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Compositions and treatment methodsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Cyclopentanohydrophenanthrene Ring System Doai, Oxygen Double Bonded To A Ring Carbon Of The Cyclopentanohydrophenanthrene Ring System, Oxygen Single Bonded To A Ring Carbon Of The Cyclopentanohydrophenanthrene Ring SystemCompositions and treatment methods description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060079492, Compositions and treatment methods. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE [0001] U.S. Provisional Patent Application, Ser. No. 60/617,293, filed Oct. 8, 2004, entitled "Use of Dienogest in Fixed Extended Cycle Hormonal Contraceptives", describes the invention, which is described in the specification hereinbelow and claimed in the claims appended hereinbelow, and provides the basis for a claim of priority for the instant invention under 35 U.S.C. 119 (e). BACKGROUND OF THE INVENTION [0002] 1. The Field of the Invention [0003] The present invention relates to a method for female hormonal contraception, which involves use of dienogest in fixed extended cycle hormonal contraceptives to avoid the bleeding problems associated with continuous use of hormonal contraceptives with other progestins and schedules. [0004] 2. Related Art [0005] The first large study based on a fixed extended oral contraceptive regimen (i.e. 90 days cycle=84 days of active pills followed by 6 hormone-free (placebo pills)) was published by Loudon and his colleagues in 1977 (British Medical Journal, 1977; 2: 487-490). In this study a monophasic oral contraceptive [50 .mu.g Ethinyl estradiol (EE)/2.5 mg lynestrenol] was used. Despite the high EE dosage intermenstrual bleeding was observed during the extended cycles in a notable number of women, which decreased with each 90-day cycle. Twenty seven percent of the patients experienced intermenstrual spotting and breakthrough bleeding during the first three-month cycle, which decreased to 4% (spotting only) in the fourth extended cycle. Intermenstrual bleeding accounted for 11% of the dropouts from the study. [0006] Seventeen years later a prospective study of continuous use of 30 .mu.g EE+150 .mu.g LNG (NORDETTE.RTM.) over 84 days followed by one week of placebo was published by Kovacs, et al (The British Journal of Family Planning, 1994; 19: 274-275). Of the 203 women who entered the study only 59 (29.1%) completed 12 months of treatment (4.times.84+7 days). The most frequent reasons for discontinuation were breakthrough bleeding in 73 patients (50.7%) and breast tenderness and headaches in 31 patients (21.5%) each. The dropout rate was highest during the first extended cycle (13 weeks) in which 34.5% (n=70) of the enrolled women were lost while the dropout rate in the second to fourth extended cycle (26, 39+52 weeks) amounted to 21.8% (43), 12.3% (25) and 3.0% (6) respectively. The authors stated that even though the ability to decrease the incidence of menstruation was appreciated by many women this was negated to some degree by the high incidence of breakthrough bleeding. [0007] Hodgen disclosed a corresponding fixed regimen for oral contraceptive use, which should maintain efficacy while providing enhanced control of endometrial bleeding (U.S. Pat. No. 5,898,032). In addition to less menstrual bleeding and patient anemia, higher compliance rates and more lifestyle convenience for patients are listed as advantages of this method. According to the claims, a monophasic combination of an estrogen and progestin is continuously administered for 60-110 consecutive days followed by 3-10 days of no administration. The claimed daily amounts of estrogen and progestin are equivalent to 5-35 .mu.g EE and 0.025-10 mg of norethindrone acetate (NETA). [0008] Other progestins like levonorgestrel (LNG), desogestrel (DSG) or 3-keto-desogestrel are also described (not including dienogest). The weight ratio of the two active ingredients (estrogen: progestin) is disclosed to be at least 1:45 and preferably at least 1:50. [0009] A respective fixed extended 91-day OC (oral contraceptive) regimen (84 days active+7 days placebo) was tested for the first time in a phase III multi-center 1-year trial versus a normal 28-day cycle (21 days active+7 placebo pills) by Anderson, et al, (Contraception, 2003; 68: 89-96). The extended cycle regimen (30 .mu.g EE/150 .mu.g LNG each, SEASONALE.RTM., Barr Laboratories) was found to result in a greater number of unscheduled (breakthrough) intermenstrual bleeding amounting to 37.6 days compared to 18.3 days for the 28-day regimen. Most notably the total days of bleeding unscheduled+scheduled (=menstrual bleeding) during the study year (364 days) were 48.2 days for the extended cycle compared to 50.8 days for the standard cycle. It is reported that for the extended cycle breakthrough bleeding (BTB) decreased with each successive cycle (84+7 each) from a median of 12 days during cycle 1 to a median of four days during cycle 4. [0010] The most common reasons given for study discontinuation were bleeding, increased weight, mood swings and acne (=adverse events). Discontinuation due to unacceptable bleeding accounted for 7.7% of the 91-day regimen patients compared to 1.8% in the 28-day regimen group. The total dropout rates amounted to 40.6% and 28.8% respectively. In the Clinical Review of NDA 21-544 (Sep. 4, 2003) for SEASONALE.RTM. besides the results for SEASONALE.RTM. also results for SEASONALE.RTM. Ultra-Lo (20 .mu.g EE/100 .mu.g LNG daily) are reported. It was observed that the fixed (84+7 days) extended regimen with a lower EE dose results in an even worse bleeding control. [0011] In a 12-months randomized multi-center study the acceptance of extended use (63+7 (pill-free) days) of a monophasic oral contraceptive with 30 .mu.g EE and 150 .mu.g desogestrel was studied by Cachrimanidou in comparison to the corresponding standard cycle product (21+7) (Contraception, 1993, 48: 205-216). Breakthrough bleeding was found to be significantly more frequent in the extended cycle (n=198) group compared to the standard cycle group (n=96). Correspondingly more women on the extended cycle product discontinued the study for bleeding problems (13% versus 2%, P<0.01). In both groups intermenstrual bleeding (breakthrough and spotting) decreased over time. Women who were already using oral contraceptives when they started the study had significantly fewer episodes of intermenstrual bleeding compared to starters. [0012] According to the authors a relatively large number of women withdrew from the trial without medical reasons (17.2% extended, 15.6% standard cycle). [0013] Hesch (U.S. Pat. No. 6,500,814) discloses a low dose extended cycle product/regimen, which according to the inventor surprisingly ensures high contraceptive reliability and prevents intermenstrual bleeding. Additionally a reduction in oral contraceptive related side effects (e.g. thrombosis) and a favorable effect on the pre-menstrual syndrome (PMS) are described. Furthermore prophylaxis and treatment of breast cancer are possible with the product according to the invention. Hesch claims continuous and uninterrupted administration of a combined hormonal contraceptive for a period of greater than 110 days. Various natural or synthetic estrogens and progestins (not including dienogest) are described. When EE is used its dosage is claimed to be between 1-20 .mu.g/day. [0014] Kulmann (WO 02/22110) discloses another process for hormonal contraception, which reduces the number of withdrawal bleedings while ensuring reliable contraception. The process is characterized by a sequence of successive extended cycles (="taking periods") with increasing duration. Thus for example the patient may start with one taking period of 21 active tablets followed by 7 placebos (21/7) which is followed by a taking period of n.times.42/7. With the exception of the final taking period the duration of all prior periods is predetermined (fixed). According to the invention it is also possible to successively reduce the hormone dosage (various disclosed progestins including dienogest and/or estrogens) between taking periods. [0015] Sulak, et al. (Am J. Obstet. Gynecol, 2002; 186:1142-1149) retrospectively studied the acceptance of extended cycle use in a larger number of patients with hormone withdrawal symptoms. Patients were allowed to alter their standard 21+7 regimen by extending a specific number of weeks such as 6, 9 or 12 or extending until breakthrough bleeding or spotting developed, stopping for 3-7 days and resuming. If they completed 12 weeks of active pills and wished to continue without a hormone-free break they were allowed to do so. All patients were prior pill users taking monophasic pills with 30-35 .mu.g ethinyl estradiol and one of the following progestins: norethindrone, levonorgestrel, norgestimate or desogestrel. Of the 267 patients who initiated the extended cycle regimen 57 (21%) chose to stop using oral contraceptives for various reasons like worsening of side effects including nausea, headache, acne, leg cramps, high blood pressure, yeast infections, breakthrough bleeding and PMS (24 patients) and a desire for pregnancy (13 patients). Of the 210 patients who continued to use OCs, 38 (18%) chose to return to the standard 21/7 regimen most commonly due to breakthrough bleeding (11 patients), breakthrough spotting (9) and heavy withdrawal bleeding (2 patients). [0016] Zahradnik and Moore (in: Elstein, M., "Extragenital Effects of Oral Contraceptives", Carnforth: Parthenon Publishers, 1997; pp 53-60) studied the contraceptive efficacy, cycle stability, tolerability and compliance of a new standard cycle (21+7 (tablet-free interval)) contraceptive containing 30 .mu.g EE+2 mg dienogest (VALETTE.RTM.). It was found that the severity and quantity of intermenstrual bleeding, spotting and breakthrough bleeding decreased during the course of the one year phase III study (12 cycles). Additionally a pronounced effect on the severity of dysmenorrhea was found which disappeared nearly completely during the study. These effects on bleeding were regarded as highly relevant for the good acceptance of this low-dose oral contraceptive. [0017] Continuous use of VALETTE.RTM. (30 .mu.g EE+2 mg dienogest) over 189 days followed by a hormone-free interval of seven days has been studied in 30 women in a private gynecological practice (Wiegratz, et al., Contraception, 2004; 69: 37-42)). Subsequently the women were treated for three standard cycles (21+7 days). Irregular bleeding (BTB+spotting) as well as hormone-related symptoms were recorded in daily diaries. [0018] Irregular bleeding occurred in 40% of the treated women just once while 17% recorded more than two episodes. During the second cycle of treatment (day 21-42) 53% of the women recorded irregular bleeding (mostly spotting) while during the fourth cycle (day 63-84) only 10% still recorded bleeding. Most of the women who had more than two bleeding episodes were first-time users (starters). The lowest bleeding rate was observed during the fifth cycle (3%), which increased to 17% during days 147-168 (cycle 8). Only 50% of the treated women experienced withdrawal bleeding (menstruation) during the 7 day hormone-free interval following the 189 day extended cycle. [0019] All women completed the 189-day extended OC treatment. However, only 18 women (60%) chose to continue the extended regimen while 4 (13%) women each either returned to the normal cycle use or switched to another OC. In the same publication Wiegratz, et al., reported the findings of a survey among German women and gynecologists regarding their attitude towards long-cycle treatment with oral contraceptives. It was found that only 26-35% of the surveyed women between the age of 15 and 49 years wished to have regular menstrual cycles (once a month) while 5-15% preferred 4 menstruations per year. Only 11-14% of women are willing to suppress menstruation continuously or for a prolonged period of time while 32-54% would suppress menstrual bleeding only sporadically. Reasons for not using extended cycle OCs included fear of pregnancy (43-72%) and fear of adverse effects (50-62%). [0020] According to the prior art in the field of extended cycle regimens (see above) it was assumed that stable fixed extended cycles (i.e. acceptable bleeding control) could be obtained and maintained even during the first year of continuous oral contraceptive administration irrespective of the employed progestin. However, in contrast to the claims of Hodgen (U.S. Pat. No. 5,898,032) oral contraceptives with standard progestins do not provide enhanced control of endometrial bleeding compared to the respective standard cycle products during extended cycle use. Thus various independent clinical studies with fixed extended cycle oral contraceptives demonstrated unacceptable bleeding control for standard progestins, for example levonorgestrel (Anderson et al., Kovacs et al.) and desogestrel (Cachrimanidou et al.) disclosed by Hodgen. Most notably very high dropout rates were observed in these studies, mainly due to the bleeding problems (i.e. high rate of intermenstrual bleeding). [0021] Various researchers addressed the problem of intermenstrual bleeding during fixed extended cycle oral contraceptive use. Thus Hesch (U.S. Pat. No. 6,500,814) discloses continuous use of low dose OCs (1-20 .mu. EE/day) for a period of greater than 110 days, which prevents intermenstrual bleeding. Various progestins (not including dienogest) are claimed. [0022] Kulmann (WO 02/22110), on the other hand, discloses an extended regimen, which is characterized by a sequence of successive fixed extended cycles with increasing duration. This regimen is supposed to circumvent the problems of the fixed extended cycle regimens irrespective of the employed progestin (incl. dienogest). Continue reading about Compositions and treatment methods... 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