WO2018011338A1

WO2018011338A1 - Orthodontic bracket etchant composition and use thereof

Info

Publication number: WO2018011338A1
Application number: PCT/EP2017/067692
Authority: WO
Inventors: Sanjukta Deb; Van P Thompson; Ali Ibrahim
Original assignee: Kings College London
Current assignee: Kings College London
Priority date: 2016-07-13
Filing date: 2017-07-13
Publication date: 2018-01-18
Anticipated expiration: 2019-01-13
Also published as: GB201612138D0

Abstract

The present invention relates to an orthodontic bracket etchant composition comprising calcium phosphate and an aqueous solution of an etchant acid, wherein the calcium phosphate is present in the composition at a concentration of 0.5 g to 1.5g per mL of aqueous solution of the etchant acid, use of the composition in preparing a tooth prior to attaching an orthodontic bracket thereto, a method of etching tooth enamel prior to fixing an orthodontic bracket thereto, a kit including the orthodontic bracket etchant composition, and a method of preparing the orthodontic etchant composition.

Description

ORTHODONTIC BRACKET ETCHANT COMPOSITION AND USE THEREOF TECHNICAL FIELD The present invention relates to an orthodontic bracket etchant composition, its use in preparing a tooth prior to attaching an orthodontic bracket thereto, a method of etching tooth enamel prior to fixing an orthodontic bracket thereto, a kit including an orthodontic bracket etchant composition, and a method of preparing an orthodontic etchant composition. These compositions may limit the degree of enamel demineralisation and allow for reprecipitation of a mineral phase similar to enamel mineral during etching.

BACKGROUND

Orthodontic brackets are used in dentistry to align and straighten teeth, and to help position teeth with regard to a person's bite. A number of orthodontic brackets are attached to the patient's teeth (in situ). The orthodontic brackets are linked by an arch wire, which puts pressure on the brackets and teeth in order to move the teeth into the desired position.

In order to transfer the pressure from the arch wire to the tooth, the orthodontic bracket must be securely attached to each tooth. Typically, each orthodontic bracket is fixed to a tooth buccal enamel using a bonding or adhesive material. Accordingly, bonding agents for orthodontic brackets must have sufficient bond strength to preclude bond failure under the pressure of the arch wire.

Traditionally, the application of an orthodontic bracket to a tooth has used separate etchant, primer and adhesive compositions in the so-called "etch and rinse" method. In this method, etching of the tooth using an etchant, for example a strong acid, such as 37% phosphoric acid, is performed, before rinsing the etchant with water. Optionally a primer layer, such as a bifunctional material having both phosphate groups and acrylate groups, is added to the etched area of the tooth. Then, an adhesive composition, such as an acrylate monomer composition, is added to the etched area of the tooth or to the bracket and the bracket is placed on the etched area of the tooth. Curing, for example, with UV or visible light, may be required to set the adhesive composition and attach the orthodontic bracket to the tooth.

More recently, self-etching adhesive materials have been introduced in orthodontics to simplify the bonding process by reducing the bonding steps and eliminating the need for separate etching and priming. Self-etching adhesives may be one-step or two-step adhesives. In two-step self-etching adhesives, the etchant is combined with the primer alone. The combined etchant and primer compositions are applied, before the adhesive composition is added. In one-step self-etching adhesives, the etchant is combined with the adhesive. Once the orthodontic brackets are no longer required (in other words, the teeth have been moved to the desired positions) the orthodontic brackets are removed from the teeth.

However, removal in many cases threatens damage of the enamel on the tooth. Enamel demineralisation is a common occurrence and the need to remove residual adhesive using burs from the enamel surface after bracket debonding may cause further enamel damage. Even with no or minimal enamel damage the removal of residual adhesive and subsequent polishing of the enamel surface post treatment adds to chair time. As such, bonding agents for the orthodontic brackets are generally required to have a bond strength sufficient to preclude bond failure, but not so strong as to threaten enamel damage upon removal. Enamel damage can be caused when the bracket is physically removed from the tooth, from removal of any residual bonding agent (adhesive) from the tooth after removal, or a combination of the two.

The bonding strength of these bonding agents varies depending on the composition of the bonding agent. It is generally thought that a shear bond strength (SBS) of around 10 MPa is sufficient to withstand the forces both of the arch wire and of use of the mouth. In addition, there is generally a correlation between shear bond strength and the possibility of enamel damage to the tooth. There is still a need for a bonding agent system for orthodontic brackets that provides a satisfactory balance between bonding strength to retain the orthodontic bracket on the tooth while minimising or eliminating the risk of enamel damage on removal of the bracket and/or through removal of residual adhesive.

Commonly used orthodontic brackets are ceramic and metal orthodontic brackets. Metal orthodontic brackets have the advantage that they are generally flexible and tend to cause less enamel damage upon removal of the bracket when compared to ceramic brackets. However, ceramic brackets are increasingly popular, in particular with adult human users of orthodontic brackets, because ceramic brackets can be coloured to resemble the colour of teeth, and therefore be cosmetically less noticeable. However, ceramic braces tend to be more brittle than metal braces resulting in making the removal of the orthodontic brackets at the end of treatment more difficult and time consuming, with an increased risk of enamel damage.

SUMMARY OF THE INVENTION

There is a need for an orthodontic adhesion system that provides satisfactory bond strength to the tooth, but minimises enamel damage on removal. It is also important that the removal of brackets leaves minimum or no remnants of the adhesive on the enamel to avoid damage associated with its removal and reduce the time required for debonding procedures. The present invention provides an orthodontic bracket etchant composition that allows satisfactory bond strength of the orthodontic bracket to the tooth using known bonding adhesives, while minimising or eliminating the risk of enamel damage on the tooth while also reducing the amount of adhesive remaining on the tooth. At its most general, the present invention provides an orthodontic bracket etchant composition including a tooth etchant and calcium phosphate.

In a first aspect, the present invention provides an orthodontic bracket etchant composition comprising calcium phosphate and an aqueous solution of an etchant acid.

In a second aspect, the present invention provides a method of fixing an orthodontic bracket to a tooth, the method including the step of applying an orthodontic bracket etchant composition to a surface of the tooth, wherein the orthodontic bracket etchant composition comprises calcium phosphate and an aqueous solution of an etchant acid.

In a third aspect, the present invention provides the use of an orthodontic bracket etchant composition in a method of fixing an orthodontic bracket to a surface a tooth of a patient, wherein the orthodontic bracket etchant composition comprises calcium phosphate and an aqueous solution of an etchant acid.

In a fourth aspect, the present invention provides an orthodontic bracket etchant composition container unit including a container housing a single dose volume or a multiple dose volume of the orthodontic etchant composition.

In a fifth aspect, the present invention further provides an orthodontic bracket etchant pre-composition container unit including a container housing a calcium phosphate composition including calcium phosphate and an etchant acid composition including an aqueous solution of etchant acid, wherein the calcium phosphate composition and the etchant acid composition are included in separate compartments of the container.

In a sixth aspect, the present invention provides a kit for fixing an orthodontic bracket to a tooth, the kit comprising a calcium phosphate composition including calcium phosphate and an etchant acid composition including an aqueous solution of an etchant acid.

In a seventh aspect, the present invention provides a kit including an orthodontic bracket etchant composition comprising calcium phosphate and an aqueous solution of an etchant acid, and at least one of an orthodontic bracket adhesive composition, an orthodontic bracket primer composition and/or an orthodontic bracket. In an eighth aspect, the present invention provides a method of preparing an orthodontic bracket etchant composition, the method including the step of mixing a calcium phosphate with an aqueous solution of an etchant acid.

In particular embodiments of these aspects, the calcium phosphate is present in the orthodontic bracket etchant composition at a concentration of 0.5 g to 1 .5 g per mL of aqueous solution of the etchant acid.

DETAILED DESCRIPTION

The present invention will now be described in more detail with reference to the

accompanying figures.

Figure 1 shows an SEM image of an etch pattern produced by a 37% solution of phosphoric acid.

Figure 2 shows an SEM image of the etch pattern produced by an orthodontic bracket etchant composition according to the present invention.

Figure 3 shows an SEM image of the enamel surface of a tooth following etching with conventional 37% phosphoric acid solution, orthodontic bracket adhesion and subsequent orthodontic bracket de-bonding.

Figure 4 shows an SEM image of the enamel surface of a tooth following etching with an orthodontic bracket etchant composition according to the present invention, orthodontic bracket adhesion and subsequent orthodontic bracket de-bonding.

Calcium phosphate

The orthodontic bracket etchant composition of the present invention includes calcium phosphate. Calcium phosphate as used herein is the family of substances containing calcium ions together with phosphates, metaphosphates or pyrophosphates and mixtures thereof. In addition, the substances may contain hydrogen or hydroxide ions.

Many forms of calcium phosphate are known per se and can be used in the present invention. Examples of calcium phosphate include but are not limited to monocalcium phosphate (Ca(H2PC>4)2), dicalcium phosphate (CaHPC , also known as dibasic calcium phosphate), tricalcium phosphate (Ca3(PC>4)2, also known as tribasic calcium phosphate or tricalcic phosphate), hydroxyapatite (CasCPC MOH)), apatite (including hydroxylapatite, fluorapatite and chlorapatite and mixtures thereof, Caio(P04)6(OH, F, Cl)2,), octacalcium phosphate (Ca8H2(P0₄)6), and tetracalcium phosphate (Ca4(P04)20), and mixtures thereof. Crystalline forms of the different types of calcium phosphate are known per se. The calcium phosphate may be in an anhydrous form or may be in a hydrate crystalline form, such as a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, or pentahyrdate. For example, monocalcium phosphate may be anhydrous or in the form of monohydrate (or mixtures thereof). Dicalcium phosphate may be dihydrate, a hemihydrate or anhydrous forms (or mixtures thereof). Octacalcium phosphate may, for example, be in the

pentahydrate form.

The calcium phosphate crystalline form may be in a particular crystalline phase. For example, the calcium phosphate may be otricalcium phosphate, a'-tricalcium phosphate, or β-tricalcium phosphate.

The orthodontic bracket etchant composition may include a mixture of different forms of calcium phosphate. For example, the composition may include two, three, four or more forms of calcium phosphate.

The calcium phosphate may be added to the composition as a mixture of two or more forms of calcium phosphate. For example, the compositions may be formed by including a mixture of tricalcium phosphate (in particular β-tricalcium phosphate) and hydroxyapatite or by including a mixture of monocalcium phosphate monohydrate and β-tricalcium phosphate.

The mixture of tricalcium phosphate (in particular β-tricalcium phosphate) and hydroxyapatite is also known as biphasic calcium phosphate. Biphasic calcium phosphate may include further forms of calcium phosphate as impurities, such as calcium pyrophosphate, CaP2C and apatite.

The mixture of calcium phosphate forms may be included in approximately equimolar ratios. In a particular embodiment, the orthodontic bracket etchant composition is formed from approximately equimolar amounts of monocalcium phosphate monohydrate and β- tricalcium phosphate. In these embodiments, the molar ratio of monocalcium phosphate monohydrate to β-tricalcium phosphate may be in the range of 0.75: 1 to 1 .25: 1 .

It should be noted that one or more forms of calcium phosphate may convert to one or more other forms of calcium phosphate in situ in the composition. For example, monocalcium phosphate monohydrate and β-tricalcium phosphate in the composition (when used) may generate dicalcium phosphate dihydrate (DCPDA).

Aqueous solution of Etchant Acid

The orthodontic bracket etchant composition includes an aqueous solution of an etchant acid. Etchant acids are known per se, and include (but not limited to) solutions of perchloric acid, hydroiodic acid, hydrobromic acid, hydrochloric acid, sulphonic acid, p-toluenesulfonic acid, methane sulphonic acid, phosphoric acid, pyruvic acid, maleic acid, oxalic acid, citric acid, nitric acid, lactic acid and sulphuric acid, as well as salts of the acids, such as monosodium citrate.

In some embodiments, the etchant acid is selected from the group consisting of phosphoric acid, pyruvic acid, maleic acid, oxalic acid, citric acid and hydrochloric acid. In particular embodiments, the etchant acid is phosphoric acid. In some embodiments, phosphoric acid is the sole etchant acid in the orthodontic bracket etchant composition.

The concentration of the etchant acid is not particularly limited. In general, the concentration will depend on the type of etchant acid and the calcium phosphate present in the

composition. The concentration of the etchant acid may be selected such that the orthodontic bracket etchant composition has a pH in the range of 0.5 to 3.0, in the range of 1 to 2, or in the range 1 .0 to 2,0. When the etchant acid is phosphoric acid, the aqueous solution of etchant acid may be 20 to 50 % phosphoric acid, 30 to 40 % phosphoric acid, or 35 to 38 % phosphoric acid.

Concentration of calcium phosphate in the composition

The calcium phosphate may be present in the composition in the range of 5 g to 15 g per 10 mL of aqueous solution of etchant acid (0.5 g to 1 .5 g of calcium phosphate per mL of aqueous solution of etchant acid). In other words, 5 g to 15 g of calcium phosphate (in total, either as a single form or a mixture) may be included for every 10 mL of aqueous solution of etchant acid in the composition. In some embodiments, the composition includes 7 g to 13 g of calcium phosphate per 10 mL of aqueous solution of etchant acid (0.7 g to 1 .3 g of calcium phosphate per mL of aqueous solution of etchant acid). In some embodiments 8 g to 12 g of calcium phosphate per 10 mL of aqueous solution of etchant acid (0.8 g to 1 .2 g of calcium phosphate per mL of aqueous solution of etchant acid).

Form of Composition

The aqueous solution of etchant acid may be in the form of a liquid or a gel. When the composition is in the form of a gel, the composition may include one or more gelling agents. Etchant composition gelling agents are known per se.

Typically, the calcium phosphate is at least partially insoluble in the etchant acid.

Accordingly, the orthodontic bracket etchant composition may be in the form of a paste. More specifically, at least some of the calcium phosphate may be dispersed or suspended in the liquid or gel aqueous solution of the etchant acid. Other Components

The orthodontic bracket etchant composition may include one or more additional components. Such components may be any component typically included in etchant compositions. For example, the orthodontic bracket etchant composition may include one or more colourants.

In some embodiments, the orthodontic bracket etchant composition is an orthodontic etch-and-rinse etchant composition. The orthodontic etch-and-rinse etchant composition may be substantially free of a primer component and an adhesive component. In some embodiments, the orthodontic etch-and-rinse etchant composition consists essentially of calcium phosphate and the aqueous solution of etchant acid. In other words, the orthodontic etch-and-rinse etchant composition is substantially free of other components.

In alternative embodiments, the orthodontic bracket etchant composition is an orthodontic self-etching primer composition comprising calcium phosphate, a primer component and an aqueous solution of an etchant acid. The primer component may be a bifunctional phosphate/carboxylate component, such as a methacrylated phosphoric acid ester.

Examples of primer components include, but are not limited to 10-methacryloyloxyethyl- dihydrogenphosphate (10-MDP), 4-methacryloxyethyl trimellitate anhydride (4-META), Phenyl-P, methacryloyloxydodecylpyridinium bromide (MDPB), 4-methacryloyloxyethyl trimellitic acid (4-MET), 1 1 -methacryloyloxy-1 ,1 -undecanedicarboxylic acid (MAC- 10), 4- acryloyloxyethyl trimellitate anhydride (4-AETA), 2-methacryloyloxyethyl dihydrogen phosphate.

In further embodiments, the orthodontic bracket etchant composition is an orthodontic self-etching adhesive composition comprising calcium phosphate, an adhesive component and an aqueous solution of an etchant acid. The orthodontic self-etching adhesive composition may further include a primer component. The adhesive component may be an acrylate monomer. Examples of acrylate monomers include, but are not limited to

Bis-Glycidyl methacrylate (BisGMA), Urethane Dimethacrylate (UDMA) and Triethylene glycol Dimethacrylate (TEGDMA). The acrylate monomer may be combined with one or more inorganic fillers. Such fillers include quartz, borosilicate glass, lithium aluminium silicate or barium aluminium silicate. The inorganic filler, if present, may be included as particles. The size of the inorganic filler particles is not particularly limited, and may be in the range of 0.1 to 10 microns or 0.5 to 6 microns. Orthodontic bracket etchant composition container units

The present invention also provides an orthodontic bracket etchant composition container unit including a container housing a single dose volume or a multiple dose volume of the orthodontic etchant composition. A single dose volume of the composition may be used to treat 2 or 3 teeth, around 16 teeth or around 32 teeth. A multiple dose volume of the composition may be used to treat more than 32 teeth. In this way, the container unit can be supplied in a suitable form to suit an orthodontic practitioner's preference. Typically, around 0.1 to 1.0 mL (or even 0.1 to 0.5 mL) of the orthodontic bracket etchant composition as described herein is required to prepare each tooth in order to attach an orthodontic bracket. In some embodiments, the orthodontic bracket etchant composition container unit includes 0.2 to 3.0 mL, 0.3 to 2.0 mL or 0.4 to 1.5 mL of the orthodontic bracket etchant composition. In this way, each orthodontic bracket etchant composition container unit may provide orthodontic bracket etchant composition to treat 2 or 3 teeth.

In alternative embodiments, the orthodontic bracket etchant composition container unit includes 1 .5 to 15 mL, 3 to 10 mL or 4.5 to 8 mL of the orthodontic bracket etchant composition. In this way, each orthodontic bracket etchant composition container unit may provide orthodontic bracket etchant composition to treat around 16 teeth.

In other embodiments, the orthodontic bracket etchant composition container unit includes 3 to 30 mL, 6 to 20 mL or 9 to 16 mL of the orthodontic bracket etchant composition. In this way, each orthodontic bracket etchant composition container unit may provide orthodontic bracket etchant composition to treat around 32 teeth.

In further alternative embodiments, the orthodontic bracket etchant composition container unit includes 30 mL or more, 50 mL or more, 100 mL or more, or 500 mL or more of the orthodontic bracket etchant composition. In this way, the orthodontic bracket etchant composition container unit may provide orthodontic bracket etchant composition to treat more than 32 teeth.

The container of the container unit is not particularly limited. The container housing a single dose volume of the orthodontic etchant composition may be a syringe or a blister pack. The container housing a multiple dose volume of the orthodontic etchant composition may be jar, tub or bottle. Orthodontic bracket etchant pre-com position container units

The present invention further provides an orthodontic bracket etchant pre-composition container unit including a calcium phosphate composition including calcium phosphate and an etchant acid composition including an aqueous solution of etchant acid, wherein the calcium phosphate composition and the etchant acid composition are included in separate compartments of the container unit. In other words, the calcium phosphate composition and the etchant acid composition of the pre-composition container are separated and not mixed during storage. The calcium phosphate composition and the etchant acid composition of the pre-composition container may then be combined to form the orthodontic bracket etchant composition as described herein before use.

The calcium phosphate composition includes calcium phosphate. The calcium phosphate composition is typically a dry powder composition. In other words, the calcium phosphate composition is substantially free of liquid components, such as solvents (e.g. water). The calcium phosphate composition may include any other dry components of the orthodontic bracket etchant composition. Alternatively, the calcium phosphate composition may consist essentially of calcium phosphate. As described above, the calcium phosphate may be in a single form or a mixture of forms.

The etchant acid composition including an aqueous solution of etchant acid. The etchant acid may be in liquid or gel form. The etchant acid composition may include any other components (such as gelling agents and/or primer components) of the orthodontic bracket etchant composition. Alternatively, the calcium phosphate composition may consist essentially of an aqueous solution of etchant acid.

The orthodontic bracket etchant pre-composition container unit can include a single dose volume of each of the calcium phosphate composition and the etchant acid composition or a multiple dose volume of each of calcium phosphate composition and the etchant acid composition. A single dose volume of each composition may be mixed and then provide orthodontic bracket etchant composition to treat 2 or 3 teeth, around 16 teeth or around 32 teeth. A multiple dose volume of each composition may be mixed and then provide orthodontic bracket etchant composition to treat more than 32 teeth. In some embodiments, the orthodontic bracket etchant pre-composition container unit includes 0.1 to 1 .0 g, 0.2 to 0.75 g, or 0.3 to 0.6 g of calcium phosphate composition, and 0.1 to 2.0 ml_, 0.2 to 1 .5 mL or 0.3 to 1 .0 mL of the etchant acid composition. In this way, the calcium phosphate composition and the etchant acid composition of each orthodontic bracket etchant pre-composition container unit may be mixed and then provide orthodontic bracket etchant composition to treat 2 or 3 teeth. In alternative embodiments, the orthodontic bracket etchant pre-composition container unit includes 0.75 to 7.5 g, 1.5 to 5 g, or 2 to 4 g of calcium phosphate composition, and 0.75 to 10 ml_, 1.5 to 7.5 mL or 2 to 5 mL of the etchant acid composition. In this way, the calcium phosphate composition and the etchant acid composition of each orthodontic bracket etchant pre-composition container unit may be mixed and then provide orthodontic bracket etchant composition to treat around 16 teeth.

In other embodiments, the orthodontic bracket etchant pre-composition container unit includes 1 .5 to 15 g, 3 to 10 g, or 4 to 8 g of calcium phosphate composition, and 1 .5 to

20 mL, 3 to 15 mL or 4 to 10 mL of the etchant acid composition. In this way, the calcium phosphate composition and the etchant acid composition of each orthodontic bracket etchant pre-composition container unit may be mixed and then provide orthodontic bracket etchant composition to treat around 32 teeth.

In further alternative embodiments, the orthodontic bracket etchant composition container unit includes 15 g or more, 50 g or more, 100 g or more, or 200 g mL or more of the calcium phosphate composition, and 20 mL or more, 75 mL or more, 150 mL or more, or 250 mL or more of the etchant acid composition. In this way, the calcium phosphate composition and the etchant acid composition of each orthodontic bracket etchant pre-composition container unit may be mixed and then provide orthodontic bracket etchant composition to treat more than 32 teeth.

In particular embodiments, the orthodontic bracket etchant pre-composition container unit includes 0.2 to 0.6 g of a calcium phosphate composition consisting essentially of calcium phosphate and 0.3 to 0.6 mL of an etchant acid composition consisting essentially of an aqueous solution of etchant acid, wherein the calcium phosphate composition and the etchant acid composition are included in separate compartments of the container unit. In other particular embodiments, the orthodontic bracket etchant pre-composition container unit includes 2 to 3.5 g of a calcium phosphate composition consisting essentially of calcium phosphate and 2.5 to 3.5 mL of an etchant acid composition consisting essentially of an aqueous solution of etchant acid, wherein the calcium phosphate composition and the etchant acid composition are included in separate compartments of the container unit. In further particular embodiments, the orthodontic bracket etchant pre-composition container unit includes 4 to 7 g of a calcium phosphate composition consisting essentially of calcium phosphate and 5 to 7 mL of an etchant acid composition consisting essentially of an aqueous solution of etchant acid, wherein the calcium phosphate composition and the etchant acid composition are included in separate compartments of the container unit. The container of the container unit is not particularly limited, but will typically include a compartment containing the calcium phosphate composition and a separate compartment containing the etchant acid composition.

Kit

The present invention also provides a kit including:

(i) a calcium phosphate composition including calcium phosphate and an etchant acid composition including an aqueous solution of etchant acid; or

(ii) the orthodontic bracket etchant composition as described herein and at least one of an orthodontic bracket adhesive composition, an orthodontic bracket primer composition and/or one or more orthodontic brackets.

The kit either includes the orthodontic etchant composition as described herein (i.e. in a pre- mixed form) or includes two separate compositions, namely, a calcium phosphate

composition and an etchant acid composition, ready to mix to form the orthodontic etchant composition before use.

When the kit includes a calcium phosphate composition and an etchant acid composition, the compositions are designed to be mixed before use to form an orthodontic bracket etchant composition as described herein. In these embodiments, the kit may include the calcium phosphate composition and the etchant acid composition in separate container units (e.g. a calcium phosphate composition container unit and an etchant acid composition container unit) or as one or more orthodontic bracket etchant pre-composition container units as described herein. When the kit includes the_calcium phosphate composition and the etchant acid composition in separate container units, the amounts of each composition may be the amounts provided in relation to the orthodontic bracket etchant pre-composition container units as described herein. The calcium phosphate composition container unit and/or an etchant acid composition container unit may include any container as described herein.

In some embodiments, the kit includes the orthodontic bracket etchant composition and the orthodontic bracket etchant composition is contained within an orthodontic bracket etchant composition container as described herein.

In some embodiments, the kit is a single-dose kit. For example, the kit may include (i) an orthodontic bracket etchant composition container unit including a single dose volume or a multiple dose volume of the orthodontic etchant composition or (ii) an orthodontic bracket etchant pre-composition container unit as described herein including a single dose volume of each of the calcium phosphate composition and the etchant acid composition or a multiple dose volume of each of calcium phosphate composition and the etchant acid composition. Additionally or alternatively, the kit may include a single dose orthodontic bracket adhesive composition and/or a single dose orthodontic bracket primer composition. In other words, when present, the single dose orthodontic bracket adhesive composition and/or a single dose orthodontic bracket primer composition may include sufficient composition to treat a single patient.

The orthodontic bracket adhesive composition may be any known orthodontic bracket adhesive composition. Examples of commercial orthodontic bracket adhesive compositions include: APC™ Flash-Free Adhesive, APC™ II Adhesive, APC™ Plus Adhesive,

Transbond™ Plus Color Change Adhesive, Transbond™ XT Light Cure Adhesive,

Concise™ Orthodontic Chemical Cure Adhesive, or Unite™ Bonding Adhesive (available from 3M/Unitek); Grengloo™, Blugloo™, or Enlight™ LV (available from Ormco), Rely-a- Bond™, Phase II™, Light Bond™, Pad Lock™ or Quick Cure™ (available from Reliance Orthodontic Product, Inc); Resilience™ bonding adhesive (available from Orthotechnology, USA); or Ideal™, Ideal™ 1 , OrthoLoc No-Mix, NeoBond™, NeoBond™ Light Cure, or Xeno Ortho (available from Dentsply). When present, the kit may include the orthodontic bracket adhesive composition contained in a syringe. The orthodontic bracket primer composition may be any known orthodontic bracket primer composition. Examples of commercial orthodontic bracket primer compositions include: Transbond™ MIP Moisture Insenstive Primer, Transbond™ XT Primer (both available from 3M/Unitek), and Resilience bonding primer (available from Orthotechnology, USA). When present, the kit may include the orthodontic bracket primer composition contained in a syringe.

The primer and/or adhesive compositions may be present in the kit as a single component composition or multi-component composition suitable for mixing into a single composition before use.

The single component composition may be suitable for immediate use. The single component composition may include more than one constituent in the composition, but is described as single component herein as the composition is already mixed. Single component compositions are typically stable over extended periods of time under storage conditions such that they have a suitable shelf-life as a single component composition.

The multi-component compositions (for example, a two-component composition) typically require mixing of the multiple components shortly (typically immediately) before use. Multi- component compositions are typically unstable over extended periods of time under storage conditions. As such, separation of the components during storage is required to preserve shelf-life of the compositions.

When the kit includes one or more orthodontic brackets, the orthodontic bracket may be a metal orthodontic bracket or a ceramic orthodontic bracket. In particular embodiments, the kit includes one or more ceramic orthodontic brackets. The kit may optionally include 16 or 32 orthodontic brackets.

In some embodiments, the kit includes the orthodontic etchant composition described herein, an orthodontic bracket adhesive composition and an orthodontic bracket primer composition.

In other embodiments, the kit includes the orthodontic etch-and-rinse etchant composition described herein, an orthodontic bracket adhesive composition and an orthodontic bracket primer composition. In further embodiments, the kit includes the orthodontic self-etching primer composition described herein and an orthodontic bracket adhesive composition

Use of the Orthodontic Bracket Etchant Composition

The present invention provides a method of attaching an orthodontic bracket to a tooth comprising the step of:

(i) applying an orthodontic bracket etchant composition as described herein to a surface of the tooth.

Typically, the tooth will have been prepared for orthodontic bracket attachment before the step of applying the orthodontic bracket etchant composition. Tooth preparation prior to orthodontic bracket attachment may involve pumicing for around 10 seconds followed by water irrigation and drying.

The surface of the tooth may be dried by any known technique. For example, the surface of the tooth may be dried by contact with an absorbent material, by air-drying or a combination thereof. Air-drying may be performed for at least 1 second, at least 5 seconds or at least 10 seconds. Air-drying may be performed in the range of 1 to 30 seconds, or in the range of 5 to 20 seconds

In particular embodiments, the orthodontic bracket etchant composition is placed onto the surface of the tooth and left for a time in the range of 15 to 45 seconds before removal of the orthodontic bracket etchant composition from the tooth. Optionally, the orthodontic bracket etchant composition may be polished on the surface for 5 to 10 seconds immediately before removal of the orthodontic bracket etchant composition from the tooth. In particular embodiments, the orthodontic bracket etchant composition may be polished on the surface for 5 to 10 seconds immediately before removal of the orthodontic bracket etchant composition from the tooth when no pumicing of the tooth has been performed during tooth preparation before the step of applying the orthodontic bracket etchant composition.

The step of removing the orthodontic bracket etchant composition from the tooth may be performed by rinsing the tooth with water, wiping the tooth or a combination thereof. When the orthodontic bracket etchant composition is removed by rinsing with water, the water may be applied for at least 5 seconds, at least 10 seconds, at least 15 seconds. For example, the water may be applied for 15 to 30 seconds. When the orthodontic bracket etchant composition is removed from the surface of the tooth, the surface of the tooth may be further dried, for example by any oil free technique. For example, the surface of the tooth may be dried by contact with an absorbent material, by air- drying or a combination thereof. Air-drying may be performed for at least 10 seconds. Air- drying may be performed in the range of 10 to 20 seconds.

The method may include a step of applying an orthodontic bracket primer composition to an area of the tooth having been treated with the orthodontic bracket etchant composition. The orthodontic bracket primer composition may be any orthodontic bracket primer composition, and in particular, may be any orthodontic bracket primer composition described herein.

The method may include a step of applying a layer of orthodontic bracket adhesive composition to a bonding surface of an orthodontic bracket before the orthodontic bracket is placed onto the tooth. The orthodontic bracket adhesive composition may be any orthodontic bracket adhesive composition, and in particular, may be any orthodontic bracket adhesive composition described herein.

The method may include a step of placing an orthodontic bracket onto an area of a tooth having been treated with the orthodontic bracket etchant composition, such that a layer of an orthodontic bracket adhesive composition is present between the tooth and the orthodontic bracket.

The method may include the step of removing excess adhesive composition from the tooth. In particular embodiments, excess orthodontic bracket adhesive composition is removed after the orthodontic bracket is placed on the tooth with a layer of the orthodontic bracket adhesive composition present between the tooth and the orthodontic bracket.

When a light curing orthodontic bracket adhesive composition is used, the method may include a step of light curing the orthodontic bracket adhesive composition after the orthodontic bracket is placed on the tooth with a layer of the orthodontic bracket adhesive composition present between the tooth and the orthodontic bracket. When a heat curing orthodontic bracket adhesive composition is used, the method may include a step of heat curing the orthodontic bracket adhesive composition after the orthodontic bracket is placed on the tooth with a layer of the orthodontic bracket adhesive composition present between the tooth and the orthodontic bracket.

The method may include preforming one or more of the steps for two or more orthodontic brackets, attaching each orthodontic bracket to a separate tooth.

Typically, the tooth is a mammalian tooth. In particular embodiments, the tooth is a human tooth.

In particular embodiments, the method is in vivo. In other words, the tooth may be in situ, such as in place in the patient's mouth. In alternative embodiments, the method is ex vivo. In other words, the tooth has been removed from a patient.

The present invention further provides an orthodontic bracket etchant composition for use in the method of attaching an orthodontic bracket to a tooth described herein.

Method of Preparing the Orthodontic Bracket Etchant Composition

The present invention provides a method of preparing the orthodontic bracket etchant composition, the method including the step of mixing calcium phosphate with an aqueous solution of an etchant acid. The calcium phosphate may be in any form as described herein. The calcium phosphate may be in two or more forms when mixed with the etchant acid. For example, monocalcium phosphate monohydrate and tricalcium phosphate may be mixed with the etchant acid to form the composition. The two or more forms of calcium phosphate may be mixed in approximately equimolar ratios.

The calcium phosphate and the aqueous solution of an etchant acid may be mixed until a substantially homogenous mixture is formed. The mixing may take 15 seconds, 20 seconds, 30 seconds 45 seconds, 60 seconds or more. The mixing may take 2 minutes, 1 minute or less. The mixing may take in the range of 15 seconds to 2 minutes or 20 seconds to 2 minutes.

The method of preparing the etchant composition may include the addition of one or more other components, such as gelling agents, colourants, primer components and/or adhesive components. In a particular embodiment, the orthodontic bracket etchant composition is an orthodontic bracket etch-and-rinse composition comprising calcium phosphate and a 37 % aqueous solution of phosphoric acid, and being substantially free of primer components and adhesive components.

The preferred and optional features of each aspect of the invention are the preferred and optional features of each other aspects of the invention. In particular, the preferred and optional features of the orthodontic bracket etchant composition of the first aspect of the invention may be the optional and preferred features of the methods, use, container units and kit of the other aspects of the invention.

EXAMPLES

Abbreviations

β-TCP - beta-tricalcium phosphate

MCPM - monocalcium phosphate monohydrate

SBS - shear bond strength

ARI - Artun adhesive remnant index

Example 1 - orthodontic bracket etchant composition ("37PA")

Equimolar amounts of β-TCP (0.187g) and MCPM (0.150g) powders and 37% phosphoric acid (0.4 mL) were mixed on a glass slab for 30 seconds until a homogenous paste was obtained. The resulting composition was ready to use as the orthodontic bracket etchant composition. Example 2 - Attachment of orthodontic brackets to teeth

Etching

The resulting paste of Example 1 was applied as an etchant onto an enamel surface of a tooth prepared for orthodontic bracket attachment (pumicing followed by air drying) and left for 30 seconds. Immediate water irrigation was then carried out in some samples ("37PA" in the results section), while the etchant was rubbed on the enamel surface for 5 seconds before water irrigation in other samples ("37PA + P" in the results section). Then, water irrigation was carried out for 20 seconds, followed by air drying (5-10 seconds) such that the tooth was ready for the bracket bonding procedure. Figure 1 shows SEM image of the etch pattern on a tooth produced by etching the tooth with a conventional 37% phosphoric acid etchant. The resulting etch pattern is rough and leaves an irregular enamel surface. Figure 2 shows an SEM image of the etch pattern on a tooth produced by an etchant composition according to the present invention. The resulting etch pattern results in a smoothly pitted enamel surface with calcium phosphate re-precipitation.

Bracket Bonding

A thin layer of bonding primer, Transbond XT primer, 3M was applied onto the etched enamel of the tooth and spread by air-jet for 3 seconds. The bracket base was loaded with the adhesive, Transbond XT adhesive, 3M and placed on the buccal enamel surface with a pressing force of 300g (Correx force gauge, Bern, Switzerland) for 10 seconds to ensure an even adhesive thickness between the bracket and enamel. Excess composite was removed by a probe. Light curing (Elipar Deep Cure-S, 3M ESPE,

Intensity 1470 mW/cm²) was applied for 20 seconds (10 seconds on mesial side and 10 seconds on distal side) with a distance of 2 mm, according to the manufacturer instructions.

After bracket bonding, the bonded teeth were left undisturbed for 30 minutes. One set of teeth were then tested for initial SBS and ARI. The rest of the teeth were stored in distilled water at 37°C for at least 24 hours followed by thermocycling over either 1000 cycles or 5000 cycles (4 days) between 5 and 55°C before bracket de-bonding procedure to assess the SBS and ARI. Example 3 - Bracket De-Bonding

In order to examine the bracket bonding strength, the SBS test was performed.

An occluso-gingival load was applied to produce a shear force at the bracket-tooth interface, accomplished with the flattened end of a steel rod attached to the crosshead of a universal testing machine (Instron, Model 5569A). The bond strength was measured at a crosshead speed of 0.5 mm per minute. The load applied at the time of fracture was recorded in Newtons and then calculated by dividing the de-bonding force by the bracket base surface area to yield megapascal (MPa) as a unit. The clinically acceptable target shear bond strengths taken is in the range of 6-10 MPa. After de-bonding, the tooth and its corresponding bracket were viewed on a stereomicroscope (X10 magnification) and scored according to the Artun adhesive remnant index (ARI) (Artun and Bergland, 1984):

Score 0: No adhesive left on the tooth.

Score 1 : Less than half of the adhesive left on the tooth.

Score 2: More than half of the adhesive left on the tooth.

Score 3: All adhesive left on the tooth, with a distinct impression of the bracket mesh.

Figure 3 shows an SEM image of the enamel surface of a tooth having been etched with conventional 37% phosphoric acid solution, orthodontic bracket adhesion and subsequent orthodontic bracket de-bonding. The image shows enamel chipping (see arrow) and marked remnant adhesive left after bracket de-bonding (centre of Figure).

Figure 4 shows an SEM image of the enamel surface of a tooth having been etched with an etchant composition according to the present invention, orthodontic bracket adhesion and subsequent orthodontic bracket de-bonding. The image shows smooth, unblemished enamel with no remnant adhesive left after bracket de-bonding.

The shear bond strength and adhesive remnant index for:

A: metal brackets fixed to enamel and debonded after 30 minutes after bonding

B: metal brackets fixed to enamel, 24 hours immersion in distilled water at 37°C followed by thermocycling for 1000 cycles, and then debonded;

C: metal brackets fixed to enamel, 24 hours immersion in distilled water at 37°C followed by thermocycling for 4 days (5000 cycles), and then debonded;

D: sapphire (ceramic) brackets fixed to enamel and debonded after 30 minutes after bonding;

E: sapphire (ceramic) brackets fixed to enamel 24 hours immersion in distilled water at 37°C followed by thermocycling for 1000 cycles, and then debonded;

F: sapphire (ceramic) brackets fixed to enamel 24 hours immersion in distilled water at 37°C followed by thermocycling for 4 days (5000 cycles), and then debonded.

SBS and ARI were analysed for tooth samples etched with:

37 % phosphoric acid gel as the control etchant ("control"); Example 1 with 30 second placement on the enamel surface before etchant removal ("37PA"); and

Example 1 with 30 second placement on the enamel surface, polishing or rubbing of the etchant on the tooth for 5 seconds and then etchant removal ("37PA + P").

Results

A:

Metal brackets initial shear bond strength (SBS) and adhesive remnant index (ARI) scores of 3 groups measured 30 minutes after bonding.

The results above show that the etchant composition of Example 1 provides a mean SBS in the region of 13-14 MPa, while scoring an ARI of zero on all samples. In contrast, the mean SBS for the control set of samples was 17.2 MPa and only one sample scored an ARI of zero.

B:

Metal brackets shear bond strength (SBS) and adhesive remnant index (ARI) scores of 3 groups measured after 24 hours immersion in distilled water at 37°C and 1000 cycles of thermocycling.

Groups No. of Mean SBS S.D. ARI Scores

Samples (MPa) 0 1 2 3

Control 20 23 5.8 2 7 6 5

37PA 20 14.2 4.9 20 0 0 0

37PA + P 20 13.8 3.0 20 0 0 0 The results above show that the etchant composition of Example 1 provides a mean SBS in the region of 14 MPa, while scoring an ARI of zero on all samples. In contrast, the mean SBS for the control set of samples was 23 MPa and only two samples scored an ARI of zero. C:

Metal brackets shear bond strength (SBS) and adhesive remnant index (ARI) scores of 3 groups measured after immersion in distilled water for 24 hours at 37°C followed by 5000 cycles of thermocycling.

The results above show that the etchant composition of Example 1 provides a mean SBS in the region of 18-20 MPa, while scoring an ARI of zero almost on all samples. In contrast, the mean SBS for the control set of samples was 26.8 MPa and only 3 samples scored an ARI of zero.

D:

Sapphire brackets initial shear bond strength (SBS) and adhesive remnant index (ARI) scores of 3 groups measured within 30 minutes after bonding.

The results above show that the etchant composition of Example 1 provides a mean SBS in the region of 16-17 MPa, while scoring an ARI of zero or 1 on almost all of the samples. In contrast, the mean SBS for the control set of samples was around 20 MPa and all of the samples scored an ARI of two or three (with the majority of samples scoring 3). Sapphire brackets shear bond strength (SBS) and adhesive remnant index (ARI) scores of 3 groups measured after 24 hour immersion in distilled water at 37°C and 1000 cycles thermocycling.

The results above show that the etchant composition of Example 1 provides a mean SBS in the region of 16-17 MPa, while scoring an ARI of zero on almost all of the samples. In contrast, the mean SBS for the control set of samples was around 27 MPa and almost all of the samples scored an ARI of three.

F:

Sapphire brackets shear bond strength (SBS) and adhesive remnant index (ARI) scores of 3 groups measured after immersion in distilled water for 24 hours at 37°C followed by 5000 cycles thermocycling.

The results above show that the etchant composition of Example 1 provides a mean SBS in the region of 21 -23 MPa, while scoring an ARI of zero on almost all of the samples. In contrast, the mean SBS for the control set of samples was around 30 MPa and almost all of the samples scored an ARI of three. As can be seen from the results, the orthodontic bracket etchant composition of Example 1 can be applied to teeth resulting in sufficient bonding strength with extremely low ARI or zero scores on bracket debonding. Example 4 - Extended Testing

Tooth samples with brackets bonded to them as set out in Example 2 Bracket were further tested under extended conditions.

The shear bond strength and adhesive remnant index were measured for:

G: metal brackets fixed to enamel, 24 hour immersion in distilled water at 37°C followed by debonding;

H: metal brackets fixed to enamel, 30 day immersion in distilled water at 37°C followed by debonding;

I: metal brackets fixed to enamel, 30 day acid challenge followed by debonding;

J: sapphire (ceramic) brackets fixed to enamel, 24 hour immersion in distilled water at 37°C followed by debonding;

K: sapphire (ceramic) brackets fixed to enamel, 30 day immersion in distilled water at 37°C followed by debonding;

L: sapphire (ceramic) brackets fixed to enamel, 30 day acid challenge followed by debonding.

30 Day Acid Challenge

A hydrochloric acid solution having a pH of 2.5 was prepared by diluting 1 M hydrochloric acid to reach the required pH.

Specimens were subjected to acidic attack by immersing the specimen in the pH 2.5 acidic solution using a protocol of 3 sessions per day. Each session involved immersion in the acid solution for 5 minutes. Each session was separated by equal intervening intervals of immersion of the specimen in distilled water at 37 °C for 2 hours. Samples were kept in distilled water (pH = 6) at 37°C for the rest of the day to simulate the wet oral environment.

The distilled water and acidic solutions were replenished after each session, and samples were washed and air dried before and after each session. SBS and ARI were analysed for tooth samples etched with:

37 % phosphoric acid gel as the control etchant ("control");

Example 1 with 30 second placement on the enamel surface before etchant removal ("37PA"); and

Results

G: Metal brackets subjected to 24 hour day water storage

Groups No. of Mean SBS S.D. ARI Scores

Samples (MPa) 0 1 2 3

Control 20 24.8 5.8 2 6 6 6

37PA 20 18.2 7.2 17 3 0 0

37PA + P 20 18.7 6.0 16 4 0 0

In addition, two of the six control samples with an ARI score of 1 also exhibited enamel cracking upon debonding, and two of the six control samples with an ARI score of 2 also exhibited enamel fracture. None of samples from either the 37PA or 37PA + P group displayed any enamel cracking or enamel fracture upon debonding.

H: Metal brackets subjected to 30 day water storage

Groups No. of Mean SBS S.D. ARI Scores

Samples (MPa) 0 1 2 3

Control 15 24.0 7.8 2 3 4 6

37PA 15 17.3 5.9 13 2 0 0

37PA + P 15 18.2 5.9 1 1 4 0 0

In addition, two of the four control samples with an ARI score of 2 also exhibited enamel cracking upon debonding. None of samples from either the 37PA or 37PA + P group displayed any enamel cracking or enamel fracture upon debonding. I: Metal brackets subjected to 30 day acid challenge

In addition, two of the seven control samples with an ARI score of 1 also exhibited enamel fracture upon debonding. None of samples from either the 37PA or 37PA + P group displayed any enamel cracking or enamel fracture upon debonding.

J: Ceramic brackets subjected to 24 hour water storage

Groups No. of Mean SBS S.D. ARI Scores

Samples (MPa) 0 1 2 3

Control 20 32.1 8.2 0 6 4 10

37PA 20 25.4 7.5 13 7 0 0

37PA + P 20 26.0 8.4 12 8 0 0

In addition, three of the four control samples with an ARI score of 2 also exhibited enamel cracking upon debonding, and four of the ten control samples with an ARI score of 3 also exhibited enamel fracture upon debonding. None of samples from either the 37PA or 37PA + P group displayed any enamel cracking or enamel fracture upon debonding.

K: Ceramic brackets subjected to 30 day water storage

In addition, two of the five control samples with an ARI score of 1 also exhibited enamel cracking upon debonding, and one of the eight control samples with an ARI score of 3 also exhibited enamel fracure upon debonding. None of samples from either the 37PA or 37PA + P group displayed any enamel cracking or enamel fracture upon debonding. L: Ceramic subjected to 30 day acid challenge

Groups No. of Mean SBS S.D. ARI Scores

Samples (MPa) 0 1 2 3

Control 15 29.7 6.8 0 2 2 1 1

37PA 15 18.5 6.9 12 3 0 0

37PA + P 15 17.8 7.1 10 5 0 0

In addition, two of the eleven control samples with an ARI score of 3 also exhibited enamel fracture upon debonding. None of samples from either the 37PA or 37PA + P group displayed any enamel cracking or enamel fracture upon debonding.

References:

Artun J, Bergland S. Clinical trials with crystal growth conditioning as an alternative to acid- etch enamel pretreatment. Am J Orthod 1984; 85: 333-340.

Claims

1 . An orthodontic bracket etchant composition comprising calcium phosphate and an aqueous solution of an etchant acid, wherein the calcium phosphate is present in the composition at a concentration of 0.5 g to 1.5g per mL of aqueous solution of the etchant acid.

2. The orthodontic bracket etchant composition according to claim 1 wherein the

calcium phosphate is selected from the group consisting of monocalcium phosphate (Ca(H2PC>4)2), dicalcium phosphate (CaHPC , also known as dibasic calcium phosphate), tricalcium phosphate (Ca3(PC>4)2, also known as tribasic calcium phosphate or tricalcic phosphate), hydroxyapatite (CasCPC MOH)), apatite (including hydroxylapatite, fluorapatite and chlorapatite and mixtures thereof, Caio(P04)6(OH, F, Cl)2,), octacalcium phosphate (Ca8H2(P0₄)6), and tetracalcium phosphate

(Ca4(P04)20), and mixtures thereof.

3. The orthodontic bracket etchant composition according to any one of the preceding claims wherein the etchant acid is selected from the group consisting of phosphoric acid, pyruvic acid, maleic acid, oxalic acid, citric acid and hydrochloric acid.

4. The orthodontic bracket etchant composition according to claim 3 wherein the

etchant acid is phosphoric acid.

5. The orthodontic bracket etchant composition according to any one of the preceding claims wherein the composition has a pH in the range of 1 to 2.

6. The orthodontic bracket etchant composition according to any one of the preceding claims wherein the composition is substantially free of a primer component and an adhesive component.

7. The orthodontic bracket etchant composition according to any one of claims 1 to 5 wherein the composition further comprises a primer component and/or an adhesive component.

8. A method of fixing an orthodontic bracket to a tooth, the method including the step of applying an orthodontic bracket etchant composition to a surface of the tooth, wherein the orthodontic bracket etchant composition comprises calcium phosphate and an aqueous solution of an etchant acid, and wherein the calcium phosphate is present in the composition at a concentration of 0.5 g to 1 .5g per mL of aqueous solution of the etchant acid.

9. Use of an orthodontic bracket etchant composition in a method of fixing an

orthodontic bracket to a tooth of a patient, wherein the orthodontic bracket etchant composition comprises calcium phosphate and an aqueous solution of an etchant acid, wherein the calcium phosphate is present in the composition at a concentration of 0.5 g to 1.5 g per mL of aqueous solution of the etchant acid.

10. A kit for fixing an orthodontic bracket to a tooth, the kit comprising an orthodontic bracket etchant composition comprising calcium phosphate and an aqueous solution of an etchant acid, and at least one of an orthodontic bracket adhesive composition, an orthodontic bracket primer composition and/or an orthodontic bracket, wherein the calcium phosphate is present in the composition at a concentration of 0.5 g to 1.5 g per mL of aqueous solution of the etchant acid.

1 1 . An orthodontic bracket etchant composition container unit including a container housing a single dose volume or a multiple dose volume of the orthodontic etchant composition according to any one of claims 1 to 8.

12. An orthodontic bracket etchant pre-composition container unit including a container housing a calcium phosphate composition including at least 0.1 g of calcium phosphate and an etchant acid composition including at least 0.1 mL of an aqueous solution of etchant acid, wherein the calcium phosphate composition and the etchant acid composition are included in separate compartments of the container.

13. The orthodontic bracket etchant pre-composition container unit according to claim 14 wherein the container includes 4 to 7 g of a calcium phosphate composition consisting essentially of calcium phosphate and 5 to 7 mL of an etchant acid composition consisting essentially of an aqueous solution of etchant acid, wherein the calcium phosphate composition and the etchant acid composition are included in separate compartments of the container unit.

14. A method of preparing an orthodontic bracket etchant composition, the method

including the step of mixing a calcium phosphate with an aqueous solution of an etchant acid at a concentration of 0.5g to 1.5 g of calcium phosphate per mL of aqueous solution of the etchant acid.