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(11) EP 1 558 265 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/585 (2006.01) A61P 15/00 (2006.01) 06.01.2010 Bulletin 2010/01 (86) International application number: (21) Application number: 03769738.0 PCT/IB2003/004946

(22) Date of filing: 05.11.2003 (87) International publication number: WO 2004/041289 (21.05.2004 Gazette 2004/21)

(54) USE OF FOR THE TREATMENT OF VERWENDUNG VON DROSPIRENON ZUR BEHANDLUNG VON HYPERTENSION UTILISATION DE LA DROSPIRENONE POUR LE TRAITMENT DE L’HYPERTENSION

(84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR WO-A-01/52857 WO-A-02/09683 HU IE IT LI LU MC NL PT RO SE SI SK TR WO-A-02/17895 WO-A-02/055086 US-A1- 2002 136 775 (30) Priority: 05.11.2002 PCT/IB02/04628 05.11.2002 US 287780 • NORMAN P. ET AL: ’Drospirenone’ DRUGS OF THE FUTURE vol. 25, no. 12, December 2000, (43) Date of publication of application: pages 1247 - 1256, XP000993474 03.08.2005 Bulletin 2005/31 • KRATTENMACHER R.: ’Drospirenone: pharmacology and of a unique (73) Proprietor: Bayer Schering Pharma ’ CONTRACEPTION vol. 62, July Aktiengesellschaft 2000, pages 29 - 38, XP000993492 13353 Berlin (DE) • BERGER V. ET AL: ’Influence of different on blood pressure of non- (72) Inventor: MEYERHOFER, Siegried anaesthetized male spontaneously hypertensive 1230 Vienna (AT) rats’ CONTRACEPTION vol. 46, 1992, pages 83 - 97 (74) Representative: Plougmann & Vingtoft A/S • WHITE W. ET AL: ’Effects of a new hormone Sundkrogsgade 9 therapy, drospirenone and 17-ß-estradiol, in P.O. Box 831 postmenopausal women with hypertension’ 2100 Copenhagen Ø (DK) HYPERTENSION vol. 48, 26 June 2006, pages 246 - 253

Remarks: The file contains technical information submitted after the application was filed and not included in this specification

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 558 265 B1

Printed by Jouve, 75001 PARIS (FR) 1 EP 1 558 265 B1 2

Description [0005] Eplerenone is a steroidal drug with receptor blocker activity. Eplerenone is reported as being Field of invention effective in the treatment of aldosterone-mediated dis- eases such as cardiovascular diseases (Martin and [0001] The present invention is directed to the use of 5 Krum; Eplerenone. Current opinion in investigational treatment or Drospirenone as the sole therapeutically ac- drugs, 2001, 2(4), 521-525). Eplerenone has a selective tive agent for the prevention of hypertension. binding to the receptor in that other steroidal receptors are not affected, such as the estro- Background genic and progestational receptors. Eplerenone has 10 been shown to provide cardioprotection in both women [0002] In women, the risk of developing hypertension and men (Hamedii and Chadow: The promise of selective and/or cardiovascular diseases increases after entering aldosterone for the treatment of hy- the menopause, where ovulation stops (Affalo-Calderon pertension and congestive . Curr Hypertens B. HRT, women, and heart disease: what we need to Rep, 2000, Aug 2(4), 378-383, Delayani et al: Epler- know about prevention, Medscape Cardiology 6(2), 15 enone; a selective aldosterone receptor antagonist 2002). It is thought that the treatment of post-menopausal (SARA), cardiovascular Drug Rev 2001 FAII, 19(3) women with would antagonise the risk of hy- 185-200). pertension and/or cardiovascular diseases, such as hy- [0006] Another drug substance is (17- pertension. However, the risk of developing hypertension hydroxy-7-alpha-mercapta-3-oxo-17-alpha-pregn-4- and/or cardiovascular diseases by the current forms of 20 ene-21-carboxylic acid gamma-lactone acetate), which hormone replacement therapy has not yet been verified has been shown to decrease the morbidity and mortality (Nelson et al. Post-menopausal hormone replacement among patients with severe heart failure who were al- therapy. J Am Medical Ass, August 21, 2002, vol 288, no ready receiving ACE inhibitor therapy. Thus, an additive 7, pp 872-891). effect was observed (Pitt et al; the effect of Spironolac- [0003] Hypertension has for many years been thought 25 tone on morbidity and mortality in patients with severe to be the pre-dominant factor in the development of car- heart failure. New Engl. J Med, vol 341, no 10, pp 709717, diovascular diseases, but it has now been questioned to 1999). what extent anti-hypertensive agents such as ACE inhib- [0007] Aldosterone antagonists have been used in the itors prevents the development of cardiovascular diseas- treatment of aldosterone mediated pathogenic effects es in women. ACE inhibitors act through maintaining 30 such as hypertension and/or cardiovascular diseases in electrolyte homeostasis via the renin-angiotensin-aldos- a subject that has salt sensitivity or an elevated dietary terone system (RAAS) such that plasma levels of the sodium intake or both by administering one or more al- mineralocorticoid hormone, aldosterone, are reduced dosterone antagonists such as Spironolactone (WO due to the inhibiting of the angiotensin converting en- 01/95892). zyme. Aldosterone is known to exert its activities through 35 [0008] WO 02/09759 relates to the treatment of inflam- activation of mineralocorticoid receptors in the epithelia mation-related cardiovascular disorders such as ae- of the kidney, colon and sweat glands, whereby aldos- therosclerosis in a subject by administering an aldoster- terone promotes the retention of sodium and the excre- one antagonist and a cyclooxygenase-2 inhibitor. The tion of . aldosterone antagonist being a -type com- [0004] However, recently it has been shown that min- 40 pound (Spironolactone) and an epoxy-steroidal aldoster- eralocorticoid receptors are also present in the cardio- one antagonist. vascular system, such as in the heart and blood vessels, [0009] WO 01/34132 relates to the treatment, inhibit- as well as in the brain (Delayani JA: Mineralocorticoid ing or preventing pathogenic change resulting from vas- receptor antagonists; the evolution of utility and pharma- cular injury in a human subject by administering an al- cology. Kidney INt, 2000 Apr 57(4) 1408-1411). Moreo- 45 dosterone antagonist. ver, animal and human studies point to the fact that al- [0010] WO 95/15166 relates to the treatment with an dosterone plays a role in the pathogenesis of cardiovas- aldosterone antagonist such as Spironolactone and cular and renal diseases independent of the well-known epoxymexrenone for inhibiting myocardial fibrosis in that mechanism involving activation of the angiotensin to an- the dosage used may not disrupt a patient’s normal elec- giotensin II (Stier et al, aldosterone as a mediator in car- 50 trolyte and water-retention balance. diovascular injury. Cardiol Rev 2002, mar-Apr 10(2), [0011] Drospirenone (DRSP), a 17α-spirolactone is an 97-102). Thus, it is to be expected that aldosterone via analogue to Spironolactone. Drospirenone has unlike its activation of the mineralocorticoid receptors in the other known progestins biochemical and pharmacologi- heart, blood vessels or brain will mediate several patho- cal profiles similar to endogenous progesterone, espe- physiological actions like for example stroke, cardiac fi- 55 cially with regard to the anti-mineralocorticoid activity in brosis, ventricular hypertrophy, myocardial necrosis, the epithelia of the kidney, colon and sweat glands and heart failure (congestive heart failure), sudden cardiac the anti-androgenic activity (Krattenmacher R; Dros- death and/or . pirenone: pharmacology and pharmacokinetics of a

2 3 EP 1 558 265 B1 4 unique . Contraception 2000, Jul, 62(1), enous levels of progesterone may begin to become de- 29-38; Norman P, Drospirenone. Drugs of the future ficient when women enters the age of forties or in the 2000, 25(12, 1247-1256). Therefore, Drospirenone is period of peri-menopause. After entering meno-pause, thought to mediate the natural anti-aldosterone and va- the endogenous levels of progesterone are absent. soactive properties of endogenous progesterone in wom- 5 [0018] Accordingly, it has been found that Dros- en. It is known that Drospirenone binds to mineralocor- pirenone, a drug substance with analogous progestation- ticoid receptors in competition with aldosterone so as to al as well as anti-mineralocorticoid activity as progester- provide a strong anti-mineralocorticoid activity. Dros- one, antagonises the action of aldosterone on mineralo- pirenone is about 8 times as potent as Spironolactone corticoid receptors in the heart, blood vessels and brain, (Pollow et al; dihydrospirorenone, a novel synthetic pro- 10 resulting in the potential prevention of cardiovascular dis- gestagen, characterisation of binding to different recep- eases in women. This observation has great significance tor proteins. Contraception, 1992, 46, 561-574). to women with the risk of developing cardiovascular dis- [0012] Drospirenone Is known from the patent DE eases, such as women with deficient levels of endog- 19633685 and the patent application WO 98067838, both enous progesterone or women with a history of cardio- relate to a process for producing Drospirenone, 6β,7β; 15 vascular diseases in their family. Advantageously, wom- 15β;16β-dimethylene-3-oxo-17α-preg-4-ene-21,17-car- en can be offered cardioprotective treatment simultane- bolactone. ously with the treatment of symptoms and diseases as- [0013] Plasma aldosterone levels may be affected by sociated with deficient levels of progesterone, such as administering Drospirenone: In a study implying admin- irregular bleeding, abnormal bleeding, endometrioses istration of Drospirenone alone or Drospirenone in com- 20 and symptoms on peri-menopause. bination with ethinylestradiol demonstrated that the plas- [0019] Thus, the present invention relates to the use ma aldosterone levels increased in both groups of ther- of Drospirenone for the preparation of a solid dosage unit apy. (Oelkers et al: Effect of an oral contraceptive con- comprising Drospirenone as the sole therapeutically ac- taining Drospirenone in the renin-angiotensin-aldoster- tive agent for the treatment or prevention of hypertension, one system In healthy female volunteers, Gynecol endo- 25 wherein said solid dosage unit contains a dose of 2, 2.5 crinol 2000, 14, 204-213). or 3 mg Drospirenone. [0014] Furthermore, it has been shown that Dros- pirenone in combination with 17β-estradiol further reduc- Detailed description es hypertension in postmenopausal women that suffer from hypertension and is in therapy with an ACE inhibitor, 30 [0020] As stated, the invention lies in part in the hitherto Enalapril (Preston et al, Additive effect of drospirenone/ unknown cardioprotective effect in women when being 17β-estradiol in hypertensive postmenopausal women in therapy with Drospirenone. Drospirenone is a drug receiving Enalapril (Am J Hypertension, 2002, 15 substance having aldosterone antagonising activity due (816-822). to binding to mineralocorticoid receptors in competition [0015] Drospirenone is further known from its use in 35 with aldosterone. However, Drospirenone does also contraception (WO 01/15701) and for managing HRT in have progestational activity. post-menopausal women (WO 01/52857). [0021] It is thought that the cardioprotective effect re- [0016] Finally, subcutaneous administration of Dros- sults from the anti-aldosterone activity of Drospirenone pirenone (2 and 10 mg, respectively) in male spontane- on mineralocorticoid receptors in the heart, the vascular ously hypertensive rats has been described (Berger et 40 system and brain. al; Influence of different progestogens on blood pressure [0022] As used herein, the following phrases and terms of non-anaesthetized male spontaneously hypertensive are defined: rats. Contraception, 1992, 46, 83-97). [0023] The term "preventing" includes either preven- tion of the onset of a clinical manifestation of a symptom, Summary of the invention 45 disease or disorder altogether or preventing the onset of a preclinically evident stage of a disease or disorder in a [0017] It is currently considered problematic that the woman. For example, the prevention of hypertension hormone replacement therapy used in the clinic today may be determined as the reduction in diastolic and/or does not reduce the risk of hypertension and/or cardio- systolic blood pressure. vascular diseases in post-menopausal women. For many 50 [0024] Preferably, the therapeutic uses of the present years it has been the theory that replacement invention reduce the risk of hypertension by at least 50%, therapy would reduce the occurrence of cardiovascular such as at least 60, 70, 80 or 90%. diseases in post-menopausal women. However, it has [0025] A number of animal’ models for the investigation been found that endogenous progesterone may protect of the hypertension effect of a therapeutically active a woman from developing cardiovascular diseases be- 55 agent are available. Experiments can be carried out in cause of the antagonising effect of aldosterone, such as rodents that are made hypertensive using surgical alter- the antagonism of aldosterone on mineralocorticoid re- ations, or in spontaneously hypertensive rodent treated ceptors In the heart, blood vessels and brain. Endog- with a stroke-prone substance.

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[0026] For example, arterial hypertension can be in- woman. duced in rodents using different techniques: [0035] The therapeutic uses the invention are directed to women having the need or desire of being protected a) renovascular hypertension induced by surgically from hypertension. In general, the therapy and medica- placing a constricting band around the right renal 5 ments of the invention are directed to a woman above a artery, to induce unilateral renal ischemia. specified age for reducing the risk of hypertension. b) infrarenal banding to mechanically constrict blood Therefore, in some preferable embodiments, the thera- flow through the aorta below the junction where the peutic uses are applied to a woman above a critical age, renal arteries branch off. (elevated blood pressure for example a woman who may have no clinical symp- in the kidneys). 10 toms of hypertension, the only criterion being that she is c) aldosterone infused directly into the rodents at a above a critical age. The critical age will vary from pop- fixed rate via an implanted pump. ulation to population according to the incidence of cardi- ovascular disease or according to other factors such as [0027] The spontaneously hypertensive rodents of the diet or smoking. The critical age can be determined sim- stroke-prone substrate is characterised by an increased 15 ply by determining the age above which 80%, such as development of severe hypertension, cerebrovascular 85%, 90% or 95% of the deaths from heart failure or lesions, and malignant nephrosclerosis. cardiac infarct occur. Typically the characteristic age is [0028] During the treatment period, the rodents are above 35, such as above 40, 45 and 47, and may range monitored for hypertension, and plasma aldosterone, from about the age from about 40 to 65. systolic and diastolic blood pressure, left ventricular and 20 [0036] In some embodiments of the invention, the ther- diastolic pressure, left ventricular dP/dt, body weight, and apeutic uses of the invention are intended to healthy heart rate. women irrespective of their age, e.g. women with a systo- [0029] At the end of the treatment period, the rodents lic blood pressure less than 140 mm Hg such as less are sacrificed and compared between the different than 130 mm Hg or 120 mm Hg or a diastolic blood pres- groups of treated with either an active agent or placebo, 25 sure less than 105 mm Hg, such as less than 95 mm Hg, by examination of the heart, microscopic evaluation of 85mm Hg or 75 mm Hg or combinations of said systolic the cerebrovascular damages and/or histopathologic blood pressure and diastolic blood pressure. An alterna- analysis of the kidneys. tive characteristic of a healthy woman relates to the body [0030] Other models of investigating hypertension ef- mass Index. Thus, in some embodiments of the inven- fects are mentioned in Delyani et al; effect of a selective 30 tion, the woman has a body mass index in the range from aldosterone receptor antagonist in myocardial infarction. about 16 to 35 in that the body mass index in older woman Am J Physiol Heart Circ Physiol, vol 50, H647-H654, may be in the higher end of that range without being 2001. denoted obesive. Normally, to ensure low risk of [0031] The term "Drospirenone" is intended to include hypertension , the body-mass index should be lower than any geometric isomer of Drospirenone. 35 35. Therefore, the body-mass index of a woman is pref- [0032] As stated, Drospirenone is the only therapeuti- erably in the range from about 18 to 32, even more pref- cally active agent included in the dosage unit. In the erably in the range from about 18 to 29, most preferably present context, the term "sole therapeutically active in the range from about 19 to 28, such as most preferably agent" is denoted to mean that substantially no other drug in the range from about 20 to 27. substances is included in the dosage unit. However, 40 [0037] Alternatively, the therapy of the invention is some drug substances can be allowed as long as they used in women with an estimated risk of hypertension are not regarded as therapeutically relevant for the treat- above a specified level, ment of hypertension or are present in a dose insufficient wherein the risk is determined by measurement of risk to prevent or treat hypertension . Moreover, other hor- factors used in conjunction with a person’s age and sex. monal agents such as estrogens are excluded from the 45 Thus, in one embodiment, the woman is susceptible to composition. an aldosterone-mediated disease, such as [0033] The composition is intended for being adminis- hypertension . Thus, in some embodiments the woman tered to a woman so as to treat or prevent the develop- can be hypertensive. ment of hypertension. The administered dose is, 2, 2.5, [0038] Moreover, a woman susceptible to hyperten- or 3 mg dependent on the woman and the intention of 50 sion may be characterised by having deficient endog- preventing or treating hypertension enous levels of progesterone, such as a woman in peri- [0034] Unlike earlier publications, it is found that pre- menopause or in post-menopause or a woman with ir- vention of hypertension in a woman can sufficiently be regular or abnormal bleeding, or such as a pregnant achieved upon administering the Dropirenone as the sole woman in risk of miscarriage. Thus, in some embodi- therapeutically active agent. That is to say that co-ad- 55 ments of the invention, the therapeutic methods or med- ministering of Drospirenone with anti-hypertensive drugs icaments of the invention may be used to women having or estrogens is not critical for achieving sufficient preven- symptoms, diseases or disorders associated with defi- tion of hypertension and/or cardiovascular diseases in a cient endogenous levels of progesterone, or to women

4 7 EP 1 558 265 B1 8 in need of progesterone replacement therapy, such as a gen. Menopause is usually recognised by the cessation woman having irregular bleeding, abnormal bleeding, en- of menstrual periods. Other symptoms of menopause in- dometrioses and/or lack of ovulation. clude flashes, mood changes, and difficulty in sleeping [0039] Typically, the therapeutic uses may also be ap- and vaginal dryness. In the present context, the term plied to a healthy woman but nevertheless in the risk of 5 menopause is to be understood as the last natural (ovary developing hypertension . The woman may previously -induced) menstruation. If a woman is not menstruating have been diagnosed as having had the clinical symp- because she has had a hysterectomy or endometrial ab- toms of hypertension, irrespective of age or the values lation, other symptoms of menopause often alert her that of risk factors. Therefore, in some embodiments of the menopause is starting. The average age of the onset of invention, the woman having risk or even Increased risk 10 menopause is 51 years, and it most commonly occurs of hypertension is a woman with a systolic blood pressure from age 47 to 53. The term "post-menopause" is the greater than 130 mm Hg or a diastolic blood pressure phase that begins at menopause and continues until greater than 85 mm Hg or both. Furthermore, the woman death. in risk may also be characterised by having activities ratio [0045] Accordingly, in some embodiments of the in- of plasma aldosterone (ng/dL) to plasma renin (ng/mL/hr) 15 vention, the woman is a post-menopausal woman, e.g. greater than about 30. Women with risk factors can pro- a woman with deficient levels of endogenous estrogen. mote the development of arteriosclerosis. Such risk fac- [0046] The therapeutic uses of the invention do not tors are smoking, overweight, stress, genetic disposition, comprise concurrent administration of an estrogen i.e. high blood pressure, disorders of lipid metabolism, lack an estrogen is excluded. of exercise and/or diabetes. 20 [0047] The Drospirenone may be delivered daily for a [0040] In particular embodiments of the invention, the number of days within each cycle of 21 to 35 days, pref- therapeutic uses are preferably directed to a peri-meno- erably within each cycle of 28 days. Cycle is intended to pausal woman. mean a period of time that is repeated for every 21 to 35 [0041] The term "peri-menopause" characterises the days. In some embodiments the delivery of the Dros- period immediately before and after the onset of meno- 25 pirenone may be for at least 5 days up to 35 days. pause, and averages 4 years. Furthermore, the peri- [0048] In other embodiments the Drospirenone is de- menopause is characterised by abnormal and irregular livered for at least 10 days, such as 12 days, such as 15 bleeding. The peri-menopausal phase begins with the days, such as 20 days, such as 21, 22, 23, 24, 25, 26, onset of climacteric symptoms when the cycle becomes 27, or 28 days within each cycle of 21 to 35 days, pref- irregular and ends one year after menopause. The end 30 erably 28 days. In some embodiments the delivery is in of peri-menopausal phase can be identified after a pro- interrupted manner, which means that the Drospirenone tracted period of time without bleeding. is delivered for a period of time, which is followed by a [0042] That is to say that the peri-menopause is the period with no Drospirenone delivered, which is then fol- period before entering menopause. Thus, in interesting lowed by a period with delivery of the Drospirenone. Also, embodiments of the invention the woman is in the age 35 it means that no Drospirenone is delivered for a period from about 40 to 55. The suitable age may also be from of time, followed by delivery of Drospirenone, followed about 45 to 53, about 45 to 52, 46 to 52, 48 to 52 or from by no delivery of Drospirenone. This cycling of delivery about 47 to 51 dependent on when the individual women of Drospirenone may be repeated 1 to 10 times within a experiences irregular bleeding or other symptoms on de- cycle of 21 to 35 days. That is to say that each delivery ficient endogenous levels of progestogen. However, the 40 of Drospirenone may for example be conducted for 1, 3, uses of the invention may not be limited to women of that 7, 14 or 21 days. The length of the period with delivery age. Some women enter the menopause in a much of Drospirenone may be similar, minor or greater than younger age such as for example when they are in theirs the period with no delivery. In some embodiments, the thirties due to hypogonadal activities. Other women will Drospirenone is administered sequentially, which relates enter the menopause upon hysterectomy. 45 to an interrupted manner. [0043] As mentioned, low endogenous levels of pro- [0049] In other embodiments, the Drospirenone is ad- gesterone are an indication of peri-menopause in a wom- ministered continuously within a treatment cycle of 21 to an. However, post-menopausal women does also have 35 days. low endogenous levels of progesterone or even lack of [0050] The Drospirenone dose may vary throughout progesterone for which reason post-menopausal women 50 the period of 21 to 35 days or it may be the same. Thus, may benefit from the additional prevention of develop- in some embodiments, the dose delivered varies ment of hypertension upon administering Drospirenone throughout the period of 21 to 35 days. For example, the according to the invention . As mentioned, the therapeu- dose may be lower in the first half, such as within the first tic methods and uses do not necessarily imply that the 10 days, of the period of 21 to 35 days than in the second post-menopausal women are in estrogen replacement 55 half, such as the last 10 days, of the period of 21 to 35 therapy. days. Conversely, it may also be suitable to use a higher [0044] The term "menopause" characterises the time dose in the first half, such as within the first 10 days, of in a woman’s life when the ovaries stop producing estro- the period of 21 to 35 days than in the second half, such

5 9 EP 1 558 265 B1 10 as the last 10 days of the period of 21 to 35 days. corn starch, modified starch, drospirenone, lactose [0051] The composition to be used according to the monohydrate and activating the fluidised bed. An aque- invention may be formulated in any suitable manner. In ous solution of polyvinylpyrrolidone 25,000 in purified wa- suitable embodiments of the invention, the composition ter is sprayed continuously onto the fluidised bed while is formulated , as a solid dosage unit for oral administra- 5 drying by heating the air stream of the fluidised bed. At tion. the end of the process magnesium stearate is sucked [0052] The solid dosage units may be selected from into the granulator and mixed with the granules by main- the group consisting of uncoated tablets, modified-re- taining the fluidised bed. The resulting granulate is lease tablets, gastro-resistant tablets, orodispersible tab- pressed into cores by compression using a rotary lets, effervescent tablets, chewable tablets, soft cap- 10 tablet press. sules, hard capsules, modified-release capsules, gastro- resistant capsules, uncoated granules, effervescent granules, coated granules, gastro-resistant granules, Claims modified -release granules, and powders for oral admin- istration. 15 1. Use of drospirenone for the preparation of a solid [0053] Moreover, an interesting embodiment of the in- dosage unit comprising drospirenone as the sole vention comprises a dosage unit wherein the dros- therapeutically active agent for the treatment or pre- pirenone is in micronized form or in the form of a cyclo- vention of hypertension, wherein said solid dosage dextrin inclusion complex. unit contains a dose of 2, 2.5 or 3 mg drospirenone. [0054] The dosage unit of the present invention com- 20 prises carriers or excipients, which may act to promote 2. Use according to claim 1, wherein said solid dosage dissolution of both active substances. Examples of such unit is for the treatment or prevention of hypertension carriers and excipients include substances that are read- in a woman. ily soluble in water such as cellulose derivatives, car- boxymethyl cellulose, hydroxypropyl cellulose, hydroxy- 25 3. Use according to claim 2, wherein said woman Is a propyl methyl cellulose, gelled starch, gelatin or polyvi- peri-menopausal woman. nylpyrrolidone. In particular, it is anticipated that polyvi- nylpyrrolidone might be particularly helpful to promote 4. Use according to claim 2, wherein said woman is a dissolution. post-menopausal woman. [0055] The term "pharmaceutically acceptable carriers 30 and excipients" is intended to mean substances, which 5. Use according to any of the preceding claims, where- are substantially harmless to the individual to which the in said drospirenone is micronized. dosage unit will be administered. Such an excipient nor- mally fulfils the requirements given by the national drug agencies. Official pharmacopeias such as the British 35 Patentansprüche Pharmacopeia, the United States of America Pharmaco- peia and the European Pharmacopeia set standards for 1. Verwendung von Drospirenon zur Herstellung einer well-known pharmaceutically acceptable excipients. festen, Drospirenon als einzigen therapeutischen [0056] Suitable pharmaceutically acceptable excipi- Wirkstoff enthaltenden Dosierungseinheit zur Be- ents according to the invention include all kinds that may 40 handlung oder Prävention von Bluthochdruck, wobei be used for solid dosage units. die feste Dosierungseinheit eine Dosis von 2, 2,5 oder 3 mg Drospirenon enthält. Example 1 2. Verwendung nach Anspruch 1, wobei die feste Do- [0057] A composition comprising Drospirenone may 45 sierungseinheit für die Behandlung oder Prävention be manufactured in the following manner: von Bluthochdruck bei einer Frau bestimmt ist.

Tablet cores of the following composition 3. Verwendung nach Anspruch 2, wobei es sich bei der Drospirenone (preferably micronised) 3.00 mg Frau um eine perimenopausale Frau handelt. lactose monohydrate 45.2 mg 50 corn starch 14.40 mg 4. Verwendung nach Anspruch 2, wobei es sich bei der modified starch 9.60 mg Frau um eine postmenopausale Frau handelt. polyvinylpyrrolidone 25,000 4.00 mg 5. Verwendung nach einem der vorhergehenden An- magnesium stearate 0.80 mg 55 sprüche, wobei das Drospirenon mikronisiert ist. are prepared by charging a fluidised bed granulator with

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Revendications

1. Utilisation de la drospirénone pour la préparation d’une unité de dosage solide comprenant la drospi- rénone en tant que seul agent thérapeutiquement 5 actif destiné au traitement ou à la prévention de l’hy- pertension, caractérisée en ce que ladite unité de dosage solide contient une dose de 2, 2,5 ou 3 mg de drospirénone. 10 2. Utilisation selon la revendication 1, caractérisée en ce que ladite unité de dosage solide est destinée au traitement ou à la prévention de l’hypertension chez une femme. 15 3. Utilisation selon la revendication 2, caractérisée en ce que ladite femme est une femme péri-ménopau- sée.

4. Utilisation selon la revendication 2, caractérisée en 20 ce que ladite femme est une femme post-ménopau- sée.

5. Utilisation selon l’une quelconque des revendica- tions précédentes, caractérisée en ce que ladite 25 drospirénone est micronisée.

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REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• WO 0195892 A [0007] • DE 19633685 [0012] • WO 0209759 A [0008] • WO 98067838 A [0012] • WO 0134132 A [0009] • WO 0115701 A [0015] • WO 9515166 A [0010] • WO 0152857 A [0015]

Non-patent literature cited in the description

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