpyridinium chloride; sulfobutyl Sodium dioctyl sulphate; polyoxyethylene alkyl phenyl ethers, such as nonoxynol ether 9, nonoxynol ether 10 and octoxynol 9; poloxamer (polyoxyethylene and polyoxypropylene) Segmented copolymer); polyoxyethylene fatty acid glycerides and oils, such as polyoxyethylene (8) caprylic/capric monoglyceride and diglyceride (eg Gattefoss) The Labrasol ^TM), polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkyl ethers, such as polyoxyethylene (20) cetyl ether group eighteen; polyoxyethylene fatty esters, such as polyoxyethylene (40) stearate; polyoxyethylene sorbitan esters, for example polysorbate 20 and polysorbate 80 (e.g., ICI's Tween ^TM 80); propylene glycol fatty acid esters, Such as propylene glycol laurate (such as Gattefoss The Lauroglycol ^TM); sodium lauryl sulfate; and salts of fatty acids, such as oleic acid, sodium oleate and triethanolamine oleate; fatty acid glycerides, such as glyceryl monostearate; sorbitan esters such as sorbitan Sugar alcohol monolaurate, sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate; tyloxapol, and mixtures thereof. If such wetting agents are present, they together comprise from about 0.25% to about 15%, from about 0.4% 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 one or more pharmaceutically acceptable lubricants (including anti-adherents and/or slip agents) as excipients. The suitable lubricants include the following individually or in combination of agents: the mountain崳glyceride (glyceryl behapate) (e.g. Compritol ^TM 888); stearic acid and salts thereof, including magnesium stearate, calcium stearate and sodium stearate ; hydrogenated vegetable oils (e.g., Sterotex ^TM); colloidal silicon dioxide; talc; waxes; boric acid; sodium benzoate; sodium acetate; sodium fumarate II; chloride; DL-leucine; PEG (e.g., Carbowax ^TM 4000 and Carbowax ^TM 6000); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate. If such lubricants are present, they collectively comprise from about 0.1% to about 10%, from about 0.2% to about 8%, or from about 0.25% to about 5% by weight of the total 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 that is 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 0.25% to about 5%, or from about 0.5% 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 cerium oxide, starch, talc, tricalcium phosphate, powdered cellulose and magnesium tristearate. 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% to about 5%, from about 0.001% to about 2%, or from about 0.001% to about 1%, by total weight of the composition.

Exemplary antioxidants for use in the present invention include, but are not limited to, dibutylhydroxytoluene, butylhydroxymethoxybenzene, potassium metabisulfite, and the like. If necessary, the one or more antioxidants are typically from about 0.01% to about 2.5%, such as about 0.01%, about 0.05%, about 0.1%, about 0.5%, about 1%, about 1.5%, about 1.75% by weight. An amount of about 2%, about 2.25%, or about 2.5% 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, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate or butyl p-hydroxybenzoate, benzyl alcohol, phenylethyl alcohol , benzethonium, methyl or propylparaben, sorbic acid or a combination thereof. Typically, optionally, the preservative is present in an amount from about 0.01% to about 0.5% or from about 0.01% to about 2.5% by weight.

In one embodiment, the compositions of the present invention optionally comprise 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, as described above. Phosphate, citrate, borate, acetate, bicarbonate and carbonate.

Non-limiting examples of suitable buffering agents include aluminum hydroxide, magnesium hydroxide, aluminum glycinate, calcium acetate, calcium hydrogencarbonate, calcium borate, calcium carbonate, calcium citrate, calcium gluconate, calcium glycophosphate, hydrogen. Calcium oxide, calcium lactate, calcium phthalate, calcium phosphate, calcium succinate, calcium tartrate, dibasic sodium phosphate, dipotassium hydrogen phosphate, dipotassium phosphate, disodium hydrogen phosphate (disodium hydrogen phosphate), disodium succinate, anhydrous aluminum hydroxide gel, magnesium acetate, magnesium aluminate, magnesium borate, magnesium hydrogencarbonate, magnesium carbonate, magnesium citrate, magnesium gluconate, magnesium hydroxide, lactic acid Magnesium, magnesium aluminate magnesium sulphate, magnesium oxide, magnesium phthalate, magnesium phosphate, magnesium citrate, magnesium succinate, magnesium tartrate, potassium acetate, potassium carbonate, potassium hydrogencarbonate, 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 , sodium hydrogen phosphate, Sodium oxide, sodium lactate, sodium phthalate, sodium phosphate, sodium polyphosphate, sodium pyrophosphate, trisodium hydrogencarbonate, sodium succinate, sodium tartrate, sodium tripolyphosphate, synthetic hydrotalcite, tetrapotassium pyrophosphate, pyrophosphate Tetrasodium, tripotassium phosphate, trisodium phosphate and trometarnol. (Partially based on the catalogue provided in The Merck Index, Merck & Co. Rahway, N.J. (2001)). Further, any two or more combinations or mixtures of the above buffers can be used in the pharmaceutical compositions described herein. 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, if desired.

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. The term "functional agent" as used herein refers to any excipient that improves the flavor or odor of the compositions of the present invention, or that 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 any agent that sweetens the pharmaceutical composition or provides flavor to the pharmaceutical composition. Optionally, a functional agent is typically present in the compositions of the invention in an amount from about 0.1 mg/mL to about 10 mg/mL, from about 0.5 mg/mL to 5 mg/mL, or from about 1 mg/mL.

Exemplary sweeteners or flavoring agents include, but are not limited to, gum arabic syrup, aniseed brain, anise oil, aromatic tincture, benzaldehyde, benzaldehyde tincture, 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, mash Oil, dextrose, hairy grass, hairy grass extract, hairy grass syrup, aromatics, ethyl acetate, ethyl vanillin, cumin oil, ginger, ginger extract, ginger oleoresin, Dextrose, glucose, sugar, maltodextrin, glycerin, licorice, licorice tincture, licorice extract, pure licorice extract, licorice extract, licorice syrup, honey, etc. (iso-alcoholic elixir) , lavender oil, lemon oil, lemon tart, mannitol, methyl salicylate, nutmeg oil, bitter orange tart, bitter orange oil, neroli oil, orange flower water, orange oil, bitter orange peel , orange peel, orange peel, orange peel syrup, mint, peppermint oil, peppermint, mint water Phenylethanol, raspberry juice, raspberry syrup, rosemary oil, rose oil, rose water (concentrate), saccharin, saccharin calcium, saccharin sodium, sarsaparilla syrup, salsa, sorbitol solution, green Peppermint, spearmint oil, sucrose, sucralose, syrup, thyme oil, tolu balsam, tolu gum syrup, vanilla, vanilla extract, vanilla extract, wild cherry syrup or combinations thereof.

Exemplary taste masking agents include, but are not limited to, cyclodextrins, cyclodextrin emulsions, cyclodextrin particles, cyclodextrin complexes, or combinations thereof.

Exemplary suspending agents include, but are not limited to, sorbitol syrup, methylcellulose, dextrose/syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, and hydrogenated edible fat.

Exemplary emulsifiers include, but are not limited to, lecithin, sorbitan monooleate, and gum arabic. Non-aqueous vehicles include, but are not limited to, edible oils, almond oil, fractionated coconut oil, oily esters, propylene glycol, and ethanol.

The excipients described above can have a variety of effects as are known in the art. For example, starch can be used as a filler as well as a disintegrant. The classification of the above excipients should not be construed as limiting in any way.

The compositions of the present invention can be administered in any manner including, but not limited to, orally, parenterally, sublingually, transdermally, rectally, transmucosally, topically, via inhalation, via buccal administration, or combinations thereof. Parenteral administration includes, but is not limited to, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intrathecal, intra-articular, intracisternal, and intraventricular administration.

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. In general, however, the dosage for human treatment is typically in the range of from about 0.001 mg/kg to about 500 mg/kg per day, for example from about 1 [mu]g/kg to about 1 mg/kg per day or about 1 [mu]g/kg per day. Up to about 100 μg/kg. For most large mammals, the total daily dose is from about 1 mg to 100 mg, preferably from about 2 mg to 80 mg. The dosing regimen can be adjusted to provide the 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 day.

Illustratively, the compositions of the present invention can be administered to an individual to provide the individual with an antiestrogens in an amount of from about 1 [mu]g/kg to about 1 mg/kg body weight, for example about 1 [mu]g/kg, about 25 [mu]g/kg, about 50 [mu]g/kg. About 75 μg/kg, about 100 μg/kg, about 125 μg/kg, about 150 μg/kg, about 175 μg/kg, about 200 μg/kg, about 225 μg/kg, about 250 μg/kg, about 275 μg/kg, about 300 μg/kg. About 325 μg/kg, about 350 μg/kg, about 375 μg/kg, about 400 μg/kg, about 425 μg/kg, about 450 μg/kg, about 475 μg/kg, about 500 μg/kg, about 525 μg/kg, about 550 μg/kg. About 575 μg/kg, about 600 μg/kg, about 625 μg/kg, about 650 μg/kg, about 675 μg/kg, about 700 μg/kg, about 725 μg/kg, about 750 μg/kg, about 775 μg/kg, about 800 μg/kg. About 825 μg/kg, about 850 μg/kg, about 875 μg/kg, about 900 μg/kg, about 925 μg/kg, about 950 μg/kg, about 975 μg/kg, or about 1 mg/kg body weight.

In a preferred embodiment, the compositions of the present invention comprise trans-clomiphene at a dose between 1 mg and about 200 mg (although the optimal dosage is determined to be within the skill of the average). The composition may comprise a dose 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, 180 mg, 190 mg, 200 mg or a trans-clomiphene. The composition may also comprise ratios of about 71/29, 72/28, 73/27, 74/26, 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 , trans/clomiphene and cis-clomiphene, 94/6, 95/5, 96/4, 97/3, 98/2, 99/1, 99.5/0.5 or between them. The trans isomers of clomiphene 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, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 days or more than 31 days. The compositions may also be administered for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more. The compositions may also be administered for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more years. 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, the compositions can be administered for a period of 1, 2, 3, 4, 5, or more weeks, followed by a period of time, followed by 1, 2, 3, 4, 5, or 5 weeks or more. The time of administration, 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

Clomiphene and its isomers against male sputum serum testosterone and cholesterol Influence

1.5 mg/kg clomiphene (clomiphene citrate), enclommomim (trans-clomiphene) or beclomid (cis-clomiphene) were administered to adult male ticks for 12 consecutive days. The samples analyzed were the sera taken on the first treatment day (Day 0) prior to administration of the test article, after 12 days of treatment (Day 12), and 7 days after the final treatment (End or Clearance).

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 three groups 7 days after the treatment (clearing period). However, on day 6 compared to clomiphene and beclomid (p=0.03 and p=0.00002, respectively), and on day 12 compared to beclomid (p=0.047), Enkromid produces higher levels of testosterone. The clopidogrel did not significantly increase total serum testosterone to any degree. Animals receiving clomiphene showed a greater change in total testosterone levels after day 6 and day 6 compared to animals receiving Encromet, as judged by their coefficient of variation. When considering the time course of action (Figure 3), compared to the baseline or day 0 values, we determined that only Encrometa had a statistically significant increase in total serum testosterone on Day 6 and Day 12. In addition, 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. Enkromydi is clearly better and more consistent than Cromidy itself, while Beclos is ineffective.

There was no change in serum LH or FSH. 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. During the study of the group receiving encrometa, serum prolactin (PRL) decreased, indicating the role of antiestrogens, which has been partially described (Ben-Jonathan and Hnasko, 2001) and based on Expected by the fact that men are older, with a decrease in testosterone and an increase in prolactin (Feldman et al., 2002).

2. Effect on cholesterol levels

Treatment with encrometide tends to reduce serum cholesterol and 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. Further analysis was performed as the observed trends for the two isomers showed an opposite effect on cholesterol levels in the short term.

Detailed analysis indicated that enkromide caused a 8% reduction in serum cholesterol levels. Conversely, treatment with clopidogrel resulted in a 22% increase in serum cholesterol levels. Treatment with clomiphene resulted in a slight increase in serum cholesterol levels. It is known that encrometa and clopidogrel have estrogen agonist activity or antagonist activity (alternatively), so the opposite effect of these isomers on serum cholesterol levels is not unexpected. These results indicate that Enkromid can be used to treat patients with high cholesterol levels. These results also indicate that encrometol can be more beneficial to serum cholesterol than benclomimeter if used for long-term use to increase the level of testosterone.

3. Impact on clinical chemistry parameters

At the beginning of the study, the mean values of the parameters between the three groups did not differ for any of the test parameters, as determined by the variance analysis or by the Kruskal-Wallis test. All groups showed normal values for each parameter except: (1) serum sodium; a related calculation parameter, anion gap, which was low for 9 sputum throughout the trial; (2) serum glucose; and (3) BUN It is higher on day 0 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 Encromet group. value. The values of serum sodium and anion gap appear to be abnormalities associated with this group.

Encrometi and Zhukroomi have a substantial impact on the red blood cell population, and Zhukeromei has a substantial impact on hematocrit. All compounds decreased mean cell heme concentration (MCHC) on day 0 or at the endpoint. The mean cellular hemoglobin (MCH) did not change, and the mean cell volume (MCV) increased, so it was predicted that MCHC would decrease. Although hematocrit is expected to increase hematocrit, only the clomiphene treatment (which does not increase total serum testosterone) shows a statistical difference. It is obvious that the characteristics of the red blood cell population of men who have used clinical trials with clopidogrel should be monitored. It is expected that Enkromydi 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 279 versus female 348). This is most likely due to hormones. Since the encrometa group showed an increase in testosterone, the decrease in platelet count compared to the change in testosterone in this group was secondary. In addition, treatment with encrometa resulted in platelet counts reaching their normal male levels from day 0, which is the upper end of the normal range for this group. Enkromid is not necessarily expected to have a detrimental effect on platelets.

Both clomiphene citrate, enclamidin, and clopidogrel have an effect on the white blood cell (WBC) population, most notably the increase in lymphocyte and eosinophil counts in encromet. These effects are not as simple as they seem. Encrometi seems 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, at which point the value is reduced below the normal range. (This procedure reflects the relative length of time required to affect changes in the white blood cell population.) There are very few serotypes in the white blood cell population of sputum, so the effect is likely to be due to changes in the compound itself rather than testosterone. 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. Along with this, the most interesting thing is the report of lymphocytes. Treatment with encommide resulted in an increase in lymphocyte counts and percentages in the population. While the mean percentage of lymphocytes remained in the normal range, the net effect was an increase in lymphocyte counts after the use of enkromide, taking into account the trend of increased white blood cell counts. 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, such individuals are often treated with agents intended to increase testosterone. Low liver and kidney toxicity and beneficial effects on cholesterol and lipids are also highly preferred properties of any drug intended for use in HIV-anodic men who have been compromised by the disease.

The increase in serum glucose production was within the normal range with clomiphene or clopidogrel. In the case where the average serum glucose value is higher in Encrometa on day 0, the treatment does not increase the mean serum glucose value. There is no evidence that Enkromid has a detrimental effect on blood 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. An increase in the level of enzymes in the serum indicates liver damage. At the end of the study at the Cromiform group, ALT/SGPT was below the allowable range, although the difference during the treatment period was not statistically significant. The changes caused by Encrometi and Beclozomim are within the normal range. AST is reduced during pregnancy; therefore the role of estrogen agonists (such as clopidogrel) in reducing marginal AST levels can be explained. Alkaline phosphatase (ALP) is also found in the liver and is elevated in a variety of disease conditions. The reduction in ALP further confirmed that the liver was not damaged. There was no change in serum albumin (also liver production). Strong inhibition of serum albumin over a prolonged period of time promotes free serum steroid hormone levels in humans, although sex hormone binding globulin plays a more important role. As a bottom line, no compound can be associated with liver damage based on the parameters determined.

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 Enkromidyl can be expected to be more favorable results than the use of Beclozil.

Despite changes in BUN and BUN/creatinine during the study of the clomimites and encromets, no determinate changes in creatinine demonstrated no renal dysfunction. Loss of glomerular filtration capacity will result in an increase in BUN. Humans have reduced BUN due to malnutrition (which is unlikely in a controlled setting) or high fluid intake (possibly accompanied by edema). Furthermore, although total serum testosterone increased between day 0 and day 12 using enkromide, there was no difference between serum creatinine values, demonstrating that muscle mass did not increase during this short interval.

All animals had serum sodium levels below the reference value throughout the study. For the clomiphene and the clopidogrel group, serum carbon dioxide was higher than the reference value on day 12. Throughout the study, all animals had lower serum anion gaps similar to the sodium results. Encrometi increases this parameter toward the normal value. 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.

The above results indicate that encrometa is more effective than clomiphene or beclomid in increasing total serum testosterone. It is clear that clopidogrel is not effective, and this shortcoming limits the use of clomiphene for any use of gonadal infertility, especially since it considers that the clomiphene component of the clomiphene has a longer half-life, so Will dominate the loop over time.

Enkromidy seems to be relatively advantageous in all respects when compared to the cemetery and often even the clos. This is especially true when considering the tendency of encromet to lower cholesterol and liver enzymes (as opposed to the trend to increase the same parameters with clopidogrel). If the CD4+ subpopulation of lymphocytes can be shown not to decrease or increase, then the surprising trend of increasing the lymphocyte count of encommide may be useful for men with AIDS.

Example 2

Method for treating fasting glucose abnormalities by administering trans-clomiphene and a mixture of trans-clomiphene and cis-clomiphene having a ratio greater than 71/29

Individuals continued for 8 to 12 hours on an empty stomach overnight, after which blood samples were taken and fasting blood glucose levels were measured.

Individuals with a fasting blood glucose level between 110 mg/dl and 125 mg/dl were given a daily dose of 1.5 mg/kg clomiphene, wherein the ratio of trans-clomiphene to cis-clomiphene was 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

Method for treating insulin resistance by administering trans-clomiphene and a mixture of trans-clomiphene and cis-clomiphene having a ratio greater than 71/29

For example, as described in Defronzo et al., Am. J. Physiol. 237: E214-E223 (1979), for example, using high insulin blood-normal blood glucose clamps, and/or as in Matthews et al., Diabetologia. 28:412-419 ( As described in 1985), the insulin sensitivity of an individual was assessed using an in vivo balanced insulin resistance assessment model (HOMA-IR).

Individuals with insulin resistance were given a daily dose of 1.5 mg/kg clomiphene, wherein the ratio of trans-clomiphene to cis-clomiphene was 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

Method for treating type 2 diabetes by administering trans-clomiphene and a mixture of trans-clomiphene and cis-clomiphene having a ratio greater than 71/29

Individuals diagnosed with Type 2 diabetes were administered a daily dose of 1.5 mg/kg clomiphene, wherein the ratio of trans-clomiphene to cis-clomiphene was greater than 71/29. Glucose, insulin, and optionally plasma triglyceride levels are monitored at regular intervals to adjust the dosage and dosage frequency to achieve therapeutic benefit from insulin response and/or blood glucose levels.

Example 5

Compare Androxal ^TM with Androgel

Placebo-controlled study of excitation in Hackensack, New Jersey clinical study of Advanced Biological Research Corporation (ABR) to the center of oral administration on the gonads of male low energy Androxal ^TM (trans-clomiphene) to Androgel Compare. Androgel (Solvay Pharmaceuticals, Inc.) consists of a cream administered to exogenous steroids in a transdermal matrix.

The study enrolled 62 testosterone level of less than 300ng / dl (normal 298-1034ng / dl) of male gonadal low energy, randomly divided into six different groups (ARM), three doses of Androxal ^TM (12.5mg, 25mg and 50mg ), placebo, and two Androgel High dose and low dose. Each of the placebo and Androxal ^TM in half the sum of men randomly assigned to 1 day and 14 day time clinical experiences to determine the group of periodic variations of pharmacokinetic parameters for Androxal ^TM and the testosterone. Department of placebo and Androxal ^TM dose administered in a blinded manner. Androgel Creams are administered in an open label. Half Androgel The patient experienced clinical time similar to other patients in the study. After two weeks of drug exposure, the patient was followed for another 7 to 10 days to determine the status of their testosterone levels. Unlike placebo, the study's Androxal ^TM or Androgel No side effects were recorded in the group.

1. Effect on the level of testosterone

All doses of Androxal ^TM or Androgel A statistically significant change in testosterone compared to baseline testosterone levels was generated (Figure 5). Low, medium and high doses of Androxal ^TM were reached 169ng / dl, 247ng / dl and 294ng / dl of the average increase, and Androgel 5G dose (minimum approved dose), and Androgel A dose of 10G (the highest approved dose) produced a change of 212 ng/dl and 363 ng/dl compared to baseline. This equivalence with their change by the Androxal ^TM reached no difference statistically. This does not show Androxal ^TM and Androgel The difference seems to be made by using Androgel Caused by the result of the height change obtained at the time. For example, 50mg dose of Androxal ^TM increase the average total testosterone after 15 days to 589 ± 172ng / dl, coefficient of variation (CV) of 29% and similar to the placebo group (36%). On the other hand, Androgel 5G and 10G obtained an average total ketamine value of 473±289ng/dl and 608±323ng/dl, respectively, and CV was 61% and 53%.

Androxal ^TM therapy after 14 days, all doses are associated with a total testosterone day week mode (similar to the placebo group), that is the apex of the morning, noon and night for the lowest point rise. Do not want to be bound by theory, be attributed to this mode of mode of action of Androxal ^TM, which appears as shown below under the hypothalamus via the on - axis of the pituitary is mediated. Use Androgel The men’s day pattern is almost flat. However, Androgel The spike in total steroids is drug-related and often exceeds a normal high level of 1,034 ng/dl. Some use Androgel Individuals of 10G can achieve a peak level of total steroids greater than 2500 ng/dl.

Interestingly, in the follow-up period after treatment with Androxal ^TM (i.e., daily oral treatment was stopped after 7-10 days) the levels of total serum testosterone unexpectedly high duration. Also, with high dose AndroGel Compared to 1%, at the highest dose of Androxal ^TM, total serum testosterone levels significantly higher (p = 0.017, t- test).

2. Impact on LH and FSH levels

Treatment with Androxal ^(TM) resulted in a statistically significant increase in serum levels of LH in gonadal low energy male individuals (Figure 6). As in the case of total serum testosterone in (i.e. after cessation of treatment at the daily oral 7-10 days) for keeping track of high levels of three doses of Androxal ^TM serum levels of LH has unexpectedly continued. Compare it with AndroGel Treatment initially reduced LH and rebounded significantly to the level before treatment.

In males the gonads low energy individuals with Androxal ^TM treatment also produced a significant increase (FIG. 7) on the serum levels of FSH statistics. The pattern is similar to the increase seen in the LH FSH case, i.e., all doses of Androxal ^TM promote serum FSH, and its continued high tracking of AndroGel Inhibition of serum FSH levels and discontinuation of treatment resulted in a rebound in serum FSH to a concentration more similar to that before treatment.

3. Impact on other clinical chemistry parameters

The effect on serum dihydroxy steroid (DHT) levels was also measured. Use Androxal ^TM of male total testosterone to DHT favorable changes. For example, using a dose of 50mg Androxal ^TM men DHT / TT ratio of 0.83, in comparison with the placebo group ratio of 1.07. Instead, any one of Androgel The DHT/TT ratio of the group was >1.5. These results indicate the use of Androgel Men get DHT faster than total steroids. So compared to using Androgel The normal levels of DHT in males treated with therapy are disturbed.

Results of clinical chemistry parameters also indicated unexpectedly the use of male Androxal ^TM triglycerides non dose-dependent decrease. The reduction in triglycerides averaged 19.1% after two weeks of therapy. It is compared to the 5.9% reduction in the placebo group, and for Androgel 5G and 10G increased by 0.3% and 22% respectively.

4. Discussion

Based on this research, we concluded that Androxal ^TM as a potential therapy has many potential advantages. Androxal ^TM seems highly consistent way to increase total testosterone and no abnormal high peak serum testosterone within the normal range. In addition, the use of trans-clomiphene to treat men with secondary gonadal dysfunction provides a novel approach that may counteract such as Androgel One of the main side effects of exogenous therapy. Exogenous therapy provides negative feedback to stop FSH and LH production. FSH is an essential reproductive hormone and stimulates sperm production in men. Due to its effect on FSH, long-term exposure to exogenous steroids leads to reduced sperm synthesis, resulting in temporary infertility due to low sperm count, resulting in testicular contraction due to testicular volume and seminiferus tubule The level of sperm production is related. The increase in FSH levels also indicates Androxal ^TM is used to treat male (including low energy male gonads) infertility. In addition, Androxal ^TM serum testosterone, FSH and LH levels to extend the indication of the impact of Androxal ^TM can be changed or the dose administered according to schedule, perhaps even making it possible to treat non-daily or periodic treatment.

Example 5

Effect of trans-clomiphene on fasting glucose levels

Placebo-controlled study to determine the orally administered Androxal ^TM (trans-clomiphene) and Androgel The effect on blood sugar levels. Androgel (Solvay Pharmaceuticals) consists of a cream administered to exogenous steroids in a transdermal matrix.

The gonadal low-energy male (testosterone less than 300 ng/dl) recruited by the Institute has a wide range of body mass index (BMI). Patients were randomized into three different groups, 50mg dose of Androxal ^TM, the placebo and the high dose of Androgel . Department of placebo and Androxal ^TM dose administered in a blinded manner. Androgel Creams are administered in an open label. The fasting glucose level of the patient was monitored immediately before treatment (baseline) and at regular intervals during the study period. Unlike placebo, the study's Androxal ^TM or Androgel No side effects were recorded in the group.

Figure 8 depicts baseline blood glucose levels for each treatment group. The patients in each treatment group were differentiated according to BMI on the chart. The dark bar graph depicts baseline blood glucose in patients with BMI > 26 (EP300) in each treatment group. Light bar graphs depict baseline blood glucose in patients with a BMI < 27 in each treatment group. As can be seen from Figure 8, baseline blood glucose was significantly elevated in patients with BMI > 26 in all treatment groups relative to baseline blood glucose in patients with a BMI < 27.

Figure 9 depicts changes in serum glucose compared to 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. The light bar graph depicts changes in serum glucose from patients with BMI < 27 compared to baseline. As can be seen from Figure 9, treatment with Androxal for patients with BMI > 26 was effective in lowering serum glucose levels throughout the treatment period, with a decrease of approximately 24 mg/dl during the 3rd and 4.5th months observed.

Figure 10 depicts a patient with BMI > 26 (EP300) in Androgel Changes in serum glucose compared to baseline in the placebo-treated group. The dark bar graph depicts changes in serum glucose from patients in the placebo group compared to baseline. Light bar chart depicting Androgel Changes in serum glucose of patients in the treatment group compared to baseline. As can be seen from Figure 10, patients with a BMI > 26 were observed in Androgel There was no significant difference in serum glucose from baseline in the placebo-treated group.

These data show that Androxal ^TM has been developed in reducing metabolic syndrome and patients with low normal or below normal testosterone levels of fasting glucose (and insulin resistance associated with it) aspect surprisingly effective, and show Androxal ^TM in the treatment of metabolic syndrome and Efficacy in relation to conditions such as high glucose levels, high triglyceride levels, high cholesterol levels, insulin resistance, hypertension, and obesity. In contrast, administration of exogenous steroids is ineffective in reducing glucose levels in patients with developed metabolic syndrome and having low or normal lower tonicosterone. Based on these data, it is also expected to Androxal ^TM effective for the treatment of male and female individuals of type 2 diabetes.

Figure 1 is a representative graph of the characteristics of total serum steroids normally secreted in healthy males (young and older males).

Figure 2 shows the chemical structure of clomiphene citrate.

Figure 3 is a graph showing the serum testosterone of Clomid, Clomiphene, Enclomid, and Zuclomid. Graphical representation of the horizontal time course.

Figure 4 is a graph showing the cholesterol levels of male cockroaches treated with clomiphene (clomiphene citrate), encommide (trans-clomiphene), and clopidogrel (cis-clomiphene). An illustration of the time course.

Figure 5 shows Androxal ^TM or Androgel The effect on the level of testosterone.

Figure 6 shows Androxal ^TM or Androgel The impact on LH levels.

Figure 7 shows Androxal ^TM or Androgel Impact on FSH levels.

Figure 8 shows Androxal ^TM , Androgel Baseline blood glucose in the placebo treatment group.

Figure 9 shows the effect on blood glucose levels of Androxal ^TM.

Figure 10 shows Androgel The effect on blood sugar levels.

Claims (5)

An anti-clomiphene formula (trans -clomiphene) or a salt thereof use, its supply line for the manufacture of preventing or treating disease, and low energy secondary gonadal having a body mass index greater than an individual medicine of type 2 diabetes 26 Product, wherein the pharmaceutical product comprises about 100% trans-clomiphene and about 0% cis-clomiphene. The use of the first aspect of the patent application, wherein the dose of the trans-clomiphene is from about 12.5 mg to about 50 mg. The use of the second item of the patent application, wherein the dose is 12.5 mg, 25 mg or 50 mg. The use of claim 1, wherein the individual has a fasting glucose level of greater than 140 mg/dl prior to administration. The use of the first aspect of the patent application, wherein the individual has a testosterone level of less than 300 ng/dl.