US008173626B2

(12) United States Patent (10) Patent No.: US 8,173,626 B2 Hausknecht (45) Date of Patent: May 8, 2012

(54) METHODS, DOSING REGIMENS AND OTHER PUBLICATIONS MEDICATIONS USING ANT-PROGESTATIONAL AGENTS FOR THE Lumsden and Wallace, Bailliere's Clinical Obstetrics and Gynaecol TREATMENT OF DISORDERS ogy, 1998; 12(2): 177-195.* Eldar-Geva, Bailliere's Clinical Obstetrics and Gynaecology, (75) Inventor: Richard Hausknecht, Bronx, NY (US) 1998; 12(2):269-288.* Chwalisz et al., Presentation at Advances in Leiomyoma Research (73) Assignee: Danco Laboratories LLC, New York, 2nd NIH International Congress, Feb. 2005, Bethesda, MD.* NY (US) Chu et al. Successful Long-Term Treatment of Refractory Cushings Disease with High-Dose (RU486). J. Clin. Endocrinol. (*) Notice: Subject to any disclaimer, the term of this Metab. Aug. 2001, vol. 86, No. 8, pp. 3568-3573. patent is extended or adjusted under 35 Eisinger et al., Low-Dose Mifepristone for Uterine Lelomyomata. J. U.S.C. 154(b) by 1328 days. Obstet. Gynecol., Feb. 2003, vol. 101, No. 2, pp. 243-250. Xu et al. The Journal of Clinical Endocrinology & Metabolism (21) Appl. No.: 11/715,509 90(2):953-961 (2005). NIH Record, 57(24): 1-12, Dec. 2, 2005. (22) Filed: Mar. 8, 2007 * cited by examiner (65) Prior Publication Data US 2007/021330.6 A1 Sep. 13, 2007 Primary Examiner — San-Ming Hui (74) Attorney, Agent, or Firm — Don J. Pelto, Esquire; Related U.S. Application Data Sheppard, Mullin, Richter & Hampton LLP (60) Provisional application No. 60/780,047, filed on Mar. 8, 2006. (57) ABSTRACT (51) Int. Cl. A6 IK3I/56 (2006.01) The present invention relates to the treatment of disorders (52) U.S. Cl...... 514/179 using anti-progestational agents. More specifically, the (58) Field of Classification Search ...... 514/179 present invention relates to the treatment of disorders using See application file for complete search history. low doses of anti-progestational agents. Compared to dosages and lengths of treatment taught by the prior art, the described (56) References Cited methods, dosing regimens and medications use effective dos ages and lengths of treatment that are lower and/or shorter U.S. PATENT DOCUMENTS than previously thought possible. 5,468,741 A 11, 1995 Yen 6,043,234. A 3/2000 Stockemann et al. 6,451,780 B1 9, 2002 ChwalSZ et al. 47 Claims, 5 Drawing Sheets

Treatment (nx22) Placebo (r.20) Mean Mean SD) Mediary Range SD) Median Range Age ty) 41,862 43. 295 43.2 (4.7) 30 lody mass index (kg/m. 31.7 (8.7) S. 2-5 27. 5.6) 26 0-39 Education ty) 4.6 (2.3 - 2. 15. 2.5) s 1-22 Gravidity 2.6 (2. 3. e 2.ii 2, .) Parity .8 (.6) t .65 b. Uterine volume (m. 79 (663) 1732,88 449 (236) 3. 20-1,03 African American n (8) 1 (50 -- (55) - SE), standard deviation. U.S. Patent May 8, 2012 Sheet 1 of 5 US 8,173,626 B2

Figure 1

Treatment (ne22) Placebo (n=20) Mean Mean (SO) Media Range (SD) Mediar Range Age ty 4.1.86.2 43. S5 43.2 (1.7) f 30 Body mass index (kg/m. 3,7 (8.7) S. 2-5 2. 5.6) O-3) Education (y) 4.6 (2.3 2.9 15. 2.5) s Gravidity 2.6 (2.1) 3 2.8 2, .) O7 Parity 1.8 (1.6) - .6 .5 2 b literiric voluntern 79 (663) i 3.288 449 (236) 3. 2003 African American n (i)) 50 r 1 (55) - S), standard deviation. U.S. Patent May 8, 2012 Sheet 2 of 5 US 8,173,626 B2

Figure 2

Placebo Treatment U.S. Patent May 8, 2012 Sheet 3 of 5 US 8,173,626 B2

Figure 3

U.S. Patent May 8, 2012 Sheet 4 of 5 US 8,173,626 B2

Figure 4

U.S. Patent May 8, 2012 Sheet 5 of 5 US 8,173,626 B2

Figure 5

US 8,173,626 B2 1. 2 METHODS, DOSING REGIMENS AND Overview of Diagnosis and Treatment, www.womenshealth MEDICATIONS USING services.com (last visited Dec. 12, 2005). Other studies have ANT-PROGESTATIONAL AGENTS FOR THE found that uterine leiomyomata are clinically apparent in TREATMENT OF DISORDERS about 25% to about 50% of women (Buttram & Reiter, 36 Fertil. Steril. 433-45 (1981)), although careful pathologic CROSS REFERENCE TO RELATED examination of the uterus Suggests that the prevalence may be APPLICATION as high as about 80%. Cramer & Patel, 94 Am. J. Clin. Pathol. 435-38 (1990). This application claims the benefit, under 35 U.S.C. S 119, The severity of symptoms associated with uterineleiomyo of provisional U.S. Application Ser. No. 60/780,047, filed 10 mata, as well as their prevalence, requires a treatment for this Mar. 8, 2006, the entire contents and substance of which is condition. Previously, the only effective treatment for uterine hereby incorporated by reference. leiomyomata was hysterectomy, an unacceptable treatment option for many women. FIELD OF THE INVENTION Because hysterectomy is an unacceptable treatment option 15 for many women, other procedures have been developed. For The present invention relates to the treatment of disorders example, myomectomy, the Surgical removal of leiomyomata using anti-progestational agents. More specifically, the from the uterus was developed as an alternative in some cases. present invention relates to the treatment of disorders using Uterine artery embolization has also been developed. In this low doses of anti-progestational agents. The disorders treated radiologic procedure, uterine arteries are partially blocked, can be, but are not limited to, benign gynecological disorders. thus decreasing blood flow to the uterine leiomyomata inhib iting their growth and/or Survival. BACKGROUND OF THE INVENTION Myomectomy can be an effective treatment in some patients, however, there are risks associated with it. Some of plays a major role in reproductive health and these risks include Scarring and infection. In some cases, functioning. Its effects on, for example, the uterus, breast, 25 scarring after myomectomy can lead to infertility. Studies of cervix and hypothalamic-pituitary unit are well established. It the effectiveness of uterine artery embolization have indi also has extra-reproductive activities that are less well stud cated that most Subjects have a significant decrease in bleed ied. Such as effects on the brain, the immune system, the ing symptoms, as well as a reduction in uterine size. However, vascular endothelial system and on lipid metabolism. Given uterine artery embolization may also have serious conse this wide array of effects, it is apparent that compounds which 30 quences including infection, massive uterine bleeding, and mimic Some of the effects of progesterone (agonists), antago uterine necrosis, requiring emergency Surgery. Barbieri, 42 nize these effects (antagonists) or exhibit mixed effects (par Clin. Obstet. Gynecol. 196-205 (1999). Subjects can also tial agonists or mixed agonist/antagonist) can be useful in experience significant uterine pain, ischemia, and hypoxic treating a variety of medical conditions. changes following embolization. American College of Obste Information indicating that anti-progestational agents 35 tricians and Gynecologists (ACOG) Practice Bulletin, No. 16 could be effective in a number of medical conditions is avail (May 2000). Based on these negative effects, a need for an able. For example, this information has been Summarized in a acceptable treatment option for uterine leiomyomata report from the Institute of Medicine compiled by Donaldson remains. et al., Editors, Clinical Applications of Mifepristone (RU Although the mechanisms leading to uterine leiomyomata 486) and Other Anti-progestational agents, Committee on 40 tumorogenesis are not completely understood, evidence Sug Anti-progestational agents: Assessing the Science, Institute gests that the development of uterine leiomyomata is ovarian of Medicine, National Academy Press, (1993). The following dependent. Murphy et al., 76(2) J. Clin. Endocrinol. discussion regarding uterine leiomyomata highlights one 513-517 (2005) and Buttram et al., 36 Fertil. Steril. 433 non-limiting example of Such uses. (1981) which are both incorporated herein by reference. Part Uterine leiomyomata (also called leiomyomas or fibroids) 45 of this evidence comes from the findings that uterineleiomyo are monoclonal, generally benign, Smooth muscle tumors of mata contain both estrogen and progesterone receptors (Wil the myometrium, the muscular portion of the uterus com son et al., 55 Obstet. Gynecol. 20-4 (1980); Soules & posed of smooth muscle and connective tissue. While these McCarty 143 Am. J. Obstet. Gynecol. 6-11 (1980)) and that tumors are generally benign, they nonetheless can cause a both of these hormones are thought to be involved in tumor variety of troubling symptoms. For example, uterine lei 50 formation. See www.womenshealth services.com, Supra. Fur omyomata can cause pain in the lower back and abdomen, ther, estrogen and growth hormone are thought to act syner excessive menstrual bleeding (both in terms of volume and gistically to stimulate leiomyomata growth as the two are length of menstrual periods or bleeding between menses elevated during pregnancy when the growth of leiomyomata resulting in anemia and fatigue), pressure on the urinary blad is rapid. That progesterone may play a role in uterine lei der resulting in frequent urination and/or pressure on the 55 omyomata growth is Suggested by the finding of increased rectum causing constipation. Large leiomyomata can press on mitotic count in leiomyomata obtained during the secretory the ureters (tubes going from the kidneys to the bladder) phase than in the proliferative phase of the menstrual cycle. causing obstruction or blockage of urine which can lead to Kawaguchi et al. 160 Am. J. Obstet. Gynecol. 637 (1988). kidney damage. Uterine leiomyomata also can cause infertil Additionally, when the GnRH-agonist and a progesterone ity. In some cases, uterine leiomyomata can cause infertility 60 were co-administered, the expected regression of leiomyo by impairing the uterine lining, blocking the fallopian tubes, mata size seen with GnRH-agonist alone is not achieved. or altering the position of the cervix, thus inhibiting sperm Friedman et al., 49 Fertil. Steril. 404 (1988); Wilson et al., 55 from reaching the uterus. Obstet. Gynecol. 22 (1980); Soules et al., 143 Am. J. Obstet. Uterine leiomyomata are common. Some studies suggest Gynecol. 6 (1982). In addition to endogenous hormones, that about 20% to about 30% of all women over the age of 30 65 Xenoestrogens in the environment (e.g., organochlorine pes have leiomyomata, and an estimated 50% to about 75% of ticides, pharmacologic compounds) are also of potential con African American women have leiomyomata. Fibroids: An cern as these environmental estrogens have been shown to US 8,173,626 B2 3 4 promote the growth of uterine leiomyomata. Uterine for treatments for other progesterone-related disorders that Fibroids, www.raysahelian.com/fibroids (last visited Dec. are not associated with these drawbacks. 12, 2005). Based on the foregoing, the potential for treating uterine SUMMARY OF THE INVENTION leiomyomata by manipulating endogenous hormone levels emerged. One Such treatment involves the use of gonadotro Methods, dosing regimens and medications have now been pin releasing hormone agonists (GnRH agonists such as discovered which provide a means for treating progesterone Lupron(R), Synarel R) or Zoladex(R) which induce a low-estro related disorders but with a markedly lower dosage level or gen state. Medical Treatment for Fibroids, www.fibroids.net shorter time period of administration than employed previ 10 ously. These methods, dosing regimens and medications can (last visited Dec. 12, 2005). GnRHagonist treatment has been treat progesterone-related disorders at doses that avoid or shown to reduce uterine volume by about 50% after about lessen the occurrence or severity of adverse side effects found three months of GnRH agonist therapy. Id. GnRH agonist at higher doses. In one embodiment, the low-dose methods, treatment has also been shown to stop menstrual flow (amen dosing regimens and medications of the present invention are orrhea) allowing women with bleeding-induced anemia to 15 used to treat uterine leiomyomata. significantly increase their iron stores. Id. Unfortunately, ces Specifically, and in one embodiment, the present invention sation of GnRH agonist treatment is followed by a rapid shows that about 2.5 mg mifepristone provides an effective regrowth of uterine leiomyomata and of the uterus to pre treatment dosage for progesterone-related disorders. The treatment volume. Id. Additionally, because bone health also present invention also shows that about 5.0 mg mifepristone requires estrogen, long term use of GnRH agonists can sig provides an effective treatment dosage for progesterone-re nificantly decrease bone density and can lead to bone loss or lated disorders when administered for about one month. osteoporosis. Id. Currently, therefore, use of GnRH agonists These lower dosages and/or shorter time periods of adminis alone for treatment of uterine leiomyomata is usually limited tration can have fewer or less severe side effects and adverse to a short one to three month preoperative course to shrink the reactions than those observed with previously-used higher uterus to facilitate a Surgical procedure or to induce amenor 25 doses and/or longer time periods of treatment. Doses as low as rhea to improve hematologic condition before Surgery. Id. 1.0 mg or below can also provide effective treatments for The use of anti-progestational agents as a treatment for progesterone-related disorders. uterine leiomyomata has also emerged. Mifepristone (RU One embodiment of the present invention includes a 486; also sold by Danco Laboratories, Inc. under the trade method comprising administering an anti-progestational name MifepreX(R) is an anti-progestational agent with anti 30 agent to a patient in an amount that is less than 5.0 mg. progesterone and effects that binds to In some embodiments of the methods of the present inven progesterone receptors more competitively than progesterone tion, the less than 5.0 mg amount of the anti-progestational agent that is administered is selected from the group consist itself, thus blocking the actions of progesterone. The inhibi ing of about 0.1 mg, about 0.15 mg, 0.25 mg, about 0.5 mg. tion of progesterone triggers the shedding of the uterine wall, 35 about 0.75 mg, about 1.0 mg, about 1.25 mg, about 1.50 mg. much like a normal menstruation. about 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg. Mifepristone has been shown to produce an equivalent about 2.75 mg, about 3.0 mg, about 3.25 mg, about 3.5 mg. amount of uterine shrinkage and rates of amenorrhea to about 3.75 mg, about 4.0 mg, about 4.25 mg, about 4.5 mg and GnRHagonists. Kettel et al., 60 Fertil. Steril. 642-46 (1993); about 4.75 mg. Murphy et al., 76.J. Clin. Endocrinol. Metab. 513-17 (1993); 40 In some embodiments of the methods of the present inven Murphy et al., 64. Fertil. Steril. 187-90 (1995). Mifepristone tion, the less than 5.0 mg amount of the anti-progestational has also been shown to reduce uterine leiomyomata size. agent is selected from the group consisting of less than about Eisinger et al., 101(2) Obstet. Gynecol. 243-50 (2003). Thus, 4.75 mg, less than about 4.5 mg, less than about 4.25 mg, less clinical studies of mifepristone for the treatment of uterine than about 4.0 mg, less than about 3.75 mg, less than about 3.5 leiomyomata have Suggested that mifepristone can result in 45 mg, less than about 3.25 mg, less than about 3.0 mg, less than symptomatic improvement. These studies, however, have about 2.75 mg, less than about 2.5 mg, less than about 2.25 recommended using doses of mifepristone such as 50 mg or mg, less than about 2.0 mg, less than about 1.75 mg, less than 10 mg. Eisinger et al., Supra; Murphy et al., Supra. One study about 1.50 mg, less than about 1.25 mg, less than about 1.0 has confirmed the effectiveness of mifepristone at 5 mg when mg, less than about 0.75 mg, less than about 0.5 mg, or less administered for 6 months. Eisinger et al., Supra. While these 50 than about 0.25 mg, and less than about 0.75 mg. doses of mifepristone can help to treat uterine leiomyomata, In some embodiments, the less than 5.0 mg amount of the anti-progestational agent is administered to treat a non-ma there are problems associated with them. For example, the lignant gynecological disorder selected from the group con highest described doses. Such as 50 mg, can increase the sisting of uterine leiomyomata, premenstrual syndrome, pre prevalence and severity of hot flashes, can cause an elevation 55 menstrual dysphoric disorder, dysfunctional uterine in hepatic enzymes and in some cases, due to mifepristone's bleeding, polycystic ovarian syndrome, adenomyomas, poly antiglucocorticoid activity can result in deleterious side menorrhea, dysmenorrhea, severe dysmenorrhea, menor effects including, without limitation, depriva rhagia, breakthrough bleeding, intermittent bleeding, tion in the tissue and the pituitary gland resulting in an endometriosis, ovarian cysts, irregular withdrawal bleeding, increase in serum ACTH and , as well as overt Symp 60 hirsutism, iron deficiency anemia, acne, benign breast dis toms including complaints of anorexia, nausea, dizziness, ease, catamenial symptoms, pelvic inflammatory disease, weakness and somnolence. While the lower described doses, loss of bone density, endometriosis, breast cancer, ovarian Such as 10 mg, can cause less severe drawbacks, these doses cancer, uterine cancer and prostate cancer or for its use in can still be associated with side effects such as increased hot male contraception, anti-glucocorticoid effects or labor and flashes, potentially interfering with patient compliance. 65 delivery. Therefore, a need exists for a uterine leiomyomata treatment Additional embodiments of the present invention include that is not associated with these drawbacks. A need also exist methods comprising administering an anti-progestational US 8,173,626 B2 5 6 agent to a patient for a duration of less than about 10 weeks, present invention, the anti-progestational agent is mifepris less than about 9 weeks, less than about 8 weeks, less than tone. In an additional embodiment of the methods of the about 7 weeks, less than about 6 weeks, less than about 5 present invention, the anti-progestational agent is not mife weeks, less than about 4 weeks, less than about 3 weeks, less pristone. than about 2 weeks, and less than about 1 week. In another embodiment of the methods of the present In another embodiment of the methods of the present invention, the anti-progestational agent is an progesterone invention, an anti-progestational agent is administered to a receptor active antagonist selected from one or more of the patient for a duration of less than one month. group consisting of mifepristone, , Org 31710, In some embodiments of the methods of the present inven Org 31806, RTI-3021-012, and RTI-3021-022. In an addi tion, the anti-progestational agent that is administered for less 10 tional embodiment, the anti-progestational agent is not mife than about 10 weeks is administered in an amount selected pristone. from the group consisting of about 0.1 mg, about 0.15 mg. In another embodiment of the methods of the present 0.25 mg, about 0.5 mg, about 0.75 mg, about 1.0 mg, about invention, the one or more anti-progestational agents is 1.25 mg, about 1.50 mg, about 1.75 mg, about 2.0 mg, about administered after the conclusion of a treatment selected from 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg, about 15 3.25 mg, about 3.5 mg, about 3.75 mg, about 4.0 mg, about the group consisting of the administration of birth control 4.25 mg, about 4.5 mg and about 4.75 mg. pills to treat severe dysmenorrhea, polymenorrhea or dys In further embodiments of the methods of the present functional uterine bleeding, the administration of GnRhana invention, the anti-progestational agent that is administered logues to treat uterine leiomyomata or endometriosis, myo for less than about 10 weeks is administered in an amount mectomy to treat uterine leiomyomata, uterine artery selected from the group consisting of less than about 4.75 mg. embolization to treat uterine leiomyomata, endometrial abla less than about 4.5 mg, less than about 4.25 mg, less than tion to treat menorrhagia or polymenorrhea and ultrasound about 4.0 mg, less than about 3.75 mg, less than about 3.5 mg. therapy to treat uterine leiomyomata. less than about 3.25 mg, less than about 3.0 mg, less than In another embodiment of the methods of the present about 2.75 less than about 2.5 mg, less than about 2.25 mg. 25 invention, the one or more anti-progestational agents is less than about 2.0 mg, less than about 1.75 mg, less than administered to shrink uterine leiomyomata before a Surgical about 1.50 mg, less than about 1.25 mg, less than about 1.0 treatment. In another embodiment of the methods of the mg, less than about 0.75 mg, less than about 0.5 mg, or less present invention, the Surgical treatment is selected from the than about 0.25 mg, and less than about 0.75 mg. group consisting of hysterectomy, myomectomy, uterine In some embodiments, an anti-progestational agent is 30 artery embolization and endometrial ablation. administered to a patient for less than about 10 weeks to treat In another embodiment of the methods of the present a non-malignant gynecological disorder selected from the invention, the one or more anti-progestational agents is group consisting of uterine leiomyomata, premenstrual Syn administered concurrently with a treatment selected from the drome, premenstrual dysphoric disorder, dysfunctional uter group consisting of depo-provera acetate to treat break ine bleeding, polycystic ovarian syndrome, adenomyomas, 35 through bleeding and/or intermittent bleeding, polymenorrhea, dysmenorrhea, severe dysmenorrhea, men containing IUDs to treat breakthrough bleeding and/or inter orrhagia, breakthrough bleeding, intermittent bleeding, mittent bleeding and cortisol or synthetic cortisol-like bioac endometriosis, ovarian cysts, irregular withdrawal bleeding, tive agents to treat excessive adrenal secretions. hirsutism, iron deficiency anemia, acne, benign breast dis In another embodiment of the methods of the present ease, catamenial symptoms, pelvic inflammatory disease, 40 invention, the one or more anti-progestational agents is loss of bone density, endometriosis, breast cancer, ovarian administered daily. In another embodiment of the methods of cancer, uterine cancer and prostate cancer or for its use in the present invention, the mifepristone is administered daily. male contraception, anti-glucocorticoid effects or labor and In another embodiment of the methods of the present inven delivery. tion, the one or more anti-progestational agents is adminis Another embodiment of the present invention includes a 45 tered intermittently. In another embodiment of the methods of method comprising administering an anti-progestational the present invention, the mifepristone is administered inter agent to a patient in an amount of about 0.1 mg to about 0.2 mittently. mg to treat a non-malignant gynecological disorder selected In another embodiment of the methods of the present from the group consisting of uterine leiomyomata, premen invention, the administration route is selected from the group strual syndrome, premenstrual dysphoric disorder, dysfunc 50 consisting of oral administration, Sublingual administration, tional uterine bleeding, polycystic ovarian syndrome, buccal administration, nasal administration, transdermal adenomyomas, polymenorrhea, dysmenorrhea, severe dys administration, vaginal administration, rectal administration, menorrhea, menorrhagia, breakthrough bleeding, intermit intravenous administration, Subcutaneous administration, tent bleeding, endometriosis, ovarian cysts, irregular with intraperitoneal administration, parenteral administration, drawal bleeding, hirsutism, iron deficiency anemia, acne, 55 intramuscular administration, depot administration, topical benign breast disease, catamenial symptoms, pelvic inflam administration, intrauterine administration, inhalation matory disease, loss of bone density, endometriosis, breast administration, implant administration and ocular adminis cancer, ovarian cancer, uterine cancer and prostate cancer or tration. for its use in male contraception, anti-glucocorticoid effects In another embodiment of the methods of the present or labor and delivery wherein the patient weighs more than 60 invention, the administration occurs through a form selected 110 pounds. from the group consisting of one or more of a tablet, a capsule, In another embodiment of the methods of the present a cachet, a dragee, a pill, pellets, granules, a powder, a solu invention, the anti-progestational agent is selected from one tion, an emulsion, a fluid emulsion, a Suspension, a fluid or more of the group consisting of mifepristone, onapristone, Suspension, a semi-solid, an ointment, a paste, a cream, a gel, , ZK 112.993, Org31710, Org33628. Org31806, 65 a jelly, a foam, an implant, a patch and a spray. In another CDB-2914, CDB-4124, RJW, asoprisnil, J900, J956, J912 embodiment of the methods of the present invention, the form and J 1042. In another embodiment of the methods of the is a Sustained release form. US 8,173,626 B2 7 8 In another embodiment of the methods of the present dysfunctional uterine bleeding, polycystic ovarian syndrome, invention, the patient is a pre-menopausal female over the age adenomyomas, polymenorrhea, dysmenorrhea, severe dys of 18. In another embodiment of the methods of the present menorrhea, menorrhagia, breakthrough bleeding, intermit invention, the patient has at least one uterine leiomyomata tent bleeding, endometriosis, ovarian cysts, irregular with that is 22.5 cm in size. In another embodiment of the methods drawal bleeding, hirsutism, iron deficiency anemia, acne, of the present invention, the patient has a total uterine Volume benign breast disease, catamenial symptoms, pelvic inflam of 2160 cc. matory disease, loss of bone density, endometriosis, breast In another embodiment of the methods of the present cancer, ovarian cancer, uterine cancer and prostate cancer or invention, the method further comprises administering a for its use in male contraception, anti-glucocorticoid effects maintenance dose to the patient after a round of treatment has 10 or labor and delivery. been completed. In another embodiment of the dosing regimens of the The present invention also comprises dosing regimens. In present invention, the anti-progestational agent that is one embodiment of the dosing regimens of the present inven directed to be administered for less than one month is admin tion, the dosing regimen comprises an anti-progestational istered in an amount selected from the group consisting of agent that is directed to be administered to a patient in an 15 about 0.1 mg, about 0.15 mg 0.25 mg, about 0.5 mg, about amount that is less than 5.0 mg to treat a non-malignant 0.75 mg, about 1.0 mg, about 1.25 mg, about 1.50 mg, about gynecological disorder selected from the group consisting of 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about uterine leiomyomata, premenstrual syndrome, premenstrual 2.75 mg, about 3.0 mg, about 3.25 mg, about 3.5 mg, about dysphoric disorder, dysfunctional uterine bleeding, polycys 3.75 mg, about 4.0 mg, about 4.25 mg, about 4.5 mgandabout tic ovarian syndrome, adenomyomas, polymenorrhea, dys 4.75 mg. menorrhea, severe dysmenorrhea, menorrhagia, break In another embodiment of the dosing regimens of the through bleeding, intermittent bleeding, endometriosis, present invention, the anti-progestational agent that is ovarian cysts, irregular withdrawal bleeding, hirsutism, iron directed to be administered for less than one month is admin deficiency anemia, acne, benign breast disease, catamenial istered in an amount selected from the group consisting of less symptoms, pelvic inflammatory disease, loss of bone density, 25 than about 4.75 mg, less than about 4.5 mg, less than about endometriosis, breast cancer, ovarian cancer, uterine cancer 4.25 mg, less than about 4.0 mg, less than about 3.75 mg, less and prostate cancer or for its use in male contraception, anti than about 3.5 mg, less than about 3.25 mg, less than about 3.0 glucocorticoid effects or labor and delivery. mg, less than about 2.75 mg, less than about 2.5 mg, less than In another embodiment of the dosing regimens of the about 2.25 mg, less than about 2.0 mg, less than about 1.75 present invention, the less than 5.0 mg amount of the anti 30 mg, less than about 1.50 mg, less than about 1.25 mg, less than progestational agent that is directed to be administered is about 1.0 mg, less than about 0.75 mg, less than about 0.5 mg. selected from the group consisting of about 0.1 mg, about or less than about 0.25 mg, and less than about 0.75 mg. 0.15 mg, 0.25 mg, about 0.5 mg, about 0.75 mg, about 1.0 mg. Another embodiment of the dosing regimens of the present about 1.25 mg, about 1.50 mg, about 1.75 mg, about 2.0 mg. invention comprises an anti-progestational agent that is about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg. 35 directed to be administered to a patient in an amount of about about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4.0 mg. 0.1 mg to about 0.2 mg to treat a non-malignant gynecological about 4.25 mg, about 4.5 mg and about 4.75 mg. disorder selected from the group consisting of uterine lei In another embodiment of the dosing regimens of the omyomata, premenstrual syndrome, premenstrual dysphoric present invention, the less than 5.0 mg amount of the anti disorder, dysfunctional uterine bleeding, polycystic ovarian progestational agent that is directed to be administered is 40 syndrome, adenomyomas, polymenorrhea, dysmenorrhea, selected from the group consisting of less than about 4.75 mg. severe dysmenorrhea, menorrhagia, breakthrough bleeding, less than about 4.5 mg, less than about 4.25 mg, less than intermittent bleeding, endometriosis, ovarian cysts, irregular about 4.0 mg, less than about 3.75 mg, less than about 3.5 mg. withdrawal bleeding, hirsutism, iron deficiency anemia, acne, less than about 3.25 mg, less than about 3.0 mg, less than benign breast disease, catamenial symptoms, pelvic inflam about 2.75 mg, less than about 2.5 mg, less than about 2.25 45 matory disease, loss of bone density, endometriosis, breast mg, less than about 2.0 mg, less than about 1.75 mg, less than cancer, ovarian cancer, uterine cancer and prostate cancer or about 1.50 mg, less than about 1.25 mg, less than about 1.0 for its use in male contraception, anti-glucocorticoid effects mg, less than about 0.75 mg, less than about 0.5 mg, or less or labor and delivery wherein the patient weighs more than than about 0.25 mg, and less than about 0.75 mg. 110 pounds. Another embodiment of the dosing regimens of the present 50 In another embodiment of the dosing regimens of the invention comprises an anti-progestational agent that is present invention, the anti-progestational agent is selected directed to be administered to a patient for less than one from one or more of the group consisting of mifepristone, month. onapristone, lilopristone, ZK 112.993, Org 31710, Org Another embodiment of the dosing regimens of the present 33628, Org 31806, CDB-2914, CDB-4124, RJW, asoprisnil, invention comprises an anti-progestational agent that is 55 J900, J956, J912 and J1042. In another embodiment of the directed to be administered to a patient for a duration selected dosing regimen of the present invention, the anti-progesta from the group consisting of less than about 10 weeks, less tional agent is mifepristone. In an additional embodiment, the than about 9 weeks, less than about 8 weeks, less than about anti-progestational agent is not mifepristone. 7 weeks, less than about 6 weeks, less than about 5 weeks, less In another embodiment of the dosing regimens of the than about 4 weeks, less than about 3 weeks, less than about 60 present invention, the anti-progestational agent is a progest 2 weeks, and less than about 1 week. erone receptor active antagonist selected from one or more of Another embodiment of the dosing regimens of the present the group consisting of mifepristone, onapristone, Org31710, invention comprises an anti-progestational agent that is Org 31806, RTI-3021-012, and RTI-3021-022. In an addi directed to be administered to a patient for less than one tional embodiment, the anti-progestational agent is not mife month to treat a non-malignant gynecological disorder 65 pristone. selected from the group consisting of uterine leiomyomata, In another embodiment of the dosing regimens of the premenstrual syndrome, premenstrual dysphoric disorder, present invention, the one or more anti-progestational agents US 8,173,626 B2 10 is directed to be administered after the conclusion of a treat The present invention also comprises medications. In one ment selected from the group consisting of the administration embodiment, the medication of the present invention is an of birth control pills to treat severe dysmenorrhea, polymen anti-progestational agent that is administered to a patient in orrhea or dysfunctional uterine bleeding, the administration an amount that is less than 5.0 mg to treat a non-malignant of GnRh analogues to treat uterine leiomyomata or gynecological disorder selected from the group consisting of endometriosis, myomectomy to treat uterine leiomyomata, uterine leiomyomata, premenstrual syndrome, premenstrual uterine artery embolization to treat uterine leiomyomata, dysphoric disorder, dysfunctional uterine bleeding, polycys endometrial ablation to treat menorrhagia or polymenorrhea tic ovarian syndrome, adenomyomas, polymenorrhea, dys and ultrasound therapy to treat uterine leiomyomata. menorrhea, severe dysmenorrhea, menorrhagia, break In another embodiment of the dosing regimens of the 10 through bleeding, intermittent bleeding, endometriosis, present invention, the one or more anti-progestational agents ovarian cysts, irregular withdrawal bleeding, hirsutism, iron is directed to be administered to shrink uterine leiomyomata deficiency anemia, acne, benign breast disease, catamenial before a surgical treatment. In another embodiment of the symptoms, pelvic inflammatory disease, loss of bone density, dosing regimens of the present invention, the Surgical treat endometriosis, breast cancer, ovarian cancer, uterine cancer ment is selected from the group consisting of hysterectomy, 15 and prostate cancer or for its use in male contraception, anti myomectomy, uterine artery embolization, and endometrial glucocorticoid effects or labor and delivery. ablation. Another embodiment of the medications of the present In another embodiment of the dosing regimens of the invention includes a medication that is an anti-progestational present invention, the one or more anti-progestational agents agent that is administered to a patient for less than one month is directed to be administered concurrently with a treatment to treat a non-malignant gynecological disorder selected from selected from the group consisting of depo-provera acetate to the group consisting of uterine leiomyomata, premenstrual treat breakthrough bleeding and/or intermittent bleeding, syndrome, premenstrual dysphoric disorder, dysfunctional levonorgestrel containing IUDs to treat breakthrough bleed uterine bleeding, polycystic ovarian syndrome, adenomyo ing and/or intermittent bleeding and cortisol or synthetic cor mas, polymenorrhea, dysmenorrhea, severe dysmenorrhea, tisol-like bioactive agents to treat excessive adrenal secre 25 menorrhagia, breakthrough bleeding, intermittent bleeding, tions. endometriosis, ovarian cysts, irregular withdrawal bleeding, In another embodiment of the dosing regimens of the hirsutism, iron deficiency anemia, acne, benign breast dis present invention, the one or more anti-progestational agents ease, catamenial symptoms, pelvic inflammatory disease, is directed to be administered daily. In another embodiment of loss of bone density, endometriosis, breast cancer, ovarian the dosing regimens of the present invention, the mifepristone 30 cancer, uterine cancer and prostate cancer or for its use in is directed to be administered daily. In another embodiment of male contraception, anti-glucocorticoid effects or labor and the dosing regimens of the present invention, the one or more delivery. anti-progestational agents is directed to be administered Another embodiment of the medications of the present intermittently. In another embodiment of the dosing regimens invention includes a medication that is an anti-progestational of the present invention, the mifepristone is directed to be 35 agent that is administered to a patient in an amount of about administered intermittently. 0.1 mg to about 0.2 mg to treat a non-malignant gynecological In another embodiment of the dosing regimens of the disorder selected from the group consisting of uterine lei present invention, the directed administration route is omyomata, premenstrual syndrome, premenstrual dysphoric selected from the group consisting of oral administration, disorder, dysfunctional uterine bleeding, polycystic ovarian Sublingual administration, buccal administration, nasal 40 syndrome, adenomyomas, polymenorrhea, dysmenorrhea, administration, transdermal administration, vaginal adminis severe dysmenorrhea, menorrhagia, breakthrough bleeding, tration, rectal administration, intravenous administration, intermittent bleeding, endometriosis, ovarian cysts, irregular Subcutaneous administration, intraperitoneal administration, withdrawal bleeding, hirsutism, iron deficiency anemia, acne, parenteral administration, intramuscular administration, benign breast disease, catamenial symptoms, pelvic inflam depot administration, topical administration, intrauterine 45 matory disease, loss of bone density, endometriosis, breast administration, inhalation administration, implant adminis cancer, ovarian cancer, uterine cancer and prostate cancer or tration and ocular administration. for its use in male contraception, anti-glucocorticoid effects In another embodiment of the dosing regimens of the or labor and delivery wherein the patient weighs more than present invention, the administration is directed to occur 110 pounds. through a form selected from the group consisting of one or 50 In another embodiment of the medications of the present more of a tablet, a capsule, a cachet, a dragee, a pill, pellets, invention, the anti-progestational agent is selected from one granules, a powder, a solution, an emulsion, a fluid emulsion, or more of the group consisting of mifepristone, onapristone, a Suspension, a fluid Suspension, a semi-solid, an ointment, a lilopristone, ZK 112.993, Org 31710, Org33628. Org31806, paste, a cream, a gel, a jelly, a foam, an implant, a patch and CDB-2914, CDB-4124, RJW, asoprisnil, J900, J956, J912 a spray. In another embodiment of the dosing regimens of the 55 and J1042. In another embodiment of the medications of the present invention, the form is a Sustained release form. present invention, the anti-progestational agent is mifepris In another embodiment of the dosing regimens of the tone. In an additional embodiment, the anti-progestational present invention, the patient is a pre-menopausal female over agent is not mifepristone. the age of 18. In another embodiment of the dosing regimen In another embodiment of the medications of the present of the present invention, the patient has at least one uterine 60 invention, the anti-progestational agent is a progesterone leiomyomata that is 22.5 cm in size. In another embodiment receptor active antagonist selected from one or more of the of the dosing regimen of the present invention, the patient has group consisting of mifepristone, onapristone, Org 31710, a total uterine volume of 2160 cc. Org 31806, RTI-3021-012, and RTI-3021-022. In an addi In another embodiment of the dosing regimens of the tional embodiment, the anti-progestational agent is not mife present invention, the dosing regimen further comprises a 65 pristone. maintenance dose that is directed to be administered to the In another embodiment of the medications of the present patient after a first round of treatment has been completed. invention, the medication is administered after the conclusion US 8,173,626 B2 11 12 of a treatment selected from the group consisting of the the group consisting of about 0.1 mg, 0.15 mg, 0.25 mg, about administration of birth control pills to treat severe dysmenor 0.5 mg, about 0.75 mg, about 1.0 mg, about 1.25 mg, about rhea, polymenorrhea or dysfunctional uterine bleeding, the 1.50 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, about administration of GnRh analogues to treat uterine leiomyo 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.25 mg, about mata or endometriosis, myomectomy to treat uterine lei 3.5 mg, about 3.75 mg, about 4.0 mg, about 4.25 mg, about omyomata, uterine artery embolization to treat uterine lei 4.5 mg and about 4.75 mg. In another embodiment of the omyomata, endometrial ablation to treat menorrhagia or medications of the present invention, the maintenance dose is polymenorrhea and ultrasound therapy to treat uterine lei selected from the group consisting of less than about 4.75 mg. omyomata. less than about 4.5 mg, less than about 4.25 mg, less than In another embodiment of the medications of the present 10 about 4.0 mg, less than about 3.75 mg, less than about 3.5 mg. invention, the medication is administered to shrink uterine less than about 3.25 mg, less than about 3.0 mg, less than leiomyomata before a Surgical treatment. In another embodi about 2.75 mg, less than about 2.5 mg, less than about 2.25 ment of the medications of the present invention, the Surgical mg, less than about 2.0 mg, less than about 1.75 mg, less than treatment is selected from the group consisting of hysterec about 1.50 mg, less than about 1.25 mg, less than about 1.0 tomy, myomectomy, uterine artery embolization and 15 mg, less than about 0.75 mg, less than about 0.5 mg, or less endometrial ablation. than about 0.25 mg, and less than about 0.75 mg. In another embodiment of the medications of the present In another embodiment of the medications of the present invention, the medication is administered concurrently with a invention, the first round of treatment is selected from the treatment selected from the group consisting of depo-provera group consisting of the use of an anti-progestational agent to acetate to treat breakthrough bleeding and/or intermittent treat uterine leiomyomata, premenstrual syndrome, premen bleeding, levonorgestrel containing IUDs to treat break strual dysphoric disorder, dysfunctional uterine bleeding, through bleeding and/or intermittent bleeding and cortisol or polycystic ovarian syndrome, adenomyomas, polymenor synthetic cortisol-like bioactive agents to treat excessive rhea, dysmenorrhea, severe dysmenorrhea, menorrhagia, adrenal Secretions. breakthrough bleeding, intermittent bleeding, endometriosis, In another embodiment of the medications of the present 25 ovarian cysts, irregular withdrawal bleeding, hirsutism, iron invention, the medication is administered daily. In another deficiency anemia, acne, benign breast disease, catamenial embodiment of the medications of the present invention, the symptoms, pelvic inflammatory disease, loss of bone density, medication is mifepristone and is administered daily. In endometriosis, breast cancer, ovarian cancer, uterine cancer another embodiment of the medications of the present inven and prostate cancer or for its use in male contraception, anti tion, the medication is administered intermittently. In another 30 glucocorticoid effects or labor and delivery. embodiment of the medications of the present invention, the In another embodiment of the medications of the present medication is mifepristone and is administered intermittently. invention, the maintenance dose is administered concurrently In another embodiment of the medications of the present with a treatment selected from the group consisting of depo invention, the administration route of the medication is provera acetate to treat breakthrough bleeding or intermittent selected from the group consisting of oral administration, 35 bleeding, levonorgestrel (or agents similar to levonorgestrel) Sublingual administration, buccal administration, nasal containing IUDs to treat breakthrough bleeding or intermit administration, transdermal administration, vaginal adminis tent bleeding and cortisol or synthetic cortisol-like bioactive tration, rectal administration, intravenous administration, agents to treat excessive adrenal secretions. Subcutaneous administration, intraperitoneal administration, In another embodiment of the medications of the present parenteral administration, intramuscular administration, 40 invention, the maintenance dose is administered daily. In depot administration, topical administration, intrauterine another embodiment of the medications of the present inven administration, inhalation administration, implant adminis tion, the maintenance dose is administered intermittently. tration and ocular administration. In another embodiment of the medications of the present In another embodiment of the medications of the present invention that contain a maintenance dose, the medications invention, the medication is in a form selected from the group 45 administration route is selected from the group consisting of consisting of one or more of a tablet, a capsule, a cachet, a oral administration, Sublingual administration, buccal admin dragee, a pill, pellets, granules, a powder, a solution, an emul istration, nasal administration, transdermal administration, Sion, a fluid emulsion, a Suspension, a fluid Suspension, a vaginal administration, rectal administration, intravenous semi-solid, anointment, a paste, a cream, a gel, a jelly, a foam, administration, Subcutaneous administration, intraperitoneal an implant, a patch and a spray. In another embodiment of the 50 administration, parenteral administration, intramuscular medications of the present invention, the medication is in a administration, depot administration, topical administration, Sustained release form. intrauterine administration, inhalation administration, In another embodiment of the medications of the present implant administration and ocular administration. invention, the medication is given to a patient that is a pre In another embodiment of the medications with a mainte menopausal female over the age of 18. In another embodi 55 nance dose of the present invention, the administration of the ment of the medications of the present invention, the medi medication occurs through a form selected from the group cation is given to a patient that has at least one uterine consisting of one or more of a tablet, a capsule, a cachet, a leiomyomata that is 22.5 cm in size. In another embodiment dragee, a pill, pellets, granules, a powder, a solution, an emul of the medications of the present invention, the medication is Sion, a fluid emulsion, a Suspension, a fluid Suspension, a given to a patient that has a total uterine Volume of 2160 cc. 60 semi-solid, anointment, a paste, a cream, a gel, a jelly, a foam, In another embodiment of the medications of the present an implant, a patch and a spray. In another embodiment of the invention, the medication comprises a maintenance dose to be medications with a maintenance dose of the present inven administered after one of the above described methods or tion, the administration of the medication occurs through a dosing regimens. In another embodiment of the medications Sustained release form. of the present invention, the maintenance dose comprises 65 In another embodiment of the medications with a mainte mifepristone. In another embodiment of the medications of nance dose of the present invention, the medication is admin the present invention, the maintenance dose is selected from istered to a pre-menopausal female over the age of 18. US 8,173,626 B2 13 14 In another embodiment of the medications with a mainte syndrome, adenomyomas, polymenorrhea, dysmenorrhea, nance dose of the present invention, the medication is admin severe dysmenorrhea, menorrhagia, breakthrough bleeding, istered to a patient that has at least one uterine leiomyomata intermittent bleeding, endometriosis, ovarian cysts, irregular that is 22.5 cm in size. withdrawal bleeding, hirsutism, iron deficiency anemia, acne, In another embodiment of the medications with a mainte benign breast disease, catamenial symptoms, pelvic inflam nance dose of the present invention, the medication is admin matory disease, loss of bone density, endometriosis, breast istered to a patient that has a total uterine volume of 2160 cc. cancer, ovarian cancer, uterine cancer and prostate cancer or In another embodiment of the medications with a mainte for its use in male contraception, anti-glucocorticoid effects nance dose of the present invention, the medication comprises or labor and delivery. an anti-progestational agent that is directed to be adminis 10 tered to a patient in an amount that is less than 5.0 mg to treat In another embodiment of the business methods of the a non-malignant gynecological disorder selected from the present invention, the dosing regimen directs the anti-proges group consisting of uterine leiomyomata, premenstrual Syn tational agent to be administered in an amount selected from drome, premenstrual dysphoric disorder, dysfunctional uter the group consisting of about 0.1 mg, about 0.15 mg, 0.25 mg. ine bleeding, polycystic ovarian syndrome, adenomyomas, 15 about 0.5 mg, about 0.75 mg, about 1.0 mg, about 1.25 mg. polymenorrhea, dysmenorrhea, severe dysmenorrhea, men about 1.50 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg. orrhagia, breakthrough bleeding, intermittent bleeding, about 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.25 mg. endometriosis, ovarian cysts, irregular withdrawal bleeding, about 3.5 mg, about 3.75 mg, about 4.0 mg, about 4.25 mg. hirsutism, iron deficiency anemia, acne, benign breast dis about 4.5 mg and about 4.75 mg. ease, catamenial symptoms, pelvic inflammatory disease, In another embodiment of the business methods of the loss of bone density, endometriosis, breast cancer, ovarian present invention, the dosing regimen directs the anti-proges cancer, uterine cancer and prostate cancer or for its use in tational agent to be administered in an amount selected from male contraception, anti-glucocorticoid effects or labor and the group consisting of less than about 4.75 mg, less than delivery. about 4.5 mg, less than about 4.25 mg, less than about 4.0 mg. In another embodiment of the medications with a mainte 25 less than about 3.75 mg, less than about 3.5 mg, less than nance dose of the present invention, the medication comprises about 3.25 mg, less than about 3.0 mg, less than about 2.75 an anti-progestational agent that is directed to be adminis mg, less than about 2.5 mg, less than about 2.25 mg, less than tered to a patient for less than one month to treat a non about 2.0 mg, less than about 1.75 mg, less than about 1.50 malignant gynecological disorder selected from the group mg, less than about 1.25 mg, less than about 1.0 mg, less than consisting of uterine leiomyomata, premenstrual syndrome, 30 about 0.75 mg, less than about 0.5 mg. or less than about 0.25 premenstrual dysphoric disorder, dysfunctional uterine mg, and less than about 0.75 mg. bleeding, polycystic ovarian syndrome, adenomyomas, poly In another embodiment of the business methods of the menorrhea, dysmenorrhea, severe dysmenorrhea, menor present invention, the dosing regimen directs that the anti rhagia, breakthrough bleeding, intermittent bleeding, progestational agent that is administered for less than one endometriosis, ovarian cysts, irregular withdrawal bleeding, 35 month be administered in an amount selected from the group hirsutism, iron deficiency anemia, acne, benign breast dis consisting of about 0.1 mg, about 0.15 mg, 0.25 mg, about 0.5 ease, catamenial symptoms, pelvic inflammatory disease, mg, about 0.75 mg, about 1.0 mg, about 1.25 mg, about 1.50 loss of bone density, endometriosis, breast cancer, ovarian mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 cancer, uterine cancer and prostate cancer or for its use in mg, about 2.75 mg, about 3.0 mg, about 3.25 mg, about 3.5 male contraception, anti-glucocorticoid effects or labor and 40 mg, about 3.75 mg, about 4.0 mg, about 4.25 mg, about 4.5 delivery. mg and about 4.75 mg. The present invention also includes business methods. One In another embodiment of the business methods of the embodiment of the business methods of the present invention present invention, the dosing regimen directs that the anti comprises providing to a consumer an anti-progestational progestational agent that is administered for less than one agent and a dosing regimen wherein the dosing regimen 45 month be administered in an amount selected from the group directs the anti-progestational agent to be administered to a consisting of less than about 4.75 mg, less than about 4.5 mg. patient in an amount that is less than 5.0 mg to treat a disorder less than about 4.25 mg, less than about 4.0 mg, less than selected from the group consisting of uterine leiomyomata, about 3.75 mg, less than about 3.5 mg, less than about 3.25 premenstrual syndrome, premenstrual dysphoric disorder, mg, less than about 3.0 mg, less than about 2.75 mg, less than dysfunctional uterine bleeding, polycystic ovarian syndrome, 50 about 2.5 mg, less than about 2.25 mg, less than about 2.0 mg. adenomyomas, polymenorrhea, dysmenorrhea, severe dys less than about 1.75 mg, less than about 1.50 mg, less than menorrhea, menorrhagia, breakthrough bleeding, intermit about 1.25 mg, less than about 1.0 mg, less than about 0.75 tent bleeding, endometriosis, ovarian cysts, irregular with mg, less than about 0.5 mg, or less than about 0.25 mg, and drawal bleeding, hirsutism, iron deficiency anemia, acne, less than about 0.75 mg. benign breast disease, catamenial symptoms, pelvic inflam 55 In another embodiment of the business methods of the matory disease, loss of bone density, endometriosis, breast present invention, the anti-progestational agent is selected cancer, ovarian cancer, uterine cancer and prostate cancer or from one or more of the group consisting of mifepristone, for its use in male contraception, anti-glucocorticoid effects onapristone, lilopristone, ZK 112.993, Org 31710, Org or labor and delivery. 33628, Org 31806, CDB-2914, CDB-4124, RJW, asoprisnil, In another embodiment of the business methods of the 60 J900, J956, J912 and J1042. In another embodiment of the present invention, the method comprises providing to a con business methods of the present invention, the anti-progesta Sumer an anti-progestational agent and a dosing regimen tional agents is mifepristone. In an additional embodiment, wherein the dosing regimen directs the anti-progestational the anti-progestational agent is not mifepristone. agent to be administered for less than one month to treat a In another embodiment of the business methods of the disorder selected from the group consisting of uterine lei 65 present invention, the anti-progestational agent is selected omyomata, premenstrual syndrome, premenstrual dysphoric from one or more of the group consisting of mifepristone, disorder, dysfunctional uterine bleeding, polycystic ovarian onapristone, Org31710, Org31806, RTI-3021-012, and RTI US 8,173,626 B2 15 16 3021-022. In an additional embodiment, the anti-progesta of treatment. In another embodiment of the business methods tional agent is not mifepristone. of the present invention, the business method further com In another embodiment of the business methods of the prises providing a maintenance dose of the anti-progesta present invention, the dosing regimen directs the anti-proges tional agent to a consumer. tational to be administered after the conclusion of a treatment In another embodiment of the business methods of the selected from the group consisting of the administration of present invention, the anti-progestational agent is mifepris birth control pills to treat severe dysmenorrhea, polymenor tone and the maintenance dose is selected from the group rhea or dysfunctional uterine bleeding, the administration of consisting of about 0.1 mg, about 0.15 mg, 0.25 mg, about 0.5 GnRh analogues to treat uterine leiomyomata or endometrio mg, about 0.75 mg, about 1.0 mg, about 1.25 mg, about 1.50 sis, myomectomy to treat uterine leiomyomata, uterine artery 10 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 embolization to treat uterine leiomyomata, endometrial abla mg, about 2.75 mg, about 3.0 mg, about 3.25 mg, about 3.5 tion to treat menorrhagia or polymenorrhea and ultrasound mg, about 3.75 mg, about 4.0 mg, about 4.25 mg, about 4.5 therapy to treat uterine leiomyomata. mg and about 4.75 mg. In another embodiment of the business methods of the In another embodiment of the business methods of the present invention, the dosing regimen directs the anti-proges 15 present invention, the anti-progestational agent is mifepris tational to be administered to shrink uterine leiomyomata tone and the maintenance dose is selected from the group before a surgical treatment. In another embodiment of the consisting of less than about 4.75 mg, less than about 4.5 mg. business methods of the present invention, the Surgical treat less than about 4.25 mg, less than about 4.0 mg, less than ment is selected from the group consisting of hysterectomy, about 3.75 mg, less than about 3.5 mg, less than about 3.25 myomectomy, uterine artery embolization and endometrial mg, less than about 3.0 mg, less than about 2.75 mg, less than ablation. about 2.5 mg, less than about 2.25 mg, less than about 2.0 mg. In another embodiment of the business methods of the less than about 1.75 mg, less than about 1.50 mg, less than present invention, the dosing regimen directs the anti-proges about 1.25 mg, less than about 1.0 mg, less than about 0.75 tational to be administered concurrently with a treatment mg, less than about 0.5 mg, or less than about 0.25 mg, and selected from the group consisting of depo-provera acetate to 25 less than about 0.75 mg. treat breakthrough bleeding or intermittent bleeding, In another embodiment of the business methods of the levonorgestrel containing IUDs to treat breakthrough bleed present invention, the dosing regimen directs daily adminis ing or intermittent bleeding and cortisol or synthetic cortisol tration of the maintenance dose. In another embodiment of like bioactive agents to treat excessive adrenal Secretions. the business methods of the present invention, the dosing In another embodiment of the business methods of the 30 regimen directs intermittent administration of the mainte present invention, the dosing regimen directs the anti-proges nance dose. tational to be administered daily. In another embodiment of In another embodiment of the business methods of the the business methods of the present invention, the dosing present invention, the dosing regimen directs the administra regimen directs the anti-progestational to be administered tion of the maintenance dose to be through a route selected intermittently. 35 from selected from the group consisting of oral administra In another embodiment of the business methods of the tion, Sublingual administration, buccal administration, nasal present invention, the dosing regimen directs the administra administration, transdermal administration, vaginal adminis tion of the anti-progestational agent to be through a route tration, rectal administration, intravenous administration, selected from the group consisting of oral administration, Subcutaneous administration, intraperitoneal administration, Sublingual administration, buccal administration, nasal 40 parenteral administration, intramuscular administration, administration, transdermal administration, vaginal adminis depot administration, topical administration, intrauterine tration, rectal administration, intravenous administration, administration, inhalation administration, implant adminis Subcutaneous administration, intraperitoneal administration, tration and ocular administration. parenteral administration, intramuscular administration, In another embodiment of the business methods of the depot administration, topical administration, intrauterine 45 present invention, the maintenance dose is provided in a form administration, inhalation administration, implant adminis selected from the group consisting of one or more of a tablet, tration and ocular administration. a capsule, a cachet, a dragee, a pill, pellets, granules, a pow In another embodiment of the business methods of the der, a solution, an emulsion, a fluid emulsion, a suspension, a present invention, the directed administration occurs through fluid Suspension, a semi-solid, an ointment, a paste, a cream, a form selected from the group consisting of one or more of a 50 a gel, a jelly, a foam, an implant, a patch and a spray. In tablet, a capsule, a cachet, a dragee, a pill, pellets, granules, a another embodiment of the business methods of the present powder, a solution, an emulsion, a fluid emulsion, a Suspen invention, the maintenance dose is provided as a Sustained Sion, a fluid Suspension, a semi-solid, an ointment, a paste, a release form. cream, a gel, a jelly, a foam, an implant, a patch and a spray. In another embodiment of the business methods of the In another embodiment of the business methods of the present 55 present invention, the dosing regimen directs the administra invention, the form is a Sustained release form. tion to occur in a pre-menopausal female over the age of 18. In another embodiment of the business methods of the In another embodiment of the business methods of the present present invention, the patient is a pre-menopausal female over invention, the dosing regimen directs the administration to the age of 18. In another embodiment of the business methods occur in a patient that has at least one uterine leiomyomata of the present invention, the patient has at least one uterine 60 that is 22.5 cm in size. In another embodiment of the business leiomyomata that is 22.5 cm in size. In another embodiment methods of the present invention, the dosing regimen directs of the business methods of the present invention, the patient the administration to occur in a patient that has a total uterine has a total uterine volume of 2160 cc. Volume of 2160 cc. In another embodiment of the business methods of the In another embodiment, a business method is provided present invention, the dosing regimen further directs the 65 comprising the step of providing to a consumer an anti administration of a maintenance dose of an anti-progesta progestational agent and a dosing regimen wherein the dosing tional agent to the patient after the completion of a first round regimen directs the anti-progestational agent to be adminis US 8,173,626 B2 17 18 tered to a patient to treat a disorder selected from the group for its use in male contraception, anti-glucocorticoid effects consisting of uterine leiomyomata, premenstrual syndrome, or labor and delivery wherein the antiprogestational agent is premenstrual dysphoric disorder, dysfunctional uterine not mifepristone. bleeding, polycystic ovarian syndrome, adenomyomas, poly In another embodiment of the non-mifepristone methods menorrhea, dysmenorrhea, severe dysmenorrhea, menor of the present invention, the anti-progestational agent is rhagia, breakthrough bleeding, intermittent bleeding, administered in an amount selected from the group consisting endometriosis, ovarian cysts, irregular withdrawal bleeding, of about 0.1 mg, about 0.15 mg, 0.25 mg, about 0.5 mg, about hirsutism, iron deficiency anemia, acne, benign breast dis 0.75 mg, about 1.0 mg, about 1.25 mg, about 1.50 mg, about ease, catamenial symptoms, pelvic inflammatory disease, 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about loss of bone density, endometriosis, breast cancer, ovarian 10 cancer, uterine cancer and prostate cancer. 2.75 mg, about 3.0 mg, about 3.25 mg, about 3.5 mg, about In an additional embodiment of the business methods of the 3.75 mg, about 4.0 mg, about 4.25 mg, about 4.5 mg, about invention, the anti-progestational agent is provided to a con 4.75 mg, about 5.0 mg, about 5.25 mg, about 5.5 mg, about Sumer in units of less than about 5.0 mg and the dosing 5.75 mg, about 6.0 mg, about 6.25 mg, about 6.5 mg, about regimen directs the anti-progestational agent to be adminis 15 6.75 mg, about 7.0 mg, about 7.25 mg, about 7.5 mg, about tered in an amount less than 5.0 mg per day, or the anti 7.75 mg, about 8.0 mg, about 8.25 mg, about 8.5 mg, about progestational agent is provided in units of less than about 2.5 8.75 mg, about 9.0 mg, about 9.25 mg, about 9.5 mg, about mg and the dosing regimen directs the anti-progestational 9.75 mg, about 10.0 mg, about 10.25 mg, about 10.5 mg. agent to be administered in an amount less than 2.5 mg per about 10.75 mg, about 11.0 mg, about 11.25 mg, about 11.5 day, or the anti-progestational agent is provided in equivalent mg, about 11.75 mg, about 12.0 mg, about 12.25 mg, about dosage units of less than about 1.25 mg of the anti-progesta 12.5 mg, about 12.75 mg, about 13.0 mg, about 13.25 mg, tional agent and the dosing regimen directs the anti-proges about 13.5 mg, about 13.75 mg, about 14.0 mg, about 14.25 tational agent to be administered in an amountless than 1.25 mg, about 14.5 mg, about 14.75 mg, about 15.0 mg, about mg per day. In another embodiment of the business methods 15.25 mg, about 15.5 mg, about 15.75 mg, about 16.0 mg. of the invention, the anti-progestational agent is provided in 25 about 16.25 mg, about 16.5 mg, about 16.75 mg, about 17.0 an amount of less than about 40 units, and the dosing regimen mg, about 17.25 mg, about 17.5 mg, about 17.75 mg, about directs the anti-progestational agent to be administered for 18.0 mg, about 18.25 mg, about 18.5 mg, about 18.75 mg, less than one month. about 19.0 mg, about 19.25 mg, about 19.5 mg, about 19.75 In another embodiment of the business methods of the mg, about 20.0 mg, about 20.25 mg, about 20.5 mg, about invention, the anti-progestational agent is selected from the 30 20.75 mg, about 21.0 mg, about 21.25 mg, about 21.5 mg. group consisting of mifepristone, onapristone, lilopristone, about 21.75 mg, about 22.0 mg, about 22.25 mg, about 22.5 ZK 112.993, Org 31710, Org 33628, Org 31806, CDB-2914, mg, about 22.75 mg, about 23.0 mg, about 23.25 mg, about CDB-4124, RJW, asoprisnil, J900, J956, J912 and J1042. In 23.5 mg, about 23.75 mg, about 24.0 mg, about 24.25 mg. another embodiment of the business methods of the inven about 24.5 mg, about 24.75 mg, about 25.0 mg, about 25.25 tion, the anti-progestational agent is mifepristone. In an addi 35 mg, about 25.5 mg and about 25.75 mg. tional embodiment, the anti-progestational agent is not mife In another embodiment of the non-mifepristone methods pristone. of the present invention, the anti-progestational agent is In another embodiment of the business methods of the administered in an amount selected from the group consisting invention, the dosing regimen directs the anti-progestational of less than about 4.75 mg, less than about 4.5 mg, less than agent to be administered to the patient as a maintenance dose 40 about 4.25 mg, less than about 4.0 mg, less than about 3.75 in an amount less than 2.5 mg after administering the anti mg, less than about 3.5 mg, less than about 3.25 mg, less than progestational agent in an amount less than 5 mg. In some about 3.0 mg, less than about 2.75 mg, less than about 2.5 mg. embodiments of the business methods of the invention, the less than about 2.25 mg, less than about 2.0 mg, less than dosing regiment directs both the anti-progestational agent to about 1.75 mg, less than about 1.50 mg, less than about 1.25 be administered daily. 45 mg, less than about 1.0 mg, less than about 0.75 mg, less than In another embodiment of the business methods of the about 0.5 mg, or less than about 0.25 mg, and less than about invention, the anti-progestational agent is provided as a first 0.75 mg. set of equivalent dosage units, each comprising less than In another embodiment of the non-mifepristone methods about 5.0 mg of the anti-progestational agent, and a second set of the present invention, the anti-progestational agent is of equivalent dosage units, each comprising less than about 50 selected from one or more of the group consisting of onapris 2.5 mg of the anti-progestational agent. tone, lilopristone, ZK 112.993, Org 31710, Org 33628, Org Embodiments of the present invention also include meth 3.1806, CDB-2914, CDB-4124, RJW, asoprisnil, J900, J956, ods, dosing regimens, medications, maintenance doses and J912 and J 1042. business methods where mifepristone is excluded as an anti In another embodiment of the non-mifepristone methods progestational agent. For example, in one embodiment of the 55 of the present invention, the anti-progestational agent is methods of the present invention the method comprises selected from one or more of the group consisting of mife administering an anti-progestational agent to a patient to treat pristone, onapristone, Org31710, Org31806, RTI-3021-012, a disorder selected from the group consisting of uterine lei and RTI-3021-022. omyomata, premenstrual syndrome, premenstrual dysphoric In another embodiment of the non-mifepristone methods disorder, dysfunctional uterine bleeding, polycystic ovarian 60 of the present invention, the one or more anti-progestational syndrome, adenomyomas, polymenorrhea, dysmenorrhea, agents is administered after the conclusion of a treatment severe dysmenorrhea, menorrhagia, breakthrough bleeding, selected from the group consisting of the administration of intermittent bleeding, endometriosis, ovarian cysts, irregular birth control pills to treat severe dysmenorrhea, polymenor withdrawal bleeding, hirsutism, iron deficiency anemia, acne, rhea or dysfunctional uterine bleeding, the administration of benign breast disease, catamenial symptoms, pelvic inflam 65 GnRh analogues to treat uterine leiomyomata or endometrio matory disease, loss of bone density, endometriosis, breast sis, myomectomy to treat uterine leiomyomata, uterine artery cancer, ovarian cancer, uterine cancer and prostate cancer or embolization to treat uterine leiomyomata, endometrial abla US 8,173,626 B2 19 20 tion to treat menorrhagia or polymenorrhea and ultrasound mia, acne, benign breast disease, catamenial symptoms, pel therapy to treat uterine leiomyomata. Vic inflammatory disease, loss of bone density, endometrio In another embodiment of the non-mifepristone methods sis, breast cancer, ovarian cancer, uterine cancer and prostate of the present invention, the one or more anti-progestational cancer or for its use in male contraception, anti-glucocorti agents is administered to shrinkuterine leiomyomata before a 5 coid effects or labor and delivery wherein the antiprogesta Surgical treatment. In another embodiment of the non-mife tional agent is not mifepristone. pristone methods of the present invention, the Surgical treat In another embodiment of the non-mifepristone dosing ment is selected from the group consisting of hysterectomy, regimens of the present invention, the anti-progestational myomectomy, uterine artery embolization and endometrial agent is directed to be administered to the patient in an ablation. 10 amount selected from the group consisting of about 0.1 mg, In another embodiment of the non-mifepristone methods about 0.15 mg 0.25 mg, about 0.5 mg, about 0.75 mg, about of the present invention, the one or more anti-progestational 1.0 mg, about 1.25 mg, about 1.50 mg, about 1.75 mg, about agents is administered concurrently with a treatment selected 2.0 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about from the group consisting of depo-provera acetate to treat 3.0 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about breakthrough bleeding or intermittent bleeding, levonorg- 15 4.0 mg, about 4.25 mg, about 4.5 mgandabout 4.75 mg, about estrel containing IUDs to treat breakthrough bleeding or 5.0 mg, about 5.25 mg, about 5.5 mg, about 5.75 mg, about intermittent bleeding and cortisol or synthetic cortisol-like 6.0 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg, about bioactive agents to treat excessive adrenal Secretions. 7.0 mg, about 7.25 mg, about 7.5 mg, about 7.75 mg, about In another embodiment of the non-mifepristone methods 8.0 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about of the present invention, the anti-progestational agent is 20 9.0 mg, about 9.25 mg, about 9.5 mg, about 9.75 mg, about administered daily. In another embodiment of the non-mife 10.0 mg, about 10.25 mg, about 10.5 mg, about 10.75 mg, pristone methods of the present invention, the anti-progesta about 11.0 mg, about 11.25 mg, about 11.5 mg, about 11.75 tional agent is administered intermittently. In another mg, about 12.0 mg, about 12.25 mg, about 12.5 mg, about embodiment of the non-mifepristone methods of the present 12.75 mg, about 13.0 mg, about 13.25 mg, about 13.5 mg, invention, the administration is selected from the group con- 25 about 13.75 mg, about 14.0 mg, about 14.25 mg, about 14.5 sisting of oral administration, Sublingual administration, buc mg, about 14.75 mg, about 15.0 mg, about 15.25 mg, about cal administration, nasal administration, transdermal admin 15.5 mg, about 15.75 mg, about 16.0 mg, about 16.25 mg, istration, vaginal administration, rectal administration, about 16.5 mg, about 16.75 mg, about 17.0 mg, about 17.25 intravenous administration, Subcutaneous administration, mg, about 17.5 mg, about 17.75 mg, about 18.0 mg, about intraperitoneal administration, parenteral administration, 30 18.25 mg, about 18.5 mg, about 18.75 mg, about 19.0 mg. intramuscular administration, depot administration, topical about 19.25 mg, about 19.5 mg, about 19.75 mg, about 20.0 administration, intrauterine administration, inhalation mg, about 20.25 mg, about 20.5 mg, about 20.75 mg, about administration, implant administration and ocular adminis 21.0 mg, about 21.25 mg, about 21.5 mg, about 21.75 mg. tration. about 22.0 mg, about 22.25 mg, about 22.5 mg, about 22.75 In another embodiment of the non-mifepristone methods 35 mg, about 23.0 mg, about 23.25 mg, about 23.5 mg, about of the present invention, the administration occurs through a 23.75 mg, about 24.0 mg, about 24.25 mg, about 24.5 mg. form selected from the group consisting of one or more of a about 24.75 mg, about 25.0 mg, about 25.25 mg, about 25.5 tablet, a capsule, a cachet, a dragee, a pill, pellets, granules, a mg and about 25.75 mg. powder, a solution, an emulsion, a fluid emulsion, a Suspen In another embodiment of the non-mifepristone dosing Sion, a fluid Suspension, a semi-solid, an ointment, a paste, a 40 regimens of the present invention, the anti-progestational cream, a gel, a jelly, a foam, an implant, a patch and a spray. agent is directed to be administered to the patient in an In another embodiment of the non-mifepristone methods of amount selected from the group consisting of about less than the present invention, the form is prepared as a Sustained about 4.75 mg, less than about 4.5 mg, less than about 4.25 release form. mg, less than about 4.0 mg, less than about 3.75 mg, less than In another embodiment of the non-mifepristone methods 45 about 3.5 mg, less than about 3.25 mg, less than about 3.0 mg. of the present invention, the patient is a pre-menopausal less than about 2.75 mg, less than about 2.5 mg, less than female over the age of 18. In another embodiment of the about 2.25 mg, less than about 2.0 mg, less than about 1.75 non-mifepristone methods of the present invention, the mg, less than about 1.50 mg, less than about 1.25 mg, less than patient has at least one uterine leiomyomata that is 22.5 cm about 1.0 mg, less than about 0.75 mg, less than about 0.5 mg. in size. In another embodiment of the non-mifepristone meth- 50 or less than about 0.25 mg, and less than about 0.75 mg. ods of the present invention, the patient has a total uterine In another embodiment of the non-mifepristone dosing Volume of 2160 cc. regimens of the present invention, the anti-progestational In another embodiment of the non-mifepristone methods agent is selected from one or more of the group consisting of of the present invention, the method further comprises admin onapristone, lilopristone, ZK 112.993, Org 31710, Org istering a maintenance dose to the patient after the completion 55 33628, Org 31806, CDB-2914, CDB-4124, RJW, asoprisnil, of a first round of treatment. J900, J956, J912 and J 1042. Embodiments of the present invention also include non In another embodiment of the non-mifepristone dosing mifepristone dosing regimens. In one embodiment of the regimens of the present invention, the anti-progestational dosing regimens of the present invention, the anti-progesta agent is selected from one or more of the group consisting of tional agent that is directed to be administered to a patient to 60 mifepristone, onapristone, Org31710, Org 31806, RTI-3021 treat a disorder selected from the group consisting of uterine 012, and RTI-3021-022. leiomyomata, premenstrual syndrome, premenstrual dyspho In another embodiment of the non-mifepristone dosing ric disorder, dysfunctional uterine bleeding, polycystic ova regimens of the present invention, the one or more anti rian syndrome, adenomyomas, polymenorrhea, dysmenor progestational agents is directed to be administered after the rhea, severe dysmenorrhea, menorrhagia, breakthrough 65 conclusion of a treatment selected from the group consisting bleeding, intermittent bleeding, endometriosis, ovarian cysts, of the administration of birth control pills to treat severe irregular withdrawal bleeding, hirsutism, iron deficiency ane dysmenorrhea, polymenorrhea or dysfunctional uterine US 8,173,626 B2 21 22 bleeding, the administration of GnRh analogues to treat uter syndrome, premenstrual dysphoric disorder, dysfunctional ine leiomyomata or endometriosis, myomectomy to treat uterine bleeding, polycystic ovarian syndrome, adenomyo uterine leiomyomata, uterine artery embolization to treat mas, polymenorrhea, dysmenorrhea, severe dysmenorrhea, uterine leiomyomata, endometrial ablation to treat menor menorrhagia, breakthrough bleeding, intermittent bleeding, rhagia or polymenorrhea and ultrasound therapy to treat uter endometriosis, ovarian cysts, irregular withdrawal bleeding, ineleiomyomata. hirsutism, iron deficiency anemia, acne, benign breast dis In another embodiment of the non-mifepristone dosing ease, catamenial symptoms, pelvic inflammatory disease, regimens of the present invention, the one or more anti loss of bone density, endometriosis, breast cancer, ovarian progestational agents is directed to be administered to shrink cancer, uterine cancer and prostate cancer or for its use in uterine leiomyomata before a Surgical treatment. In another 10 embodiment of the non-mifepristone dosing regimens of the male contraception, anti-glucocorticoid effects or labor and present invention, the Surgical treatment is selected from the delivery. In this embodiment the antiprogestational agent is group consisting of hysterectomy, myomectomy, uterine not mifepristone. artery embolization and endometrial ablation. In another embodiment of the non-mifepristone medica In another embodiment of the non-mifepristone dosing 15 tions of the present invention, the medication includes a dos regimens of the present invention, the one or more anti age of an anti-progestational agent selected from the group progestational agents is directed to be administered concur consisting of about 0.1 mg, about 0.15 mg, 0.25 mg, about 0.5 rently with a treatment selected from the group consisting of mg, about 0.75 mg, about 1.0 mg, about 1.25 mg, about 1.50 depo-provera acetate to treat breakthrough bleeding or inter mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mittent bleeding, levonorgestrel containing IUDs to treat mg, about 2.75 mg, about 3.0 mg, about 3.25 mg, about 3.5 breakthrough bleeding or intermittent bleeding and cortisol mg, about 3.75 mg, about 4.0 mg, about 4.25 mg, about 4.5 or synthetic cortisol-like bioactive agents to treat excessive mgandabout 4.75 mg, about 5.0 mg, about 5.25 mg, about 5.5 adrenal Secretions. mg, about 5.75 mg, about 6.0 mg, about 6.25 mg, about 6.5 In another embodiment of the non-mifepristone dosing mg, about 6.75 mg, about 7.0 mg, about 7.25 mg, about 7.5 regimens of the present invention, the anti-progestational 25 mg, about 7.75 mg, about 8.0 mg, about 8.25 mg, about 8.5 agent is directed to be administered daily. In another embodi mg, about 8.75 mg, about 9.0 mg, about 9.25 mg, about 9.5 ment of the non-mifepristone dosing regimens of the present mg, about 9.75 mg, about 10.0 mg, about 10.25 mg, about invention, the anti-progestational agent is directed to be 10.5 mg, about 10.75 mg, about 11.0 mg, about 11.25 mg, administered intermittently. about 11.5 mg, about 11.75 mg, about 12.0 mg, about 12.25 In another embodiment of the non-mifepristone dosing 30 mg, about 12.5 mg, about 12.75 mg, about 13.0 mg, about regimens of the present invention, the directed administration 13.25 mg, about 13.5 mg, about 13.75 mg, about 14.0 mg. is selected from the group consisting of oral administration, about 14.25 mg, about 14.5 mg, about 14.75 mg, about 15.0 Sublingual administration, buccal administration, nasal mg, about 15.25 mg, about 15.5 mg, about 15.75 mg, about administration, transdermal administration, vaginal adminis 16.0 mg, about 16.25 mg, about 16.5 mg, about 16.75 mg, tration, rectal administration, intravenous administration, 35 about 17.0 mg, about 17.25 mg, about 17.5 mg, about 17.75 Subcutaneous administration, intraperitoneal administration, mg, about 18.0 mg, about 18.25 mg, about 18.5 mg, about parenteral administration, intramuscular administration, 18.75 mg, about 19.0 mg, about 19.25 mg, about 19.5 mg, depot administration, topical administration, intrauterine about 19.75 mg, about 20.0 mg, about 20.25 mg, about 20.5 administration, inhalation administration, implant adminis mg, about 20.75 mg, about 21.0 mg, about 21.25 mg, about tration and ocular administration. 40 21.5 mg, about 21.75 mg, about 22.0 mg, about 22.25 mg. In another embodiment of the non-mifepristone dosing about 22.5 mg, about 22.75 mg, about 23.0 mg, about 23.25 regimens of the present invention, the directed administration mg, about 23.5 mg, about 23.75 mg, about 24.0 mg, about occurs through a form selected from the group consisting of 24.25 mg, about 24.5 mg, about 24.75 mg, about 25.0 mg. one or more of a tablet, a capsule, a cachet, a dragee, a pill, about 25.25 mg, about 25.5 mg and about 25.75 mg. pellets, granules, a powder, a solution, an emulsion, a fluid 45 In another embodiment of the non-mifepristone medica emulsion, a Suspension, a fluid Suspension, a semi-solid, an tions of the present invention, the medication includes a dos ointment, a paste, a cream, a gel, a jelly, a foam, an implant, age of an anti-progestational agent selected from the group a patch and a spray. In another embodiment of the non consisting of less than about 4.75 mg, less than about 4.5 mg. mifepristone dosing regimens of the present invention, the less than about 4.25 mg, less than about 4.0 mg, less than form is prepared as a Sustained release form. 50 about 3.75 mg, less than about 3.5 mg, less than about 3.25 In another embodiment of the non-mifepristone dosing mg, less than about 3.0 mg, less than about 2.75 mg, less than regimens of the present invention, the patient is a pre-meno about 2.5 mg, less than about 2.25 mg, less than about 2.0 mg. pausal female over the age of 18. In another embodiment of less than about 1.75 mg, less than about 1.50 mg, less than the non-mifepristone dosing regimens of the present inven about 1.25 mg, less than about 1.0 mg, less than about 0.75 tion, the patient has at least one uterine leiomyomata that is 55 mg, less than about 0.5 mg, or less than about 0.25 mg, and 22.5 cm in size. In another embodiment of the non-mifepris less than about 0.75 mg. tone dosing regimens of the present invention, the patient has In another embodiment of the non-mifepristone medica a total uterine volume of 2160 cc. tions of the present invention, the anti-progestational agent is In another embodiment of the non-mifepristone dosing selected from one or more of the group consisting of onapris regimens of the present invention, the dosing regimen further 60 tone, lilopristone, ZK 112.993, Org 31710, Org 33628, Org directs the administration of a maintenance dose to the patient 3.1806, CDB-2914, CDB-4124, RJW, asoprisnil, J900, J956, after the completion of a first round of treatment. J912 and J 1042. The present invention also includes non-mifepristone In another embodiment of the non-mifepristone medica medications. In one embodiment of the medications of the tions of the present invention, the anti-progestational agent is present invention comprises an anti-progestational agent and 65 selected from one or more of the group consisting of mife is administered to a patient to treat a disorder selected from pristone, onapristone, Org31710, Org31806, RTI-3021-012, the group consisting of uterine leiomyomata, premenstrual and RTI-3021-022. US 8,173,626 B2 23 24 In another embodiment of the non-mifepristone medica strual dysphoric disorder, dysfunctional uterine bleeding, tions of the present invention, the one or more anti-progesta polycystic ovarian syndrome, adenomyomas, polymenor tional agents is administered after the conclusion of a treat rhea, dysmenorrhea, severe dysmenorrhea, menorrhagia, ment selected from the group consisting of the administration breakthrough bleeding, intermittent bleeding, endometriosis, of birth control pills to treat severe dysmenorrhea, polymen ovarian cysts, irregular withdrawal bleeding, hirsutism, iron orrhea or dysfunctional uterine bleeding, the administration deficiency anemia, acne, benign breast disease, catamenial of GnRh analogues to treat uterine leiomyomata or symptoms, pelvic inflammatory disease, loss of bone density, endometriosis, myomectomy to treat uterine leiomyomata, endometriosis, breast cancer, ovarian cancer, uterine cancer uterine artery embolization to treat uterine leiomyomata, and prostate cancer or for its use in male contraception, anti endometrial ablation to treat menorrhagia or polymenorrhea 10 and ultrasound therapy to treat uterine leiomyomata. glucocorticoid effects or labor and delivery wherein the anti In another embodiment of the non-mifepristone medica progestational agent is not mifepristone. tions of the present invention, the one or more anti-progesta In another embodiment of the non-mifepristone medica tional agents is administered to shrink uterine leiomyomata tions of the present invention, the maintenance dose is before a surgical treatment. In another embodiment of the 15 selected from the group consisting of about 0.1 mg, about non-mifepristone medications of the present invention, the 0.15 mg, 0.25 mg, about 0.5 mg, about 0.75 mg, about 1.0 mg. Surgical treatment is selected from the group consisting of about 1.25 mg, about 1.50 mg, about 1.75 mg, about 2.0 mg. hysterectomy, myomectomy, uterine artery embolization and about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg. endometrial ablation. about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4.0 mg. In another embodiment of the non-mifepristone medica about 4.25 mg, about 4.5 mgandabout 4.75 mg, about 5.0 mg. tions of the present invention, the one or more anti-progesta about 5.25 mg, about 5.5 mg, about 5.75 mg, about 6.0 mg. tional agents is administered concurrently with a treatment about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7.0 mg. selected from the group consisting of depo-provera acetate to about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8.0 mg. treat breakthrough bleeding or intermittent bleeding, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9.0 mg. levonorgestrel containing IUDs to treat breakthrough bleed 25 about 9.25 mg, about 9.5 mg, about 9.75 mg, about 10.0 mg. ing or intermittent bleeding and cortisol or synthetic cortisol about 10.25 mg, about 10.5 mg, about 10.75 mg, about 11.0 like bioactive agents to treat excessive adrenal Secretions. mg, about 11.25 mg, about 11.5 mg, about 11.75 mg, about In another embodiment of the non-mifepristone medica 12.0 mg, about 12.25 mg, about 12.5 mg, about 12.75 mg. tions of the present invention, the anti-progestational agent is about 13.0 mg, about 13.25 mg, about 13.5 mg, about 13.75 administered daily. In another embodiment of the non-mife 30 mg, about 14.0 mg, about 14.25 mg, about 14.5 mg, about pristone medications of the present invention, the anti 14.75 mg, about 15.0 mg, about 15.25 mg, about 15.5 mg, progestational agent is administered intermittently. about 15.75 mg, about 16.0 mg, about 16.25 mg, about 16.5 In another embodiment of the non-mifepristone medica mg, about 16.75 mg, about 17.0 mg, about 17.25 mg, about tions of the present invention, the administration is selected 17.5 mg, about 17.75 mg, about 18.0 mg, about 18.25 mg, from a route selected from the group consisting of oral admin 35 about 18.5 mg, about 18.75 mg, about 19.0 mg, about 19.25 istration, Sublingual administration, buccal administration, mg, about 19.5 mg, about 19.75 mg, about 20.0 mg, about nasal administration, transdermal administration, vaginal 20.25 mg, about 20.5 mg, about 20.75 mg, about 21.0 mg. administration, rectal administration, intravenous adminis about 21.25 mg, about 21.5 mg, about 21.75 mg, about 22.0 tration, Subcutaneous administration, intraperitoneal admin mg, about 22.25 mg, about 22.5 mg, about 22.75 mg, about istration, parenteral administration, intramuscular adminis 40 23.0 mg, about 23.25 mg, about 23.5 mg, about 23.75 mg. tration, depot administration, topical administration, about 24.0 mg, about 24.25 mg, about 24.5 mg, about 24.75 intrauterine administration, inhalation administration, mg, about 25.0 mg, about 25.25 mg, about 25.5 mg and about implant administration and ocular administration. 25.75 mg In another embodiment of the non-mifepristone medica In another embodiment of the non-mifepristone medica tions of the present invention, the administration occurs 45 tions of the present invention, the maintenance dose is through a form selected from the group consisting of one or selected from the group consisting of less than about 4.75 mg. more of a tablet, a capsule, a cachet, a dragee, a pill, pellets, less than about 4.5 mg, less than about 4.25 mg, less than granules, a powder, a solution, an emulsion, a fluid emulsion, about 4.0 mg, less than about 3.75 mg, less than about 3.5 mg. a Suspension, a fluid Suspension, a semi-solid, an ointment, a less than about 3.25 mg, less than about 3.0 mg, less than paste, a cream, a gel, a jelly, a foam, an implant, a patch and 50 about 2.75 mg, less than about 2.5 mg, less than about 2.25 a spray. In another embodiment of the non-mifepristone mg, less than about 2.0 mg, less than about 1.75 mg, less than medications of the present invention, the form is prepared as about 1.50 mg, less than about 1.25 mg, less than about 1.0 a Sustained release form. mg, less than about 0.75 mg, less than about 0.5 or less than In another embodiment of the non-mifepristone medica about 0.25 mg, and less than about 0.75 mg. tions of the present invention, the patient is a pre-menopausal 55 In another embodiment of the non-mifepristone medica female over the age of 18. In another embodiment of the tions of the present invention, the maintenance dose is admin non-mifepristone medications of the present invention, the istered after a first round of treatment selected from the group patient has at least one uterine leiomyomata that is 22.5 cm consisting of the use of an anti-progestational agent to treat in size. In another embodiment of the non-mifepristone medi uterine leiomyomata, premenstrual syndrome, premenstrual cations of the present invention, the patient has a total uterine 60 dysphoric disorder, dysfunctional uterine bleeding, polycys Volume of 2160 cc. tic ovarian syndrome, adenomyomas, polymenorrhea, dys In another embodiment of the non-mifepristone medica menorrhea, severe dysmenorrhea, menorrhagia, break tions of the present invention, medication comprises a main through bleeding, intermittent bleeding, endometriosis, tenance dose of an anti-progestational agent that is adminis ovarian cysts, irregular withdrawal bleeding, hirsutism, iron tered after an anti-progestational agent is administered to a 65 deficiency anemia, acne, benign breast disease, catamenial patient to treat a disorder selected from the group consisting symptoms, pelvic inflammatory disease, loss of bone density, of uterine leiomyomata, premenstrual syndrome, premen endometriosis, breast cancer, ovarian cancer, uterine cancer US 8,173,626 B2 25 26 and prostate cancer or for its use in male contraception, anti group consisting of about 0.1 mg, about 0.15 mg, 0.25 mg. glucocorticoid effects or labor and delivery. about 0.5 mg, about 0.75 mg, about 1.0 mg, about 1.25 mg. In another embodiment of the non-mifepristone medica about 1.50 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg. tions of the present invention, the maintenance dose is admin about 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.25 mg. istered concurrently with a treatment selected from the group about 3.5 mg, about 3.75 mg, about 4.0 mg, about 4.25 mg. consisting of depo-provera acetate to treat breakthrough about 4.5 mg and about 4.75 mg, about 5.0 mg, about 5.25 mg. bleeding or intermittent bleeding, levonorgestrel containing about 5.5 mg, about 5.75 mg, about 6.0 mg, about 6.25 mg. IUDs to treat breakthrough bleeding or intermittent bleeding about 6.5 mg, about 6.75 mg, about 7.0 mg, about 7.25 mg. and cortisol or synthetic cortisol-like bioactive agents to treat about 7.5 mg, about 7.75 mg, about 8.0 mg, about 8.25 mg. excessive adrenal secretions. 10 about 8.5 mg, about 8.75 mg, about 9.0 mg, about 9.25 mg. In another embodiment of the non-mifepristone medica about 9.5 mg, about 9.75 mg, about 10.0 mg, about 10.25 mg. tions of the present invention, the maintenance dose is admin about 10.5 mg, about 10.75 mg, about 11.0 mg, about 11.25 istered daily. In another embodiment of the non-mifepristone mg, about 11.5 mg, about 11.75 mg, about 12.0 mg, about medications of the present invention, the maintenance dose is 12.25 mg, about 12.5 mg, about 12.75 mg, about 13.0 mg. administered intermittently. 15 about 13.25 mg, about 13.5 mg, about 13.75 mg, about 14.0 In another embodiment of the non-mifepristone medica mg, about 14.25 mg, about 14.5 mg, about 14.75 mg, about tions of the present invention, the medication's administra 15.0 mg, about 15.25 mg, about 15.5 mg, about 15.75 mg, tion route is selected from the group consisting of oral admin about 16.0 mg, about 16.25 mg, about 16.5 mg, about 16.75 istration, Sublingual administration, buccal administration, mg, about 17.0 mg, about 17.25 mg, about 17.5 mg, about nasal administration, transdermal administration, vaginal 17.75 mg, about 18.0 mg, about 18.25 mg, about 18.5 mg, administration, rectal administration, intravenous adminis about 18.75 mg, about 19.0 mg, about 19.25 mg, about 19.5 tration, Subcutaneous administration, intraperitoneal admin mg, about 19.75 mg, about 20.0 mg, about 20.25 mg, about istration, parenteral administration, intramuscular adminis 20.5 mg, about 20.75 mg, about 21.0 mg, about 21.25 mg. tration, depot administration, topical administration, about 21.5 mg, about 21.75 mg, about 22.0 mg, about 22.25 intrauterine administration, inhalation administration, 25 mg, about 22.5 mg, about 22.75 mg, about 23.0 mg, about implant administration and ocular administration. 23.25 mg, about 23.5 mg, about 23.75 mg, about 24.0 mg. In another embodiment of the non-mifepristone medica about 24.25 mg, about 24.5 mg, about 24.75 mg, about 25.0 tions of the present invention, the administration occurs mg, about 25.25 mg, about 25.5 mg and about 25.75 mg. through a form selected from the group consisting of one or In another embodiment of the non-mifepristone business more of a tablet, a capsule, a cachet, a dragee, a pill, pellets, 30 methods of the present invention the anti-progestational agent granules, a powder, a solution, an emulsion, a fluid emulsion, is provided to a consumer in an amount selected from the a Suspension, a fluid Suspension, a semi-solid, an ointment, a group consisting of less than about 4.75 mg, less than about paste, a cream, a gel, a jelly, a foam, an implant, a patch and 4.5 mg, less than about 4.25 mg, less than about 4.0 mg, less a spray. In another embodiment of the non-mifepristone than about 3.75 mg, less than about 3.5 mg, less than about medications of the present invention, the form is prepared as 35 3.25 mg, less than about 3.0 mg, less than about 2.75 mg, less a Sustained release form. than about 2.5 mg, less than about 2.25 mg, less than about 2.0 In another embodiment of the non-mifepristone medica mg, less than about 1.75 less than about 1.50 mg, less than tions of the present invention, the medication is administered about 1.25 mg, less than about 1.0 mg, less than about 0.75 to a pre-menopausal female over the age of 18. In another mg, less than about 0.5 mg, or less than about 0.25 mg, and embodiment of the non-mifepristone medications of the 40 less than about 0.75 mg. present invention, the medication is administered to a patient In another embodiment of the non-mifepristone business that has at least one uterine leiomyomata that is 22.5 cm in methods of the present invention the anti-progestational agent size. In another embodiment of the non-mifepristone medi is selected from one or more of the group consisting of cations of the present invention, the medication is adminis onapristone, lilopristone, ZK 112.993, Org 31710, Org tered to a patient that has a total uterine volume of 2160 cc. 45 33628, Org 31806, CDB-2914, CDB-4124, RJW, asoprisnil, The present invention also includes non-mifepristone busi J900, J956, J912 and J 1042. ness methods. In one embodiment of the methods of the In another embodiment of the non-mifepristone business present invention, the business method comprises providing methods of the present invention the anti-progestational agent to a consumeran anti-progestational agent and a dosing regi is selected from one or more of the group consisting of mife men wherein the dosing regimen directs the anti-progesta 50 pristone, onapristone, Org31710, Org31806, RTI-3021-012, tional agent to be administered to a patient to treat a disorder and RTI-3021-022. selected from the group consisting of uterine leiomyomata, In another embodiment of the non-mifepristone business premenstrual syndrome, premenstrual dysphoric disorder, methods of the present invention the dosing regimen directs dysfunctional uterine bleeding, polycystic ovarian syndrome, the anti-progestational to be administered after the conclu adenomyomas, polymenorrhea, dysmenorrhea, severe dys 55 sion of a treatment selected from the group consisting of the menorrhea, menorrhagia, breakthrough bleeding, intermit administration of birth control pills to treat severe dysmenor tent bleeding, endometriosis, ovarian cysts, irregular with rhea, polymenorrhea or dysfunctional uterine bleeding, the drawal bleeding, hirsutism, iron deficiency anemia, acne, administration of GnRh analogues to treat uterine leiomyo benign breast disease, catamenial symptoms, pelvic inflam mata or endometriosis, myomectomy to treat uterine lei matory disease, loss of bone density, endometriosis, breast 60 omyomata, uterine artery embolization to treat uterine lei cancer, ovarian cancer, uterine cancer and prostate cancer or omyomata, endometrial ablation to treat menorrhagia or for its use in male contraception, anti-glucocorticoid effects polymenorrhea and ultrasound therapy to treat uterine lei or labor and delivery wherein the anti-progestational agent is omyomata. not mifepristone. In another embodiment of the non-mifepristone business In another embodiment of the non-mifepristone business 65 methods of the present invention the dosing regimen directs methods of the present invention the anti-progestational agent the anti-progestational to be administered to shrink uterine is provided to a consumer in an amount selected from the leiomyomata before a Surgical treatment. In another embodi US 8,173,626 B2 27 28 ment of the business methods of the present invention the about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4.0 mg. Surgical treatment is selected from the group consisting of about 4.25 mg, about 4.5 mgandabout 4.75 mg, about 5.0 mg. hysterectomy, myomectomy, uterine artery embolization and about 5.25 mg, about 5.5 mg, about 5.75 mg, about 6.0 mg. endometrial ablation. about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7.0 mg. In another embodiment of the non-mifepristone business about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8.0 mg. methods of the present invention the dosing regimen directs about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9.0 mg. the anti-progestational to be administered concurrently with a about 9.25 mg, about 9.5 mg, about 9.75 mg, about 10.0 mg. treatment selected from the group consisting of depo-provera about 10.25 mg, about 10.5 mg, about 10.75 mg, about 11.0 acetate to treat breakthrough bleeding or intermittent bleed mg, about 11.25 mg, about 11.5 mg, about 11.75 mg, about ing, levonorgestrel containing IUDs to treat breakthrough 10 12.0 mg, about 12.25 mg, about 12.5 mg, about 12.75 mg. bleeding or intermittent bleeding and cortisol or synthetic about 13.0 mg, about 13.25 mg, about 13.5 mg, about 13.75 cortisol-like bioactive agents to treat excessive adrenal secre mg, about 14.0 mg, about 14.25 mg, about 14.5 mg, about tions. 14.75 mg, about 15.0 mg, about 15.25 mg, about 15.5 mg, In another embodiment of the non-mifepristone business about 15.75 mg, about 16.0 mg, about 16.25 mg, about 16.5 methods of the present invention the dosing regimen directs 15 mg, about 16.75 mg, about 17.0 mg, about 17.25 mg, about the anti-progestational to be administered daily. In another 17.5 mg, about 17.75 mg, about 18.0 mg, about 18.25 mg, embodiment of the non-mifepristone business methods of the about 18.5 mg, about 18.75 mg, about 19.0 mg, about 19.25 present invention the dosing regimen directs the anti-proges mg, about 19.5 mg, about 19.75 mg, about 20.0 mg, about tational to be administered intermittently. 20.25 mg, about 20.5 mg, about 20.75 mg, about 21.0 mg. In another embodiment of the non-mifepristone business about 21.25 mg, about 21.5 mg, about 21.75 mg, about 22.0 methods of the present invention the dosing regimen directs mg, about 22.25 mg, about 22.5 mg, about 22.75 mg, about the administration to be through a route selected from the 23.0 mg, about 23.25 mg, about 23.5 mg, about 23.75 mg. group consisting of oral administration, Sublingual adminis about 24.0 mg, about 24.25 mg, about 24.5 mg, about 24.75 tration, buccal administration, nasal administration, transder mg, about 25.0 mg, about 25.25 mg, about 25.5 mg and about mal administration, vaginal administration, rectal administra 25 25.75 mg. tion, intravenous administration, Subcutaneous In another embodiment of the non-mifepristone business administration, intraperitoneal administration, parenteral methods of the present invention the maintenance dose is administration, intramuscular administration, depot adminis selected from the group consisting of less than about 4.75 mg. tration, topical administration, intrauterine administration, less than about 4.5 mg, less than about 4.25 mg, less than inhalation administration, implant administration and ocular 30 about 4.0 mg, less than about 3.75 mg, less than about 3.5 mg. administration. less than about 3.25 mg, less than about 3.0 mg, less than In another embodiment of the non-mifepristone business about 2.75 mg, less than about 2.5 mg, less than about 2.25 methods of the present invention the directed administration mg, less than about 2.0 mg, less than about 1.75 mg, less than occurs through a form selected from the group consisting of about 1.50 mg, less than about 1.25 mg, less than about 1.0 one or more of a tablet, a capsule, a cachet, a dragee, a pill, 35 mg, less than about 0.75 mg, less than about 0.5 mg, or less pellets, granules, a powder, a solution, an emulsion, a fluid than about 0.25 mg, and less than about 0.75 mg. emulsion, a Suspension, a fluid Suspension, a semi-solid, an In another embodiment of the non-mifepristone business ointment, a paste, a cream, a gel, a jelly, a foam, an implant, methods of the present invention the dosing regimen directs a patch and a spray. In another embodiment of the non daily administration of the maintenance dose. In another mifepristone business methods of the present invention the 40 embodiment of the non-mifepristone business methods of the form is provided as a Sustained release form. present invention the dosing regimen directs intermittent In another embodiment of the non-mifepristone business administration of the maintenance dose. methods of the present invention the dosing regimen directs In another embodiment of the non-mifepristone business the administration to occur in a pre-menopausal female over methods of the present invention the dosing regimen directs the age of 18. In another embodiment of the non-mifepristone 45 the administration of the maintenance dose to be through a business methods of the present invention the dosing regimen route selected from selected from the group consisting of oral directs the administration to occur in a patient with at least administration, Sublingual administration, buccal administra one uterine leiomyomata that is 22.5 cm in size. In another tion, nasal administration, transdermal administration, vagi embodiment of the non-mifepristone business methods of the nal administration, rectal administration, intravenous admin present invention the dosing regimen directs the administra 50 istration, Subcutaneous administration, intraperitoneal tion to occur in a patient with a total uterine volume of 2160 administration, parenteral administration, intramuscular CC. administration, depot administration, topical administration, In another embodiment of the non-mifepristone business intrauterine administration, inhalation administration, methods of the present invention the dosing regimen further implant administration and ocular administration. directs the administration of a maintenance dose of an anti 55 In another embodiment of the non-mifepristone business progestational agent to the patient after the completion of a methods of the present invention the maintenance dose is first round of treatment. provided in a form selected from the group consisting of one In another embodiment of the non-mifepristone business or more of a tablet, a capsule, a cachet, a dragee, a pill, pellets, methods of the present invention the business method further granules, a powder, a solution, an emulsion, a fluid emulsion, comprises providing a maintenance dose of the anti-proges 60 a Suspension, a fluid Suspension, a semi-solid, an ointment, a tational agent. paste, a cream, a gel, a jelly, a foam, an implant, a patch and In another embodiment of the non-mifepristone business a spray. In another embodiment of the non-mifepristone busi methods of the present invention the maintenance dose is ness methods of the present invention the form is provided as selected from the group consisting of about 0.1 mg, about a Sustained release form. 0.15 mg, 0.25 mg, about 0.5 mg, about 0.75 mg, about 1.0 mg. 65 In another embodiment of the non-mifepristone business about 1.25 mg, about 1.50 mg, about 1.75 mg, about 2.0 mg. methods of the present invention the dosing regimen directs about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg. the administration of the maintenance dose to occur in a US 8,173,626 B2 29 30 pre-menopausal female over the age of 18. In another Breakthrough bleeding: As used herein, the phrase “break embodiment of the non-mifepristone business methods of the through bleeding includes vaginal bleeding or staining present invention the dosing regimen directs the administra between menstrual periods that lasts for a short duration, tion of the maintenance dose to occur in a patient that has at generally less than about one hour. least one uterine leiomyomata that is 22.5 cm in size. In Intermittent bleeding: As used herein, the phrase “intermit another embodiment of the non-mifepristone business meth tent bleeding also includes vaginal bleeding between men ods of the present invention the dosing regimen directs the strual periods but that is more long-term than breakthrough administration of the maintenance dose to occur in a patient bleeding. Generally, intermittent bleeding will last for more that has a total uterine volume of 2160 cc. than about one hour. 10 Endometriosis: As used herein, "endometriosis' includes a SUMMARY OF THE DRAWINGS disease in which functioning endometrial tissue is present in sites outside the uterine cavity. The disease is frequently FIG. 1 is a table showing the characteristics of Study Sub characterized by progressive, disabling dysmenorrhea and jects randomized to the treatment group (N-22) and the pla pelvic pain around the time of the menses. cebo group (N=20). 15 Induration includes the hardening of a normally soft tissue FIG. 2 is a graph showing the change in uterine lei or organ due to inflammation, infiltration of a neoplasm oran omyoma-specific quality of life, measured using the total accumulation of blood. score on the Uterine Leiomyoma Symptom Quality of Life Dysmenorrhea: As used herein, “dysmenorrhea refers to scale, as a function of treatment duration among mifepristone pain during menstruation or just before its onset. “Just before and placebo groups. Bars represent 95% confidence intervals onset' refers to within about 24 hours before menstruation Surrounding the change in the score at each time point. begins. FIG. 3 is a graph showing the change in bleeding patterns Severe dysmenorrhea: As used herein, the phrase “severe as a function of treatment duration among mifepristone and dysmenorrhea includes pain that results in partial or total placebo groups. Bleeding patterns were measured by bleed disability during or just before menstruation. “Disability” in ing scores derived from product of bleeding intensity from 25 this context refers to a reduction in normal activity levels. pictorial blood chart and days of bleeding. Bars refer to 95% Dyspareunia includes the occurrence of pain during sexual confidence intervals surrounding changes in bleeding pat intercourse. terns at each time point. Dysfunctional Uterine Bleeding: As used herein, “dys FIG. 4 is a graph showing the change in pain, measured functional uterine bleeding includes a condition in which using the McGill Pain Questionnaire (Short Form), as a func 30 menstrual bleeding is abnormally heavy or occurs between tion of treatment duration among mifepristone and placebo periods. Dysfunctional uterine bleeding is also abnormal groups. Bars refer to 95% confidence intervals surrounding vaginal bleeding that occurs during a menstrual cycle that change in the score at each time point. produced no egg (i.e. ovulation did not take place). FIG. 5 is a graph showing the change in uterine Volumes Adenomyomas: As used herein, "adenomyomas' includes (mL), measured by vaginal and abdominal ultrasonography, 35 abnormal invasions of the uterine fibrous and muscular layers as a function of treatment duration among mifepristone and by the endometrial lining. placebo groups. Bars refer to 95% confidence intervals sur Polymenorrhea: As used herein, “polymenorrhea rounding changes in uterine Volume at each time point. includes the occurrence of menstrual cycles at frequency that is higher than normal. DETAILED DESCRIPTION OF THE INVENTION 40 Menorrhagia: As used herein, “menorrhagia' includes excessive uterine bleeding occurring at the regular intervals It is to be understood that the present invention is not ofmenstruation, the period offlow being of greater than usual limited to the particular embodiments, materials, and duration. examples described herein, as these may vary. It is also to be Hirsutism: As used herein, “hirsutism’ includes the growth understood that the terminology used herein is used for the 45 of excessive hair in women on parts of the body where exces purpose of describing particular embodiments only, and is not sive hair is generally not present, without limitation, on the intended to limit the scope of the present invention. It must be back and chest. noted that as used herein and in the appended embodiments, Concurrent Administration: As used herein, the term “con the singular forms “a,” “an and “the' include the plural current administration' includes the meaning of overlapping reference unless the context clearly dictates otherwise. Thus, 50 in duration at least in part. Under this meaning, for two for example, a reference to “a disorder” or “a medication' is bioactive agents to be administered concurrently, their a reference to one or more disorders or medications and administration occurs within a certain desired time. The bio includes equivalents thereof known to those skilled in the art active agent's administration may begin and end on the same and so forth. day. The administration of one bioactive agent can also pre Unless defined otherwise, all technical terms used herein 55 cede the administration of a second bioactive agent by one or have the same meanings as commonly understood by one of more days as long as both bioactive agents are taken on the ordinary skill in the art to which this invention belongs. Spe same day at least once. Similarly, the administration of one cific methods, devices, and materials are described, although bioactive agent can extend beyond the administration of a any methods and materials similar or equivalent to those second bioactive agent as long as both bioactive agents are described herein can be used in the practice or testing of the 60 taken on the same day at least once. The bioactive agents do present invention. not have to be taken at the same time each day to include Prior to setting forth the invention in more detail, it may be concurrent administration. helpful to provide an understanding of certain terms that will Sequential Administration: As used herein, “sequential be used hereinafter. administration' includes that the administration of two bio The term "subject as used herein, comprises any and all 65 active agents do not occur on a same day. organisms and includes the term “patient.” “Subject” may Intermittent Administration: As used herein, “intermittent refer to a human or any other animal. administration' includes the administration of a bioactive US 8,173,626 B2 31 32 agent for a period of time (“first period of administration'), condition, disorder or disease, or obtain beneficial or desired followed by a time during which the bioactive agent is not clinical results. For purposes of this invention, beneficial or taken or is taken at a lower maintenance dose (“off-period”) desired clinical results include, but are not limited to, allevia followed by a period during which the bioactive agent is tion of symptoms, diminishment of extent of a condition, administered again (“second period of administration”). Gen disorder or disease, stabilized (i.e., not worsening) state of erally, during the second phase of administration, the dosage condition, disorder or disease, delay in onset or slowing of level of the bioactive agent will match that administered condition, disorder or disease progression, amelioration of during the first period of administration. This protocol is not the condition, disorder or disease state, remission (whether required, however, and for administration to be intermittent, partial or total) or enhancement or improvement of condition, the dosage administered during the second period of admin 10 disorder or disease. Treatment can also include eliciting a istration need only be larger than that received during the clinically significant response, without excessive levels of off-period. side effects. Treatment can also include prolonging Survival Cortisolor synthetic cortisol-like bioactive agents: As used as compared to expected Survival if not receiving treatment. herein, the phrase “cortisolor synthetic cortisol-like bioactive As stated earlier, progesterone plays a major role in repro agents' includes including mineralocorticos 15 ductive health and functioning. Its effects on, for example, the teroids (including, without limitation cortisol, deoxycorticos uterus, breast, cervix and hypothalamic-pituitary unit are well terone and flurohydrocortisone) and (includ established. It also has extra-reproductive activities that are ing, without limitation, beclomethasone, , less well studied, such as effects on the brain, the immune , , , , fluo system, the vascular endothelial system and on lipid metabo cortolone, , , flurandreno lism. Given this wide array of effects, it is apparent that lide, , , , methylpred compounds which modulate the effects of progesterone can nisolone, , , and be useful in treating a variety of disease states and conditions. (acetonide)). Methods are provided herein for the treatment of progest Maintenance dose: As used herein, the phrase “mainte erone-related conditions, wherein the methods comprise nance dose' includes a dose of an administered medication 25 administering one or more anti-progestational agents. The that is lower than a previously administered dose of the same anti-progestational agent(s) may comprise any agent that medication (or a variant thereof). A maintenance dose is modulates the effect of progesterone in the Subject targeted intended to maintain the required concentration of medica for treatment, directly and/or indirectly, including but not tion in the body in order to help maintain a therapeutic effect limited to, chemical compounds, proteins, peptidomimetics, obtained during earlier treatment. As will be described more 30 antisense molecules, ribozymes and other nucleic acids. In fully below, a maintenance dose can be administered daily, various embodiments, the anti-progestational agent may more than once daily, weekly, more than once weekly, comprise a compound that modulates monthly, more than once monthly, yearly, more than once activity, Such as a progesterone receptor antagonist (e.g., an yearly and can include a set, alternating or changing number agent that inhibits one or more responses characteristic of of times per day, per week, per month or per year. 35 progesterone receptor activation); a progesterone receptor First Round of Treatment: As used herein, the phrase “first inverse agonist (e.g., an agent that blocks or inhibits a con round of treatment includes a first course of action pre stitutive progesterone receptor activity); and/or an allosteric scribed by a health care provider. In the present use, the first progesterone receptor modulator (e.g., an agent that binds to round of treatment will include the prescription or adminis a site distinct from the ligand-binding site, and modulates the tration of at least one bioactive agent although the first round 40 response of an endogenous ligand, co-activator or co-repres of treatment may also include other procedures. The pre Sor, and/or other receptor modulator). In some embodiments, scribed or administered bioactive agent will be at a higher the activity of progesterone receptor modulator requires one dose than a later maintenance dose that can be given during a or more additional co-factors or other agents. second round of treatment. In some cases, a health care pro A number of compounds have been developed to act as vider may evaluate the effectiveness of the first course of 45 anti-progestational agents. Some of these agents are proges action at the end of a first round of treatment, however, such terone antagonists, including but not limited to: mifepristone an evaluation is not required and a health care provider may (RU 486; 17-hydroxy-11-(4-dimethylaminophenyl)-17 prescribe a first round of treatment and a second round of (prop-1-ynyl)estra-4,9-dien-3-one; RU 46556 (113-(4-dim treatment (including a maintenance dose) at the same time ethylaminophenyl)-17f8-hydroxy-17C.-(3-methyl-1-buty before evaluating effectiveness of the first round of treatment. 50 nyl)-4.9-estradien-3-one; RU 49295 (11B-(4-acetophenyl)- In this situation, the first round of treatment will include the 17 B-hydroxy-17C.-(3-methyl-1-butynyl)-4.9-estradien-3- prescription or administration of at least one bioactive agent one; B-(4-N,N-dimethyl amino)-phenyl-17? 3-hydroxy (although the first round of treatment may also include other 17C.-propynyl-4,9010)-oestradiene-3-one); onapristone (ZK procedures) for a period of time, followed by a second round 98.299); ZK 112.993 11-4(4-acetylphenyl)-17-hydroxy-17 of treatment that can include the prescription or administra 55 (-propynyl)-,9-diene-3-one; Org 31710 (6C, 11B, 17(3)-11 tion of the same bioactive agents at a lower dose or one or (4-NMe-phenyl)-6-Me-4',5'-dihydrospiro oestra-4.9-diene more different bioactive agents or procedures. 17.2(3'H)-furan-3-one: Org 33628 (11 B,17C)-(4- Birth Control Pills: As used herein, the phrase “birth con acetylphenyl)-17.23-epoxy-19.24-dinorchola-4.9.20-trien trol pills' include all therapies that deliver a combination of 3-one; Org 31806 (73.11B, 17B)-11-(4-NMe-phenyl)-7- estrogen and progesterone and reduce the likelihood of ovu 60 Me-4',5'-dihydrospiro (oestra-4,9-diene-17.2"(3H)-furan)-3- lation. While the term "pill is included in the phrase, a pill is one; and lilopristone (ZK98734); CDB-2914 (17O-acetoxy not required under the adopted definition and any adminis 11B-4-N,N-dimethylaminophenyl-19-norpregna-4.9- tration route can be included under the definition. diene-320-dione); CDB-4124 (17O-acetoxy-21-methoxy Treat and Treatment: As used herein, the terms “treat' and 11B-4-N,N-dimethylaminophenyl-19-norpregna-4.9- “treatment can include both therapeutic treatment and pro 65 diene-320-dione) and RJW compound. Compounds that phylactic or preventative measures, wherein the object is to have previously been designated J867 (asoprisnil), J900, prevent or slow down (lessen) an undesired physiological J956, J912 (major metabolite of asoprisnil), J914, and J1042 US 8,173,626 B2 33 34 are all also suitable for use in accordance with the methods one antagonists inhibit the proliferative action of the proges provided herein. Such compounds include, without limita terone and reduce the number of tubular alveolar buds by 30 tion, 4-17f8-Methoxy-17C.-(methoxymethyl)-3-oxoestra-4, to 35% or more. 9-dien-113-ylbenzaldehyd-(1E)-oxim; and 4-17 B-Hy In some embodiments, the anti-progestational agent is droxy-17-O-(methoxymethyl)-3-oxoestra-4,9-dien-113-yl) selected from the group consisting of mifepristone, onapris benzaldehyd-(1E)-oxim: 4-17 B-Methoxy-17C.- tone, Org 31710, Org 31806, RTI-3021-012, and RTI-3021 (methoxymethyl)-3-oxoestra-4,9-dien-113-ylbenzaldehyd 022. Without being bound by any particular theory, it is (1E)-O-(ethoxy)carbonyl)oxim; 4-17 B-Methoxy-17C.- believed that these and other compounds act as “active (methoxymethyl)-3-oxoestra-4,9-dien-113-ylbenzaldehyd antagonists' at progesterone receptor(s), in that they not only (1E)-(O-acetyl)oxim: and 4-17B-Methoxy-17C.- 10 compete with endogenous ligands/agonists for binding to progesterone receptors, but also exert additional effects that (methoxymethyl)-3-oxoestra-4,9-dien-113-ylbenzaldehyd further antagonize progesterone receptor activity and/or the (1E)-O-(ethylamino)carbonyl)oxim. These and other effects thereof. For example, after competing with endog potentially useful agents are described in, e.g., the following enous agonists for progesterone receptor binding, mifepris publications: the aforementioned PCT applications WO 15 tone, onapristone, and other active antagonists enter the 93/21926 and WO 93/21927; U.S. Pat. No. 4,386,085; U.S. nucleus as an antagonist-receptor complex and compete with Pat. No. 4,027,019; U.S. Pat. No. 4,000,273: U.S. Pat. No. agonist-bound receptors for DNA transcriptional control 3,890,356; U.S. Pat. No. 3,622,622; U.S. Pat. No. 3,983,144: sites, such as progesterone response elements (PREs), recruit U.S. Pat. No. 3,462.466; U.S. Pat. No. 3,790,564; U.S. Pat. additional co-factors (e.g., co-repressors), and/or exert other No. 4.231,946; Pollow, et al., Contraception 40:213-32 effects that antagonize progesterone receptor function. (1989); Cook et al., Hum Reprod.: 9 Suppl 1:32-9 (1994): In some embodiments, the anti-progestational agent is a Hazra et al., . 65(3): 157-62 (2000); and Michna et compound identified as being an active progesterone receptor al., Supra, the entire disclosures of which are hereby incorpo antagonist by an assay method that detects, directly or indi rated by reference. rectly, one or more of the agent's activities, in addition to Regarding mifepristone specifically, this compound is a 25 progesterone receptor binding. In some embodiments, the synthetic 19-nonsteroid, lacking the C19-methyl group of anti-progestational agent is capable of binding to one or more natural progesterone (P) and glucocorticosteroids (G). The DNA elements targeted by progesterone receptoragonists, as bioactive agent has been found to have a high affinity for both described, e.g., in Gass et al., Endocriol. 139: 1905-1919 the progesterone receptor (PR) and the glucocorticosteroid (1998) and/or recruiting co-repressors or other co-factors that receptor (GR) and has strong antiprogesterone and antiglu 30 inhibit progesterone receptor activity, as described, e.g., in cocorticosteroid activity. Its contragestational properties and Zhanget al., Mol Endocrinol, 12:513-524 (1998) and Wagner clinical applications have been reviewed by Baulieu, 245 et al., Mol Cell Biol, 18: 1369-1378 (1998). In further Science 1351 (1989) which is incorporated herein by refer embodiments, the anti-progestational agent, alone or bound ence. Mifepristone is commercially available in a number of to a progesterone receptor or other molecule, is capable of countries and is exclusively available in the United States 35 heterodimerizing with agonist-bound progesterone recep under the tradename MifeprexR) (Danco Laboratories, Inc.). tors, as described, e.g., in DeMarzo et al., Biochemistry, In some embodiments, the anti-progestational agent is a 31:10491-10501 (1992) and Leonhardt et al., Mol Endo progesterone receptor antagonist, Such as crinol, 12: 1914-1930 (1998). In some embodiments, the LG120753, LG120830, LG100127, RWJ26329, CP8400, anti-progestational agent is a active antagonist against CP8401 and compounds described in Pooley et al., J Med 40 progesterone receptors and a competitive antagonist against Chem, 41: 3461-3466 (1998), Zhi et al., Bioorgan MedChem glucocorticoid receptors, such as the anti-progestational Lett, 10: 415-418 (2000), Palmer et al., J Steroid Biochem agents RTI-012, RTI-022, and compounds described in Wag Mol Biol 75: 33-42 (2000), Tabata et al., Eur J Pharm, 430: ner et al., Endocrinol, 140: 1449-1458 (1999). 159-165 (2001), Dukes et al., Steroids, 65: 725-731 (2000), In some embodiments, the anti-progestational agent recep Kang et al., Bioorg Med Chem Lett., Epub (2007), Combs et 45 tor is non-selective in its effects against progesterone receptor al., J Med Chem, 38: 4878-4879 (1995), and U.S. Pat. App. subtypes A and B (PR-A and PR-B, respectively), whereas in No. 20050085470 to Zhanget al. other embodiments the anti-progestational agent exhibits Also contemplated as within the scope of the present inven “subtype-selective' activity against one subtype relative to tion are inhibitors or antagonists of progesterone which the other. For example, in Some embodiments, the anti modulate the production, metabolism, and/or transport of 50 progestational agent is active against PR-A while being Sub progesterone. Examples of Suitable progesterone synthesis stantially inactive against PR-B, or vice versa. Subtype-se inhibitors include, but are not limited to: triloStane, epostane, lectivity can be measured as the ratio of ICso value for a target azastene and cyanoketone. See, for example, WO 93/21926, progesterone receptor to the ICso value for a non-target recep WO 93/21927 and Haider & Inbaraj, 73 Gen Comp Endo tor subtype. In some embodiments, a “subtype-selective' crinol, 92-5 (1989). 55 anti-progestational agent has a Subtype selectivity that is less To identify additional anti-progestational agents suitable than about 1:2, and preferably less than about 1:10, and more for use in the methods, dosing regimens and medications of preferably less than about 1:50, and most preferably less than the present invention, it is further possible to employ hereto about 1:100. fore-known biological assays for Such agents. An exemplary In some embodiments, the anti-progestational agent selec assay is described in Michna, H. et al., 38.J. Steroid Biochem. 60 tively antagonizes PR-B, which is differentially expressed in Molec. Biol. 359-65 (1991) for progesterone antagonists. In the endometrial lining (e.g., Wang et al., Mol Hum Reprod., this bioassay rats are subjected to ovariectomy on day 1. On 4(4):407-12 (1998)), relative to PR-A, which prevents side day 8 the experimental rats are administered estrone, proges effects associated with secondary activity against non-uterine terone and the progesterone antagonist daily. On day 11 the and/or other untargeted progesterone receptors. In further animals are sacrificed and the number of tubular alveolar buds 65 embodiments, the anti-progestational agent exhibits “target in the inguinal mammary gland counted in a whole mount selective' activity against progesterone receptors relative to preparation using a 40-fold magnification. Potent progester non-progesterone receptors. For example, in Some embodi US 8,173,626 B2 35 36 ments, the anti-progestational agent is Substantially inactive be understood that the conditions and disorders described or Substantially less active against glucocorticoid receptors, hereinafter in more detail and their respective symptoms and estrogen receptors, and/or other steroid receptors. In some causes can overlap. embodiments, the anti-progestational agent is a progesterone Importantly, while a role for anti-progestational agents has antagonist that is Substantially inactive against glucocorticoid been indicated in the treatment of these conditions, the prior receptors, such as ZK230211 (described, e.g., in Fuhrrmann art has suggested higher doses of anti-progestational agents et al., J Med Chem, 43: 5010-5016 (2000)), Org 31710, Org that the present invention shows are not necessary. For 3.1806, Org 33628, and compounds described in Tabata et al., example, U.S. Pat. No. 6,225,298 to Spicer et al. (issued May EurJ Pharm, 430: 159-165 (2001), Philibert et al., J Steroid 1, 2001) Suggests that an appropriate dose of mifepristone 10 could be 10 to 100 mg daily. Eisinger et al., (supra) has shown Biochem., 34(1-6): 413-7 (1989), and Pooley et al., J Med that 5 mg of mifepristone can be effective at treating uterine Chem, 41: 3461-34.66 (1998). leiomyomata when given daily for 6 months. As stated earlier, In some embodiments, the Subtype and/or target selective however, these doses and/or lengths of treatments can be activity of an anti-progestational agent is achieved by admin associated with troublesome side effects. Therefore, a need istering the agentata dosage and/or in a manner that produces 15 remains for a treatment option that does not cause these a concentration in the target organ or tissue (e.g., the uterine effects. The low dose methods, dosing regimens and medica lining) that is therapeutically effective against one or more tions of the present invention provide Such options. targeted progesterone receptors, while being Sub-therapeutic The following discussion describes a subset of the number at other receptors and/or targets. Advantageously, the Sub of progesterone-related disorders that can be beneficially type-selective activity of an anti-progestational agent results treated with the low dose methods, dosing regimens and in improved efficacy, fewer side effects, lower effective dos medications of the present invention. ages, less frequent dosing, and/or other beneficial therapeutic Uterine leiomyomata. As stated previously, uterine lei properties relative to non-selective agents. omyomata are generally non-malignant tumors that may While the anti-progestational agents described herein can occur in up to 80% of women over 30 years old. Uterine be administered as the sole active pharmaceutical agent, they 25 leiomyomata are benign growths of uterine muscle that some can also be used in combination with one or more additional times exist singly, but most often are multiple and range in active agents, such as another anti-progestational agent and/ size from microscopic to filling most of the lower abdominal or an agent with a distinct activity. When administered as a cavity. Many women with uterine leiomyomata have no combination, the therapeutic agents can be formulated as symptoms at all. For those that do, the most common com separate compositions that are administered at the same time 30 plaints are pressure symptoms and heavy, prolonged periods or sequentially at different times, or given as a single compo leading to iron-deficiency anemia, as well as painful periods sition. The invention is not limited in the sequence of admin (dysmenorrhea which can transition into severe dysmenor istration. In some embodiments, a progesterone receptor rhea). There may be pressure in the pelvic region from the modulator has a synergistic effect with the one or more addi enlarged uterus, and the resulting symptoms are often related tional active agents. In some embodiments, one or more addi 35 to where the uterine leiomyomata are exerting pressure (e.g., tional agents potentiate the effect of the progesterone receptor increased urinary frequency, constipation or difficulty with modulator and/or the progesterone receptor modulator poten bowel movements). The pressure can also cause backache, tiates the effect of the additional agent(s). Methods for assess lower abdominal discomfort, and pain during and after inter ing synergism, potentiation, and other combined pharmaco course. The presence of uterine leiomyomata can also cause logical effects are known in the art, and described, e.g., in 40 reproductive problems such as infertility, multiple miscar Chou and Talalay, Adv Enzyme Regul., 22:27-55 (1984). In riages, premature labor, or labor complications. These gener Some embodiments, combination therapy with an anti ally non-malignant tumors are one of the most common rea progestational agent and one or more additional agents, or Sons for Surgery in women during their reproductive years. with two or more anti-progestational agents, results in a Endometriosis. Many women, about 5-10% of those in enhanced efficacy, safety, therapeutic index, and/or tolerabil 45 their reproductive years, are afflicted with endometriosis. The ity, and/or reduced side effects (frequency, severity, or other current concept of endometriosis is that the endometrial aspects), dosage levels, dosage frequency, and/or treatment glands and stroma are shed through Fallopian tubes during duration relative to monotherapies with each of the compo menstruation, after which they implant onto the peritoneum, nents of the combination. and initiate growth. Initially, the existence of translocated Information indicating that anti-progestational agents 50 endometrial cells can only be proven microscopically on the would be effective in a number of medical conditions is peritoneal lining of the pelvis, or even at extra-pelvic sites available. Non-limiting examples of medical conditions or Such as the diaphragm in the upper abdomen. Murphy et al., disorders that could be treatable with the anti-progestational 46 Fert. and Sterility 522-524 (1986). But the occurrence of agent methods, dosing regimens and medication of the regular, menstrual bleeding at those sites over time leads to present invention include: uterine leiomyomata, endometrio 55 angiogenesis and growth of visible lesions where none had sis, symptoms associated with ovarian cysts, polycystic ova been visible before, and pain and infertility that develop from rian syndrome, breakthrough bleeding, intermittent bleeding, the bleeding at, and into those sites. Brosens, Supra. Symp irregular withdrawal bleeding, dysfunctional uterine bleed toms usually subside during pregnancy and lactation, after ing, adenomyomas, polymenorrhea, dysmenorrhea, severe castration premenopausally, and as the hypoestrogenemia of dysmenorrhea, menorrhagia, hirsutism, iron deficiency ane 60 the peri-menopause develops. Endometriosis is a life-long, mia, acne, benign breast disease, fluctuations in infection genetically facilitated, pathological condition that may be levels, temporomandibular disorder, catamenial symptoms, stimulated at any age by unopposed estrogen therapy to pro non-menstrual related headache, nausea, depression, duce recurrent symptoms. hypoestrogenism, pelvic inflammatory disease, loss of bone Women with endometriosis can suffer progressive, dis density, cancers, other tumors, male contraception, anti-glu 65 abling dysmenorrhea and pelvic pain around the time of cocorticoid effects, and labor and delivery. While these con menses. Brosens, 176 Am. J. Obstet. Gynecol. 263-7 (1997). ditions or disorders are described separately in places, it is to Other common symptoms and signs of endometriosis include US 8,173,626 B2 37 38 dyspareunia, pain unrelated to menses, discomfort upon pel tered as a single agent, and as part of a combined oral contra vic exam, induration, and cul de Sac tenderness. In addition, ceptive has been reported to benefit some women. Kay & pelvic pain unassociated with menses may restrict afflicted Wingrave, 1 Lancet 1437 (1983); Linos et al., 1 Lancet 1871 women to measured participation in athletic and other physi (1978). cal activities, such as dancing and hiking. About 60% of women with migraines report a relationship The peri-menstrual pain experienced by women afflicted of their occurrence with menstruation. Case & Reid, Supra. with endometriosis may be relieved in part by non-steroidal Decreasing levels of estrogen during the late luteal phase of anti-inflammatory bioactive agents (NSAIDs). But those not the menstrual cycle or abrupt withdrawal of estrogen as dur benefited adequately require ovulation-Suppressing treat ing the hormone-free period in women taking oral contracep ments and/or are treated with bioactive agents such as 10 tives are thought to trigger migraine attacks. Sulak et al., 95 or GnRH analogs that have significant side-effects. Obstet. Gynecol261-66 (2000); Kudrow, 15 Headache 36-49 Menstrual Disorders. Menstrual disorders include, but are (1975); Whitty et al., 1 Lancet 856-59 (1966). not limited to polymenorrhea, dysmenorrhea, dysfunctional Catamenial epilepsy refers to seizure disorders that occur uterine bleeding, breakthrough bleeding, intermittent bleed or worsen around menstruation. It is believed to result from ing, dysfunctional uterine bleeding, menorrhagia and 15 cyclic alterations in both ovarian hormone levels and bioac adenomyoma as well as premenstrual symptoms such as, but tive agent metabolism. Case & Reid, Supra. not limited to, those associated with premenstrual syndrome Ovarian cysts and Polycystic Ovarian Syndrome. Ovarian (PMS) or Premenstrual Dysphoric Disorder (PMDD). cysts and polycystic ovarian syndrome can cause symptoms During the luteal phase of the menstrual cycle, as many as including, but not limited to, pelvic pain, dysmenorrhea, 75% of women with regular menstrual cycles experience abnormal uterine bleeding, acne, and hirsutism. Ovarian cysts Some symptoms of premenstrual syndrome (PMS), a recur arise from functional cysts that commonly occur around mid ring, cyclical disorder involving behavioral, emotional, social cycle, when a follicle destined to become an egg fails to and physical symptoms. Steiner et al., 48 Annu. Rev. Med. mature. Instead of leaving the ovary in a process known as 447-55 (1997). Behavioral, emotional and social symptoms ovulation, it remains inside, floating in a tiny sac of fluid. It is include, but are not limited to, irritability, mood Swings, 25 that sac that eventually forms into a cyst. Although rarely depression, hostility and social withdrawal. Physical Symp malignant, ovarian cysts lead to 200,000 hospitalizations in toms include, but are not limited to, bloating, breast tender the United States each year. For some women, some studies ness, myalgia, migraines or headaches, abdominal pain, and have shown that the cysts develop cycle after cycle. Though fatigue. True PMS only occurs during the luteal phase of the ovarian cysts can sometimes be asymptomatic, they can also menstrual cycle, with a symptom-free period during the fol 30 cause pain (constant pelvic pain, pain during intercourse, pain licular phase. The etiology of PMS is still unknown. during pelvic movement, and/or pain before or after menses), A subgroup of women with PMS, about 5%, exhibit symp abnormal bleeding (lengthened, shortened, irregular and/or toms that are primarily related to a severe mood disorder. In absent menses), and/or abdominal bloating or distension. these women, the diagnosis of Premenstrual Dysphoric Dis Labor and delivery. Anti-progestational agents may be use order (PMDD), as defined in the Fourth edition of the Diag 35 ful for cervical ripening prior to labor induction Such as at nostic and Statistical Manual of Mental Disorders (DSM-IV), term or when labor must be induced due to fetal death. Anti can be applied (see “Premenstrual Dysphoric Disorder” in progestational agents may also be used to help induce labor in DSM-IV: Diagnostic and Statistical Manual of Mental Dis term or post-term pregnancies. orders, 4" Ed., American Psychiatric Association, Washing Antiglucocorticoid effects. While in most cases the anti ton, D.C., pp. 715-718 (1994)). According to the DSM-IV, a 40 glucocorticoid effects of anti-progestational agents such as woman with PMDD must have at least five premenstrual mifepristone are undesirable, they can be beneficial in some symptoms during the luteal phase, with at least one of the patients. For example, anti-progestational agents with anti symptoms being an emotional or “core” symptom. The core glucocorticoid effects, such as mifepristone, can be useful in symptoms must be irritability, anger, mood Swings, tension or the treatment of Cushing's syndrome, and could be beneficial depression (and interfere with daily activities), and must be 45 in the treatment of immune disorders. confirmed by a prospective daily rating for at least two cycles. Cancers. Anti-progestational agents may be useful for the There is also a Subgroup of women who experience severe treatment of hormone dependent cancers, including breast, PMS, which accounts for about 20% of the PMS population. uterine and ovarian cancers. See, for example, Horwitz, et al., These women experience severe emotional symptoms that do Horm Cancer, 283 pub: Birkhaeuser, Boston, Mass., ed. not fall under the strict criteria of PMDD as defined in DSM 50 Vedeckis. Anti-progestational agents have also been shown to IV but require medical attention. be effective in a model of hormone dependent prostate cancer, Catamenial symptoms. Catamenial symptoms are those which may also indicate their utility in the treatment of this associated with conditions, disorders, or diseases that can condition in men. Michna, et al., 761 Ann. N.Y. Acad Sci.224 worsen around the time of menses. Thus, a role for progest (1995). erone is indicated. Such conditions, disorders, or diseases 55 A role for progesterone (and thus anti-progestational include, but are not limited to, asthma, rheumatoid arthritis, agents in treatment) for breast cancer is described more fully. migraine headaches, seizure disorders or epilepsy, depres The breast has a tightly regulated pattern of growth primarily Sion, multiple Sclerosis and diabetes. A Subset of these con under the control of steroid hormones. The effects of steroid ditions and symptoms are described more fully below. hormones on the normal breast are increasingly well under Arthritis is a prevalent chronic condition. Hormonal fac 60 stood. Estrogen induces some breast epithelial proliferation, tors can influence the frequency and severity of arthritis. In but estrogen and progesterone together produce even greater Some women, arthritis symptoms such as joint stiffness, cell proliferation. Pike et al., 15 Epidemiol. Rev. 17-35 Swelling and pain peak during the postovulatory phase of the (1993). In non-pregnant premenopausal women, the breast menstrual cycle, and cyclic changes in local antibody release, epithelium undergoes repetitive periods of cell proliferation white blood cell Subpopulations and altered pain perception 65 and cell loss secondary to cyclic ovarian activity. In the ter have been proposed as possible mechanisms. Case, & Reid, minal duct lobular unit (TDLU) of the premenopausal breast, 158 Arch. Intern. Med. 1405-12 (1998). Estrogen adminis cell proliferation is low during the follicular phase of the US 8,173,626 B2 39 40 menstrual cycle. Following ovulation, progesterone is pro of a primary medications, wherein an anti-progestational duced by the corpus luteum and TDLU cell proliferation agent exerts a greater-than-additive effect (e.g., a synergistic increases two- to three-fold over follicular levels. Pike et al., effect) with an additional therapeutic agent in treating the supra. Consistent with the breast cell proliferation rates, the disease targeted for treatment. In some embodiments, identi size and number of terminal ductules peak during the late fying a patient in need of anti-progesterone treatment com luteal phase. Longacre & Barlow, 10 Am. J. Surg. Path. 382 prises detecting one or more genetic markers indicative of 93 (1986). If fertilization and pregnancy do not ensue, proges being predisposed to a progesterone-related disorder. terone levels fall, the rate of breast cell division decreases, and The anti-progestational agents of the present invention also a wave of cell death by apoptosis follows the peak in cell can be used, without limitation, in the form of salts derived proliferation. Anderson et al., 46 Br. J. Cancer 376-82 (1982). 10 from pharmaceutically or physiologically acceptable acids or Proliferating cell populations are more Susceptible to car bases. These salts include, but are not limited to, the following cinogenic effects, and the rise in cancer risk associated with salts with inorganic acids such as, without limitation, hydro cell proliferation is secondary to an increased chance of muta chloric acid, Sulfuric acid, nitric acid, phosphoric acid and, as tion and loss of tumor Suppressor genes. Preston-Martin et al., the case may be, such organic acids as acetic acid, oxalic acid, 50 Cancer Res. 7415-21 (1990). Thus, breast cancer risk 15 Succinic acid, and maleic acid. Other salts include, without would be predicted to increase the greatest during periods of limitation, salts with alkali metals or alkaline earth metals, exposure to both estrogen and progesterone, as in the pre Such as Sodium, potassium, calcium or magnesium in the menopausal period or in women receiving combined oral form of esters, carbamates and other conventional “pro-bio contraceptives (COCs); less during periods of exposure only active agent” forms, which, when administered in Such form, to estrogen, as in postmenopausal women receiving estrogen convert to the active moiety in vivo. replacement therapy (ERT) or in obese postmenopausal Anti-progestational agents provided herein that contain a women; and least during periods of exposure to very low chiral center include all possible stereoisomers, including levels of both hormones, as in non-obese postmenopausal racemic mixtures and compositions comprising varying pro Asian women. portions of eachenantiomer, including compositions Substan Anti-progestational agents may also be useful in treating or 25 tially free of a non-preferred enantiomer or substantially inhibiting the development of other types of cancer Such as enriched in a preferred enantiomer. Thus, for example, com meningiomas, non-malignant brain membrane tumors, that, positions comprising the Senantiomer Substantially free of although non-malignant, result in death of the patient. the Renantiomer, or the Renantiomer substantially free of the Male contraception. Anti-progestational agents, whether S enantiomer are contemplated. If a named anti-progesta acting through anti-progestational or anti-glucocorticoid 30 tional agents comprises more than one chiral center, the activity can interfere with sperm viability. Thus, the anti present disclosure includes compositions comprising mix progestational agents of the present invention could provide a tures of varying proportions of the diastereomers, as well as mechanism of male contraception. compositions comprising one or more diastereomers Substan The foregoing discussion provides a number of medical tially free of one or more of the other diastereomers. By conditions and/or disorders that could benefit from the low 35 “substantially free’ it is meant that the composition com dose anti-progestational agent methods, dosing regimens and prises less than 25%, 15%, 10%, 8%, 5%,3%, or less than 1% medications of the present invention. of the minor enantiomer or diastereomer(s). In some embodiments, low dose anti-progestational thera In some embodiments, the anti-progestational agents is an pies described herein comprise a step of identifying a patient antisense nucleotide (e.g., siRNA) that specifically hybrid in need of anti-progesterone treatment, and administering to 40 izes with the cellular mRNA and/or genomic DNA corre the patient an effective, progesterone receptor-modulating sponding to the gene(s) of a target progesterone receptor, or a amount of an anti-progestational agent. In various embodi molecule that otherwise modulates progesterone receptor ments, identifying a patient in need of anti-progesterone treat activity, so as to inhibit their transcription and/or translation, ment comprises identifying a patient who has or will be or a ribozyme that specifically cleaves the mRNA of a target exposed to a factor or condition known to enhance the pro 45 protein. Antisense nucleotides and ribozymes can be deliv duction or effect of progesterone, including but not limited to ered directly to cells, or indirectly via an expression vector pregnancy, menstruation, or medications that enhance the which produces the nucleotide when transcribed in the cell. amount and/or activity of progesterone (e.g., birth control). In Methods for designing and administering antisense oligo Some embodiments, identifying a patient in need of anti nucleotides and ribozymes are known in the art. progesterone treatment comprises identifying a patient Suf 50 The medications of the present invention can be adminis fering from one or more symptoms caused or exacerbated by tered by any route where they are active. For example, admin the effects of progesterone, including but not limited to, uter istration can be, without limitation, oral, injectable (without ine leiomyomata, arthritis, menstrual disorders (e.g., PMS), limitation, parenteral, Subcutaneous, intravenous, intramus pregnancy-related fatigue and/or depression, post-partum cular, intraperitoneal, or by depot injections), topical, trans depression, and migraines. 55 dermal, intravaginal, intrauterine, Sublingual, buccal, rectal, In some embodiments, identifying a patient in need of by inhalation, through implants or through ocular routes. anti-progesterone treatment comprises selecting a population Suitable pharmaceutical excipients and formulations for a or Sub-population of patients, or an individual patient, that is variety of routes of administration are known in the art and are more amenable to treatment and/or less Susceptible to side described, for example, in Remington's Pharmaceutical Sci effects than other patients having the same disease or condi 60 ences (19th ed.) (Genarro, ed. (1995) Mack Publishing Co., tion. In some embodiments, the patient has been identified as Easton, Pa.). One of ordinary skill in the art will readily being non-responsive to treatment with primary medications appreciate how the anti-progestational agents of the present for the condition(s) targeted for treatment, and the anti invention can be administered through each of the above progestational agent is administered in a method for enhanc administration routes. A description of a Subset of these ing the responsiveness of the patient to a co-existing or pre 65 administration routes is nonetheless provided. existing treatment regimen. In other embodiments, the In some embodiments, antiprogestational agents described method or treatment comprises administering a combination herein are selected, formulated, administered, and/or modi US 8,173,626 B2 41 42 fied to prevent and/or facilitate passage across one or more appropriate glidant includes, without limitation, colloidal biological barriers, including but not limited to the blood silicon dioxide. Appropriate lubricants include, without limi brain barrier, the blood-cerebrospinal fluid (CSF) barrier, the tation, talc and Stearic acids. Other commonly-used and intestinal epithelium, the placenta, and/or the mucosal lining. appropriate excipients include cellulose preparations such as, For example, in some embodiments, an anti-progestational but not limited to, maize starch, wheat starch, rice starch, agent is permeable across the gut epithelium while being potato starch, gelatin, gum tragacanth, methyl cellulose, substantially impermeable across the blood-brain barrier, so hydroxypropylmethyl-cellulose, sodium carboxymethylcel as to allow oral administration with minimal dose-limiting lulose, and polyvinylpyrrolidone (PVP). CNS side effects. Procedures for the production and manufacture of com In some embodiments, an anti-progestational agent is 10 pressed tablets and capsules are well known by those skilled selected on the basis of one or more characteristics that cor in the art (See Remington). In one embodiment, the solid oral relate with the desired permeability, such as polarity, hydro dosage forms of the present invention can include hard or soft phobicity/hydrophilicity, size, charge, and affinity for trans gelatin shells as a container for a particular mixture of anti porters, channel proteins, receptors, and other molecules progestational agents and other active or inactive ingredients. involved in transport across the barrier of interest. In some 15 Procedures for production and manufacture of hard or soft embodiments, the anti-progestational agent is conjugated to a gelatin shells are also well known in the art (See Remington). carrier that imparts the desired physical properties. For Oral dosage forms of the present invention can also come in example, a carrier molecule may comprise an internalization the form of dragees, capsules, liquids, gels, syrups, slurries, domain, Such as a peptide sequence recognized by one or Suspensions, or lozenges and the like, all formulated in well more cell-surface receptors, which facilitates the uptake of known and conventional manners. When dragees are chosen the drug into cells targeted for treatment via active transport. as a dosage form of the present invention, dragee cores can be Relevant factors and strategies for selecting and designing provided with Suitable coatings. For this purpose, concen agents with desired permeability across biological barriers trated Sugar Solutions can be used, which can optionally con are known in the art, and are described, e.g., in Sharma et al., tain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel. Pharmazie., 61 (6): 495-504 (2006), Borovac et al., J. Control 25 polyethylene glycol, and/or titanium dioxide, lacquer Solu Release, 115(3): 266-74 (2006). He et al., IntJ Pharm. Epub tions, and Suitable organic solvents or solvent mixtures. Dye (Oct. 21, 2006), Majumdar and Mitra, Expert Opin Drug stuffs or pigments can be added to the tablets or dragee Deliv., 3(4): 511-27 (2006) and Panyam and Labhasetwar, coatings for identification or to characterize different combi CurrDrug Deliv.1(3): 235-47 (2004), each of which is hereby nations of active compound doses. incorporated by reference in its entirety. Advantageously, 30 The anti-progestational agents of the present invention can anti-progestational agents administered in methods provided also be administered by injection including, without limita herein are selectively permeable so as to achieve therapeutic tion, parenteral injection, subcutaneous injection, intrave levels upon administration in targeted cells, tissues, organs, nous injection, intramuscular injection, intraperitoneal injec compartments, etc. at dosing levels, frequencies, and dura tion or by depot injection. When administered by injection, tions that avoid undesirable side effects of standard treat 35 the anti-progestational agents of the present invention can be ments involving standard preparations of the agent. formulated in aqueous Solutions, specifically in physiologi In one embodiment of the present invention, the anti cally compatible buffers such as Hanks solution, Ringer's progestational agents of the present invention can be deliv Solution, or physiological saline buffer. The Solution may ered through oral administration routes. For solid orally-ad contain formulatory agents such as Suspending, stabilizing ministrable compositions, conventional nontoxic Solid 40 and/or dispersing agents. Alternatively, the anti-progesta carriers may be used which include, without limitation, phar tional agents of the present invention can be in powder form maceutical grades of mannitol, lactose, starch, magnesium for constitution with a suitable vehicle, e.g., Sterile pyrogen Stearate, Sodium saccharine, talcum, cellulose, glucose, free water, before use. In one embodiment, adjuvants such as, Sucrose, magnesium, carbonate, and the like. Specifically, without limitation, local anesthetics, preservatives and buff and in one embodiment, oral Solid dosage forms can be com 45 ering agents can also be included in the aqueous solution. To pressed into tablets or capsules. Compressed tablets may enhance the stability of the anti-progestational agents of the contain any of the excipients described above which can present invention, the composition can be frozen after filling increase the bulk of the anti-progestational agents (and other into a vial and the aqueous solution removed under vacuum. active ingredients if included) so that production of a com The dry lyophilized powder can then be sealed in the vial and pressed tablet of practical size is possible. Binders, which are 50 an accompanying vial of water for injection can be supplied to agents which impart cohesive qualities of powdered materi reconstitute the liquid prior to use. Parenteral Suspensions can als, also can be used. Non-limiting examples of appropriate be prepared in Substantially the same manner except that the binders include starch, gelatin, Sugars such as, without limi compounds are Suspended in the vehicle instead of being tation, lactose, Sucrose, mannitol, Sorbitol or dextrose, and dissolved and sterilization cannot be accomplished by filtra natural or synthetic gums. Disintegrants also can be used to 55 tion. The compound can be sterilized by exposure to ethylene create appropriate tablets or capsules. Disintegrants can oxide before suspending in the sterile vehicle. In one embodi facilitate breakup of the tablet once ingested. Appropriate ment, a Surfactant or wetting agent can be included in the non-limiting disintegrants include, without limitation, composition to facilitate uniform distribution of the anti starches, clays, celluloses, algins, gums and crosslinked poly progestational agents of the present invention. mers, the foregoing more specifically including, without limi 60 In addition to the formulations just described, the anti tation, cross-linked polyvinyl pyrrolidone, agar, or alginic progestational agents of the present invention can also be acid or a salt thereof such as Sodium alginate. Lubricants and formulated as depot preparations. Such long acting formula glidants also can be used in the Solid oral administration tions can be administered by implantation (for example Sub forms of the present invention. These materials serve to cutaneously or intramuscularly) or by intramuscular injec reduce adhesion of the dosage form material to Surfaces in the 65 tion. In one embodiment, depot injections can be manufacturing process and also improve the flow character administered at about 1 week to about 1 month to about 6 istics of the powder material used during manufacture. An month intervals or longer. Thus, for example, the compounds US 8,173,626 B2 43 44 can be formulated with suitable polymeric or hydrophobic creams, gels and jellies, and foams; and dosage forms which materials (for example as an emulsion in an acceptable oil) or include, but are not limited to, Solutions, Suspensions, emul ion exchange resins, or as sparingly soluble derivatives, for sions, and dry powder; comprising an effective amount of example, as a sparingly soluble salt. anti-progestational agents as taught by this invention. The In one embodiment, the anti-progestational agents of the anti-progestational agents of the present invention can be present invention can be delivered through topical adminis contained in Such formulations with pharmaceutically tration. When topical administration is chosen, the anti acceptable diluents, fillers, disintegrants, binders, lubricants, progestational agents of the present invention can be formu surfactants, hydrophobic vehicles, water soluble vehicles, lated as, without limitation, Solutions, gels, ointments, emulsifiers, buffers, humectants, moisturizers, solubilizers, creams, patches, Suspensions, and the like, as are well known 10 in the art. In some embodiments, administration can be by preservatives and the like. The means and methods for admin means of a transdermal patch. In transdermal administration, istration are known in the art and an artisan can refer to the anti-progestational agents of the present invention can be various pharmacologic references for guidance. For example, applied to a plaster, or another transdermal, therapeutic sys “Modem Pharmaceutics', Banker & Rhodes, Marcel Dekker, tem. Regardless of the specific transdermal delivery method 15 Inc. 1979; and “Goodman & Gilman's The Pharmaceutical chosen, penetration enhancers, including, without limitation, Basis of Therapeutics. 6th Edition, MacMillan Publishing dimethylsulfoxide, dimethyl acetamide and dimethylforma Co., New York 1980 can be consulted. mide can be included. The dosage forms described may also be provided in Sus Implants can also be used to deliver the anti-progestational tained-release forms. AS is understood by one of ordinary agents of the present invention. Implants can comprise, with skill in the art, a chosen dosage form can be provided in a out limitation, polymeric devices which slowly release or Sustained release form by, without limitation, increasing the slowly erode and release within the body to provide appro particle size of the drug, embedding the drug in a matrix, priate amounts of anti-progestational agents over time. When coating the drug or dosage form containing the drug and/or polymers are used, appropriate polymers include, without forming complexes of the drug with materials such as ion limitation, non-toxic hydrogels, silicones, polyethylenes, 25 exchange resins. Materials that can be suitable for producing ethylene-Vinyl acetate copolymers and other biodegradable Sustained-release coatings on oral dosage forms include, polymers. Hydrogels include, without limitation, polyhy without limitation, mixtures of waxes (beeswax, camauba droxyalkyl methacrylates, polyacrylamide and poly wax, etc. with, without limitation, glyceryl monostearate, methacrylamide, polyvinylpyrrolidone and polyvinyl alco Stearic acid, palmitic acid, glyceryl monopalmitate and cetyl hol. An appropriate silicone includes, without limitation, 30 alcohol; shellac and Zein; ethylcellulose; acrylic resins, cel polydimethylsiloxane. Biodegradable polymers include, lulose acetate (including, without limitation, diacetate and without limitation, polylactic acid (PLA), polyglycolic acid triacetate); and silicone elastomers. (PGA), copolymers of PLA and PGA, and polyamides. As stated previously, the anti-progestational agents of the The implants of the present invention can include Subcu present invention can be administered in combination or con taneous devices such as those routinely used to deliver norg 35 currently with other active ingredients. For example, in one estrienone or progestin R2323 and other medicaments. Other embodiment the anti-progestational agents of the present implants include intravaginal and intrauterine implantable invention can be administered with another treatment that has devices. For vaginal administration, vaginal creams, rings been found to be useful in treating uterine-related disorders. and pessaries are also appropriate. In another embodiment, the anti-progestational agents of the In one embodiment, the present invention can include rec 40 present invention can be administered with another treatment tal compositions, such as, without limitation, Suppositories or that has been found to be useful in treating catamenial Symp retention enemas containing conventional Suppository bases toms. Non-limiting examples of these types of other treat Such cocoa butter, polyethylene glycols (carbowaxes), poly ments include GnRH agonists, such as, without limitation, ethylene Sorbitan monostearate, and mixtures of these with Lupron(R), Synarel(R) or Zolodex(R), danazol or GnRH analogs, other compatible materials to modify the melting point or 45 birth control pills, depo-provera acetate, myomectomy, uter dissolution rate. ine artery embolization, endometrial ablation, guided ultra Another embodiment of the present invention can include Sound therapy, cortisol or synthetic cortisol-like bioactive the administration of anti-progestational agents with or with agents, or levonorgestrel or similar agents. The anti-proges out other added active or inactive ingredients through inhala tational agents can also be administered after a treatment Such tion. In one embodiment, inhalation can occur through the use 50 as GnRH agonists, such as, without limitation, Lupron(R), of an aerosol spray using, without limitation, pressurized Synarel(R) or Zolodex(R), danazol or GnRH analogs, birth con packs or a nebulizer with the use of a suitable propellant such trol pills, depo-provera acetate, myomectomy, uterine artery as, without limitation, dichlorodifluoromethane, trichlorof embolization, endometrial ablation, guided ultrasound luoromethane, dichlorotetrafluoroethane, carbon dioxide or therapy, cortisol or synthetic cortisol-like bioactive agents, or other appropriate gases. In the case of a pressurized aerosol, 55 levonorgestrel or similar agents has concluded and the treat dosage amounts can be controlled by providing a valve to ment was determined to provide inadequate relief from the deliver a metered amount. Capsules and cartridges of, for condition or disorder at issue. The anti-progestational agents example, gelatin for use in an inhaler or insufflator can be can also be administered before a treatment including GnRH formulated containing a powder mix of active ingredients and agonists, such as, without limitation, Lupron(R), Synarel R. or a Suitable powder base such, without limitation, lactose or 60 Zolodex(R), danazol or GnRH analogs, birth control pills, starch. depo-provera acetate, hysterectomy, myomectomy, uterine As should be understood by the previous description of artery embolization, endometrial ablation, guided ultrasound administration routes, formulations of the present invention therapy, cortisol or synthetic cortisol-like bioactive agents, or can include, but are not limited to, tablets, capsules, cachets, levonorgestrel or similar agents. Administering the anti pellets, pills, powders and granules; topical dosage forms 65 progestational agents of the present invention at the doses which include, but are not limited to, solutions, powders, fluid described can be especially beneficial as a way to shrink emulsions, fluid Suspensions, semi-solids, ointments, pastes, uterine leiomyomata before a Surgical treatment such as, US 8,173,626 B2 45 46 without limitation, hysterectomy, myomectomy, uterine 17.5 mg, about 17.75 mg, about 18.0 mg, about 18.25 mg, artery embolization and endometrial ablation. about 18.5 mg, about 18.75 mg, about 19.0 mg, about 19.25 The anti-progestational agents of the present invention can mg, about 19.5 mg, about 19.75 mg, about 20.0 mg, about also be administered with other active ingredients. For 20.25 mg, about 20.5 mg, about 20.75 mg, about 21.0 mg. example, in one embodiment the anti-progestational agents of 5 about 21.25 mg, about 21.5 mg, about 21.75 mg, about 22.0 the present invention could be administered with vitamin D mg, about 22.25 mg, about 22.5 mg, about 22.75 mg, about and/or calcium to aid in the maintenance or prevention of 23.0 mg, about 23.25 mg, about 23.5 mg, about 23.75 mg. bone density loss. The form of vitamin D and of calcium used about 24.0 mg, about 24.25 mg, about 24.5 mg, about 24.75 in the present invention would be well known to those of skill mg, about 25.0 mg, about 25.25 mg, about 25.5 mg and about in the art, as would the amount. For example, calcium can be 10 25.75 mg. administered in the form of calcium carbonate, at a daily In further embodiments, anti-progestational agents of the dosage level of 500 mg. present invention can be administered in dosage amounts of When the anti-progestational agents of the present inven less than about 4.75 mg, less than about 4.5 mg, less than tion are administered alone (either as a first treatment or about 4.25 mg, less than about 4.0 mg, less than about 3.75 following a previous treatment with another bioactive agent 15 mg, less than about 3.5 mg, less than about 3.25 mg, less than or following a procedure), the agents can be delivered about 3.0 mg, less than about 2.75 mg, less than about 2.5 mg. between about 1 and about 12 times daily, between about 1 less than about 2.25 mg, less than about 2.0 mg, less than and about 84 times weekly, between about 1 and about 372 about 1.75 mg, less than about 1.50 mg, less than about 1.25 times monthly or between about 1 and about 4.464 times mg, less than about 1.0 mg, less than about 0.75 mg, less than yearly. When administered concurrently within another type about 0.5 mg. or less than about 0.25 mg. or less than about of medication, the two agents can be administered together in 0.75 mg. one dosage form (manufactured and by administration routes Whether administering a first round of anti-progestational described above) or can be administered in separate dosage agent treatment or a maintenance dose round of Such treat forms. When administered in separate dosage forms, the dos ment, the administration of these agents can occur, without age forms can be the same or can be different dosage forms. 25 limitation, for about 1 week, about 2 weeks, about 3 weeks, The anti-progestational agents of the present invention can about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, also be administered concurrently with three or more addi about 8 weeks, about 9 weeks, about 10 weeks, about 11 tional medication types or other treatment procedures. Con weeks, about 12 weeks, about 13 weeks, about 14 weeks, currently administered medications and/or other treatment about 15 weeks, about 16 weeks, about 17 weeks, about 18 procedures can also be administered between about 1 and 30 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 12 times daily, between about 1 and about 84 times about 22 weeks, about 23 weeks, about 24 weeks, about 25 weekly, between about 1 and about 372 times monthly or weeks, about 26 weeks, about 27 weeks, about 28 weeks, between about 1 and about 4,464 times yearly. about 29 weeks, about 30 weeks, about 31 weeks, about 32 Following the administration of an anti-progestational weeks, about 33 weeks, about 34 weeks, about 35 weeks, agent of the present invention for a period of time, a patient 35 about 36 weeks, about 37 weeks, about 38 weeks, about 39 can receive a maintenance dose of the same or a different weeks, about 40 weeks, about 41 weeks, about 42 weeks, anti-progestational agents of the present invention. The main about 43 weeks, about 44 weeks, about 45 weeks, about 46 tenance doses will generally cause a blood level of the anti weeks, about 47 weeks, about 48 weeks, about 49 weeks, progestational agents that is generally lower than that about 50 weeks, about 51 weeks, about 1 year, about 1 year observed during its administration during the first period of 40 plus any of the weekly increments described above, about 2 time. Again, the maintenance dose could be administered years plus any of the weekly described above or more. When between about 1 and about 12 times daily, between about 1 from 4.75 mg to about 5.5 mg is chosen as a dose, adminis and about 84 times weekly, between about 1 and about 372 tration will not exceed 4 weeks. When from about 0.1 mg to times monthly or between about 1 and about 4.464 times about 0.2 mg is chosen as a dose, administration can be yearly. As will be understood by one of skill in the art, the 45 limited to a patient weighing less than 110 pounds, although dosing schedule chosen will dictate the dosage used at each Such a limitation is not required. administration time. In further embodiments, antiprogestational agents The anti-progestational agents of the present invention can described herein are administered for a duration of less than be administered in dosage amounts of about 0.1 mg, about about 10 weeks, less than about 9 weeks, less than about 8 0.15 mg, 0.25 mg, about 0.5 mg, about 0.75 mg, about 1.0 mg. 50 weeks, less than about 7 weeks, less than about 6 weeks, less about 1.25 mg, about 1.50 mg, about 1.75 mg, about 2.0 mg. than about 5 weeks, less than about 4 weeks, less than about about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg. 3 weeks, less than about 2 weeks, or less than about 1 week. about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4.0 mg. The anti-progestational agents of the present invention can about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5.0 mg. be produced in the form of a kit or package, with dosages about 5.25 mg, about 5.5 mg, about 5.75 mg, about 6.0 mg. 55 arranged for proper administration. For example, in embodi about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7.0 mg. ments adopting Solid oral dosage forms, a kit can contain a about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8.0 mg. pharmaceutical package including the oral dosage form in about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9.0 mg. bottles or blister packs. If a particular kit includes a treatment about 9.25 mg, about 9.5 mg, about 9.75 mg, about 10.0 mg. regimen including concurrent administration of the anti about 10.25 mg, about 10.5 mg, about 10.75 mg, about 11.0 60 progestational agents of the present invention with another mg, about 11.25 mg, about 11.5 mg, about 11.75 mg, about treatment or the use of the anti-progestational agents of the 12.0 mg, about 12.25 mg, about 12.5 mg, about 12.75 mg. present invention following another treatment or the use of about 13.0 mg, about 13.25 mg, about 13.5 mg, about 13.75 the anti-progestational agents of the present invention fol mg, about 14.0 mg, about 14.25 mg, about 14.5 mg, about lowed by a maintenance dose, all required dosages and medi 14.75 mg, about 15.0 mg, about 15.25 mg, about 15.5 mg, 65 cations can be contained in one kit. The kit can contain these about 15.75 mg, about 16.0 mg, about 16.25 mg, about 16.5 combination-type dosages in a synchronized or fixed mg, about 16.75 mg, about 17.0 mg, about 17.25 mg, about sequence manner wherein the sequence or arrangement of the US 8,173,626 B2 47 48 dosage units is explained by instructional information found medium, such as a floppy disc, CD-ROM, DVD-ROM, Zip with or within the kit (see below). Thus, for example, a kit of disc, videotape, audiotape, flash memory device, etc. the present invention could include 180 tablets containing 2.5 Detailed instructions may not be physically associated with mg mifepristone and 180 tablets containing 1.0 mg mifepris the kit; instead, a user may be directed to an internet web site tone. In this example, the instructional information could 5 specified by the manufacturer or distributor of the kit, or provide that a 2.5 mg tablet be taken daily for about 6 months. Supplied as electronic mail. At the completion of this six months, a 1.0 mg tablet should be As should be understood, the exact formulation, route of taken daily for another about 6 months as a maintenance dose. administration, and dosage should generally be determined While this example describes one appropriate kit of the by the attending physician in view of the patient’s condition. present invention, it should not be read to limit the possible 10 Dosage amount and interval can be adjusted individually to combinations of administrations possible with the kits of the provide plasma levels of the active antiprogestational agent present invention. which is sufficient to maintain therapeutic effect. Generally, The kits of the present invention can also include injectable the desired anti-progestational agent is administered in an forms of the anti-progestational agents of the present inven admixture with a pharmaceutical carrier selected with regard tion. In one embodiment, a kit of the present invention can 15 to the intended route of administration and standard pharma contain one or more of the following in a package or con ceutical practice. tainer: (1) one or more anti-progestational agents of the In some embodiments, an effective, therapeutic amount of present invention; (2) one or more pharmaceutically accept an antiprogestational agent described herein is an amount that able adjuvant or excipient; (3) one or more vehicles for achieves a concentration of the agent within the target tissue, administration, Such as one or more Syringes; (4) one or more using the particular mode of administration, at or above the additional bioactive agents for concurrent or sequential ICs (concentration sufficient for half-maximal inhibition) administration; and (5) instructions for administration. for activity of the agent at progesterone receptors. In some Embodiments in which two or more of components (1)–(5) embodiments, the antiprogestational agent is administered in are found in the same container are also contemplated. a manner and dosage that gives a peak concentration of about When a kit is supplied, the different components of the 25 1, 1.5, 2, 2.5, 5, 10, 20 or more times the ICs concentration. composition may be packaged in separate containers and Methods for determining the concentration of a free com admixed immediately before use. Such packaging of the com pound in plasma and extracellular fluids in the CNS, as well ponents separately may permit long-term storage without pharmacokinetic properties, are known in the art, and are losing the active components functions. When more than one described, e.g., in de Lange et al., AAPS Journal, 7(3): 532 bioactive agent is included in a particular kit, the bioactive 30 543 (2005). In some embodiments, an effective amount of an agents may be (1) packaged separately and admixed sepa antiprogestational agent described herein is a dose that that rately with appropriate (similar or different) vehicles imme produces a concentration of the agent in an organ, tissue, cell. diately before use, (2) packaged together and admixed and/or other region of interest that includes the EDs (the together immediately before use or (3) packaged separately pharmacologically effective dose in 50% of subjects) with and admixed together immediately before use. If the chosen 35 little or no toxicity. compounds will remain stable after admixture, however, the In some embodiments of the methods described herein, admixture need not occur immediately before use but can administering a low dose of an anti-progestational agent occurata time before use, including in one example, minutes, allows effective treatment of a condition targeted for treat hours, days, months or years before use or in another embodi ment with substantially fewer and/or less severe side effects ment at the time of manufacture. 40 compared to existing treatment regimens. In some embodi The reagents included in particular kits of the present ments, combination therapy with an anti-progestational agent invention can be Supplied in containers of any sort Such that and one or more additional agents allows the anti-progesta the life of the different components are preserved and are not tional age and/or the one or more additional agents to be adsorbed or altered by the materials of the container. For administered at dosages that would be sub-therapeutic when example, sealed glass ampules may contain lyophilized anti 45 administered individually. In some embodiments, methods progestational agents or variants or derivatives of thereof or described herein allow treatment of certain conditions for other bioactive agents, or buffers that have been packaged which treatment with the same or similar compounds is inef under a neutral, non-reacting gas, Such as, without limitation, fective using known methods due, for example, to dose-lim nitrogen. Ampules may consist of any suitable material. Such iting side effects, toxicity, and/or other factors. as, without limitation, glass, organic polymers, such as, poly 50 In a particular embodiment of the present invention, a carbonate, polystyrene, etc., ceramic, metal or any other business method relating to providing a dosing regimen of an material typically employed to hold similar reagents. Other anti-progestational agent and sale of the dosed anti-progesta examples of suitable containers include simple bottles that tional agent may also be implemented. may be fabricated from similar substances as ampules, and In a specific embodiment of the business methods of the envelopes, that may comprise foil-lined interiors, such as 55 present invention, the method can, but need not be, imple aluminum oran alloy. Other containers include, without limi mented through computer systems. For example, a user (e.g., tation, test tubes, vials, flasks, bottles, Syringes, or the like. a health practitioner Such as a physician or a pharmacist) may Containers may have one or more sterile access ports, such as access computer systems via a computer terminal and a bottle having a stopper that can be pierced by a hypodermic through the Internet or other means. The connection between injection needle. Other containers may have two compart 60 the user and the computer system is preferably secure. ments that are separated by a readily removable membrane In practice, the user may input, for example, information that upon removal permits the components to be mixed. relating to a patient such as the patient’s disease State and Removable membranes may be, without limitation, glass, other factors relating to the patient’s treatment. The computer plastic, rubber, etc. system may then, through the use of the resident computer As stated earlier, kits can also be supplied with instruc 65 programs, provide one or more appropriate anti-progesta tional materials. Instructions may be printed on paperor other tional agent dosing regimens for the patient. The computer Substrate, and/or may be Supplied as an electronic-readable program, via the user interface, may also provide pricing and US 8,173,626 B2 49 50 cost comparisons for different anti-progestational agents, in wired, multidrop bus, any connection means that Supports conjunction with, or separate from, appropriate dosing regi bidirectional communication in a computer-related environ mens for those anti-progestational agents. ment could be used. A computer system in accordance with one embodiment of The main memory of the computer systems of the present the present invention may be, for example, an enhanced IBM 5 invention Suitably contains one or more computer programs AS/400 mid-range computer system. However, those skilled relating to anti-progestational agent administration and an in the art will appreciate that the methods and apparatus of the operating system. Computer program in memory is used in its present invention apply equally to any computer system, broadest sense, and includes any and all forms of computer regardless of whether the computer system is a complicated programs, including source code, intermediate code, machine 10 code, and any other representation of a computer program. multi-user computing apparatus or a single user device Such The term “memory” as used herein refers to any storage as a personal computer or workstation. The described com location in the virtual memory space of the system. It should puter systems Suitably comprise a processor, main memory, a be understood that portions of the computer program and memory controller, an auxiliary storage interface, and a ter operating system may be loaded into an instruction cache for minal interface, all of which are interconnected via a system 15 the main processor to execute, while other files may well be bus. Note that various modifications, additions, or deletions stored on magnetic or optical disk storage devices. In addi may be made to the computer system within the scope of the tion, it is to be understood that the main memory may com present invention Such as the addition of cache memory or prise disparate memory locations. other peripheral devices. The following Examples are provided as illustrative The processor performs computation and control functions embodiments of the present invention. It should be under of the computer system, and comprises a suitable central stood that the methods, dosing regimens and medications of processing unit (CPU). The processor may comprise a single the present invention are not limited by the following integrated circuit, such as a microprocessor, or may comprise examples. The teachings of the Examples that follow can be any Suitable number of integrated circuit devices and/or cir used by those of ordinary skill in the art as guidance in making cuit boards working in cooperation to accomplish the func 25 other, obvious variations that result in similar results as dis tions of a processor. The processor Suitably executes the closed here. PK/PD modeling computer programs of the present invention Embodiments of the present invention can also expressly within its main memory. exclude particular anti-progestational agents, conditions for In one embodiment, the auxiliary storage interface allows treatment and/or dosage amounts. For example, certain 30 embodiments of the present invention can exclude mifepris the computer system to store and retrieve information from tone as an anti-progestational agent. Other embodiments can auxiliary storage devices, such as magnetic disks (e.g., hard exclude one or more of onapristone, lilopristone, ZK disks or floppy diskettes) or optical storage devices (e.g., 112.993, Org 31710, Org 33628, Org 31806, CDB-2914, CD-ROM). One suitable storage device is a direct access CDB-4124, RJW, asoprisnil, J900, J956, J912 and J1042. storage device (DASD). A DASD may be a floppy disk drive 35 Certain embodiments of the present invention can also which may read programs and data from a floppy disk. It is exclude particular conditions for treatment. For example, cer important to note that while the present invention has been tain embodiments can exclude the treatment of uterine lei (and will continue to be) described in the context of a fully omyomata. Other embodiments can exclude one or more of functional computer system, those skilled in the art will premenstrual syndrome, premenstrual dysphoric disorder, appreciate that the mechanisms of the present invention are 40 dysfunctional uterine bleeding, polycystic ovarian syndrome, capable of being distributed as a program product in a variety adenomyomas, polymenorrhea, dysmenorrhea, severe dys of forms, and that the present invention applies equally menorrhea, menorrhagia, breakthrough bleeding, intermit regardless of the particular type of signal bearing media to tent bleeding, endometriosis, ovarian cysts, irregular with actually carry out the distribution. Examples of signal bearing drawal bleeding, hirsutism, iron deficiency anemia, acne, media include: recordable type media Such as floppy disks 45 benign breast disease, catamenial symptoms, pelvic inflam and CD ROMS, and transmission type media such as digital matory disease, loss of bone density, endometriosis, breast and analog communication links, including wireless commu cancer, ovarian cancer, uterine cancer and prostate cancer or nication links. for its use in male contraception, anti-glucocorticoid effects The computer systems of the present invention may also or labor and delivery. comprise a memory controller, through use of a separate 50 Certain embodiments of the present invention can also processor, which is responsible for moving requested infor exclude particular dosages. For example, embodiments of the mation from the main memory and/or through the auxiliary present invention can exclude one or more of the dosages storage interface to the main processor. While for the pur selected from about 0.1 mg, about 0.15 mg, 0.25 mg, about poses of explanation, the memory controller is described as a 0.5 mg, about 0.75 mg, about 1.0 mg, about 1.25 mg, about separate entity, those skilled in the art understand that, in 55 1.50 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, about practice, portions of the function provided by the memory 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.25 mg, about controller may actually reside in the circuitry associated with 3.5 mg, about 3.75 mg, about 4.0 mg, about 4.25 mg, about the main processor, main memory, and/or the auxiliary Stor 4.5 mg, about 4.75 mg, about 5.0 mg, about 5.25 mg, about age interface. 5.5 mg, about 5.75 mg, about 6.0 mg, about 6.25 mg, about Furthermore, the computer systems of the present inven 60 6.5 mg, about 6.75 mg, about 7.0 mg, about 7.25 mg, about tion may comprise a terminal interface that allows system 7.5 mg, about 7.75 mg, about 8.0 mg, about 8.25 mg, about administrators and computer programmers to communicate 8.5 mg, about 8.75 mg, about 9.0 mg, about 9.25 mg, about with the computer system, normally through programmable 9.5 mg, about 9.75 mg, about 10.0 mg, about 10.25 mg, about workstations. It should be understood that the present inven 10.5 mg, about 10.75 mg, about 11.0 mg, about 11.25 mg, tion applies equally to computer systems having multiple 65 about 11.5 mg, about 11.75 mg, about 12.0 mg, about 12.25 processors and multiple system buses. Similarly, although the mg, about 12.5 mg, about 12.75 mg, about 13.0 mg, about system bus of the preferred embodiment is a typical hard 13.25 mg, about 13.5 mg, about 13.75 mg, about 14.0 mg. US 8,173,626 B2 51 52 about 14.25 mg, about 14.5 mg, about 14.75 mg, about 15.0 active mental disorder; (X) presence of any contraindication mg, about 15.25 mg, about 15.5 mg, about 15.75 mg, about to mifepristone including adrenal insufficiency by history, 16.0 mg, about 16.25 mg, about 16.5 mg, about 16.75 mg, sickle cell disease, active liver disease (liver function tests about 17.0 mg, about 17.25 mg, about 17.5 mg, about 17.75 greater than 1.5 times upper range of normal), severe respi mg, about 18.0 mg, about 18.25 mg, about 18.5 mg, about ratory disease (PO2 saturation <92%), renal disease (serum 18.75 mg, about 19.0 mg, about 19.25 mg, about 19.5 mg, creatinine > 1.5 mg/dl), major blood clotting defect (signifi about 19.75 mg, about 20.0 mg, about 20.25 mg, about 20.5 cantly abnormal PT and PTT) and/or thromboembolic dis mg, about 20.75 mg, about 21.0 mg, about 21.25 mg, about ease (history of deep vein thrombosis or pulmonary embo 21.5 mg, about 21.75 mg, about 22.0 mg, about 22.25 mg. lus); (xi) current or recent (within the last three months) use of about 22.5 mg, about 22.75 mg, about 23.0 mg, about 23.25 10 oral systemic corticosteroids, hormones (including estro mg, about 23.5 mg, about 23.75 mg, about 24.0 mg, about gens, progestins, oral contraceptives), danazol, anticoagul 24.25 mg, about 24.5 mg, about 24.75 mg, about 25.0 mg. lants, or herbal or botanical supplements with possible hor about 25.25 mg, about 25.5 mg and about 25.75 mg. monal effects; (xii) use within the past six months of GnRH Embodiments of the present invention can also exclude analogs or Depo-ProveraR); and (xiii) current or planned use particular administration routes or dosage forms. For 15 during the study of any of the following medications or prod example, embodiments of the present invention can exclude ucts: , itraconazole, erythromycin, grapefruit one or more of oral administration, Sublingual administration, juice, rifampin, St. John's Wort, phenytoin, phenobarbital or buccal administration, nasal administration, transdermal carbamazepine administration, vaginal administration, rectal administration, Primary recruitment of subjects occurred through direct intravenous administration, Subcutaneous administration, advertising and physician referrals. Women who were Suc intraperitoneal administration, parenteral administration, cessfully prescreened were contacted by telephone and intramuscular administration, depot administration, topical invited to an Screening session?orientation. Prospective Sub administration, intrauterine administration, inhalation jects were provided with a verbal and written description of administration, implant administration and ocular adminis the study and requirements for participation. Written tration and/or one or more of tablets, capsules, cachets, dra 25 informed consent was obtained from each participant at the gees, pills, pellets, granules, powders, Solutions, emulsions, screening session/orientation, and medical record releases fluid emulsions, Suspensions, fluid Suspensions, semi-solids, were obtained and reviewed by the project gynecologist. Par ointments, pastes, creams, gels, jellies, foams, implants, ticipants who gave consent were assigned a study ID number patches and sprays. and asked to proceed further with the screening session. A Embodiments of the present invention can also exclude any 30 total of fifteen subjects enrolled in this 2.5 mg mifepristone combination of anti-progestational agents, conditions, dos study. During the screening session the following information ages, administration routes and/or dosage forms. was collected: Demographics: Name, address, phone number, primary EXAMPLES physician and/or gynecologist, date of birth, race, ethnicity, 35 occupation and years of completed education. Example 1 Medical history: Current and past medical conditions, medications and Supplements, hospitalizations, Surgery, 2.5 mg Mifepristone for the Treatment of allergies, tobacco, alcohol and illicit drug use. Gynecological Disorders Gynecologic history: Age of menarche, menstrual history, 40 gynecologic and obstetrical history, and questionnaires for A clinical study of the effectiveness of low doses of mife disease-specific and global health-related quality of life pristone, specifically 2.5 mg, for the treatment of uterine (HRQOL), bleeding and pain. leiomyomata was conducted. The study was conducted at a Physical Examination: Height, weight, blood pressure, single site in Rochester, N.Y. pulse readings, examination of the breasts, heart, lungs, abdo Subjects: Inclusion criteria for the study included that sub 45 men, and complete gynecologic examination including bi jects be (i) female; (ii) 18 years of age to premenopausal; and manual at Screening session?orientation (baseline). Height, (iii) willing and able to give informed consent and comply weight, blood pressure, pulse readings and examination of the with study requirements; and have (i) at least moderate symp breasts. toms of menorrhagia and/or pelvic pain/pressure; (ii) a total Pathology: All Subjects underwent endometrial sampling. uterine Volume greater than or equal to 160 cubic centimeters 50 Blood samples: Negative pregnancy test and normal liver (cc) by ultrasound measurement; (iii) at least one leiomyo function testing (ALT, AST), hemoglobin and FSH levels. mata 22.5 cm in size; (iv) a score of equal to or greater than Ultrasonography: All Subjects underwent abdominal and 39 on the Symptom and Quality of Life Scale: vaginal ultrasonography and uterine artery and leiomyomata (V) declined standard treatment options for symptomatic lei blood flow assessment. omyomata; and (vi) agreed to use a barrier method (condoms, 55 Specifically, uterine leiomyomata size was assessed by diaphragms) or other effective non-hormonal method of con transabdominal and/or transvaginal Sonography by a single, traception (abstinence, Sterilization) throughout participation certified and experienced ultrasonographer. Combined in the study. abdominal and vaginal ultrasonography was the standard for Exclusion criteria for the study included: (i) current or assessing leiomyomata size. Ultrasonography has been planned pregnancy during the study period; (ii) menopausal, 60 shown to be a reliable indicator of size when compared to as indicated by follicle-stimulating hormone (FSH) level of post-operative pathologic findings, (Levi et al., 55 Acta. the reference laboratory; (iii) currently breast-feeding; (iv) Obstet. Gynecol. Scand. 261-66 (1976): Fedele et al., 77 untreated abnormal pap Smear, (v) presence of conditions Obstet. Gynecol. 745-48 (1991)) and magnetic imaging other than leiomyomata contributing to pain and/or bleeding: (Dueholm et al., 186 Am. J. Obstet. Gynecol. 409-15 (2002)) (vi) hemoglobin (<9.0 mg/dl. (vii) presence of adnexal masses 65 and has been the standard for study of uterine leiomyomata. or tenderness requiring further evaluation or Surgery; (viii) Borgfeldt et al., 79 Acta. Obstet. Gynecol. Scand. 202-07 grade III or IV hydronephrosis by ultrasound; (ix) severe, (2002); Verspyck et al., 89 Eur. J. Obstet. Gynecol. Reprod. US 8,173,626 B2 53 54 Biol. 7-13 (2000): Nakayama et al., 13 Gynecol. Endocrinol. tation, a decrease in the occurrence and/or severity of pelvic 382-89 (1999): Fedele et al., 88 Eur. J. Obstet. Gynecol. pain, a decrease in the occurrence and/or severity of lower Reprod. Biol. 91-4 (2000); Weeks et al., 180 Am. J. Obstet. back pain, a decrease in the occurrence and/or severity of Gynecol. t-13 (1999); Zullo et al., 5 J. Am. Assoc. Gynecol. rectal pain, a decrease in the occurrence and/or severity of Laparoscop. 361-66 (1998); de Aloysio et al., 29 Maturitas pelvic pressure, a decrease in the occurrence and/or severity 261-64 (1998); Zullo et al., 178 Am. J. Obstet. Gynecol. of bladder pressure and a decrease in urinary frequency when 108-12 (1998); Scialliet al., 64. Fertil. Steril. 313-20 (1995); compared to baseline measures and Subjects receiving pla and Lumsden et al., 101 Br. J. Obstet. Gynaecol. 438-42 cebo. (1994). The uterus was measured in three planes and a total Volume was calculated. The three largest leiomyomata were 10 Example 3 evaluated and a volume calculated for each. Endometrial thickness was measured whenever possible in the true Sagittal 1.0 mg Mifepristone for the Treatment of plane. Adnexa including ovaries were assessed in three Gynecological Disorders planes, the Volume calculated and abnormal morphology documented. A limited examination of the kidneys was per 15 A clinical study of the effectiveness of a lower dose of formed to rule out hydronephrosis. Digital images were mifepristone for the treatment of uterineleiomyomata will be stored on a disc. conducted. The methods will be carried out in a manner that At the beginning of this study, all five subjects had bleeding is similar in all material respects to those described in to start with a mean bleeding period of 25 days. The mean Example 1 except that the subjects will be given 1.0 mg uterine volume was 795 cc with a mean leiomyomata volume mifepristone or placebo for six months. (aggregated) of 187. A total of about forty subjects will enrolled in the 1.0 mg After the screening session, mifepristone was provided to study. At the beginning of the study, all forty subjects will Subjects in 2.5 mg capsules at three-month intervals. (Athe have periods of extended bleeding, with larger than average nium Laboratories, the supplier of Mifeprex R for Danco uterine Volumes and mean leiomyomata Volumes. About Laboratories provided the mifepristone in powder form. 25 twenty subjects will be given 1.0 mg mifepristone to be taken From this powder form, gelatin capsules were produced by daily. The remaining Subjects will be given a placebo medi the project pharmacist with a dosage error range of +/-3% cation to be taken daily. (0.3 mg). “Investigational study med' was printed on the Following three months of daily administration of 1.0 mg labels and all medication containers were labeled with the mifepristone, on average, treated Subjects will show a FDA IND number, subject name, and address). Subjects were 30 decrease in blood loss, uterine Volume and uterine leiomyo asked to complete a monthly checklist indicating the preva mata size, improvements in Quality of Life Scores, and lence and subjective severity of symptoms that may be asso improvements in other symptoms including without limita ciated with treatment with 2.5 mg mifepristone. Severity of tion, a decrease in the occurrence and/or severity of pelvic vaginal bleeding was also assessed by the Subjects each day pain, a decrease in the occurrence and/or severity of lower throughout the course of the study using a pictorial chart. This 35 back pain, a decrease in the occurrence and/or severity of assessment of menstrual bleeding has been previously vali rectal pain, a decrease in the occurrence and/or severity of dated. Janssen et al., 85 Obstet. Gynecol. 977-82 (1995); pelvic pressure, a decrease in the occurrence and/or severity Higham et al., 97 Br. J. Obstet. Gynecol. 734-39 (1990). of bladder pressure and a decrease in urinary frequency when In-person assessments of Subjects were taken again after compared to baseline measures and Subjects receiving pla three months of treatment with 2.5 mg mifepristone in order 40 cebo. to take additional physical measurements and administer Following six months of daily administration of 1.0 mg questionnaires for comparison with screening session values. mifepristone, symptoms will continue to improve in treated Following three months of daily administration of 2.5 mg subjects. More treated subjects will show a decrease in blood mifepristone, all Subjects became amenorrheic. Uterine and loss, uterine Volume and uterine leiomyomata size and leiomyomata volume became 653 and 139 respectively. 45 improvements in Quality of Life Scores. Further improve These numbers represent a mean decrease of 19% and 26% ments in other symptoms including without limitation, a each. Leiomyomata shrinkage ranged from 17% to 48%. All decrease in the occurrence and/or severity of pelvic pain, a five subjects also increased their mean hemoglobin by one decrease in the occurrence and/or severity of lowerback pain, point from 11 mg/dl to 12 mg/dl. a decrease in the occurrence and/or severity of rectal pain, a 50 decrease in the occurrence and/or severity of pelvic pressure, Example 2 a decrease in the occurrence and/or severity of bladder pres Sure and a decrease in urinary frequency when compared to 5.0 mg Mifepristone for the Treatment of baseline measures and placebo controls will continue to be Gynecological Disorders seen. The study will thus demonstrate the effectiveness of 1.0 55 mg daily administration of mifepristone in treating uterine A study of the effectiveness of 5.0 mg mifepristone in the leiomyomata. treatment of gynecological disorders will be carried out in a As described previously, a number of other benign gyne manner that is similar in all material respects to the 2.5 mg cological disorders share symptoms and underlying causes study except that the subjects will be given 5.0 mg mifepris with uterine leiomyomata. For example, progesterone has tone or placebo for one month. A total of about 40 subjects 60 been implicated in a wide variety of medical conditions and will be enrolled in the study with about 20 receiving daily 5.0 disorders. Therefore, the doses of mifepristone described mg mifepristone and about 20 receiving placebo. When com herein likely will have similar beneficial effects in the treat pared to placebo controls, after one month of 5.0 mg mife ment of these common disorders including, without limita pristone administration, treated Subjects will show, on aver tion, premenstrual syndrome, premenstrual dysphoric disor age, a decrease in blood loss, uterine Volume and uterine 65 der, dysfunctional uterine bleeding, polycystic ovarian leiomyomata size, improvements in Quality of Life Scores, syndrome, adenomyomas, polymenorrhea, dysmenorrhea, and improvements in other symptoms including without limi severe dysmenorrhea, menorrhagia, breakthrough bleeding, US 8,173,626 B2 55 56 intermittent bleeding, endometriosis, ovarian cysts, irregular duction will be evaluated. In group 6 the effect of 5.0 mg withdrawal bleeding, hirsutism, iron deficiency anemia, acne, mifepristone on adrenal reserve will be evaluated. benign breast disease, catamenial symptoms, pelvic inflam Blood samples will be taken from the subjects at a screen matory disease, loss of bone density, endometriosis, breast ing session and then once a month for the six month duration cancer, ovarian cancer, uterine cancer and prostate cancer and 5 of the study. Hormone levels will be measured according to for its use in male contraception, anti-glucocorticoid effects methods well known to those of skill in the art. Specifically, or labor and delivery. for subjects in Groups 1, 3 and 5, estradiol and cortisol pro duction will be measured using commercially available kits. Example 4 For example, estradiol will be measured using the Macromo 10 lecular Structure Database (MSD(R) 17B estradiol assay Long-Term Comparison of Lupron(R), 2.5 mg or 5.0 according to the manufacturers instructions. Serum cortisol mg Mifepristone for the Treatment of Gynecological will be measured by RIA using a commercially available kit Disorders from ICN Biomedicals, Inc. (Costa Mesa, Calif.) according to the manufacturer's instructions. The results of this portion of A randomized long term study examining the effectiveness 15 the study will show that estradiol and cortisol levels of sub of Lupron(R), 2.5 mg and 5.0 mg mifepristone will be under jects given 2.5 mg or 5.0 mg mifepristone do not statistically taken. The methods will be carried out in a manner that is differ from those receiving placebo at any time point tested. similar in all material respects to those described in Example For subjects in Groups 2, 4 and 6, adrenal reserve will be 1 except that subjects will be 2.5 mg mifepristone daily for measured using an ACTH stimulation test. Specifically, Sub one year, 5.0 mg mifepristone daily for one year or will be jects will be stimulated with 250 lug ACTH intravenously as a given monthly intramuscular injections of Lupron Depot R. bolus injection after an overnight fast. Blood samples will be (7.5 mg). A total of about 50 subjects will be included in each drawn at 0, 30 and 60 minutes after this ACTH stimulation. treatment group. Measures will be obtained at the screening Serum cortisol levels will again be measured by ICN Bio session as described in Example 1 and after one year of medicals commercially available RIA kit according to the treatment with three month and six month follow up measure 25 manufacturers instructions. Peak serum cortisol levels of ments after all therapy has been discontinued. 550 nmol/L or greater will be considered a normal response. The results of this study will show that administration of The results of this portion of the study show that the cortisol Lupron DepotR) (7.5 mg), 2.5 mg mifepristone and 5.0 mg response in response to ACTH stimulation of Subjects given mifepristone all improve symptoms associated with gyneco either dose of mifepristone does not statistically differ from logical disorders. Specifically, and on average, Subjects will 30 those receiving placebo at any time point tested, and with the show a decrease in blood loss, uterine Volume and uterine exception of potential outliers in all groups, all Subjects show leiomyomata size, improvements in Quality of Life Scores, peak serum cortisol levels of at least 550 nmol/L. and improvements in other symptoms including without limi tation, a decrease in the occurrence and/or severity of pelvic Example 6 pain, a decrease in the occurrence and/or severity of lower 35 back pain, a decrease in the occurrence and/or severity of Long-Term Study of 2.5 mg Mifepristone for the rectal pain, a decrease in the occurrence and/or severity of Treatment of Gynecological Disorders pelvic pressure, a decrease in the occurrence and/or severity of bladder pressure and a decrease in urinary frequency when A long-term study evaluating 2.5 mg mifepristone in the compared to baseline measures. At the three month and six 40 treatment of gynecological disorders will be undertaken. month follow up time points, subjects who had received either Again, the methods will be carried out in a manner that is 2.5 mg or 5.0 mg mifepristone or Lupron Depot(R) (7.5 mg) similar in all material respects to those described in Example continue to show improvements, on average, over baseline in 1 except that administration of 2.5 mg mifepristone will con the previously described symptoms. The positive effects of tinue for two years. About 350 subjects will be enrolled in the 2.5 mg or 5.0 mg continue at a greater degree and/or for a 45 study. Measures will be taken at the screening session and longer period of time than the positive effects observed with every four months thereafter for 10 years. Thus, the study will Lupron Depot(R) (7.5 mg). address over time the effectiveness of 2.5 mg mifepristone during the two years of treatment and thereafter for an addi Example 5 tional eight years. Mifepristone treatment will begin about 1 50 week following the screening session with baseline cortisol Effect of 2.5 mg and 5.0 mg Mifepristone on measures taken at the screening session and Subjects coming Estradiol Production, Cortisol Production and in a week later for an ACTH stimulation baseline measure. Adrenal Reserve Mifepristone administration will begin the day following each subjects ACTH stimulation baseline measure. Long About 90 subjects meeting the inclusion and exclusion 55 term observational reports on fibroid reduction, maintenance criteria of Example 1 will be recruited with about 10 subjects of fibroid reduction, recurrent bleeding associated with dif included in each group to be described. Groups 1 and 2 will be ferent endometrial states, data regarding HRQOL, bleeding given daily placebo for six months. In Group 1, the effect of and pain will be compiled as described in Example 1. Uterine placebo on estradiol and cortisol production will be evalu leiomyomata size will be measured once a year. Additionally, ated. In group 2 the effect of placebo on adrenal reserve will 60 on one visit per year, basal cortisol levels will be measured as be evaluated. Groups 3 and 4 will be given daily 2.5 mg described in Example 5. On the second visit per year, adrenal mifepristone for 6 months. In Group 3, the effect of 2.5 mg reserve will be measured, as described in Example 5. At the mifepristone on estradiol and cortisol production will be end of the treatment period, subjects will be monitored for evaluated. In group 4 the effect of 2.5 mg mifepristone on normal menstrual function. adrenal reserve will be evaluated. Groups 5 and 6 will be 65 This study will demonstrate the effectiveness of 2.5 mg given daily 5.0 mg mifepristone for 6 months. In Group 5, the mifepristone as a long-term therapy for the treatment of gyne effect of 5.0 mg mifepristone on estradiol and cortisol pro cological disorders as well as the lack of adverse side effects US 8,173,626 B2 57 58 associated with this treatment. Specifically, subjects treated Example 8 with mifepristone will show, on average, a decrease in blood loss, uterine Volume and uterine leiomyomata size, improve Intermittent Mifepristone Therapy vs. Myomectomy ments in Quality of Life Scores, and improvements in other as Long-Term Treatments for Symptomatic Uterine symptoms including without limitation, a decrease in the 5 Leiomyomata occurrence and/or severity of pelvic pain, a decrease in the occurrence and/or severity of lower back pain, a decrease in A study evaluating the effectiveness of intermittent mife the occurrence and/or severity of rectal pain, a decrease in the pristone therapy (2.5 mg) against the effectiveness of myo occurrence and/or severity of pelvic pressure, a decrease in mectomy as a treatment for symptomatic uterine leiomyo the occurrence and/or severity of bladder pressure and a 10 mata will be undertaken. The methods described in Example decrease in urinary frequency when compared to baseline 1 will be used to recruit and enroll about 100 subjects into the measures. Improvements will remain after treatment with study. 50 of the 100 subjects will be given intermittent daily mifepristone is discontinued and for at least a Subset of Sub mifepristone (2.5 mg) meaning that Subjects will alternate jects, symptoms will not return to baseline levels throughout 15 between six months of daily mifepristone (2.5 mg) and 2 the duration of the follow up period. Regarding adrenal func months of no treatment for four years. The remaining 50 tion, subjects will not significantly statistically differ from Subjects will undergo myomectomy at the beginning of the baseline measures in basal cortisol levels or after stimulation study. with ACTH and normal menstrual function will begin after During the four years of this study, measurements will be treatment ends. taken every six months. The measurements will mirror those described in Example 1 in all material regards. The results of Example 7 the study will show that both groups of subjects show, on average, a decrease in blood loss, uterine Volume and uterine leiomyomata size, improvements in Quality of Life Scores, Effect of Long-Term 2.5 mg Mifepristone Therapy 25 and improvements in other symptoms including without limi on Endometrial Thickening as Measured by Electron tation, a decrease in the occurrence and/or severity of pelvic Microscopy pain, a decrease in the occurrence and/or severity of lower back pain, a decrease in the occurrence and/or severity of rectal pain, a decrease in the occurrence and/or severity of A study evaluating the effect of long-term daily 2.5 mg 30 mifepristone administration on endometrial thickening will pelvic pressure, a decrease in the occurrence and/or severity be undertaken. The methods described in Example 1 will be of bladder pressure and a decrease in urinary frequency when used to recruit and enroll about 20 subjects into the study. compared to baseline measures. These results will demon strate that intermittent mifepristone therapy provides a treat Before mifepristone treatment begins, biopsies from the ment option that is not significantly statistically different at endometrial cavity will be obtained using a curette. Biopsies 35 will be taken on day 2 of the menstrual cycle with daily the measures and time points taken from myomectomy, a far mifepristone treatment starting thereafter. Further biopsies more invasive procedure and treatment. will be taken and analyzed as described below about every 6 Example 9 months after treatment with mifepristone begins (always on 40 day 2 of the menstrual cycle) for 5 years of treatment. Mifepristone for Prevention of Breakthrough Biopsied tissues will be processed in a standardized man Bleeding in New Starters of ner as described in Dockery et al., 11 Hum. Reprod. 2251 Depo- Acetate (DMPA) 2256 (1996) and Dockery et al., 3 Hum. Reprod. 715-20 (1988b) which are incorporated by reference herein for their 45 The following study was conducted to primarily determine descriptions of tissue processing and related techniques. Spe if mifepristone lowers the incidence of abnormal break cifically, sections will be cut on Epcon blocks on a Reichert through uterine bleeding in new starters of the progestin OMU4 microtome using glass and diamond knives to a thick contraceptive injection depo-medroxyprogesterone acetate ness of about 70 nm. The sections will be picked up on copper (DMPA). The study also will test the effect of mifepristone on grids, stained with uranyl acetate and lead citrate for electron 50 the contraceptive ability of DMPA to prevent ovulation in microscopy and examined on a JEOL 100 microscope. Dur new starters of DMPA, will test the effect of mifepristone on ing electron microscopy, a systematic series of micrographs estradiol and progesterone receptor concentrations in the of endometrial cells will be taken at an initial magnification of endometrium of new starters of DMPA, and will test the effect X2000. The following sampling strategy will be used: 10 of mifepristone on the function of estrogen receptors in the fields of view from each of six micrographs per block (two 55 endometrium of new starters of DMPA. blocks per individual), giving 120 fields for each of the sub DMPA is an effective, widely used progestin-only contra jects. Measurements will be performed at X52000 and all ceptive injection that is administered about every 3 months. magnifications will be determined using a grating replica Unfortunately discontinuation rates as high as 40% have been with 2160 squares per mm. The volume fraction (Vv) of the reported during the first year of use due to the occurrence of nucleolus or NCS to the nucleus and the Vv of tubular com 60 breakthrough bleeding. ToppoZada et al. 28 Contraception ponents to the total channel system will be obtained by point 1-20 (1983). The number of days of vaginal bleeding between counting as described in Williams (6 Practical Methods for the first and second injection can be around 30% of days and Biological Microscopy 5-84 (1977)) which is incorporated 20% of days between the second and third injection. Tyler et herein for its description of point counting and related tech al., 21 Fertil. Steril. 469 (1970). Further, irregular or pro niques. The results of this study will demonstrate no statisti 65 longed bleeding has been reported in 90% of subjects during cally significant effects of long-term mifepristone treatment the first 3 months of DMPA versus 34% during the 9-12th on endometrial thickening at any time point. month of use. Newton et al. 14 (suppl 1).J. Obstet. Gynaecol. US 8,173,626 B2 59 60 1-34 (1994). Premature discontinuation of DMPA due to is poorly controlled; (XV) hyperSensitivity to study medica these problems can lead to unintended pregnancies and tions; (Xvi) concurrent use of other investigational medica increased public health costs. tions; (Xvii) significant anemia (hemoglobin (10.8 mg/dL); DMPA acts by Suppressing gonadotropin production at the and (Xviii) women who are post-partum or post-abortion who hypothalamic pituitary level and reliably blocks the midcycle have not had at least 2 regular periods. LH surge, thus preventing ovulation. Clark et al. 75 Fertil. After obtaining informed consent, study candidates under Steril. 871 (2001). Estrogen and progesterone receptors went a screening examination and laboratory tests similar to change during the menstrual cycle, and estrogen and proges those described in Example 1. Those who passed the initial screening tests underwent a baseline month in which one terone receptor isoforms have different effects on sex steroid biopsy was performed and urine collected to measure responsive genes depending on the molecular context. Elger 10 metabolites of progesterone in order to create ovulatory ref et al., 65 Steroids 713-723 (2000). Progestin-only contracep erence ranges. Subjects who were found to be ovulatory tives effect the expression of progesterone receptors depend based on serum progesterone and who tolerated the endome ing on which specific receptor isoform was bound. Progestin trial biopsies were randomized to study medication. Subjects only contraceptives and mifepristone effect the expression of will receive a total of 4 injections of DMPA (intramuscularly estrogen receptors. In one study, women on Norplant demon 15 once every 3 months) and return to the clinic every 14 days for strated increased endometrial estrogen receptor concentra twelve 28-day cycles to receive a dose of mifepristone or tion, decreased endometrial progesterone receptor concentra placebo. Subjects will undergo 3 additional biopsies over 12 tion and decreased breakthrough bleeding when administered cycles. Cervical mucus scores will be determined at the time mifepristone orally. Cheng et al., 15 Hum. Reprod. 1969 of each biopsy. Subjects will record daily bleeding, medica (2000). tions and side effect information on diaries for the duration of The effect of mifepristone on endometrial estrogen and the study. Blood will be drawn weekly for measurement of progesterone receptors has not been examined in women serum progesterone after the initial dose of DMPA. These using DMPA, the most common progestin-only contraceptive measurements will be done on a batched basis. The entire in the United States. If mifepristone is demonstrated to study will require 50 scheduled visits and the subjects will be decrease breakthrough bleeding in new starters of DMPA, it 25 compensated as follows: reimbursement for time, travel and may encourage more women to maintain DMPA use during out of pocket expenses at a rate of S25 for each of 44 brief the first 6 months when breakthrough bleeding is at a maxi visits, S50 for the initial and exit visit and S75 for each of 4 mum and therefore reduce the number of unintended preg biopsy visits for a total of S1500 for the 13 month study. nancies. Therefore, a study was conducted to gather data on Endometrial biopsies will be analyzed using PCR and the effect of mifepristone on breakthrough bleeding in new 30 immunohistochemistry to determine concentrations of estro Starters of DMPA. gen and progesterone receptor isoforms. A portion of the Subjects: Subjects were recruited from patients presenting biopsy material will be reserved for cell culture in order to for routine gynecological care. Inclusion criteria for the study determine proliferation assays as a marker of estrogen recep included that subjects be (i) female; (ii) 18-45 years; (iii) have tor function. a history of regular menstrual cycles (cycle length 21-35 35 The primary endpoint of the study will be the number of days); (iv) agree to exclusively use non-hormonal methods of days of breakthrough bleeding during the first 6 months of contraception Such as barrier methods or sterilization (tubal DMPA. Thus a 2-sided, 0.05-level, two-sided t-test will be sterilization or vasectomy) for the duration of the study; and used to compare the group of subjects receiving mifepristone (v) provide written, informed consent to participate in the to those receiving placebo. With 25 subjects in each of the two study. 40 arms, there will be 93% power to observe a statistically sig Exclusion criteria for the study included: (i) concomitant nificant difference between the two groups using a 2-sided, use of aminoglutethimide, carbamazepine, rifampicin, 0.05 level two-sample t-test. griseofulvin, barbiturates, phenytoin Sodium, Systemically Mifepristone was provided by Danco Laboratories. Danco administered steroids and thyroid hormones; (ii) undiagnosed Laboratories provided the pure mifepristone powder for the abnormal genital bleeding; (iii) any epithelial cell abnormal 45 study. Mifepristone capsules were prepared by a member of ity as reported in the Bethesda System except reactive repara the hospital pharmacy staff by weighing 50 mg of pure pow tive changes with atypical squamous cells of undetermined der and packing it into empty opaque gel capsules. Placebo significance (ASCUS); (iv) a well-documented history of a capsules contain powdered Sugar. An amount that approxi thrombotic event including stroke or, venous thromboembo mates the volume occupied-by 50 mg of mifepristone powder lism (deep venous thrombosis or pulmonary embolus). A 50 is packed into opaque gel capsules by a member of the hos history of superficial thrombophlebitis was not an exclusion pital pharmacy staff. criterion; (V) existing thromboembolic, cardiovascular or To date, the results show that based on 1148 and 1232 cerebrovascular disorder; (vi) cholestatic jaundice of preg women-days of observation in the placebo and mifepristone nancy or past history of jaundice with prior us of hormonal groups respectively, median percentage days of bleeding was contraception; (vii) current confirmed hypertension: defined 55 30% and 11% (p<0.05). Further, no adverse events have as systolic >160 mmHG or diastolic >90 mmHG. Normal occurred to date. Thus, this study has demonstrated the effec blood pressure on anti-hypertensive medication for previous tiveness of mifepristone as a treatment to inhibit break 6 months was allowed; (viii) DMPA injection within the prior through bleeding otherwise caused by DMPA. Other mea 6 months; (ix) oral contraceptive use within the past 3 Sures and results collection are on-going. months; (X) contraceptive implants within the past 6 months; 60 (xi) IUD use within the past 3 months; (xii) heavy smoking Example 10 (>10 cigarettes per day); (xiii) active or history of hepatic or renal disease. Hepatic disease is defined as having an AST/ Low Dose Mifepristone Administered After Birth SGOT and/or ALT/SGPT 2.5 times upper limit of normal Control Pills and/or total bilirubin >2.0 mg/dL; renal disease is defined as 65 having a creatinine > 1.8 mg/dL (xiv) insulin dependent dia Birth control pills can be used as a treatment for severe betes mellitus or non-insulin dependent diabetes mellitus that dysmenorrhea, polymenorrhea and dysfunctional uterine US 8,173,626 B2 61 62 bleeding (DUB). While birth control pills can be effective at tion. Moreover, any one or more features of any embodiment reducing the symptoms associated with these conditions, they of the invention can be combined with any one or more other are not effective in some subjects. The following study will be features of any other embodiment of the invention, without conducted to confirm that a low dose of mifepristone can be departing from the scope of the invention. effective to reduce the symptoms associated with these con ditions when treatment with birth control pills has failed to Example 11 provide adequate relief. Subjects: Subjects with severe dysmenorrhea, polymenor 5 mg Daily Mifepristone for the Treatment of rhea or DUB will be recruited through direct advertising and Symptomatic Uterine Leiomyomata physician referrals. A total of 240 subjects will be included in 10 the study. Eighty subjects will have severe dysmenorrhea, A randomized, double-blinded, placebo-controlled study eighty Subjects will have polymenorrhea and eighty Subjects was carried out on the effectiveness of mifepristone, 5 mg will have DUB. All subjects will have undergone previous daily for 6 months, for treating uterine leiomyomata and its treatment for their respective condition with the use of birth related symptoms, including quality of life, bleeding, uterine control pills, the birth control pills providing inadequate relief 15 of symptoms. At the time of entering the study, Subjects will and leiomyoma size, and pain. The Study and Results are have stopped taking birth control pills as a treatment for their described in Fiscella et al., Obstetrics & Gynecology, 108(6) symptoms within the previous about 30 days. Of the eighty (2006), hereby incorporated by reference in its entirety. Eli subjects with each condition, twenty will receive placebo, gible Study Subjects included premenopausal women 18 twenty will receive 1.0 mg mifepristone, twenty will receive years of age or older who reported at least moderately severe 2.5 mg mifepristone and twenty will receive 5.0 mg mifepris leiomyoma-related symptoms (more than 39 on the Uterine tone manufactured and treated as described in Example 1. No Fibroid Symptom Quality of Life Symptom Severity Sub other medications will be taken by the subjects during the scale), had a total uterine Volume by vaginal and abdominal assessment period. ultrasound 160 mL or more and at least one leiomyoma that For polymenorrhea and DUB subjects, severity of vaginal 25 was 2.5 cm or larger, had not used short-acting hormones in bleeding will be assessed by the subjects each day throughout the past 3 months, and had not used gonadotropin-releasing the course of the study using a pictorial chart. As stated hormone analogues or other long-acting hormonal medica earlier, this assessment of menstrual bleeding has been pre tions in the past 6 months. Women were excluded if they were viously validated. Janssen et al., 85 Obstet. Gynecol. 977-82 pregnant or intended to become pregnant during the next 6 (1995); Higham et al., 97 Br. J. Obstet. Gynecol. 734-39 30 months or had major medical morbidity or severe anemia, (1990). For severe dysmenorrhea subjects, severity of disabil active mental illness, elevated liver enzymes, or Substance ity will be self-evaluated both just before the onset of and abuse. Participants agreed to use barrier contraception and during menstruation using a 6-point scale (0: no disability; 1: not to use hormonal or Surgical treatments for leiomyomata mild disability: 2: moderate disability; 3: strong disability; 4: during the course of the trial. Analgesic use was permitted. severe disability: 5: no activity possible) three times a day. All 35 Using design 42 Study Subjects were randomly assigned to subjects will also rate the occurrence or severity of any take either 5 mg mifepristone daily or a placebo, with twenty unpleasant effects of mifepristone administration daily two were randomized to treatment and 20 to placebo. Out throughout the course of the study using a 4-point scale (0: no comes were assessed using mean change in leiomyoma-spe unpleasant effects; 1: mildly unpleasant effects; 2: moder cific overall quality of life (Uterine Fibroid Symptom Quality ately unpleasant effects; 3: Strongly unpleasant effects). The 40 of Life) scale 1-100 as the primary outcome, which includes study will be conducted over about a six month period. For secondary scales to measure perceived impact of leiomyo inclusion in the severe dysmenorrhea portion of the study, a mata on activities of daily living, general concern and worry, patient must have self-evaluated with a score of three or above energy and mood, sense of self-control, self-consciousness, for at least two menstrual cycles before entering the study. and sexual functioning. Secondary measures included global The study demonstrates the usefulness of low doses of 45 health status (Medical Outcomes 36-item Short Form SF-36 mifepristone, including 1.0 mg, 2.5 mg and 5.0 mg in reduc survey) and global pain (McGill Pain Questionnaire). Each ing the symptoms associated with severe dysmenorrhea, questionnaire was administered at baseline, 1 month, 3 polymenorrhea or DUB after treatment with birth control months, and 6 months, except the McGill Pain Questionnaire, pills has failed to adequately treat the symptoms of these which was assessed monthly. Bleeding was assessed by using conditions. Regarding potential adverse effects of these doses 50 daily menstrual logs and pictorial bleeding charts. A monthly of mifepristone, there are no significant differences between blood loss index was calculated from menstrual history by the groups receiving any of the doses of mifepristone as assigning values 1-4 to each day of spotting, indicating light, compared to placebo. Thus, this study demonstrates that the moderate, and heavy flow, respectively, and then Summing administration of low doses of mifepristone are effective at the results. Monthly assessments of the presence and intensity reducing the occurrence or severity of symptoms associated 55 of likely leiomyoma symptoms (including pelvic pain, pelvic with severe dysmenorrhea, polymenorrhea or DUB and is pressure, bladder pressure, urinary frequency, low back pain, also well-tolerated by subjects at the test doses. rectal pain, and pain with intercourse) and drug adverse These data demonstrate that the present invention provides effects (including hot flushes, headache, nausea, vomiting, low dosage anti-progestational agent treatment and/or treat mood Swings, diarrhea, decreased libido, weakness, fatigue, ment with an anti-progestational agent for a shorter period of 60 and nervousness) were performed with a standardized instru time than previously known in the art. ment consisting of 5-point Likert Scale items. Uterine Volume The terms and expressions which have been employed and leiomyoma size and number were assessed by vaginal herein are used as terms of description and not of limitation, and/or abdominal ultrasonogram (depending on leiomyoma and there is no intention in the use of such terms and expres size) at baseline, 1 month, 3 months, and 6 months. The uterus sions of excluding equivalents of the features shown and 65 was measured in three planes and a total Volume calculated. described, or portions thereof, it being recognized that vari The five largest leiomyomata were identified, a volume cal ous modifications are possible within the scope of the inven culated for each of the leiomyomata, and the results Summed. US 8,173,626 B2 63 64 Baseline uterine volume was subtracted from each subse rectal pain, and pain with intercourse all showed improve quently measured uterine Volume, and Volume changes were ments in the treatment group, but not in the placebo group. analyzed. However, group differences were statistically significant only The final analysis was powered to detect a 25-point differ for pain with intercourse (P<0.05) and marginally significant ence in mean Uterine Fibroid Symptom Quality of Life 5 for pelvic pressure (P=0.06). scores. Differences in Uterine Fibroid Symptom Quality of Potential medication adverse effects were uncommon in Life scores, ultrasound measures, bleeding, pain, and other both groups. Neither the incidence nor severity of adverse longitudinal measures were assessed by using individual effects, including headache, nausea, vomiting, mood Swings, growth curve models. Independent variables included in each diarrhea, decreased libido, weakness, fatigue, hot flushes, and model were treatment group, month, and an interaction term 10 nervousness, statistically differed between the two groups. for treatment group and month (used to assess whether the Rates of women were higher among the placebo group treatment effect of mifepristone changed with time). (P<0.01). None of the participants showed abnormal liver Approximate t tests were used to test hypotheses of between function during the study. Analgesic use did not differ group and within-group differences in outcomes. between groups. No endometrial hyperplasia or other signifi Mean Uterine Fibroid Symptoms Quality of Life lei 15 cant endometrial pathology was observed during the study. omyoma-specific quality of life measures were similar Higher rates of a characteristic pattern of cystic glandular between groups at baseline. Significant improvements were dilatation were noted among the endometria of treated seen in the treatment group compared with the placebo group WOC. for leiomyoma-specific quality of life (P<0.001; FIG. 2) and At the end of the study, 19 of 20 (95%) women in the aspects including concern (P<0.001), activities (P<0.001), treatment group correctly guessed that they had been receiv energy and mood (P=0.009), control (P=0.02), self-con ing mifepristone. The remaining woman said she was unsure. sciousness (P=0.008), and sexual functioning (P=0.03). By 6 Of the 17 women in the placebo group who finished the trial, months, mean Uterine Fibroid Symptoms Quality of Life 9 (53%) correctly guessed they were not receiving the drug. 4 measures increased by an average of 50.1 of a possible 100 (24%) guessed that they had been receiving the drug, and 4 points (range 0-86), or 135%, and by 16.7 points (range 25 (24%) said they were unsure. The difference between these 14-73) among placebo controls, or a 41%. Symptom severity two groups in correct guesses is significant (Fisher exact test; decreased significantly in both the treatment and placebo P=0.007). groups, but the 6-month scores showed a significantly greater Thus, treatment with mifepristone 5 mg daily for 26 weeks decline among women receiving the treatment (67 to 21) than Substantially improved leiomyoma-specific related quality of among women receiving placebo (67 to 50). 30 life and bleeding and reduces uterine Volume and leiomyoma Treatment with mifepristone was also associated with size among women with symptomatic leiomyomata. Most of improvements in energy and fatigue, health status change, the improvement in symptoms and quality of life occurred and pain based on SF-36 subscales, but not for physical func during the first 8-12 weeks of treatmentalthough reduction in tioning, physical health, emotional health, emotional well uterine and leiomyoma Volume continued to 6 months. Com being, social functioning, or general health. Bleeding 35 parable benefits were seen in African-American and white decreased markedly among women in the treatment group but women although power to detect differences by Subgroup was not in the placebo group. By the sixth month, 9 of 22 (41%) limited. Notably, the magnitude of improvement in quality of women in the treatment group had become amenorrheic, life (using the same measure) was comparable with that compared with none of the women in the placebo group. reported in observational studies of uterine artery emboliza Mean blood loss index values were significantly lower in the 40 tion. No improvements were noted using global measures of treatment group (P<0.001; FIG. 3). Treatment had a signifi pain (McGill Pain Questionnaire) or global physical or men cant effect on mean hemoglobin levels (P<0.001); mean tal health status (SF-36) suggesting that benefits of the drug hemoglobin levels increased in the treatment group from 12.0 were confined primarily to leiomyoma-specific symptoms. to 13.5 g/dL (P<0.001) and decreased in the placebo group The drug was well tolerated, as evidenced by low dropout from 12.2 to 11.6 g/dL (P=0.11). Anemia, defined as hemo 45 rate and absence of appreciable difference in adverse effects globin levels below 12.0 g/dL, was present in 11 of 22 (50%) between treatment and control groups. No case of endome women in the treatment group and in 9 of 20 (45%) women in trial hyperplasia was noted in this study. the placebo group at baseline (Fisher exact test; P-0.05). What is claimed is: After six months of treatment, 2 of 22 (9%) women in the 1. A method of treatment comprising administering an treatment group and 12 of 20 (60%) women in the control 50 anti-progestational agent to a patient in an amount of about group were anemic (Fisher exact test; P-0.001). 3.75 mg or less to treat uterine leiomyomata, wherein the The treatment group reported decreases in pain as mea anti-progestational agent is mifepristone. sured by the McGill Pain Questionnaire (FIG. 4), but group 2. The method of claim 1, wherein said anti-progestational differences compared with the placebo group did not reach is administered to the patient for less than one month. statistical significance. 55 3. The method of claim 1, wherein said amount is about 2.5 Uterine volume (FIG. 5) decreased an average of 200 mL mg or less. among treatment group women (P=0.02) and increased an 4. The method of claim 1, wherein said amount is about average of 73 mL in the placebo group (P=0.37). The effect of 1.25 mg or less. treatment on mean uterine Volume was highly significant 5. The method of claim 1, wherein said anti-progestational (P<0.001). A secondary regression of uterine volume 60 agent is administered after the conclusion of treatment with a adjusted for individual baseline volume indicated that uterine GnRh analogue. Volumes decreased an average of 47% in the treatment group 6. The method of claim 1, wherein said anti-progestational and increased an average 10% in the placebo group. Similar agent is administered after the conclusion of a treatment and statistically significant differences in reduction in lei selected from the group consisting of myomectomy, uterine omyoma size were noted between groups. 65 artery embolization, and ultrasound therapy. Monthly reports of symptoms including pelvic pain, pelvic 7. The method of claim 1, wherein said anti-progestational pressure, bladder pressure, urinary frequency, low back pain, agent is administered prior to a Surgical treatment. US 8,173,626 B2 65 66 8. The method of claim 7, wherein said surgical treatment 26. The dosing regimen of claim 20, wherein said anti is selected from the group consisting of hysterectomy, myo progestational agent is directed to be administered prior to a mectomy, uterine artery embolization and endometrial abla Surgical treatment. tion. 27. The dosing regimen of claim 20, wherein said anti 9. The method of claim 1, wherein said anti-progestational progestational agent is directed to be administered to shrink agent is administered prior to labor and delivery. uterine leiomyomata before a Surgical treatment. 10. The method of claim 1, wherein said anti-progesta 28. The dosing regimen of claim 27 wherein said surgical tional agent is administered daily. treatment is selected from the group consisting of hysterec 11. The method of claim 1, wherein said anti-progesta tomy, myomectomy, uterine artery embolization and tional agent is administered by a route selected from the group 10 endometrial ablation. consisting of oral administration, Sublingual administration, 29. The dosing regimen of claim 20, wherein said anti buccal administration, nasal administration, transdermal progestational agent is directed to be administered prior to administration, vaginal administration, rectal administration, labor and delivery. intravenous administration, Subcutaneous administration, 15 30. The dosing regimen of claim 20, wherein said anti intraperitoneal administration, parenteral administration, progestational agent is directed to be administered daily. intramuscular administration, depot administration, topical 31. The dosing regimen of claim 20, wherein said anti administration, intrauterine administration, inhalation progestational agent is directed to be administered intermit administration, implant administration and ocular adminis tently. tration. 32. The dosing regimen of claim 20, wherein said anti 12. The method of claim 1, wherein said anti-progesta progestational agent is directed to be administered by a route tional agent is administered in a dosage form selected from selected from the group consisting of oral administration, the group consisting of a tablet, a capsule, a cachet, a dragee, Sublingual administration, buccal administration, nasal a pill, pellets, granules, a powder, a solution, an emulsion, a administration, transdermal administration, vaginal adminis fluid emulsion, a suspension, a fluid Suspension, a semi-solid, 25 tration, rectal administration, intravenous administration, an ointment, a paste, a cream, a gel, a jelly, a foam, an implant, Subcutaneous administration, intraperitoneal administration, a patch and a spray. parenteral administration, intramuscular administration, 13. The method of claim 12, wherein said dosage form is a depot administration, topical administration, intrauterine Sustained release dosage form. administration, inhalation administration, implant adminis 14. The method of claim 1, wherein said patient is a pre 30 tration and ocular administration. menopausal female over the age of 18. 33. The dosing regimen of claim 20, wherein said anti 15. The method of claim 1, wherein said patient has at least progestational agent is directed to be administered in a dosage one uterine leiomyomata that is 22.5 cm in size. form selected from the group consisting of a tablet, a capsule, 16. The method of claim 1, wherein said patient has a total a cachet, a dragee, a pill, pellets, granules, a powder, a solu uterine volume of 160 cc. 35 tion, an emulsion, a fluid emulsion, a Suspension, a fluid 17. The method of claim 1, further comprising administer Suspension, a semi-solid, an ointment, a paste, a cream, a gel, ing a maintenance dose of said anti-progestational agent to a jelly, a foam, an implant, a patch and a spray. said patient in an amount of about 2.5 mg or less after admin 34. The dosing regimen of claim 33, wherein said dosage istering said anti-progestational agent in an amount of about form is a Sustained release dosage form. 3.75 mg or less. 40 35. The dosing regimen of claim 20, wherein said patient is 18. The method of claim 17, wherein said maintenance a pre-menopausal female over the age of 18. dose is in an amountless than or equal to 50% of said amount 36. The dosing regimen of claim 20, wherein said patient of about 3.75 mg or less. has at least one uterine leiomyomata that is 2.5 cm in size. 19. The method of claim 17, wherein said anti-progesta 37. The dosing regimen of claim 20, wherein said patient tional agent in an amount of about 3.75 mg or less is admin 45 has a total uterine volume of 2160 cc. istered for less than one month. 38. The dosing regimen of claim 20, further comprising 20. A dosing regimen comprising directing an anti-proges directing a maintenance dose of said anti-progestational tational agent to be administered to a patient in an amount of agent to be administered to said patient in an amount of about about 3.75 mg or less per day to treat uterine leiomyomata, 2.5 mg or less after administering said anti-progestational wherein the anti-progestational agent is mifepristone. 50 agent in an amount of about 3.75 mg or less. 21. The dosing regimen of claim 20, wherein said anti 39. The dosing regimen of claim 38, wherein said mainte progestational agent is directed to be administered for less nance dose is directed to be administered in an amount less than one month. than or equal to 50% of said amount of about 3.75 mg or less. 22. The dosing regimen of claim 20, wherein said anti 40. The method of claim 38, wherein said anti-progesta progestational agent is directed to be administered in an 55 tional agent in an amount of about 3.75 mg or less is directed amount of about 2.5 mg or less. to be administered for less than one month. 23. The dosing regimen of claim 20, wherein said anti 41. A business method comprising the step of providing to progestational agent is directed to be administered in an a consumeran anti-progestational agent in equivalent dosage amount of about 1.25 mg or less. units of about 3.75 mg or less and a dosing regimen wherein 24. The dosing regimen of claim 20, wherein said anti 60 said dosing regimen directs said anti-progestational agent to progestational agent is directed to be administered after the be administered to a patient to treat uterine leiomyomata, conclusion of treatment with a GnRh analogue. wherein said anti-progestational agent is mifepristone and 25. The dosing regimen of claim 20, wherein said anti wherein said dosing regimen directs said anti-progestational progestational agent is directed to be administered after the agent to be administered in an amount of about 3.75 mg or less conclusion of a treatment selected from the group consisting 65 per day. of myomectomy, uterine artery embolization, and ultrasound 42. The business method of claim 41, wherein said anti therapy. progestational agent is provided in equivalent dosage units of US 8,173,626 B2 67 68 about 2.5 mg or less, and said dosing regimen directs said tered to the patient as a maintenance dose in an amount of anti-progestational agent to be administered in an amount of about 2.5 mg or less after administering said anti-progesta about 2.5 mg or less. tional agent in an amount of about 3.75 mg or less. 43. The business method of claim 41, wherein said anti 46. The business method of claim 45, wherein said dosing progestational agent is provided in equivalent dosage units of regiment directs said anti-progestational agent in an amount about 1.25 mg or less of said anti-progestational agent, and of about 3.75 mg or less and said maintenance dose in an said dosing regimen directs said anti-progestational agent to amount of about 2.5 or less to be administered daily. be administered in an amount of about 1.25 mg or less per day. 47. The business method of claim 45, wherein said anti 44. The business method of claim 41, wherein said anti progestational agent is provided as a first set of equivalent progestational agent is provided in an amount of less than 10 dosage units, each comprising about 3.75 mg or less of said about 40 dosage units, and said dosing regimen directs said anti-progestational agent, and a second set of equivalent dos anti-progestational agent to be administered for less than one age units, each comprising about 2.5 mg or less of said anti month. progestational agent. 45. The business method of claim 41, wherein said dosing regimen directs said anti-progestational agent to be adminis UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. : 8,173,626 B2 Page 1 of 1 APPLICATIONNO. : 1 1/715509 DATED : May 8, 2012 INVENTOR(S) : Richard Hausknecht It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

Claim 16, column 65, line 35: “uterine Volume of 160 cc should read -- uterine Volume of > 160 cc --.

Claim 36, column 66, line 43: “has at least one uterine leiomyomata that is 2.5 cm in size should read -- has at least one uterine leiomyomata that is > 2.5 cm in size --.

Signed and Sealed this Twenty-sixth Day of June, 2012

David J. Kappos Director of the United States Patent and Trademark Office