WO2014184644A9 - Composition comprising lactic acid bacteria and/or bifidobacteria for use in the preventive and/or curative treatment of bacterial infections and/or inflammations of the urinary tract and/or prostate which are the cause of prostatitis and prostatic hypertrophy - Google Patents

Composition comprising lactic acid bacteria and/or bifidobacteria for use in the preventive and/or curative treatment of bacterial infections and/or inflammations of the urinary tract and/or prostate which are the cause of prostatitis and prostatic hypertrophy Download PDF

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Publication number
WO2014184644A9
WO2014184644A9 PCT/IB2014/000741 IB2014000741W WO2014184644A9 WO 2014184644 A9 WO2014184644 A9 WO 2014184644A9 IB 2014000741 W IB2014000741 W IB 2014000741W WO 2014184644 A9 WO2014184644 A9 WO 2014184644A9
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dsm
strain
composition
strain lactobacillus
bacteria
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PCT/IB2014/000741
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French (fr)
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WO2014184644A1 (en
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Giovanni Mogna
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Probiotical S.P.A.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers

Definitions

  • Pathogenic bacteria belonging to the species Escherichia coli are known to be able to adhere to the epithelial cells surface of the urinary tract (urothelium). For this and other reasons, it is known that pathogenic bacteria belonging to the species Escherichia coli are responsible for more than 80% of the cases of bacterial infections of the urinary tract (UTI), which cause prostate inflammations (prostatitis).
  • compositions for use in the preventive and/or curative treatment of bacterial infections and related inflammations of the urinary tract and/or prostate having the characteristics as disclosed in the appended claim.
  • Said composition is preferably for use in the preventive and/or curative treatment of prostatitis and/or prostatic hypertrophy.
  • preventive and/or curative treatment is meant to also include circumstances wherein the urinary tract and/or prostate inflammation is limited, reduced or attenuated, which improve the health conditions of the subject being treated.
  • composition comprising a mixture of bacteria which comprises or, alternatively, consists of: strains of bacteria having both a specific antibacterial activity against E.coli and an antiinflammatory activity with stimulation of the Interleukin IL-4 and Interleukin IL-10 production, and strains of bacteria having an oxalate-degrading activity.
  • composition wherein said mixture comprises or, alternatively, consists of: at least a strain of bacteria having both a specific antibacterial activity against E.coli and an anti-inflammatory activity with stimulation of the Interleukin IL-4 and Interleukin IL-10 production, combined with at least a strain of bacteria having an oxalate-degrading activity.
  • composition comprising or, alternatively, consisting of a mixture of bacteria which comprises or, alternatively, consists of at least a strain of bacteria selected from the group comprising the strain Lactobacillus plantarum LMG P-21021 -LP01 and the strain Lactobacillus plantarum LMG P-21020 -LP02, combined with at least a strain of bacteria selected from the group comprising the strain Lactobacillus paracasei DSM 24243 -LPC09, the strain Lactobacillus gasseri DSM 18299 -LGS01 , the strain Lactobacillus gasseri DSM 18300 -LGS02, the strain Lactobacillus acidophilus DSM 24303 -LA07 and the strain Lactobacillus acidophilus DSM 21717 -LA02, for use in the preventive and/or curative treatment of the urinary tract and/or prostate inflammations.
  • the strain Lactobacillus plantarum LMG P-21021 -LP01 was deposited by Mofin Sri Company on 16.10.2001 at the BCCM LMG center.
  • the strain Lactobacillus plantarum LMG P-21020 -LP02 was deposited by Mofin Sri Company on 16.10.2001 at the BCCM LMG center.
  • strain Lactobacillus paracasei DSM 24243 -LPC09 was deposited by Probiotical S.p.A. Company on 23.11.2010 at the DSMZ center.
  • strain Lactobacillus gasseri DSM 18299 -LGS01 was deposited by Anidral Sri Company, now Probiotical S.p.A., on 24.05.2006 at the DSMZ center.
  • strain Lactobacillus gasseri DSM 18300 -LGS02 was deposited by Anidral Sri Company, now Probiotical S.p.A., on 24.05.2006 at the DSMZ center.
  • strain Lactobacillus acidophilus DSM 21717 -LA02 was deposited by Probiotical S.p.A. Company on 06.08.2008 at the DSMZ center.
  • said composition comprises or, alternatively, consists of a mixture of bacteria which comprises or, alternatively, consists of Lactobacillus plantarum LMG P-21021 -LP01 combined with at least a bacterial strain selected from the group comprising the strain Lactobacillus paracasei DSM 24243 -LPC09, the strain Lactobacillus gasseri DSM 18299 -LGS01, the strain Lactobacillus gasseri DSM 18300 -LGS02, the strain Lactobacillus acidophilus DSM 24303 -LA07 and the strain Lactobacillus acidophilus DSM 21717 -LA02; preferably in a weight ratio comprised from 3:1 to 2:1 ; even more preferably 1.5:1.
  • said composition comprises or, alternatively, consists of a mixture of bacteria which comprises or, alternatively, consists of Lactobacillus plantarum LMG P-21020 -LP02 combined with at least a bacterial strain selected from the group comprising the strain Lactobacillus paracasei DSM 24243 -LPC09, the strain Lactobacillus gasseri DSM 18299 -LGS01 , the strain Lactobacillus gasseri DSM 18300 -LGS02, the strain Lactobacillus acidophilus DSM 24303 -LA07 and the strain Lactobacillus acidophilus DSM 21717 -LA02; preferably in a weight ratio comprised from 3:1 to 2:1 ; even more preferably 1.5:1.
  • compositions further comprise a bacterial tyndallized product containing intact cells which internalized, during their production process a highly bioavailable organic zinc, preferably said cells are obtained from the strain of bacteria Bifidobacterium lactis DSM 17850 -BB1.
  • the tyndallized product is preferably in an amount comprised from 1 to 5% by weight, preferably from 2 to 3% by weight. In an embodiment 20 mg/g of composition (2% by weight) are present.
  • the composition further comprises a cranberry extract, preferably a dry cranberry extract.
  • compositions can further preferably comprise a fiber with prebiotic activity selected from inulin, fructo-oligosaccharides (FOS), galacto- and trans-galacto-oligosaccharides (GOS and TOS), gluco-oligosaccharides (GOSa), xylo-oligosaccharides, (XOS), chitosan-oligosaccharides (COS), soy- oligosaccharides (SOS), isomalto-oligosaccharides (IMOS), resistant starch, pectins, psyllium, arabino-galactans, gluco-mannans and galacto-mannans.
  • a fiber with prebiotic activity selected from inulin, fructo-oligosaccharides (FOS), galacto- and trans-galacto-oligosaccharides (GOS and TOS), gluco-oligosaccharides (GOSa), xylo-oligosaccharides, (XOS
  • prebiotic fiber is selected from fructo-oligosaccharide - FOS, preferably a short-chain fructo-oligosaccharide -FOSsc, or from galactooligosaccharides, or mixtures thereof.
  • the composition further comprises at least an active substance of plant origin selected from the group comprising or, alternatively consisting of Lycium barbarum, Coix lacrima-jobi and Cordyceps sinensis; preferably it is Lycium barbarum or a mixture of Lycium barbarum, Coix lacrima-jobi and Cordyceps sinensis.
  • compositions can further comprise a plant gum and/or a plant gelatin.
  • the plant gum and/or the plant gelatin is preferably selected from the group comprising a tannate or a gelatin tannate, an alginate, a xyloglucan or xylogel, a guar gum, a tara gum, an acacia, carob, oat, bamboo fiber, citrus fruit fibers and glucomannans.
  • it is a guar gum.
  • the selected plant gum and/or plant gelatin reduces the bacterial translocation of E.coli from the intestine to the bladder.
  • compositions can further comprise an Aloe arborescens, preferably a freeze-dried Aloe arborescens.
  • composition for use in the preventive and/or curative treatment of urinary tract and/or prostate inflammations which comprises or, alternatively, consists of:
  • a mixture of bacteria which comprises or, alternatively, consists of Lactobacillus plantarum LMG P-21021 - LP01 combined with at least a bacterial strain selected from the group comprising the strain Lactobacillus paracasei DSM 24243 -LPC09, the strain Lactobacillus gasseri DSM 18299 -LGS01 , the strain Lactobacillus gasseri DSM 18300 -LGS02, the strain Lactobacillus acidophilus DSM 24303 -LA07 and the strain Lactobacillus acidophilus DSM 21717 -LA02; preferably in a weight ratio comprised from 3:1 to 2:1 ; even more preferably 1.5:1 , (ii) a bacterial tyndallized product containing cells which internalize in their inside organic zinc, preferably said cells are obtained from the strain of bacteria Bifidobacterium lactis DSM 17850 -BB1 ,
  • a cranberry extract preferably a dry cranberry extract
  • a mixture of bacteria which comprises or, alternatively, consists of Lactobacillus plantarum LMG P-21021 - LP02, combined with at least a bacterial strain selected from the group comprising the strain Lactobacillus paracasei DSM 24243 -LPC09, the strain Lactobacillus gasseri DSM 18299 -LGS01 , the strain Lactobacillus gasseri DSM 18300 -LGS02, the strain Lactobacillus acidophilus DSM 24303 -LA07 and the strain Lactobacillus acidophilus DSM 21717 -LA02; preferably in a weight ratio comprised from 3:1 to 2:1 ; even more preferably 1.5:1 ,
  • a cranberry extract preferably a dry cranberry extract
  • a prebiotic fiber selected from fructo-oligosaccharide -FOS, preferably a short chain fructo-oligosaccharide - FOSsc, or from galactooligosaccharides GOS, or mixtures thereof,
  • a mixture of active substances of plant origin comprising or, alternatively consisting of Lycium barbarum, Coix lacrima-jobi and Cordyceps sinensis, preferably Lycium barbarum,
  • compositions of the present invention are suitable for use in the preventive and/or curative treatment of prostatitis and prostatic hypertrophy.
  • composition of the present invention due to the presence of a cranberry extract, preferably a dry extract (trade name PACran ® , a dry extract of US cranberry (Cranberry -Vaccinium macrocarpon- extract)) is capable to establishing a physical-mechanical hindrance against the Escherichia coli adhesion to the epithelial cell surface of the urinary tract (urothelium).
  • a dry extract trade name PACran ® , a dry extract of US cranberry (Cranberry -Vaccinium macrocarpon- extract)
  • the activity of said cranberry extract is mediated, in particular, by the proanthocyanidin subfraction with the trimers and tetramers characterized by A-type bonds which compete with the adhesins located on the P-type fimbriae (FimH, mannose-sensitive) which uses £. coli for mediating its anchoring to the epithelial cells through specific receptors, thereby hindering in a physical-mechanical manner its adhesion and subsequent urothelium colonization. Furthermore, the cranberry extract reduces the Lower Urinary Tract Symptoms (LUTS), a frequently observed condition.
  • LUTS Lower Urinary Tract Symptoms
  • the strain of bacteria Lactobacillus plantarum LMG P-21021 - LP01 and/or the strain of bacteria Lactobacillus plantarum LMG P-21020 -LP02, in the presence of cranberry extract, are capable to complement and enhance the physical-mechanical hindrance exerted by the cranberry extract as described above, through a barrier-type action even at intestinal level against £ coli.
  • These two strains of bacteria Lactobacillus plantarum LMG P-21021 - LP01 and Lactobacillus plantarum LMG P-21020 -LP02 have a proven E.coli activity and a high anti-inflammatory activity since they produce interleukin 4 (IL-4) and interleukin 10 (IL-10).
  • IL-4 interleukin 4
  • IL-10 interleukin 10
  • the strain of bacteria Lactobacillus plantarum LMG P-21021 - LP01 and/or the strain of bacteria Lactobacillus plantarum LMG P-21020 - LP02 are in an amount comprised from 1 to 10 billions of viable cells/dose, even more preferably from 2 to 5 billions of viable cells/dose.
  • the strains of bacteria of the present invention exert a marked barrier-type action against potential Gram- negative pathogens, with particular reference to the species Escherichia coii and a high anti-inflammatory activity since they produce interleukin 4 (IL-4) and interleukin 10 (IL-10).
  • the strains of bacteria Lactobacillus paracasei DSM 24243 - LPC09, Lactobacillus gasseri DSM 18299 -LGS01 , Lactobacillus gasseri DSM 18300 -LGS02, Lactobacillus acidophilus DSM 24303 -LA07 and Lactobacillus acidophilus DSM 21717 -LA02 are able to carry out a protective action since they exert a barrier effect to the oxalates contained in the cranberry extract, preferably in the form of dry extract.
  • the metabolization of these oxalate molecules prevents the intestinal accumulation and the systemic absorption thereof, thus avoiding the establishment and the maintenance of an inflammatory condition of the intestine, particularly disadvantageous in the occurrence of diverticula.
  • strains of bacteria Lactobacillus paracasei DSM 24243 -LPC09, Lactobacillus gasseri DSM 18299 -LGS01, Lactobacillus gasseri DSM 18300 -LGS02, Lactobacillus acidophilus DSM 24303 -LA07 and Lactobacillus acidophilus DSM 21717 -LA02 metabolize oxalates and, therefore, have a proved anti-renal gravel activity.
  • These strains of bacteria prevent the renal accumulation of oxalates thus avoiding the renal gravel formation and, thereby, impeding the establishment and the maintenance of an inflammatory condition of the urinary tract particularly disadvantageous for the health status of a bladder subjected to recurrent cystitis.
  • the presence of strains of bacteria degrading oxalates in the composition of the present invention is also important for the following reason.
  • the cranberry extract contains a fair oxalate amount. A prolonged use of cranberry extract could lead to renal gravel formation, which may force a subject to suspend the use thereof.
  • the use of strains degrading oxalates of the present invention prevents this drawback allowing a prolonged administration of cranberry extract.
  • the strains of bacteria Lactobacillus paracasei DSM 24243 -LPC09, Lactobacillus gasseri DSM 18299 -LGS01 , Lactobacillus gasseri DSM 18300 -LGS02, Lactobacillus acidophilus DSM 24303 -LA07 and Lactobacillus acidophilus DSM 21717 -LA02 are in an amount comprised from 0.5 to 2 billions of viable cells/dose, even more preferably from 1 to 1.5 billions of viable cells/dose.
  • the selected plant gum and/or plant gelatin reduces the bacterial translocation of E.coli from the intestine to the bladder.
  • it is a guar gum.
  • the guar gum exerts a mechanical action at intestinal level, hindering the adhesion of Escherichia coli and other pathogens to the mucosa of the organ, thus reducing their translocation through the intestinal wall and the subsequent risk of infection of adjacent organs.
  • the gum acts by forming a hydrophilic gel, which evenly distributes over the mucosal surface, restoring the physiological barrier effect of this organ, which typically results impaired in the event of intestinal infections by Escherichia coli or other pathogens.
  • the composition of the present invention further comprises a fiber with prebiotic activity (prebiotic fiber), which can be selected from inulin, fructo-oligosaccharides (FOS), galacto- and trans-galacto-oligosaccharides (GOS and TOS), gluco-oligosaccharides (GOSa), xylo-oligosaccharides, (XOS), chitosan-oligosaccharides (COS), soy-oligosaccharides (SOS), isomalto-oligosaccharides (IMOS), resistant starch, pectins, psyllium, arabino-galactans, gluco-mannans and galacto-mannans.
  • it is selected from short chain fructo- oligosaccharides (FOSsc) and/or galactooligosaccharides GOS which contributes to the growing and replication of the bacterial strains existing in the composition.
  • the presence of a freeze-dried Aloe arborescens in the composition of the present invention is capable to rapidly form a gel after dissolving the sachet in water, thus ensuring a mechanical barrier effect for protecting the esophageal, gastric and intestinal mucosae.
  • the freeze-dried Aloe arborescens product in addition to the physical protective action of mucosae, is capable to decrease the adhesive properties of pathogenic strains by a physical-mechanical hindrance, with particular reference to microorganisms provided with flagella, both at esophageal and gastrointestinal level.
  • the freeze-dried Aloe arborescens product is also able to decrease the gastric and intestinal permeability, thereby contributing to restoring the physiological barrier effect of such an organ and synergistically acting with the guar gum in reducing the risk of bacterial translocation from the intestine. Furthermore, Aloe arborescens has anti-inflammatory activity, thus providing a further protection at mucosal level.
  • composition of the present invention can further comprise excipients selected from natural flavors, anti- caking agents such as silicon dioxide, black carrot anthocyanins, sucralose.
  • excipients selected from natural flavors, anti- caking agents such as silicon dioxide, black carrot anthocyanins, sucralose.
  • the mixture of bacteria has a bacterial load comprised from 1 x10 8 to 1 x10 12 CFU/g of mixture.
  • the composition of the present invention which contains said mixture of bacteria has a bacterial load of about 1 x10 9 -1x10 11 CFU/composition.
  • composition further comprises:
  • a muco-adhesive gelling complex composed of EPS, exopolysaccharides of bacterial origin, produced in situ by the strain of bacterium Streptococcus thermophilus DSM 25246 (ST10) and a tara gum, a polysaccharide of plant origin.
  • the muco-adhesive gelling complex is able to establish a mechanical barrier effect throughout the gastro-intestinal tract.
  • Said composition further comprises along with the above components (d) a dry extract of US cranberry (Cranberry - PACran®), (e) a suitable amount of freeze-dried Aloe arborescens (AlagelTM), (f) an organic and highly bioavailable source of zinc (ProbioZinc®: Bifidobacterium lactis Bb1 -DSM 17850- tyndallized product containing zinc in organic form - for example titer: 20 mg/g) and, preferably, (g) three active ingredients of plant origin Lycium barbarum, Job's tears [Coix lacryma-jobi) and Cordyceps sinensis, for use in the preventive and/or curative treatment of infections and/or inflammations of the urinary tract and/or prostate (composition).
  • a dry extract of US cranberry Cranberry - PACran®
  • AlagelTM freeze-dried Aloe arborescens
  • ProbioZinc® Bifi
  • the action of physical-mechanical hindrance performed by Cranberry being present in the composition is enhanced by the presence of a suitable amount of tara gum which, due to its gelling and muco-adhesive properties, is capable to form a hydrogel within few minutes after ingestion, by virtue of its thixotropic characteristics, thus creating, in the first part of the gastrointestinal tract a mechanical barrier action against the adhesion of Escherichia coli and other pathogens to the mucosa of the organ, thereby reducing the translocation thereof through the intestinal wall and the subsequent risk of infection of adjacent organs, among which mainly the urinary tract.
  • the above-cited muco-adhesive gelling complex has an innovative property which has to be taken into account: tara gum, like all the gums of plant origin, is progressively degraded by the resident microbiota during its intestinal transit, thereby progressively reducing its gelling power of mechanical hindrance, The gradual reduction of the plant gum action is effectively counterbalanced by the gradual increase of exopolysaccharide (EPS) release in the intestinal lumen by the bacterial strain Streptococcus thermophilus DSM 25246 (ST10), which exerts its property mainly in ileum and colon.
  • EPS exopolysaccharide
  • the synergistic combination of tara gum and exopolysaccharides (EPS) produced in situ ensures the presence of gelling molecules throughout the gastro-intestinal tract, maximizing and optimizing the barrier action exerted by the composition.
  • the presence, production and retention of the hydrophillc gel in the lumen of the organ can, thus, be considered complete, with a first area wherein the plant gum action is maximum and a second area wherein the exopolysaccharide (EPS) action is maximum.
  • the composition Due also to the presence of a freeze-dried Aloe arborescens (AlagelTM) (for example 500 mg/sachet), the composition (from (a) to (f)) is capable to rapidly form a gel after dissolving the sachet in water, thereby ensuring a mechanical barrier effect for protecting the esophageal, gastric and intestinal mucosae.
  • the Aloe arborescens product besides the action of physical mucosal protection, is capable to decrease the adhesive capabilities of pathogenic strains by a physical-mechanical hindrance, with particular reference to microorganisms provided with flagella, both at esophageal and gastrointestinal level.
  • the Aloe product is also able to reduce the permeability at gastric and intestinal level, thus contributing in restoring the physiological barrier effect of such an organ and by synergistically acting with tara gum and exopolysaccharides (EPS) in reducing the risk of bacterial translocation from the intestine.
  • EPS exopolysaccharides
  • Aloe arborescens is characterized by an anti-inflammatory activity, thus providing an additional protection at mucosal level.
  • Lactobacillus plantarum LP01 (LMG P-21021) (for example 2.5 billions/daily dose) and Lactobacillus paracasei LPC09 (DSM 24243) (for example 1 billion/daily dose) mediates, also, an enhancement of the physical-mechanical hindrance described above, by a barrier-type action against £. coli even at intestinal level.
  • the Applicant carried out the selection of specific microorganisms with a marked barrier-type action against potential Gram-negative pathogens, with particular reference to the species Escherichia coli, the main role of which in UTI has been well demonstrated.
  • the barrier action was also quantified against the enterohemorrhagic serotype G157:H7, capable to produce one or more Shiga, and Klebsiella spp., toxins likewise responsible for a certain percentage of UTI, alone or combined with £ coli.
  • the strain Lactobacillus plantarum LP01 was positively selected, which is able to establish a barrier-type action against both E.coli and Klebsiella.
  • microorganism Lactobacillus paracasei DSM 24243 (LPC09) is capable to create a barrier effect to oxalates, ensuring the complete tolerability to the Cranberry extract even in subjects particularly sensitive to small concentrations of these potential inflammatory agents of the intestinal and urinary mucosae.
  • composition from (a) to (f)
  • a proper amount of highly assimilable zinc for example 2 mg of Zinc ion
  • a proper amount of highly assimilable zinc for example 2 mg of Zinc ion
  • the composition allows the composition to be further enhanced in its function for adults over 40-50 since during the aging process a general reduction of the zinc absorption capability at intestinal level is observed, thereby establishing a deficit with main consequences in the prostate health and immune system.
  • the zinc accumulated inside the microorganism cell has an assimilability more than 16- fold greater than zinc gluconate and 31.5-fold greater than zinc sulfate, as demonstrated by an in vitro study performed on Caco-2 cells, which mimic the intestinal epithelium, in a Transwell system.
  • the high assimilability of the trace element zinc allows to counterbalancing in a very effective manner the deficits even with very low dosages.
  • the organism capability to absorbing the food zinc results progressively reduced after age 50 when, simultaneously, the prostatic hypertrophy incidence increases.
  • the possibility to intake a highly assimilable food zinc source is, therefore, fundamental during the adulthood, especially after age 50.
  • the typical disorders of prostatic hypertrophy are given by the progressive obstruction to the urine flow through the urethra.
  • the incomplete bladder emptying causes, in turn, a stasis that can lead to bladder infections and inflammations, whereas the prolonged, even incomplete, obstruction can cause a renal function impairment.
  • Natural flavor cranberry; anti-caking agent silicon dioxide; black carrot anthocyanins; sucralose.
  • Natural flavor cranberry; anti-caking agent silicon dioxide; black carrot anthocyanins; sucralose.
  • composition (3-4) correspond to compositions (1-2) wherein the strain of bacteria Lactobacillus plantarum LP01 (LMG P-21021) is replaced by the strain of bacteria Lactobacillus plantarum LP02 (LMG P- 21020) and the strain of bacteria Lactobacillus paracasei LPC09 (DSM 24243) is replaced by the strain of bacteria Lactobacillus acidophilus DSM 21717 -LA02.
  • the composition of the present invention can be in solid form, for oral use, as tablet, capsule, granules or powder.
  • compositions of the present invention for example in granulated form for oral use in sachet, have a shelf-life of at least 3.5x10 9 viable cells at 24 months and at 25°C. It is recommended to take 2 sachets per day during the first 4 weeks, then to continue, for maintenance purposes, with 1 sachet per day over even long periods.
  • the compositions of the present invention are well tolerated by the organism and thus allow a continuous and prolonged use over the time without side effects.
  • FIG. 1 Cytokine profile. Mean ⁇ S.E.M. of 10 independent experiments. The statistical meaning is calculated by using the Student ' s f-test. When it is calculated relative to the basal conditions (non-stimulated PBMC), the values p ⁇ 0.05 are considered statistically significant.
  • the IL-10 production was assessed in the culture supernatant after one day from stimulation.
  • the IL-4 production was assessed in the culture supernatant after five days of stimulation. Similar results were obtained with the strain Lactobacillus plantarum LMG P-21020 -LP02.
  • Figure 1 relates to the quantification of E.coli (ATCC 8739, ATCC 10536, ATCC 35218, ATCC 25922) inhibition by the strain Lactobacillus plantarum LMG P-21021 -LP01.
  • Figure B relates to the quantification of E.coli (ATCC 8739, ATCC 10536, ATCC 35218, ATCC 25922) inhibition by the strain Lactobacillus plantarum LMG P-21020 -LP02.
  • Lactobacillus plantarum LP01 (LMG P-21021) 2.5
  • Fructo-oligosaccharides 1 ,250.00

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Abstract

The present invention relates to a composition comprising lactic bacteria and bifidobacteria for use in the preventive and/or curative treatment of bacterial infections and/or inflammations of the urinary tract and/or prostate, which are the cause of prostatitis and prostatic hypertrophy.

Description

DESCRIPTION of the invention entitled:
COMPOSITION COMPRISING LACTIC ACID BACTERIA AND/OR BIFIDOBACTERIA FOR USE IN
THE PREVENTIVE AND/OR CURATIVE TREATMENT OF BACTERIAL INFECTIONS AND/OR INFLAMMATIONS OF THE URINARY TRACT AND/OR PROSTATE WHICH ARE THE CAUSE OF
PROSTATITIS AND PROSTATIC HYPERTROPHY
The present invention relates to a composition comprising lactic bacteria and bifidobacteria for use in the preventive and/or curative treatment of bacterial infections and/or inflammations of the urinary tract and/or prostate, which are the cause of prostatitis and prostatic hypertrophy.
Pathogenic bacteria belonging to the species Escherichia coli are known to be able to adhere to the epithelial cells surface of the urinary tract (urothelium). For this and other reasons, it is known that pathogenic bacteria belonging to the species Escherichia coli are responsible for more than 80% of the cases of bacterial infections of the urinary tract (UTI), which cause prostate inflammations (prostatitis).
In view of the above, there is a need to intervene both against bacterial infections caused by E.coli and the related inflammations of the urinary tract and/or prostate.
Therefore, there is a need to efficiently intervene against pathogens belonging to the species Escherichia coli both through a barrier effect, in order to reduce the adhesion of the pathogen itself to the epithelial cells of the urinary tract, and through an anti-Eco//' activity, for hindering the development and proliferation of the pathogen itself. In particular, there is a need to have a treatment for preventing and/or curing the urinary tract infections by adopting a treatment compatible with the physiological habitat and which is well tolerated so that to be administered for a continuous use without side effects. Finally, there is a need to have a natural and effective barrier effect, in the case of both an acute episode and possible relapses, which continues over the time for ensuring a long-term protection and assuring a long-lasting effective preventive and/or curative treatment.
The Applicant, following to an extended and intense research activity, gave a response to the above-cited needs. In fact, the Applicant, after testing and studying many microorganisms, succeeded to select only some of them. The selected strains have at the same time an activity against the pathogenic bacteria E.coli which cause infections and a high anti-inflammatory activity since they are strains of bacteria producing interleukin 4 (IL-4) and interleukin 10 (1L-10).
It is an object of the present invention a composition for use in the preventive and/or curative treatment of bacterial infections and related inflammations of the urinary tract and/or prostate, having the characteristics as disclosed in the appended claim. Said composition is preferably for use in the preventive and/or curative treatment of prostatitis and/or prostatic hypertrophy.
By preventive and/or curative treatment is meant to also include circumstances wherein the urinary tract and/or prostate inflammation is limited, reduced or attenuated, which improve the health conditions of the subject being treated.
Preferred embodiments of the present invention are contemplated in the following detailed description.
In the context of the present invention by composition is meant to include a pharmaceutical composition, or a supplement product or a medical device or a food composition.
It is an object of the present invention a composition comprising a mixture of bacteria which comprises or, alternatively, consists of: strains of bacteria having both a specific antibacterial activity against E.coli and an antiinflammatory activity with stimulation of the Interleukin IL-4 and Interleukin IL-10 production, and strains of bacteria having an oxalate-degrading activity.
It is an object of the present invention a composition wherein said mixture comprises or, alternatively, consists of: at least a strain of bacteria having both a specific antibacterial activity against E.coli and an anti-inflammatory activity with stimulation of the Interleukin IL-4 and Interleukin IL-10 production, combined with at least a strain of bacteria having an oxalate-degrading activity.
It is an object of the present invention a composition comprising or, alternatively, consisting of a mixture of bacteria which comprises or, alternatively, consists of at least a strain of bacteria selected from the group comprising the strain Lactobacillus plantarum LMG P-21021 -LP01 and the strain Lactobacillus plantarum LMG P-21020 -LP02, combined with at least a strain of bacteria selected from the group comprising the strain Lactobacillus paracasei DSM 24243 -LPC09, the strain Lactobacillus gasseri DSM 18299 -LGS01 , the strain Lactobacillus gasseri DSM 18300 -LGS02, the strain Lactobacillus acidophilus DSM 24303 -LA07 and the strain Lactobacillus acidophilus DSM 21717 -LA02, for use in the preventive and/or curative treatment of the urinary tract and/or prostate inflammations.
The strain Lactobacillus plantarum LMG P-21021 -LP01 was deposited by Mofin Sri Company on 16.10.2001 at the BCCM LMG center. The strain Lactobacillus plantarum LMG P-21020 -LP02 was deposited by Mofin Sri Company on 16.10.2001 at the BCCM LMG center.
The strain Lactobacillus paracasei DSM 24243 -LPC09 was deposited by Probiotical S.p.A. Company on 23.11.2010 at the DSMZ center.
The strain Lactobacillus gasseri DSM 18299 -LGS01 was deposited by Anidral Sri Company, now Probiotical S.p.A., on 24.05.2006 at the DSMZ center.
The strain Lactobacillus gasseri DSM 18300 -LGS02 was deposited by Anidral Sri Company, now Probiotical S.p.A., on 24.05.2006 at the DSMZ center.
The strain Lactobacillus acidophilus DSM 24303 -LA07 was deposited by Probiotical S.p.A. Company on 23.11.2010 at the DSMZ center.
The strain Lactobacillus acidophilus DSM 21717 -LA02 was deposited by Probiotical S.p.A. Company on 06.08.2008 at the DSMZ center.
In a preferred embodiment, said composition comprises or, alternatively, consists of a mixture of bacteria which comprises or, alternatively, consists of Lactobacillus plantarum LMG P-21021 -LP01 combined with at least a bacterial strain selected from the group comprising the strain Lactobacillus paracasei DSM 24243 -LPC09, the strain Lactobacillus gasseri DSM 18299 -LGS01, the strain Lactobacillus gasseri DSM 18300 -LGS02, the strain Lactobacillus acidophilus DSM 24303 -LA07 and the strain Lactobacillus acidophilus DSM 21717 -LA02; preferably in a weight ratio comprised from 3:1 to 2:1 ; even more preferably 1.5:1.
In another preferred embodiment, said composition comprises or, alternatively, consists of a mixture of bacteria which comprises or, alternatively, consists of Lactobacillus plantarum LMG P-21020 -LP02 combined with at least a bacterial strain selected from the group comprising the strain Lactobacillus paracasei DSM 24243 -LPC09, the strain Lactobacillus gasseri DSM 18299 -LGS01 , the strain Lactobacillus gasseri DSM 18300 -LGS02, the strain Lactobacillus acidophilus DSM 24303 -LA07 and the strain Lactobacillus acidophilus DSM 21717 -LA02; preferably in a weight ratio comprised from 3:1 to 2:1 ; even more preferably 1.5:1.
Said compositions further comprise a bacterial tyndallized product containing intact cells which internalized, during their production process a highly bioavailable organic zinc, preferably said cells are obtained from the strain of bacteria Bifidobacterium lactis DSM 17850 -BB1. The tyndallized product is preferably in an amount comprised from 1 to 5% by weight, preferably from 2 to 3% by weight. In an embodiment 20 mg/g of composition (2% by weight) are present.
The composition further comprises a cranberry extract, preferably a dry cranberry extract.
Moreover, all the above-described compositions can further preferably comprise a fiber with prebiotic activity selected from inulin, fructo-oligosaccharides (FOS), galacto- and trans-galacto-oligosaccharides (GOS and TOS), gluco-oligosaccharides (GOSa), xylo-oligosaccharides, (XOS), chitosan-oligosaccharides (COS), soy- oligosaccharides (SOS), isomalto-oligosaccharides (IMOS), resistant starch, pectins, psyllium, arabino-galactans, gluco-mannans and galacto-mannans. Preferably said prebiotic fiber is selected from fructo-oligosaccharide - FOS, preferably a short-chain fructo-oligosaccharide -FOSsc, or from galactooligosaccharides, or mixtures thereof.
In a preferred embodiment, the composition further comprises at least an active substance of plant origin selected from the group comprising or, alternatively consisting of Lycium barbarum, Coix lacrima-jobi and Cordyceps sinensis; preferably it is Lycium barbarum or a mixture of Lycium barbarum, Coix lacrima-jobi and Cordyceps sinensis.
Said compositions can further comprise a plant gum and/or a plant gelatin. The plant gum and/or the plant gelatin is preferably selected from the group comprising a tannate or a gelatin tannate, an alginate, a xyloglucan or xylogel, a guar gum, a tara gum, an acacia, carob, oat, bamboo fiber, citrus fruit fibers and glucomannans. Preferably it is a guar gum. The selected plant gum and/or plant gelatin reduces the bacterial translocation of E.coli from the intestine to the bladder.
Said compositions can further comprise an Aloe arborescens, preferably a freeze-dried Aloe arborescens.
It is an object of the present invention the composition for use in the preventive and/or curative treatment of urinary tract and/or prostate inflammations, which comprises or, alternatively, consists of:
(i) a mixture of bacteria which comprises or, alternatively, consists of Lactobacillus plantarum LMG P-21021 - LP01 combined with at least a bacterial strain selected from the group comprising the strain Lactobacillus paracasei DSM 24243 -LPC09, the strain Lactobacillus gasseri DSM 18299 -LGS01 , the strain Lactobacillus gasseri DSM 18300 -LGS02, the strain Lactobacillus acidophilus DSM 24303 -LA07 and the strain Lactobacillus acidophilus DSM 21717 -LA02; preferably in a weight ratio comprised from 3:1 to 2:1 ; even more preferably 1.5:1 , (ii) a bacterial tyndallized product containing cells which internalize in their inside organic zinc, preferably said cells are obtained from the strain of bacteria Bifidobacterium lactis DSM 17850 -BB1 ,
(iii) a cranberry extract, preferably a dry cranberry extract,
(iv) a prebiotic fiber selected from fructo-oligosaccharide -FOS, preferably a short chain fructo-oligosaccharide - FOSsc, or from galactooligosaccharides GOS, or mixtures thereof,
(v) at least an active substance of plant origin selected from the group comprising or, alternatively consisting of Lycium barbarum, Coix lacrima-jobi and Cordyceps sinensis, preferably Lycium barbarum.
It is an object of the present invention the composition for use in the preventive and/or curative treatment of urinary tract and/or prostate inflammations, which comprises or, alternatively, consists of:
(i) a mixture of bacteria which comprises or, alternatively, consists of Lactobacillus plantarum LMG P-21021 - LP02, combined with at least a bacterial strain selected from the group comprising the strain Lactobacillus paracasei DSM 24243 -LPC09, the strain Lactobacillus gasseri DSM 18299 -LGS01 , the strain Lactobacillus gasseri DSM 18300 -LGS02, the strain Lactobacillus acidophilus DSM 24303 -LA07 and the strain Lactobacillus acidophilus DSM 21717 -LA02; preferably in a weight ratio comprised from 3:1 to 2:1 ; even more preferably 1.5:1 ,
(ii) a bacterial tyndallized product containing intact cells which internalized, during their production process a highly bioavailable organic zinc, preferably said cells are obtained from the strain of bacteria Bifidobacterium lactis DSM 17850 -BB1 ,
(iii) a cranberry extract, preferably a dry cranberry extract,
(iv) a prebiotic fiber selected from fructo-oligosaccharide -FOS, preferably a short chain fructo-oligosaccharide - FOSsc, or from galactooligosaccharides GOS, or mixtures thereof,
(v) a mixture of active substances of plant origin comprising or, alternatively consisting of Lycium barbarum, Coix lacrima-jobi and Cordyceps sinensis, preferably Lycium barbarum,
(vi) a guar gum and/or Aloe arborescens, preferably a freeze-dried Aloe arborescens. All the compositions of the present invention are suitable for use in the preventive and/or curative treatment of prostatitis and prostatic hypertrophy.
The composition of the present invention due to the presence of a cranberry extract, preferably a dry extract (trade name PACran®, a dry extract of US cranberry (Cranberry -Vaccinium macrocarpon- extract)) is capable to establishing a physical-mechanical hindrance against the Escherichia coli adhesion to the epithelial cell surface of the urinary tract (urothelium).
The activity of said cranberry extract is mediated, in particular, by the proanthocyanidin subfraction with the trimers and tetramers characterized by A-type bonds which compete with the adhesins located on the P-type fimbriae (FimH, mannose-sensitive) which uses £. coli for mediating its anchoring to the epithelial cells through specific receptors, thereby hindering in a physical-mechanical manner its adhesion and subsequent urothelium colonization. Furthermore, the cranberry extract reduces the Lower Urinary Tract Symptoms (LUTS), a frequently observed condition.
The composition of the present invention contains highly assimilable zinc (about 2 mg of zinc ion) carried by a bifidobacterium which is able to accumulate zinc inside the cell (bacterial tyndallized product) during its growing in a liquid culture medium. The zinc being accumulated inside the cell (internalized) has an assimilability 17-fold greater than zinc gluconate and 31.5-fold greater than zinc sulfate, as shown by an in vitro study carried out on Caco-2 cells in a Transwell system. This zinc ion in the form of bacterial tyndallized product is very important for the prostate function, mainly in adults.
Advantageously, the strain of bacteria Lactobacillus plantarum LMG P-21021 - LP01 and/or the strain of bacteria Lactobacillus plantarum LMG P-21020 -LP02, in the presence of cranberry extract, are capable to complement and enhance the physical-mechanical hindrance exerted by the cranberry extract as described above, through a barrier-type action even at intestinal level against £ coli. These two strains of bacteria Lactobacillus plantarum LMG P-21021 - LP01 and Lactobacillus plantarum LMG P-21020 -LP02 have a proven E.coli activity and a high anti-inflammatory activity since they produce interleukin 4 (IL-4) and interleukin 10 (IL-10).
Preferably, the strain of bacteria Lactobacillus plantarum LMG P-21021 - LP01 and/or the strain of bacteria Lactobacillus plantarum LMG P-21020 - LP02 are in an amount comprised from 1 to 10 billions of viable cells/dose, even more preferably from 2 to 5 billions of viable cells/dose. The strains of bacteria of the present invention exert a marked barrier-type action against potential Gram- negative pathogens, with particular reference to the species Escherichia coii and a high anti-inflammatory activity since they produce interleukin 4 (IL-4) and interleukin 10 (IL-10).
Advantageously, the strains of bacteria Lactobacillus paracasei DSM 24243 - LPC09, Lactobacillus gasseri DSM 18299 -LGS01 , Lactobacillus gasseri DSM 18300 -LGS02, Lactobacillus acidophilus DSM 24303 -LA07 and Lactobacillus acidophilus DSM 21717 -LA02 are able to carry out a protective action since they exert a barrier effect to the oxalates contained in the cranberry extract, preferably in the form of dry extract. The metabolization of these oxalate molecules prevents the intestinal accumulation and the systemic absorption thereof, thus avoiding the establishment and the maintenance of an inflammatory condition of the intestine, particularly disadvantageous in the occurrence of diverticula.
The strains of bacteria Lactobacillus paracasei DSM 24243 -LPC09, Lactobacillus gasseri DSM 18299 -LGS01, Lactobacillus gasseri DSM 18300 -LGS02, Lactobacillus acidophilus DSM 24303 -LA07 and Lactobacillus acidophilus DSM 21717 -LA02 metabolize oxalates and, therefore, have a proved anti-renal gravel activity. These strains of bacteria prevent the renal accumulation of oxalates thus avoiding the renal gravel formation and, thereby, impeding the establishment and the maintenance of an inflammatory condition of the urinary tract particularly disadvantageous for the health status of a bladder subjected to recurrent cystitis.
The percentage of oxalate degradation is as follows:
- Lactobacillus paracasei DSM 24243 -LPC09, greater than 68%;
- Lactobacillus gasseri DSM 18299 -LGS01 , greater than 68%;
- Lactobacillus gasseri DSM 18300 -LGS02, greater than 66%;
- Lactobacillus acidophilus DSM 24303 -LA07, greater than 54%;
- Lactobacillus acidophilus DSM 21717 -LA02, greater than 50%.
The presence of strains of bacteria degrading oxalates in the composition of the present invention is also important for the following reason. The cranberry extract contains a fair oxalate amount. A prolonged use of cranberry extract could lead to renal gravel formation, which may force a subject to suspend the use thereof. The use of strains degrading oxalates of the present invention prevents this drawback allowing a prolonged administration of cranberry extract.
Preferably, the strains of bacteria Lactobacillus paracasei DSM 24243 -LPC09, Lactobacillus gasseri DSM 18299 -LGS01 , Lactobacillus gasseri DSM 18300 -LGS02, Lactobacillus acidophilus DSM 24303 -LA07 and Lactobacillus acidophilus DSM 21717 -LA02 are in an amount comprised from 0.5 to 2 billions of viable cells/dose, even more preferably from 1 to 1.5 billions of viable cells/dose.
The composition of the present invention can further comprise at least a gum, among those described above, which decreases the bacterial translocation of E.coli from the intestine to the bladder. The gum can be a plant gum and/or a plant gelatin. The plant gum and/or the plant gelatin is preferably selected from the group comprising a tannate or a gelatin tannate, an alginate, a xyloglucan or xylogel, a guar gum, a tara gum, an acacia, carob, oat, bamboo fiber, citrus fruit fibers and glucomannans. Preferably it is a guar gum, The selected plant gum and/or plant gelatin reduces the bacterial translocation of E.coli from the intestine to the bladder. Preferably it is a guar gum. The guar gum exerts a mechanical action at intestinal level, hindering the adhesion of Escherichia coli and other pathogens to the mucosa of the organ, thus reducing their translocation through the intestinal wall and the subsequent risk of infection of adjacent organs. In particular, the gum acts by forming a hydrophilic gel, which evenly distributes over the mucosal surface, restoring the physiological barrier effect of this organ, which typically results impaired in the event of intestinal infections by Escherichia coli or other pathogens.
Moreover, the composition of the present invention further comprises a fiber with prebiotic activity (prebiotic fiber), which can be selected from inulin, fructo-oligosaccharides (FOS), galacto- and trans-galacto-oligosaccharides (GOS and TOS), gluco-oligosaccharides (GOSa), xylo-oligosaccharides, (XOS), chitosan-oligosaccharides (COS), soy-oligosaccharides (SOS), isomalto-oligosaccharides (IMOS), resistant starch, pectins, psyllium, arabino-galactans, gluco-mannans and galacto-mannans. Preferably, it is selected from short chain fructo- oligosaccharides (FOSsc) and/or galactooligosaccharides GOS which contributes to the growing and replication of the bacterial strains existing in the composition.
The presence of a freeze-dried Aloe arborescens in the composition of the present invention, in an amount for example of 500 mg/sachet, is capable to rapidly form a gel after dissolving the sachet in water, thus ensuring a mechanical barrier effect for protecting the esophageal, gastric and intestinal mucosae. The freeze-dried Aloe arborescens product, in addition to the physical protective action of mucosae, is capable to decrease the adhesive properties of pathogenic strains by a physical-mechanical hindrance, with particular reference to microorganisms provided with flagella, both at esophageal and gastrointestinal level. The freeze-dried Aloe arborescens product is also able to decrease the gastric and intestinal permeability, thereby contributing to restoring the physiological barrier effect of such an organ and synergistically acting with the guar gum in reducing the risk of bacterial translocation from the intestine. Furthermore, Aloe arborescens has anti-inflammatory activity, thus providing a further protection at mucosal level. In addition, the presence in the composition of the present invention, of at least an active substance of plant origin selected from the group comprising or, alternatively consisting of Lycium barbarum, Coix lacrima-jobi and Cordyceps sinensis, preferably Lycium barbarum, has an anti-inflammatory and de-inflammatory activity in the prostate, thus synergistically acting with the cranberry extract.
The composition of the present invention can further comprise excipients selected from natural flavors, anti- caking agents such as silicon dioxide, black carrot anthocyanins, sucralose.
The mixture of bacteria has a bacterial load comprised from 1 x108 to 1 x1012 CFU/g of mixture. The composition of the present invention which contains said mixture of bacteria has a bacterial load of about 1 x109-1x1011 CFU/composition.
It is an object of the present invention a composition comprising a mixture, which comprises or, alternatively, consists of:
- (a) a strain of bacterium Lactobacillus plantarum LP01 (L G P-21021 ) and/or
- (b) a strain of bacterium Lactobacillus paracasei LPC09 (DSM 24243), said composition further comprises:
- (c) a muco-adhesive gelling complex composed of EPS, exopolysaccharides of bacterial origin, produced in situ by the strain of bacterium Streptococcus thermophilus DSM 25246 (ST10) and a tara gum, a polysaccharide of plant origin. The muco-adhesive gelling complex is able to establish a mechanical barrier effect throughout the gastro-intestinal tract. Said composition further comprises along with the above components (d) a dry extract of US cranberry (Cranberry - PACran®), (e) a suitable amount of freeze-dried Aloe arborescens (Alagel™), (f) an organic and highly bioavailable source of zinc (ProbioZinc®: Bifidobacterium lactis Bb1 -DSM 17850- tyndallized product containing zinc in organic form - for example titer: 20 mg/g) and, preferably, (g) three active ingredients of plant origin Lycium barbarum, Job's tears [Coix lacryma-jobi) and Cordyceps sinensis, for use in the preventive and/or curative treatment of infections and/or inflammations of the urinary tract and/or prostate (composition).
The action of physical-mechanical hindrance performed by Cranberry being present in the composition (from (a) to (f)) is enhanced by the presence of a suitable amount of tara gum which, due to its gelling and muco-adhesive properties, is capable to form a hydrogel within few minutes after ingestion, by virtue of its thixotropic characteristics, thus creating, in the first part of the gastrointestinal tract a mechanical barrier action against the adhesion of Escherichia coli and other pathogens to the mucosa of the organ, thereby reducing the translocation thereof through the intestinal wall and the subsequent risk of infection of adjacent organs, among which mainly the urinary tract. Such a barrier effect is completed and extended throughout the gastro-intestinal tract by the presence of exopolysaccharides (EPS), produced in situ by the microorganism Streptococcus thermophilus DSM 25246 (ST10), which thereby enhance the viscosity of the surrounding environment through a self-regulated, even mechanical, mechanism. The ingestion of the strain of bacteria Streptococcus thermophilus DSM 25246 (ST10) carries in the human intestine a source of molecules with gelling activity, thus carrying out an action completely complementary to that of tara gum.
The above-cited muco-adhesive gelling complex has an innovative property which has to be taken into account: tara gum, like all the gums of plant origin, is progressively degraded by the resident microbiota during its intestinal transit, thereby progressively reducing its gelling power of mechanical hindrance, The gradual reduction of the plant gum action is effectively counterbalanced by the gradual increase of exopolysaccharide (EPS) release in the intestinal lumen by the bacterial strain Streptococcus thermophilus DSM 25246 (ST10), which exerts its property mainly in ileum and colon. Therefore, the synergistic combination of tara gum and exopolysaccharides (EPS) produced in situ ensures the presence of gelling molecules throughout the gastro-intestinal tract, maximizing and optimizing the barrier action exerted by the composition. The presence, production and retention of the hydrophillc gel in the lumen of the organ can, thus, be considered complete, with a first area wherein the plant gum action is maximum and a second area wherein the exopolysaccharide (EPS) action is maximum.
Due also to the presence of a freeze-dried Aloe arborescens (Alagel™) (for example 500 mg/sachet), the composition (from (a) to (f)) is capable to rapidly form a gel after dissolving the sachet in water, thereby ensuring a mechanical barrier effect for protecting the esophageal, gastric and intestinal mucosae. The Aloe arborescens product, besides the action of physical mucosal protection, is capable to decrease the adhesive capabilities of pathogenic strains by a physical-mechanical hindrance, with particular reference to microorganisms provided with flagella, both at esophageal and gastrointestinal level. The Aloe product is also able to reduce the permeability at gastric and intestinal level, thus contributing in restoring the physiological barrier effect of such an organ and by synergistically acting with tara gum and exopolysaccharides (EPS) in reducing the risk of bacterial translocation from the intestine. Furthermore, Aloe arborescens is characterized by an anti-inflammatory activity, thus providing an additional protection at mucosal level.
The presence of the two microorganisms Lactobacillus plantarum LP01 (LMG P-21021) (for example 2.5 billions/daily dose) and Lactobacillus paracasei LPC09 (DSM 24243) (for example 1 billion/daily dose) mediates, also, an enhancement of the physical-mechanical hindrance described above, by a barrier-type action against £. coli even at intestinal level. The Applicant carried out the selection of specific microorganisms with a marked barrier-type action against potential Gram-negative pathogens, with particular reference to the species Escherichia coli, the main role of which in UTI has been well demonstrated. In addition to the 4 tested £ coli strains deriving from the ATCC Collection (see Figure 1 ), the barrier action was also quantified against the enterohemorrhagic serotype G157:H7, capable to produce one or more Shiga, and Klebsiella spp., toxins likewise responsible for a certain percentage of UTI, alone or combined with £ coli. Following to this research activity, the strain Lactobacillus plantarum LP01 was positively selected, which is able to establish a barrier-type action against both E.coli and Klebsiella. Furthermore, the microorganism Lactobacillus paracasei DSM 24243 (LPC09) is capable to create a barrier effect to oxalates, ensuring the complete tolerability to the Cranberry extract even in subjects particularly sensitive to small concentrations of these potential inflammatory agents of the intestinal and urinary mucosae.
Moreover, the presence in the composition (from (a) to (f)) of a proper amount of highly assimilable zinc (for example 2 mg of Zinc ion), carried by a bifidobacterium, allows the composition to be further enhanced in its function for adults over 40-50 since during the aging process a general reduction of the zinc absorption capability at intestinal level is observed, thereby establishing a deficit with main consequences in the prostate health and immune system.
The tyndallized strain of Bifidobacterium lactis Bb1 (DSM 17850) (ProbioZinc®) existing in the composition (from (a) to (f)) carries zinc in a form highly assimilable by the organism, useful for counterbalancing the deficit derived from the aging process and specifically important for people over 40-50. Such a tyndallized bacterium, once it reaches the intestinal mucosa, releases zinc in organic form in the proximity of the enterocytes, which thus is directly absorbed through the intestinal mucosa and ready for entering the systemic circulation and exerting its effect in the organism. The zinc accumulated inside the microorganism cell has an assimilability more than 16- fold greater than zinc gluconate and 31.5-fold greater than zinc sulfate, as demonstrated by an in vitro study performed on Caco-2 cells, which mimic the intestinal epithelium, in a Transwell system.
The high assimilability of the trace element zinc allows to counterbalancing in a very effective manner the deficits even with very low dosages. A causal connection between a proper zinc intake through the food and the prevention of prostatic hypertrophy onset mainly in adulthood was demonstrated. Additionally, it has to be noted that the organism capability to absorbing the food zinc results progressively reduced after age 50 when, simultaneously, the prostatic hypertrophy incidence increases. The possibility to intake a highly assimilable food zinc source is, therefore, fundamental during the adulthood, especially after age 50. The typical disorders of prostatic hypertrophy are given by the progressive obstruction to the urine flow through the urethra. The incomplete bladder emptying causes, in turn, a stasis that can lead to bladder infections and inflammations, whereas the prolonged, even incomplete, obstruction can cause a renal function impairment.
Thus, it is clear that in men with prostatic hypertrophy there is a greater risk of urinary tract infection (UTI) onset, and that they can primarily and specifically benefit from the positive effects of the present composition (from (a) to
(f))- Furthermore, the preferred presence of the (g) three active ingredients of plant origin Lycium barbarum, Job's tears (Co/x lacryma-jobi) and Cordyceps sinensis mediates an improving action of prostate health in men mainly over 50. In particular, they carry out an action as prostatic anti-inflammatory and de-inflammatory agents, thus synergistically acting with the cranberry extract and the other ingredients with a mechanical action of the composition (from (a) to (f)).
Example of composition No.1 in sachet granules:
Ingredients
- Lactobacillus plantarum LMG P-21021 -LP01 , 100 mg;
- Lactobacillus paracasei DSM 24243 -LPC09, 50 mg;
- Zinc ion in form of bacterial tyndallized product B, lactis DSM 17850 - BB1 , 75 mg;
- Cranberry extract (Cranberry PACran®), 125 mg;
- Short chain fructo-oligosaccharides -FOSsc 1500 mg/dose
- Lycium barbarum, 50 mg.
Excipients
Natural flavor cranberry; anti-caking agent: silicon dioxide; black carrot anthocyanins; sucralose.
Example of composition No.2 in sachet granules:
Ingredients
- Lactobacillus plantarum LMG P-21021 -LP01, 100 mg;
- Lactobacillus paracasei DSM 24243 -LPC09, 50 mg;
- Zinc ion in form of bacterial tyndallized product B. lactis DSM 17850 - BB1 , 125 mg;
- Cranberry extract (Cranberry PACran®), 250 mg;
- Short chain fructo-oligosaccharides -FOSsc 1250 mg/dose
- Lycium barbarum, Co/x lacrima-jobi and Cordyceps sinensis, 50 mg each;
- Guar gum, 150 mg;
- Freeze-dried Aloe arborescens, 250 mg.
Excipients
Natural flavor cranberry; anti-caking agent: silicon dioxide; black carrot anthocyanins; sucralose.
Examples of composition (3-4) correspond to compositions (1-2) wherein the strain of bacteria Lactobacillus plantarum LP01 (LMG P-21021) is replaced by the strain of bacteria Lactobacillus plantarum LP02 (LMG P- 21020) and the strain of bacteria Lactobacillus paracasei LPC09 (DSM 24243) is replaced by the strain of bacteria Lactobacillus acidophilus DSM 21717 -LA02. The composition of the present invention can be in solid form, for oral use, as tablet, capsule, granules or powder.
The compositions of the present invention, for example in granulated form for oral use in sachet, have a shelf-life of at least 3.5x109 viable cells at 24 months and at 25°C. It is recommended to take 2 sachets per day during the first 4 weeks, then to continue, for maintenance purposes, with 1 sachet per day over even long periods. The compositions of the present invention are well tolerated by the organism and thus allow a continuous and prolonged use over the time without side effects.
Cytokines with immunoregulatory action
This study assessed the induction of cytokines IL-4 and IL-10, which represent the main cytokines with immunoregulatory action. As shown in figure A, the tested strains of bacteria Lactobacillus plantarum LMG P- 21021 -LP01 and Lactobacillus plantarum LMG P-21020 -LP02 are able to induce a statistically significant growth relative to the basal conditions in both the cytokines.
Figure A. Cytokine profile. Mean ± S.E.M. of 10 independent experiments. The statistical meaning is calculated by using the Student's f-test. When it is calculated relative to the basal conditions (non-stimulated PBMC), the values p<0.05 are considered statistically significant. The IL-10 production was assessed in the culture supernatant after one day from stimulation. The IL-4 production was assessed in the culture supernatant after five days of stimulation. Similar results were obtained with the strain Lactobacillus plantarum LMG P-21020 -LP02.
Figure 1 relates to the quantification of E.coli (ATCC 8739, ATCC 10536, ATCC 35218, ATCC 25922) inhibition by the strain Lactobacillus plantarum LMG P-21021 -LP01.
Figure B relates to the quantification of E.coli (ATCC 8739, ATCC 10536, ATCC 35218, ATCC 25922) inhibition by the strain Lactobacillus plantarum LMG P-21020 -LP02.
A further example of formulation is disclosed below:
Declared
Amount
Raw material Name/Strain load
(mg/dose)
(BLN/dose)
Cranberry Extract 500.00
Freeze-dried Aloe arborescens 500.00 Tara gum 250.00
Lactobacillus plantarum LP01 (LMG P-21021) 2.5
Lactobacillus paracasei LPC09 (DSM 24243) 1
Streptococcus thermophilus ST10 (DSM 25246) 1
Fructo-oligosaccharides (FOS) 1 ,250.00
B. lactis Bb1 able to internalize organic Zinc (titer
100.00
20 mg/g, 2%)
Lycium barbarum 100.00
Job's tears (Coix lacryma-jobi) 100.00
Cordyceps sinensis 100.00
Sorbitol 1 ,000.00
Natural flavor cranberry 300.00
Black carrot anthocyanins 20.00
Sucralose 8.00
TOTAL 4,610.00

Claims

1. A composition comprising a mixture of bacteria, which comprises or, alternatively, consists of:
- at least a strain of bacterium selected from the group comprising the strain Lactobacillus plantarum LMG P- 21021 (LP01) and the strain Lactobacillus plantarum LMG P-21020 (LP02), combined with;
- at least a strain of bacteria selected from the group comprising the strain Lactobacillus paracasei DSM 24243 (LPC09), the strain Lactobacillus gasseri DSM 18299 (LGS01), the strain Lactobacillus gasseri DSM 18300 (LGS02), the strain Lactobacillus acidophilus DSM 24303 (LA07) and the strain Lactobacillus acidophilus DSM 21717 (LA02)
for use in the preventive and/or curative treatment of infections and/or inflammations of the urinary tract and/or prostate.
2. The composition for use according to claim 1 , wherein said mixture of bacteria comprises or, alternatively, consists of Lactobacillus plantarum LMG P-21021 (LP01), combined with at least a strain of bacteria selected from the group comprising the strain Lactobacillus paracasei DSM 24243 (LPC09), the strain Lactobacillus gasseri DSM 18299 (LGS01), the strain Lactobacillus gasseri DSM 18300 (LGS02), the strain Lactobacillus acidophilus DSM 24303 (LA07) and the strain Lactobacillus acidophilus DSM 21717 (LA02) preferably in a weight ratio comprised from 3:1 to 2:1; even more preferably 1.5:1 ,
3. The composition for use according to claim 1 , wherein said mixture of bacteria comprises or, alternatively, consists of Lactobacillus plantarum LMG P-21020 (LP02), combined with at least a strain of bacteria selected from the group comprising the strain Lactobacillus paracasei DSM 24243 (LPC09), the strain Lactobacillus gasseri DSM 18299 (LGS01 ), the strain Lactobacillus gasseri DSM 18300 (LGS02), the strain Lactobacillus acidophilus DSM 24303 (LA07) and the strain Lactobacillus acidophilus DSM 21717 (LA02) preferably in a weight ratio comprised from 3:1 to 2:1 ; even more preferably 1.5:1.
4. The composition for use according to any one of the preceding claims, wherein said composition further comprises a bacterial tyndallized product containing intact cells which internalized, during their production process, highly bioavailable organic zinc, preferably said cells are obtained from the strain of bacteria Bifidobacterium lactis DSM 17850 -BB1.
5. The composition for use according to any one of the preceding claims, wherein said composition further comprises a cranberry extract, preferably a dry cranberry extract.
6. The composition for use according to any one of the preceding claims, wherein said composition further comprises a prebiotic fiber selected from inulin, fructo-oligosaccharides (FOS), galacto- and trans-galacto- oligosaccharides (GOS and TOS), gluco-oligosaccharides (GOSa), xylo-oligosaccharides, (XOS), chitosan- oligosaccharides (COS), soy-oligosaccharides (SOS), isomalto-oligosaccharides (IMOS), resistant starch, pectins, psyllium, arabino-galactans, gluco-mannans and galacto-mannans; preferably, it is selected from short chain fructo-oligosaccharides (FOSsc) and/or galactooligosaccharides GOS or mixtures thereof.
7. The composition for use according to any one of the preceding claims, wherein said composition further comprises at least an active substance of plant origin selected from the group comprising or, alternatively consisting of Lycium barbarum, Coix lacrima-jobi and Cordyceps sinensis, preferably Lycium barbarum.
8. The composition for use according to any one of the preceding claims, wherein said composition further comprises:
- a plant gum and/or a plant gelatin which is selected from the group comprising a tannate or a gelatin tannate, an alginate, a xyloglucan or xylogel, a guar gum, a tara gum, an acacia, carob, oat, bamboo fiber, citrus fruit fibers and glucomannans; preferably it is a guar gum; and/or
- Aloe arborescens, preferably freeze-dried Abe arborescens.
9. The composition for use according to any one of the preceding claims, wherein said composition comprises or, alternatively, consists of:
(i) a mixture of bacteria which comprises or, alternatively, consists of:
- Lactobacillus plantarum LMG P-21021 -LP01 , combined with at least a strain of bacteria selected from the group comprising the strain Lactobacillus paracasei DSM 24243 -LPC09, the strain Lactobacillus gasseri DSM 18299 -LGS01 , the strain Lactobacillus gasseri DSM 18300 -LGS02, the strain Lactobacillus acidophilus DSM 24303 -LA07 and the strain Lactobacillus acidophilus DSM 21717 -LA02; or
- Lactobacillus plantarum LMG P-21020 -LP02, combined with at least a strain of bacteria selected from the group comprising the strain Lactobacillus paracasei DSM 24243 -LPC09, the strain Lactobacillus gasseri DSM 18299 -LGS01 , the strain Lactobacillus gasseri DSM 18300 -LGS02, the strain Lactobacillus acidophilus DSM 24303 -LA07 and the strain Lactobacillus acidophilus DSM 21717 -LA02; preferably in a weight ratio comprised from 3:1 to 2:1 ; even more preferably 1.5:1 ,
(ii) a bacterial tyndallized product containing intact cells which internalized, during their production process, highly bioavailable organic zinc, preferably said cells are obtained from the strain of bacteria Bifidobacterium lactis DSM 17850 -BB1 , (iii) a cranberry extract, preferably a dry cranberry extract,
(iv) a prebiotic fiber selected from a fructo-oligosaccharide -FOS, preferably a short chain fructo-oligosaccharide -FOSsc, or from galacto-oligosaccharides GOS, or mixtures thereof,
(v) at least an active substance of plant origin selected from the group comprising or, alternatively consisting of Lycium barbarum, Coix lacrima-jobi and Cordyceps sinensis, preferably Lycium barbarum; preferably said composition further comprises a guar gum and/or Aloe arborescens, preferably freeze-dried Aloe arborescens; said compositions being for use in the preventive and/or curative treatment of prostatitis and prostatic hypertrophy.
10. The composition for use according to any one of the preceding claims, wherein said composition comprises a mixture comprising or, alternatively, consisting of:
- (a) a strain of bacterium Lactobacillus plantarum LP01 (LMG P-21021 ) and/or
- (b) a strain of bacterium Lactobacillus paracasei LPC09 (DSM 24243); said composition further comprises:
- (c) a muco-adhesive gelling complex comprised of EPS, exopolysaccharides of bacterial origin, produced in situ by the strain of bacterium Streptococcus thermophilus DSM 25246 (ST10) and a tara gum, a polysaccharide of plant origin,
- (d) a dry cranberry extract (Cranberry - PACran®),
- (e) an amount of freeze-dried Aloe arborescens (Alagel™),
- (f) an organic and highly bioavailable source of zinc represented by the strain of bacterium Bifidobacterium lactis Bb1 -DSM 17850- tyndallized product containing organic zinc.
11. The composition for use according to claim 10, wherein said composition further comprises (g) three active substances of plant origin Lycium barbarum, Job's tears (Coix lacryma-jobi) and Cordyceps sinensis.
PCT/IB2014/000741 2013-05-14 2014-05-14 Composition comprising lactic acid bacteria and/or bifidobacteria for use in the preventive and/or curative treatment of bacterial infections and/or inflammations of the urinary tract and/or prostate which are the cause of prostatitis and prostatic hypertrophy WO2014184644A1 (en)

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