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US 20120189599Al (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0189599 A1 Lindemann et al. (43) Pub. Date: Jul. 26, 2012

54 FOR ORAL P u bl'lcatlon ' Cl assl'? cation' ADMINISTRATION, COMPRISING AT LEAST (51) Int Cl ONE ESTROGEN AND/OR AT LEAST ONE A 62K é5/74 (200601) GESTAGEN AND AT LEAST ONE PROBIOTIC A611) 15/02 (200601) BACTERIAL STRAIN A61P 5/34 (2006.01) A61P 13/00 (2006.01) (75) Inventors: Stefanie Lindemann, Berlin (DE);

Sascha General, Berlln (52) US. Cl...... 424/93.45; 424/93.4 (73) Assignee: BAYER PHARMA 57 ABSTRACT AKTIENGESELLSCHAFT, ( ) Berlin (DE) The present invention relates to a medicament for oral admin istration containing at least one estrogen and/or one gestagen and at least one probiotic bacterial strain, such as for example (21) APP1- NOJ 13/322,131 laclobacillus species. _ The medicament according to the invention is used either for (22) PCT Flled: May 14’ 2010 oral contraception or for hormone therapy (HT), during Which it can simultaneously serve for the stabilization of the (86) PCT No.1 PCT/EP2010/002965 vaginal environment and hence the prevention of infectious diseases, such as for example vaginal mycosis, bacterial vagi § 371 (0X1), nosis and/or bladder in?ammation (bacterial cystitis) or the (2)’ (4) Date; API-_ 12, 2012 prevention of urogenital symptoms, e. g. dyspareunia and dys uria. (30) Foreign Application Priority Data The present invention further relates to pharmaceutical com bination preparations Which contain dosage units containing May 22, 2009 (DE) ...... 102009022947.7 an aforesaid medicament and further dosage units containing May 27, 2009 (DE) ...... 1020090236325 exclusively a probiotic bacterial strain. US 2012/0189599 A1 Jul. 26, 2012

MEDICATION FOR ORAL siderable burden on the budget available for health care. ADMINISTRATION, COMPRISING AT LEAST Additional costs to the state and to society arise through the ONE ESTROGEN AND/OR AT LEAST ONE losses of Working hours caused thereby. GESTAGEN AND AT LEAST ONE PROBIOTIC [0011] Urogenital tract infections, such as for example bac BACTERIAL STRAIN terial vaginosis, are a risk factor for premature births or are associated With an increased risk of the Woman giving birth prematurely (Nelson). [0001] The present invention relates to a medicament, Which contains at least one estrogen and/or at least one [0012] In perimeno- and postmenopausal Women, oWing to gestagen and at least one probiotic bacterial strain (eg a the estrogen de?ciency, the natural, laclobacillus-containing laclobacillus). vaginal ?ora is suppressed by uropathogenic microbes and [0002] The medicament according to the invention is con thus the vaginal environment is destabiliZed. ?gured such that it can be used either for oral contraception or [0013] In peri- and postmenopausal Women, the estrogen for hormone therapy (HT) and thus at the same time can be de?ciency leads to a reduction in the supply of glycogen used for stabilization of the vaginal environment and hence positive vaginal epithelium and associated thereWith to a the prevention of infectious diseases, such as for example reduction in the naturally occurring laclobacilli. As a result, vaginal mycosis, bacterial vaginosis and/or bladder in?am this leads to a destabiliZation of the vaginal environment mation (bacterial cystitis) or the prevention of urogenital associated With a shift in the vaginal pH. These changes in the symptoms, eg dyspareunia and dysuria. vaginal environment have the same consequences (patho [0003] The pharmaceutical ?rms active in the ?eld of fer genic microbial invasion) as already described for premeno tility control are constantly endeavoring to improve the exist pausal Women. ing contraceptives. This includes not only increasing contra ceptive reliability by development of neW substances and [0014] The terms pre-, peri- and postmenopausal are uti improved comfort of use. Rather they are also pursuing inno liZed in the context of the present invention in the manner vative approaches to the combination of contraception and familiar to the person skilled in the art. disease prevention. [0015] As Women’s age increases, the risk factors, such as [0004] In premenopausal Women, the vaginal environment for example age-related anatomical changes, immunological is shifted toWards the neutral to basic by sexual activity, factors and/or reduced perfusion, also increase. Associated oWing to the pH of the ejaculate. This has the consequence With this there is increasing incidence and chroni?cation With that the vaginal ?ora only capable of existence in the acidic increasing age. In particular, the treatment of older, often also range, eg the naturally occurring laclobacilli, is suppressed multimorbid female patients necessitates a systematic treat or replaced by urinary pathogens groWing in the basic range ment of urogenital tract infections. In this patient clientele, (Candida, E. coli, A. vaginae or G. vaginalis). often under polypharmacological treatment, the risk of [0005] As a result, for sexually active Women there is an undesired drug interactions also increases With each addi increased risk of contracting the aforesaid urogenital tract tional therapy. infections or symptoms. Admittedly, current standard thera [0016] After the treatment of genital tract infections pies (metronidaZole, clindamycin and antimycotics, etc.) already described above, as a rule there folloWs the adminis enable substantial eradication of the pathogenic microbial tration of laclobacillus-containing vaginal tablets or capsules ?ora; hoWever because of their mechanism of action they are for restoration of the healthy vaginal environment. not capable of restoring the natural vaginal environment, including laclobacillus coloniZation (Marellli). [0017] Here in some preparations a small addition of estro gens, for example estriol in the medicament Gyno?or®, is [0006] Associated With this is an increased risk of reinfec given to increase glycogen release and associated thereWith to tion resulting in chroni?cation. In addition, because of the provide a further nutritional basis for the laclobacilli. repeated treatments, there is an increased risk of the develop ment of a microbial ?ora largely resistant to standard thera [0018] The positive effects of laclobacillus administration pies (Cribby; Hay). in patients suffering from bacterial vaginosis (Anukam; May) [0007] The symptoms associated With these infections lead or from urogenital tract infections (Falagas; Reid a)) have to considerable psychological stress in the Women affected been described many times in recent years. resulting in frequent medical consultations and/ or inadequate [0019] The currently available, exclusively vaginal, pre self-medication. Depending on the colonization status as sentations of laclobacilli do not alloW the continuation of the regards the probiotic bacterial species (rectal or intravaginal), treatment during the vulnerable menstruation phase. Like age, race/ethnic origin, education level and social status of the Wise, the vaginal application of tablets and suppositories Woman, there is a high incidence of urogenital tract infection, leads to undesired, compliance-inhibiting effects, for e.g. bacterial vaginosis (Johannsen). example the out?oW of formulation residues, and to stinging, [0008] Literature statements on the incidence of bacterial itching and redness. vaginosis vary from 4 to 60% depending on the population [0020] It has hoWever already been described that by means studied. In the USA, for example, up to one third of all of oral administration of certain probiotic strains (Lacloba sexually mature Women contract bacterial vaginosis cillus rhamnosus GR-l, Laclobacillus reulerii RC-l4) it is (AllsWorth). possible to restore the normal vaginal ?ora in postmenopausal [0009] 70 to 75% of all Women contract vulvovaginal vagi Women (Petricevic). nosis at least once in their life: 40 to 50% of all Women [0021] It had already previously been shoWn that lacloba contract it several times (Sobel). cilli (Laclobacillus rhamnosus, Laclobacillus fermenlum) [0010] Because of their high incidence and their high can reach the vaginal region after oral administration relapse rate, the urogenital tract infections represent a con (Marelli; Reid b)). US 2012/0189599 A1 Jul. 26, 2012

[0022] The adhesion of the laclobacilli as a function of the [0029] Hence one embodiment of the present invention menstrual cycle (and hence as a function of the particular relates to a medicament for oral administration containing at hormone status) has already been demonstrated in ex vivo/in least one estrogen and/or one gestagen and at least one pro vitro studies (Chan). biotic bacterial strain. [0023] The connection betWeen a loW estrogen level and [0030] Further embodiments are stated in the dependent reduced laclobacillus coloniZation can also be observed in claims 2 to 14. postmenopausal Women (Falagas). [0024] The present invention is based on the objective of [0031] A further embodiment consists of a multiphase creating a contraceptive or an HT preparation Which mini pharmaceutical combination preparation (kit) containing at miZes the diseases described or the disease risks due to sexual least 20 daily dosage units containing a medicament for oral activity in the aforesaid patient groups. administration containing at least one estrogen and/or one [0025] The invention is also based on the objective of dis gestagen and at least one probiotic bacterial strain and at least covering a medicament or treatment regime in the form of a one daily dosage unit containing at least one probiotic bacte pharmaceutical composition (kit), Which ensures that the user rial strain, Wherein the number of all dosage units contained of the medicament or the pharmaceutical composition in the kit is at least 28 and the dosage units are arranged such according to the invention is also still reliably protected that ?rst the dosage units containing the medicament for oral against urogenital tract infections for a further period after administration containing at least one estrogen and/or one discontinuation. gestagen and at least one probiotic bacterial strain and then [0026] According to the invention, a combination prepara the dosage units containing only the probiotic bacterial strain tion is proposed, Which is suitable for simultaneous oral use are to be taken. of the contraceptive or HT preparation and of the probiotic bacterial strain. [0032] Concerning further embodiments for the pharma [0027] Hormonal, oral contraceptives in every case contain ceutical combination preparation according to the invention, a gestagen (so-called POPs, only pill); hoWever reference is made to the dependent claims 16 to 22. in most cases they contain an estrogen (in most cases this is [0033] If it is an oral contraceptive, the pharmaceutical ethinylestradiol) and a gestagen. Here, different administra combination preparation according to the invention is in par tion and dosage regimes are knoWn. ticular administered as a 21 +7 or as a 24+4 regime, i.e. 21 or [0028] An HT preparation in every case contains an estro 24 daily dosage units containing an estrogen and gestagen gen (preferably this is estradiol or estradiol valerate; hoWever, and a probiotic bacterial strain and 7 or 4 daily dosage units ethinylestradiol is also possible) and in most cases also a containing exclusively a probiotic bacterial strain. gestagen. Here too, different administration and dosage [0034] These tWo regimes are represented diagrammati regimes are knoWn. cally in the folloWing tWo ?gures l) and H): US 2012/0189599 A1 Jul. 26, 2012

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[0035] Further, it is possible to use the medicament accord , , acetophenide, nestorone, ing to the invention in an extended administration cycle (“ex , 17-hydroxyprogesterone esters, 19-nor-17hy tended regimen”) or in a ?exible administration cycle. droxyprogesterone, 17alpha-ethinyl-testosterone, l7alpha [0036] Only the oral administration of the probiotic bacte ethinyl- 1 9-nor-testo sterone, d-17beta-acetoxy-13beta-ethyl rial strain in a pharmaceutical combination preparation for 17alpha-ethinyl-gon-4-en-3-one oxime or the compounds contraception enables the full expression of the already men disclosed in WO 00/66570, in particular tanaproget. tioned synergistic effects of the estrogen on the stabiliZation , , , , of the vaginal environment and the treatment With the lacto and are preferred. Drospirenone is bacilli in the vulnerable phase of menstruation. particularly preferred. [0037] In postmenopausal Women, the advantage consists [0042] As estrogens in the medicament according to the in the fact that on account of the oral administration route the invention or in the pharmaceutical combination preparation treatment can be continued Without restriction in spite of the according to the invention, ethinylestradiol, mestranol, symptoms attendant on dyspareunia and dysuria. quinestranol, estradiol, esters of estradiol, in particular the [0038] In every case through the administration of the com valerate or benZoate thereof, estrone, estrane, estriol, estetrol bination of oral contraceptive or orally administered HT and conjugated equine estrogens are possible. Here ethi preparation and the probiotic bacterial strain, a continuous nylestradiol, estradiol and estradiol valerate are preferred, presentation of the probiotic bacterial strain is achieved. and ethinylestradiol is particularly preferred. Because of the simultaneous ingestion With the contraceptive [0043] The quantities of the particular gestagens and/or or the HT preparation, compliance is increased. As a result of estrogens correspond to the quantities usually knoWn in oral this, Women in a risk group (sexually active Women or peri contraceptives or in oral HT preparations. and postmenopausal Women) are treated continuously With [0044] For example for the gestagens mentioned beloW probiotic bacterial strains and, attendant on this, With stabili these are normally as folloWs: Zation/restoration of the healthy vaginal environment. As a result, improved and continuous protection against urogenital tract infections and symptoms is achieved. Drospirenone 0.5-5 mg [0039] Through the administration of the medicament or Levonorgestrel 30-250 pg the pharmaceutical combination preparation according to the Norgestimate 180-250 pg invention, stabiliZation of the vaginal pH (3.5-4.2) over sev 0.5-1 mg 1-2 mg eral Weeks to several months after discontinuation of inges 20-150 pg tion of the medicament or the pharmaceutical combination Dienogest 1-3 mg preparation is achieved (specialist information on Gynof 60-75 pg lor®). This solves the initially posed problem of still reliably Tibolone 2.5 mg protecting the user against urogenital tract infections With the medicament or the pharmaceutical combination preparation [0045] According to the present invention, the daily admin for a certain time after discontinuation. istered preferred quantity of drospirenone is 0.5 to 5 mg. In [0040] The ascent of uropathogenic microbes from the one oral contraceptive (Yasmin®,YAZ®), 3 mg are contained vaginal mucosa and the cervical in?ammation environment per dosage unit. For the oral HT preparationAngeliq®, modi developing therefrom, particularly in the ?rst trimester, is a ?cations With different quantities of drospirenone, for knoWn risk factor for pregnant Women to give birth prema example With 1 or 2 mg of drospirenone, have been devel turely (Simhan). In particular With the early onset of a preg oped. nancy after ceasing taking the medicament, the user is thereby [0046] For the estrogens mentioned beloW, the quantity of still protected against urogenital tract infections for a certain estrogen used according to the invention is about: time. As a result, an important risk factor for giving birth prematurely is excluded. [0041] As gestagens, for example the folloWing substances can be used in the medicament according to the invention or Ethinylestradiol 10-50 pg Estradiol 1-4 mg in the pharmaceutical combination preparation according to Estradiolvalerate 1-4 mg the invention: levonorgestrel, norgestimate, norethisterone, Mestranol 50 [lg dydrogesterone, drospirenone, 66, 76,156, 16[3-dimethylen 3-oxo-17-pregna-4,9(11)-dien-21, 17[3-carbolactone (:9,11 dehydro-drospirenon:WO 2009/ 14681 1), 3-beta-hydroxy [0047] According to the present invention, the preferred desogestrel, 3-ketodesogestrel (:), daily administered quantity in an oral contraceptive for 17-deacetylnorgestimate, 19-norprogesterone, acetoxypreg example based on ethinylestradiol is 10 to 50 pg, particularly nenolone, , amgestone, , cyprot preferably 10 to 30 pg, quite particularly preferably 20 to 30 erone, , desogestrel, dienogest, dihydrogester [lg one, , , ethynodiol diacetate, [0048] Oral HT preparations usually contain betWeen 1 and ?urogestone acetate, gastrinone, gestodene, , 2 mg of estradiol. hydroxymethylprogesterone, hydroxyprogesterone, [0049] Probiotic bacterial strain is understood to mean (:lynoestrenol), mecirogestone, medroxyproges either a single bacterial strain or also a combination of several terone, , , , norethindrone such strains. (:norethisterone), norethynodrel, (including [0050] As examples of probiotic bacterial strains to be used d-norgestrel and dl-norgestrel), , normethis according to the invention in the medicament according to the terone, progesterone, , (17alpha)-17-hydroxy invention or in the pharmaceutical combination preparation 1 1-methylen-19-norpregna-4,15-dien-20-yn-3-one, according to the invention, the folloWing may be mentioned: US 2012/0189599 A1 Jul. 26, 2012

[0051] Bi?dobaclerium strains, lactobacillus species, such the milling process, the dry poWder of Laclobacillus acido as for example Laclobacillus reuleri, Laclobacillus reulerii philus obtained is for example mixed With one or more phar RC-14, Laclobacillus delbrueckii, Laclobacillus gasseri, maceutical additives. As suitable additives, for example lac Laclobacillusjensenii, Laclobacillus calenaforme, Lactoba tose, sucrose, microcrystalline cellulose, mannitol, calcium cillus paracasei, Laclobacillus paracasei Lbp PBOl, Lacto carbonate, magnesium stearate, high disperse silicon dioxide, bacillus casei, Laclobacillus acidophilus, Laclobacillus aci antioxidants, vitamins and trace elements may be mentioned dophilus Lba EBOl, Laclobacillus acidophilus Lba EB02, (WO 2005060937; EP 00931543; WO 2000195918). Laclobacillus crispalus, Laclobacillus crispalus CTV05, [0057] Suitable production processes for hormone prepa Laclobacillus salivarius, Laclobacillus brevis, Laclobacillus rations (oral contraceptives or HT preparations) are very Well fermenlum, Laclobacillusfermenlum RC-14, Laclobacillus knoWn to the person skilled in the art. fermenlum B-54, Laclobacillus planlarum, Laclobacillus [0058] The combination of lactobacillus preparations and planlarum Lbpl PB02, Laclobacillus Lbxx EB03, Lactoba hormone preparations is for example effected by ?lling into cillus Lbxx PB03, Laclobacillus rhamnosus, Laclobacillus capsules. For this, for example hard gelatin capsules are rhamnosus GR-1 and other genera or bacterial strains With opened, and each ?lled ?rst With a hormone-containing tablet essentially the same properties. or ?lm-coated tablet and then each ?lled With a de?ned vol [0052] Preferably the probiotic bacterial strain is Lactoba ume of a lactobacillus preparation in poWder form and then cillus reuleri, Laclobacillus gasseri, Laclobacillus crispalus sealed. and Laclobacillus rhamnosus or a combination of these pre [0059] Example concerning cell count stability from the ferred strains or a combination of at least one of these strains production of a probiotic for an oral dosage form: With at least one other of the strains from the above list. [0053] The daily dosage of probiotic bacterial strain is 107 to 1011 CFU (colony forming units), and the daily dosage is Cell type LaclobaciZZus acidophilus preferably 107 to 109 CFU. Preparation LaclobaciZZus powder 5 x 1010 CFU/ g Drug form Capsule (oral) 5 x 109 CFU/capsule FORMULATION Stability after one year Room temperature 5 x 107 CFU/capsule storage at 2-8° C. 5 x 108 CFU/capsule [0054] The person skilled in the art is familiar With the fact that in the production of medicaments containing lactobacil lus strains Which belong to the Lactobacteriaceae family and [0060] In Women treated With a medicament according to as obligate anaerobes excrete lactic acid, limitations have to the invention or With a pharmaceutical combination prepara be considered: thus lactobacillus preparations such as for tion according to the invention, compared to untreated example dry poWders from Laclobacillus acidophilus, Which Women, i.e. Women Who received only an oral contraceptive is mostly obtained from a fermentation process by cell con or oral HT preparation With no probiotic bacterial strain, a centration folloWed by freeZe-drying, are particularly sensi stabiliZation of the vaginal environment and associated there tive on the one hand to moisture and elevated temperature and With a loWer incidence of the urogenital tract infections on the other hand to mechanical stress. On the other hand, for described Was observed during the treatment and for a Week medicaments containing hormone active substances, in many further after the end of the treatment. cases production processes such as Wet granulation, tablet ting and ?lm-coating from aqueous ?lm suspensions are used, Literature so that tablets or ?lm-coated tablets are obtained as drug [0061] AllsWorth J. E. et al.: Prevalence of Bacterial Vagi forms. HoWever, during Wet granulation and ?lm-coating, the nosis. Obstetrics & Gynecology, Vol. 109, No. 1, 114-120, medicament to be produced is exposed to a moist, Warm January 2007 environment, and during tabletting the formulation compo [0062] Anukam K C, et al: Clinical study comparing pro nents are compressed by the application of high pressures. biotic Laclobacillus GR-1 and RC-14 With metronidaZole OWing to the aforesaid sensitivity of lactobacillus prepara vaginal gel to treat symptomatic bacterial vaginosis. tions, it is therefore not surprising that medicaments for oral Microbes-Infec (8, No. 12-13, 2772-6, 2006) use containing lactobacillus are predominantly marketed as [0063] Chan R. C. Y. et al.: Adherence of Cervical, vaginal non-compressed or only slightly compressed drug forms, for and Distal Urethral Normal Microbial Flora . . . Journal of example as apportioned poWders or in capsules or in the form Urology. 1984, Vol. 131, March, 596-601 of only slightly compressed cheWable tablets. [0064] Cribby S., et al: vaginal Microbiola and the Use of [0055] Formulations for use according to the present inven Probiotics. Interdisciplinary Perspectives on Infectious tion are therefore preferably produced in a manner Wherein Diseases Volume 2008, Article ID 256490 ?rstly production processes suitable for the lactobacillus [0065] Specialist information Gyno?or®, Stand 2007 preparations and for the hormones are each used separately [0066] Falagas M E, et al: Probiotics for prevention of from one another and then the lactobacillus preparation and recurrent urinary tract infections in Women: A revieW of the hormone preparation are combined in one medicament. evidence from microbiological and clinical studies. Drugs [0056] Suitable production processes for lactobacillus 2006, Vol/Iss/Pg. 66/9 (1253-1261), ISSN: 0012-6667 preparations are knoWn to the person skilled in the art. These [0067] Hay P.: Recurrent Bacterial Vaginosis. Curr Opin in many cases comprise a fermentation process for cell pro Infect Dis 22: 82-86, 2009 duction, cell concentration by centrifugation or separation [0068] J ohannsen E, et al: urogenital infections and probi and a drying process by lyophiliZation With the addition of otics. South African Journal of Obstretics and Gynecology several pharmaceutical additives. As suitable additives for the 2004, Vol/Iss/Pg. 10/3 (69-71), ISSN: 0038-2329 freeZe-drying, for example sucrose, microcrystalline cellu [0069] Kirjavainen P, et al: Expression of anti-microbial lose, mannitol, calcium carbonate, magnesium stearate or defence factors in vaginal mucosa folloWing exposure to high disperse silicon dioxide can be used. After completion of Laclobacillus rhamnosus GR-1. not published 2008 US 2012/0189599 A1 Jul. 26, 2012

[0070] Marelli G, et al: Laclobacilli for prevention of uro and dl-norgestrel), norgestrienone, normethisterone, proges genital infections: a revieW. European revieW for medical terone, quingestanol, (17alpha)-17-hydroXy-11-methylen and pharmacological sciences, March-April 2004, vol. 8, 19-norpregna-4,15-dien-20-yn-3-one, tibolone, trimege no. 2, p. 87-95, 118 refs, ISSN: 1128-3602 stone, , nestorone, promegestone, [0071] May A D, et al: Colonization of the rectum by Lac 17-hydroxyprogesterone esters, 1 9-nor-17hydroxyprogester Zobacillus species and decreased risk of bacterial vagino one, 17alpha-ethinyl-testo sterone, 17alpha-ethinyl-19-nor sis. The Journal of infectious diseases, 1 Aug. 2005, vol. testosterone, d-17beta-acetoXy-13beta-ethyl-17alpha-ethi 192, no. 3, p.394-8, ISSN: 0022-1899 nyl-gon-4-en-3 -one oxime or tanaproget. [0072] Melis G B, et al: Role of pH as a regulator of vaginal 4. The medicament as claimed in claim 1, characteriZed in physiological environment. Minerva Ginecol 52 (4) (111 that it contains several probiotic bacterial strains. 21) (2000) [0073] Milsom I, et al: Rational prescribing for postmeno 5. The medicament as claimed in claim 4, characteriZed in pausal urogenital complaints. DRUGS AGING 9 (2) 78-86 that it contains tWo probiotic bacterial strains. (1 996)1 996 6. The medicament as claimed in claim 1, characteriZed in [0074] Morelli L, et al: UtiliZation of the intestinal tract as that the probiotic bacterial strain or the probiotic bacterial a delivery system for urogenital probiotics. J Clin Gastro strains is/are selected from the group of bi?dobacterium enterol 2004; 38(6): 107-10 strains, laclobacillus species, such as for example Lacloba [0075] Nelson D. B.: Preterm Labor and bacterial vagino cillus reuleri, Laclobacillus reulerii RC-l4, Laclobacillus sis-associated bacteria among urban Women. J. Perinat. delbrueckii, Laclobacillus gasseri, Laclobacillus jensenii, Med. 37 (2009) 130-134 Laclobacillus calenaforme, Laclobacillus paracasei, Lacto [0076] Petricevic L et al: RandomiZed, double-blind, pla bacillus paracasei Lbp PBOl, Laclobacillus casei, Lacloba cebo-controlled study of oral laclobacilli to improve the cillus acidophilus, Laclobacillus acidophilus Lba EBOl, vaginal ?ora of postmenopausal Women. European Journal Laclobacillus acidophilus Lba EB02, Laclobacillus crispa of Obstetrics & Gynecology and Reproductive Biology Zus, Laclobacillus crispalus CTV05, Laclobacillus sali 141 (2008) 54-57 varius, Laclobacillus brevis, Laclobacillusfermenlum, Lac [0077] Reid G et al a): urogenital infections in Women: can Zobacillusfermenlum RC-l4, Laclobacillusfermenlum B-54, probiotic help? Postgraduate medical journal, August Laclobacillus planlarum, Laclobacillus planlarum Lbpl 2003, vol. 79, no. 934, p. 428-32, 40 refs, ISSN: 0032-5473 PB02, Laclobacillus LbXX EB03, Laclobacillus LbXX PB03, b): Oral use of Laclobacillus rhamnosus GR-l and Lacto Laclobacillus rhamnosus, Laclobacillus rhamnosus GR-l bacillus fermenlum GR-14 signi?cantly alters vaginal and other genera or bacterial strains With essentially the same ?ora: randomiZed . . . FEMS Immunol Med Microbiol properties. 2003; 35: 131-4 7. The medicament as claimed in claim 6, characteriZed in [0078] Silva C, et al: Effects of estrogen administration on that at least one of the probiotic bacterial strains is selected the coloniZation capability of laclobacilli and Escherichia from the group of Laclobacillus reuleri, Laclobacillus gas coli in the urinary tracts of mice. Methods Mol Biol 268 seri, Lucio-bacillus crispalus and Laclobacillus rhamnosus. [0079] Simhan H. N. et al: First-trimester cervical in?am 8. The medicament as claimed in claim 1, characteriZed in matory milieu and subsequent early preterm birth. Ameri that the folloWing are contained as the daily dosage of a can Journal of Obstetrics and Gynecology, 2009, 299:377. gestagen e1 -377.e4 [0080] Sobel J. D.: Vulvovaginal candidosis. Lancet 2004; 369: 1 961-71 Drospirenone 0.5-5 mg 1. A medicament for oral administration containing at least Levonorgestrel 30-250 pg one estrogen and/or one gestagen and at least one probiotic Norgestirnate 180-250 pg bacterial strain. Norethisterone acetate 0.5-1 mg Cyproterone acetate 1-2 mg 2. The medicament as claimed in claim 1, characteriZed in Desogestrel 20-150 pg that the estrogen is selected from the group of the compounds Dienogest 1-3 mg of ethinylestradiol, mestranol, quinestranol, estradiol, and Gestodene 60-75 pg esters of estradiol, in particular the valerate or benZoate Tibolone 2.5 mg thereof, estrone, estrane, estriol, estetrol and conjugated equine estrogens. 9. The medicament as claimed in claim 8, characteriZed in 3. The medicament as claimed in claim 1, characteriZed in that as the daily dosage 0.5 to 3 mg of drospirenone are that the gestagen is selected from the group of the compounds contained in an oral contraceptive. of levonorgestrel, norgestimate, norethisterone, dydrogester 10. The medicament as claimed in claim 8, characteriZed in one, drospirenone, 6[3,7[3;15B,16[3-dimethylen-3-oxo-17 that as the daily dosage 0.5 to 2 mg of drospirenone are pregna-4,9(1 1)-dien-21,17[3-carbolactone, 3beta-hydroxy desogestrel, 3-keto-desogestrel, 17-deacetylnorgestimate, contained in an oral HT preparation. 19-norprogesterone, acetoXy-, allylestrenol, 11. The medicament as claimed in claim 1, characteriZed in amgestone, chlormadinone, cyproterone, demegestone, that the folloWing are contained as the daily dosage of an desogestrel, dienogest, dihydrogesterone, dimethisterone, estrogen ethisterone, ethynodiol diacetate, ?urogestone acetate, gas trinone, gestodene, gestrinone, hydroxymethylprogesterone, hydroXy-progesterone, lynestrenol, mecirogestone, medrox Ethinylestradiol 10-50 pg yprogesterone, megestrol, melengestrol, nomegestrol, nore Estradiol 1-4 mg thindrone, norethynodrel, norgestrel (including d-norgestrel US 2012/0189599 A1 Jul. 26, 2012

16. The kit as claimed in claim 15 containing 20 to 30 daily -continued dosage units containing a medicament as claimed in claim 1, and 1 to 10 daily dosage units containing a probiotic bacterial Estradiolvalerate 1-4 mg strain. Mestranol 50 pg. 17. The kit as claimed in claim 16 containing 21 to 26 daily dosage units containing a medicament as claimed in claim 1, 12. The medicament as claimed in claim 11, characterized and 2 to 7 daily dosage units containing a probiotic bacterial in that as the daily dosage 10 to 50 pg, or 10 to 30 pg, or 20 to strain, Wherein the number of all do sage units contained in the 30 pg of ethinylestradiol are contained in an oral contracep kit is 28. tiVe. 13. The medicament as claimed in claim 11, characterized 18. The kit as claimed in claim 15 containing 21 to 26 daily in that as the daily dosage 0.5 to 2 mg of estradiol are con dosage units containing a medicament as claimed in claim 1 tained in an oral HT preparation. and 2 to 7 daily dosage units containing a probiotic bacterial 14. The medicament as claimed in claim 1, characterized in strain. that as the daily dosage of probiotic bacterial strain 107 to 101 1 19. The kit as claimed in claim 15 containing 21 daily CFU (colony forming units), preferably 107 to 109 CPU, are dosage units containing a medicament as claimed in claim 1 contained. and 7 daily dosage units containing a probiotic bacterial 15. A kit containing at least 20 daily dosage units contain strain. ing a medicament as claimed in claim 1 and at least one daily 20. The kit as claimed in claim 15 containing 24 daily dosage unit containing at least one probiotic bacterial strain, dosage units containing a medicament as claimed in claim 1 Wherein the number of all dosage units contained in the kit is and 4 daily dosage units containing a probiotic bacterial at least 28 and the dosage units are arranged such that ?rstly strain. the dosage units containing the medicament as claimed in one 21-22. (canceled) of the previous claims and next the dosage units containing only the probiotic bacterial strain are to be taken.