Title of Invention	ORAL COMPOSITION COMPRISING AN ALKYLHYDROXYBENZOATE
Abstract	1. Oral composition comprising an alkyl hydroxybenzoate represented by formula 1 Formula 1 : wherein R is a n-octyl; and an antimicrobially effective amount of a divalent metal ion source, wherein the divalent metal is zinc.

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FORM -2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION (See Section 10) ORAL COMPOSITION COMPRISING AN ALKYLHYDROXYBENZOATE HINDUSTAN LEVER LIMITED, a company incorporated under the Indian Companies Act, 1913 and having its registered office at Hindustan Lever House, 165/166, Backbay Reclamation, Mumbai -400 020, Maharashtra, India The following specification particularly describes the nature of the invention and the manner in which it is to be performed. ORIGINAL 00129/MUMNP/2004 GRANTED 24-2-2006 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date 6 March 2003 (06.03.2003) PCT WO 03/017962 A1 (10) International Publication Number WO 03/017962 Al (51) International Patent Classification7: A6IK 7/24 (21) International Application Number: PCT/EP02/09166 (22) International Filing Date: 15 August 2002 (15.Uii.2002) English English (25) Filing Language: (26) Publication Language; (30) Priority Data: 01307269.9 01310338.7 24 August 2001 (24.08.2001) EP 11 December 2001 (11.12.2001) EP (71) Applicant (for AE, AL AM, AT, AZ BA, BE, BF, BG, BJ, BR, BY, CF, CG, CH, CI, CM, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, ES, FI, FR, GA, GE, GN, GQ, GR, GW, HR, HU, ID, IS, IT, JP, KG, KP. KR, KZ, LC, LR, LT, LU, IV, MA, MC. MD, MG, MK, ML, MR, Aft', NE, NL, NO, PH, PL, PT, RO, RU, SE, SI, SK, SN, TD, TG, TJ, TM. TN, TR, UA, UZ, VN, YU only): UNILEVER N.V. INUNLJ; Weena 455, NL-3013 AL Rotterdam (NL). (71) Applicant (for AG, AU, BB, BZ, CA, CY, GB, GD, GH, GM, IK II.. KK l-K. IS, MN, MW, MT. NT, OM, SI), SG, SL.SZTT.TZ, UG, ZA, ZM, ZW only): UNILEVER PLC fGB/GBl; UNILEVER HOUSE, Blackfriars, London, Greater London EC4P 4BQ (GB). (71) Applicant (for IN only): HINDUSTAN LEVER LTD (72) Inventors: CROMWELL, Victoria; Quarry Road East, Bebington, Wirral, Merseyside CH63 3JW (GB). FRE-UNSCHT, Peter; Quarry Raod East, Bebington, Wirral, UN/IN]; HINDUSTAN LEVER HOUSE, 165-166 Back--'bay Reclamation, 400 020 Mumbai (IN). Merseyside CH63 3JW (GB). HALL, Peter, John; 237 Spital Road, Bromborough, Wirral. Merseyside L62 2AF (GB). LITTLEWOOD, David, Thomas; Quarry Road East, Bebington, Wirral, Merseyside CH63 3JW (GB). (74) Agent: ROSEN JACOBSON, Frans; Unilever Patent Department, Olivier van Noortlaan 120, NL-3133 AT Vlaardingen (NL). (81) Designated States (national): AE, AG, AL, AM, AT (util¬ity model), AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU, CZ (utility model), CZ, DE (util¬ity model), DE, DK (utility model), DK, DM, DZ, EC, EE (utility model), EE, ES, FTtfittoty model), FI, GB, GD, GE, GH, GM, HR, HU, ID, n/lN/S, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LUTLV, MA, MD, MG, MK, MN, MW, MX, MX, NO, NZ, OM, PI I, PL, PT, RO, RU, SI), SE, SG, SI. SK (utility model), SK, SL, TJ, TM, TN, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZM, ZW. (84) Designated States (regional): ARIPO patent (GH, GM, KE, LS, MW. MZ, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European patent (AT, BE, BG, CH, CY, CZ, DE, DK, EE, HS, FI, h'R, GB, OR, IK, IT, I.U, MC, NL, PT, SK, SK, TR), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). Published: ■with international search report — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of amendments For two-letter codes and other abbreviations, refer to the "Guid¬ance Notes on Codes and A bbreviations " appearing at the begin¬ning of each regular issue of the PCT Gazette. (54) Title: ORAL COMPOSITION COMPRISING AN ALKYLHYDROXYBENZOATE (57) Abstract: Oral composition comprising an alkyl hydroxyben-zoate represented by formula I, wherein R represents a straight chain alkyl gruup comprising at least eight carbon atoms. The present invention relates to an oral composition comprising an alkyl hydroxybenzoate. Alkyl hydroxybenzoates (parabens) are known in the art where the alkyl group is methyl. For example, methyl hydroxybenzoate is mentioned, albeit fleetingly, for use in medicinal and oral care preparations as a preservative (WO 10 00/09507 and WO 00/69401). In addition, US 5 094 841 (Fine) discloses the use of heptyl paraben as a preservative in an oral care formulation. However, it also states that the preferred preservatives are 15 methyl and propyl paraben and only ever states that they may be included in small amounts (0,1%) to provide a preservative effect. EP-A2-0 161 898 (Unilever) discloses that an oral 20 composition can comprise non-cationic antimicrobial agents selected from the esters of p-hydroxybenzoic acid, especially the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, hexyl, heptyl and benzyl esters. 25 We have found that there exists a range of compounds which exhibit surprisingly high antibacterial efficacy and are not disclosed for use in oral compositions in the prior art. Accordingly, the invention provides oral composition 30 comprising an alkyl hydroxybenzoate represented by"formula 1 wherein R represents a straight chain alkyl group comprising at least eight carbon atoms. The alkyl group of the compound according to formula 1 is a straight chain alkyl comprising at least eight carbon atoms. Preferably, the alkyl group comprises no more than 30 carbon atoms. More preferably the alkyl group comprises from 8 to 15 carbon atoms, especially from 8 to 10 and most preferably 8. Further, the alkyl group may be substituted or unsubstituted. Preferred alkyl groups include octyl, nonyl, decyl, undecyl and dodecyl. More preferably the alkyl group is n-octyl. Such compounds may be made by simple esterification of 4-hydroxybenzoic acid with the respective alcohol. Such a process is a simple step for the man skilled in the art to carry out. The most preferred antimicrobial agent is n-octyl parahydroxy benzoic acid because it has the greatest antimicrobial effect against the commonly present oral microflora. Many of the other parabens are effective only against certain of these bacteria or are less effective against the same range of microflora. The compound according to formula 1 is preferably present in an amount such that an antibacterial effect can be provided. In practice this ranges from 0.15 to 30% by weight of the composition according to the invention. Preferably, in an amount ranging from 0.2 to 10% by weight and even more preferably from 0.1 to 3.5% by weight. The composition according to the invention may also comprise a divalent metal salt. Preferably, the divalent metal salt is a salt selected from the group consisting of zinc- and stannous salts such as zinc citrate, zinc sulphate, zinc glycinate, sodium zinc citrate, stannous pyrophosphate and mixtures thereof. The preferable divalent metal salt is zinc citrate. Suitably, the amount of divalent metal salt ranges from 0.01 to 10% by weight of the composition, preferably from 0.05 to 5% by weight, more preferably from 0.1 to 2% by weight and especially preferably from 0.3 to 0.9% by weight of the composition. The oral composition according to the invention comprise further ingredients which are common in the art, such as: antimicrobial agents, e.g. Triclosan, chlorhexidine, sanguinarine extract, metronidazole, quaternary ammonium compounds, such as cetylpyridinium chloride; bis-guanides, such as chlorhexidine digluconate, hexetidine, octenidine, alexidine; and halogenated bisphenolic compounds, such as 2,2' methylenebis-(4-chloro-6-bromophenol); anti-inflammatory agents such as ibuprofen, flurbiprofen, aspirin, indomethacin etc. ; anti-caries agents such as sodium- and stannous fluoride, aminefluorides, sodium monofluorophosphate, sodium trimeta phosphate and casein; plague buffers such as urea, calcium lactate, calcium glycerophosphate and strontium polyacrylates; vitamins such as Vitamins A, C and E; 15 plant extracts; desensitising agents, e.g. potassium citrate, potassium chloride, potassium tartrate, potassium bicarbonate, 23 potassium oxalate, potassium nitrate and strontium salts; anti-calculus agents, e.g. alkali-metal pyrophosphates, hypophosphite-containing polymers, organic phosphonates and phosphocitrates etc.; 5 biomolecules, e.g. bacteriocins, antibodies, enzymes, etc; flavours, e.g. peppermint and spearmint oils; 30 proteinaceous materials such as collagen; preservatives; opacifying agents; colouring agents; pH-adjusting agents; sweetening agents; pharmaceutically acceptable carriers, e.g. starch, sucrose, water or water/alcohol systems etc.; surfactants, such as anionic, nonionic, cationic and zwitterionic or amphoteric surfactants; 15 particulate abrasive materials such as silicas, aluminas, calcium carbonates, dicalciumphosphates, calcium pyrophosphates, hydroxyapatites, trimetaphosphates, insoluble hexametaphosphates and so on, including 20 agglomerated particulate abrasive materials, usually in amounts between 3 and 60% by weight of the oral care composition. humectants such as glycerol, sorbitol, propyleneglycol, 25 xylitol, lactitol etc.; binders and thickeners such as sodium carboxymethyl-cellulose, xanthan gum, gum arabic etc. as well as syntheti polymers such as polyacrylates and carboxyvinyl polymers such as Carbopol®; polymeric compounds which can enhance the delivery of active ingredients such as antimicrobial agents can also be included; 5 buffers and salts to buffer the pH and ionic strength of the oral care composition; and other optional ingredients that may be included are e.g. bleaching agents such as peroxy compounds e.g. potassium peroxydiphosphate, effervescing systems such as sodium bicarbonate/citric acid systems, colour change systems, and so on. Liposomes may also be used to improve delivery or stability 10 of active ingredients. The oral compositions may be in any form common in the art, e.g. toothpaste, gel, mousse, aerosol, gum, lozenge, powder, cream, etc. and may also be formulated into systems for use 20 in dual-compartment type dispensers. Embodiments according to the invention shall now be discussed with reference to the following non-limiting examples. EXAMPLE 1 The following method is used to assess the antimicrobial efficacy of the agents according to formula 1. 30 The seed stock of the bacterial strains, E. cloacae, A. naeslundii, S. sanguis (facultative anaerobes) and F. nucleatum and V. parvula (obligate anaerobes) is stored frozen in 1.5 ml aliquots. From the stock, an appropriate dilution of bacteria is added to BHI (dilution 1:500 for E. cloacae; dilution 1:200 for A. naeslundii,; dilution 1:100 for S. sanguis; dilution 1:20 for F. nucleatum; and dilution 1:20 for V. parvula). For the two obligate anaearobic strains, F, nucleatum and V. parvula, the BHI medium is supplemented with Oxyrase (100 µl/5 ml), Oxyrase for Broth is a sterile enzyme additive which is used to produce anaerobic conditions in a wide variety of bacteriological broth medium. The cells in the BHI broth are added to 96 well plates at a volume of 180 µl/well. The compounds to be tested are added to the wells (20 µl/well) to give final assay concentrations over the desired range. The plates are incubated at 37° C for specific period of time, determined separately for each bacterial culture. After the incubation period the optical density is measured using a Bio-Tek EL 340 Microplate Biokinetics® reader. For studies carried out with Alamar Blue® to monitor the growth of the cultures, fluorescence is measured using a Tecan Spectrafluor® fluorescence plate reader. In order to establish a correlation between absorbance at 550 nm and cell density, a sequence of dilutions for each of the five organisms was made from a culture derived from the original stock vial. The facultative anaerobic cultures were incubated at 37°C at a shaker setting of 250 rpm. The anaerobic cultures were incubated in Oxyrase® broth at 37°C without shaking. After the incubation period, a serial dilution series covering the range of 10 to 1200 was made. Dilution samples were read on the Bio-Tek Biokinetics® plate reader at 550 nm. Data will be expressed as Percent of Control. Positive controls (no sample) will be run with culture in the presence of 1.0 % DMSO. Negative controls (no culture) will be run with media in the presence of 1.0 % DMSO. 10 Additionally, standard compounds (Chlorhexidine acetate, and Cetyl pyridinium chloride) may also be employed as Reference controls. 15 Percent of control is calculated by the following formula: % of Control = [Sample - Negative Control]X 100 [Positive - Negative Control] Calculation of MIC values were carried out using the XL fit 20 program after plotting the dose response curves. EXAMPLE 2 The antimicrobial efficacy (MIC values) of agents according 25 to formula 1 and also some agents which do not form part of the invention are as follows: Actinomyces naeslundii Fusobacterium nucleatum Streptococcus sanguis Veilonella Parvula R of Formula 1 • Comparative examples methyl >128 >128 128 128 ethyl >128 >128 >128 >128 propyl >128 128 128 >128 isopropyl >l28 94 128 >128 butyl >128 32.5 128 128 isobutyl >128 42. 7 128 128 benzyl 128 42 128 42 heptyl 42 42 14.2 42 Example according to the invention n-octyl 14 14.2 2.7 42 The agent according to Formula 1 where R is n-octyl can be seen to have a greater antimicrobial efficacy and greater 6 spectrum of activity against oral bacteria than any of the other parabens. EXAMPLE 3 The following is a formulation according to the present invention. It is made by known processes. Ingredient %w/w 15 70% aq.sorbitol Saccharin Polyethylene glycol Titanium dioxide Sodium fluoride 45.0 0.2 2.0 1.0 0.32 9.0 10.0 1.6 Thickening silica Abrasive silica SLS Sodium carboxymethylcellulose 0.8 Flavour 1.0 Zinc citrate trihydrate 0.75 n-Octyl paraben 1.0 Water to 100 We claim 1. Oral composition comprising an alkyl hydroxybenzoate represented by formula 1 Formula 1 : wherein R is a n-octyl; and an antimicrobially effective amount of a divalent metal ion source, wherein the divalent metal is zinc. 2. Composition as claimed in claim 1 and comprising an orally acceptable carrier. 3. Composition as claimed in any preceding claim and selected from the group consisting of pastes, gels, foams, liquids, powders, chewing gums, wherein the composition is suitable for use in dental care. 4. Composition as claimed in any preceding claim, wherein the composition comprises from 0.2 to 5% by weight of the alkyl hydroxybenzoate. Dated this 20 th day of February 2004. Abhishek Sen of S. Majumdar & Co. Applicant's agent

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00129-mumnp-2004-cancelled pages(20-02-2004).pdf

00129-mumnp-2004-claims(granted)-(24-02-2006).doc

00129-mumnp-2004-claims(granted)-(24-02-2006).pdf

00129-mumnp-2004-correspondence(ipo)-(26-08-2008).pdf

00129-mumnp-2004-correspondence1(22-06-2005).pdf

00129-mumnp-2004-correspondence2(15-10-2007).pdf

00129-mumnp-2004-form 13(17-10-2007).pdf

00129-mumnp-2004-form 18(22-06-2005).pdf

00129-mumnp-2004-form 1a(20-02-2004).pdf

00129-mumnp-2004-form 2(granted)-(24-02-2006).doc

00129-mumnp-2004-form 2(granted)-(24-02-2006).pdf

00129-mumnp-2004-form 3(20-02-2004).pdf

00129-mumnp-2004-form 5(13-02-2006).pdf

00129-mumnp-2004-form-pct-ipea-409(20-02-2004).pdf

00129-mumnp-2004-form-pct-isa-210(20-02-2004).pdf

00129-mumnp-2004-others document(15-10-2007).pdf

00129-mumnp-2004-power of attorney(13-02-2006).pdf