FIELD OF THE INVENTION

The invention relates to a cranberry composition for the treatment and/or prevention of vaginal and urinary tract infections.

BACKGROUND OF THE INVENTION Orally administered cranberry juice is believed to have advantageous properties with respect to bacterial infections in the urinary system. It has been postulated that its effect can be ascribed to proanthocyanidins and other assumed active ingredients that may inhibit the adhesion of E coli bacteria to the bladder. The properties ascribed to cranberry juice have led to several concentrated cranberry extracts commercially available as food supplements, in particular in the form of tablets and gelatin capsules for oral administration. The effectiveness of commercially available extracts may vary, depending on the extraction method, and the quality and type of cranberry used.

Several different types of cranberries are known, in particular Vaccinium oxycoccos or Oxycoccus palustris (Common Cranberry or Northern Cranberry, Vaccinium microcarpum or Oxycoccus microcarpus (Small Cranberry). Vaccinium macrocarpon or Oxycoccus macrocarpus (Large cranberry, American Cranberry, Bearberry) and Vaccinium erythrocarpum or Oxycoccus erythrocarpus (Southern Mountain Cranberry).

OBJECT AND SUMMARY OF THE INVENTION

Surprisingly, it was discovered that cranberry extracts are not only effective for the treatment of urinary tract infections, but are also effective for the treatment and/or prevention of vaginal infections.

Vaginal Infections, in particular bacterial infections, are a serious health problem, affecting one of every three women during their lifetime. The most well known types are bacterial and fungal infections. Such infections are usually treated with common antibiotics. However, after a first antibiotics treatment, 30 percent will suffer from recurrence within three months, and 80 percent within nine months. The invention provides a composition for use in the treatment and/or prevention of urinary tract and vaginal infections, comprising at least a cranberry extract and optionally other active ingredients and/or excipients. The cranberry extract was shown to have a positive effect against infectious micro-organisms, in particular micro- organisms associated with vaginal infections such as bacterial vaginosis and vulvovaginal candidiasis, and urinary tract infections, in particular infections by E.coli. The cranberry extract creates an environment unfavorable to infectious microorganisms.

Preferably, the composition is formulated for vaginal administration. The vaginal administration of cranberry extracts was shown to be particularly effective method. Vaginal administration is particularly effective in the treatment of vaginal infections, but also showed to be effective for urinary tract infections as an alternative to oral administration.

It is preferred if the composition is formulated as a solid composition for vaginal administration, preferably a tablet or capsule. Solid formulations are easier to store and handle. The solid form also allows for easy administration by insertion into the vagina, and convenient dosing by a user by taking one or multiple dose units. In addition to the cranberry active component, such a formulation would comprise excipients forming a solid matrix that would disintegrate in the vaginal environment. A combination of polyethylene glycol and crospovidone, with a filler material such as magnesium stearate, showed to be suitable for forming a tablet matrix for solid cranberry extracts. It is advantageous if the composition comprises at least one prebiotic digestible by lactobacillus bacteria. Vaginal administration of the prebiotic combined with cranberry extract contributes to the restoration of the naturally present acidophilic Lactobacillus balance. One or more of such prebiotic substances can be added, alone or as a combination.

Preferably, the at least one prebiotic is selected from the group consisting of lactitol, lactulose, fructooligosaccharid, trans-galacto-oligosaccharide, xylo-oligosaccharide, manno-oligosaccharide and inuline. Lactitol was found to be a particularly effective prebiotic when combined with cranberry extract.

Advantageously, the composition has a vaginal pH normalizing effect when applied. An infected vagina typically has a raised pH above 4.5, typically in the range of 5-6, whereas a healthy vagina typically has a pH in the range of 3.8-4.5. Lowering this increased pH of the infected vagina contributes to creating an undesirable environment for the infectious micro-organisms, and contributes to curing and preventing the infection.

It is preferred if the composition also comprises a hydrophilic gellant. A hydrophilic gellant enables the effective spreading of the active cranberry substance and polyol over the infected area. The gellant also improves the time the active ingredients are retained on the infected area. Combinations of multiple components can be used to form an effective gel matrix.

Preferably, the gellant comprises at least one water-soluble polymer selected from the group consisting of hyaluronic acid, carrageenan, glycerin, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxyethyl methyl cellulose, hydroxypropyl methylcellulose (HPMC) and carboxymethyl cellulose (CMC). Such gellants are typically used as a salt derivative, for instance a sodium salt.

A particularly effective gellant is hyaluronic acid, which was found to also contribute to normalizing the vaginal pH.

In a preferred embodiment, the composition comprises a combination of cranberry extract, lactitol and hyaluronic acid.

Preferably, a single dose of the composition comprises at least 100 mg cranberry extract, preferably at least 200 mg, more preferably at least 400 mg. Administering at least 100 mg cranberry showed a pH normalizing effect in the vagina, and a decrease in symptoms of the infections, and was shown to be in particular effective against bacterial infections. Preferably, higher doses such as at least 200 mg or at least 400 mg are used, allowing for a faster effect. For fungal infections, preferably higher doses are used.

In a preferred embodiment, the composition is for the use in the treatment and/or prevention of bacterial or fungal vaginal infections, in particular infections selected from bacterial vaginosis and vulvovaginal candidiasis. The cranberry composition is particularly effective in the treatment and/or prevention of bacterial vaginosis. The composition is also for the use in the treatment and/or prevention of bacterial urinary tract infections, in particular E.Coli infections.

It is a further object of the invention to enable an improved treatment or prevention of urinary tract infections.

The invention provides a composition for the treatment or prevention of urinary tract infections (UTI), comprising an herbal extract or mixture of extracts having anti-adhesive effect bacteria in the urinary tract, in particular E. coli, at least one diuretic, and optionally other active ingredients and/or excipients.

The combination of an herbal extract preventing or reversing the adhesion of bacteria with a diuretic showed a synergistic effect in treating and/or preventing urine tract infections. An improvement in beneficial effect was noted for a combination of cranberry extract and a diuretic was larger than treatment compared to the cranberry extract as such.

Several herbal extracts having an anti-adhesive effect bacteria in the urinary tract can be used, preferably the various types of cranberry and blueberry. Other ingredients and excipients may include for instance fillers to enable the easy processing into tablets, such as magnesium stearate, sucrose, lactose; starches, cellulose or modified cellulose such as microcrystalline cellulose and cellulose ethers such as hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC); and sugar alcohols such as xylitol, sorbitol and maltitol. Flavors to improve palatability may be used, including various fruit flavorings such as strawberry, peach, raspberry or apricot. Colorants may also be added for a distinguishing visual appearance.

It is preferred if the herbal extract comprises at least on extract selected from the group consisting of Vaccinium macrocarpon (cranberry), Vaccinium oxycoccos or Oxycoccus palustris (Common Cranberry or Northern Cranberry, Vaccinium microcarpum or

Oxycoccus microcarpus (Small Cranberry). Vaccinium macrocarpon or Oxycoccus macrocarpus (Large cranberry, American Cranberry, Bearberry), Vaccinium erythrocarpum or Oxycoccus erythrocarpus (Southern Mountain Cranberry) and Vaccinium angustifolium (Blueberry). Most preferably, the herbal extract comprises at least an extract of Vaccinium macrocarpon (cranberry). This cranberry has a good availability and showed excellent properties against urinary tract infections. The diuretic may be either natural of synthetic. Well known diuretics include hydrochlorothiazide, acetazolamide. methazolamide, spironolactone, amiloride, triamterene. Natural diuretics or mixtures thereof are preferred, though.

It is advantageous if the diuretic comprises at least one extract derived from the group consisting of Solidago virgaurea (goldenrod), Orthosiphon stamineus (java tea), Levisticum officinale (lovage), Petroselinum crispum (parsley), Asparagus officinalis (asparagus), and Juniperus communis (Common Juniper). Extracts of these herbs are commercially available. Most preferably, the diuretic comprises an extract derived from Solidago virgaurea (goldenrod) or Juniperus (juniper). (Goldenrod is also known as Golden Rod, Verge d'Or, Solidago, Goldruthe, Woundwort, and Aaron's Rod. Various types of juniper may be used, in particular Juniperus communis, Juniperus chinensis or Juniperus angosturana.

Preferably, the composition comprises a combination of extracts of Vaccinium macrocarpon (cranberry) and Solidago virgaurea (goldenrod).

Another preferred embodiment combines of Vaccinium macrocarpon (cranberry) and Juniperus (juniper). Juniper showed to particularly advantageous when combined with cranberry. A disadvantage is that Juniperus is believed to cause health risks for pregnant women for babies during the lactation period.

It is preferred if the amount of diuretic by weight is lower than the amount of anti- adhesive. Depending on the type of diuretic used, the amount of diuretic by weight could be at least 5 times lower than the amount of anti-adhesive. This ensures the anti- adhesive effect prevails over the diuretic effect. Having more diuretic than anti-adhesive increases the risk of a prevailing diuretic effect, which may be inconvenient for the user. It is advantageous if the composition is an essentially solid composition. Solid compositions have an improved storage life over liquid compositions. Preferably, the composition is a lyophilized powder. Lyophilized or freeze-dried compositions are relatively easy to dose and may be used for the preparation of dosage forms such as capsules and tablets.

The invention further comprises a capsule or tablet comprising a composition according to any of the preceding claims. The dosage form, preferably a capsule or a tablet, comprising a composition as described above, preferably comprises a dose of at least 400 mg of extract of Vaccinium macrocarpon (cranberry), and at least 10 mg of Solidago virgaurea, and optionally other active ingredients and/or excipients. It is preferred if the capsule is essentially free of gelatin. Gelatin and other animal- derived materials have an increased risk of contamination and therefore require additional safety checks.

Preferably, the dosage form is a capsule made of a water-soluble polymer material. It is advantageous if the water-soluble polymer material comprises at least one compound selected from the group consisting of methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxyethyl methyl cellulose, hydroxypropyl methylcellulose (HPMC) and carboxymethyl cellulose (CMC).

DESCRIPTION OF PREFERRED EMBODIMENTS

The invention will now be further elucidated by the following non-limiting examples. All ingredients are commercially available. A. Vaginal formulations

For vaginal infections, the following formulations for vaginal administration were prepared. These formulations were prepared as solid tablets for vaginal administration. These tablets are unsuitable for oral administration because the lactitol has undesirable laxative effects, flatulence and cramps when digested. Also, lactitol will not be taken up effectively through the gastrointernal tract and will usually not reach the vaginal area through the oral route.

Example 1

%w/w mg

Cranberry extract 49 200

Lactitol monohydrate 25 100 Polyethylene glycol

Crospovidone

Magnesium stearate

Total 406

This is a relatively low dose 200 mg cranberry extract tablet. The combination of cranberry extract and lactitol is the active combination leading to normalizing (lowering) the pH of the infected vagina. Polyethylene glycol, crospovidone and magnesium stearate are excipients that allow for preparing the tablet matrix that slowly disintegrates in the vagina. Polyethylene and crospovidone also act as glidants.

The relatively small tablets allow for easy insertion and varying the administered dose by using multiple tablets. An effective dose regimen would be 1 tablet in the morning, one around lunch time, one in the evening and one before sleep 1 /1 /1 /1 .

Example 2

%w/w mg

Cranberry extract 45 450

Lactitol monohydrate 30 300

Hyaluronic acid 2 16

Polyethylene glycol 21 210

Crospovidone 2 16

Magnesium stearate 1 8

Total 1000

This is a relatively high dose 450 mg cranberry extract tablet. The combination of cranberry extract and lactitol is the active combination leading to normalizing (lowering) the pH of the infected vagina, which is for enhanced by the addition of hyaluronic acid. Polyethylene glycol, crospovidone and magnesium stearate are excipients that allow for preparing the tablet matrix that slowly disintegrates in the vagina.

The relatively large dose allows for a less frequent dose regimen easy insertion and varying the administered dose by using multiple tablets. An effective dose regimen would be 1 tablet in the morning, and one before sleep. For severe infections, the dose could be doubled. Comparative in vitro tests

The vaginal formulations were tested in vitro for efficacy against a number of common bacterial and fungal vaginal infections, in particular: bacterial vaginosis and vulvovaginal candidiasis, The formulation indicates a curing effect against each of these infections. The best results were found against bacterial infections. Test results indicated a lowered chance for recurrence of infection, indicating efficacy as both a curing as well as a preventive treatment. In dose-effect studies for cranberry alone, a minimal 20% growth inhibitory effect for bacterial vaginosis was shown at concentrations corresponding to a dose of 100 mg cranberry extract when administered to the vagina. For fungal infections, the 20% growth inhibition was observed at concentrations corresponding to a dose of 300 mg cranberry extract.

Comparative In vivo test

A preliminary test was performed on women sufffering from bacterial or fungal vaginal infection with an increased pH (typically above pH 5), using the formulation according to Example 2. The composition had a pH lowering effect when applied to infected women, normalizing the pH to the regular physiological levels in the range of 3.8-4.5.

In the recovery of pH in the vagina to the physiological levels (3.8-4,5), lactitol monohydrate acts as a prebiotic which in turn stimulates the restoration of the natural present acidophilic Lactobacillus balance. As a result of this, the accompanying symptoms such as: unpleasant odor, itching and irritation associated with vaginal infections are treated. In case of prevention the active ingredients maintain the natural pH and flora of the vagina, preventing a disturbance in the bacteriological flora of the vagina. In conclusion, the cranberry preparation showed to be particularly effective against various vaginal infections, with particularly good effect in the treatment and preventions of bacterial vaginosis.

B. Oral Formulations

The following oral formulations were particularly effective for treating or preventing urinary tract infections. Example 3

This example uses a combination of cranberry extract (Vaccinium macrocarpon) and golden rod (Solidago virgaurea). Purified potato starch (Amylum solani) was used as a filler. The ingredients were mixed using conventional techniques, and encapsulated in hydroxypropyl methylcellulose (HPMC)-based two-piece capsules. The table indicates the components of the composition in a single dose hydroxypropyl methylcellulose capsule.

%w/w mg

Cranberry extract 70 500

Solidago virgaurea extract 10 75

Amylum solani 4 25

Example 4

%w/w mg

Cranberry extract 70 500

Solidago virgaurea extract 50 Solidago virgaurea herb 50

Example 5

Example 5 is a powder formulation that uses a combination of cranberry extract ( Vaccinium macrocarpon) and juniper (Juniperus communis). Purified potato starch (Amylum solani) was used as a filler. The ingredients were mixed using conventional techniques, and encapsulated in hydroxypropyl methylcellulose (HPMC)-based two- piece capsules for oral use. The table indicates the components of the composition and the hydroxypropyl methylcellulose capsule.

Juniperus extracts are commercially available in 1 :5 to 1 :25 extracts. The extract used herein is a 20:1 extract, being an equivalent of 1 gram of dried juniper fruit per powder dose. A dosage of at least 2 doses per day (equivalent of 2 grams of dried juniper fruit) is recommended for a good preventive or curative effect when combined with cranberry extract.

%w/w mg

Cranberry extract 70 500

Juniperus extract 10 100

Amylum solani 4 ₂ 5

Ex-vivo E.coli anti-adhesion test

The effect of cranberry extracts was tested ex vivo on E. coli in an ex-vivotests. A randomized, double-blinded, placebo controlled crossover trial was conducted to determine the ex vivo uropathogenic bacterial P-type anti-adhesion activity (AAA) in human urine following consumption of either 500-mg cranberry extract capsule as shown in example 1 , or a placebo capsule with a 7-day wash-out period, measured over a 60-hr time frame with product taken orally at the beginning of the test period only.

The cranberry capsules had a higher total AAA than Placebo over all time periods for all participants combined. These results were highly significant (p<0.0001 ). By time period, AAA of cranberry capsules was significantly higher than Placebo from 9 to 36 hours after ingestion (p<0.0001 at 9 and 24 hours, and p=0.0003 at 36 hours). Placebo ingestion resulted in no significant AAA at any time period.

The experiment shows that the oral administration of the product has an anti-adhesive effect for E.coli in the urinary tract.

E. coli in vivo

A dose-dependent study was also carried out to understand the impact and safety profile of a standardized whole cranberry product comparable to the formulation in the examples on reducing the recurrences of symptomatic UTI in culture-positive subjects. A 90- day randomized clinical trial including an untreated control group with a total of 60 female subjects between 18-40 years of age was conducted. The safety was assessed by evaluation of biochemical and hematological parameters on days 10, 30, 60 and 90 during the study, comparing the values with those at the baseline. At the end of the study, there was significant reduction (p<0.05) in the subjects positive for E. coli in both the high dose and low dose treatment groups, compared to baseline evaluation. Symptomatic relief was also reported in the low and high dose treatment groups, while none was reported by subjects in the untreated control group. In conclusion, the standardized cranberry product was effective in safely reducing the number of E. coli positive subjects at both the 500 mg and 1000 mg dose levels and in ameliorating the symptoms of UTI in these subjects.

Efficacy test women

In a randomized double blind trial, the efficacy of cranberry extracts combined with juniper extracts was tested against a placebo as a prophylactic against urinary tract infections. For the test, a daily dose of 1000 mg cranberry extract and 100 mg juniper extract was used, based on the daily intake of two capsules according to example 3.

The efficacy of the formulation was tested in women with at least one UTI in the previous 12 months. The participants were randomized to either treatment with 1000 mg/day cranberry extract and 100 mg juniper extract (n=59) or placebo only containing filler material (n=66). During 6 months, 18 UTI events occurred in the placebo group and 8 UTI events in the treated group. This indicates that the combination of cranberry and juniper is effective in

Qualitative comparative tests

In an initial comparative test, test persons regularly suffering from bladder infections were given cranberry extract capsules, and indicated that these cranberry extract tablets helped to alleviate bladder infection, and also the bladder infections appeared to be less frequent.

Test persons from the same group were also given the tablets having a combination of cranberry with golden rod or cranberry with juniper. 70% of the test persons indicated that they experienced an improved positive effect on their bladder infections.

Surprisingly, it was found that the vaginal administration of the formulation according to Example 2 not only showed a curative effect against vaginal infections, but also against urinary tract infections. Hence, the vaginal administration route was found to be a viable alternative route for treating urinary tract infections.