Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
  • A61P5/30—Oestrogens

Definitions

• the present invention relates to compositions and methods for treating cancer and associated diseases. Specifically, the present invention relates to the use of a selective estrogen receptor modulator such as trans-clomiphene or a metabolite thereof to treat cancer in a subject by reducing the level of insulin- like growth factor- 1 (IGF-1) in the subject.
• a selective estrogen receptor modulator such as trans-clomiphene or a metabolite thereof to treat cancer in a subject by reducing the level of insulin- like growth factor- 1 (IGF-1) in the subject.
• IGF insulin-like growth factor
• IGF-1 insulin-like growth factor-1
• IGF-2 various cognate binding proteins
• IGF-BPs various cognate binding proteins
• IGF-R IGF-insulin hybrid receptor proteins
• IGF-R insulin-like growth factor-R
• IGN-R IGF-insulin hybrid receptor proteins
• IGFs are growth stimulatory peptides, structurally similar to insulin, that participate in the regulation of mitogenesis, cellular differentiation, and apoptosis. Normally, IGF-1 is produced predominately by the liver and largely functions as an endocrine hormone.
• IGF-1 signaling pathways have been described in multiple tumors including osteosarcomas, breast, bladder, gynecological, gastrointestinal, prostate and lung cancers. Animal and human studies have shown that in such cancers IGF-1 also functions as a paracrine and autocrine hormone, being produced by the tumor cells and interacting with IGF-R, which is frequently overexpressed by the tumor cells as well. [Arnaldez and Helman, Hematol. Oncol. Clin. North Am., 26:527 (2012)]. Numerous studies have established a relationship between high serum levels of IGF-1 and increased cancer incidence and mortality. Thus, the IGF axis provides new
• IGF-R was first identified as a promising therapeutic target over 20 years ago when Arteaga and Osbourne reported that antibodies against IGF-R inhibited growth of breast cancer cells in vitro [Arteaga and Osborne, Cancer Res 49:6237 (1989)]. Since then, as many as 30 different agents targeting IGF-R have been developed and over 60 clinical trials evaluating anti-IGF-R therapies have been reported [reviewed in
• figitumumab and related anti-IGF-R mAbs remain among the best therapeutic candidates available and methods to increase treatment efficacy and prevent or reduce side effects would be invaluable for deploying this drug class in routine clinical use.
• IGF-R mAb therapy targets the signal transduction tyrosine kinase activity of IGF-R (IGFR-TKI).
• IGFR-TKI signal transduction tyrosine kinase activity of IGF-R
• the biochemical strategy is similar to EGFR-TKI drugs such as gefitinib, erlotinib and others, which have already been approved for treatment of lung, hepatocellular and renal cancers.
• IGFR- TKIs compete for the ATP binding site of IGF-R and block the transition of the receptor to the phosphorylated active conformation.
• Initial clinical results report similar side effects as observed with IGF-R mAbs, especially with respect to hyperglycemia.
• IGFR-TKI treatment seems to suffer the same problems with cross-talk between the IGF-R and INS-R systems.
• the effect may be due to more than just crosstalk since the ATP binding domains of IGF-R, INS-R and IGN-R are virtually identical and IGFR-TKI drugs likely bind each of the receptor species with equivalent or nearly equivalent affinity.
• a third approach to targeting IGF-R for cancer therapy involves antisense oligonucleotides (IGFR-ASO) that selectively target and destroy IGF-R transcripts prior to translation.
• IGFR-ASO antisense oligonucleotides
• Preclinical studies have developed a number of promising candidates, including at least one IGFR-ASO capable of suppressing growth of a paclitaxel resistant prostate tumor model.
• the specificity of the IGFR-ASO strategy holds great promise for avoiding the cross talk issues observed with IGF-R mAb and IGFR-TKI therapies, in particular the tendency to provoke hyperglycemia.
• the biology of the system is complex and it isn't certain that IGFR-ASOs will prove clinically useful.
• a pilot clinical study indicated that the IGFR-ASO was well tolerated but this approach suffers from poor half-life and delivery problems. No oral delivery route is available and routine clinical use of such compounds will require overcoming this limitation.
• IGF-BPs are quite selective for their specific cognate IGF and preclinical work has shown that these proteins exhibit pro- apoptotic, anti-proliferative and anti-angiogenic properties.
• IGF-BPs are quite selective for their specific cognate IGF and preclinical work has shown that these proteins exhibit pro- apoptotic, anti-proliferative and anti-angiogenic properties.
• Unfortunately there are no clinical studies of this approach and not all in vitro results have been replicated in animal models. Though promising, much work remains to be done to develop this strategy into a useful therapy.
• Tamoxifen is a triphenylalkylene derivative that binds to the estrogen receptor (ER). It has both estrogenic and antiestrogenic actions, depending on the target tissue. It is strongly antiestrogenic to mammary epithelial cells, hence its use in both the prevention and treatment of breast cancer. Tamoxifen was originally screened in a program oriented to discovering new contraceptive agents. Although it was not a useful drug for control of fertility, tamoxifen was eventually discovered to be useful for clinical treatment of breast cancer. The therapeutic mechanisms of tamoxifen are complex, the primary effect of tamoxifen is exerted via estrogen receptors, but the drug may also modulate IGF-1 levels as well.
• Tamoxifen is a pro-drug requiring metabolic activation by hepatic cytochrome P450 enzymes.
• CYP2D6 is instrumental in converting the
• CYP3 A4 also plays a key role in activating tamoxifen or 4-hydroxy-tamoxifen to the N-desmethyl form. Extensive pharmacogenomic analyses of tamoxifen metabolism show that certain human alleles of CYP2D6 are incapable of activating tamoxifen to endoxifen and thus patients with these alleles receive no benefit from treatment with tamoxifen.
• Clomiphene Another structurally similar triphenylalkylene derivative with both estrogenic and antiestrogenic activities is clomiphene.
• Clomiphene blocks normal estrogen feedback on the hypothalamus and subsequent negative feedback on the pituitary. This leads to increases in luteinizing hormone and follicle stimulating hormone.
• increased levels of these gonadotropins results in the production of higher testosterone levels from the Leydig cells of the testes.
• these increased levels of gonadotropins results in ovulation.
• Clomiphene citrate has been used to treat female infertility for many years with a relatively low level of serious side effects.
• clomiphene is a mixture of two geometric isomers which are referred to as cis,-Z-, clomiphene (cis- clomiphene, or zuclomiphene) and trans-, ⁇ -, clomiphene, (traw-clomiphene or enclomiphene).
• Ernst et al. also noted that (the trans-isomef) is antiestrogenic, while the cz ' s-isomer is the more potent and more estrogenic form, but has also been reported to have anti-estrogenic activity [Ibid.].
• the isolated tram-isomer of clomiphene has been developed to treat, inter alia, secondary hypogonadism in men and is currently in Phase III trials as Androxal®.
• clomiphene is metabolized to the 4-hydroxy and N-dealkyl forms by the liver enzymes CYP2D6 and CYP3A4, respectively [Ghobadi, et al., Drug Metab. Pharmacokinet 23: 101 (2008) and Murdter et al., Hum. Mol. Genet. 21 : 1 145 (2012)].
• Murdter has also shown that 4-hydroxy-ira -clomiphene ((E)-40H- clomiphene) and N-desethyl-4-hydroxy-tr ns-clomiphene ((E)-DE-4-OH-clomiphene) are strong ligands for the human estrogen receptor [Ibid.].
• the present invention is related to methods for reducing the level of insulin-like growth factor- 1 (IGF-1) in the serum of a subject in need thereof comprising administering to the subject an effective amount of a composition comprising an antiestrogen or an analog or pharmaceutically acceptable salt thereof.
• the subject may be a human male or female with a serum IGF-1 level above the normal range, including without limitation, with IGF-1 levels above 300 ng/ml, above 350 ng/ml, above 400 ng/ml or above 500 ng/ml.
• the antiestrogen is a selective estrogen receptor modulator (SERM).
• a human male with elevated IGF-1 levels is administered a composition comprising trans- clomiphene or an analog or pharmaceutically acceptable salt thereof wherein the composition is substantially free of cis-clomiphene.
• trans-clomiphene analogs for use according to the invention are (E)-4-OH-Clomiphene (Fig. 2) and (E)- 4-OH-desethyl Clomiphene (Fig. 3).
• the present invention provides a method of treating cancer comprising administering to a subject in need thereof, a composition
• the subject may be a human male or female with elevated serum IGF-1 levels.
• the cancer is selected from the group consisting of lung, hepatocellular, breast, renal, gastrointestinal, uterine, ovarian, osteosarcoma and bladder cancer.
• the antiestrogen may be a SERM and in a particularly preferred embodiment, the composition comprises about 0% to 29% weight/weight of (cis, -Z-, trans-clomiphene) (hereinafter "cw-clomiphene") and about 100% to 71% w/w (trans-, E-, cw-clomiphene) (hereinafter "trara-clomiphene”) as active agent or an analog or pharmaceutically acceptable salt thereof.
• the composition may consist essentially of trans-clomiphene or a salt thereof.
• the present invention is also related to a method of treating elevated IGF-1 levels comprising administering to a subject in need thereof, a composition comprising an effective amount of an antiestrogen, preferably a SERM such as trans-clomiphene or an analog or pharmaceutically acceptable salt thereof.
• a composition comprising an effective amount of an antiestrogen, preferably a SERM such as trans-clomiphene or an analog or pharmaceutically acceptable salt thereof.
• the subject may be a human male or female.
• the present invention also provides a method for reducing or delaying tumor growth in a subject relative to an untreated subject, comprising administering an IGF-1- reducing amount of a composition comprising an antiestrogen, preferably a SERM such as trans-clomiphene, to the subject.
• a composition comprising an antiestrogen, preferably a SERM such as trans-clomiphene
• the subject may be a human male or female.
• the present invention also provides a method for suppressing the pituitary production of human growth hormone (hGH) comprising administering an effective amount of an antiestrogen, preferably a SERM such as trans-clomiphene or an analog or pharmaceutically acceptable salt thereof, to a subject.
• the subject may be a human male or female.
• the present invention also provides a method for preventing cancer or reducing the risk of cancer in a subject with type 2 diabetes comprising administering to the subject an IGF-1- lowering amount of an antiestrogen, preferably a SERM such as trans-clomiphene or an analog or pharmaceutically acceptable salt thereof.
• the subject may be a human male or female.
• the antiestrogen is co-administered to the subject with metformin, phenformin, or buformin which act to further reduce the risk of cancer through activation of AMP-activated protein kinase (AMPK) and suppression of mTor.
• metformin metformin
• phenformin or buformin which act to further reduce the risk of cancer through activation of AMP-activated protein kinase (AMPK) and suppression of mTor.
• AMPK AMP-activated protein kinase
• the present invention also provides a combination therapy whereby a composition comprising an effective amount of an antiestrogen, preferably a SERM such as trans-clomiphene or an analog or pharmaceutically acceptable salt thereof, is sequentially or simultaneously co-administered with one or more additional agents.
• an antiestrogen preferably a SERM such as trans-clomiphene or an analog or pharmaceutically acceptable salt thereof
• the antiestrogen is co-administered with one or more agents designed to further reduce serum IGF-1 levels or IGF-1 signaling through its receptor such as anti-IGF receptor antibodies, IGF receptor-related kinase inhibitors, IGF receptor antisense oligonucleotides or IGF binding protein(s).
• the antiestrogen is co-administered with one or more chemopreventive agents that may reduce cancer risk such as metformin, phenformin, or buformin or the like which act through activation of AMPK and suppression of the downstream mTor pathway.
• one or more chemopreventive agents that may reduce cancer risk such as metformin, phenformin, or buformin or the like which act through activation of AMPK and suppression of the downstream mTor pathway.
• the antiestrogen is co-administered with one or more chemotherapeutic agents that preferentially target proliferating cells such as a taxane, cisplatin, carboplatin, 5-fiuorouracil, irinotecan, topotecan, hydroxyurea, VM-26, vincristine, vinblastine, vinorelbine, cyclophosphamide, doxorubicin, bleomycin and the like.
• FIG. 1 demonstrates effect of AndroxalTM and Testim on total serum IGF-1 levels.
• FIG. 2 shows the chemical structure of (E)-4-OH-Clomiphene.
• FIG. 3 shows the chemical structure of (E)-4-OH-DE-Clomiphene.
• FIG. 4 shows the chemical structure of (Z)-4-OH-Clomiphene.
• FIG.5 shows the chemical structure of 4-OH-Pyrrolidinotamoxifen.
• FIG.6 shows the chemical structure of 4-OH-Toremifene.
• FIG. 7 shows the chemical structure of 4-OH-Fixed Ring Tamoxifen.
• FIG. 8 shows the chemical structure of 4-methoxy-N-diethylated
• FIG. 9 shows the chemical structure of 4-hydroxyl pyrrolidinotamoxifen.
• FIG. 10 shows the chemical structure of 4-OH-Fispemifme.
• the present invention provides methods for reducing IGF-1 levels in a subject in need of such treatment.
• the present invention is based on the surprising discovery that /ra/w-clomiphene is useful for significantly reducing the level of serum IGF-1.
• Clomiphene is thought to exert its effects at the level of the hypothamus-pituitary axis by specifically stimulating secretion of the gonadotropic hormones LH and FSH.
• trans-clomiphene suppresses the pituitary production of GH thereby reducing the endocrine stimulated production of liver IGF- 1.
• the activity of trans-clomiphene in reducing serum IGF-1 levels renders the compositions useful for treating a variety of cancers having strong expression or overexpression of IGF-1 as a common underlying etiology.
• the compositions are administered to a subject with a serum IGF-1 level above the normal range such as above such as above 250 ng/ml, above 300 ng/ml, above 350 ng/ml, above 400 ng/ml, above 450 ng/ml or above 500 ng/ml.
• the subject may have a serum IGF-1 level between 300 and 1200 ng/ml or any range there between.
• the normal range of IGF-1 level in a human depends on both age and gender and can be determined e.g. with reference to Friedrich N. et ah, Growth Horm. IGF Res., 18(3):228-37 (2008).
• the present invention provides methods for reducing serum IGF-1 levels in a subject and methods for treating cancer in a subject comprising administration of a composition comprising an effective amount of clomiphene or one of its triphenylalkylene analogs .
• the composition consists essentially of trans-clomiphene or a metabolite selected from (E)-4-OH-clomiphene (Fig. 2) and (E)- 4-OH-desethyl-clomiphene (Fig. 3).
• the subject may be a human male or female.
• cancer relates to cancer as defined by the National Cancer Institutes' Dictionary of Cancer Terms or any other recognized definition of this syndrome. Synonyms for "cancer” used in the art include; Carcinoma, which is a general term for cancers that begin in the skin or in tissues that line or cover internal organs; Sarcoma, which is a general term of cancers that begin in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue; Leukemia denotes cancers that starts in blood-fomiing tissue such as the bone marrow; Lymphoma and Multiple Myeloma are cancers that begin in the cells of the immune system.
• cancer also refers to carcinoma, sarcoma, leukemia, lymphoma and multiple myeloma.
• cancers are often described by the locus within the body in which they occur.
• testicular cancer may refer to carcinomas or sarcomas originating in the testes
• ovarian cancer may refer to carcinomas of sarcomas originating in the ovaries.
• Breast cancer may be a carcinoma, sarcoma or lymphoma originating in the breast or mammary tissues.
• Lung cancers may be carcinomas, sarcomas, lymphomas or multiple myelomas of the lungs.
• Cancer cells originating in one portion of the body may migrate to other portions of the body by a process known as metastasis.
• a tumor formed from cancer cells that have migrated from another part of the body is called a "metastatic tumor” or a “metastatic cancer.”
• Metastatic cancer spread throughout the body or it can be narrowly isolated to a single locus or a limited set of loci within the body. Metastatic tumors may have differentiated from one another, or from the source tumor so that they respond differently to particular anticancer treatments.
• the term "serum IGF-1” refers to circulating IGF-1 in the serum that is not bound to an IGF binding protein. In this respect it should be understood that the level of serum IGF-1 is dependent on the production of IGF-1 by hepatocytes and the concentration of IGF-1 binding proteins which sequester IGF-1.
• the family of triphenylalkylene derivatives representing analogs of clomiphene is defined here to include all unmodified cis and trans forms, as well as each of the 4- hydroxylated, the N-dealkylated and the 4-hydroxy-N-dealkylated analogs of clomiphene, tamoxifen, pyrrolidinotamoxifen, toremifene, fixed ring tamoxifen, fispemifene, as well as all other molecules with substantially similar structures.
• a composition comprising an effective amount of an antiestrogen, preferably a SERM such as /ra3 ⁇ 4y-clomiphene, is used to treat a cancer in a subject with an elevated level of serum IGF-1.
• the cancer may include, without limitation, carcinomas, sarcomas, leukemias, lymphomas, multiple myelomas whether metastatic or not located in any portion of the body.
• the cancer is characterized by elevated levels of serum IGF-1.
• the subject may be a human male or female.
• the known treatment regimen may target the IGF axis including without limitation medications such as anti-IGF receptor antibodies, IGF receptor related-kinases, and IGF receptor antisense oligonucleotides.
• the known treatment regimen may comprise one or more chemotherapeutic agents that preferentially target cancer cells. In this respect, it known that cancer cells can produce IGF-1 which acts in an autocrine/paracrine fashion.
• cancer cell-targeting chemotherapeutic agents include, without limitation, chemotherapies targeting the EGF axis, or estrogen receptor medicants, alkylating drugs such as cyclophosphamide, antimetabolites such as 5-flurouracil, antitumor antibiotics such as bleomycin, plant alkaloids such as vinbastine, topoisomerase inhibitors such as etoposide, immunotherapies and the like.
• alkylating drugs such as cyclophosphamide
• antimetabolites such as 5-flurouracil
• antitumor antibiotics such as bleomycin
• plant alkaloids such as vinbastine
• topoisomerase inhibitors such as etoposide
• immunotherapies immunotherapies and the like.
• compositions may prove effective in association with radiation therapies targeted against cancers.
• Compositions of the invention may be simultaneously, separately or sequentially administered with any of the aforementioned known treatment regimens.
• composition comprising an effective amount of an antiestrogen is used to treat elevated levels of IGF- 1 in a subject.
• the subject may be male or female.
• a patient with cancer and an elevated serum level of IGF- 1 levels is administered a composition comprising an effective amount of an antiestrogen, preferably /ram-clomiphene. Whether a patient has an elevated serum level of IGF-1 is determined with reference to the patient's age and gender as described above.
• the cancer patient may an IGF-1 level above about 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1010, 1020, 1030, 1040, 1050 or 1060 ng/m
• the cancer patient has an IGF level above the normal range for example, above 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050 ng/ml or any range therebetween such as between 300-1050, 400-1050 or 500-1050 ng/ml.
• the composition may comprise an amount of an antiestrogen, preferably ⁇ rara-clomiphene, effective to lower the cancer patient's IGF-1 level into the normal range for example, below about 500, 400, 300, 250, or 200 ng/ml.
• the subject in need of treatment by any of the methods of the present invention is a secondary hypogonadal male.
• the subject in need of treatment by any of the methods of the present invention is a human male with a body mass index of at least 20, at least 21, at 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31 or at least 32.
• the subject in need of treatment may be a human male with a body mass index of at least 25.
• the subject in need of treatment by any of the methods of the present invention is a human male or female with type 2 diabetes in which case the compositions of the invention are preferentially administered as part of a dosage regimen designed to reduce the risk of cancer.
• the subject is a human male with type 2 diabetes and the antiestrogen, preferably a SERM such as tnms-clomiphene, is co-administered sequentially or simultaneously to the subject with metformin, phenformin, or buformin.
• a patient with a single cancer or metastasizing cancers and an elevated serum IGF-1 level is administered one or more dosages of an effective amount of a composition comprising ⁇ ram-clomiphene at a dosage between one mg to about 200 mg (although the determination of optimal dosages is within the level of ordinary skill in the art) in order to treat the cancer.
• Cis- clomiphene may also be present in the composition so long as the ratio of trans- clomiphene to cz ' s-clomiphene is greater than 71/29. Analogs of the trans- and cis- isomers of clomiphene such as those described in Ernst, et al. supra and the metabolites described herein are also useful in the practice of the present invention.
• compositions of the invention are effective to lower IGF-1 levels in a subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%), at least 35% or at least 40% over the course of the treatment.
• the compositions may be effective to lower serum IGF-1 levels in a subject by between 15% and 40%.
• compositions are effective to reduce serum IGF-1 levels into the normal range with respect to the subject's gender and age during the course of administration for example with reference to the Mayo Clinic Reference Values for IGF-1 [available at www.mayomedicallaboratories.com/test- catalog/Clinical+and+Interpretive/83357, last accessed October 22, 2012].
• compositions of the invention may be in the form of sustained release formulations prepared as described for example in U.S. Patent No. 6,221,399, Japanese patent 4- 312522, 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 Inch Pharm. 21 (20):2323-2337 (1995); U.S. Patent Nos.
• a preferred antiestrogen for use in the methods of the invention is raw-clomphene an effective dose of which may range from 1 to 200 mg or from 5 to 100 mg.
• the dosage of trans-clomphene may also be from 12.5 to 50 mg.
• the dosage of trara-clomphene may also be 12.5 mg , 25 mg or 50 mg.
• beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state and remission (whether partial or total), whether detectable or undetectable.
• Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment. Individuals in need of treatment include those already with the condition or disorder as well as those prone to develop the condition or disorder or those in whom the condition or disorder is to be prevented.
• modulate refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired clinical parameter.
• beneficial or desired clinical results include, but are not limited to, correcting of clinical parameter, diminishment of extent of clinical parameter, stabilized (i.e., not worsening) clinical parameter and delay or slowing of extent of clinical parameter.
• antiestrogen it is meant a compound that prevents estrogens from expressing their effects on estrogen dependent target tissues consequently antagonizing a variety of estrogen-dependent processes. Based on the unexpected finding that the antiestrogenic irara-clomiphene isomer is useful in reducing serum IGF-1 levels, it is expected that other compounds with antiestrogenic activity will be useful in the present invention. In all cases, antiestrogens useful in the practice of the instant invention are those capable of reducing IGF- 1 levels in a mammal. Without wishing to be bound by theory, it is believed that administration of antiestrogens will result in reducing IGF-1 levels by blocking growth hormone driven hepatic production of endocrine IGF-1.
• Antiestrogens useful in the practice of the instant invention may be pure antiestrogens or may have partial estrogenic action as in the case of the selective estrogen receptor modulators (SERMs) which exhibit antiestrogenic properties in some tissues and estrogenic tissues in others.
• SERMs selective estrogen receptor modulators
• SERMs of the invention include, without limitation, triphenylalkylenes, which include : 2- [4-( 1 ,2-diphenylbut- 1 -enyl)phenoxy] - ⁇ , ⁇ -dimethyl-ethanamine (tamoxifen) and other compounds described in U.S. Patent No. 4,536,516, incorporated herein by reference; 4' -hydroxy-2- [4-( 1 ,2-diphenylbut- 1 -enyl)phenoxy]-N,N-dimethyl- ethanamine (4'-hydroxytamoxifen) and other compounds described in U.S. Patent No.
• SERMS of the invention also include, without limitation, benzothiphene derivatives such as: [6-hydroxy-2-(4-hydroxyphenyl)-benzothiophen-3-yl]-[4-[2-(l- piperidinyl)ethoxy)phenyl]-methanone (raloxifene) and other compounds described in U.S. Patent Nos. 4,418,068 and 5,393,763, both of which are incoiporated herein by reference; LY353381 ; and LY335563 and other compounds described in WO
• chromans such as 3,4- trans-2,2-dimethyl-3-phenyl-4-[4-(2-(2-(pyrrolidin-l-yl)ethoxy)phenyl]-7- methoxychroman (levormeloxifene) and other compounds described in WO 97/25034, WO 97/25035, WO 97/25037 and WO 97/25038; and l-(2-((4-(-methoxy-2,2, dimethyl-3-phenyl-chroman-4-yl)-phenoxy)-ethyl)-pyrrolidine (centchroman) and other compounds described in U.S. Patent No. 3,822,287, incorporated herein by reference.
• SERMs of the invention include, without limitation, the compounds described in 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, each of which is incorporated herein by reference.
• antiestrogens of the invention include: 6a-chloro-16a- 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- phenylethenyl]phenoxy]ethyl]-pyrrolidine (nitromifene/CN-55,945-27); and l-[2-[p- (3 ,4-Dihydro-6-methoxy-2 -phenyl- 1 -naphthyl)phenoxy]ethyl]pyrrolidine (nafoxidene).
• antiestrogens of the invention include indoles such as those disclosed in 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 Nos. 6,503,938 and 6,069,153, both of which are incorporated herein by reference.
• antiestrogens of the invention include 2-[3-(l-cyano-l- methyl-ethyl)-5-(lH-l,2,4-triazol-l-ylmethyl)phenyl]-2-methyl-propanenitrile
• Patent 5,047,431 incorporated herein by reference; 2a,3a-Epithio-5oc-androstan- 17 ⁇ - ⁇ 1 (epitiostanol); 2 ,3a-Epitio-5a-androstane-17 -yl-l-methoxycyclopentyloxy (mepitiostane); 4-[(2Z,4Z)-4-(4-hydroxyphenyl)hexa-2,4-dien-3-yl]phenol (cycladiene) and other compounds described in U.S. Pat. Nos.
• Still other antiestrogens of the invention include, without limitation: (2e)-3-(4- ((le)-l,2-diphenylbut-l-enyl)phenyl)acrylic acid (GW5638), GW7604 and other compounds described in Wilson et ah, Endocrinology, 138(9): 3901-3911 (1997) and WO 95/10513; 1 -[4-(2-diethylaminoethoxy)phenyl]-2-(4-methoxyphenyl)- 1 -phenyl- ethanol (MER-25), N,N-diethyl-2-[4-(5-methoxy-2-phenyl-3H-inden- 1 - yl)phenoxy]ethanamine hydrochloride (U-1 1,555A), l-[2-[4-(6-methoxy-2-phenyl-3,4- dihydronaphthalen-l-yl)phenoxy]ethyl]pyrrolidine hydrochloride (
• Still other antiestrogens of the invention include, without limitation: nonsteroidal estrogen receptor ligands such as those described in U.S. Patent Nos.
• compositions of the invention comprise one or more pharmaceutically acceptable salts of an antiestrogen.
• the salt compound obtained may be either in neutral or salt form. Salt forms include hydrates and other solvates and also crystalline polymorphs. Both the free base and the salts of these end products may be used in accordance with the invention.
• Acid addition salts may be transformed into the free base using basic agents such as alkali or by ion exchange.
• the free base obtained may also form salts with organic or inorganic acids.
• acids which form suitably pharmaceutically acceptable salts.
• examples of such acids are hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, aliphatic acid, alicyclic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, fumaric acid, maleic acid, hydroxymaleic acid, pyruvic acid, aspartic acid, glutamic acid, p-hydroxybenzoic acid, embonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, phenylacetic acid, mandelic acid, alogenbensenesulfonic acid, toluenesulfonic acid, galactaric acid, galacturonic acid or naphthalenesulfonic acid. All crystalline form
• Base addition salts may also be used in accordance with the invention and may be prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.
• the free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner.
• Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkali earth metals or organic amines. Examples of metals used as cations are sodium, potassium, calcium, magnesium and the like.
• Suitable amines are amino acids such as lysine, choline, diethanolamine, ethylenediamine, N-methylglucamine and the like.
• compositions of the instant invention can be prepared in the form of a dose unit or dose units suitable for oral, parenteral, transdermal, rectal, transmucosal, or topical administration.
• Parenteral administration includes, but is not limited to, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intrathecal, and intraarticular.
• oral administration or “orally deliverable” herein include any form of delivery of a therapeutic agent or a composition thereof to a subject wherein the agent or composition is placed in the mouth of the subject, whether or not the agent or composition is swallowed.
• oral administration includes buccal and sublingual as well as esophageal (e.g. inhalation) administration.
• compositions of the present invention are formulated as rectal suppositories, which may contain suppository bases including, but not limited to, cocoa butter or glycerides.
• compositions of the present invention may also be formulated for inhalation, which may be in a form including, but not limited to, a solution, suspension, or emulsion that may be administered as a dry powder or in the form of an aerosol using a propellant, such as dichlorofuoromethane or trichlorofluoromethane.
• a propellant such as dichlorofuoromethane or trichlorofluoromethane.
• compositions of the present invention may also be formulated for transdermal delivery, for example as a cream, ointment, lotion, paste, gel, medicated plaster, patch, or membrane.
• Such compositions can comprise any suitable excipients, for example penetration enhancers and the like.
• compositions of the present invention may also be formulated for parenteral administration including, but not limited to, by injection or continuous infusion.
• Formulations for injection may be in the form of suspensions, solutions, or emulsions in oily or aqueous vehicles. Such compositions may also be provided in powder form for reconstitution with a suitable vehicle including, but not limited to, sterile, pyrogen- free water, WFI, and the like.
• Compositions of the present invention may also be formulated as a depot preparation, which may be administered by implantation or by intramuscular injection. Such compositions may be formulated with suitable polymeric or hydrophobic materials (as an emulsion in an acceptable oil, for example), ion exchange resins, or as sparingly soluble derivatives (as a sparingly soluble salt, for example).
• compositions of the present invention may also be formulated as a liposome preparation.
• Liposome preparations can comprise liposomes which penetrate the cells of interest or the stratum corneum and fuse with the cell membrane resulting in delivery of the contents of the liposome into the cell.
• liposomes such as those described in U.S. Patent No. 5,077,211 to Yarosh, U.S. Patent No. 4,621,023 to Redziniak et ah, or U.S. Patent No. 4,508,703 to Redziniak et al. can be used.
• a composition of the invention can be in the form of solid dosage units such as tablets, (e.g. suspension tablets, bite suspension tablets, rapid dispersion tablets, chewable tablets, effervescent tablets, bilayer tablets, etc), caplets, capsules (e.g., a soft or a hard gelatin capsule), powder (e.g. a packaged powder, a dispensable powder or an effervescent powder), lozenges, sachets, cachets, troches, pellets, granules,
• tablets e.g. suspension tablets, bite suspension tablets, rapid dispersion tablets, chewable tablets, effervescent tablets, bilayer tablets, etc
• caplets e.g., a soft or a hard gelatin capsule
• powder e.g. a packaged powder, a dispensable powder or an effervescent powder
• lozenges e.g. a packaged powder, a dispensable powder or an effervescent powder
• a preferable dosage form is a soft or hard gelatin capsule.
• Tablets can be prepared according to any of the many relevant, well known pharmacy techniques.
• tablets or other solid dosage forms can be prepared by processes that employ one or a combination of methods including, without limitation, (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion.
• the individual steps in the wet granulation process of tablet preparation typically include milling and sieving of the ingredients, dry powder mixing, wet massing, granulation and final grinding.
• Dry granulation involves compressing a powder mixture into a rough tablet or "slug" on a heavy-duty rotary tablet press. The slugs are then broken up into granular particles by a grinding operation, usually by passage through an oscillation granulator.
• the individual steps include mixing of the powders, compressing (slugging) and grinding (slug reduction or granulation).
• solid dosage forms can be prepared by mixing an antiestrogen with one or more pharmaceutical excipients to form a substantially homogenous preformulation blend.
• the preformulation blend can then be subdivided and optionally further processed (e.g. compressed, encapsulated, packaged, dispersed, etc.) into any desired dosage forms.
• Compressed tablets can be prepared by compacting a powder or granulation composition of the invention.
• the term "compressed tablet” generally refers to a plain, uncoated tablet suitable for oral ingestion, prepared by a single compression or by pre- compaction tapping followed by a final compression. Tablets of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of improved handling or storage characteristics. In one embodiment, any such coating will be selected so as to not substantially delay onset of therapeutic effect of a composition of the invention upon administration to a subject.
• the term “compressed tablet” generally refers to a plain, uncoated tablet suitable for oral ingestion, prepared by a single compression or by pre- compaction tapping followed by a final compression. Tablets of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of improved handling or storage characteristics. In one embodiment, any such coating will be selected so as to not substantially delay onset of therapeutic effect of a composition of the invention upon administration to a subject.
• sustained tablet refers to a compressed tablet that rapidly
• Suitable liquid dosage forms of a composition of the invention include solutions, aqueous or oily suspensions, elixirs, syrups, emulsions, liquid aerosol formulations, gels, creams, ointments, etc. Such compositions may also be formulated as a dry product for constitution with water or other suitable vehicle before use.
• liquid or semi-solid compositions upon storage in a closed container maintained at either room temperature, refrigerated (e.g. about 5 -10 C) temperature, or freezing temperature for a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, exhibit at least about 90%, at least about 92.5%, at least about 95%, or at least about 97.5% of the original antiestrogen compound present therein.
• compositions of the invention can, if desired, include one or more
• excipient herein means any substance, not itself a therapeutic agent, used as a carrier or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a unit dose of the composition.
• Excipients include, by way of illustration and not limitation, diluents, disintegrants, binding agents, adhesives, wetting agents, lubricants, glidants, surface modifying agents or surfactants, fragrances, suspending agents, emulsifying agents, nonaqueous vehicles, preservatives, antioxidants, adhesives, agents to adjust pH and osmolarity (e.g. buffering agents), preservatives, thickening agents, sweetening agents, flavoring agents, taste masking agents, colorants or dyes, penetration enhancers and substances added to improve appearance of the composition.
• pH and osmolarity e.g. buffering agents
• Excipients optionally employed in compositions of the invention can be solids, semi-solids, liquids or combinations thereof.
• Compositions of the invention containing excipients can be prepared by any known technique of pharmacy that comprises mixing an excipient with a drug or therapeutic agent.
• compositions of the invention optionally comprise one or more
• Suitable diluents include, either individually or in combination, lactose, including anhydrous lactose and lactose monohydrate; starches, including directly compressible starch and hydrolyzed starches (e.g., CelutabTM and EmdexTM); mannitol; sorbitol; xylitol; dextrose (e.g., CereloseTM 2000) and dextrose monohydrate; dibasic calcium phosphate dihydrate; sucrose-based diluents; confectioner's sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate; granular calcium lactate trihydrate; dextrates; inositol;
• hydrolyzed cereal solids amylose; celluloses including microcrystalline cellulose, food grade sources of a- and amorphous cellulose (e.g., RexcelTM) and powdered cellulose; calcium carbonate; glycine; bentonite; polyvinylpyrrolidone; and the like.
• diluents if present, constitute in total about 5% to about 99%, about 10% to about 85%, or about 20% to about 80%, of the total weight of the composition.
• Any diluent or diluents selected preferably exhibit suitable flow properties and, where tablets are desired, compressibility.
• extragranular microcrystalline cellulose that is, microcrystalline cellulose added to a wet granulated composition after a drying step
• hardness for tablets
• disintegration time for disintegration time
• compositions of the invention optionally comprise one or more
• Suitable disintegrants include, either individually or in combination, starches, including sodium starch glycolate (e.g. , ExplotabTM of Pen West) and pregelatinized corn starches (e.g., NationalTM 1551 , NationalTM 1550, and
• ColocornTM 1500 clays (e.g., VeegumTM HV), celluloses such as purified cellulose, microcrystalline cellulose, methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose, croscarmellose sodium (e.g., Ac-Di-SolTM of FMC), alginates, crospovidone, and gums such as agar, guar, xanthan, locust bean, karaya, pectin and tragacanth gums.
• clays e.g., VeegumTM HV
• celluloses such as purified cellulose, microcrystalline cellulose, methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose
• croscarmellose sodium e.g., Ac-Di-SolTM of FMC
• alginates e.g., Ac-Di-SolTM of FMC
• crospovidone e.g., Ac-Di-SolTM of FMC
• alginates e
• Disintegrants may be added at any suitable step during the preparation of the composition, particularly prior to a granulation step or during a lubrication step prior to compression. Such disintegrants, if present, constitute in total about 0.2% to about 30%, about 0.2% to about 10%, or about 0.2% to about 5%, of the total weight of the composition.
• compositions of the invention optionally comprise one or more
• binding agents or adhesives as excipients, particularly for tablet formulations.
• Such binding agents and adhesives preferably impart sufficient cohesion to the powder being tableted to allow for normal processing operations such as sizing, lubrication, compression and packaging, but still allow the tablet to
• binding agents and adhesives include, either individually or in combination, acacia; tragacanth; sucrose; gelatin; glucose; starches such as, but not limited to, pregelatinized starches (e.g. , NationalTM 151 1 and NationalTM 1500); celluloses such as, but not limited to, methylcellulose and carmellose sodium (e.g. , TyloseTM); alginic acid and salts of alginic acid; magnesium aluminum silicate; PEG; guar gum; polysaccharide acids;
• povidone for example povidone K-15, -30 and K-29/32;
• binding agents and/or adhesives constitute in total about 0.5% to about 25%, about 0.75% to about 15%, or about 1% to about 10%, of the total weight of the composition.
• compositions of the invention optionally comprise one or more
• Non-limiting examples of surfactants that can be used as wetting agents in compositions of the invention include quaternary ammonium compounds, for example benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride, dioctyl sodium sulfosuccinate, polyoxyethylene .alkylphenyl ethers, for example nonoxynol 9, nonoxynol 10, and octoxynol 9, poloxamers (polyoxyethylene and polyoxypropylene block copolymers),
• quaternary ammonium compounds for example benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride, dioctyl sodium sulfosuccinate, polyoxyethylene .alkylphenyl ethers, for example nonoxynol 9, nonoxynol 10, and octoxynol 9, poloxamers (polyoxyethylene and polyoxypropylene block copolymers),
• polyoxyethylene fatty acid glycerides and oils for example polyoxyethylene (8) caprylic/capric mono- and diglycerides (e.g., LabrasolTM of Gattefosse),
• propylene glycol fatty acid esters for example propylene glycol laurate (e.g., LauroglycolTM of Gattefosse), sodium lauryl sulfate, fatty acids and salts thereof, for example oleic acid, sodium oleate and triethanolamine oleate, glyceryl fatty acid esters, for example glyceryl monostearate, sorbitan esters, for example sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate, tyloxapol, and mixtures thereof.
• Such wetting agents if present, constitute in total about 0.25% to about 15%, about 0.4% to about 10%, or about 0.5% to about 5%, of the total weight of the composition.
• compositions of the invention optionally comprise one or more
• Suitable lubricants include, either individually or in combination, glyceryl behapate (e.g. , CompritolTM 888); stearic acid and salts thereof, including magnesium (magnesium stearate), calcium and sodium stearates; hydrogenated vegetable oils (e.g.
• SterotexTM colloidal silica
• talc waxes
• boric acid sodium benzoate
• sodium acetate sodium fumarate
• sodium chloride DL-leucine
• PEG e.g., CarbowaxTM 4000 and CarbowaxTM 6000
• sodium oleate sodium lauryl sulfate
• magnesium lauryl sulfate Such lubricants, if present, constitute in total about 0.1% to about 10%, about 0.2% to about 8%o, or about 0.25% to about 5%, of the total weight of the composition.
• Suitable anti-adherents include talc, cornstarch, DL-leucine, sodium lauryl sulfate and metallic stearates.
• Talc is an anti-adherent or glidant used, for example, to reduce formulation sticking to equipment surfaces and also to reduce static in the blend.
• One or more anti-adherents, if present, constitute about 0.1% to about 10%, about 0.25% to about 5%, or about 0.5% to about 2%, of the total weight of the composition.
• Glidants can be used to promote powder flow of a solid formulation. Suitable glidants include colloidal silicon dioxide, starch, talc, tribasic calcium phosphate, powdered cellulose and magnesium trisilicate. Colloidal silicon dioxide is particularly preferred.
• compositions of the present invention can comprise one or more anti-foaming agents.
• Simethicone is an illustrative anti-foaming agent.
• Anti-foaming agents, if present, constitute about 0.001% to about 5%, about 0.001% to about 2%, or about 0.001% to about 1%, of the total weight of the composition.
• antioxidants for use in the present invention include, but are not limited to, butylated hydroxytoluene, butylated hydroxyanisole, potassium
• One or more antioxidants are typically present in a composition of the invention in an amount of about 0.01% to about 2.5%, for example about 0.01%, about 0.05%, about 0.1%, about 0.5%, about 1%, about 1.5%, about 1.75%, about 2%, about 2.25%, or about 2.5%, by weight.
• compositions of the invention can comprise a preservative.
• Suitable preservatives include, but are not limited to, benzalkonium chloride, methyl, ethyl, propyl or butylparaben, benzyl alcohol, phenylethyl alcohol, benzethonium, methyl or propyl p-hydroxybenzoate and sorbic acid or combinations thereof.
• the optional preservative is present in an amount of about 0.01 % to about 0.5% or about 0.01% to about 2.5%, by weight.
• compositions of the invention optionally comprise a buffering agent.
• Buffering agents include agents that reduce pH changes.
• Illustrative classes of buffering agents for use in various embodiments of the present invention comprise a salt of a Group IA metal including, for example, a bicarbonate salt of a Group IA metal, a carbonate salt of a Group IA metal, an alkaline or alkali earth metal buffering agent, an aluminum buffering agent, a calcium buffering agent, a sodium buffering agent, or a magnesium buffering agent.
• Suitable buffering agents include carbonates, phosphates, bicarbonates, citrates, borates, acetates, phthalates, tartrates, succinates of any of the foregoing, for example sodium or potassium phosphate, citrate, borate, acetate, bicarbonate and carbonate.
• Non-limiting examples of suitable buffering agents include aluminum, magnesium hydroxide, aluminum glycinate, calcium acetate, calcium bicarbonate, calcium borate, calcium carbonate, calcium citrate, calcium gluconate, calcium glycerophosphate, calcium hydroxide, calcium lactate, calcium phthalate, calcium phosphate, calcium succinate, calcium tartrate, dibasic sodium phosphate, dipotassium hydrogen phosphate, dipotassium phosphate, disodium hydrogen phosphate, disodium succinate, dry aluminum hydroxide gel, magnesium acetate, magnesium aluminate, magnesium borate, magnesium bicarbonate, magnesium carbonate, magnesium citrate, magnesium gluconate, magnesium hydroxide, magnesium lactate, magnesium metasilicate aluminate, magnesium oxide, magnesium phthalate, magnesium
• buffering agents can be used in the pharmaceutical compositions described herein.
• One or more buffering agents are present in compositions of the invention in an amount of about 0.01% to about 5% or about 0.01% to about 3%, by weight.
• compositions the invention may include one or more agents that increase viscosity.
• agents that increase viscosity include, but are not limited to, methylcellulose, carboxymethylcellulose sodium, ethylcellulose, carrageenan, carbopol, and/or combinations thereof.
• one or more viscosity increasing agents are present in compositions of the invention in an amount of about 0.1% to about 10%, or about 0.1% to about 5%, by weight.
• compositions of the invention comprise an
• organoleptic agent to improve the organoleptic properties of the composition.
• organoleptic agent refers to any excipient that can improve the flavor or odor of, or help mask a disagreeable flavor or odor of a composition of the invention.
• agents include sweeteners, flavoring agents and/or taste masking agents.
• Suitable sweeteners and/or flavoring agents include any agent that sweetens or provides flavor to a pharmaceutical composition.
• Optional organoleptic agents are typically present in a composition of the invention in an amount of about 0.1 mg/ml to about 10 mg/ml, about 0.5 mg/ml to 5 mg/ml or about 1 mg/ml.
• Illustrative sweeteners or flavoring agents include, without limitation, acacia syrup, anethole, anise oil, aromatic elixir, benzaldehyde, benzaldehyde elixir, cyclodextrins, caraway, caraway oil, cardamom oil, cardamom seed, cardamom spirit, cardamom tincture, cherry juice, cherry syrup, cinnamon, cinnamon oil, cinnamon water, citric acid, citric acid syrup, clove oil, cocoa, cocoa syrup, coriander oil, dextrose, eriodictyon, eriodictyon fluidextract, eriodictyon syrup, aromatic,
• Illustrative taste masking agents include, but are not limited to, cyclodextrins, cyclodextrins emulsions, cyclodextrins particles, cyclodextrins complexes, or combinations thereof.
• Illustrative suspending agents include, but are not limited to, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel, and hydrogenated edible fats.
• Illustrative emulsifying agents include, but are not limited to, lecithin, sorbitan monooleate, and acacia.
• Nonaqueous vehicles include, but are not limited to, edible oils, almond oil, fractionated coconut oil, oily esters, propylene glycol, and ethyl alcohol.
• excipients can have multiple roles as is known in the art.
• starch can serve as a filler as well as a disintegrant.
• the classification of excipients above is not to be construed as limiting in any manner.
• compositions of the present invention may 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, intraarticular, intracisternal and intraventricular.
• a therapeutically effective amount of the composition required for use in therapy varies with the length of time that activity is desired, and the age and the condition of the patient to be treated, among other factors, and is ultimately determined by the attendant physician.
• doses employed for human treatment typically are in the range of about 0.001 mg/kg to about 500 mg/kg per day, for example about 1 ⁇ g/kg to about 1 mg/kg per day or about 1 ⁇ g/kg to about 100 ⁇ g/kg per day.
• the total daily dosage is from about 1 to 100 mg, preferably from about 2 to 80 mg.
• the dosage regimen may be adjusted to provide the optimal therapeutic response.
• the desired dose may be conveniently administered in a single dose, or as multiple doses administered at appropriate intervals, for example as two, three, four or more subdoses per day.
• a composition of the invention may be administered to a subject to provide the subject with an antiestrogen in an amount of about 1 g/kg to about 1 mg/kg body weight, for example about 1 ⁇ g/kg, about 25 ⁇ g/kg, about 50 ⁇ g/kg, about 75 ⁇ g/kg, about 100 ⁇ g/kg, about 125 ig/kg, about 150 ⁇ g/kg, about 175 ⁇ g/kg, about 200 ⁇ g/kg, about 225 ⁇ g/kg, about 250 ⁇ g/kg, about 275 ⁇ g/kg, about 300 ⁇ g/kg, about 325 ⁇ g kg, about 350 ⁇ g/kg, about 375 ⁇ g/kg, about 400 ⁇ g/kg, about 425 ⁇ g/kg, about 450 ⁇ g/kg, about 475 ⁇ g/kg, about 500 ⁇ g/kg, about 525 ⁇ g/kg, about 550 ⁇ g/kg, about 575 ⁇ g/kg
• compositions according to the present invention comprise /rara-clomiphene at a dosage between one mg to about 200 mg (although the determination of optimal dosages is with the level of ordinary skill in the art).
• the composition may comprise traw-clomiphene at a dosage 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 there between.
• the composition may also comprise tra/M-clomiphene and cw-clomiphene at a ratio 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, 94/6, 95/5, 96/4, 97/3, 98/2, 99/1, 99.5/0.5 or there between.
• Analogs of the trans- and cis- isomers of clomiphene such as those described in Ernst, et al. supra are also useful in the practice of the present invention.
• compositions of the present invention may also be administered long-term.
• the compositions may be administered for a period of at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 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 an administration period of at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12 or more months.
• the compositions may also be administered for an administration period of at least 1, 2, 3, 4, 5, 6, 7 8, 9, 10 or more years.
• the composition may be administered daily or periodically such as every other day and the like.
• compositions of the present invention may also be administered
• compositions may be administered for an administration period of 1, 2, 3, 4, 5, or more weeks, followed by a period of discontinuance, followed by an administration period of 1, 2, 3, 4, 5 or more weeks, and so on.
• trans-clomiphene After 3 months of treatment (V4), serum IGF-1 levels were significantly reduced in the trans-clomiphene group to below 80 ng/ml; no corresponding reduction was observed in the Testim® group. IGF-1 levels remained depressed in the trans-clomiphene group after 6 months of treatment (V5); the Testim® group again exhibited no change in IGF-1 at the 6 month time point. Thus, circulating serum IGF-1 levels were reduced over 40% in subjects administered tram--clomiphene whereas exogenous testosterone had no effect on circulating serum IGF-1. Importantly, aside from low testosterone, these subjects were otherwise healthy - thus, administering trans-clomiphene provides an effective method for reducing serum levels of IGF-1 produced by the liver (i.e. growth-hormone dependent IGF-1).
• Another study measured serum IGF-1 levels in human males with low/low- normal testosterone following treatment with tra/w-clomiphene. Briefly 38 males were administered trans-clomiphene at 12.5mg per day, 35 males were administered trans- clomiphene at 25 mg per day and 43 males were administered a placebo (control group). Serum IGF-1 levels were measured by immunoenzymometric assay as described above at baseline and following three months of treatment with trans- clomiphene or placebo for each treatment group. The results are presented in Table 1 below and demonstrate a -32% mean reduction in serum IGF-1 levels for the 12.5 mg group and a 36% mean reduction for the 25 mg group.
• trara-clomiphene significantly lowers serum IGF-1 levels thereby rendering the SERM useful for treating a variety of cancers in which IGF-1 is strongly expressed or overexpressed. Without being bound by theory, it is believed that trara-clomiphene suppresses the production of hepatic IGF-1 by an endocrine-dependent mechanism thereby reducing the concentration of circulating serum IGF-1.
• Subjects with cancer may be treated by a protocol similar to that reported in Example 1.
• free circulating IGF-1 levels would be established prior to drug treatment and then monitored through the course of treatment.
• the drug could be trans- clomiphene, or it could be any of the antiestrogenic analogs of tram-clomiphene or a combination of various antiestrogens including /rara-clomiphene.
• trans- clomiphene or it could be any of the antiestrogenic analogs of tram-clomiphene or a combination of various antiestrogens including /rara-clomiphene.
• Example 1 drug treatment would continue until circulating IGF-1 levels were determined to reach normal and stable levels or the cancer was treated.
• Subjects with cancer undergoing treatment with anti-IGF-R antibodies such as figitumumab may benefit from prior or simultaneous treatment with /rara-clomiphene or other antiestrogens to reduce free circulating IGF-1.
• free circulating IGF-1 levels would be established prior to antiestrogen treatment. If high levels of IGF- 1 are detected, indicating that the subject was unlikely to respond positively to antibody therapy, the subject would be treated with trara-clomiphene or another antiestrogen to reduce circulating IGF-1. Once the IGF-1 level is reduced to an acceptable level, therapeutic antibody treatment would commence.
• Subjects with cancer undergoing treatment with tyrosine kinase inhibitors effective against IGF-R may benefit from prior or simultaneous treatment with trans- clomiphene or other antiestrogens to reduce circulating IGF-1.
• free circulating IGF-1 levels would be suppressed prior to, or concomitant with, treatment with tyrosine kinase inhibitors effective against IGF-R.
• Subjects with cancer undergoing treatment with IGF-BPs to reduce the level of free circulating IGF- 1 may benefit from prior or simultaneous treatment with trans- clomiphene or other antiestrogens to reduce production of circulating IGF-1.
• free circulating IGF-1 levels would be suppressed prior to, or concomitant with, treatment with IGF-BP.
• Subjects with cancer undergoing treatment with IGF-ASOs to reduce the amount of IGF-R present on tumor cells may benefit from prior or simultaneous treatment with fr-am-clomiphene or other antiestrogens to reduce production of circulating IGF-1.
• free circulating IGF-1 levels would be suppressed prior to, or concomitant with, treatment with IGF-ASOs.

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• 2013
  • 2013-10-22 WO PCT/US2013/066141 patent/WO2014070523A1/en not_active Ceased
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