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 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 . 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 300-900 mg/day Slight, irregular blood loSS. 40 acetate 2-5 mg/day The present invention has for its object to provide a acetate 1-5 mg/day d- 30-150 ugrfday substitution therapy wherein the above described drawbacks 30-150 ugrfday occur to a much lesser extent, with the objective of inducing 30-150 ugrfday amenorrhoea with negligible blood loSS over a long period 0.2-2 mg/day, (many months to years). 45 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 could be A preparation for oral contraceptive according to the obtained in the case of more than 90% of the women, 15 invention comprises tablets of type A comprising 20 lig wherein the clinical tolerance was perceived as optimal, aethinyl-estradiol and 75 luggestoden, and tablets of type B wherein the woman did not discern any Subjective difference comprising 30 ug aethinyl-estradiol and 75uggestoden and between a fixed or changing estrogens dose with a period 50 tug . The tablets A and B are used in four icity of about one week. alternating periods of each six days. After four periods the Using the preparations according to the invention as oral contraceptive intermediate bleeding will be Substantially whole cycle is repeated without allowing a free period. reduced. EXAMPLE 7 EXAMPLE 1. A preparation according to the invention for hormone A preparation according to the invention comprised tab 25 Substitution treatment comprises tablets of type A compris lets of the type A which contained 10 gamma aethinyl ing 2 ug estradiol Valerianate and 50 luggestoden. The tablets estradiol, 1 mg estradiol Valerianate and 0.5 mg of type B comprised 3 tug estradiol valerianate and 25-100 norethisterone, and tablets of the type B which contained 15 tug Onapristone. By alternatingly administering the tablets. A gamma instead of 10 gamma aethinyl-estradiol. By alter and B over a time period of Seven days amennorrhoea could natingly administering the tablets A and B over a time period be induced without blood loss for a very long period of time. of 7 days an amenorrhoea could be induced without blood loSS for a very long period of time. It is obvious for a skilled perSon in the examples in asSociation with intermittently given antiprogestogen or EXAMPLE 2 anti-estrogen can be alternated alone or simultaneous with 35 estrogens and/or progeStagens. For instance, the antiproge A preparation according to the invention contained 1 mg Stagen is added in a constant dose to the actual and the above norethisterone or 0.5 mg cyproterone acetate and 2 mg mentioned combinations of estrogens and progeStagens in estradiol Valerianate. The preparation moreover contained products for hormone replacement therapy and for contra tablets of the type B having 3 mg instead of 2 mg estradiol ception. Valerianate. By using the preparation with alternate admin 40 istering (4-5 days) of the tablets A and B or B and A an I claim: amenorrhoea could be induced without blood loss for a 1. Preparation for Substitution therapy and for oral con longer period of time. traception comprising at least one progestogen and at least one estrogen having dosing means in association therewith EXAMPLE 3 wherein the progestogen dose is Substantially constant and 45 the estrogen dose varies to oscillate between an estrogen A preparation according to the invention comprised tab dominant period and a progestogen-dominant period with a lets of the type A which contained 15 gamma aethinyl periodicity of less than 10 days such that blood loss is estradiol and 1 mg estradiol Valerianate and 1 mg norethis substantially avoided. terone. The preparation moreover contained tablets of the 2. Preparation as claimed in claim 1, wherein Said peri type B having 1.5 mg instead of 1 mg norethisterone. By 50 odicity amounts to 2-9 dayS. alternatingly administering the tablets A and B with a 3. Preparation as claimed in claim 1, wherein the dose of periodicity of 4–7 days an amenorrhoea could be induced progestogen is Substantially constant and the dose of estro without blood loss for a very long period of time. gen oscillates. 4. Preparation as claimed in claim 1, wherein the dose of EXAMPLE 4 55 progestogen and the dose of estrogen oscillate in Such a dose A preparation according to the invention for oral contra ratio that blood loss is substantially avoided. ceptive with optimal cycle control comprises tablets of type 5. Preparation as claimed in claim 1, wherein the A comprising 20 lug aethinyl-estradiol and 75 luggestoden. progestogen comprises The preparation contained tablets of type B comprising 30 60 tug instead of 20 lug aethinyl-estradiol. Tablets A and B are progesterone 300-900 mg/day used in four alternating periods of six dayS. 0.2-5 mg/day medroxyprogesterone acetate 1-5 mg/day EXAMPLE 5 d-norgestrel 30-150 ugrfday desogestrel 30-150 ugrfday A preparation according to the invention for oral contra 65 norgestimate 30-150 ugrfday ceptive with optimal cycle control comprises tablets of type cyproterone acetate 0.2-2 mg/day, A comprising 15 lug aethinyl-estradiol and 75 luggestoden, 5,827,843

-continued -continued gestodene 10-150 lug?day conjugated Oestrogen 0.3-1.25 mg/day 3-ketodesogestrel 10-150 lug?day oestriol 1-4 mg/day, drospirenon 0.2-3.0 mg/day 5 or combinations thereof. 7. Preparation as claimed in claim 1, further comprising or combinations thereof. anti-progestogen. 6. Preparation as claim 1, wherein the estrogens com- 8. Preparation as claimed in claim 1, further comprising prises 10 anti-estrogen. 9. Preparation as claimed in claim 1, further containing the progestogen and/or estrogen in an oral, transdermal, aethinvestradiolE. valerianate 5-151-4 gammafdaE. y parenteral and/or implantable application form. Oestradiol 1-2 mg/day

UNITED STATES PATENT ANDTRADEMARK OFFICE CERTFCATE OF CORRECTION PATENT NO. : 5, 827,843 DATED October 27, 1998 INVENTOR(s) : Philippe R.M. W. G. Koninckx

it is certified that error appears in the above-identified patent and that said letters Patent is hereby Corrected as shown below: column 1 Line 29 "is closely as possible" should read - - as closely as possible -- . column 1 Line 37 "continuousl" should read -- Continuously - . Column 1 Line 38 "endomotrium" should read -- endometrium- . Column 1 Line 60 "blooding" should read - -bleeding - . Column 5 Line 9 claim 6 "as claim 1" should read -- as claimed in claim 1 -- . Column 5 Line 9 Claim 6 "estrogens comprises" should read --estrogen comprises -- .

Signed and Sealed this Twenty-ninth Day of June, 1999 2.76%-ya

Q. TODD DICKINSON Attesting Officer Acting Commissioner of Patents and Tradeniarks