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(19) United States (12) Patent Application Publication (10) Pub 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 MEDICATION 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
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