WO 2012/017186 Al © o

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(19) World Intellectual Property OrganizationInternational Bureau

(10) International Publication Number(43) International Publication Date ft ft i

9 February 2012 (09.02.2012) WO 2012/017186 Al

(51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,A01N 43/16 (2006.01) A61K 31/353 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,A01N 65/00 (2009.01) A01N 65/36 (2009.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,A61K 8/49 (2006.01) A01N 65/08 (2009.01) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,A61K 8/60 (2006.01) A01P 1/00 (2006.01) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,

ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI,(21) International Application Number: NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,

PCT/GB20 10/05 1301 SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,

(22) International Filing Date: TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.

6 August 2010 (06.08.2010) (84) Designated States (unless otherwise indicated, for every

(25) Filing Language: English kind of regional protection available): ARIPO (BW, GH,GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG,

(26) Publication Language: English ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,

(71) Applicant (for all designated States except US): CIT- TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,

ROX LIMITED [GB/GB]; Unit 11 Harvard Industrial EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU,

Estate, Kimbolton Cambridgeshire PE28 0NJ (GB). LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK,SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,

(72) Inventor; and GW, ML, MR, NE, SN, TD, TG).(75) Inventor/Applicant (for US only): RIPLEY, Ian

[GB/GB]; Unit 9, River Court, Brighouse Road, Riverside Published:

Park, Middlesbrough Yorkshire TS2 1RT (GB). — with international search report (Art. 21(3))

(74) Agents: avidity IP et al; Merlin House, Falconry Court, — before the expiration of the time limit for amending theBaker's Lane, Epping, Essex CM 16 5DQ (GB). claims and to be republished in the event of receipt of

amendments (Rule 48.2(h))(81) Designated States (unless otherwise indicated, for every

kind of national protection available): AE, AG, AL, AM,

0 0

©

o(54) Title: COMPOSITIONS COMPRISING OLEUROPEINS AND FLAVANOIDS AND THEIR USE

(57) Abstract: Compositions are described which comprise a flavanoid, or preferably a mixture of flavanoids, and oleuropein oran acetylated derivative thereof. The use of such compositions as a pathenogenicide is also described.

COMPOSITIONS COMPRISING OLEUROPEINS AND FLAVANOIDS AND THEIR USE

The present invention relates to compositions and their uses in eradicating

or ameliorating unwanted infestations. More particularly the invention

relates to compositions and their uses which comprise a flavanoid

component and an oleuropein component. Such compositions are aptly

employed t o eliminate or reduce the presence of unwanted bacteria or

other undesirable organisms.

A variety of flavanoids have been suggested as anti-microbial agents.

PCT/GB2007/002756 and PCT/GB2007/002758 describe particularly

effective compositions containing flavanoids. However, the effectiveness

of known compositions of bioflavanoids would benefit from enhancement.

The present invention is based on the finding that certain combinations of

agents are particularly effective in eliminating or reducing unwanted

bacteria and other undesirable organisms.

The present invention provides a pharmaceutical composition which

comprises a first component being a flavanoid component and a second

component being an oleuropein component.

The first component will be a one or more flavanoids of Formula (I) :

wherein wherein R1 is hydroxyl or methoxyl and R2 is hydrogen, hydroxyl

or methoxyl and X is hydrogen or a saccharide.

The second component will be oleuropein or an acetylated derivative

thereof. Oleuropein is (4S,5E,6S)-4-[2-[2-(3,4-dihydroxyphenyl)ethoxy]-

2-oxoethyl]- 5-ethylidene-6-[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-

(hydroxymethyl)- 2-tetrahydropyranyl]oxy]-4H-pyran-3-carboxylic acid,

methyl ester.

Aptly in the first component R2 is hydrogen and R1 is in the 3- or 4-

position. Alternatively, aptly in the first component R2 is 3-hydroxy and

R1 is 4-methoxyl.

Suitably X in a compound of the Formula (I) is H.

Suitably X in a compound of Formula (I) is a saccharide.

Favourably X is a disaccharide.

Suitable disaccharides include combinations of two monosaccharide,

suitably pyranoses, linked by a glycosidic bond, for example rhamnose

and glucose, for example L-rhamnose and D-glucose.

Suitable disaccharides can have the structure:

wherein one of R3 and R4 is H and the other OH or both are H or both are

OH. Aptly R3 is H and R4 is OH so that the disaccharide is rutinose.

Favoured aglycones of flavonoids for use in this invention are the

disaccharides 6-0-(alpha-L-rhamnopyranosyl)-beta-D-glucopyranose, also

known as rutinose, and 2-0-(alpha-L-rhamnopyra-nosyl)-beta-D-

glucopyra-rose.

It is presently believed that the first component very suitably comprises

narangin or neohesperidin or mixtures thereof. Mixtures of one or both of

narangin and neohesperidin with for example, one, two or three other

flavanoids of the Formula I are presently believed particularly favoured for

use in this invention. Such mixtures can be obtained from extraction from

bitter oranges.

Suitable compounds of Formula (I) include Neoeriocitrin, Isonaringin,

Narangin, Hesperidin, Neohesperidin, Neodiosmin, Naringenin, Poncirin

and Rhiofolin.

Favoured compositions for use include those which comprise either of

naringin and neohespiridin or both.

Particularly aptly the invention will contain naringin and neohesperidin and

other flavonoids of the Formula (I).

The mixture of flavonoids may aptly contain more than one of

neohesperidin, naringin, isocriocrin, isonaringin, naringin, hesperidine,

neohesperidin, neocliomin, naringenin, poncrin and rhiofolin. Such a

mixture of flavonoids can be obtained from bitter oranges, see for

example PCT/GB2007/002756. Suitable mixtures can include 2, 3, 4, 5,

6, 7, 8, 9 or more compounds of formula (I). Thus a mixture comprising

2, 3, 5, 6, 7, 8 or 9 of the above named flavonoids is apt, for example

containing 3, or containing 4, or containing 5, or containing 6, or

containing 7, or containing 8 or containing 9 of said flavonoids.

It is presently believed that mixtures of such flavonoids have advantages

over the use of a single flavonoid. It is particularly advantageous that

extract of bitter oranges may be employed without the need for isolating

individual flavonoids if desired. The use of the composition generally

comprising biomass enhances solubility of the flavanoids. Generally the

flavanoids are present in mixtures with biomass by about 10% to 75%,

more aptly 30% to 60%, for example 40% to 50%, preferably about 45%.

The biomass comprises pectins and other sugar derived materials.

Typically about 40% of low molecular weight pectins are present.

If it is desired to avoid biomass, other solubilising agents such as dextrins,

for example cyclodextrin, may be employed if desired.

Aptly the mixture of flavonoids will comprise at least 25%, more suitably

at least 40% and preferably at least 50% of narangin. More aptly the

mixture will contain up to 65% of narangin.

Aptly the mixture of flavonoids will comprise at least 15%, more suitably

at least 20% and preferably at least 25% of neohesperidin. More aptly

the mixture will contain up to 35% of neohesperidin.

In a favoured form the mixture will contain at least 75% of neohesperidin

and narangin.

It is presently believed that particularly suitably the second component is

oleuropein. Aptly this is obtained from extraction from the leaf of the

olive, for example olea europea. Such extracts typically contain 5% to

80% wt/wt, more aptly 10 to 70%, for example 20% wt/wt.

The other components of the extract will often contain pectins and the

like.

A particular advantage of many compositions of the invention is that they

may employ compounds of natural origin. Thus, for example, it is

preferred to employ a first component which may be obtained from bitter

oranges and a second component which may be obtained from the olive.

However synthetically or semi-synthetically obtained compounds may be

employed if desired instead of the ones directly extracted from natural

sources although this tends to be less favourable in view of cost.

The compositions of this invention may show synergistic anti-microbial

effectiveness. Such synergistic compositions are preferred.

It is presently believed that best synergy occurs wherein the first

component and the second component are present in ratios (wt/wt of

flavanoids to oleuropein) of 5 :1 to 1:4, more aptly 2 :1 to 1:2, favourably

1:2 to 1:1 and preferably 3 :2 .

Such compositions may desirably contain a first component which is a

mixture of flavanoids of Formula (I) wherein 50% - 100% (wt/wt) is

composed of narangin and/or neohesperidin. It is presently believed that

the first component may favourably contain a mixture of flavanoids

containing 60% - 100% of narangin and neohesperidin, for example 65 -

75% of narangin and neohesperidin.

Such compositions may preferably contain 3,4-dihydroxyphenylethanol as

the second component or a mixture of compounds of formula I I in which

3,4-dihydroxyphenylethanol is present by at least 50% (wt/wt), and more

aptly at least 80% (wt/wt).

It has been found that compositions of this invention are particularly

effective in the presence of a third component, which is one or more

organic acids.

A surprisingly effective third component is salicylic acid or its

pharmaceutically acceptable salt optionally together with a further organic

acid or pharmaceutically acceptable salt.

It is believed favoured that the salicylic acid is present in the acid rather

than its salt.

Similarly, a further organic acid if present is similarly in the form of the

acid rather than its salt. Suitable further organic acids include acids of up

t o 8 carbon atoms which are monobasic (i.e. 1 C0 2H group), di-basic or

tri-basic acid which optionally contain 1, 2 or 3 hydroxyl groups. Such

further organic acid may be one or more of citric acid, malic acid, latic

acid, tartaric acid, fumaric acid and the like.

Such compositions can provide an approximately neutral or acid pH, when

used, for example of from 3-8, more aptly 3.5-7, for example 4-5.

At present it is preferred to employ salicylic acid and citric acid in

compositions.

In compositions containing a first component, a second component and a

third component, the weight/weight ratio of the compound(s) of Formula

(I) plus the compound(s) of Formula (II) to salicylic acid or

pharmaceutically acceptable salt thereof is 2 :1 to 1:7, more aptly 1:1 to

1:5, favourably 2 :3 to 1:3 and preferably is 2 :5.

When the third component also comprises a further organic acid (such as

those named above), the weight/weight ratio of salicylic acid t o further

organic acid may be 2 :1 to 1:5, more aptly 1:1 to 1:3, for example 3 :5 .

Such compositions may include a solubilising agent for the salicylic acid,

for example a dextrin such as cyclodextrin.

Compositions of the invention may be adapted for application to external

surfaces including external surfaces of plants or animals, or for internal

administration to an animal. Often the animal is a human.

The compositions of the invention show activity against a wide range of

organisms including gram positive bacteria, gram negative bacteria, fungi,

virus, protazoans and insect parasites. Particularly surprising the

compositions may be employed against difficult bacteria such as

methicillin resistant staphylococcus aureus (MRSA), Clostridium difficile

(C.diff) helicobacter pyroli (H.py), and vancomycin resistant

enterobacteria. The compositions of this invention may also be used

against norovirus and other pathogens whereby transmission is by contact

or air.

The compositions may be administered systemically or locally if an animal

is t o be treated. Suitable animals include humans and food and

companion animals such as cows, pigs, horses, chickens, sheep, goats,

dogs and cats. Hence the compositions may be formulated for oral

administration, topical administration, injection or the like as required by

the medical practitioner. Particularly suitably such compositions are

suitable for use t o treat humans.

Suitable oral and topical compositions include those analogous to those

described in PCT/GB2007/002756 and PCT/GB2007/002758. Injectable

forms may be put up in conventional manner, for example as aqueous

solutions or dispersions.

The compositions of the invention are also useful for use in conjunction

with a further antibacterial agent. Thus for example, if used t o treat a

patient suffering from MRSA, the compositions may be used in conjunction

with a β-lactam or other antibiotic or antibacterial agent. Suitable β-

lactam antibiotics include, a penicillin such as methicillin, flucloxacillin,

ampicillin, amoxicillin optionally with clavulanic acid, a cephalosporin, or a

carbopenem such as imipenem or the like. The composition as a single

composite form or as two or three forms, for example one of dosage form

will contain the β-lactam or other antibiotic and another composition will

comprise the first and second components. Hence the β-lactam antibiotic

can be administered separately from component I and I I (and if desired

first and second components may also be administered separately from

the further antibacterial agent). The compositions of the invention

containing the first and second components adapted for oral

administration and the further antibacterial agent adopted for oral

administration (for orally administrable antibiotic such as amoxicillin) or

for injection (for injected antibiotics such as methicillin or imipenem) may

also be used together with vancomycin.

Patients suffering with infections caused by C. diff and H.py may be

treated similarly. The preferred route of administration of all three agents

is orally when the β-lactam or other antibiotic is orally effective, especially

for the treatment as gastric infections of H.py. However, if an antibiotic is

employed that is best administered by injection that may be done in

conjunction with the oral administration of the compositions of the

invention.

Since the compositions of the invention are particularly effective for

sterilizing surfaces, they are very suitably formulated in a composition

useful for external use.

These may be in the form of solutions, gels, soaps, body wash, shampoo,

dusting powders and aerially dispersible powder and liquids and the like.

Such compositions may be used t o reduce the bacterial count on body

surfaces, clothing and in the general environment particularly in hospitals,

ambulances, nursing homes especially for the elderly or the like where it

is particularly desirable to reduce the presence of bacteria such as MRSA,

C. diff or the like.

Compositions suitable for washing the hands are particularly useful.

Such compositions may also be employed to wash stethoscopes.

The substantivity of the compositions (as opposed t o rapid diminution of

effectiveness of ethanol) is an advantage.

If external surfaces of enclosed spaces, such as ambulances, operating

theatres, wards, kitchens (and even mortuaries) and so on are t o be

treated, it is particularly suitable to do so by "misting". I n this a fine

aerial dispersion of powder or microdroplets of composition are dispersed

within the enclosed space. This can then offer a non-toxic alternative to

the presently employed methods which often employ noxious gases.

Since the compositions of the invention have such low toxicity they may

be employed on patients and their visitors and associated clothing, linen

and the like by "misting". Such "misting" is of use in vehicles such as

ambulances which are required to be free of pathogens but likewise free

of residual odors that are typically left following the use of noxious gases.

This equally applies to other areas requiring treatment. Compositions

used in this way may be in the form of a dispersible liquid, for example

akin t o the soap or shampoo or skin foaming compositions described

hereinafter. These can also be used t o what the surfaces to similar ends.

A particular use includes antibacterial soaps, detergents, lotions and the

like for treating inter alia human skin and hair in order t o reduce or

eliminate undesired organisms.

Thus it is possible by using compositions of this invention prevented in

such forms, t o treat hands, the face and skin generally and the hair, both

on the head and elsewhere. This can be employed to reduce bacterial

count and so help t o reduce the spread of methicillin resistant

staphylococcus aureas, Clostridium difficile and other bacteria. Similarly,

the composition may be used t o reduce microorganisms associated with

acne, body odor or the like. A further benefit is that such compositions

may be used t o reduce viral transmission, for example for influenza virus,

which can occur by hand contamination. Other virus that may be on the

skin or membranes include HIV, herpes and the like which are also

minimized by use of the compositions of the invention adapted for

administration to the skin or membranes.

Parasite infestation may be treated with compositions of the invention.

Such parasites include internal parasites such as protozoa which can lead

t o diseases of humans such as malaria, leishumaniasis and

trypanosomiasis and various diarrhoeas. Other internal parasites that

may be treated include flukes. External parasites that may be treated

include lice, especially head lice, and scabies and fleas. Soaps and

shampoos are favoured for such external application although solutions,

lotions and gels are also particularly suitable.

Fungi for treatment include those responsible for dandruff, thrush,

athlete's foot and the like, for example, Candida albicans. Conditions such

as dandruff may be treated with soaps and shampoos but other

formulation types named herein may also be used. Athlete's foot may

also be treated with dusting powder. Candida albicans or other infecting

agents in the vagina may be put up in the form or a pessary.

A particular use for the compositions of the invention includes

mouthwashes, toothpastes and other forms suitable for use in the buccal

cavity. Such forms may be formulated as indicated in the PCT

applications referred t o herein before.

The compositions of the invention may also be used for the prophylaxis or

treatment of dandruff or the like.

Compositions of the invention may therefore also suitably contain a

pharmaceutically acceptable salt of choline such as choline chloride. This

can enhance effectiveness further against organisms such as c . diff.

Formulations may be composed of conventional carriers as long as they

are compatible with the first, second and optionally third component of

the compositions herein.

Thus soaps, shampoos and the like may aptly contain surfactants. Many

conventional surfactants may be employed but it appears certain effective

formulations will employ non-ionic surfactants. Particularly effective non-

ionic surfactants include alkyl polycyclosides and/or alkenyl polyglycosides

(APGs) such as those containing up t o 10 sugar residues coupled t o a

hydrocarbon chain. Oligomerisation of up t o about 4 sugar residues can

be desirable. Such surfactants are available under the trade name

"Plantacare" for example from Henkel as "Plantacare 2000".

I n some compositions minor amounts of typical anionic surfactants may

be employed together with the non-ionic surfactant. Amphoteric

surfactants may also be present, for example and preferably, with the

non-ionic surfactants, for example those having secondary or tertiary

amino and water solubilising anionic groups, such as sulphate, phosphate,

phosphonate or carboxylate groups. Such amphoteric surfactants include

those available under trade names such as Miranol (of Rhone-Poulenc)

and Betain, such as Dehyton from Henkel.

The compositions of the invention may optionally comprise thickening

agents. Suitable thickening agents include polysaccharide thickeners such

as xanthan gums, gellan gums, pectins, carageenans and the like. An apt

thickening agent is xanthan gum such as Keltrol CG which is a high

molecular weight polysaccharide produced by microbial fermentation.

Viscosity may also be selected by use of an amphoteric surfactant such as

a cocamido-propyl betain or Tego Betain F50 as a thickening as well as

surfactant agent.

The compositions of the invention may be employed for the treatment of

food stuffs to reduce or eliminate unwanted pathogens or organisms

leading to reduction in storage life of food stuffs. Thus vegetable, fruits

and meat may be treated, for example lettuce, tomatoes, cucumbers,

peppers, cereals such as wheat and maize, fruit such as apples, grapes,

pears and figs, and meats such as beef, pork, lamb, bacon and the like.

Methods of treatment include washing, misting and the like.

The hand sterilization test method used in the Examples was as follows:

Experimental procedure:

1) Application of the contamination fluid.

Each of the twelve subjects was asked t o wash their hands for one minute

in soft soap t o remove natural commensal organisms and dried thoroughly

on a paper towel. The hands were then contaminated with very large

numbers of bacteria well in excess of that experienced in normal everyday

occurrence. The hands were immersed in the contamination fluid

(containing an overnight culture of the test organism in this instance E.

coli at a concentration of approximately 108 cfu per ml) in a suitable sized

container for five seconds. The hands were removed from the

contamination fluid and surplus liquid allowed to drain back into the

container. This time the hands were allowed to air dry for approximately

three minutes holding them horizontally with fingers spread out and

rotating them to and fro t o avoid the formation of droplets.

2) Prevalues.

Immediately after drying, each of the twelve subjects was asked t o rub

their fingertips, including the thumbs for one minute on the base of a petri

dish, using a separate petri dish for each hand, containing 10ml of

maximum recovery diluent (MRD) without neutraliser, in order to assess

the release of test organisms before treatment of the hands. Dilutions of

these sample fluids were prepared to 10 3 and 10 4 . A 1ml aliquot of each

dilution for each hand was placed in a separate petri dish 10 - 15ml of

Tryptone Soy Agar sterilised and cooled t o 45°C added and mixed

thoroughly. Plates were allowed to set and incubated at 37°C for twenty

four hours. Each plate was then examined for growth of the test

organism.

3) Hygienic Handwash procedure.

Each of the twelve subjects was asked t o pour 3ml of soft soap into the

cupped hands pre-moistened with tap water and wash their hands in

accordance with a standard handwash procedure. This comprises five

strokes backwards and forwards palm to palm, right palm over left

dorsum and left palm over right dorsum, palm to palm with fingers

interlaced, back of fingers to opposing palms with fingers interlocked,

rotational rubbing of right thumb clasped in left palm and left thumb

clasped in right palm, rotational rubbing with clasped fingers of right hand

in palm of left hand and clasped fingers of left hand in right palm using as

much lukewarm water as is needed to produce a lather. After sixty

seconds the hands are rinsed under running tap water for fifteen seconds

from distal t o proximal with fingertips upright.

4) Handwash procedure with test product (P).

After first wetting the hands and arms with water approximately 3ml of a

composition of the Examples was applied and rubbed thoroughly onto

these areas using the technique described above and this is then rinsed

off with running water. The total washing time is limited to sixty seconds

and the time for final rinse is not included in the washing time. To avoid

recontamination of the sample area (i.e. the fingertips) subjects are

requested t o hold their hands such that the fingertips are pointing

upwards. Wrists and forearms are wiped dry by another person.

Example 1

Surgical Sanitizer

Water (481. 5g; 96.3%) was added to a beaker and stirring commenced.

Keltrol CG-SFT (9.0g; 1.8%) was added and stirring continued until

dissolved. Citrox HXT powder (2.5g; 0.5%) was added and stirring

continued until dissolved. White willow bark extract (2.0g; 0.4%) was

added and stirring continued until dissolved. Glycerol (5.0g; 1.0%) was

added and stirring continued until dissolved.

The resulting viscous gel was de-aerated. The pH was 4-5. The viscosity

7000-10000 cp at 20°C (spindle 4/0 rpm). The pH may be adjusted with

citric acid if required to bring it within the stated range.

Citrox HXT powder comprises on a wt/wt basis 7.5% HPLC 45%, citric acid

30%, willow bark extract 50% and olea Europeae extract 12.5%.

HPLC-45% contained 45% by weight of a mixed of flavanoids together

with residues of extraction from bitter oranges.

The Willow Bark extract contains 90% of salicylic acid.

The Olea Europeae extract contains 20% of oleuropein.

The mixture of flavanoids in HPLC-45 comprises:

Example 2

Liquid Hand Soap

Water (362g, 72.4%) was added t o a beaker and stirring commenced.

Keltrol CG-SFT (9g, 1.8%), Plantacare 2000 (67. 8g, 13.6%), Tego Betain

F50 (lOg, 2%), glycerol (lOg, 2%) and Citrox HXT powder were

sequentially added with stirring until complete dissolution occurred prior

to adding subsequent ingredients.

The product was a clear viscous gel, pH 4.8 to 5 was a viscosity of about

4000 cp at 20°C (spindle 4/10 rpm).

Citrox HXT powder and Keltrol CG-SFT were as described in Example 1 .

Plantacare 2000 is an aqueous solution containing 6.78g of the surfactant

agent.

Tego Betain F50 is an aqueous solution containing 3.22g of the surfactant

agent.

Example 3

Hand Foam Composition

This was prepared by mixing as described in Example 1.

When tested against test organism according to BS EN 13727 under dirty

conditions (interfering substances bovine albumin and sheep

erythrocytes), a five minute contact time at 20°C, satisfactory bactericidal

activity was observed when the test organism was (i) MRSA (ATCC33591)

and Clostridium difficile (NCTC 11209). When tested against spores of

this C. difficile according to En 13704, satisfactory sporicidal activity was

found with a 15 minute contact time at 20°C.

Example 4

Sanitizing Gel

This was prepared by mixing as described in Example 1.

When tested by the methods detailed in Example 1, the gel provided

satisfactory bactericidal activity against the MRSA and satisfactory

sporidical activity against the C. difficile.

Example 5

Liquid Soap

Olive leaf extract 0.0625%

Citric acid 0 .15%

Salicylic acid 0.25%

Dermosoft GMCY 1.0%

Water 72.66%

When used herein HPLC 45% means a mixture containing 45% of

bioflavanoids and 55% of other matter from extraction of bitter oranges.

The bioflavanoids comprised narangin (about 52%), neohesperidin 28%,

poncirin (4%), naringenin (3%), hesperidin (3%), neodiosmin (3%),

isonaringin (3%), isocriocrin (2%), other minor t o 100%.

Example 6

Gel

Example 3 may be repeated replacing HPLC 45% with an equal weight of

a 1:1 mixture of narangin and nehesperidin.

Example 7

Aerially Dispersible Form

The hand foam composition of Example 3 is used in a commercial misting

device t o produce a mist for disinfection of surfaces.

Example 8

A commercial hand held misting device is used t o direct mist at the

surfaces in an ambulance and t o the air space. The misting is continued

until the operative is satisfied surfaces have been thoroughly treated.

The ambulance may be occupied twenty minutes after the completion of

the misting.

Claims

1 . A composition comprising a flavanoid component and an oleuropein

component wherein :

(a) the flavanoid component is one or more flavanoids of

Formula (I) :

wherein R1 is hydroxyl or methoxyl and R2 is hydrogen, hydroxyl or

methoxyl and X is hydrogen or a saccharide; and

(b) the oleuropein component is oleuropein or an acetylated

derivative thereof.

2 . A composition as claimed in claim 1 wherein R1 is 4-hydroxy or

methoxy group.

3 . A composition as claimed in claims 1 or 2 wherein R1 is 4-hydroxy

and R2 is hydrogen.

4 . A composition as claimed in any of claims 1 or 2 wherein R1 is 4-

methoxy and R2 is 3-hydroxy.

5 . A composition as claimed in any of claims 1 to 4 wherein X is

hydrogen.

6 . A composition as claimed in any of claims 1 to 4 wherein X is a

saccharide.

7 . A composition as claimed in any of claims 1 to 4 wherein X is a

disaccharide.

8 . A composition as claimed in claim 7 wherein disaccharide is

rutinose.

9 . A composition as claimed in any of claims 1 to 8 wherein the first

component comprises narangin or neohesperidine or mixtures thereof

optionally with one or more other flavanoids of the Formula (I).

10. A composition as claimed in claim 9 which comprises 50 - 55% of

narangin, 25 - 30% of neohesperidin and 15 - 25% of one or more other

flavanoids of the Formula (I).

11. A composition as claimed in any of claims 1 to 10 wherein the

hydroxyphenylethanol component comprises oleuropein or a mono- or di-

acetylated derivative thereof.


oleuropein component is oleuropein.


flavanoid component is an extract of bitter oranges.


oleuropein component is an extract of the olive.


weight ratio of the flavanoid component to the oleuropein component is

5 :1 to 1:4.

16. A composition as claimed in claim 15 wherein the ratio is 2 :1 to

1:2 .

17. A composition as claimed in claim 16 wherein the ratio is 1:2 t o

1:1 .

18. A composition as claimed in claim 17 wherein the ratio is 3 :2.

19. A composition as claimed in any of claims 1 to 18 which further

comprises (c) salicylic acid or pharmaceutically acceptable salt thereof.

20. A composition as claimed in claim 19 wherein the weight ratio of

the flavanoid component plus the oleuropein component to salicylic acid or

pharmaceutically acceptable salt thereof is 2 :1 to 1 :7 (i.e. (a+b):c is 2 :1

to 1:7).

21. A composition as claimed in claim 20 wherein the ratio of a+b:c is

1:1 to 1:5 .

22. A composition as claimed in claim 21 wherein the ratio of a+b:c is

2 :3 to 1:3 .

23. A composition as claimed in claim 22 wherein the ratio is 2 :5 .

24. A composition as claimed in any of claims 1 to 23 which comprises

a further organic acid such as citric acid, malic acid, lactic acid, tartaric

acid, fumaric acid or other di- or tri-basic organic acid of up to 8 carbon

atoms optionally substituted by 1, 2 or 3 hydroxyl groups; of a

pharmaceutically acceptable salt thereof.


comprises citric acid or a pharmaceutically acceptable salt thereof.

26. A composition as claimed in claim 25 wherein the citric acid or a

salt thereof is contained in a willow bark extract.

27. A composition as claimed in any of claims 23 t o 26 wherein the

weight ratio of the further organic acid or pharmaceutically acceptable salt

thereof to salicylic acid is 2 :1 to 1:5 .

28. A composition as claimed in claim 27 wherein the ratio is 1:1 to

1:3 .

29. A composition as claimed in claim 28 wherein the weight ratio is 3

to 5 .

30. A composition as claimed in any of claims 19 t o 29 wherein the

salicylic acid is present together with a solubilising agent therefore.

31. A composition as claimed in claim 30 wherein the solubilising agent

is a dextrin.

32. A composition as claimed in claim 31 wherein the dextrin is

cyclodextrin.

33. A composition as claimed in any of claims 1 to 31 for use as a

pathenogenicide.

34. A composition as claimed in any of claims 1 to 31 for use as an

antibacterial agent.


antiviral agent or an antifungal agent.


antiparasitical agent.

37. A composition as claimed in claim 36 for use against protozoa.

38. A composition as claimed in claim 31 for the prophylaxis or

treatment of an insect infestation such as an external parasite, for

example head lice.

39. A composition as claimed in claim 34 for use against multiple

resistant staphylococcus aureus.

40. A composition as claimed in claim 34 for use against Clostridium

difficile.

41. A composition as claimed in claim 34 for use against (a)

helicobacter pyroli or (b) vancomycin resistant strains of enterobacter or

staphylococcus or other pathogen whereby transmission is by contact or

air, for example, norovirus.

42. A composition as claimed in claim 35 for use against influenza virus.

43. A composition as claimed in claim 35 for use against human

immunodeficiency virus.

44. A composition as claimed in claim 33 for washing food stuffs.

45. A composition as claimed in claim 33 for sterilizing local

environments, for example medical premises, hotels, ships or aircraft.

46. A composition as claimed in claim 45 wherein the local environment

is a hospital ward, operating theatre, corridor or ambulance.

47. A composition as claimed in claim 33 for sterilizing clothing,

exposed body parts, stethoscopes or surgical instruments.


comprises an additional antibacterial agent for simultaneous or

consecutive use.

49. A composition as claimed in claim 48 wherein the additional

antibacterial agent is a β-lactam antibiotic.

50. A composition as claimed in claim 49 wherein the β-lactam

antibiotic is amoxicillin.

51. A composition as claimed in claim 49 wherein the β-lactam

antibiotic is a carbopenem such as imipenem.

52. A composition according to any of claims 1 to 5 1 in the form of a

pharmaceutical composition which also comprises a pharmaceutically

acceptable carrier.

53. A composition according to any of claims 1 to 51 in the form of a

toothpaste, mouthwash, mouth spray or mouth rinse.

54. A composition according to any of claims 1 to 5 1 in the form of a

water based composition of pH 3 to 8.5.

55. A composition according to claim 54 wherein the pH is from 5 t o 8 .

56. A composition according to any of claims 1 to 53 wherein the

composition is in an orally administrable unit dosage form.


multidose composition from which a unit dose may be withdrawn.

58. A unit dose form as claimed in claim 56 which contains from 25 mg

to 500 mg of the flavanoid component.

59. A unit dose form as claimed in claim 58 which contains from 50 mg

to 1000 mg of flavanoid component.

60. A unit dose form as claimed in claim 58 which contains 100 mg to

500 mg of flavanoid component.

61. A multidose form as claimed in claim 57 in the form of a liquid from

which unit doses may be withdrawn.


soap or shampoo.


mistable powder or liquid.

64. A composition according t o any of claims 1 to 34 which comprises

by weight:

(a) flavanoid component 5 - 10%;

(b) hydroxyphenylethanol component 10 - 15%;

(c) salicylic acid or pharmaceutically acceptable salt thereof 45 -

55%;

(d) citric acid or a pharmaceutically acceptable salt thereof 25 -

35%.

65. A composition as claimed in claim 64 in the form of a powder

comprising (a) 7.5%, (b) 12.5%, (c) 50% and (d) 30%.

66. A composition as claimed in claims 64 or 65 which comprises an

aqueous solution of (a), (b), (c) and (d).

67. A composition as claimed in claim 66 which further comprises a

solubilising agent.

68. A composition as claimed in claim 67 wherein the solubilising agent

is a dextrin.

69. A composition as claimed in claim 68 wherein the dextrin is

cyclodextrin.

70. A method of pathogenicide which comprises bringing into contact

with the pathogen a composition as claimed in any of claims 1 to 69.

71. A method as claimed in claim 70 wherein the method of

pathogenicide is (a) a method of reducing or eliminating pathogenic

bacteria, (b) a method of reducing pathogenic virus, for example,

norovirus or influenza, or (c) other microbial pathogen transmissible by

contact or air.

72. A method as claimed in claim 7 1 wherein the pathogenic bacteria is

MRSA, Clostridium difficile or helicobacterpyroli.

73. A method as claimed in claim 72 wherein the pathogenic bacteria

reduced or eliminated is Clostridium difficile and its spores.

74. A method as claimed in any of claims 70 t o 73 wherein the method

comprises the composition to an external surface.

75. A method as claimed in claim 74 wherein the external surface is of

a human or animal subject.

76. A method as claimed in claim 74 wherein the external surface is of

a food stuff, cloths, medical establishments, hospital wards, hospital

corridors, hospital waiting rooms, hospital operating theatres,

ambulances, hospital devices such as stethoscopes, catheters and surgical

instruments, and ships and aircraft cabins.

77. A method as claimed in any of claims 70 t o 76 wherein the external

surface is washed with a solution of the composition.

78. A method as claimed in any of claims 70 t o 76 wherein the external

surface is misted with a solution of the composition.

79. A method as claimed in claim 70 wherein the pathogen is a virus,

fungus or parasite.

80. A method as claimed in claim 79 wherein the virus is influenza virus

or human immunodeficiency virus.

81. A method as claimed in claim 79 wherein the fungus is a yeast such

as Candida albicans or is aspergillius.

82. A method as claimed in claim 79 wherein the parasite is an internal

parasite such as a protozoan or fluke, for example malaria.

83. A method as claimed in claim 79 wherein the parasite is an external

parasite such as an insect, for example lice, fleas or scabies.

A . CLASSIFICATION O F SUBJECT MATTER

INV. A01N43/16 A01N65/00 A61K8/49 A61K8/60 A61K31/353A01N65/36 A01N65/08 AOlPl/00

ADD.According to International Patent Classification (IPC) or to both national classification and IPC

B . FIELDS SEARCHED

Minimum documentation searched (classification system followed by classification symbols)

A01N A61K

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practical, search terms used)

EPO-Internal , WPI Data

C . DOCUMENTS CONSIDERED TO B E RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

X EP 2 027 783 Al ( FURFURAL ESPANOL S A 1-9 ,[ES] ) 25 February 2009 (2009-02-25) 11-18,

33-37 ,39-47 ,52-61 ,63

Y paragraphs [0001] , [0011] , [0013] , 10[0014] , [0016] , [0020] - [0030]c l aim 1

Y 0 2008/009958 Al (0RALDENT LTD [GB] ; 1-32 ,RI PLEY IAN [GB] ; THOMAS HOWARD [GB] ) 34-37 ,24 January 2008 (2008-01-24) 39-69c i ted i n the appl i cati onpage 6 , l i ne 14 - l i ne 28Tabl e ; page 7page 10, l i ne 26 - l i ne 27page 12 , l i ne 25 - l i ne 31pages 1-3 , 5-7

-/--

Further documents are listed in the continuation of Box C . X I See patent family annex.

* Special categories of cited documents :"T" later document published after the international filing date

or priority date and not in conflict with the application but"A" document defining the general state of the art which is not cited to understand the principle o r theory underlying the

considered to be of particular relevance invention"E" earlier document but published on or after the international "X" document of particular relevance; the claimed invention

filing date cannot be considered novel o r cannot be considered to"L" documentwhich may throw doubts on priority claim(s) o r involve an inventive step when the document is taken alone

which is cited to establish the publication date of another "Y" document of particular relevance; the claimed inventioncitation or other special reason (as specified) cannot be considered to involve an inventive step when the

"O" document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu¬other means ments, such combination being obvious to a person skilled

"P" document published prior to the international filing date but in the art.

later than the priority date claimed "&" document member of the same patent family

Date of the actual completion of the international search Date of mailing of the international search report

11 January 2012 18/01/2012

Name and mailing address of the ISA/ Authorized officer

European Patent Office, P.B. 5818 Patentlaan 2NL - 2280 HV Rijswijk

Tel. (+31-70) 340-2040,Fax: (+31-70) 340-3016 Habermann , Jbrg

C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT


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Patent document Publication Patent family Publicationcited in search report date member(s) date

EP 2027783 Al 25-02-2009 EP 2027783 Al 25-02-2009ES 2288123 Al 16-12-2007US 2010022464 Al 28-01-2010O 2007141352 Al 13-12-2007

W0 2008009958 Al 24-01-2008 CA 2658468 Al 24 -01 -2008CA 2658710 Al 24 -01 -2008CN 101495089 A 29 -07 -2009CN 101495090 A 29 -07 -2009EP 2043592 Al 08 -04 -2009EP 2043593 Al 08 -04 -2009GB 2440440 A 3 -01 -2008P 2009544603 A 17 -12 -2009P 2009544604 A 17 -12 -2009

US 2010055053 Al 04 -03 -2010US 2010068157 Al 18 -03 -2010WO 2008009956 Al 24 -01 -2008WO 2008009958 Al 24 -01 -2008

WO 0103681 A2 18 -01 -2001 AU 6174900 A 30-01-2001CA 2375647 Al 18-01-2001EP 1223928 A2 24-07-2002P 2003504327 A 04-02-2003

WO 0103681 A2 18-01-2001

WO 2008143137 Al 27-11 -2008 TW 200906380 A 16-02-2009WO 2008143137 Al 27-11-2008

P 8317782 A 03 -12 -1996 JP 3571111 B2 29-09-2004JP 8317782 A 03-12-1996

W0 9856345 Al 17-12-1998 AU 742341 B2 20-12-2001AU 8257698 A 30-12-1998CA 2293330 Al 17-12-1998CN 1265024 A 30-08-2000EP 0996417 Al 03-05-2000JP 2001515514 A 18-09-2001WO 9856345 Al 17-12-1998

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