JP2007197459A - Ultra low dose contraceptive with less menstrual bleeding and sustained efficacy - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for contraception imparting less menstrual bleeding, less patient anemia, less total exposure to medication, higher compliance rates and better lifestyle convenience for patients. <P>SOLUTION: The invention relating to the method of contraception involves administering a combination of estrogen and progestin for 60-110 consecutive days in which the daily amounts of estrogen and progestin are equivalent to about 5-35 mcg of ethinyl estradiol and about 0.025 to 10 mg of norethindrone acetate, respectively. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to ultra-low dose contraceptives with reduced and maintained efficacy of menstrual bleeding.

  The ovary / menstrual cycle is a complex event characterized by an estrogen-rich follicular phase and a post-ovulatory progesterone-rich luteal phase. Each has a duration of approximately 14 days and causes a menstrual interval of approximately 28 days. Endometrial tissue responds to changes in the hormonal environment.

  The start of menstruation is the start of a new menstrual cycle and is counted as the first day. During a span of about 5 to 7 days, the decay of the corpus luteum during the unfertilized menstrual cycle is associated with a lack of progesterone secretion, so that the surface layer of the endometrium that has grown and developed during the preceding ovarian menstrual cycle is gradually detached To do. Ovarian follicular maturation causes an increase in circulating levels of estrogen, which in turn leads to new endometrial proliferation.

  Predominant ovarian follicles generally experience ovulation during the middle of the menstrual cycle from the 12th day to the 16th day, converting from a dominant estrogen source to a dominant progesterone source (luteal). Increased concentrations of progesterone in the blood transform the increased endometrium during the secretory phase where tissue growth quickly relieves, causing the formation of endometrial glands or organs. If the ovulated oocyte is fertilized fertilely and continues its embryonic division, the secreted endometrium and the conceptus will contact to cause implantation beginning 6-8 days after fertilization. obtain.

  If an ongoing pregnancy is established via implantation, the embryo will attach and take root in the secretory endometrium and begin to produce human chorionic gonadotropin (HCG). The HCG in turn stimulates dilated luteal function, i.e., progesterone production is increased and menstruation does not occur in the fertilized menstrual cycle. Then pregnancy is established.

  In the non-fertilized menstrual cycle, decreased concentrations of prostaglandins in the blood cause endometrial tissue detachment. This starts a subsequent menstrual cycle.

  Manipulation of the hormone and uterine environment can provide contraception, as the increase in endometrium helps prepare the uterus for impending pregnancy. For example, estrogen is known to reduce follicle stimulating hormone secretion by feedback inhibition. Under certain circumstances, estrogens can also inhibit luteinizing hormone secretion, again by negative feedback. Under normal circumstances, circulating estrogen spikes found just before ovulation induce a surge of gonadotropin hormones that occur just before ovulation and cause ovulation. High doses of estrogen immediately after sexual intercourse can interfere with conception, possibly because it interferes with implantation.

  Progestins can also provide contraception. Endogenous progesterone after estrogen affects changes in endometrial progesterone and periodic changes in cells and tissues in the cervix and vagina. Progestin administration makes cervical mucus dense, mucous and cellular, which appears to impede sperm transport. Progestin administration also inhibits luteinizing hormone secretion and blocks ovulation in humans.

  The most common form of oral contraception is the pill combining estrogen and progestin, called a combined oral contraceptive preparation.

  Instead, there are contraceptive preparations that contain only progestins. However, the progestin alone preparation has a different range of side effects than the combined preparation, particularly in external bleeding. The resulting combined preparation is a more preferred oral contraceptive for use today (Sheth et al., Contraception 25: 243, 1982).

  When oral contraceptives are at higher doses, the 7-day “pill-free” or conventional 21-day pill pack with placebo intervals works well, while doses are given for both estrogen and progestin compositions. As it gradually decreases, the problem of bleeding gradually increases, especially in the early months of oral contraceptive use, but in some patients it is persistent.

  Since the advent of combined estrogen-progestin pharmacotherapy as an oral contraceptive, there has been a stable down-regulation of daily estrogen dosage. At the same time, if the exposure to progestin is also diminished, the reduced androgenicity persists the advanced preference. These indications that come together in the prescription are present in various regimes, both in a single phase and in multiple phases. Each has their own advantages and disadvantages. Proposed accumulation of "lipophilic" progestins than all today's oral contraceptives maintain the incidence and severity of estrogen-linked coagulation disease, as well as potentially favorable high density lipoprotein cholesterol levels in the circulation Much safer with respect to negative effects.

[Conventional technology]
U.S. Pat.No. 4,390,531 teaches a three-phase regimen, each phase using about 20-40 mcg ethinylestradiol, the first and third phases using 0.3-0.8 norethindrone, the second phase Then use twice the amount of norethindrone. These three phases consume 21 days in a 28 day cycle. EP 0 226 279 argues that this regimen is associated with a high incidence of external bleeding, and if the amount of estrogen in any two phases is never the same, the ethinylestradiol Substitute a 3-phase oral contraceptive regimen that uses relatively low amounts (10-50 μg) and relatively high amounts of norethindrone acetate (0.5-1.5 mg). About 7 days of “remaining” phase is used in this regimen.

  US Pat. No. 5,098,714 teaches osmotic oral dosage forms. One “pill” is administered per day, but the administration is effectively multi-phased. The dosage form is constructed to provide an initial pulsed administration of estrogen and progestin following a long-term administration of estrogen.

  EP 0 253 607 discloses a single phase contraceptive preparation comprising units having 0.008-0.03 mg ethinylestradiol and 0.025-0.1 mg desogestrel (or equivalent), and Describes a regimen administered over a period of 23-25 days, preferably over a period of 24 days, followed by a pill-free period of 2-5 days. The purpose of this regimen is to provide hormone replacement therapy and contraceptive protection for premenopausal women in need thereof by providing a low amount of estrogen in combination with an “very low dose progestogen”.

  In 1989, with the accumulated data derived from advances in oral contraceptive pill formulations containing only 20-35 μg estrogen per day, the Food and Drug Administration's Fertility and Maternal Health Drugs Advisory Committee It was spurred to recommend low-dose oral contraceptive instructions to healthy, non-smoking women even during pre-menopausal ages. In Japan, oral contraceptives are initially evaluated for safety and efficacy, as well as socially acceptable.

  U.S. Pat.No. 5,552,394 has reduced external bleeding after the first cycle, including administering a combination of estrogen and progestin in a single phase for 23-25 consecutive days in a 28-day cycle Describe female contraceptive methods characterized by incidence, in which the daily amounts of estrogen and progestin are equal to about 5-35 mcg ethinylestradiol and about 0.025 to 10 mg norethindrone acetate, respectively, and estrogen and progestin The weight ratio is at least 1:45 calculated as ethinylestradiol: norethindrone acetate.

  In establishing an estrogen-progestin regimen as an oral contraceptive, two major issues must be addressed. First, efficacy must be maintained, and second, further folds in the control of endometrial bleeding must be avoided. Even very low dose oral contraceptive products, which are generally commercially available, are effective, but the general case of bleeding control problems increases as dosage decreases and external bleeding ( Unsettled spill or spot) or abstinence amenorrhea during “pill-free” weeks (menstrual periods are expected).

  It is an object of the present invention to provide new estrogen-progestin combinations and / or regimens for the use of oral contraceptives that maintain efficacy and provide increased control of endometrial bleeding. The regimen increases the response by including less stop / start changes per year and also causes less blood loss in anemic patients. Having few menstrual intervals can increase lifestyle and convenience. This and other objects of the present invention will become apparent to those skilled in the art from the following detailed description.

  The present invention relates to a female contraceptive method characterized by reducing the number of menstrual periods of withdrawal symptoms per year. More particularly, the present invention relates to a female contraceptive method comprising preferably single phase administration of 60-110 consecutive days estrogen-progestin combination followed by 3-10 days non-administration. The daily dose of estrogen and progestin is equal to about 5-35 mcg ethinyl estradiol and about 0.025-10 mg norethindrone acetate, respectively.

[Embodiment of the Invention]
In accordance with the present invention, a combined dosage form of estrogen and progestin is given to a woman in need of contraception for 60 to 110 consecutive days, preferably about 80-90 days, followed by 3 to 10 days, preferably Administered preferably in a single phase at a dose free interval of about 5-8 days, in which the daily administration of estrogen and progestin is equivalent to about 5-35 mcg ethinylestradiol and about 0.025 to 10 mg norethindrone acetate, respectively . In a dosing schedule with 84 days of administration followed by 7 days of pill-free, there are only 4 treatments and menstrual cycles per year.

  Preferred estrogens and progestins are ethinylestradiol and norethindrone acetate, although other estrogens and progestins can be used. The weight ratio of these two active substances is at least 1:45, preferably 1:50. The preferred amount of ethinyl estradiol is about 10-20 mcg and the preferred amount of norethindrone is about 0.25-1.5 mg. Other estrogens differ in potency from ethinyl estradiol. For example, 30 mcg ethinyl estradiol is roughly equivalent to 60 mcg mestranol or 2,000 mg 17β-estradiol. Similarly, other progestins differ in potency from norethindrone acetate. Therefore 3.5 mg norethindrone acetate is roughly equivalent to 1 mg levonorgestrel or desogestrel and 3-keto desogestrel, and about 0.7 mg guestden. The values given above are for ethinyl estradiol and norethindrone acetate, and if different estrogens and progestins are used, adjustments in quantity should be made based on relative potency. The correlation in titer between various estrogens and progestins is known.

  Other usable estrogens include estradiol such as acetic acid, sulfuric acid, valeric acid, benzoic acid, esters of estrone and ethinyl estradiol, complexed equine estrogens, agnostic antiestrogens, and selected estrogens Receptor modulators are included. The estrogen is administered in any conventional manner, by any route, active orally or percutaneously. Most estrogens are orally active, so the oral route of administration is preferred. Thus, the dosage form can be a tablet, dragee, capsule or pill containing estrogen (and preferably progestin) and a suitable pharmaceutically acceptable carrier.

  Pharmaceutical formulations containing a progestin and a suitable carrier can be in solid dosage forms, including tablets, capsules, cachets, small pills, pills, powders or granules. Typical dosage forms include solutions, powders, liquid emulsions, liquid suspensions, semisolids, ointments, pastes, creams, gels or jellies, foams and controlled release depot entities. It is. And parenteral dosage forms include solutions, suspensions, emulsions or dry powders containing an effective amount of progestin as taught in the present invention. The active ingredient progestin is a pharmaceutically acceptable diluent, filter, disintegrant, binder, lubricant, surfactant, hydrophobic excipient, water-soluble excipient, emulsifier, buffer, wet diluent It is known in the art that it can be included in the formulation in addition to wetting agents, solubilizers, preservatives and the like. Means and methods for administration are known in the art and one skilled in the art may refer to various pharmacological references for guidance. For example, "Modern Pharmaceutics", Banker & Rhodes, Marcel Dekker, Inc. 1979; "Goodman & Gilman's The Pharmaceutical Basis of Therapeutics", 6th edition, MacMillan Publishing Co., New York 1980.

  The pharmaceutical formulation may be provided in kit form comprising at least about 60, and preferably at least about 84 tablets intended for continuous ingestion for consecutive days, up to 110 tablets. Preferably, administration comprises at least 60 days daily using tablets containing both estrogen and progestin, followed by at least 3 days using placebo.

  In order to further illustrate the present invention, specific examples are given below. It will be appreciated, however, that these examples are for illustrative purposes only and are not intended to limit the scope of the invention.

[Example]
(Example 1)
The study was conducted in a fully officially approved animal laboratory, including the National Institute of Health's "Guide for Care and Use of Laboratory Animals", thePublic Health Services'"Principles for the Care and Use of Laboratory Animals", and It follows the animal care and use committee with the observation standards set forth in the United States Department of Agriculture's Implementation Regulations of the 1985 Amendments for the Animal Welfare Act.

  Ten adult cynomolgus monkeys (macaca fasicularis) with normal expected ovulatory menstrual cycle (28.9 ± 3.1 days per month before the start of the study) are selected. Its spontaneous menstrual duration is 3.4 ± 1.4 days. The average body weight of monkeys is 4.9 ± 1.1 kg (X ± SEN). They are individually housed in a controlled environment (12 hours light period and 23 ° C). Their food is a primate diet (Purina, St. Louis, MO) sold with unlimited water.

  The monkeys are randomly divided into two groups (each N = 5). The study begins with spontaneous menstruation in the pretreatment control cycle. Instead, at the beginning of the next voluntary menstruation, they receive extremely low dose oral contraceptives on the first day of the cycle for 60 consecutive days each, followed by 3 non-treatment days, or Received in 84 consecutive days of treatment followed by 7 non-treatment days. These regimens continue for 3 treatment cycles. The study is subsequently terminated for each primate group during the untreated spontaneous ovulation menstrual cycle.

  Blood from the thigh is collected daily and every 3 days between all three treatment cycles except the pre-treatment and post-treatment cycles and the number of days between `` pill-free '' intervals, estradiol, progesterone, FSH and LH Freeze serum for later RIA. The bleeding profile continues to be recorded with a daily swab to the vagina, which indicates spontaneous menstruation, withdrawal bleeding, external bleeding or withdrawal amenorrhea. External bleeding is defined as detectable bleeding outside the vagina during the first 8 days after the last dose of oral contraceptive or after the start of spontaneous menstruation in a non-treatment cycle.

  Since the goal is to test ultra-low dose oral contraceptives, the medication should be adjusted to the lower body weight (than humans) of these laboratory primates. The dose of ethinyl estradiol is 1.2 μg / day, while the dose of norethindrone acetate is 0.06 mg / day. This “in-flight” re-formulation was accomplished by grinding a commercially available single phase pill (Loestrin 1/20, Parke Davis, Morris Plains, NJ) to powder, which was originally Contains 1 mg norethindrone acetate and 20 μg ethinylestradiol per tablet, included in a 21-day pack with a convenient 7 iron-containing placebo.

  In comparison to human dose equivalents, the daily dose received by monkeys (monkey body weight is about 5 kg and female body weight is about 50 kg) is 12 μg ethinylestradiol and 0.6 mg norethindrone acetate. is there. Therefore, this ultra-low dose oral contraceptive prescription is 40% in daily exposure to estrogen-progestin compared to one of the lowest estrogen dose combination oral contraceptives commercially available today in the United States or Europe. % Decrease. On a yearly basis, there are 63 additional doses when using a routine 84-day ultra-low dose regimen plus a 7-day pill-free interval versus a routine 21 + 7-day protocol In view of this, exposure to pharmaceuticals was reduced by more than 26% per year compared to the commercial product Loestrin 1/20.

(Example 2-5)
The method of Example 1 is repeated using the following estrogen and progestin combinations:

  Application of the compounds, compositions and methods of the present invention to the described medical or pharmaceutical uses may be accomplished by any clinical, medical, and pharmaceutical methods and techniques known to those skilled in the art now or in the future. Can be accomplished. Thus, the various embodiments described above are intended to illustrate the present invention, and it is anticipated that various changes and modifications may be made in the methods of the present invention without departing from the spirit and scope of the invention. Like.

Claims (4)

A pharmaceutical kit comprising a prescription and a placebo, wherein the prescription comprises a combination of estrogen and progestin, and the daily intake of estrogen and progestin is equal to 30 mcg ethinylestradiol and 0.25 to 1.5 mg norethindrone acetate, respectively In the pharmaceutical kit, the prescription is taken orally for 84 consecutive days, followed by placebo orally taken for 7 days, reducing the number of menstrual periods per year to 4, for female contraception Pharmaceutical kit. 2. The pharmaceutical kit according to claim 1, wherein the estrogen is ethinyl estradiol. The pharmaceutical kit according to claim 1 or 2, wherein the progestin is norethindrone acetate. The pharmaceutical kit according to claim 1 or 2, wherein the progestin is levonorgestrel.