USOO5827843A United States Patent (19) 11 Patent Number: 5,827,843 Koninckx (45) Date of Patent: Oct. 27, 1998 54 PREPARATION FOR SUBSTITUTION 58 Field of Search ............................................... 514/170 THERAPY, CONTAINING AT LEAST ONE PROGESTOGEN AND AT LEAST ONE 56) References Cited ESTROGEN FOREIGN PATENT DOCUMENTS 75 Inventor: Philippe Robert Marie Wilhelmus A275716 7/1988 European Pat. Off.. Ghislain Koninckx, Bierbeek, Belgium A279977 8/1988 European Pat. Off.. A346014 12/1989 European Pat. Off.. 73 ASSignee: Saturnus A.G., Luxembourg, Germany A559240 9/1993 European Pat. Off.. 21 Appl. No.: 605,118 Primary Examiner Zohreh Fay Attorney, Agent, or Firm Webb Ziesenheim Bruening 22 PCT Filed: Sep. 8, 1994 Logsdon Orkin & Hanson, P.C. 86 PCT No.: PCT/EP94/02997 57 ABSTRACT S371 Date: Jun. 4, 1996 The invention relates to a preparation for Substitution S 102(e) Date: Jun. 4, 1996 therapy and oral contraception comprising at least one progestogen and at least one estrogen in which the estrogen 87 PCT Pub. No.: WO95/07081 dose varies with a periodicity such that blood loss is sub Stantially avoided, wherein the periodicity is preferably leSS PCT Pub. Date: Mar. 16, 1995 than 10 days, more preferably less than 7 days, Such as 30 Foreign Application Priority Data preparations containing the progestogen and/or estrogen in Sep. 9, 1993 NL Netherlands ........................... 93.01562 aliansdermal, parenteral and/or implantable applica (51) Int. Cl. ............................................... A61K 31/56 52 U.S. Cl. .............................................................. 514/170 9 Claims, No Drawings 5,827,843 1 2 PREPARATION FOR SUBSTITUTION Such that estrogen-dominant and progestogen-dominant THERAPY, CONTAINING AT LEAST ONE periods occur alternatingly with a Sufficiently short period PROGESTOGEN AND AT LEAST ONE icity. This short periodicity in the estrogen dose is necessary ESTROGEN to avoid blood loss. Purely by administering a dose of progestogen or estro This application is a 371 of PCT/EP94/62997 filed Sep. gen Substantially constant in time and an estrogen or 8, 1994. progestogen varying in time between at least two dose The present invention relates to a preparation for Substi levels, it was possible to induce the desired amenorrhoea tution therapy and for oral contraception. More particularly while no blood loSS occurred over a longer period. the present invention on the one hand relates to relieving the The invention therefore relates to a preparation for effects which occur because the ovaries decrease or Stop Substitution therapy and for oral contraception comprising at production of female hormones, for instance during the least one progestogen and at least one estrogen in which the menopause. The Substitution therapy is mainly intended to estrogen dose varies with a periodicity Such that blood loSS induce amenorrhoea with negligible blood loSS. is Substantially avoided. During and after the menopause these effects comprise 15 It is noted that the preparation is formulated Such that a hot flushes and nocturnal Sweating, atrophy of the vagina Substantially constant blood concentration is obtained for which can result in Sexual difficulties, bone decalcification, progestogen or estrogen, while the estrogen concentration in increase in heart and blood vessel disorders and psychic the blood varies between two blood concentrations. The Symptoms with a causal connection that is usually difficult periodicity must be Sufficiently Short and is generally leSS to demonstrate. than 10 days. The periodicity is usually less than 7 days. The Up to the present different types of substitution therapy periodicity generally lies between 2–9 days, preferably have been applied comprising a hormone treatment with one between 2-6 days. It will however be apparent that the or more estrogens and one or more progestogens. periodicity is dependent on the estrogens and progestogens According to a first therapy, low doses of estrogens and used and the applied doses. Both the periodicity and con progestogens are administered, but Such a treatment is 25 centrations of estrogen and progestogen are easy to deter ineffective in respect of the decalcification and heart and mine by routine experimentation. blood vessel disorders. According to an embodiment of the invention the prepa In another therapy the natural cycle of estrogens and ration contains a constant progestogen dose, while the progestogens is followed is closely as possible. This treat estrogen dose oscillates between two levels. This prepara ment inevitably results in menstruation and has the advan tion is recommended because there is a greater certainty of tage of a reduced risk of cancer of the uterus. avoiding blood loSS Over a longer period. According to yet another therapy only estrogens are According to another embodiment the preparation con administered in a dose which lies below the threshold for tains Oscillating doses of progestogen and estrogen, in menstrual bleeding. This treatment has the drawback how varying ratioS however Such that blood loSS is avoided and ever of an increased risk of cancer of the uterus. 35 amenorrhoea is induced. According to a most recently known therapy estrogens Use can be made in general of all known progestogens, and progestogens are administered continuous Such that the Such as endomotrium does not proliferate. This therapy has the drawback however of an unacceptably high incidence of progesterone 300-900 mg/day Slight, irregular blood loSS. 40 norethisterone acetate 2-5 mg/day The present invention has for its object to provide a medroxyprogesterone acetate 1-5 mg/day d-norgestrel 30-150 ugrfday substitution therapy wherein the above described drawbacks desogestrel 30-150 ugrfday occur to a much lesser extent, with the objective of inducing norgestimate 30-150 ugrfday amenorrhoea with negligible blood loSS over a long period cyproterone acetate 0.2-2 mg/day, (many months to years). 45 gestodene 10-150 lug?day On the other hand, the present invention relates to 3-ketodesogestrel 10-150 lug?day preparations designed for oral contraception with Substan drospirenon 0.2-3.0 mg/day tially continuous application. In continuous application of oral contraceptive fre or combinations thereof. It is noted that the preparation can quently intermediate bleedings occur. The preparations 50 contain one or more progestogens and estrogens. according to the present invention are designed to induce It will be apparent that the quantity of progestogen and menstrual bleeding with a regular menstrual bleeding, with estrogen depends on the person (constitution and age), the an extended cycle or eventually a constant amenorrhoea, but progestogen(s) and estrogen(s), anti-progestogen and anti characterized by an optimal (cycle) control and/or by a estrogen for use and the form of administering Same. Substantially reduced Ocurrence of intermediate bleeding. 55 The progestogen and estrogen can each be present in an EP-A-559 240 discloses preparations for Substitution oral, transdermal, parenteral or implantable application form therapy and oral contraception in which the estrogen dose is for Substitution therapy. The preparation can for instance constant and the progestagen dose is periodically alternated. comprise an application form which contains the progesto However, the improvement in inhibiting endometrium gen and estrogen, and a Second like application form which blooding is minor. Above that, Since the use of higher 60 contains the progestogen and an increased dose of estrogen. progestogen doses provided better results than lower doses The progestogen and estrogen can of course be present in it appears illogical to use periodically varying estrogen like but Separate forms of application or in mutually differ doses. ing forms of application. The progestogen can for instance The present invention is based on the finding that Supris be an implantable application form while the estrogens is ingly when using periodically varying estrogen doses the 65 administered orally, transdermally or parenterally in a dose occurence of blood loSS and intermediate bleeding is Sub which takes account of the required time period according to Stantially avoided. The estrogen dose is herein oscillated the invention. 5,827,843 3 4 The oral application form to be used comprises tablets, and tablets of type B comprising 25 ug instead of 15 lug capsules, Syrup, Solutions. The transdermal forms of appli aethinyl-estradiol. Tablets A and B are used in Six alternating cation comprise gels, plasters. Strips can for instance be periods of four dayS. used wherein tablets with progestogen and estrogens in the desired ratio and periodicity are arranged in time Sequence. In example 4 and 5 only aethinyl-estradiol is used in order The parenteral application form comprises injection fluid to use a estrogen dose which is as low as possible. However, and the like. The implantable application form comprises for higher estrogen doses may be used. Instead of using a example a known implantable Sustained release preparation. constant progestogen dose fluctuating doses may be use The preparations for oral contraceptive comprise estro fluctuating Simultaneously and/or progressively in View of gens and progestogens in common form. the varying estrogen dose. Preparations according to the invention were adminis tered over a period of 3-12 months to 40 women in the EXAMPLE 6 menopause. By making use of the combination preparations according to the invention a constant amenorrhoea