DE102018127408A1 - Cranberry extract PAC-A composition and its use in the prevention and / or treatment of urinary tract infections - Google Patents

Abstract

The present invention relates to a composition containing at least one cranberry extract with a high content of proanthocyanidins of type A (PAC-A) for the treatment and / or prevention of urinary tract infections, in particular recurrent urinary tract infections. The composition preferably contains at least one oxalic acid-free cranberry extract with a high content of type A proanthocyanidins (PAC-A). The aforementioned composition preferably further contains vitamin B7 and is used to promote the regeneration of the epithelium of the urinary organs and the urinary tract.

Description

The present invention relates to a composition containing at least one cranberry extract with a high content of proanthocyanidins of type A (PAC-A) for the treatment and / or prevention of urinary tract infections, in particular recurrent urinary tract infections. The composition preferably contains at least one oxalic acid-free cranberry extract with a high content of proanthocyanidins of type A (PAC-A). The aforementioned composition preferably further contains vitamin B7 and is used to promote the regeneration of the epithelium of the urinary organs and the urinary tract.

In the prior art, a variety of herbal preparations are known, which are recommended as food supplements for urinary tract infections, such as. B. the product Avitale®, which advertises to contain 19 mg proanthocyanidins per capsule. It is used for urinary tract infections and especially for recurrent urinary tract infections after antibiosis. This and other products based on a cranberry extract with similar compositions do not differentiate between the different proanthocyanidins. The content of type A proanthocyanidins is essential for the effect in urinary tract infections.

However, in connection with most products based on a cranberry extract, a recommended daily dose of 36 mg of proanthocyanidins (PACs) is discussed in the prior art. This daily dose is not medically proven and is not in any standard. This is often the subject of controversy. This is rightly so, since it is not the total content of the various PACs that is relevant, but the content of the effective proanthocyanidins of type A. Often the total PAC content is incorrectly advertised as the PAC-A content. The consumer is unable to understand how the stated content was determined.

It is important to pay attention to the method with which the content of proanthocyanidins was measured and with which method the content of type A of the proanthocyanidins was determined. The frequently used photometric or spectrophotometric measurement is faulty and not sufficiently sensitive, so that it is not possible to differentiate between the different monomers, dimers and trimers of the proanthocyanidins. This leads to false statements about the content of type A proanthocyanidins in the advertised products based on a cranberry extract. The person skilled in the art knows today that cranberry extracts and products with proven PAC contents, which were determined by means of photometric or spectrophotometric measurement, do not allow any statement about the content of PAC-A. Because it is not the PAC-A content that is measured, but only the total content of PACs.

Therefore, only those cranberry extracts and products based on a cranberry extract that have determined the content of proanthocyanidins using a sensitive method, e.g. B. by means of high performance liquid chromatography (HPLC), ultra high performance liquid chromatography (UHPLC), ultra high performance liquid chromatography (UHPLC) coupled with mass spectroscopy (UHPLC-MS), gel permeation chromatography (GPC) or capillary electrophoresis.

It is therefore an object of the present invention to provide a composition and products comprising the composition which contain a high proportion of the active compound of the proanthocyanidins of type A and which are used for the treatment and / or prevention of urinary tract infections, in particular recurrent urinary tract infections can. The aim is to provide a composition in the form of a product, such as a food supplement, food and / or medical device, which can be used alone or in combination with a medicament in the prevention and / or treatment of urinary tract infections, in particular recurrent urinary tract infections. It is also an object of the present invention to provide the positive effect of various compounds with regard to the maintenance and / or regeneration of healthy urinary tract, in particular a healthy microflora of the urinary tract. Furthermore, a method for the production of products containing the aforementioned composition with a high proportion of proanthocyanidins of type A is to be provided, and it is also an object of the present invention

The present invention therefore relates to a composition comprising at least one cranberry extract containing greater than or equal to 1% by weight of type A proanthocyanidins (PAC-A) per gram of cranberry extract, in particular measured by means of UHPLC with mass spectrometry coupling (UHPLC-MS ), preferably greater than or equal to 1.1% by weight, greater than or equal to 1.2% by weight, greater than or equal to 1.3% by weight, greater than or equal to 1.4% by weight and particularly preferably greater than or equal to 1.5 % By weight. In a special one Embodiment comprises the composition greater than or equal to 2.0% by weight, greater than or equal to 2.5% by weight, greater than or equal to 3.0% by weight, greater than or equal to 4% by weight, greater than or equal to 5% by weight, Greater than or equal to 10.0% by weight to greater than or equal to 15% by weight of proanthocyanidins of type A (PAC-A). The composition preferably comprises an extract of the species Vaccinium macrocarpon. The composition preferably comprises at least one cranberry extract containing less than or equal to 15% by weight of proanthocyanidins of type A (PAC-A), preferably measured by means of UHPLC with coupling to mass spectrometry.

In a particular embodiment, the composition according to the invention contains at least one cranberry extract with less than or equal to 10 mg oxalic acid per 100 g of cranberry extract, less than or equal to 8 mg, less than or equal to 6.5 mg, less than or equal to 5 mg and preferably less than or equal to 4 mg of oxalic acid per 100 g cranberry extract, measured in a 5: 1 cranberry extract. The cranberry extract according to the invention is particularly preferably free of oxalic acid, this being based in each case on the limit of quantification of the measurement method used.

Oxalic acid (oxalate) occurs mainly in plants and plant foods and is in the form of a potassium, sodium, magnesium and / or ammonium salt. Oxalic acids can lead to the formation of kidney stones through the metabolism of humans in combination with calcium ions. It is therefore preferred to use plant-based ingredients, in particular cranberry extracts, with the lowest possible level of oxalic acid and preferably completely cranberry extracts completely free of oxalic acid in the composition according to the invention.

According to the invention, a cranberry extract from one of the species Vaccinium macrocarpon, Vaccinium oxycoccos and / or Vaccinium vitis-idaea is used. A cranberry extract from the species Vaccinium macrocarpon with a high content of proanthocyanidins of type A (PAC-A) is preferably used. When combining more than one cranberry extract, extracts of different species can be used. Preferably only those cranberry extracts are used which are free from oxalic acid and particularly preferably contain a high content of type A (PAC-A) proanthocyanidins, preferably greater than or equal to 1% by weight of type A (PAC-A) proanthocyanidins per gram Cranberry extract.

Cranberry species comprising Vaccinium macrocarpon, Vaccinium oxycoccos and / or Vaccinium vitis-idaea, and preferably Vaccinium macrocarpon, contain three type A proanthocyanidin trimers, namely epicatechin- (4β → 6) -epicatechin- (4β → 8.2β → O → 7 ) -epicatechin, epicatechin (4β → 8.2β → O → 7) -epicatechin- (4β → 8) -epicatechin, and epicatechin- (4β → 8) -epicatechin- (4β → 8.2β → O → 7) -epicatechin and a type-A proanthocyanidin dimer epicatechin (4β → 8.2β → O → 7) -epicatechin (A2). In addition, there are monomers and B-type proanthocyanidins which occur in the cranberry species, the antibacterial activity, preferably in inhibiting the adhesion of p-fimbriated bacteria, being attributed to the type-A proanthocyanidins.

Particularly preferred are cranberry extracts whose content of proanthocyanidins and of PAC-A was determined by means of ultra high performance liquid chromatography (UHPLC) with UV detection and preferably by means of liquid chromatography with mass spectrometry coupling (LC / MS, HPLC-MS), such as shown in the present examples.

The cranberry extract used according to the invention, preferably from the species Vaccinium macrocarpon, is an ethanolic extract (greater than or equal to 70% ethanol, the rest being water). Other suitable solvents for producing the extract used according to the invention are water, 1,2-propylene glycol, aqueous ethanol, ethanol, in particular greater than or equal to 70% to less than or equal to 100% ethanol, greater than or equal to 70% ethanol, methanol, acetone , Chloroform, n-butanol, hexane, ethyl acetate, diethyl ether or a mixture of at least two of the aforementioned solvents. Preferred solvents are those that can be removed completely, especially without harmful or irritating residues. According to the invention, at least one ethanol extract of Vaccinium macrocarpon (70% ethanol) was used.

In one embodiment of the composition according to the invention, a dry and solvent-free cranberry extract with a high content of proanthocyanidins of type A (PAC-A) is particularly preferably used. “Solvent-free” in the sense of the invention means a residual solvent content of less than or equal to 10% by weight, preferably less than or equal to 8% by weight, less than or equal to 5% by weight, less than or equal to 4% by weight, less than or equal to 3% by weight , less than or equal to 2% by weight, less than or equal to 1% by weight, particularly preferably less than or equal to 0.1% by weight, based on the total weight of the respective cranberry extract.

In a further embodiment, the composition according to the invention contains at least one cranberry extract which contains greater than or equal to 5% by weight of proanthocyanidins (PAC) per gram of cranberry extract. The cranberry extract used according to the invention preferably contains a total PAC content of greater than or equal to 7% by weight, greater than or equal to 10% by weight, greater than or equal to 15% by weight, greater than or equal to 20% by weight, greater than or equal to 25 % By weight, greater than or equal to 35% by weight, greater than or equal to 35% by weight to greater than or equal to 40% by weight.

In a further embodiment, the composition according to the invention contains vitamin B7 (biotin), preferably greater than or equal to 0.001% by weight, based on the total content of the composition according to the invention (ad 100% by weight) and in particular in addition to PAC-A. Vitamin B7 is not only important for a healthy and normal energy and macronutrient metabolism and for normal functioning of the nervous system, but also essential for the skin and mucous membrane. The special combination with at least one cranberry extract, in particular PAC-A, and vitamin B7 combines the advantages of both compounds in the prevention and / or treatment of urinary tract infections, in particular in the regeneration of a healthy microflora of the epithelium, in particular the urothelium, of the urinary tract .

The water-binding activity of biotin keeps the mucous membrane moist. The moisture film on the mucous membrane inhibits colonization (adhesion) by pathogens of the mucous membrane (protection). PAC-A inhibit the adhesion of pathogens, in particular fimbrated pathogens, preferably bacteria, to the mucous membrane through interaction with the fimbriae (defense). A combination of the protective effect of biotin directly on the mucous membrane and the damaging / inhibitory effect of PAC-A on pathogens is a preferred combination of two different strategies - protection and defense - in maintaining and / or regenerating a healthy microflora of the epithelium, especially the urothelium, the urinary tract. Therefore, a composition according to the invention comprising at least one cranberry extract containing greater than or equal to 1% by weight of proanthocyanidins of type A (PAC-A) per gram of cranberry extract, in particular measured by means of UHPLC with mass spectrometry coupling (UHPLC-MS), is preferably larger equal to 1.1% by weight, greater than or equal to 1.2% by weight, greater than or equal to 1.3% by weight, greater than or equal to 1.4% by weight and particularly preferably greater than or equal to 1.5% by weight and containing vitamin B7, preferably greater than or equal to 0.001% by weight, based on the total content of the composition according to the invention (ad 100% by weight) is particularly preferred. In particular for use in the prevention and / or treatment of urinary tract infections, preferably recurrent urinary tract infections in the sense of the invention.

• - mindestens ein Säuerungsmittel, vorzugsweise Preiselbeerfruchtpulver,
• - Vitamin C und/oder
• - Spargelwurzelextrakt, vorzugsweise enthaltend Asparagusinsäure und seine Derivate.

In a further embodiment, the composition according to the invention, in particular for use in the prevention and / or treatment of urinary tract infections, preferably also includes recurrent urinary tract infections in the sense of the invention

• at least one acidulant, preferably cranberry powder,
• - Vitamin C and / or
• - Asparagus root extract, preferably containing aspartic acid and its derivatives.

Acidifying agents in the sense of the invention include acidifying agents selected from a naturally occurring acidifying agent, preferably of vegetable origin. The vegetable acidulant is preferably selected from plants containing fruit acid, such as soft fruits (grapes), pome and stone fruits, apple, citrus fruits and / or tropical fruits. Examples include citric acid, malic acid, malate, tartaric acid, tartrate and / or grape acid. L-malic acid / malate are found in pome and stone fruit. L-tartaric acid / tartrate and derivatives (magnesium and potassium tartrate) are mainly found in grapes. Other acids include fumaric acid, ascorbic acid and / or citric acid.

An extract powder of one of the aforementioned acidifying agents is preferably used and particularly preferably a cranberry fruit powder.

The asparagus root extract contained according to the invention in the composition is obtained from the asparagus root. Asparagus root contains saponins and fructans, but also important minerals (potassium, calcium, phosphorus), vitamins (B1, B2, C) and trace elements (zinc, molybdenum). Asparagus also contains a high proportion of sulfur-containing compounds that bind harmful substances (such as heavy metals) in the body and make them water-soluble. With this property, the asparagus root extract helps the kidney to excrete harmful substances.

The ingredients of the asparagus root, in particular asparagine and its derivatives, have a detoxifying, diuretic and cleansing effect, support liver function and free the blood of harmful substances Fabrics and stimulate the flooding. A practical side effect of the asparagus root extract is that the patient concerned receives immediate feedback from taking the composition according to the invention. The aspartic acid and its derivatives in asparagus root extract are sulfur-containing compounds which are broken down by the body's metabolism to the metabolites 2-propenthioic acid S-methyl ester (thioacrylic acid S-methyl ester) and / or 3- (methylthio) thiopropionic acid S-methyl ester. These metabolites are excreted in the urine in conjunction with a strong urine smell. The strong smell gives the patient the effect after taking the composition according to the invention and the progress of the therapy.

Alternatively or in combination with an asparagus root extract, an extract of parsley herb can also be used. Like the asparagus rootstock, parsley contains dehydrating ingredients e.g. B. flavones, flavonoids, terpenes, etc.

The composition according to the invention can contain at least one auxiliary. Auxiliaries are known to the person skilled in the art and include carriers, preservatives, antioxidants, stabilizers, vitamins, colorants, odor improvers, flavors, fillers, flavorings, acidulants, emulsifiers, stabilizers, sweeteners, humectants, mold release agents, thickeners, strengthening agents, disintegrants, lubricants, disintegrants, lubricants , Mold release agents, flow regulators, solvents, emulsifiers, solubilizers, solubilizers, wetting agents, salt formers, buffers, gel formers, thickeners, film formers, binders, sorbents, plasticizers, matrix formers, polymers and / or retarding agents.

Retarding properties have e.g. the excipients ethyl and methyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate phthalate and hydroypropyl methyl cellulose phthalate.

Flavorings are used to cover a potentially unpleasant taste or to determine a desired taste. For this purpose, z. B. mint, anise, fennel, menthol, fruit taste such as cranberry, apple and other citrus fruits. The cranberry extract used is preferably the flavoring itself.

Particularly preferred auxiliaries are maltodextrin, silicon dioxide, acesulfame K, sucralose, carrot concentrate and / or thistle concentrate. Preferred fillers include cellulose (microcrystalline), silicon dioxide (precipitated), magnesium stearate (vegetable). Further preferred auxiliaries, in particular for coating solid forms of the composition according to the invention, include hydroxypropylmethylcellulose (E464), titanium dioxide (E171), talc (E553b), hydroxypropylcellulose (E463), miglyol, iron oxides and iron hydroxides (E172), real carmine (E120) and / or biochar (E153).

• - größer gleich 0,1 Gew.-% PAC-A, vorzugsweise aus mindestens einem Cranberry-Extrakt von Vaccinium macrocarpon
• - größer gleich 5 Gew.-% Säuerungsmittel, bevorzugt größer gleich 10 Gew.-%, vorzugsweise Preiselbeerfruchtpulver
• - größer gleich 5 Gew.-% Spargelwurzelextrakt, bevorzugt größer gleich 10 Gew.-%,
• - größer gleich 2 Gew.-% Vitamin C, bevorzugt größer gleich 4 Gew.-%, und/oder
• - größer gleich 0,001 Gew.-% Vitamin B7, bevorzugt größer gleich 0,002 Gew.-%,

jeweils bezogen auf den Gesamtgehalt der Zusammensetzung (ad 100 Gew.-%).In a further embodiment, the composition according to the invention comprises

• - Greater than or equal to 0.1% by weight of PAC-A, preferably from at least one cranberry extract from Vaccinium macrocarpon
• - greater than or equal to 5% by weight of acidulant, preferably greater than or equal to 10% by weight, preferably cranberry fruit powder
• greater than or equal to 5% by weight of asparagus root extract, preferably greater than or equal to 10% by weight,
• - Greater than or equal to 2% by weight of vitamin C, preferably greater than or equal to 4% by weight, and / or
• greater than or equal to 0.001% by weight of vitamin B7, preferably greater than or equal to 0.002% by weight,

each based on the total content of the composition (ad 100 wt .-%).

In a further embodiment, the composition according to the invention is in solid form, liquid form or as a mixture of solid and liquid forms. In a further embodiment, the composition according to the invention for oral administration is in solid form, liquid form or as a mixture of solid and / or liquid forms. Preferably in solid form and particularly preferably in solid dry form as a compact for oral administration. In a special embodiment, the compact is coated in order to eliminate the hygroscopic properties.

Solid forms include tablet, pellet, powder, granules, effervescent tablet, dry juice, dragee, globules, capsule and lyophilisate. Liquid forms include suspension, solution, dispersion, tincture, Concentrate, juice and tea. Mixtures include jelly, spray and pastes and are also referred to as semi-solid forms.

Tablets in the sense of the invention include simple tablets, lozenges, sublingual and buccal tablets, orally dispersible tablets, solution, micro, chewable and effervescent tablets, spot, framework and multilayer tablets, dragées and pellets. Preference is given to gastric acid-resistant tablets and particularly preferably to gastric acid-resistant tablets with a delayed release.

Formulations for oral administration preferably include solid forms such as tablets, liquid forms such as juice or concentrate and mixtures such as jelly capsules (hard gelatin capsules, soft gelatin capsules).

• - größer gleich 80 mg mindestens eines Cranberry-Extrakt enthaltend größer gleich 0,5 Gew-%PAC-A bezogen auf 1 Gramm Cranberry-Extrakt, vorzugsweise größer gleich 80 mg bis kleiner gleich 300 mg Cranberry-Extrakt, größer gleich 85 mg, 90 mg, 100 mg, 110 mg, 120 mg, 150 mg, 180 mg Cranberry-Extrakt und besonders bevorzugt größer gleich 200 mg mindestens eines Cranberry-Extraktes enthaltend größer gleich 0,5 Gew-% PAC-A bezogen auf 1 Gramm Cranberry-Extrakt und vorzugsweise von Vaccinium macrocarpon,
• - größer gleich 100 mg mindestens eines Säuerungsmittels ausgewählt aus Preiselbeerfruchtpulver,
• - größer gleich 100 mg Spargelwurzelextrakt,
• - größer gleich 40 mg Vitamin C und
• - größer gleich 8 µg Biotin (Vitamin B7), vorzugsweise größer gleich 9 µg, vorzugsweise größer gleich 10 µg, vorzugsweise größer gleich 12 µg, vorzugsweise größer gleich 13 µg, vorzugsweise größer gleich 15 µg, vorzugsweise größer gleich 17 µg, vorzugsweise größer gleich 20 µg und besonders bevorzugt größer gleich 12,5 µg.

In a further embodiment, the composition according to the invention is in solid form, preferably comprising a compact

• greater than or equal to 80 mg of at least one cranberry extract containing greater than or equal to 0.5% by weight of PAC-A based on 1 gram of cranberry extract, preferably greater than or equal to 80 mg to less than or equal to 300 mg of cranberry extract, greater than or equal to 85 mg, 90 mg, 100 mg, 110 mg, 120 mg, 150 mg, 180 mg cranberry extract and particularly preferably greater than or equal to 200 mg of at least one cranberry extract containing greater than or equal to 0.5% by weight of PAC-A based on 1 gram of cranberry extract and preferably from Vaccinium macrocarpon,
• - greater than or equal to 100 mg of at least one acidifying agent selected from cranberry powder,
• - greater than or equal to 100 mg asparagus root extract,
• - greater than or equal to 40 mg of vitamin C and
• - Greater than or equal to 8 µg biotin (vitamin B7), preferably greater than or equal to 9 µg, preferably greater than or equal to 10 µg, preferably greater than or equal to 12 µg, preferably greater than or equal to 13 µg, preferably greater than or equal to 15 µg, preferably greater than or equal to 17 µg, preferably greater than or equal to 20 µg and particularly preferably greater than or equal to 12.5 µg.

• - 200 mg mindestens eines Cranberry-Extraktes, umfassend größer gleich 80 mg eines Cranberry-Extraktes von Vaccinium macrocarpon mit größer gleich 1,2 Gew.-%, 1,3 Gew.-%, 1,4 Gew.-%, 1,5 Gew.-% PAC-A und 120 mg eines anderen Cranberry-Extraktes,
• - 100 mg Preiselbeerfruchtpulver als Säuerungsmittel
• - 100 mg Spargelwurzelextrakt
• - 40 mg Vitamin C und
• - 12,5 µg Biotin (Vitamin B7).

A particular embodiment of the composition according to the invention, in particular for use in the prevention and / or treatment of urinary tract infections, preferably recurrent urinary tract infections, comprises

• 200 mg of at least one cranberry extract, comprising 80 mg or more of a cranberry extract of Vaccinium macrocarpon greater than or equal to 1.2% by weight, 1.3% by weight, 1.4% by weight, 1, 5% by weight of PAC-A and 120 mg of another cranberry extract,
• - 100 mg cranberry fruit powder as an acidulant
• - 100 mg asparagus root extract
• - 40 mg of vitamin C and
• - 12.5 µg biotin (vitamin B7).

Preferably at least 80 mg of the cranberry extract is an extract of Vaccinium macrocarpon with a content of greater than or equal to 1.2 mg PAC-A, greater than or equal to 1.3 mg PAC-A, greater than or equal to 1.4 mg PAC-A, or greater than or equal to 1.5 mg PAC-A, measured by means of LC / MS, UHPLC-MS and the other 120 mg or less, another cranberry extract. The aforementioned embodiment has the advantage that the composition already contains half the recommended daily dose of vitamin C and half the daily dose of biotin. The recommended daily intake of biotin and vitamin C is achieved by taking 2 × 1 tablet per day.

In a further embodiment, the composition according to the invention is in the form of a food supplement, food and / or medical product or is an additive to other medicaments and / or foods.

So far, cranberry extracts and compositions containing at least one cranberry extract have not been recognized by the health authorities. A future recognition of a proven content of the active compound PAC-A cannot be excluded.

The effectiveness of type A proanthocyanidins (PAC-A) is due to the inhibitory effect of bacterial adhesion to the urinary tract epithelium, particularly urothelium. In particular, the adhesion of Escherichia coli is inhibited by PAC-A. PAC-A are polyphenols (tannins) with a strong interaction with proteins and glycoproteins and therefore have an interaction with adhesion molecules and fimbriae, in particular P-fimbriae, of bacteria, whereby the bacterial adhesion to the urothelium is disrupted and inhibited. This is especially true for Escherichia coli. Consequently, PAC-A compounds have an inhibitory effect on the interaction between microbial, preferably bacterial, adhesion molecules and the surface proteins of the mucous membrane, e.g. B. Urotehl. In particular, PAC-A compounds block the binding sites on the adhesion molecules. PAC-A compounds therefore also have an inhibitory effect on pathogenic biofilm formation.

The composition according to the invention is preferably in solid form as a food supplement, preferably as a gastric acid-resistant tablet, or as a liquid form, preferably as a concentrate, juice or beverage. A concentrate, juice or drink can also be kept as food. The composition according to the invention can also be introduced as an additive in a food or nutritional supplement.

Another object of the present invention is the composition according to the invention, preferably containing at least one cranberry extract with a high content of type A proanthocyanidins (PAC-A), for use in the prevention and / or treatment of urinary tract infections comprising uncomplicated urinary tract infections, recurrent urinary tract infections , recurrent urinary tract infections after antibiosis, cystitis, recurrent cystitis, pyelonephritis, recurrent pyelonephritis, urethritis, recurrent urethritis, nosocomially acquired urinary tract infections and / or urinary tract infections related to catheters and / or cystoscopy. It is particularly preferred to use the composition according to the invention for the treatment and / or prevention of recurrent urinary tract infections.

In the case of recurrent urinary tract infections, a distinction can be made between relapse and reinfection, the most common case being reinfection. According to the invention, use in reinfections as defined below is preferred. Relapses are due to the persistence of the pathogen and often occur within 14 days after the start of prescribed therapy. Relapse can be attributed to an insufficient dosage of the selected drug and / or resistance of the pathogen. Therefore, another antibiotics of several days, preferably ten days, is often carried out with another antibiotic. Reinfections arise from new infections. In such cases, short-term antibiosis in combination with preventive measures is often recommended. Combination therapy in the sense of the present invention is particularly preferred in the case of reinfection comprising uncomplicated urinary tract infections, recurrent urinary tract infections, recurrent urinary tract infections after antibiosis, cystitis, recurrent cystitis, pyelonephritis, recurrent pyelonephritis, urethritis and / or recurrent urethritis.

Another object of the present invention is the composition according to the invention, preferably containing at least one cranberry extract with a high content of proanthocyanidins of type A (PAC-A), for use in combination with a medicament, preferably an antibiotic, in the prevention and / or treatment (synonym: combination therapy) of urinary tract infections including uncomplicated urinary tract infections, recurrent urinary tract infections, recurrent urinary tract infections after antibiosis, recurrent cystitis, pyelonephritis, recurrent pyelonephritis, urethritis and / or recurrent urethritis and / or urinary infections and / or urinary tract infections and acquired or associated with or or a cystoscopy.

• - Anatomische Anomalitäten (z.B. Reflux, Markschwammniere)
• - Funktionelle Störungen (z.B. neurogene Blasenentleerungsstörungen)
• - Obstruktion (z.B. BPH, Urethralklappen)
• - Nosokomial erworbene HWI (z.B. Dauerkatheter, Zystoskopie)
• - Diabetes mellitus
• - Immunsuppression
• - Urolithiasis und
• - Niereninsuffizienz.

Die erfindunsgemäße Zusammensetzung kann in Rücksprache mit dem Arzt als Begleitpräparat und in Kombination mit einem Arzneimittel zur Unterstützung des Heilungsprozesses und insbesondere zur Prävention eines Rezidivs verwendet werden.Urinary tract infections are divided into complicated and uncomplicated urinary tract infections. Complicated urinary tract infections are particularly prevalent in patients with special risk factors for a severe course, consequential damage or treatment failure. This includes pregnant women, children and patients with the following dispositions:

• - Anatomical abnormalities (e.g. reflux, marrow kidney)
• - functional disorders (e.g. neurogenic voiding disorders)
• - obstruction (e.g. BPH, urethral valves)
• - UTIs acquired nosocomially (e.g. permanent catheter, cystoscopy)
• - Diabetes mellitus
• - Immunosuppression
• - urolithiasis and
• - renal failure.

In consultation with the doctor, the composition according to the invention can be used as an accompanying preparation and in combination with a medicament to support the healing process and in particular to prevent recurrence.

Uncomplicated urinary tract infections occur without other concomitant diseases, which can be treated with antibiosis according to the usual method and / or with the composition according to the invention. The affected patient, man or woman, often wishes to avoid antibiosis due to the known side effects. In these cases, patients look for herbal alternatives. For such cases and with early detection, the treatment of urinary tract infections can be carried out in the sense of the present invention. The composition according to the invention is preferably used in the treatment and / or prevention of uncomplicated urinary tract infections, recurrent urinary tract infections, recurrent urinary tract infections after antibiosis, cystitis, recurrent cystitis, pyelonephritis, recurrent pyelonephritis, urethritis and / or recurrent urinary infections and preferably for the prevention of acquired urinary infections , Urinary tract infections in connection with catheters, a cystoscopy and / or a corresponding relapse.

Recurrent urinary tract infections within the meaning of the invention are recurrent urinary tract infections caused by the same or a different pathogen of the urinary tract, kidney, kidney pelvis, kidney cup, ureter, bladder and / or urethra and include recurrent cystitis, recurrent pyelonephritis, recurrent urethritis and / or others recurrent urinary tract infections after antibiosis or regardless of antibiosis. The recurrence may be a urinary tract infection of the same organ or another organ of the urinary organs defined herein, including the urinary tract, kidney, renal pelvis, kidney cups, ureter, bladder and urethra.

• - größer gleich 0,1 Gew.-% PAC-A, vorzugsweise aus mindestens einem Cranberry-Extrakt von Vaccinium macrocarpon
• - größer gleich 5 Gew.-% Säuerungsmittel, bevorzugt größer gleich 10 Gew.-%, vorzugsweise Preiselbeerfruchtpulver
• - größer gleich 5 Gew.-% Spargelwurzelextrakt, bevorzugt größer gleich 10 Gew.-%,
• - größer gleich 2 Gew.-% Vitamin C, bevorzugt größer gleich 4 Gew.-%, und/oder
• - größer gleich 0,001 Gew.-% Vitamin B7, bevorzugt größer gleich 0,002 Gew.-%,

jeweils bezogen auf den Gesamtgehalt der Zusammensetzung (ad 100 Gew.-%) und besonders bevorzugt wird bei der Prävention und/oder Behandlung von Harnwegsinfekten eine erfindungsgemäße Zusammensetzung verwendet, welche umfasst

• - 200 mg mindestens eines Cranberry-Extraktes, vorzugsweise aus einem Cranberry-Extrakt von Vaccinium macrocarpon
• - 100 mg Preiselbeerfruchtpulver als Säuerungsmittel
• - 100 mg Spargelwurzelextrakt
• - 40 mg Vitamin C und
• - 12,5 µg Biotin (Vitamin B7),

wobei mindestens 80 mg des mindestens einen Cranberry-Extraktes ein Extrakt von Vaccinium macrocarpon mit einem Gehalt von größer gleich 1,2 mg PAC-A, größer gleich 1,3 mg PAC-A, größer gleich 1,4 mg PAC-A, größer gleich 1,5mg ist, gemessen mittels LC/MS, UHPLC-MS und vorzugsweise frei von Oxalsäure. Diese Ausführungsform hat den Vorteil, dass die Zusammensetzung bereits die halbe empfohlene Tagesdosis an Vitamin C und die halbe Tagesdosis an Biotin enthält und somit im Rahmen der erfindungsgemäßen gemessen Verwendung, vorzugsweise bei einer Dosierung von 2 × 1 Tablette pro Tag, die Behandlung und/oder Prävention von Harnwegsinfekten im Sinne der Erfindung durch ausreichend Vitamin C und Vitamin B7 unterstützt.In a particular embodiment of the use according to the invention of the composition defined herein, the composition is used in combination (as combination therapy) with at least one medicament for the treatment and / or prevention of urinary tract infections. The embodiment of the composition according to the invention is preferably used in the sense of the invention, the composition comprising

• - Greater than or equal to 0.1% by weight of PAC-A, preferably from at least one cranberry extract from Vaccinium macrocarpon
• - greater than or equal to 5% by weight of acidulant, preferably greater than or equal to 10% by weight, preferably cranberry fruit powder
• greater than or equal to 5% by weight of asparagus root extract, preferably greater than or equal to 10% by weight,
• - Greater than or equal to 2% by weight of vitamin C, preferably greater than or equal to 4% by weight, and / or
• greater than or equal to 0.001% by weight of vitamin B7, preferably greater than or equal to 0.002% by weight,

in each case based on the total content of the composition (ad 100% by weight) and particularly preferably in the prevention and / or treatment of urinary tract infections, a composition according to the invention is used which comprises

• - 200 mg of at least one cranberry extract, preferably from a cranberry extract from Vaccinium macrocarpon
• - 100 mg cranberry fruit powder as an acidulant
• - 100 mg asparagus root extract
• - 40 mg of vitamin C and
• - 12.5 µg biotin (vitamin B7),

wherein at least 80 mg of the at least one cranberry extract is an extract of Vaccinium macrocarpon with a content greater than or equal to 1.2 mg PAC-A, greater than or equal to 1.3 mg PAC-A, greater than or equal to 1.4 mg PAC-A, greater is 1.5 mg, measured by means of LC / MS, UHPLC-MS and preferably free of oxalic acid. These Embodiment has the advantage that the composition already contains half the recommended daily dose of vitamin C and half the daily dose of biotin and thus in the context of the measured use according to the invention, preferably at a dosage of 2 × 1 tablet per day, the treatment and / or prevention of urinary tract infections in the sense of the invention supported by sufficient vitamin C and vitamin B7.

The choice of a suitable drug for the treatment of urinary tract infection in the sense of the invention is made by the treating doctor.

Common methods of treatment of urinary tract infections in the sense of the invention include treatment with antibiotics. Usually for 3-14 days, with short therapy being preferred. For urethritis and cystitis, preferably for 3 days. For pyelonephritis, preferably for 14 days. Suitable antibiotics include beta-lactam antibiotics, cephalosporins, penicillin, amoxicillin, cefaclor, cotrimaxozole, nitrofurantoin, fosfomycin, quinolones, norfloxacin, ciprofloxacin, ofloxacin, trimethoprom, sulfamethoximoxole and / or. In addition to antibiotics, pain relievers, e.g. B. ibuprofen or paracetamol.

Thus, in the sense of the invention it is preferred to use the composition according to the invention defined herein in combination with at least one medicament for the treatment and / or prevention of urinary tract infections, the composition according to the invention being used for at least the duration of the medicament administered, preferably an antibiotic, and preferably in solid form is administered orally. Preferably, the composition according to the invention defined herein is used for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30 after the end of the drug intake Continued for days. If necessary, the intake can be continued, with a dosage of 2 × 1 tablet per day being preferred.

Regardless of the duration of the antibiotic intake, the composition according to the invention, preferably orally, can be administered. The advantage of the combination therapy in the sense of the invention is that the drug treats the acute urinary tract infection and at the same time a recurrence is prevented and / or treated by the use according to the invention of the composition defined herein. This applies particularly to uncomplicated urinary tract infections, recurrent urinary tract infections, recurrent urinary tract infections after antibiosis, cystitis, recurrent cystitis, pyelonephritis, recurrent pyelonephritis, urethritis and / or recurrent urethritis, nosocomially acquired urinary tract infections and / or associated with urinary tract infections and / or.

Therefore, the composition according to the invention is preferably used preventively before, during and / or after antibiosis, preventively before and / or during an upcoming hospital stay in connection with catheterization and preventively before and / or during an upcoming cystoscopy. The composition according to the invention is preferably used preventively if there are signs of a cold, if there is a personal disposition to frequent bladder infections and / or preventively before / during a vacation or swimming in open waters.

As an alternative to the antibiotic, the doctor can prescribe treatment with D-mannose, the D-mannose being used as a medical device primarily for the prevention and also for the treatment of cystitis. The effects are based on the inhibition of the interaction of the bacterial P-fimbriae with the urothelium. A combination of D-mannose and the composition according to the invention combines the advantages of the active compounds comprising PAC-A, vitamin C and / or vitamin B7 described herein with the advantages of D-mannose.

In a special embodiment of the use according to the invention, the mucous membrane and / or the urothelium of the urinary tract, urinary bladder, ureter, urethra, kidney pelvis and / or kidney cups are protected, their regeneration is promoted and / or the colonization is inhibited by pathogens.

Colonization in the sense of the invention comprises the adhesion of pathogens, preferably bacteria, to the epithelium, preferably to the urothelium, the urinary tract, the kidney, renal pelvis, kidney cups, the ureter, the urinary bladder and / or the urethra, which by the use of the invention Composition is inhibited. Preferably the ureter, bladder and / or urethra.

Pathogens in the sense of the invention include Escherichia coli, Staphylococcus saprophyticus, Proteus mirabilis, Klebsiell, Enterococci, Staphylococci, Pseudomonas, Candida, Mycoplasmas, Ureaplasmas, Chlamydia, Gonococci and / or Mycobacterium tuberculosis.

The composition according to the invention is preferably used in the treatment and / or prevention of bacterial urinary tract infections, preferably caused by Escherichia coli, Staphylococcus saprophyticus, stickies, enterococci, staphylococci and / or Pseudomonas.

The composition according to the invention preferably has an antibacterial action against Escherichia coli, staphylococci, S. aureus, Pseudomonas, P. aeruginosa and / or C. albicans. Therefore, a particular advantage of the use of the composition according to the invention is the antibacterial effect against pathogens causing urinary tract infections.

In a particular embodiment of the use according to the invention of the composition according to the invention, a daily dose of at least 3.0 mg PAC-A is administered and preferably a dosage unit of the composition according to the invention contains at least half the daily dose of PAC-A, preferably measured by means of LC / MS, HPLC-MS .

In a particular embodiment of the use of the composition according to the invention, the composition is administered, preferably in solid form, twice a day, preferably orally.

• - Bereitstellen mindestens eines Cranberry-Extraktes mit größer gleich 1 Gew.-% PAC-A pro Gramm Cranberry Extrakt, vorzugsweise aus mindestens einem Cranberry-Extrakt von Vaccinium macrocarpon und vorzugsweise gemessen mittels LC/MS, HPLC-MS,
• - Bereitstellen von Vitamin B7,
• - optional Bereitstellen mindestens eines Säuerungsmittel, mindestens eines Spargelwurzelextraktes und/oder Vitamin C,
• - optional Bereitstellen mindestens eines Hilfsstoffes,
• - Mischen der Bestandteile und
• - Erhalt einer Zusammensetzung im Sinne der Erfindung, vorzugsweise einer Zusammensetzung enthaltend
  • - größer gleich 0,1 Gew.-% PAC-A, vorzugsweise aus mindestens einem Cranberry-Extrakt von Vaccinium macrocarpon
  • - größer gleich 5 Gew.-% Säuerungsmittel, bevorzugt größer gleich 10 Gew.-%, vorzugsweise Preiselbeerfruchtpulver
  • - größer gleich 5 Gew.-% Spargelwurzelextrakt, bevorzugt größer gleich 10 Gew.-%,
  • - größer gleich 2 Gew.-% Vitamin C, bevorzugt größer gleich 4 Gew.-%, und/oder
  • - größer gleich 0,001 Gew.-% Vitamin B7, bevorzugt größer gleich 0,002 Gew.-%,
  wobei alle Gew.-% Angaben sich auf das Gesamtgewicht der Zusammensetzung (ad. 100 Gew.-%) beziehen.

Another object of the present invention is a method for producing the composition according to the invention comprising the steps

• Provision of at least one cranberry extract with greater than or equal to 1% by weight of PAC-A per gram of cranberry extract, preferably from at least one cranberry extract from Vaccinium macrocarpon and preferably measured by means of LC / MS, HPLC-MS,
• - providing vitamin B7,
• optionally providing at least one acidulant, at least one asparagus root extract and / or vitamin C,
• optionally providing at least one auxiliary,
• - Mixing the ingredients and
• - Obtaining a composition according to the invention, preferably containing a composition
  • - Greater than or equal to 0.1% by weight of PAC-A, preferably from at least one cranberry extract from Vaccinium macrocarpon
  • - greater than or equal to 5% by weight of acidulant, preferably greater than or equal to 10% by weight, preferably cranberry fruit powder
  • greater than or equal to 5% by weight of asparagus root extract, preferably greater than or equal to 10% by weight,
  • - Greater than or equal to 2% by weight of vitamin C, preferably greater than or equal to 4% by weight, and / or
  • greater than or equal to 0.001% by weight of vitamin B7, preferably greater than or equal to 0.002% by weight,
  where all percentages by weight relate to the total weight of the composition (ad. 100 percent by weight).

• - wird die Zusammensetzung zu einer festen Form, vorzugsweise zu einem Pressling, geformt,
• - die feste Form mindestens einmal beschichtet und
• - eine beschichtete Tablette erhalten, vorzugsweise eine magensäureresistente Tablette.

In a special embodiment of the method according to the invention,

• the composition is shaped into a solid form, preferably into a compact,
• - The solid form coated at least once and
• - receive a coated tablet, preferably an enteric tablet.

Examples

Example 1: Determination of the Proanthocyanidins Content

The cranberry extract powder was homogenized and crushed. The extraction of the proanthocyanidins (synonym procyanidin) was carried out using a mixture of acetone / water / formic acid (volume mixing ratio 70: 30: 0.5) in an ultrasonic bath.

• Eluentengemisch 1: Wasser mit Ameisensäure
• Eluentengemisch 2: Acetonitril mit Ameisensäure

• Procyanidin A1: 20,06 min
• Procyanidin A2: 21,41 min
• A-Typ Trimer 1: 15,22 min
• A-Typ Trimer 2: 17,56 min
• A-Typ Trimer 3: 17,42 min
• A-Typ Trimer 4: 18,65 min
• A-Typ Trimer 5: 19,75 min
• A-Typ Trimer 6: 21,05 min
• A-Typ Trimer 7: 21,81 min
• A-Typ Trimer 8: 23,29 min

The UHPLC-MS method is known to the person skilled in the art and was carried out according to Jungfer et al. carried out, the retention times being decisive for the identification of the compounds for the determination of the selected compound.

• Eluent mixture 1: water with formic acid
• Eluent mixture 2: acetonitrile with formic acid

• Procyanidin A1: 20.06 min
• Procyanidine A2: 21.41 min
• A-type trimer 1: 15.22 min
• A-type trimer 2: 17.56 min
• A-type trimer 3: 17.42 min
• A-type trimer 4: 18.65 min
• A-type trimer 5: 19.75 min
• A-type trimer 6: 21.05 min
• A-type trimer 7: 21.81 min
• A-type trimer 8: 23.29 min

Standard used: proanthocyanidins A2;

Proanthocyanidins (synonym Procyanidin) were also named according to Jungfer et al. (Elvira Jungfer, Benno F. Zimmermann, Axel Ruttkat, and Rudolf Galensa "Comparing Procyanidins in Selected Vaccinium Species by UHPLCMS2 with Regard to Authenticity and Health Effects", dx.doi.org / 10.1021 / jf303100q - J. Agric. Food Chem. 2012, 60, 9688-9696)

In the present case, a cranberry extract powder of the species Vaccinium macrocarpon of an ethanolic extract was analyzed. Procyanidin A1 (mg / g): (Method: HPLC-UV / VIS-MS / MS; IK2025) 1.0 Procyanidin A2 (mg / g): (Method: HPLC-UV / VIS-MS / MS; IK2025) 9.4 A-type trimer 1 (mg / g): (method: HPLC-UV / VIS-MS / MS; IK2025) 0.3 A-type trimer 2 (mg / g): (method: HPLC-UV / VIS-MS / MS; IK2025) 0.3 A-type trimer 3 (mg / g): (method: HPLC-UViVIS-MSIMS; IK2025) <0.3 * A-type trimer 4 (mg / g): (method: HPLC-UV / VIS-MS / MS; IK2025) 3.4 A-type trimer 5 (mg / g): (method: HPLC-UV / VIS-MS / MS: IK2025) <0.3 * A-type trimer 6 (mg / g): (method: HPLC-UV / VIS-MS / MS: IK2025) <0.3 * A-type trimer 7 (mg / g): (method: HPLC-UV / VIS-MS / MS; IK2025) 1.8 A-type trimer 8 (mg / g): (method: HPLC-UV / VIS-MS / MS; IK2025) 3.2 Sum of A-type procyanidins (mg / g): (method: HPLC-UV / VIS-MS / MS; IK2025) 19.5 *: The specified value corresponds to the limit of determination.

Example 2: Determination of the oxalic acid content

The content of oxalic acid was determined enzymatically using the "ENZYTEC TM OXALIC ACID" test kit from R-Biopharm AG and is based on a photometric measurement at 590 nm. The intensity of the color is proportional to the concentration of the oxalate in the sample

Result:

Oxalic acid (mg / 100g): (Method: Enzymatics; 1K0144) <3 * *: The specified value corresponds to the limit of quantification.

Example 2: Investigation of the effectiveness of urinary tract infections in an epidemiological study

Composition used

• - 80 mg eines Cranberry-Extrakt von Vaccinium macrocarpon mit einem Gehalt von 1,56 mg PAC-A, gemessen wie in Beispiel 1 beschrieben
• - 120 mg eines zweiten Cranberry-Extraktes von Vaccinium macrocarpon
• - 100 mg Preiselbeerfruchtpulver als Säuerungsmittel
• - 100 mg Spargelwurzelextrakt
• - 40 mg Vitamin C und
• - 12,5 µg Biotin (Vitamin B7).

mit einem Gesamtgewicht von 927 mg einschließlich Hilfsstoffe und Beschichtung.

• 80 mg of a cranberry extract from Vaccinium macrocarpon with a content of 1.56 mg PAC-A, measured as described in Example 1
• - 120 mg of a second cranberry extract from Vaccinium macrocarpon
• - 100 mg cranberry fruit powder as an acidulant
• - 100 mg asparagus root extract
• - 40 mg of vitamin C and
• - 12.5 µg biotin (vitamin B7).

with a total weight of 927 mg including auxiliaries and coating.

The composition was used in a dry form as a tablet.

Dosage: 2 × 1 tablet per day

With this dosage, at least a daily dose of 3.12 mg PAC-A is achieved. At the same time, the daily dose of vitamin C and biotin is achieved.

Diagnosis

• - Urine stix
• - urine culture

Patient groups

Regardless of gender and age, the patients were divided into at least two groups, preferably three.

Group A

Patients with a first-time urinary tract infection

Group B

Patients with a recurrent urinary tract infection

Group C

Patients with single or multiple antibiotic resistance, and thus inaccessibility of antibiosis. Regardless of a residual or recurrent urinary tract infection.

Treatment / prevention

If urine culture positive for bacteria in> 10 ³ CFUs, an antibiogram and resistance determination were carried out.

Single administration of the composition according to the invention

Dosage of the composition 2 × 1 a tablet for at least 10 days, 20 and 30 days. Repetition of taking in selected cases.

Combination therapy: administration of antibiotics in combination with the composition according to the invention

Antibiotic administration as prescribed by the doctor

Dosage of the composition 2 × 1 a tablet for up to 8 weeks

The composition according to the invention is taken at the same time as the prescribed antibiotic.

observation

• T0: Anamnese und Diagnostik
• T1: 4 Wochen nach T0
• T2: 8 Wochen nach T0

values

• T0: medical history and diagnosis
• T1: 4 weeks after T0
• T2: 8 weeks after T0

Claims (16)

Comprehensive composition - At least one cranberry extract containing greater than or equal to 1% by weight proanthocyanidins of type A (PAC-A) per gram of cranberry extract. Composition according to Claim 1 , wherein the at least one cranberry extract contains greater than or equal to 5% by weight of proanthocyanidins (PAC) per gram of cranberry extract. Composition according to Claim 1 or 2nd , wherein the composition further comprises - Vitamin B7 Composition according to one of the Claims 1 to 3rd , wherein the composition further comprises - at least one acidifying agent - vitamin C and / or - asparagus root extract. Composition according to one of the Claims 1 to 4th , comprising - greater than or equal to 0.1% by weight of PAC-A, - greater than or equal to 5% by weight of acidulant - greater than or equal to 5% by weight of asparagus root extract - greater than or equal to 2% by weight of vitamin C and / or - greater than or equal to 0.001% by weight of vitamin B7 in each case based on the total content of the composition (ad 100% by weight). Composition according to one of the Claims 1 to 5 , wherein the composition is in solid form, liquid form or as a mixture of solid and liquid forms. Composition according to one of the Claims 1 to 6 , in which it is in solid form, comprising - greater than or equal to 80 mg of at least one cranberry extract containing greater than or equal to 0.5% by weight of PAC-A based on 1 gram of cranberry extract, - greater than or equal to 100 mg of at least one acidifying agent selected from cranberry fruit powder , - greater than or equal to 100 mg asparagus root extract, - greater than or equal to 40 mg of vitamin C and - greater than or equal to 8 µg biotin (vitamin B7). Composition according to one of the Claims 1 to 7 , for oral administration in solid, liquid form or as a mixture of solid and / or liquid forms. Composition according to one of the Claims 1 to 8th which is available as a food supplement, food and / or medical device. Composition according to one of the Claims 1 to 9 for use in the prevention and / or treatment of urinary tract infections, including uncomplicated urinary tract infections, recurrent urinary tract infections, recurrent urinary tract infections after antibiosis, cystitis, recurrent cystitis, pyelonephritis, recurrent pyelonephritis, urethritis, recurrent urethritis and urinary infections related to or related to urinary infections or nosokomial infections and / or a cystoscopy. Composition for use according to Claim 10 , wherein the composition is used in combination with at least one medicament for the treatment and / or prevention of urinary tract infections. Composition for use according to Claim 10 or 11 , in which the mucous membrane and / or urothelium of the urinary tract, urinary bladder, ureter, urethra and / or renal pelvis are protected, the regeneration of which is promoted and / or the colonization is inhibited by pathogens. Composition for use according to one of the Claims 10 to 12th , wherein a daily dose of at least 3.0 mg PAC-A is administered and preferably a dosage unit contains at least half the daily dose of PAC-A. Composition for use according to one of the Claims 10 to 13 wherein the composition is administered twice a day. Process for the preparation of a composition according to one of the Claims 1 to 14 , comprising the steps - providing at least one cranberry extract with greater than or equal to 1% by weight of PAC-A per gram of cranberry extract, - providing vitamin B7, - optionally providing at least one acidifying agent, at least one asparagus root extract and / or vitamin C, - Mixing the ingredients and obtaining a composition. Procedure according to Claim 15 , - wherein the composition is shaped into a solid form, preferably into a compact, - the solid form is coated at least once and - a coated tablet is obtained.