WO2018010962A1

WO2018010962A1 - Oral care composition comprising composite particles containing cationic germicide

Info

Publication number: WO2018010962A1
Application number: PCT/EP2017/066089
Authority: WO
Inventors: Somnath Das; Amitava Pramanik
Original assignee: Unilever N.V.; Unilever Plc; Conopco, Inc., D/B/A Unilever
Priority date: 2016-07-14
Filing date: 2017-06-29
Publication date: 2018-01-18
Also published as: BR112019000655A2; CN109475473A; EP3484435A1

Abstract

The invention relates to an oral care composition comprising composite particles, said particles containing: · a water-insoluble inorganic component having the formula Ca_n(X)_x(AO_y)_z;, wherein: X is selected from OH, F and Cl; A is selected from C, P, Si and combinations thereof; n = 1 to 5; x = 0 or 1; y = 3 or4; z =1 to 3; and · cationic germicide, wherein said particles are flaky shaped, having a thickness of 15 to 80 nm. The oral care composition prevents the formation of biofilm, aids remineralization of damaged enamel, provides prolonged teeth whitening as well as prolonged, residual antimicrobial activity.

Description

ORAL CARE COMPOSITION COMPRISING COMPOSITE PARTICLES

CONTAINING CATIONIC GERMICIDE

Technical field of the invention

The present invention relates to an oral care composition comprising composite particles, said particles containing a water-insoluble inorganic component, such as hydroxyapatite, and a cationic germicide, such as cetylpyridinium chloride.

The oral care composition of the present invention prevents the formation of biofilm, aids remineralization of damaged enamel and provides prolonged teeth whitening. Furthermore, the oral care composition provides prolonged, residual antimicrobial activity.

Background of the invention

Therapies for treating oral disease are primarily directed to active plaques, i.e., bacterial deposits on the surface of a tooth. Such therapies primarily rely on patient self-care, which typically consists of tooth brushing and interstitial hygiene using either dental floss or a toothpick.

Toothpaste is used to promote oral hygiene: it serves as an abrasive that aids in removing the dental plaque and food from the teeth, assists in suppressing halitosis, and delivers active ingredients (most commonly fluoride) to help prevent tooth decay (dental caries) and gum disease (gingivitis). Abrasives constitute at least 50% of a typical toothpaste. Representative abrasives include particles of aluminum hydroxide (AI(OH)3), calcium carbonate (CaCOs), various calcium hydrogen phosphates, various silicas and zeolites, and hydroxyapatite (Ca5(P04)30H).

Antiseptic agents have been used to inhibit the formation of dental plaque. Cetyl pyridinium chloride and chlorhexidine, for example, are cationic germicides used for such purposes. Dental hygiene and denture preparations typically contain anti-plaque and/or anti-tartar agents, as well as antimicrobial agents. Antimicrobial action may only briefly affect the formation of plaque by either reducing the colony number of bacteria in the

mouth/dentures or by killing bacteria trapped in film. There is accordingly a need for oral compositions and methods that have prolonged, residual antimicrobial activity.

US 2012/0251981 describes a method for preventing or treating periodontal disease, comprising:

• providing an antimicrobial composition disposed within a reservoir fluidly connected to an exterior surface of an applicator, said applicator having a frictional stress value sufficient to cause mechanical displacement of a biofilm present on a surface of the tooth, or said applicator comprising pores having a diameter of 0.1-1000 μηη, or both;

• dispensing said antimicrobial composition through said applicator onto said exterior surface of said applicator; and

• applying the antimicrobial composition to an oral cavity surface.

The antimicrobial composition can include hydroxyapatite having a particle size ranging from 10-200 nm. The antimicrobial composition can also contain one or more of:

fluoride, triclosan, sodium bicarbonate, sweetening agent, detergent, chlorhexidine, cetylpyridinium, stannous fluoride and an amine fluoride.

Soriano de Souza et al. (Adsorption of chlorhexidine on synthetic hydroxyapatite and in vitro biological activity, Colloids and Surfaces B: Biointerfaces 87 (201 1 ) 310-318) describes adsorption of chlorhexidine on synthetic hydroxyapatite (HA). Tubes containing 100 mg of HA sintered at 1 100 °C were incubated with aqueous

chlorhexidine digluconate (CHX) solution. After incubation time, the solid was centrifuged. The HA/CHX inhibited Enterococcus faecalis growth for up to 6 days, revealing that binding to HA did not affect antimicrobial activity of CHX and reduced bacterial adhesion. According to the authors these results suggest that HA/CHX association could result in a potential adjuvant antimicrobial system for clinical use. Cheng et al. (Antibacterial and physical properties of calcium-phosphate and calcium- fluoride nanocomposites with chlorhexidine, Dental Materials 28 (2012) 573-583) describes the antibacterial properties of calcium-phosphate nanocomposites with chlorhexidine (CHX). CHX was frozen via liquid nitrogen and ground to obtain a particle size of 0.62 microns. A nanocomposite was fabricated with amorphous calcium phosphate (ACP) + 10% CHX. Adding CHX fillers to ACP was found to greatly increase the antimicrobial capability. Nanocomposites with CHX reduced the biofilm metabolic activity by 10-20 folds and reduced the acid production, compared to the controls. WO 2007/137606 describes biologically active nanoparticles of a carbonate-substituted non-stoichiometric hydroxyapatite, having a crystallinity degree lower than 40% a length (L) from 20-200 nm, a width (W) of 5-30 nm and an aspect ratio (L/W) of 2 to 40. These nanoparticles preferably have a flattened acicular shape which is most adapted to interact with the dentine and enamel surface (page 6, lines 1 -2). The nanoparticles may contain an effective amount of an antibacterial metal ion, wherein the metal is preferably selected from Zn, Cu and Ag (page 10, lines 1 -14).

Korean patent application KR 1020030016539 relates to toothpaste compositions containing granules of inorganic water-insoluble material that have been coated with cetylpyridinium chloride. These granules have a particle size in the range of 100 to 750 μηη. The examples of the Korean patent application describe the preparation of such granules by coating silica particles with a coating solution that contains cetylpyridinium chloride and water-soluble polymer. US2003/175217 A1 (Kropf Christian) discloses thixotropic oral and dental care agents containing one or more nano particulate inorganic compounds selected from the group consisting of metal oxides, metal oxide hydrates, metal hydroxides, metal carbonates, metal phosphates and of metal silicates. Amongst all other usual ingredients, reference is made to the inclusion of antibacterial, plaque-inhibiting substances like chlorhexidine and triclosan.

EP2810917 A1 (UAB Moksliniu Lab, 2014) discloses a method to prepare calcium hydroxyapatite nano crystals of the desired morphology intended for the treatment of skeletal disorders. US4273759 A (Colgate Palmolive, 1981 ) discloses antibacterial oral compositions containing an antibacterial antiplaque agent such as cetyl pyridinium chloride and an peroxy diphosphate salt for reducing the staining of dental surfaces without substantially diminishing the antibacterial and antiplaque activity of the agent.

VISWANATH B ET AL: "Controlled synthesis of plate-shaped

hydroxyapatite and implications for the morphology of the apatite phase

in the bone", BIOMATERIALS, ELSEVIER SCIENCE PUBLISHERS BV., BARKING, GB, vol. 29, no. 36, 1 December 2008 (2008-12-01 ), pages 4855-4863, discloses a general methodology for predicting the conditions for the formation of plate-shaped structures by precipitation. It also discloses several applications of such materials.

NORBERTO ROVERI ET AL: "Surface Enamel Remineralization: Biomimetic Apatite Nanocrystals and Fluoride Ions Different Effects", JOURNAL OF NANOMATERIALS, vol. 2, no. 2, January 2009 (2009-01 -01 ), pages 1 149-9, discloses a method for altered enamel surface remineralization by carbonate-hydroxyapatite nanocrystals which mimic the composition, structure, nanodimensions, and morphology of dentine apatite crystals and resemble closely natural apatite chemical-physical properties. NORBERTO ROVERI ET AL: "Evolving application of biomimetic

nanostructured hydroxyapatite", NANOTECHNOLOGY, SCIENCE AND

APPLICATIONS, 1 November, 2010 (2010-1 1 -01 ), page 107, discloses the

applications of biomimetic synthetic calcium phosphates, details the main

characteristics of bone and tooth, where the calcium phosphates are present, and discusses the chemical-physical characteristics of biomimetic calcium phosphates, methods of synthesizing them, and some of their biomedical applications.

Summary of the invention The inventors have developed an oral care composition that prevents the formation of biofilm, aids remineralization of damaged enamel, provides prolonged teeth whitening as well as prolonged, residual antimicrobial activity. The oral care composition of the present invention comprises composite particles that contain a water-soluble inorganic compound in combination with a cationic germicide, have a flaky shape and a thickness of 15-80 nm. More particularly, the oral care composition comprises composite particles containing:

· a water-insoluble inorganic component having the formula Ca_n(X)x(AOy)_Z;,

wherein:

X is selected from OH, F and CI;

A is selected from C, P, Si and combinations thereof;

n = 1 to 5;

x = 0 or 1 ;

y = 3 or4;

z =1 to 3; and

• cationic germicide,

wherein said particles are flaky shaped, having a thickness of 30 to 50 nm.

Examples of water-insoluble inorganic components that can be applied in the oral care composition include hydroxyapatite, fluorapatite, chlorapatite, calcium carbonate and calcium silicate. Examples of cationic germicides that can be used include

cetyl pyridinium halides and chlorhexidine.

Although the inventors do not wish to be bound by theory, it is believed that the aforementioned composite particles are deposited into the teeth crevices, thereby replenishing lost enamel and brightening the teeth (whitening). Additional benefits are realized by the slow release of cationic germicide from the deposited composite particles. In particular, this slow release provides prolonged antimicrobial activity and effectively prevents the formation of biofilm. The composite particles can be used as an abrasive component in toothpaste in the same way as common abrasives.

The compositions of the present invention may also advantageously be used as an antiseptic composition in other areas than oral care.

Detailed description of the invention Accordingly, a first aspect of the invention relates to a composition comprising composite particles, said particles containing:

• a water-insoluble inorganic component having the formula Ca_n(X)x(AOy)_Z;,

wherein:

X is selected from OH, F and CI;

A is selected from C, P, Si and combinations thereof;

n = 1 to 5;

x = 0 or 1 ;

y = 3 or4;

z =1 to 3; and

• cationic germicide,

wherein said particles are flaky shaped, having a thickness of 15 to 80 nm.

The term 'water-insoluble' as used herein refers to a material that has a solubility in demineralized water at 20°C of less than 10 mg/l.

The term 'germicide' as used herein refers to a disinfectant that can safely be used in oral care compositions. The term 'cationic germicide' refers to an ionic germicide that contains at least one cation.

The composite particle of the present invention is considered to be flaky when its least dimension is less than 60% of its mean dimension.

The composite particle is considered to be flaky and elongated when it is flaky and when its length is greater than 180% of its mean dimension.

The composition according to the present invention encompasses oral care compositions containing small amounts of the composite particles as well as compositions containing high levels of these composite particles and that can be applied as ingredients in oral care compositions. The composition of the present invention typically contains at least 5 wt.% of the composite particles. More preferably, the composition contains 15-60 wt.% and most preferably 30-50 wt.% of the composite particles. According to a particularly preferred embodiment, the composite particles have a surface Zeta Potential of more than +10 mV, more preferably of +15 to +40 mV.

Zeta potential is a scientific term for electrokinetic potential in colloidal dispersions, usually denoted using the Greek letter zeta (ζ). The zeta potential is the potential difference between the dispersion medium and the stationary layer of fluid attached to the dispersed particle. The zeta potential is a key indicator of the stability of colloidal dispersions. The magnitude of the zeta potential indicates the degree of electrostatic repulsion between adjacent, similarly charged particles in a dispersion. For molecules and particles that are small enough, a high zeta potential (e.g. in excess of +40 mV) will confer stability, i.e., the solution or dispersion will resist aggregation. When the potential is small, attractive forces may exceed this repulsion and the dispersion may break and flocculate.

The inorganic component in the present composition is preferably selected from Ca₅(P0₄)3(OH); Ca₅(P0₄)₃F; Ca₅(P0₄)₃CI; CaC0₃; Ca₂Si0₄ and combinations thereof. Even more preferably, the inorganic component is selected from Ca5(P0₄)3(OH);

Ca5(P0₄)3F; Cas(P0₄)3CI and combinations thereof. Most preferably, the inorganic component is Ca5(P0₄)3(OH), i.e. hydroxyapatite. According to another preferred embodiment the inorganic component is present in the composite particles in crystalline form.

In one embodiment of the invention, the cationic germicide in the composite particles is a cationic quaternary ammonium compound, preferably cetyl pyridinium halide, more preferably cetyl pyridinium chloride.

In accordance with another embodiment, the cationic germicide is a cationic bisbiguanide, preferably a chlorhexidine. The composite particles in the composition of the present invention typically contain 90- 99.95 wt.% of the inorganic component and 0.05-10 wt.% of the cationic germicide. More preferably, the composite particles contain 92-97 wt.% of the inorganic component and 3-8 wt.% of the cationic germicide.

The combination of the inorganic component and the cationic germicide typically represents at least 95 wt.%, most preferably at least 97 wt.% of the composite particles. The composite particles in the present composition preferably have a thickness in the range of 20-70 nm, most preferably of 30-50 nm.

The composite particles preferably are flaky and elongated in shape. Typically, the composite particles have a length of at least 100 nm, more preferably of 150-750 nm, most preferably of 200 to 500 nm.

According to a particularly preferred embodiment, the composite particles have a length:thickness ratio of at least 3:1 preferably at least 5:1. According to a particularly preferred embodiment of the present invention, the composition containing the composite particles is an oral care composition containing 5-90 wt.%, preferably 16-60 wt.% and most preferably 30-50 wt.% of the composite particles. Examples of oral care compositions according to the present invention include toothpaste, tooth powder, tooth soap mouthwash. More preferably, the oral care composition is a toothpaste or tooth powder. Most preferably, the oral care composition is a toothpaste. The toothpaste according to the present invention typically comprises one or more of:

• 5-25 wt.% of a polishing agent, preferably a polishing agent selected from the

group of silicic acids, aluminum hydroxide, aluminum oxide, chalk, calcium pyrophosphate, dicalcium phosphate dihydrate and combinations thereof;

• 0.25-4 wt.% of anionic surfactant; • 5-60 wt.% of at polyvalent alcohol selected from sorbitol, glycerol, 1 ,2-propylene glycol and combinations thereof.

More preferably, the toothpaste contains at least two of the above mentioned three types of ingredients in a concentration as indicated.

In accordance with another the composition contains at least 50 wt.%, preferably at least 80 wt.% of the composite particles. Such compositions can suitably be applied as in an ingredient in the manufacture of oral care products. The composition preferably is a slurry that can easily be mixed into an oral care composition.

Another aspect the invention relates to the use of a composition as defined herein before as a dentifrice or in the manufacture of a dentifrice.

Yet another aspect of the invention relates to a method of preparing composite particles as defined herein, said method comprising the steps of:

• providing an aqueous solution of a water soluble calcium salt and a cationic germicide;

• adding disodium hydrogen phosphate while maintaining a pH of at least 8, preferably while maintaining a pH in the range of 10 to 12;

· keeping the resulting mixture at a temperature of at least 50 °C, preferably of 60 to 90°C for at least 60 minutes, preferably for at least 180 minutes to precipitate the composite particles; and

• recovering the composite particles. According to a particularly preferred embodiment, the pH is maintained at pH of at least 8 by the addition of sodium hydroxide, potassium hydroxide or a combination thereof.

The invention is further illustrated by means of the following examples. Examples

Example 1

100 ml. solutions of reactants with varied concentrations and additives were prepared in distilled water on the basis of the formulations shown in Table 1 (using a 20% NaOH solution to adjust pH).

Table 1

¹ Deposited onto HA particles using the modified Turkevich process as described in Discuss. Faraday Soc. 55-75, (1951 )

The mixtures were poured in hydrothermal bottles. The bottles were stoppered and heated at 90 °C for 3 hours. After the reaction the hydroxyapatite (HA) particles that had formed were filtered, washed with copious amount of water and ethanol and dried under vacuum. The flake-shaped HA particles that were formed had an average length of approximately 250 nm and an average thickness of approximately 60 nm.

Example 2

The performance of the HA particles of Example 1 was evaluated by analysing their antimicrobial efficacy.

Slurries were prepared by vortexing 50 mg of the HA particles in 1 ml distilled water. Next, each of the slurries was added to one side of a square HA disk having dimension of 2 cm X 2 cm and allowed to dry under laminar flow (laminar flow was used to avoid contamination with atmospheric bacteria).

S. mutans UA159 was inoculated in Tryptone yeast extract (TY medium) broth overnight at 37°C in 5% CO2 incubator. Overnight culture was diluted in the ratio 1 :20 in low molecular weight medium (LMW i.e TY medium filtered through 10KDa filter), and incubated at 37°C until they reach 0.5OD (mid log phase). The mid log phase culture was diluted to 1 :250 in LMW medium containing 2% sucrose.

2 ml of the above culture was added into 12 well plate and the aforementioned coated HA disks were immersed into each well and incubated for overnight at 37°C, 5% CO2 incubator. At the end of the incubation period (21 h) the disks were stained with erythrosin. Erythrosin was extracted using 0.1 N NaOH and absorbance measured at 540 nm. The lower the absorbance of the dye on the disk the higher is the antimicrobial activity. The results are summarized in Table 2

Table 2

In addition, cell viability after treatment with the different particles was measured using plate count method. The lower the cell count on the disk, the higher is the antimicrobial activity. The results are summarized in Table 3.

Table 3

No. Coating of HA disk log CFU/ml

1 no coating (control) 6.9

2 HA particles without additive 6.8

3 HA particles containing silver nanoparticle 7.2

4 HA particles containing cetylpyridinium chloride 1 .5

Claims

1. A composition comprising composite particles, said particles containing:

(i) a water-insoluble inorganic component having the formula Ca_n(X)x(AOy)_Z;, wherein:

X is selected from OH, F and CI;

A is selected from C, P, Si and combinations thereof;

n = 1 to 5;

x = 0 or 1 ;

y = 3 or4;

z =1 to 3; and

(ii) cationic germicide,

wherein said particles are flaky shaped, having a thickness of 15 to 80 nm.

2. Composition according to claim 1 , wherein the composite particles have a surface Zeta Potential of more than +10 mV, preferably of +15 to +40 mV.

3. Composition according to claim 1 or 2, wherein the inorganic component is

selected from Ca₅(P0₄)3(OH); Ca₅(P0₄)₃F; Ca₅(P0₄)₃CI; CaC0₃; Ca₂Si0₄ and combinations thereof.

4. Composition according to claim 3, wherein the inorganic component is

Ca₅(P0₄)₃(OH).

5. Composition according to any of clams 1 to 4, wherein cationic germicide is a

cationic quaternary ammonium compound, preferably cetyl pyridinium halide.

6. Composition according to claim 5, wherein the cationic germicide is a cationic bisbiguanide, preferably a chlorhexidine.

7. Composition according to any of claims 1 to 6, wherein the composite particles contain 90-99.95 wt.% of the inorganic component and 0.05-10 wt.% of the cationic germicide.

8. Composition according to any of claims 1 to 7, wherein the composite particles have a length of at least 100 nm.

9. Composition according to any of claims 1 to 8, wherein the composite particles have a length:thickness ratio of at least 3:1 preferably at least 5:1 .

10. Composition according to any of claims 1 to 9, wherein the composition is an oral care composition containing 5-90 wt.% of the composite particles.

1 1. Composition according to any of claims 1 to 10, wherein the composition is a toothpaste.

12. Composition according to any of claims 1 to 1 1 , wherein the composition contains at least 30 wt.%, preferably at least 80 wt.% of the composite particles.

13. Use of a composition according to any of claims 1 to 12 as a dentifrice or in the manufacture of a dentifrice.

14. A method of preparing composite particles as defined in claim 1 , said method comprising the steps of:

• adding disodium hydrogen phosphate while maintaining a pH of at least 8;

• keeping the resulting mixture at a temperature of at least 50 °C for at least 60 minutes to precipitate the composite particles; and

• recovering the composite particles.

15. Method according to claim 14, wherein pH is maintained at pH of at least 8 by the addition of sodium hydroxide, potassium hydroxide or a combination thereof.