GB2396811A

GB2396811A - Compositions comprising plant extract and sugar for use in inhibiting bacterial proliferation

Info

Publication number: GB2396811A
Application number: GB0329467A
Authority: GB
Inventors: Paul Clayton; Helen Conn
Original assignee: Forum Bioscience Holdings Ltd
Current assignee: Forum Bioscience Holdings Ltd
Priority date: 2002-12-23
Filing date: 2003-12-19
Publication date: 2004-07-07
Also published as: GB0329467D0; WO2004056380A2; WO2004056380A3; GB0230042D0; AU2003292447A1

Abstract

A composition comprising an extract from a plant that is a member of the Ericaceae, Rosaceae, Pinaceae or Vitaceae family and at least one sugar that is not metabolised or is only partly metabolised by the human or animal body. The sugar is preferably a monosaccharide such as L-arabinose, L-fucose, D-mannose, L- rhamnose, L-xylose, lyxose or galactose. A preferred composition comprises an extract of cranberry with D-mannose. These compositions may be used to treat bacterial infection caused by E. coli, particularly urinary tract infections (UTIs). Compositions comprising an anthocyanidin or a proanthocyanidin and at least one sugar that is not metabolised or is only partly metabolised by the human or animal body are also described.

Description

1 239681 1 Composition comprising plant extract and a sugar for use in

inhibiting bacterial proliferation

Description

s The present invention relates to compositions comprising extracts from certain plant species, or compounds derived therefrom, and a sugar that is not metabolised or is only partly metabolised by the human or animal body, such as D-mannose.

The invention also relates to compositions for use in preventing or treating bacterial infections, particularly infections caused by E. coli, and, especially, urinary tract 0 infections (UTIs), as well as to processes for making such compositions.

Millions of people each year are diagnosed with urinary tract infections, which can affect the bladder and also even the kidneys. E.coli bacteria are the most common pathogen associated with these infections, causing over 80% of urinary tract infections. Moreover, a large proportion of people suffer recurrent infections and are, therefore, forced to resort to extended use of antibiotics. Unfortunately, however, extended use of antibiotics can lead to deleterious side effects. In particular, the overuse of antibiotics can kill off the body's symbiotic bacteria, such as, for example, enteric bacteria, which are vital in order to provide the conditions required to maintain health. In addition, the use of antibiotics over a prolonged period can also cause toxic reactions due to the development of allergy. Another disadvantage with the overuse of antibiotics is that it can cause pathogen resistance, thereby possibly eventually rendering many bacterial infections untreatable.

Moreover, only a few of the commonly used antibiotics achieve adequate levels in the urinary tract to be fully effective. Consequently, there exists a need for a safe alternative to antibiotics suitable for preventing and treating UTIs and not having the aforementioned disadvantages.

Extracts from certain species of Vaccinium, especially Vaccinium macrocarpon, i.e., cranberries, and in particular cranberry juice, have been shown to be useful in reducing the symptoms and the bacteria associated with UTIs (Avorn et al., 1994, J. Am. Med. Soc. 271:751-754). Originally, it was thought that cranberry juice simply made the urine more acidic, thereby hindering bacterial proliferation. Studies have reported, however, that consumption of cranberry juice does not acidify the urine as was previously believed. Despite this, UTI sufferers continue to use cranberry juice with beneficial results. Recent research has now led to the discovery that certain cranberry juice compounds help relieve UTIs, not by any process of acidification, s but rather due to their ability to inhibit the adhesion of type 1 (implicated in bladder infections) and P-type (implicated in kidney infections) E.coli bacteria phenotypes to the epithelial cells that line the urinary tract (Sobota, 1984, J. Urol. 131:1013-1016; Schmidt & Sobota, 1988, Microbios. 55:173- 181; Zafriri etal., 1989, Antimicrob.

Agents Chemo. 33:92-98). In particular, it has been reported that the fructose 0 present in cranberry juice may be responsible for the inhibition of type-1 E.eoli to uroepithelial cells (Zafriri et al., 1989, Antimicrob. Agents Chemo. 33:92-98). Work by other research groups has led to the discovery that proanthocyanidins, which are also present in cranberry juice, may possess anti-adherence activity against P-type E.coli (see, for example, International patent application no. PCT/US98/18267).

Proanthocyanidins are polyphenolic molecules found in fruits, berries and other plant material and belong to the flavanoid family of compounds, which also include catechins and anthocyanins. It is thought that the proanthocyanidins are capable of blocking the interaction between bacterial hmbriae and the bacterial-binding receptors found on the surface of bladder or kidney epithelial cells, and thereby preventing adherence of the bacteria to bladder or kidney cells. As a result of not being able to bind to the epithelial cells of the urinary tract, the bacteria are carried harmlessly out of the body when passing urine and their virulence is greatly reduced.

This anti-adherence property is also advantageous since it eliminates selective pressure to develop antibiotic resistance that can occur during multiplication of bacteria in the presence of antibiotics.

Because of the high sugar and calorie content of cranberry juice, however, coupled with the amount required each day for optimum effect, preventing or treating a urinary tract infection by consuming cranberry juice is not ideal. In addition, due to its high acidity, the juice often causes stomach upsets and the relatively large amount of certain simple sugars it contains, such as fructose, can disrupt insulin levels, which may in turn contribute to a number of chronic diseases. An alternative approach is to use another sugar that is able to prevent or treat urinary tract - 3 infections, without having the disadvantages associated with sugars such as fructose.

This sugar is D-mannose and is currently used in the United States of America to treat urinary tract infections (D-mannose is available from Wilke Resources, Inc., 14321 W. 96th Terrace, Lenexa, KS 66215, United States of America). Research has s shown that mannose possesses anti-adherence activity against type-1 E.coli (Iwahi et al., 1982,J. Med. Microbiol. 15(3): 303- 16). In the presence of mannose, E.coli exhibit a greater affinity for the mannose than the epithelial surface of the bladder, the result being that the E.coli either rapidly detaches from the bladder wall and attaches to the mannose or attaches to the mannose before it can attach to the 0 bladder epithelial cells. The free-floating bacteria can, therefore, now pass from the body via the urine stream. Many people, however, find mannose unpalatable, inconvenient or too unfamiliar.

It is an object of the present invention to overcome some of the aforementioned disadvantages by providing a composition capable of preventing or treating infections caused by both type-1 and P-type E.coli.

Accordingly, in a first aspect of the invention, there is provided a composition comprising an extract from a plant that is a member of the Ericaceae, Rosaceae, Pinaceae or Vitaceae family and at least one sugar that is not metabolized or is only partly metabolized by the human or animal body. The compositions of the invention are advantageously able to inhibit the proliferation of both type 1 and P- type E.coli by preventing these bacteria from attaching to the epithelial cells of the urinary tract. In a preferred embodiment, the plant is a fruit-bearing plant and is, 2s preferably, a species of Vaccinium. More preferably, the plant bears berries, particularly ones that are red, blue or purple in colour such as, for example, blueberries, bilberries, cowberries, cranberries, crowberries, farkleberries, lingonberries, partridgeberries, huckleberries, whortleberries or sparkleberries. In a preferred embodiment the fruit-bearing plant is Vaccininm macrocarpon or Vaccinium yrtillm and the extract is cranberry or bilberry extract, respectively. The plant extract may be prepared by conventional extraction techniques, such as drying, grinding, pressing, pulping, pulverization, lyophilization, solvent extraction, steam distillation and the like. Preferably, the extract is in the form of a juice or - 4 concentrate, or is dried. In an especially preferred embodiment, the plant extract is an extract of cranberries. Suitable cranberry extracts may be prepared, for example, by methods such as those disclosed in published International patent applications numbers WO 99/12541 and WO 03/084559, or can be obtained commercially, for s example, from Freeman Industries LLC, 100 Marbledale Road, Tuckahow, NY 10707-3420, United States of America. The relatively small volumes of extract that need to be consumed by an individual, and the associated low amount of fructose, acidity and calories, makes the composition of the invention particularly beneficial, especially for diabetics and very small children, compared to currently used treatments. In addition, as the components making up the composition are all naturally occurring, the treatment is also particularly suitable for pregnant women and creates no disruption or imbalance in normal body micro flora. The extract, preferably, comprises at least one polyphenolic compound, preferably a flavonoid compound selected from the group consisting of anthocyanidins, proanthocyanidins, flavanols, flavones, flavanones and isoflavanones. In particular, the flavanoid compound is, preferably, an anthocyanidin or a proanthocyanidin.

Advantageously, these compounds may also inhibit the biosynthesis of bacterial fimbriae per se, without which adhesion and, therefore, infection cannot occur. In a preferred embodiment, the sugar does not, advantageously, significantly disrupt naturally occurring bacteria in the gut. Preferably, the sugar is absorbed in the upper part of the digestive tract and at least a portion of the sugar in the composition is excreted in the urine. In particular, at least 30% by weight of the total amount of sugar present in the composition is excreted in the urine, preferably at least 50% by weight of the total amount, preferably at least 90% by weight of the total amount. Preferably, the sugar is capable of achieving a concentration of between 0.01 to 1000 g/ml, preferably 0.1 to 500 g/ml, most preferably 1 to 250 g/ml, in the urine. In a preferred embodiment, the sugar is a monosaccharide.

Preferably, said at least one sugar is a hexose, a pentose or a mixture thereof, preferably, selected from the group consisting of L-Arabinose, LFucose, D Mannose, L-Rhamnose, L-Ribose, L-Xylose, Lxyose and Galactose.

Advantageously, mannose in particular is orally absorbed in both normal individuals and even in patients with Carbohydrate Deficient Glycoprotein Syndrome. In addition, althougl1 mannose is a simple sugar, very little of it is metabolised and it is - 5 highly water-soluble and, as such, it has a clearance halftime of approximately 4 hours. These features enable it to be rapidly absorbed and excreted and, accordingly, extremely suitable for preventing or treating urinary tract infections (D- mannose can be obtained from Wilke Resources, Inc., 14321 W. 96th Terrace, Lenexa, KS 66215, United States of America).

In a second aspect of the invention, there is provided a composition comprising an anthocyanidin or a proanthocyanidin compound and at least one sugar that is not metabolised or is only metabolised by the body to such an extent that it is present in 0 measurable amounts in the urine.

In a third aspect of the invention, there is provided a composition comprising an extract from cranberries and D-mannose.

In a preferred embodiment, the compositions according to the invention in its first, second and third aspect are in the Gown of a powder, liquid, suspension, paste, emulsion, capsule, tablet, lozenge, syrup or drink, preferably a capsule or a drink.

In a fourth aspect of the invention, there is provided a composition according to the invention in its first, second and third aspects for use in preventing or treating a bacterial infection, preferably, a bacterial infection caused by E.eoli. In particular, the bacterial infection is a urinary tract infection (UTI), preferably, cystitis. In a preferred embodiment, 1 to 60 grams, preferably, 5 to 45 grams, preferably, 10 to 30 grams, of said at least one sugar is administered per day. In this embodiment, the composition is, preferably, formulated for administration twice a day, three times a day or four times a day. In a preferred embodiment, the composition is formulated in 2.5 gram dose aliquots. In another preferred embodiment the composition is formulated for administration every 2-3 hours, preferably over a course of 2-3 days.

Most preferably, the composition is formulated in 2.5 gram dose aliquots for administration every 2-3 hours, over a course of 2-3 days. The composition can be formulated for oral, parenteral, intravenous, subcutaneous, transdermal or transmucosal administration. - 6

In particular, a composition according to the invention can be made by taking 30g of D-mannose and combining it with between 3pg to 3g of cranberry powder. This composition may then be available as a sachet of powder to be ultimately dissolved in between 250mls to 3 litres, preferably, 1 to 11/ litres, of water, fruit juice, milk or s drinking yoghurt, or other such solutions, or combinations thereof, prior to consumption. Alternatively, as well as being directly available as a powder or drink, the compositions of the invention may also be available as a capsule, tablet, lozenge or syrup. The composition can be taken all at once, at set intervals over a certain period or as divided doses. Moreover, larger quantities of D-mannose (such as, for example, 40g, 50g or 60g) and the associated amount of cranberry powder (such as, for example, 4g to 4g, 5g to 5g or 6,ug to 6g, respectively) can be used depending upon the severity and nature of the bacterial infection being treated.

A composition according to the invention suitable for the prophylactic treatment of a urinary tract bacterial infection can be made by taking 10g of D-mannose and combining it with between log to lg of cranberry powder. This composition can then be processed and administered as described in the preceding paragraph.

Smaller quantities of D-mannose (such as, for example, 7g, 5g or 2g) and the associated amount of cranberry powder (such as, for example, 0.7g to 0.7g, 0.5pg to 0.5g or 0.2g to 0.2g, respectively) can be used though.

In a fifth aspect of the invention, there is provided the use of a composition as claimed in any of the preceding claims for the manufacture of a medicament for use in preventing or treating a bacterial infection.

In a sixth aspect of the invention, there is provided a method of manufacturing a composition of the invention comprising the step of mixing an extract from a fruit- bearing plant and at least one sugar that is not metabolised or is only partly metabolised by the human or animal body.

The following examples are provided merely to illustrate the various aspects of the invention and to assist in their understanding. They should not be construed as in any way limiting the scope of thc prcscnt invention. - 7

Example 1

A composition according to the invention is made by taking 30g of DMannose and s combining it with 3g of cranberry powder. This composition is then dissolved by stirring at ambient temperature in 1 litre of still mineral water prior to consumption.

The drink produced is then taken in one sitting.

Example 2

A composition according to the invention is made by taking 40g of LRibose and combining it with 4g of huckleberry powder. This composition is then dissolved by stirring at ambient temperature in 1 litre of fresh orange juice prior to consumption.

The drink produced is then taken in one sitting.

Example 3

A composition according to the invention is made by taking 10g of DMannose and combining it with 1g of cranberry powder. This composition is then dissolved by stirring at ambient temperature in 1'/z litres of fresh orange juice prior to consumption. The drink produced is then sipped throughout the day.

Example 4

A composition according to the invention is made by taking 20g of LArabinose and combining it with 2,ug of whortleberry powder. This composition is then dissolved by stirring at ambient temperature in 11/2 litres of fresh apple juice prior to consumption. The drink produced is then sipped throughout the day.

Example 5

A composition according to the invention is made by thoroughly mixing 20g of L-Ribose and 2mg of bilberry powder with 350 ml of drinking yoghurt in a sealed container by shaking and inverting the container. The composition so obtained is then consumed in one sitting.

- -

Example 6

A composition according to the invention is made by mixing 100g of LArabinose with 25mg of huckleberry powder. The resultant dry powder is then used to fill 100 extra large gelatin capsules, which are sealed by conventional crimping means. One s capsule is taken with liquid every 2-3 hours.

Example 7

A composition according to the invention is made by mixing 150g of Galactose and 22.5mg of blueberry powder. The resultant dry powder is directly compressed into 100 tablets. Two tablets are to be taken with liquid every 2-3 hours.

Example 8

A composition according to the invention is made by mixing 300g of LFucose and 45mg of sparkleberry powder. The resultant dry powder is then mixed with sufficient amounts of sodium citrate and sodium carbonate to form the desired tablet size and directly compressed into 100 tablets. One effervescent tablet is then dissolved in 250ml of still mineral water. The drink produced is then taken in one sitting. Such drinks should be taken every 2-3 hours.

Example 9

A composition according to the invention is made by mixing 62.5g of DMannose and 6.25mg of cranberry powder with sufficient water to produce 125 ml syrup.

One 5ml spoonful of syrup is to be taken every 4-6 hours.

Example 10

A composition according to the invention is made by mixing 250g of LArabinose with 25,ug of whortleberry powder. The resultant blend is then formulated into 100 lozenges. One lozenge is to be chewed or sucked every 2-3 hours.

Claims

Claims 1. A composition comprising an extract from a plant that is a

member of the Ericaceae, Rosaceae, Pinaceae or Vitaceae family and at least one sugar s that is not metabolised or is only partly metabolised by the human or animal body.
2. A composition as claimed in claim 1, wherein said plant is a fruitbearing plant.
3. A composition as claimed in claim 2, wherein said fruit-bearing plant is a member of the Ericaceae family.
4. A composition as claimed in claim 3, wherein said fruit-bearing plant is a species of Vaccinium.
5. A composition as claimed in any of claims 2 to 4, wherein said fruit is a berry.
6. A composition as claimed in claim 5, wherein said berry is a red, blue or purple berry.
A composition as claimed in claim 6, wherein said berry is a blueberry, bilberry, cowberry, cranberry, crowberry, farkleberry, lingonberry, 2s partridgeberry, huckleberry, whortleberry or sparkleberry.
8. A composition as claimed in claim 7, wherein said fruit-bearing plant is Vaccinium macrocarpon and said extract is a cranberry extract.
9. A composition as claimed in claim 7, wherein said fruit-bearing plant is Vaccinium myrtillum and said extract is a bilberry extract. -
10. A composition as claimed in any one of the preceding claims, wherein said extract is in the form of a juice or concentrate.
11. A composition as claimed in any one of the preceding claims, wherein s said extract is in the form of a dried extract.
12. A composition as claimed in any one of the preceding claims, wherein said extract comprises at least one polyphenolic compound.
13. A composition as claimed in claim 12, wherein said polyphenolic compound is a flavonoid compound.
14. A composition as claimed in claim 13, wherein said flavonoid compound is selected from the group consisting of anthocyanidins, proanthocyanidins, flavanols, flavones, flavanones and isoflavanones.
15. A composition as claimed in claim 14, wherein said flavanoid compound is an anthocyanidin or a proanthocyanidin.
16. A composition as claimed in any one of the preceding claims, wherein said sugar does not significantly disrupt naturally occurring bacteria in the gut.
17. A composition as claimed in claim 16, wherein said sugar is absorbed in the upper part of the digestive tract.
18. A composition as claimed in any one of the preceding claims, wherein at least a portion of said sugar in the composition is excreted in the urine.
19. A composition as claimed in claim 18, wherein at least 30% by weight of the total amount of sugar present in the composition is excreted in the urine. - 11
20. A composition as claimed in claim 19, wherein at least 50% by weight of the total amount of sugar present in the composition is excreted in the urine.
21. A composition as claimed in claim 20, wherein at least 90% by weight of the total amount of sugar present in the composition is excreted in the urme.
22. A composition as claimed in any one of the preceding claims, wherein said sugar is capable of achieving a concentration of between 0.01 to 1000 g/ml in the urine.
23. A composition as claimed in claim 22, wherein said sugar is capable of achieving a concentration of between 0.1 to 500 1lg/ml in the urine.
24. A composition as claimed in claim 23, wherein said sugar is capable of achieving a concentration of between 1 to 250 1lg/ml in the urine.
25. A composition as claimed in any one of the preceding claims, wherein said sugar is a monosaccharide.
26. A composition as claimed in any one of the preceding claims, wherein said sugar is a hexose, a pentose or a mixture thereof.
27. A composition as claimed in claim 26, wherein said sugar is selected from the group consisting of L-Arabinose, L-Fucose, D-Mannose, L Rhamnose, L-Ribose, L-Xylose, Lxyose and Galactose.
28. A composition comprising an anthocyanidin or a proanthocyanidin compound and at least one sugar that is not metabolised or is only metabolised by the body to such an extent that it is still present in measurable amounts in the urine. - 1-
29. A composition comprising an extract from cranberries and D-mannose.
30. A composition as claimed in any one of the preceding claims, in the form of a powder, liquid, capsule, tablet, syrup or drink. s
31. A composition as claimed in claim 30, in the form of a capsule or a drink.
32. A composition as claimed in any one of the preceding claims for use in preventing or treating a bacterial infection.
33. A composition as claimed in claim 32 for use in preventing or treating a bacterial infection caused by E.coli.
34. A composition as claimed in claim 32 or claim 33, wherein said bacterial infection is a urinary tract infection (UTI).
35. A composition as claimed in claim 34, wherein said urinary tract infection is cystitis.
36. A composition as claimed in any one of claims 32 to 35, wherein 10 to 30 grams of said at least one sugar is administered per day.
37. A composition as claimed in any one of claims 32 to 36, wherein the composition is formulated for administration twice a day, three times a day or four times a day.
38. A composition as claimed in claim 37, wherein the composition is formulated for oral, parenteral, intravenous, subcutaneous, transdermal or transmucosal administration.
39. Use of a composition as claimed in any one of the preceding claims for the manufacture of a medicament for use in preventing or treating a bacterial infection. - 13
40. A method of manufacturing a composition as claimed in any one of claims 1 to 38, comprising the step of mixing an extract from a fruit bearing plant and at least one sugar that is not metabolised or is only s partly metabolised by the human or animal body.