DE102017113263A1 - Pharmaceutical composition containing bacterial strains of the family Lactobacillaceae and whey - Google Patents

Abstract

The invention relates to a pharmaceutical composition comprising probiotic bacterial strains of the family Lactobacillaceae and whey. The invention further relates to the use of the pharmaceutical composition for the prophylaxis and / or treatment of vaginal, gastrointestinal and / or urogenital disorders and dairy products, nutraceuticals, nutritional supplements, medical devices and / or pharmaceutical compositions containing the pharmaceutical composition.

Description

Field of the invention

The invention relates to a pharmaceutical composition comprising probiotic bacterial strains of the family Lactobacillaceae and whey. The invention further relates to the use of the pharmaceutical composition for the prophylaxis and / or treatment of vaginal, gastrointestinal and / or urogenital disorders and dairy products, nutraceuticals, dietary supplements, medical devices and / or pharmaceuticals containing the pharmaceutical composition.

State of the art

Lactic acid bacteria are living organisms that interact symbiotically with the skin and mucous membranes of animals and humans and on the root system of the plant in the form of a mutualism. Probiotics are the "extract" of these lactic acid bacteria, which are administered to generate health benefits. Especially in the gastrointestinal tract, the upper respiratory tract and the vagina. Probiotics are already being used orally for the treatment of colds, vaginosis, diarrhea and urinary tract infections ( At the. J. Health Syst. Pharm. 2001, 58 (12): p 1101-1109 ).

The woman's vagina is a partial internal organ with external contact. In order to be able to sharply separate the outside and inside of a body, biology has embraced various mechanisms and has equipped this milieu with various modules.

Primarily, it is the epithelium, the first cell layer that has contact with the outside world. In order to prevent a build-up of harmful microorganisms, this cell layer must be able to react immunologically to this intruder so far that no damaging influences arise.

Significantly involved is the plant flora, called "Döderleinflora", which was discovered at the beginning of the 20th century and through its metabolism can produce an acid environment with a pH of about 4 ( Switzerland Rundsch Med Prax. 1975 Oct 7; 64 (40): 1289-94 ). The produced lactic acid from the bacterial metabolism of the glycogen in the vaginal mucosa has a low pH. As a result, organisms that are not part of the plant flora find it difficult to assert themselves.

Most of the lactic acid bacteria found there, especially Lactobacillus acidophilus and Lactobacillus crispatus, have the ability to produce the bacteriocin hydrogen peroxide. This protects their own terrain. All other lactic acid bacteria such as L. delbruekii, L. jensenii, L. buchneri, L. gasseri and Bifidobacterium, with their metabolism, form an environment in which pathogenic bacteria are difficult to colonize.

In addition, immunological processes are initiated via receptors (toll-like receptors) on the surface cells of the vaginal epithelium, which in turn affect the entire mucous membrane of the vagina ( At J Reprod Immunol. 2008 Jan; 59 (1): 35-43 ). Similar to the epithelial cell layers of the intestine, where about 80% of the entire body's immune system is controlled via the intestine, a similar process is to be assumed for the vaginal mucosa.

Whey (also called whey, cheese milk, Scotch, Sirte, Waddike, Wedicke or Zieger) is the aqueous greenish-yellow residual liquid that is produced during cheese production. It is the liquid part that can be separated into cheese or cottage cheese after the milk has coagulated. There are two types of whey: sweet whey (also called whey whey), which is produced when you make milk with cheese making cheese, and sour whey, which is formed when milk is decomposed by lactic acid bacteria.

Whey consists of 94% water, 4 to 5% lactose and is almost fat free. In addition, it contains lactic acid, vitamins B ₁ , B ₂ (this causes the greenish color) and B ₆ and potassium, calcium, phosphorus and other minerals, but especially 0.6 to 1% whey protein. Whey contains significantly less protein than milk. In particular, unlike milk, it hardly contains casein. In milk, however, casein is the main protein. Sweet whey has a pH of 5.6 or more, acid whey 5.1 or less.

For goat whey there is evidence of antioxidant processes ( Kerasioti, E. et al., Increase in antioxidant activity by sheep / goat whey protein by nuclear factor-like 2 (Nrf2) is cell type dependent, Food Chem Toxicol, 2016 Nov; 97: 47-56 ).

Lactic acid bacteria form an ecosystem in the vagina, which is also known as Döderleinflora - as mentioned - and form a natural protection of the vagina against pathological bacteria and overgrowth of pathogenic bacteria (Srinivasan, S. et al., The human vaginal bacterial biota and bacterial vaginosis, interdisciplinary.Perspect.Infect.Dis, 2008; 750479).

There are numerous studies that have shown that external, probiotic, intravaginal Lactobacilli lead to an improvement in the rate of infection of bacterial vaginitis and urinary tract infections ( Barrons, R. et al. Use of Lactobacillus Probiotics for Bacterial Genitourinary Infections in Women: A Review. Clin.Ther. 2008; 30: 453-468 ; Randomized, placebo-controlled phase 2 trial of a Lactobacillus crispatus probiotic given intravaginally for prevention of recurrent urinary tract infection, Stapleton et al., Clin Infect Dis., 2011; 52 (10): 1212-7 ; Probiotics for the treatment of bacterial vaginosis, Brown, D., Alternative Medicine Alert, 2012; 15 (3): 1-29 ; Bacterial vaginosis: a review of clinical trials with probiotics, Mastromarino, P. et al., 2013, New Microbiolocica, 36, 229-238 ; Use of lactobacillus probiotics for bacterial genitourinary infection in women: a review, Barrons, R. et al., Clinical Therapeutics, 2008, 30, 453-467 ; Efficacy of vaginal probiotic capsules for recurrent bacterial vaginosis: a double-blind, randomized, placebo-controlled study, Ya, W. et al., Am J Fruits Gynecol, 2010, 203, 120.e1-6 ; The role of vaginal Lactobacillus rhamnosus (Normogin®) in a controlled prospective pilot study, Parma, M. et al., Eur Rev Med Pharmacol Sci, 2013, 17, 1399-1403 ).

As mentioned, the normal vaginal flora is dominated by Lactobacillus species that produce substances that control the growth of pathogens. Bacterial vaginosis (BV) is a clinical condition characterized by a decrease in Lactobacillus species and an increased growth of anaerobic and mycoplasma bacteria. Some studies suggest that bacterial vaginosis may be associated with the development of inflammatory pelvic diseases and premature births. Furthermore, patients with bacterial vaginosis appear to be at an increased risk of having sexually transmitted diseases (STDs), including human immunodeficiency virus (HIV) infection ( Curr Infect Dis Rep 2001 Apr, 3 (2) 152-155, J Infect Dis 2002 Jan 1, 185 (1): 69-73 ), to get.

By administering Lactobacilli, it is possible to regenerate the vaginal flora of women with bacterial vaginosis. Bacterial vaginosis is one of the most common female gynecological problems. The vaginal infection is often caused by Candida albicans. The presence of lactobacilli is important for the maintenance of the intestinal microbial ecosystem. Lactobacilli has been shown to inhibit the growth of pathogenic bacteria such as Listeria monocytogenes, Escherichia coli, Salmonella spp. and others own. This inhibition could be due to the production of inhibitory compounds such as organic acids, hydrogen peroxide, bacteriocins or reuterin ( App. Environ. Microbiol., 1999, 65 (11) pp. 4949-4956 ).

It has also been shown that lactobacilli and its surfactant production can serve as adhesion suppressants of uropathogenic bacteria ( Role played by lactobacilli in controlling the population of vaginal pathogens, Soledad, B. et al., 2000, Microbes and Infection, 2, 543-546 ).

Here, the biofilm serves as a bacterial strategy to remain in inhospitable places. The resulting matrix and microbial behavior produces microbial resistance to antimicrobial agents, immune system and stressors ( Biofilms of vaginal Lactobacillus reuteri and Lactobacillus rhamnosus: kinetics of formation and matrix characterization, Leccese Terraf, MC et al., 2016, Arch Microbiol, 198, 689-700 ).

The hydrogen peroxide of intravaginal producing lactobacilli may further prevent bacterial vaginitis (hydrogen peroxide producing lactobacilli in women with vaginal infections, Mijač, Vd et al., European Journal of Obstetrics & Gynecology and Reproductive Biology, 2006, 129, 69-76 ).
discloses therapeutically beneficial strains of L. acidophilus and, more particularly, a strain characterized in that an average of at least 50 bacteria could adhere to a human intestinal mucosal cell after a five minute incubation of the bacteria with the cell.

WO 99/45099 discloses a new strain of L. plantarum LB 931. This strain can be used to treat or prevent urogenital infections. The strain was able to adhere well to vaginal epithelial cells as well as to inhibit or prevent the growth of various bacterial strains.

US 5,645,830 relates to Lactobacillus compositions and methods of using the compositions to prevent urogenital infections.

US ( WO 98/46261 ) discloses new strains, e.g. BL crispatus CTV-05, isolated from vaginal smears. The strain is characterized by an increased ability to adhere to vaginal epithelial cells and produce hydrogen peroxide.

EP 0956858 discloses the use of various strains of Lactobacillus alone or in combination. The strains were selected for their ability to attach to HeLa cells and produce hydrogen peroxide.

EP 1485463 A2 describes new Lactobacillus strains that can be used as probiotics or together with a prebiotic as a synbiotic. Furthermore, the use of the strains for the prevention or treatment of vaginal infections, urogenital infections and gastrointestinal diseases is described.

task

The object of the invention is to provide pharmaceutical formulations of suitable probiotic bacterial strains of the family Lactobacillaceae in combination with whey. In particular, the present invention relates to Lactobacillus acidophilus strain LA13100, Lactobacillus casei strain LA13120, Lactobacillus crispatus strain LA13130; Lactobacillus rhamnosus strain LA13220 and its ability to be used for the prophylaxis and / or treatment of vaginal, gastrointestinal and / or genitourinary disorders.

Another object of the present invention is to provide dairy products, nutraceuticals, nutritional supplements, medical devices and / or pharmaceutical compositions containing the pharmaceutical composition and the ability to prevent and / or treat vaginal, gastrointestinal and / or urogenital diseases to be used.

A further object of the present invention is to provide female sanitary napkin, sanitary napkin, panty liner, impregnated tampon, toilet tissue, panty guard and / or incontinence protector containing the pharmaceutical composition and also having the ability to prevent and / or treat vaginal, gastrointestinal and or urogenital diseases.

solution

This object is achieved by the invention with the features of the independent claim. Advantageous developments of the invention are characterized in the subclaims. The wording of all claims is hereby incorporated by reference into the content of this specification. The invention also includes all reasonable and in particular all mentioned combinations of independent and / or dependent claims.

In the following, individual process steps are described in more detail. The steps do not necessarily have to be performed in the order given, and the method to be described may also have other steps not mentioned.

DEFINITIONS

By "excipient" is meant any non-active ingredient that is added to form part of the final formulation.

By "probiotic" is meant a viable microbial supplement that has a positive impact on the patient through its effects vaginal, gastrointestinal (gastrointestinal) and / or urogenital tract.

A "prebiotic" is used herein as a substrate which has a beneficial effect on a probiotic and thus on the individual patient taking the probiotic.

A "patient" is used herein as a person suffering from any clinical condition associated with a microbial imbalance as well as a person prophylactically using bacterial preparations.

1. a) mindestens einen probiotischen Bakterienstamm aus der Familie der Lactobacillaceae und
2. b) Molke

einen positiven - und insbesondere synergistisch positiven - Einfluss auf einen Patienten ausüben kann.Surprisingly, it has been found that a pharmaceutical composition containing

1. a) at least one probiotic bacterial strain of the family Lactobacillaceae and
2. b) whey

can exert a positive - and especially synergistic - positive influence on a patient.

The Lactobacillaceae form a family of Gram-positive bacteria of the order Lactobacillales. By fermentation, they produce lactic acid and thus belong to the lactic acid bacteria, to which a few other families are placed, which are united in the systematics in the order of Lactobacillales. Many species of this family are important to the food industry. They are used for the production of dairy products, but they can also occur as pests (for example in the brewery). As a rule, they do not harm humans, they are apathetic.

The Lactobacillaceae family currently comprises three genera: the lactobacilli (Lactobacillus), the pediococci (Pediococcus) and Sharpea. The latter contains only one species, Sharpea azabuensis. The species Paralactobacillus selangorensis is now a synonym of Lactobacillus selangorensis.

Preferably, the pharmaceutical composition contains at least three, preferably four, probiotic bacterial strains of the family Lactobacillaceae.

In a preferred embodiment, the probiotic bacterial strains are selected from the genus Lactobacillus.

As listed, Lactobacillus is the name of a genus of Gram-positive, mostly rod-shaped bacteria from the family Lactobacillaceae. Its name is "Germanized" also as Laktobazillus (plural: Laktobazillen) written. Lactobacillus belongs together with other bacterial genera to the lactic acid bacteria, they all produce by fermentation lactic acid.

The Lactobacillus species are important to the food industry. They are used for the production of dairy products and beer specialties. As a rule, they do not harm humans, they are apathetic.

In terms of their characteristics, the members of the genus Lactobacillus do not form a single group, so individual species are grouped into subgroups. Within the system, it can be observed that individual species are new or no longer of the genus.

In a further preferred embodiment, probiotic bacterial strains of the genus Lactobacillus are Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus crispatus and / or Lactobacillus rhamnosus. Particularly preferred are the Lactobacilli strains Lactobacillus acidophilus strain LA13100, Lactobacillus casei strain LA13120, Lactobacillus crispatus strain LA13130 and / or Lactobacillus rhamnosus strain LA13220. In a further preferred embodiment, these can also be administered together with a pharmaceutically acceptable carrier and / or diluent.

In a further preferred embodiment of the invention, the pharmaceutical composition is characterized in that the whey of mammals selected from the group of equidae (Equus, for example, horses, donkeys) or cloven-hoofed animals (Artiodactyla or Paraxonia, for example, cattle, pigs, camels, Goats, sheep). Preferably, the pharmaceutical composition is characterized in that the whey contained therein is derived from ruminants (Ruminantia, for example cattle, goats, sheep). It is particularly preferred if the whey is derived from goats (Capra).

Goat's milk contains about 2.8 to 3.5% protein, about 2.7 to 3.5% fat and about 4.4% lactose. In terms of nutritional value and dry matter, goat's milk differs only slightly from cow's milk. However, goat's milk contains more short- and medium-chain fatty acids than cow's milk. These fatty acids are more easily assimilated by the body than long-chain ones and are therefore more digestible. In addition, the fat globules of goat's milk are smaller than those of cow's milk. The many small fat globules result in a larger overall surface and thus a larger attack surface for enzymes, which further improves the digestibility. It is also said that goat's milk is already "naturally homogenized". Homogenization (mechanical splitting of the fat globules) as in cow's milk is therefore not necessary in view of the digestibility of goat's milk. This eliminates the health disadvantages partially associated with homogenization. The proteins of goat's milk are particularly digestible. Goat's milk has a lower content of casein and a higher content of water-soluble whey protein than cow's milk. In many places, sheep's and goat's milk is recommended as an alternative to cow's milk allergy. Studies show that many cow hypoallergenics can tolerate goat's milk.

From the production of organic goat whey. Whey produced in goat cheese production is freshly frozen and lyophilized, ie freeze-dried and applied as a powder. Due to the very gentle process, most substances are contained, which would also be present in the fresh state: Pro and prebiotics, proteins, nutrients.

Preferably, the milk from which the whey is derived comes from goats which are not kept in a stable. Such animals are less susceptible to infectious diseases. This is particularly preferably so-called organic goat's milk, i. The goats graze outside, have an outdoor spout and a healthy, herb-rich feed base, so that the - supposedly strict - goat's milk taste is very mild to slightly aromatic. Furthermore, the whey of such goats is characterized by the fact that any seasonal differences in the measured contents of goat whey could be largely avoided.

In a further preferred embodiment of the invention, the whey originates from many individual goat milk fractions, for example from at least 100, preferably at least 200, goats. A whey derived from many goats shows many advantages over whey obtained from a few goats. It is e.g. polyvalent, i. it shows a high degree of homogeneity and the concentration of the active substances or their activities are independent of the lot. It can be manufactured in accordance with the EU GMP guidelines (Quality Assurance Guidelines for Production, Equipment, Media and Clean Room Environment in the Production of Medicines and Active Ingredients, Cosmetics, Food and Feed).

In a preferred embodiment, the whey is present as a concentrate, preferably as a powder, in particular as a lyophilisate. This can be done, for example, by the fact that the whey produced in the (goat) I cheese production freshly by means of freeze-drying, also referred to as lyophilization, lyophilization or sublimation drying, is treated. Freeze-drying is understood to mean a process for the gentle drying of products. Freeze-drying is based on the physical process of sublimation: In the process, the ice crystals sublimate directly into the gaseous state without the intervening appearance of a liquid phase. The final product of the freeze-drying is called lyophilisate. Freeze-drying is used especially for thermally sensitive products. This very gentle process ensures that, as far as possible, all substances which would also be present in the fresh state are present, including prebiotics, proteins, nutrients, etc. In this context, it should be mentioned that the whey according to the invention is preferably Sour whey acts. As mentioned, in the sweet whey, the milk is thickened by the addition of rennet (an enzyme from the calf's stomach). In acid whey, lactic acid bacteria are used to initiate the coagulation process. It settles on sour milk or quark, which can then be processed into cheese. What remains is the sour whey.

The pharmaceutical composition preferably contains cellulose and / or lactose in addition to the probiotic bacterial strains and the whey. Pharmaceutically acceptable carriers and / or diluents or diluents include all formulations which ensure ready administration of the pharmaceutical composition. These are known to those skilled means that are encompassed by the present invention.

In a further preferred embodiment, the lactobacilli are present in concentrations of 10 ⁵ to 10 ¹³ colony forming units (CFU) per gram of Lactobacillus, preferably in concentrations of 10 ⁶ to 10 ¹² colony forming units (CFU) per gram of Lactobacillus. This may concern one of the strains, several of the strains, or all strains used. Preferably, the bacteria used according to the invention are used directly, more preferably in a lyophilized form.

In principle, the pharmaceutical composition according to the invention can be present in all pharmaceutically useful administration forms known to the person skilled in the art, for example as powder, capsules, spray, gel, cream, a solution, for example a solution for lavages, a beverage, a cosmetic, an ovule, a vaginal insert , Liquid, suppositories, tablets and / or a microencapsulated product which may contain excipients for proper administration. It may be in pure form, but also as a concentrate, e.g. present as a powder concentrate, a particularly preferred embodiment of the invention. In addition, it may all be for use as a pharmaceutical composition and according to the chosen application or administration form (for example endobronchial, enteral, epidural, inhalative, intraarterial, intraarticular, intragastric, intracardiac, intracutaneous, intralumbaral, intralymphatic, intramammary, intramuscular, intraneural, intraperitoneal, intrapleural, intrapulmonary, intratracheal, intraurethral, intrathecal, intravenous, intranasal, oral (also effective locally if, for example, it is held in the oral cavity for a few minutes and then gargled with it, for example at the first sign of tonsillitis , Pharyngitis, laryngitis In the prodromal stage of influenza, patients may experience elimination or alleviation of subjective symptoms such as fever, limb / back pain or fatigue) peroral, parenteral, percutaneous, peridural, perineural, rectal, sublingual, subconjunctival, subcutaneous, systemic , topically, transdermally, vaginally) necessary fillers and additives known to those skilled in the art, for example fillers, binders, disintegrants, lubricants and e.g. also in the freeze-dried state. The person skilled in the corresponding formulation aids are known and are also included according to the invention.

To increase the ability of the pharmaceutical formulation of the present invention to adhere to a mucous membrane, mucosal binders may be added to the pharmaceutical composition of the present invention. Preferably, the pharmaceutical composition contains up to about 10% of mucosal binder. The preferred mucosal binder is a hydrocolloid, preferably the hydrocolloid is selected from the group consisting of xanthan gum, locust bean gum (product derived from Ceretonia siliqua (carob tree)) and / or alginate, most preferably the hydrocolloid is xanthan gum (bacterial polysaccharide produced by Xanthomonas campestris).

In a particularly preferred embodiment, the pharmaceutical composition is used as a vaginal composition. Preferably, this vaginal composition still contains a substrate. Preferably, this substrate is not fermented by Candida albicans or Gram-negative pathogenic bacteria.

In order to initially give the bacteria optimal growth conditions and thus recolonise the bacteria by adherence in vivo, it is important to incorporate a substrate, ie a specific nutritional growth medium for the bacteria, in the formulation. The substrate serves as a functional prebiotic which, together with the probiotic, has a synergistically positive effect on the patient. Lactose is an example of such Substrate. It may be relevant to provide a bacterial formulation with a substrate that is not a substrate for Candida albicans and Gram negative pathogenic bacteria.

Vaginal formulations may be provided which include a substrate that is not fermented by Candida albicans. Preferably, the substrate is an oligosaccharide, more preferably the substrate is lactitol, oligofructose and / or lactulose, in particular the substrate is lactitol.

The effect of lactitol on the in vitro adherence of lactobacilli has been studied in the past. It was found that the lactitol does not affect the overall ability of the Lactobacilli strains to adhere to the cells and thus will not affect the in vivo adherence.

In a preferred embodiment of the present invention, a substrate which is not or not readily fermented by Candida albicans or Gram-negative pathogenic bacteria is used in the preparation of a vaginal formulation. This substrate is preferably an oligosaccharide, more preferably the substrate is lactitol, oligofructose and / or lactulose, and most preferably the substrate is lactitol.

As mentioned, Candida albicans or Gram-negative pathogenic bacteria are unable to ferment certain oligosaccharides. Therefore, preferably substrates are used, which are selected according to the intended purpose. As has been stated, such a substrate is preferably an oligosaccharide, particularly preferably oligofrucose and / or a disaccharide, in particular lactose. These can be used in the vaginal formulation as a substrate. Lactose is used primarily as a substrate, if no pathogens are to be fought, which can implement / ferment lactose itself.

• - Bakterien: Eines der häufigsten Beschwerdebilder einer Scheideninfektion stellt die bakterielle Vaginose (BV) dar. Dabei kommt es zur Verdrängung der gesunden Scheidenflora durch meist anaerobe (ohne Sauerstoff überlebensfähige) Bakterien. In bis zu 70 Prozent der Fälle kann der Erreger Gardnerella vaginalis (früher: Haemophilus vaginalis) im Scheidensekret nachgewiesen werden. Daher wird vielfach von einer Gardnerellen-Infektion gesprochen. Weiterhin finden sich auch Bakterien der Gattungen Mobiluncus oder Bacteroides. Als wichtigste Komplikation einer bakteriellen Vaginose ist die Gefahr von Frühgeburten zu nennen. Weitere Bakterien, die für eine Infektion der Scheide verantwortlich gemacht werden können, sind Streptokokken, Staphylokokken oder Enterokokken.
• - Pilze: Die häufigste Pilzinfektion der Scheide wird durch den Sprosspilz Candida albicans verursacht. Sprosspilze finden sich gelegentlich in kleinen Mengen auch im gesunden Scheidenmilieu. Damit es zu einer Pilzinfektion kommen kann, muss sich zuvor das Milieu der Scheide entsprechend verändern - sprich, die Standardflora aus Milchsäurebakterien muss bereits gestört sein. Dies kann durch eine Therapie mit Antibiotika oder eine Grunderkrankung wie Diabetes mellitus bedingt sein. Auch Personen mit einer Schwäche des Immunsystems leiden gehäuft an Pilzinfektionen. In seltenen Fällen können auch Dermatophyten (Hautpilze) für eine Pilzinfektion der Scheide verantwortlich sein.
• - Viren: Die wichtigsten viralen Infektionen im Bereich der Scheide werden durch Humane Papilloma-Viren (HPV) und durch Herpes simplex-Viren (HSV) bedingt.

In a particularly preferred embodiment of the present invention, the pharmaceutical or vaginal composition is used for the prophylaxis and / or treatment of vaginal, gastrointestinal (gastrointestinal) diseases and / or urogenital diseases, in particular vaginal, gastrointestinal and / or urogenital infections. According to the invention, vaginal infections include diseases caused by bacteria, fungi, viruses and / or unicellular organisms (protozoa). Examples of vaginal disorders included in the invention, in particular vaginal infections, are:

• - Bacteria: Bacterial vaginosis (BV) is one of the most common symptoms of vaginal infection. It displaces the healthy vaginal flora through mostly anaerobic (without oxygen survivable) bacteria. In up to 70 percent of cases, the pathogen Gardnerella vaginalis (previously: Haemophilus vaginalis) can be detected in the vaginal secretions. Therefore, many talk about a Gardnerella infection. Furthermore, there are also bacteria of the genera Mobiluncus or Bacteroides. The most important complication of bacterial vaginosis is the risk of premature birth. Other bacteria responsible for vaginal infection include streptococci, staphylococci or enterococci.
• - Mushrooms: The most common fungal infection of the vagina is caused by the filamentous fungus Candida albicans. Mushrooms are sometimes found in small quantities in healthy vaginal milieu. In order for a fungal infection to occur, the milieu of the vagina must first change accordingly - that is, the standard flora of lactic acid bacteria must already be disturbed. This may be due to antibiotic therapy or underlying disease such as diabetes mellitus. Even people with a weakness of the immune system are more likely to suffer from fungal infections. In rare cases, dermatophytes (skin fungi) may be responsible for a fungal infection of the vagina.
• - Viruses: The most important vaginal viral infections are caused by human papilloma viruses (HPV) and herpes simplex viruses (HSV).

Human Papilloma Viruses: Of the more than 120 strains of HP virus known today, about 30 are affected by the genital or urinary tract of humans. The prevalence rate with HP viruses is very high in the population with up to 80 percent. The transmission is usually through sexual intercourse or contaminated objects and devices such as towels or toilets. So-called low-risk viruses (especially HPV 6 and HPV 11) cause benign, sometimes very stressful condylomas (genital warts) in the genital area. Chronic infection with high-risk viruses (especially HPV 16 and HPV 18) may lead to the formation of so-called cervical intraepithelial neoplasms and, subsequently, the development of cervical cancer.

Herpes simplex viruses: Infections with herpes simplex viruses - the types HSV 1 and HSV 2 are classified - are among the most common sexually transmitted diseases. In about 90 percent of cases, genital herpes will be affected by an HSV-2 Causes infection. In most cases, genital herpes in women affects the external genitals (vulva), but can also affect the vagina. In Germany, a rate of infection with HSV 2 of up to 25 percent is suspected. In HSV infections, a distinction is made between a primary infection and a reactivation of the virus: Although primary infections are usually associated with much stronger symptoms, they can also be very symptom-poor, so that many initial infections are not recognized. This circumstance is particularly important in obstetrics, because it can lead to infection of the newborn during birth. A herbal infection of the child resulting from the birth process can lead to the most serious damage to the nervous system and even the death of the child. After a first infection, the herpes viruses remain in nerve cells for life and can be activated by external stimuli - such as illness, hormonal changes or stress - again. The risk of neonatal infection during labor is much lower in such cases.

- Protozoa:

Among the parasitic organisms that infest the vagina, Trichomonas vaginalis is of particular importance. This pathogen has adapted to the conditions in the vagina, the man on the area of the prostate. Trichomonas vaginalis is a single-celled organism that can move through filiform processes (called flagella). The transmission of trichomonads occurs almost exclusively via sexual intercourse. After an acute, usually painful infection of the vagina, the parasites can remain in the vagina for a long time without treatment and thus lead to a chronic infection. In males, an infection usually runs "mute", ie without the appearance of symptoms, so that the affected person does not notice the colonization by parasites. For this reason, a treatment of the sexual partner should always be carried out.

• • starke Schmerzen, die vor allem beim Geschlechtsverkehr auftreten,
• • starke Rötungen der vaginalen Schleimhaut sowie
• • ein unangenehmer vaginaler Ausfluss (Fluor).

Since many pathogens may be responsible for a vaginal infection, the severity of the symptoms can vary widely. The course of an infection is also dependent on individual factors, such as the immune status of a woman. In the foreground of a vaginal infection usually stand

• • severe pain, especially during intercourse,
• • severe redness of the vaginal mucosa as well
• • an unpleasant vaginal discharge (fluorine).

However, it can also lead to asymptomatic progressions. The nature and odor of the vaginal discharge already make it possible to draw conclusions about the pathogen: bacterial vaginosis is characterized by a fishy-smelling, partly greenish secretion. A similar finding may also result from infection by trichomonads, which also foamy discharge is typical here. In a fungal infection, the picture may range from a local whitish fungal lining of the vaginal wall to an odorless pot-like discharge.

HPV infection with low-risk viruses can lead to the development of painless genital warts (condyloma). The expression of the genital warts can be very different and range from very small flat warts to very voluminous growth forms (giant condylomas).

Primary HSV infection can cause generalized disease symptoms such as fever, muscle aches and tiredness. In the genital area, characteristic vesicles can form on a red background, which are associated with severe itching and pain. In addition, swelling of the local lymph nodes may occur. Almost asymptomatic courses are possible with initial infections.

When reactivation of the HS virus, the course of infection is usually much weaker than in the course of the primary infection. Typically, so-called prodromes or precursor symptoms occur here. Such signs - such as tickling or discomfort - can precede the typical cold sore for several hours to days.

According to the invention, examples of gastrointestinal (gastric / intestinal) diseases, in particular gastrointestinal infections, are infections that affect the whole or parts of the gastrointestinal tract and can be caused by various pathogens (bacteria, viruses, fungi and worms). Known viral pathogens are, for example, Rota, adeno, human noroviruses, sapoviruses and astroviruses. Bacterial pathogens may be, for example, Salmonella, Campylobacter, Shigella, Yersinia, Clostridium difficile, Escherichia and Vibrio cholerae. Also, protozoa such as amoebae and giardia can cause the corresponding diseases. The mechanism of how the infection leads to the symptoms may vary. Predominantly the pathogens lead to a destruction of the mucous membrane of different extent. As a result, the food ingested in the stomach and intestine can no longer be digested. The undigested food binds water and makes the stool thin. In some bacterial gastrointestinal infections, the production of bacterial toxins (toxins) by the pathogens to an increased salt and Water loss through the mucosal cells of the intestine. This is the case, for example, with a special variety of Escherichia coli bacteria, a causative agent of typical traveler's diarrhea.

According to the invention, examples of urogenital diseases, in particular urogenital infections, are infections that affect the whole or parts of the urogenital tract and can be caused by various pathogens (bacteria, viruses, fungi and worms).

Urogenital tract infections are among the most common infections. They are associated with high direct treatment costs, indirect costs of lost time and a reduction in quality of life. For Europe there are no data on prevalence and economic importance. In the United States, urogenital infections are the cause of a visit to a doctor in more than 7 million cases each year. Approximately 15% of ambulatory antibiotic prescriptions are used for these infections, the direct cost of which is estimated at more than US $ 1 billion. More than 100,000 patients are hospitalized every year, mostly for pyelonephritis.

In the hospital, infections of the genitourinary tract are the most frequent infections with> 40%, in most cases they are catheter-associated. More than 25% of patients requiring more than seven days of urinary catheter drainage develop infection, with the risk increasing by 5% each day. The additional cost of an episode of these nosocomial infections is estimated at $ 500 to $ 1,000.

Urological infections are usually the result of ascending infections of the urethra by Enterobacteriaceae, in particular by Escherichia coli. Urinary tract infections are caused by a pathogenic invasion of these pathogens into the urinary tract, which leads to an inflammatory response of the urothelium. Women are at a higher risk because of their anatomical conditions, as are patients with urinary catheters or instrumental procedures in the genitourinary tract. However, urological infections can also be caused by hematogenous or lymphogenic spread. The hematogenous pathogenesis is known for the pathogens Staphylococcus aureus, Candida albicans, Salmonella spp or Mycobacterium tuberculosis, which are less common in the urological field. Virulence and pathogenicity of the pathogens are dependent on pathogen-specific factors (eg presence of pili) and patient-specific factors (eg obstructions, urine catheters, reduced immune status).

The classification of infections of the urological and male genital area after the localization (cystitis, pyelonephritis, urethritis, epididymitis, prostatitis, orchitis), the presence of pathogenic agents is also possible in the other sections of the genitourinary tract at the same time.

The treatment plan of these various diseases depends on the disease, but also on the product used and its mode of administration, as well as the patient, who are known in the art. For example. For example, a vaginal capsule regimen may require that a vaginal capsule be taken twice a day for seven days.

In a preferred embodiment of the present invention, the pharmaceutical or vaginal composition is used for the preparation of a dairy product, a nutraceutical, nutritional supplements, medical devices and / or drugs. If dairy products are produced, in a preferred embodiment the bacterial strains are incorporated into the milk product such that oral administration is possible. A variety of dairy products included in the invention include yoghurt, quark, milk, cheese and the like.

If functional foods (nutraceuticals) are prepared, the bacterial strains are incorporated into the functional foods (nutraceutical) in a further preferred embodiment in such a way that oral administration is possible. A selection of functional foods (nutraceuticals) according to the invention are products which are advertised and used to supplement the diet (for example dietary supplements) or with a positive effect on the health. Further examples of functional food products encompassed by the invention are freeze-dried and / or microencapsulated products for easy administration of food products.

In another preferred embodiment, an absorbent product is provided, such as a feminine sanitary napkin, sanitary napkin, panty liner, impregnated tampon, toilet tissue, Panty Guard, and / or an incontinence guard having a pharmaceutical or vaginal composition of the invention. The compositions of the invention, particularly the bacterial strains and goat whey, are incorporated into the absorbent products to allow for the practical administration of the respective compositions during use of the absorbent product. Preferably, the probiotic bacteria used in the absorbent product are used in bacterial concentrations of 10 ⁵ to 10 ¹³ CFU Lactobacillus, preferably 10 ⁶ to 10 ¹² CFU per gram of Lactobacillus. This can be one of the trunks, several of the Strains, or all strains used. Preferably, the bacteria used according to the invention are used directly, more preferably in a lyophilized form.

In a further preferred embodiment, pharmaceutical or vaginal compositions according to the invention are administered for the prophylaxis and / or treatment of microbial imbalances in mammals. Administration is carried out in an amount of the corresponding compositions known to the person skilled in the art and effective. For example. according to the invention, the administration is in the form of e.g. Capsules to obtain in vivo a stable microbial ecosystem of the mammal, especially humans.

Further details and features will become apparent from the following description of preferred embodiments in conjunction with the subclaims. In this case, the respective features can be implemented on their own or in combination with one another. The possibilities to solve the problem are not limited to the embodiments. For example, area information always includes all - not mentioned - intermediate values and all imaginable subintervals. Numerous modifications and developments of the described embodiments can be realized.

Results section

The aim of the study:

To study the clinical effect of vaginal capsules in women with bacterial vaginosis (BV).

Furthermore, a possible synergistic effect in its activity with lactic acid bacteria and whey should be demonstrated.

The study has two arms: a verum group in use and a comparator without goat whey.

Material and methods:

Originating specificities:

The strains have been obtained from healthy children or adults. After numerous tests (stability to gastric and intestinal transit, genetic stability, metabolic behavior and peculiarities, e.g., hydrogen peroxide generator, antimicrobial properties, etc.), the strain which met and cultured most of the criteria was isolated.

• - Wasserstoffperoxid Produzent
• - Milchsäureproduzent
• - Kultur von gesunden Kindern
• - Resistenz gegen Gallensalze und Magensäure
• - Resistenz gegen Wasserstoffperoxid und Sauerstoffradikale
• - Stickoxidfänger
• - 16S rDNA Sequenziert
• - API 50CHL Zuckerfermentation Identifikation
• - stabile HPLC Fermentationsmuster von Metaboliten nach mehrfacher Subkultur

Lactobacillus acidophilus, LA13100:

• - hydrogen peroxide producer
• - Lactic acid producer
• - Culture of healthy children
• - Resistance to bile salts and stomach acid
• - Resistance to hydrogen peroxide and oxygen radicals
• - Nitric oxide scavenger
• - 16S rDNA Sequencing
• - API 50CHL sugar fermentation ID
• - stable HPLC fermentation patterns of metabolites after multiple subculture

• - Kultur von gesunden Kindern
• - Resistenz gegen Gallensalze und Magensäure
• - Resistenz gegen Oxydradikale
• - Milchsäureproduzent
• - 16S rDNA Sequenziert
• - API 50CHL Zuckerfermentation Identifikation

Lactobacillus casei, LA13120:

• - Culture of healthy children
• - Resistance to bile salts and stomach acid
• - Resistance to oxide radicals
• - Lactic acid producer
• - 16S rDNA Sequencing
• - API 50CHL sugar fermentation ID

• - Kultur von gesunden Erwachsenen
• - Resistenz gegen Gallensalze und Magensäure
• - Milchsäureproduzent
• - Antimikrobielle Eigenschaften
• - Wasserstoffperoxidbildner
• - Wasserstoffperoxidstabilität und Oxidradikale
• - Inhibiert: Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa
• - 16S rDNA Sequenziert
• - API 50CHL Zuckerfermentation Identifikation

Lactobacillus crispatus, LA13130:

• - Culture of healthy adults
• - Resistance to bile salts and stomach acid
• - Lactic acid producer
• - Antimicrobial properties
• - Hydrogen peroxide generator
• - Hydrogen peroxide stability and oxide radicals
• - Inhibited: Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa
• - 16S rDNA Sequencing
• - API 50CHL sugar fermentation ID

• - Kultur von gesunden Erwachsenen
• - Resistenz gegen Gallensalze und Magensäure
• - Milchsäureproduzent
• - Antimikrobielle Eigenschaften
• - Wasserstoffoxidbildner
• - 16S rDNA Sequenziert
• - API 50CHL Zuckerfermentation Identifikation

Lactobacillus rhamosus, LA13220:

• - Culture of healthy adults
• - Resistance to bile salts and stomach acid
• - Lactic acid producer
• - Antimicrobial properties
• - Hydrogen oxide generator
• - 16S rDNA Sequencing
• - API 50CHL sugar fermentation ID

The cellulose capsules are easy to introduce and dissolve completely in aqueous medium, so that the ingredients in the vaginal milieu can empty.

A capsule consists of:

• Lactobacillus: 20 mg pro Tagesdosis
• Ziegenmolke (Caprisan®): 90 mg pro Tagesdosis
• Lactose Ph.Eur. (Capsulac60): 30 mg pro Tagesdosis

* Rohstoff mit Ziegen-Molkepulver aus biologischer LandwirtschaftA cellulose casing, lactose (Capsulac60), goat whey (Caprisan® *) and Lactobacillus acidophilus LA13100, Lactobacillus casein LA13120, Lactobacillus crispatus LA13130, Lactobacillus rhamnosus LA13220.

• Lactobacillus: 20 mg per daily dose
• Goat whey (Caprisan®): 90 mg per daily dose
• Lactose Ph. Eur. (Capsulac60): 30 mg per daily dose

* Raw material with goat's whey powder from organic farming

We examined 40 women between 18 and 49 years old with diagnosed bacterial vaginosis.

• - grauer oder weißlicher Ausfluss
• - pH-Wert höher als 4,5
• - positiver Geruchsstest

The criteria of a BV were:

• - gray or whitish discharge
• - pH higher than 4.5
• - positive odor test

After positive testing and enrollment of the women in the study, women were randomized into the two arms and treated once daily for 1 week (verum group with Caprisan® 21/40 and control product without Caprisan®: 19/40).

After this week and after 4 weeks, the women were re-ordered and after the o.g. Criteria for BV re-examined.

Result:

After questioning, cumulative results in 31 out of 40 (77.5%) women showed positive results. Burning, itching and foul-smelling discharge ceased after 7 days of use and still showed an improvement in the response rate up to the time of follow-up.

When only lactic acid bacteria alone were used without Caprisan®, 12 out of 19 (63%) women benefited from the treatment compared to 19 out of 21 (90.5%) in the verum group who benefited from the treatment (P = 0, 04)

On average, in 25 out of 40 women, after 5 days of application of the vaginal capsules, there was a marked improvement in the symptoms of BV.

The vaginal application was described as uncomplicated and easy to perform in 38 out of 40 women.

No side effects were reported during use.

Summary:

In 77.5% of women, the use of vaginal capsules showed a marked improvement or cure of BV. There was also a synergistic effect with Caprisan® as a significant improvement in the overall result (90.5%, P = 0.04).

Most women had recurrent BV for several years, which was partly treated by self-medication or by doctor consultation with antimycotic or antibiotic therapy.

The therapy with the vaginal capsules could be described as very user-friendly and safe.

quoted literature

• US 5,032,399
• WO 99/45099
• US 5,645,830
• US 6,093,394 ( WO 98/46261 )
• EP 0956858
• EP 1485463 A2

(siehe Würdigung des Standes der Technik)cited patent literature

• US 5,032,399
• WO 99/45099
• US 5,645,830
• US 6,093,394 ( WO 98/46261 )
• EP 0956858
• EP 1485463 A2

(see appreciation of the state of the art)

• Probiotics: „living drugs“. Elmer GW, Am. J. Health Syst. Pharm. 2001, 58 (12): p 1101-1109
• [New vaginal desinfectant, treating with consideration the döderleinflora, for the therapy of unspecific vaginitis (author's trans1)], [Article in German], Hauser GA, Schweiz Rundsch Med Prax. 1975 Oct 7; 64(40):1289-94
• The role of toll-like receptor ligands/agonists in protection against genital HSV-2 infection, Gill N. et al., Am J Reprod Immunol. 2008 Jan; 59(1): 35-43
• Kerasioti, E. et al., Increase in antioxidant activity by sheep/goat whey protein through nuclear factor-like 2 (Nrf2) is cell type dependent, Food Chem Toxicol, 2016 Nov; 97:47-56
• Srinivasan, S. et al., The human vaginal bacterial biota and bacterial vaginosis. Interdisciplinary Perspect Infect. Dis. 2008; 750479 Barrons, R. et al. Use of Lactobacillus probiotics for bacterial genitourinary infections in women: A review. Clin. Ther. 2008; 30:453-468 ;
• Randomized, Placebo-Controlled Phase 2 Trial of a Lactobacillus crispatus Probiotic Given Intravaginally for Prevention of Recurrent Urinary Tract Infection, Stapleton, A. E. et al., Clin Infect Dis., 2011; 52(10):1212-1217 ;
• Probiotics for the treatment of bacterial vaginosis, Brown, D., Alternative Medicine Alert, 2012; 15(3):1-29 ;
• Bacterial vaginosis: a review on clinical trials with probiotics, Mastromarino, P. et al., 2013, New Microbiol., 36, 229-238 ;
• Efficacy of vaginal probiotic capsules for recurrent bacterial vaginosis: a double-blind, randomized, placebo-controlled study, Ya, W. et al., Am J Obstet Gynecol., 2010, 203, 120.e1-6 ;
• The role of vaginal Lactobacillus Rhamnosus (Normogin®) in preventing Bacterial Vaginosis in women with history of recurrences, undergoing surgical menopause: a prospective pilot study, Parma, M. et al., Eur Rev Med Pharmacol Sci, 2013, 17, 1399-1403
• Role played by lactobacilli in controlling the population of vaginal pathogens, Soledad, B. et al., 2000, Microbes and Infection, 2, 543-546 ;
• Biofilms of vaginal Lactobacillus reuteri CRL 1324 and Lactobacillus rhamnosus CRL 1332: kinetics of formation and matrix characterization;, Leccese Terraf, M.C. et al., 2016, Arch Microbiol, 198, 689-700 ;
• Hydrogen peroxide producing lactobacilli in women with vaginal infections, Mijac, V. et al., European Journal of Obstetrics & Gynecology and Reproductive Biology, 2006, 129, 69-76 ;
• Role of Vaginal Flora As a Barrier to HIV Acquisition, Schwebke JR., Curr Infect Dis Rep 2001 Apr, 3 (2) 152-155
• Interrelationships among human immunodeficiency virus type 1 infection, bacterial vaginosis, trichomoniasis, and the presence of yeasts; Moodley P. et al., J Infect Dis 2002 Jan 1, 185 (1): 69-73 Screening of probiotic activities of forty-seven strains of Lactobacillus spp. by in vitro techniques and evaluation of the colonization ability of five selected strains in humans, Jacobsen CN et al., App. Environ. Microbiol., 1999, 65 (11) S. 4949-4956

quoted non-patent literature

• Probiotics: "living drugs". Elmer GW, Am. J. Health Syst. Pharm. 2001, 58 (12): p 1101-1109
• [New vaginal desinfectant, treating with consideration of the dorsal flora, for the therapy of unspecific vaginitis (author's trans1)], [Article in German], Hauser GA, Switzerland Rundsch Med Prax. 1975 Oct 7; 64 (40): 1289-94
• The role of toll-like receptor ligands / agonists in protection against genital HSV-2 infection, Gill N. et al., Am J Reprod Immunol. 2008 Jan; 59 (1): 35-43
• Kerasioti, E. et al., Increase in antioxidant activity by sheep / goat whey protein by nuclear factor-like 2 (Nrf2) is cell type dependent, Food Chem Toxicol, 2016 Nov; 97: 47-56
• Srinivasan, S. et al., The human vaginal bacterial biota and bacterial vaginosis. Interdisciplinary Perspect Infect. Dis. 2008; 750479 Barrons, R. et al. Use of Lactobacillus probiotics for bacterial genital infections in women: A review. Clin. Ther. 2008; 30: 453-468 ;
• Randomized, Placebo-Controlled Phase 2 Trial of a Lactobacillus crispatus Probiotic Given Intravaginally for Prevention of Recurrent Urinary Tract Infection, Stapleton, AE et al., Clin Infect Dis., 2011; 52 (10): 1212-1217 ;
• Probiotics for the treatment of bacterial vaginosis, Brown, D., Alternative Medicine Alert, 2012; 15 (3): 1-29 ;
• Bacterial vaginosis: a review of clinical trials with probiotics, Mastromarino, P. et al., 2013, New Microbiol., 36, 229-238 ;
• Efficacy of vaginal probiotic capsules for recurrent bacterial vaginosis: a double-blind, randomized, placebo-controlled study, Ya, W. et al., Am J Obstet Gynecol., 2010, 203, 120.e1-6 ;
• The role of vaginal Lactobacillus rhamnosus (Normogin®) in women with history of recurrence, undergoing surgical menopause: a prospective pilot study, Parma, M. et al., Eur. Rev. Med Pharmacol Sci, 2013, 17, 1399- 1403
• Role played by lactobacilli in controlling the population of vaginal pathogens, Soledad, B. et al., 2000, Microbes and Infection, 2, 543-546 ;
• Biofilms of vaginal Lactobacillus reuteri CRL 1324 and Lactobacillus rhamnosus CRL 1332: kinetics of formation and matrix characterization; Leccese Terraf, MC et al., 2016, Arch Microbiol, 198, 689-700 ;
• Hydrogen peroxide producing lactobacilli in women with vaginal infections, Mijac, V. et al., European Journal of Obstetrics & Gynecology and Reproductive Biology, 2006, 129, 69-76 ;
• Role of Vaginal Flora As a Barrier to HIV Acquisition, Schwebke JR., Curr Infect Dis Rep 2001 Apr, 3 (2) 152-155
• Interrelationships among human immunodeficiency virus type 1 infection, bacterial vaginosis, trichomoniasis, and the presence of yeasts; Moodley P. et al., J Infect Dis 2002 Jan 1, 185 (1): 69-73 Screening of probiotic activities of forty-seven strains of Lactobacillus spp. by in vitro techniques and evaluation of the colonization ability of five selected strains in humans, Jacobsen CN et al., App. Environ. Microbiol., 1999, 65 (11) pp. 4949-4956

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• WO 9945099 [0018, 0100]
• US 5645830 [0019, 0100]
• WO 9846261 [0020, 0100]
• EP 0956858 [0021, 0100]
• EP 1485463 A2 [0022, 0100]
• US 5032399 [0100]
• US 6093394 [0100]

Cited non-patent literature

• At the. J. Health Syst. Pharm. 2001, 58 (12): p 1101-1109 [0002]
• Switzerland Rundsch Med Prax. 1975 Oct 7; 64 (40): 1289-94 [0005]
• At J Reprod Immunol. 2008 Jan; 59 (1): 35-43 [0007]
• Kerasioti, E. et al., Increase in antioxidant activity by sheep / goat whey protein by nuclear factor-like 2 (Nrf2) is cell type dependent, Food Chem Toxicol, 2016 Nov; 97: 47-56 [0010, 0101]
• Barrons, R. et al. Use of Lactobacillus Probiotics for Bacterial Genitourinary Infections in Women: A Review. Clin.Ther. 2008; 30: 453-468 [0012]
• Stapleton et al., Clin Infect Dis., 2011; 52 (10): 1212-7 [0012]
• Brown, D., Alternative Medicine Alert, 2012; 15 (3): 1-29 [0012]
• Mastromarino, P. et al., 2013, New Microbiolocica, 36, 229-238 [0012]
• Barrons, R. et al., Clinical Therapeutics, 2008, 30, 453-467 [0012]
• Ya, W. et al., Am J Fruits Gynecol, 2010, 203, 120.e1-6 [0012]
• Parma, M. et al., Eur Rev Med Pharmacol Sci, 2013, 17, 1399-1403 [0012]
• Curr Infect Dis Rep 2001 Apr, 3 (2) 152-155, J Infect Dis 2002 Jan 1, 185 (1): 69-73 [0013]
• App. Environ. Microbiol., 1999, 65 (11) pp. 4949-4956 [0014]
• Role played by lactobacilli in controlling the population of vaginal pathogens, Soledad, B. et al., 2000, Microbes and Infection, 2, 543-546 [0015, 0101]
• Biofilms of vaginal Lactobacillus reuteri and Lactobacillus rhamnosus: kinetics of formation and matrix characterization, Leccese Terraf, MC et al., 2016, Arch Microbiol, 198, 689-700 [0016]
• Mijač, V.d. et al., European Journal of Obstetrics & Gynecology and Reproductive Biology, 2006, 129, 69-76 [0017]
• Probiotics: "living drugs". Elmer GW, Am. J. Health Syst. Pharm. 2001, 58 (12): p 1101-1109 [0101]
• Hauser GA, Switzerland Rundsch Med Prax. 1975 Oct 7; 64 (40): 1289-94 [0101]
• The role of toll-like receptor ligands / agonists in protection against genital HSV-2 infection, Gill N. et al., Am J Reprod Immunol. 2008 Jan; 59 (1): 35-43 [0101]
• Srinivasan, S. et al., The human vaginal bacterial biota and bacterial vaginosis. Interdisciplinary Perspect Infect. Dis. 2008; 750479 Barrons, R. et al. Use of Lactobacillus probiotics for bacterial genital infections in women: A review. Clin. Ther. 2008; 30: 453-468 [0101]
• Randomized, Placebo-Controlled Phase 2 Trial of a Lactobacillus crispatus Probiotic Given Intravaginally for Prevention of Recurrent Urinary Tract Infection, Stapleton, A.E. et al., Clin Infect Dis., 2011; 52 (10): 1212-1217 [0101]
• Probiotics for the treatment of bacterial vaginosis, Brown, D., Alternative Medicine Alert, 2012; 15 (3): 1-29 [0101]
• Bacterial vaginosis: a review of clinical trials with probiotics, Mastromarino, P. et al., 2013, New Microbiol., 36, 229-238 [0101]
• Efficacy of vaginal probiotic capsules for recurrent bacterial vaginosis: a double-blind, randomized, placebo-controlled study, Ya, W. et al., Am J Obstet Gynecol., 2010, 203, 120.e1-6 [0101]
• The role of vaginal Lactobacillus rhamnosus (Normogin®) in women with history of recurrence, undergoing surgical menopause: a prospective pilot study, Parma, M. et al., Eur. Rev. Med Pharmacol Sci, 2013, 17, 1399- 1403 [0101]
• Biofilms of vaginal Lactobacillus reuteri CRL 1324 and Lactobacillus rhamnosus CRL 1332: kinetics of formation and matrix characterization ;, Leccese Terraf, M.C. et al., 2016, Arch Microbiol, 198, 689-700 [0101]
• Hydrogen peroxide producing lactobacilli in women with vaginal infections, Mijac, V. et al., European Journal of Obstetrics & Gynecology and Reproductive Biology, 2006, 129, 69-76 [0101]
• Role of Vaginal Flora As a Barrier to HIV Acquisition, Schwebke JR., Curr Infect Dis Rep 2001 Apr, 3 (2) 152-155 [0101]
• Interrelationships among human immunodeficiency virus type 1 infection, bacterial vaginosis, trichomoniasis, and the presence of yeasts; Moodley P. et al., J Infect Dis 2002 Jan 1, 185 (1): 69-73 [0101]
• Screening of probiotic activities of forty-seven strains of Lactobacillus spp. by in vitro techniques and evaluation of the colonization ability of five selected strains in humans, Jacobsen CN et al., App. Environ. Microbiol., 1999, 65 (11) pp. 4949-4956 [0101]

Claims (14)

Pharmaceutical composition comprising: a) at least one probiotic bacterial strain of the family Lactobacillaceae and b) whey. Pharmaceutical composition according to Claim 1 comprising at least three, preferably four, probiotic bacterial strains of the family Lactobacillaceae. Pharmaceutical composition according to one of Claims 1 or 2 , characterized in that the probiotic bacterial strains are selected from the genus Lactobacillus. Pharmaceutical composition according to Claim 3 comprising: Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus crispatus and / or Lactobacillus rhamnosus, preferably Lactobacillus acidophilus strain LA13100, Lactobacillus casei strain LA13120, Lactobacillus crispatus strain LA13130 and / or Lactobacillus rhamnosus strain LA13220, optionally together with a pharmaceutically acceptable carrier and / or extender. Pharmaceutical composition according to one of the preceding claims, characterized in that the whey of mammals selected from the group of equidae (Equus) or cloven-hoofed animals (Artiodactyla or Paraxonia), preferably of ruminants (Ruminantia), in particular of goats (Capra), is derived. Pharmaceutical composition according to Claim 5 , characterized in that the whey is present as a concentrate, preferably as a powder, in particular as a lyophilisate. Pharmaceutical composition according to one of Claims 3 to 6 , characterized in that at least 10 ⁵ to 10 ¹³ , preferably 10 ⁶ to 10 ¹² , colony forming units (CFU) of lactobacillus per gram is included. A pharmaceutical composition according to any one of the preceding claims in the form of a suspension, spray, gel, cream, powder, capsule, lavage solution, beverage, cosmetic, ovule, vaginal insert, tablets and / or microencapsulated product , A vaginal composition according to any one of the preceding claims, comprising a substrate. Vaginal composition after Claim 9 wherein the substrate is not fermented by Candida albicans or Gram-negative pathogenic bacteria, preferably the substrate is an oligosaccharide, in particular oligofrucose and / or a disaccharide, more preferably lactose. Use of a pharmaceutical composition or a vaginal composition according to any one of Claims 1 to 10 for the prophylaxis and / or treatment of vaginal, gastrointestinal (gastrointestinal) diseases and / or urogenital diseases, in particular vaginal, gastrointestinal and / or urogenital infections. Use of a pharmaceutical composition or a vaginal composition according to any one of Claims 1 to 10 for the preparation of a milk product, a nutraceutical, nutritional supplements, medical devices and / or pharmaceuticals. An absorbent product such as a feminine sanitary napkin, sanitary napkin, panty liner, impregnated tampon, toilet tissue, panty guard and / or incontinence protector comprising the pharmaceutical or vaginal composition of any one of Claims 1 to 10 , A method for the prophylaxis and / or treatment of microbial imbalances in mammals comprising administering an effective amount of a pharmaceutical or vaginal composition according to any one of Claims 1 to 10 ,