WO2007141330A1

WO2007141330A1 - Novel compounds

Info

Publication number: WO2007141330A1
Application number: PCT/EP2007/055654
Authority: WO
Inventors: Eugen Barbu; David Raymond Churchley; Thomas Geoffrey Nevell; Gareth David Rees; John Tsibouklis
Original assignee: Glaxo Group Limited
Priority date: 2006-06-09
Filing date: 2007-06-08
Publication date: 2007-12-13
Also published as: GB0611493D0

Abstract

The present invention relates to a novel polymer, to a process for its preparation, to oral care compositions comprising such polymer and to its use in the prevention, inhibition and treatment of dental erosion, tooth wear, dentine hypersensitivity, anti-staining of dental enamel and anti-adhesion of oral bacteria.

Description

Novel Compounds

Tooth mineral is composed predominantly of calcium hydroxyapatite, Ca_Io(PO₄MOH)₂, which may be partially substituted with anions such as carbonate or fluoride, and cations such Zn and Mg. Tooth mineral may also contain non-apatitic mineral phases such as octacalcium phosphate and calcium carbonate.

Tooth loss may occur as a result of dental caries, which is a multifactorial disease where bacterial acids such as lactic acid produce sub-surface demineralisation that does not fully remineralise, resulting in progressive tissue loss and eventually cavity formation. The presence of a plaque biofilm is a prerequisite, and acidogenic bacteria such as S. mutans may become pathogenic when levels of easily fermentable carbohydrate, such as sucrose, are elevated for extended periods of time.

Even in the absence of disease, loss of dental hard tissues can occur as a result of acid erosion and/or physical wear; these processes are believed to act synergistically. Exposure of the dental hard tissues to acid causes demineralisation, resulting in surface softening and a decrease in mineral density. Under normal physiological conditions, demineralised tissues self-repair through the remineralising effects of saliva. Saliva is supersaturated with respect to calcium and phosphate, and in healthy individuals saliva secretion serves to wash out the acid challenge, and raises the pH so as to alter the equilibrium in favour of mineral deposition.

Dental erosion (i.e. acid erosion or acid wear) is a surface phenomenon that involves demineralisation, and ultimately complete dissolution of the tooth surface by acids that are not of bacterial origin. Most commonly the acid will be of dietary origin, such as citric acid from fruit or carbonated drinks, phosphoric acid from cola drinks and acetic acid such as from vinaigrette. Dental erosion may also be caused by repeated contact with hydrochloric acid (HCl) produced by the stomach, which may enter the oral cavity through an involuntary response such as gastroesophageal reflux, or through an induced response as may be encountered in sufferers of bulimia.

Tooth wear is caused by attrition and/or abrasion. Attrition occurs when tooth surfaces rub against each other, a form of two-body wear. An often dramatic example is that observed in subjects with bruxism, a grinding habit where the applied forces are high, and is characterised by accelerated wear, particularly on the occlusal surfaces. Abrasion occurs as a result of three-body wear and the most common example is that associated with brushing with a toothpaste. In the case of fully mineralised enamel, levels of wear caused by commercially available toothpastes are minimal and of little or no clinical consequence. However, if enamel has been demineralised and softened by exposure to an erosive challenge, the enamel becomes more susceptible to tooth wear. Dentine is much softer than enamel and consequently is more susceptible to wear. Subjects with exposed dentine should avoid the use of highly abrasive toothpastes, such as those based on alumina. Again, softening of dentine by an erosive challenge will increase susceptibility of the tissue to wear.

Dentine is a vital tissue that in vivo is normally covered by enamel or cementum depending on the location i.e. crown versus root respectively. Dentine has a much higher organic content than enamel and its structure is characterised by the presence of fluid-filled tubules that run from the surface of the dentine-enamel junction to the odontoblast/pulp interface. It is widely accepted that the origins of dentine hypersensitivity relate to changes in fluid flow in exposed tubules, the hydrodynamic theory, that result in stimulation of mechanoreceptors thought to be located close to the odontoblast/pulp interface. Not all exposed dentine is sensitive since it is generally covered with a smear layer, an occlusive mixture comprised predominantly of minerals and proteins derived from dentine itself, but also contains organic components from saliva. Over time, the lumen of the tubule may become progressively occluded with mineralised tissue. The formation of reparative dentine in response to trauma or chemical irritation of the pulp is also well documented. Nonetheless, an erosive challenge can remove the smear layer and tubule "plugs" causing outward dentinal fluid flow, making the dentine much more susceptible to external stimuli such as hot, cold and pressure. As previously indicated, an erosive challenge can also make the dentine surface much more susceptible to wear. In addition, dentine hypersensitivity worsens as the diameter of the exposed tubules increases, and since the tubule diameter increases as one proceeds in the direction of the odontoblast/pulp interface, progressive dentine wear can result in an increase in hypersensitivity, especially in cases where dentine wear is rapid.

Loss of the protective enamel layer through erosion and/or acid-mediated wear will expose the underlying dentine, and are therefore primary aetiological factors in the development of dentine hypersensitivity.

It has been claimed that an increased intake of dietary acids, and a move away from formalised meal times, has been accompanied by rise in the incidence of dental erosion, tooth wear and hypersensitivity. In view of this, oral care compositions which help prevent and/or treat dental erosion, tooth wear and hypersensitivity would be advantageous.

WO9616630 claims the use of fluorocarbon-containing coatings to reduce adhesion of bacteria and proteinaceous substances to the surfaces of the oral environment.

US6184339 claims the use of fluorinated monomers and prepolymers for use in combination with particulate fillers as dental composites which may be polymerised in situ by photocuring.

EP0310919 claims the use of adhesive fluoropolymer compositions for bonding and as a composite resin for hard tissue restorations.

None of the aforementioned patents are claimed for use as inhibitors of dietary acid demineralisation, anti-staining or hard tissue erosion. Furthermore, none of the patents consider the potential use of such inventions for preventing or treating dentine hypersensitivity. Surprisingly it has now been found that demineralisation of dental hard tissues by dietary acids and consequent erosion and/or tooth wear may be reduced or prevented by the use of an oral care composition comprising novel comb fluropolymers. Further, the fluropolymers in question have also been shown to reduce dentine permeability in the industry standard hydraulic conductance (Hc) model. This model is a well recognised and accepted model for anti-sensitivity agents whose mode of action is based on tubule occlusion (Outhwaite, W. C, Mc Kennzie, D. M., and Pashley, D. H., (1974), A Versatile Split Chamber Device for Studying Dentine Permeability. Journal of Dental Research, 57, 1503.)

Accordingly, the present invention provides a comb fluoropolymer of formula (I):

(CF₂)_n

R2

(I)

Wherein:

R is H or a C₁ - Ci₀ alkyl group,

R¹ is H or CH₃, R² is trifluoromethyl or branched perfluoroalkyl group, R³ is H or -CH=CH₂, y is an integer between 1 and 1,000,000,000, z is an integer between 0 and 1 ,000,000, n is an integer between 1 and 100, m in an integer between 1 and 100, with the proviso that y + z > 100.

Suitably, polymers prepared in the bulk, in suspension or in solution have typical number- average molecular weights (GPC, polymethyl methacrylate standards) in the range 0.8 ^χ 10⁴ to 1.2 x 10⁵ and polydispersity indexes in the range 1.7 - 12.9. Similarly, materials prepared in emulsion have preferred number-average molecular weights (GPC, polymethyl methacrylate standards) in the range 0.7 x 10⁶ to 1.0 ^χ 10⁶ and polydispersity indexes in the range 1.7 - 2.3.

Suitably n is from 1 to 20, more suitably 6 to 12.

Suitably m is from 1 to 10, more suitably 1 to 3.

Suitably the ratio of y to z ranges from 1 :10 to 10: 1, suitably 1 :5 to 5: 1 and more suitably from 1 :2 to 2: 1.

More suitably fluoropolymers polymers are: PPFDA - poly(perfluorodecyl acrylate); PPFDMA - poly(perfluorodecyl methacrylate); PNFBEA - poly(nonafluorobutylethyl acrylate), and 2/1 A (2:1 copolymer of IH, IH, 2¹H 2 'H-perfluorodecyl acrylate and 2- hydroxyethyl acrylate).

Fluoropolymers of the present invention may be synthesised by the radical-induced, chain- growth polymerisation reaction of the appropriate monomer or mixture of monomers to yield the corresponding homopolymer or copolymer. Dependant upon the demands of the preferred formulation system and within the reactivity limitations of each monomer type, such reactions may be carried out in the bulk, in solution, in suspension or in an emulsion. Suitably the polymers of the present invention are nanoparticles with a size range of from about 1 to 999nm, more suitably 10 to 500nm and most suitably 80 to lOOnm.

Further the polymers of the present invention are suitably prepared as aqueous suspensions. More suitably the polymers of the present invention are prepared as an aqueous nano-suspension by emulsion polymerisation.

In a further aspect of the present invention there is provided an oral care composition for the reduction or prevention of dental erosion, tooth wear and dentine hypersensitivity comprising a comb fluropolymer of formula (I).

Compositions of the present invention comprise from 0.01 - 90% w/w of fluoropolymer, more suitably 0.1 to 10% w/w. Preferably the fluoropolymer is present in the composition as an aqueous nanosuspension with a particle size in the range of 1 to 999nm.

Compositions of the present invention have also been found to be useful in anti-staining of dental enamel and in anti-adhesion of oral bacteria to dental tissue.

Preferably compositions of the present invention will further comprise a source of soluble fluoride ions such as those provided by sodium fluoride, sodium monofluorophosphate, tin (II) fluoride or an amine fluoride in an amount to provide from 25 to 3500 ppm fluoride, preferably from 100 to 1500 ppm.

Compositions of the present invention will contain appropriate formulating agents such as abrasives, surfactants, thickening agents, humectants, flavouring agents, sweetening agents, opacifying or colouring agents, preservatives and water, selected from those conventionally used in the oral care composition art for such purposes. Examples of such agents are as described in EP 929287.

Additional oral care actives may also be included in the compositions of the present invention. The oral compositions of the present invention are typically formulated in the form of toothpastes, sprays, mouthwashes, gels, lozenges, chewing gums, tablets, pastilles, instant powders, oral strips and buccal patches.

As fluoropolymers exert their effect via a passive occlusion mechanism, the efficacy of oral care compositions containing fluoropolymers of the present invention to prevent and/or treat dentine hypersensitivity may be further enhanced by inclusion of a nerve- desensitising potassium salt such as potassium citrate, potassium chloride, potassium bicarbonate, potassium gluconate and especially potassium nitrate. The compositions of the present invention may also contain additional occlusion agents whose mode of action involves reaction in situ such as strontium salts of chloride, acetate or nitrate. Additional passive occlusion agents that may be incorporated into the compositions of the present invention include silicas, titanium oxide and organic thickening systems such as cellulose polymers, guar gum and polyacrylic acid.

The compositions according to the present invention may be prepared by admixing the ingredients in the appropriate relative amount in any order that is convenient and thereafter, and if necessary, adjustment of the pH to the desired value.

In a still further aspect the present invention provides a method of combating dental erosion and/or tooth wear and preventing or treating dentine hypersensitivity which comprises applying an effective amount of a composition comprising a fluoropolymer as herein before described to an individual in need thereof. Additionally, such a composition has benefit in treating caries.

The invention will now be illustrated by way of the following non-limiting examples.

Example 1

Preparation of homopolymers

To IH, IH, 2 H, 2 H-perfluorodecyl acrylate (inhibitor-free; 15.0 g, 28.9 mmol) in perfluorodecalin (2.68 g; 5.80 mmol) was added sodium dodecyl sulphate (SDS) (750 mg) in deionised water (DI) (85 g). The resultant mixture was sonicated (0 ⁰C, 40 min) to form an emulsion. This was transferred to a 5-necked reaction vessel equipped with an overhead stirrer, double-walled condenser, nitrogen inlet and dropping funnel and was degassed by nitrogen purge (2 h). Following the addition of potassium persulphate (150 mg in 2.5 ml of water), the mixture was heated (80 ⁰C) and stirred (600 rpm) for 24 h to give a polymeric mini-emulsion, which was allowed to cool to room temperature under constant stirring. The polymer particles were separated by centrifugation (40,000 rpm), followed by the removal of SDS by repeated washes with water, and then by the Soxhlet extraction (petroleum ether 40 - 60 ⁰C) of perfluorodecalin. The isolated polymer was dried to constant weight (4O⁰C, vacuum).

Mini-emulsions were also prepared with 7H,7H,2H,2H-perfluorodecyl methacrylate, 7H₎7H,2H,2H-perfluorohexyl acrylate and 7H7H-perfluorobutyl acrylate.

Example 2 Preparation of copolymers

Inhibitor- free 7H 7H,2H,2H-perfluoroalkyl acrylates or methacrylates and 2-hydroxyethyl acrylate or methacrylate, in molar ratios in the range 5 : 1 to 1 : 5, were placed in a series of quickfit test tubes. Propan-2-ol was added to each tube (1 g of monomer to 2 ml of freshly distilled propan-2-ol) along with 1,1-azobiscyclohexanecarbonitrile (1 %w/w of monomer). After freeze-thaw degassing, the tubes were placed in an oil bath (70 ⁰C, 72 h) and, following the removal of propan-2-ol by rotary evaporation, the isolated polymeric products were purified by Soxhlet extraction (methanol or diethyl ether) and dried in vacuo (0.5 mbar, 8 h, room temperature).

Example 3.

Inhibition of acid demineralisation by fluoropolymer compositions

Ηydroxyapatite (HA) -coated microtitre plates were prepared by suspending, with stirring,

HA powder (2.0 g) in acetone (200 ml). Aliquots (60 μl) of the homogenous suspension were transferred into a 96 well polystyrene microtitre plate, and then placed on an orbital shaker operating at 50 rpm (room temperature). After evaporation of the acetone, loosely bonded HA was removed by rinsing the plates with DI (x5). The coated microplates were dried overnight and sealed until required. Prior to use, the HA plates were hydrated in DI for 60 min. Aqueous suspensions of the polymer under test (1.0 % w/v; 200 μl) were added to each well and the plate transferred to an orbital shaker (50 rpm) at room temperature for 30 min. Sodium fluoride (300 μg ml^"1 fluoride ion) and deionised water were employed as the positive and negative controls respectively. After exposure to the treatments, the plates were rinsed (x5) with DI and 0.10 M aqueous acetate buffer (200 μl, pH 4.0) was added to each well, as an erosive challenge. The microplate was repositioned on the orbital shaker for a further 60 min. Thereafter, aliquots (50 μl) were removed from each well into a new microplate plate containing vanadomolybdate reagent (50 μl per well). After a further 5 min, phosphate release was determined by measuring the absorbance at 450nm using a 96 well plate reader (Wallac Victor 1420 Multilabel Counter).

Codes: PPFDA - poly(perfluorodecyl acrylate); PPFDMA - poly(perfluorodecyl methacrylate); PNFBEA - poly(nonafluorobutylethyl acrylate); 2/1 A (2:1 copolymer of lH,lH,2H,2H-perf[uorodecyl acrylate and 2-hydroxy ethyl acrylate).

Water NaF PPFDA PPFDMA PNFBEA 2/1A

Treatment

Figure 1. Inhibition of HA demineralisation by selected fluoropolymers tested as aqueous dispersions at 0.50% w/v. The magnitude Of A₄₅₀ is directly related to the concentration of released phosphate determined using a vanadomolybdate reagent. DI and 300 μg ml^"1 fluoride were included as the negative and positive controls respectively. Example 4.

Reduction in Dentine Permeability

Caries-free human third molars were extracted from patients who had given informed consent. Dentine discs were prepared by sectioning the tooth parallel to the occlusal surface below the crown and above the root canal. Dentine discs were stored in 0.90 % saline until required. To remove the smear layer formed during cutting and expose the dentinal tubules, the dentine discs were etched in aqueous EDTA (0.50 M) for two minutes. Hydraulic conductance (Hc) experiments were performed using a Pashley flow apparatus according to established procedures [1,2].

PPFDMA, PNFBEA and 2/1 A were selected for screening in the Hc model. The disodium salt of octadecene-cø-1-maleic acid (PA- 18) is a tubule occlusion agent that is used commercially in a number of anti-sensitivity toothpastes. Aqueous dispersions (1.0 % w/w) of the polymers were applied to dentine specimens by brushing, and the Pashley flow apparatus was used to determine permeability to simulated dentinal fluid; the permeability of the uncoated, but pellicilised, dentinal specimen provided the baseline value for each measurement.

PA-18 PPFDMA PNFBEA 2/1 A

Polymer

Figure 2. Reduction in dentine permeability to simulated dentinal fluid following treatment of specimens with selected fluoropolymers and with the PA-18 positive control. The data, summarised in Figure 2, show that all three fluoropolymer coatings effect a reduction in dentinal permeability. The copolymer 2/1 A, which reduced dentinal permeability by 54%, exhibited a statistically superior occlusion capacity than that achieved with PDFDMA or with PNFBEA (p<0.05); its performance was not statistically different from that of PA- 18, the positive control, which was found to reduce dentinal permeability by 62%.

References

1. Pashley D, Matthews W, Zhang Y, Johnson M. Fluid shifts across human dentine in vitro in response to hydrodynamic stimuli. Archs Oral Biol 1996; 41: 1065-72.

2. Pashley D, Matthews W. The effect of outward forced connective flow on inward diffusion in human dentine in vitro. Archs Oral Biol 1993; 38: 577-582.

Claims

1. A comb fluoropolymer of formula (I):

(CF₂)_n

R²

(I)

Wherein:

R is H or a Ci - Ci₀ alkyl group,

R¹ is H or CH₃, R² is trifluoromethyl or branched perfluoroalkyl group,

R³ is H or -CH=CH₂, y is an integer between 1 and 1,000,000,000, z is an integer between 0 and 1,000,000, n is an integer between 1 and 100, m in an integer between 1 and 100, with the proviso that y + z > 100.

2. A polymer as claimed in claim 1 wherein n is from 1 to 20.

3. A polymer as claimed in claim 1 wherein m is from 1 to 10

4. A polymer as claimed in any one of claims 1 to 3 wherein the ratio of z to y is in the range from 1 : 10 to 10:1.

5. A polymer as claimed in any one of claims 1 to 3 selected from poly(perfluorodecyl acrylate), poly(perfluorodecyl methacrylate), poly(nonafluorobutylethyl acrylate) or 2/1 A (2:1 copolymer of 1H,1H,2H,2H- perfluorodecyl acrylate and 2-hydroxyethyl acrylate).

6. A process for the preparation of a polymer according to any one of the proceeding claims comprising reacting the appropriate monomer or mixture thereof in solution, in suspension or in an emulsion.

7. An oral care composition comprising a polymer according to any one of claims 1 to 5 and an orally acceptable carrier or excipient.

8. An oral care composition as claimed in claim 7 wherein the polymer is present in an amount from 0.01 to 90% w/w.

9. An oral care composition as claimed in claim 7 or 8 wherein the polymer is present as an aqueous nano suspension with a particle size in the range of 1 to 999nm.

10. Use of a polymer as claimed in any one of claims 1 to 5 in the manufacture of an oral care composition for combating dental erosion and/or tooth wear and preventing or treating dentine hypersensitivity.

11. Use of a polymer as claimed in any one of claims 1 to 5 in the manufacture of an oral care compositon for anti-staining of dental enamel and in anti-adhesion of oral bacteria to dental tissue.

12. A method of combating dental erosion and/or tooth wear and preventing or treating dentine hypersensitivity which comprises applying an effective amount of a composition comprising a fluoropolymer as herein before described to an individual in need thereof.