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Composition 1 he present invention relates to oral hygiene compositions for use in the prophylaxis and/or treatment of halitosis, periodontal disease and related disorders.
The term"periodontal disease"includes any inflammatory disease of the periodontium (tooth-surrounding tissue). Related disorders affecting the gingiva are also included herein.
Periodontal disease is the major cause of tooth loss in adults and results from the accumulation of dental plaque in the gingival sulcus leading to crevice or pocket formation between teeth and gums. It is generally believed to be mediated by a complex interaction between the host immune system and specific oral microbial pathogens. The microflora of the periodontal pocket and of the anaerobic pit of the tongue is diverse and complex and comprises mainly gram-negative obligate
anaerobes and various spirochaetes. Of these Porphyromonas gingivalis, Prevotella intermedia, Bacteroides forsythus, Treponema denticola, Wollinella recta and Fusobacterium nucleatum are regarded as being important in the etiology of periodontal disease. Such anaerobes are also implicated in the development of halitosis.
The ability of such organisms to survive in the periodontal pocket is dependent, in part, on the existence of a low reduction potential (Eh). The Eh is a measure of the oxidizing or reducing power of a system. The more positive the Eh, the more oxidizing the system; the more negative the Eh, the more reducing the system. The oral cavity has a diverse range of reduction potenual values; a clear. tooth surface which has a ready supply of molecular oxygen may have a value of around +200mV, the gingival crevice may have values in the region of +70mV and the periodontal pocket, which may be rich in reduced bacterial metabolites but low in molecular oxygen may have a value as low as-300m V.
Current methods of treating halitosis, periodontal disease and related disorders have involved the physical removal of plaque from the gingival crevice with possible adjunctive use of antiseptics and antibacterials. This approach is deemed both labour intensive and time consuming. Furthermore the use of
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antibiotics and antiseptics is inadvisable, ince they generally lead to the development of a resistant microflora.
Molecular oxygen-supplying substances, such as chromic acid, sodium perborate, zinc peroxide and hydrogen peroxide have also been used. Of the oxygen-supplying substances only hydrogen peroxide remains in clinical use.
Whilst this peroxide has some antimicrobial activity, adversely it is known to cause tissue injury and to delay wound healing.
An alternative approach to such treatments is to change the microbial environment to such an extent that the microganisms located therein are unable to survive. One way of achieving this is may be to raise the Eh of the periodontal pocket through the local application of redox compounds (in their oxidized states).
US Patent 5087451 describes the topical administration of electron acceptors to raise the reduction potential of the gingival sulcus or crevice or periodontal pocket in order to treat periodontal disease and related disorders. Electron acceptors or compounds having reduction potentials well above that prevailing in the diseased site are said to inhibit growth of the anearobic pathogens responsible for the disease.
Thus redox organic dyes in the oxidised form such as methylene blue and patent blue V having reduction potentials of + 1 lmV and +750mV are preferred whilst indigo carmine which has a much lower redox potential, minus 125mV, is said not to be suitable.
The activity of certain antibacterial nitro-compounds against Bacteroides fragilis has been shown to be related to their electron affinity values (Reynolds, A. V., Journal of Antimicrobial Chemotherapy. 1981 :, 91-99). It was concluded in that study that nitro-compounds having in particular low electron affinities, ie negative reduction potentials between minus 460 and minus 500mV, had the greatest antibacterial activity against B. Fragilis. This finding was contrasted with other data suggesting that the activity of nitro-compounds against E. coli shows the reverse correlation ie compounds with more positive reduction potentials having the highest activity against E. coli.
Contrary to the teaching of US 5087451 it has now been discovered surprisingly that electron acceptors having reduction potentials lower than minus185mV can be used to combat the effects of P. gingivalis in halitosis and/or periodontal disease and related disorders.
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Accordingly the present invention provides an oral hygiene composition comprising an orally acceptable electron acceptor having a reduco. potential less than minus 185mV and an orally acceptable carrier or excipient. Suitably the electron acceptor has a reduction potential greater than minus 550mV. Preferably the electron acceptor has a reduction potential greater than minus 460mV and even more preferably the electron acceptor has a reduction potential greater than minus 300mV.
Suitable electron acceptors of the present invention include nitro-containing antibacterial compounds. Representative examples of these are disclosed in the hereinbefore described Reynolds paper and include nitrofuran and nitroimidazole compounds. Suitable nitrofuran compounds include nitrofurantoin and nitrofurazone. Suitable nitroimidazole compounds include benznidazole, nimorazole, tinidazole and metronidazole. Nitrofurantoin is the preferred electron acceptor. Nitrofurantoin is an orally-administered nitrofuran derivative, conventionally used as an antibiotic in the treatment of uncomplicated lower urinary tract infections.
When administered topically such nitro-containing antibacterial compounds have the ability to kill P. gingivalis through a combined antibacterial and redoxmediated effect. Thus lower quantities of nitro-containing antibacterials can be administered due to the enhanced killing power caused by the redox-mediated effects of topically applied compositions.
Suitably the electron acceptors present of the compositions are present in an amount appropriate to prote an effective dose, and this will depend on the pharmacological properties of the compound employed. Normally a single dose used to treat an adult human will provide from about 0.0001 to 1 %, generally 0.001 to 0. 1 % w/w of the composition of the electron acceptor. For example a suitable single dose of nitrofurantoin lies in the range 0.002mg to 2. Omg.
Preferably compositions of the present invention comprise a topically retainable carrier so as to prolong the residence time of the electron acceptor at the diseased site in particular in the gingival sulcus or crevice or in the periodontal pocket. In prolonging the residence period at the site of action, it is ensured that the electron acceptor is given sufficient opportunity in which to act against the offending microorganism.
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Topically retainable carriers suitable for use in the present invention include bioadhesive agents. Bioadhesive materials have e eived considerable attention as platforms for controlled drug delivery. They can be targeted to specific drug administration sites, prolong residence time and ensure optimal contact with the contact surface. Many different types of bioadhesive materials both natural and synthetic can be used in the design of controlled drug delivery systems. Natural materials include chitosan, xanthan gum, sodium alginate/alginic acid, gelatin, zein, guar gum, carrageenan, gum acacia and gum karaya. Synthetic materials include polymers of acrylic acid or acrylic acid derivatives eg carbopol and polycarbophil.
Cellulose derivatives which are bioadhesives include sodium carboxymethylcellulose, hydroxymethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC) and methyl cellulose. Other bioadhesive polymers include poly (ethylene oxide) (PEO), polyvinylpyrrolidone (PVP), polyvinylalcohol (PVA) and polyvinylpyrrolidone/maleic anhydride copolymers.
Suitably the bioadhesive agent is present in an amount ranging from 0.01 to 30%, preferably 0.1 to 15%, more preferably 1 to 5% by weight of the composition.
Suitable oral hygiene compositions of the present invention include conventional presentations such as dentifrices, gels, mouthwashes, gargles irrigating solutions and presentations for sucking or chewing such as gums pastilles and lozenges. Preferably such compositions are in the form of a gel or solid matrix which can be applied directly to the gingival sulcus or crevice or periodontal pocket.
Examples of olid matrices are described in US Patent 5087451 and include plasters strips or microspheres.
Compositions of the present invention will contain appropriate formulating agents such as abrasives, surfactants, humectants, thickening agents, flavouring agents, sweetening agents, pacifying or colouring agents, preservatives and water, selected from those conventionally used in the oral hygiene composition art for such purposes and which are compatible with the electron acceptor and the topically retainable carrier.
Suitable surfactants for use in compositions according to the present invention include, for instance, anionic, nonionic, cationic and amphoteric surfactants or mixtures thereof.
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Suitable anionic surfactants include alkali metal (Ci2-l8) alkyl sulphates, for instance sodium lauryl sulphate, ar ; 'acyl sarcosinates and N-acyl taurines in which the acyl moiety has from 12 to 16 carbon atoms, for instance, N-lauroyl, Nmyristoyl and N-palmitoyl sarcosine alkali metal salts.
Suitable nonionic surfactants include, for example, alkylpolyglucosides for instance the products marketed under the trade name'Plantacare'by Henkel, polyethoxylated sorbitol esters, in particular polyethoxylated sorbitol monoesters, for instance, PEG (40) sorbitan di-isostearate, and the products marketed under the trade name'Tween'by ICI; polycondensates of ethylene oxide and propylene oxide (poloxamers), for instance the products marketed under the trade name'Pluronic' by BASF-Wyandotte; condensates of propylene glycol; polyethoxylated hydrogenated castor oil, for instance, cremophors; and sorbitan fatty esters.
Suitable amphoteric surfactants include, for example, long chain imidazoline derivatives such as the product marketed under the trade name'Miranol C2M'by Miranol; long chain alkyl betaines, such as the product marketed under the tradename'Empigen BB'by Albright + Wilson, and long chain alkyl amidoalkyl betaines, such as cocamidopropylbetaine, and mixtures thereof.
Suitable cationic surfactants include the D, L-2-pyrrolidone-5-carboxylic acid salt of ethyl-N-cocoyl-L-arginate, marketed under the trade name CAE by Ajinomoto Co. Inc. , and cocamidopropyl PG dimonium chloride phosphate and lauramidopropyl PG dimonium chloride phosphate, available under the trade names Monaquat PTC and Monaquat PTL, respectively, from Mona Corporation.
Advantageously, the surfactant is present in the range 0.005 to 20%, preferably 0. 1 to 10%, more preferably 0.1 to 5% by weight of the total composition.
Suitable thickening agents for gel or dentifrice formulations include, for instance, nonionic thickening agents such as, for example, (Cl-6) alkylcellulose ethers, for instance methylcellulose; hydroxy (C) alkylcellulose ethers, for instance hydroxyethylcellulose and hydroxypropylcellulose ; (C2-6) alkylen oxide modified (C1-6) alkylcellulose ethers, for instance hydroxypropyl methylcellulose ; and mixtures thereof. Other thickening agents such as natural and synthetic gums or gum like material such as Irish Moss, xanthan gum, gum tragacanth, sodium carboxymethylcellulose, polyvinyl pyrrolidone, starch and thickening silicas may
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also be used. Preferably the thickening agent is xanthan gum It will be appreciated that certain thickening al ; nts may also function as a bioadhesive agent.
Advantageously the thickening agent is present in the range 0.01 to 30%, preferably 0.1 to 15 %, more preferably 1 to 5 %, by weight of the total composition.
Suitable humectants for use in compositions of the invention include for instance, glycerine, xylitol, sorbitol, propylene glycol or polyethylene glycol, or mixtures thereof; which humectant may be present in the range from 5 to 30%, preferably 5 to 20%, more preferably 5 to 15% by weight of the total composition.
Suitable abrasives for use in dentifrice compositions of the present invention include calcium carbonate, calcium phosphates, calcium pyrophosphate, insoluble sodium metaphosphate, sodium aluminosilicate, alumina, hydrated alumina, zinc orthophosphate, plastic particles, and silica, of which silica is the preferred abrasive.
Suitable silicas include natural amorphous silicas, such as, for instance, diatomaceous earth, and synthetic amorphous silicas, such as precipitated silicas and silica gels, including silica xerogels. Suitable silica xerogels are described in US 3,538, 230. Suitable grades of precipitated silicas have BET surface areas in the range 20 to 300, preferably 20 to 100 m2/g and median agglomerate sizes in the range 2 to 50, preferably 5 to 30m.
Suitable precipitated silicas and silica xerogels are those marketed under the trade names Sident and Syloblanc, by Degussa and W R Grace Corporation Davison Chemical Division, respectively. Advantageously, the silica is a"low anion"silica. As used herein, the term"low-anion"silicas refers to those : which anionic impurities such as sodium sulphate and sodium silicate which normally arise during the course of the manufacturing process are kept to a minimum, through careful control of the manufacturing process."Low anion"silicas suitably have less than 1%, preferably less than 0. 5% advantageously less than 0. 25% by weight of anionic impurities. Suitable such"low anion"silicas are described in EP 0 368 130 (Procter & Gamble), EP 0 315 503 and EP 0 396 459 (Rhone-Poulenc) and WO 90/05113 (J. M. Huber Corp). Alternatively, grades of commercially available silica with ionic impurities may be rendered suitable by washing thereof with deionised water. Conductivity measurements on the water after washing may be used to monitor the efficacy of such washing. Suitably the conductivity of the water after
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washing is reduced to less than 200IlSiemens/cm. Suitable"low anion"silicas include ric", rade RP93 available from Rhone-Poulenc.
Suitably, dentifrice compositions will have from 5 to 80%, preferably from 10 to 60% by weight of the abrasive.
Compositions according to the present invention will have a pH which is orally acceptable, typically ranging from about pH 4 to 10, e. g. 5. 5 to 8.
Compositions according to the present invention may be prepared by admixing the ingredients in the appropriate relative amounts in any order that is convenient and thereafter and if necessary adjusting the pH to give the final desired value.
The present invention provides for the use of the electron acceptors as hereinbefore identified in the manufacture of a topically retainable composition for the prophylaxis and therapeutic treatment of halitosis, periodontal disease and related disorders.
The invention will now be illustrated by the following examples :
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Example 1: Gel formulation (pH 5.6) w/w (%) Nitrofurantoin 0.0024 Hydroxypropylcellulose 2.5 Ethanol 4 Sodium Acetate 0.7 Glacial acetic acid 0.0313 Water to 100 Example 2: Mouthwash formulation (pH 5.6) w/w (%) Nitrofurantoin 0.0024 Ethanol 15 Sodium Acetate 0.7 Glacial acetic acid 0.0313 Poloxamer surfactant 0.5 Flavours 0.1 Water to 100 Example 3: Effect of Nitro-containing Elec@ on Acceptors on the Reduction Potential and Survival of Broth Cultures of P. gingivalis W50Test compounds were prepared as 0.3 M stock solutions using dimethyl sulphoxide (DMSO) as solvent.
In an anaerobic cabinet at 37 C, 2ml of a culture of P. gingivalis, grown anaerobically for 48 hours in Wilkins-Chalgrin (WC) Broth supplemented with 5 g/ml haemin and 0. 5J.. lg/ml menadione, was added to 2ml of pre-reduced (48 hours) WC Broth supplemented with 5g/ml haemin and 0. 5 g/ml menadione.
In duplicate, 40 ul of each test compound stock solution was added to the above prepared culture to give a final concentration of 3. 0mM and then incubated
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anaerobically at 37 C for un to 48 hours. Either deionised water or 1 % DMSO (final concentration) were used as controls. Samples were taken for vbi"counting and reduction potential measurements were determined at set time points.
Viable counts was determined by performing serial dilutions of culture down to 10-8 by transferring 1001l1 volumes sequentially into 4 x 9ml volumes of PBS.
Miles and Misra counts were carried out on blood agar and incubated for 48 hours.
Reduction potential values were taken 5 minutes after the electrode was placed into the incubation solution to allow for reading to steady. The pH reading was converted to mV using the following equation: mV= 2.303*8. 3144*D*7-A*1000/96485 A = pH reading on display and D = absolute temperature measured in K (i. e. measured temp + 273)The following results were obtained:
Agent Reduction Potential mV CFU/rnl (Time (h) ) 0 3 24 0 3 24 Nitrofurazone-171-267-266 3. 0x107 7. 2x10' < 5000 Nitrofurantoin -176 -212 -193 6. 4x108 < 5000 < 5000 Tinidazole-180-252-252 1. 2x105 < 5000 < 5000 DMSO (control)-154-314-307 6. 5x108 8. 3x108 1. 0x109
The Eh of the P. gingivalis culture immediately following the addition of DMSO (control) was-154mV. This dropped to-314 mV after 3 hours and then measured -307mV 1fter 24 hours. Viable counts steadily increased gradually over 24 hours to give counts of 6. 5xlO'cfu/ml, 8. 3xlOcfu/ml and l. 0x109 cfu/ml at zero, 3 and 24 hours respectively.
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The results indicate that the test compounds increase the reduction potential when compared with the control agent (DMSO). In add :., and contrary to the results observed in the control experiments, cell counts were reduced significantly to undetectable levels over the period of 3-24 hrs in the cultures containing the test compounds.
The results confirm that the test compounds are highly effective against P. gingivalis, implicated in various oral health diseases including halitosis and/or periodontal disease and related disorders. Therefore these compounds can be expected to be of use in the topical treatment of such disorders.