WO1986006274A1

WO1986006274A1 - Dental treatment

Info

Publication number: WO1986006274A1
Application number: PCT/GB1986/000222
Authority: WO
Inventors: Brian Edward Causton
Original assignee: National Research Development Corporation
Priority date: 1985-04-23
Filing date: 1986-04-22
Publication date: 1986-11-06
Also published as: GB2174301A; GB2174301B; GB8609791D0; JPS62502547A; GB8510310D0; EP0258241A1

Abstract

Dental cavities may be lined, prior to filling, with a paste comprising an aqueous phase containing Ca2+, PO43- and F- and having a pH between 5 and 7 and, despersed therein, particles of hydroxy apatite, the surfaces of which have thereon a protective layer of calcium phosphate. The paste becomes unstable in the presence of the dentine of the tooth to deposit a hydroxy apatite layer on the dentine. The paste may be prepared by contacting hydroxy apatite particles with a saturated aqueous solution of calcium phosphate having a pH of between 4.6 and 8.5 whereby a calcium phosphate protective layer forms on the surface of the particles and removing any excess liquid, e.g. by decanting, to give a paste.

Description

DENTAL TREATMENT

This invention relates to a composition for use in dental treatment and also to dental treatment using such composition.

Once the enamel covering has been removed on a tooth, the dentine below is exposed. Dentine contains tubules which contain living cell processes and nerve fibres. These dentine tubules run perpendicularly from the surface of the tooth and directly to the pulp. Exposure of the dentine tubules to saliva and its cytotoxins can result in secondary caries, pulpitis, abscess formation, all of which cause pain to the patient and require additional removal of tooth structure.

During cavity preparation for tooth filling, the dentist will normally expose dentine and remove all the dentine which has deteriorated before a filling is applied. It is desirable to maintain as much dentine as possible to cut down on the time for cavity preparation with a view to making dental treatment less unpleasant by reducing the use of the drill. This is particularly important in the treatment of difficult or hypersensitive patients. In addition as much dentine as possible should be conserved since it has no equal as a material for constructing the inner parts of teeth (certainly better than composites or amalgams) .

Against this it is necessary to try to ensure that all deteriorated dentine is removed with conventional tooth filling techniques. Any infected parts remaining may cause deterioration of dentine remaining under the filling and this will require the filling, and further dentine, to be removed before the filling is replaced by a larger one.

Deterioration of the remaining dentine may also result from leakage of e.g. saliva around the margins and under the filling. Again if this occurs it is necessary for the filling and the newly deteriorated dentine to be removed and a larger filling is then applied.

Another difficulty with the successful filling of teeth is that filling material will bond more strongly to enamel than it will to dentine. Filling adhesives used generally wet the more hydrophobic enamel material more than the dentine.

It is known to treat enamel lesions in teeth with calcium phosphate-containing mineralising mouthwashes whereby a hydroxy apatite deposit is built up on the tooth enamel. R.S. Levine (Brit. Dent. J. 1975, 138, 249) describes the use of mineralising mouthwashes for the remineralisation of enamel caries by the prolonged use of calcium phosphate solution.

It is also known to mineralise dentine using calcium phosphate solutions. In this way dentine which has been partially demineralised can be remineralised. This remineralisation is particularly attractive since, if patients could be treated in this way, it would offer an opportunity of retaining deteriorated dentine when filling a tooth rather than having to remove it all. Further, by mineralisation, the tubules of the dentine may be occluded by hydroxy apatite deposit, effectively sealing the dentine against infection and the dentine may become hypermineralised whereby a layer of hydroxy apatite having an enamel-like structure is built up on the dentine surface. This pseudo-enamel layer on the dentine is strongly adherent and protects the dentine therebelow. Moreover dental filling materials adhere well to it. The use of mineralising solutions in the treatment of dentine, in particular the improved bonding of dental filling material has been discussed in B.E. Causton et al, Brit. Dent. J. 1976, _140, 339, Brit. Dent. J. 1982, 152., 9-11, J. Dent. Res. 1981, 1315-1320 and 1321-1324.

While the mineralisation of dentine would be of great interest for dental treatment and to provide a good surface for the adhesion of dental filling, the solutions themselves, while interesting for in vitro experimentation, are not suitable for the treatment of patients. In particular the known solutions, which generally must be metastable in order that they deposit a hydroxy apatite layer on dentine, have a very short shelf life and they have to be prepared immediately before application. Thus the solution cannot be supplied as such to a dentist. Also to obtain an adequate mineralisation the solutions require use of such large volumes and/or over such long periods of time that their practical application is ji vivo not possible.

According to the present invention, there is provided a storage stable paste comprising: (i) an aqueous phase containing Ca 2+ and PO.3- and having a pH between 5 and 7; and

(ii) dispersed in (i), particles of hydroxy apatite, the surfaces of which have thereon a protective layer comprising a calcium phosphate, the paste being unstable in the presence of dentine to deposit hydroxy apatite on the dentine.

The paste according to the present invention has sufficient stability to be stored, e.g. on a dentist's shelf, for prolonged periods. In the presence of dentine, however, the paste becomes unstable and a mineralising layer of hydroxy apatite is deposited from the paste on to the tooth to occlude dentine tubules and hypermineralise the dentine to provide a pseudo-enamel layer to which filling material bonds more strongly than to the dentine itself. In use, the paste according to the invention can be applied by a dentist as a thin layer, e.g. about 1mm thick, over the surface of a dental cavity of a patient after drilling and the tooth is filled. Then, while the filling is in situ, there becomes"deposited from the paste on to the dentine of the tooth a hydroxy apatite mineralising layer. This means that there forms under the filling a pseudo-enamel layer which both occludes the dentine tubules against infection and provides for good bonding of the filling material. In this way the dentine becomes sealed against further infection meaning that, if it is eventually necessary to remove the filling, the dentine below is less likely to have suffered secondary caries. Moreover the paste can act as a buffer and neutralises any acid leaking from the oral cavity or any acid biproducts of dental materials. When the paste of the present invention has been used and a filling is replaced, there will be less need to enlarge the cavity by removal of further dentine. Further, since the mineralisation of the dentine may remineralise partially demineralised dentine, when making the initial cavity, the dentist may be able to leave some damaged dentine, to be remineralised, rather than having to remove all deteriorated dentine as he would conventionally have had done. This means that using the paste according to the invention it is unnecessary for the dentist to remove as much damaged dentine as with conventional treatments.

The invention also provide a method for preparing a storage stable paste for use in dental treatment which method comprises contacting particles of hydroxy apatite with a saturated aqueous solution comprising calcium phosphate having a pH of between 4.6 and 8.5 whereby a protective layer comprising calcium phosphate forms on the surface of the particles, and, after protective layer has formed, if desired, removed an excess liquid, e.g. by decanting, to give a paste. The paste according to the present invention is a metastable system. It has storage stability but becomes unstable in the presence of dentine. While it is not wished in any way to be bound by theory, it is believed that the composition and behaviour of the paste according to the present invention derives from the complex structures and behaviour of the calcium phosphates themselves. What it is believed occurs when the paste according to the present invention comes into contact with dentine is that the change in pH, which this causes, results in the calcium phosphate protective layer on the hydroxy apatite particles being removed by going into solution. Some of this calcium phosphate may be deposited as hydroxy apatite on the dentine. Also the hydroxy apatite of the paste particles themselves, having lost the -protective layer, now enters into solution and becomes deposited on the dentine as a mineralising layer.

It is most important that the hydroxy apatite in the particles of the present paste is in a form which, in the presence of dentine, deposits hydroxy apatite. For example if there is used a particle material which is too insoluble, even in the presence of dentine the particles themselves will not dissolve in the aqueous phase of the paste and will not accordingly deposit hydroxy apatite on the dentine. Indeed there may be a tendency for the enamel of the tooth to become dissolved in the aqueous phase of the paste if very insoluble material is used. Thus the hydroxy apatite material used according to the present invention will be a high solubility one having a higher water solubility than the exactly stoichiometric material.

Particularly suitable for use in the paste according to the present invention is water deficient, preferably highly crystalline, hydroxy apatite. This known material is deficient in water of crystallisation and may be prepared by dehydration of hydroxy apatite under dehydration conditions (see for example Verbeeck et al. Caries Res. 14; 311-314 (1980)). Crystals of the water deficient material under X-ray crystallography are shown to be highly crystalline and apatite in structure with normal apatite dimensions except for one reduced dimension. The water deficient material generally has a slightly higher solubility than normal stoichiometric crystalline hydroxy apatite.

The water deficient material may be prepared by heating the stoichiometric material at a temperature at which water of crystallisation is lost, generally between 900°C and 1200°C. For example it may be prepared by compacting industrial hydroxy apatite powder, and heating in a tube furnace at temperatures between 900°C and 1200"C and flushed with atmospheric carbon dioxide-scrubbed steam. The material thus sintered is then ground to a fine powder. The sinter may contain some tricalcium phosphate but this is lost under aqueous conditions.

The paste according to the invention may be prepared by contacting the particles of hydroxy apatite with a saturated aqueous solution of calcium phosphate having a pH between 4.6 and 8.5 whereby a protective layer of calcium phosphate forms on the particles, and, after the protective layer has formed, removing any excess liquid to give a paste. The addition of the hydroxy apatite particles to the saturated aqueous solution of calcium phosphate causes calcium phosphate to crystallise on to the particle surfaces. In this way a protective layer is formed over the hydroxy apatite. After the protective layer has formed any excess liquid can be removed, e.g. decanted off. The composition of the calcium phosphate protective layer obtained in this way appears to depend for example on its age. Again this composition is believed to derive from the complexity of the calcium phosphates. Thus there will normally be deposited, on the hydroxy apatite particles, a protective layer of initially predominantly dicalciu phosphate dihydrate crystals and the layer appears to mature and then octacalcium phosphate crystals and subsequently tricalcium phosphate predominate. The protective layer obtained after some storage will normally comprise a mixture of at least octacalcium phosphate crystals and tricalcium phosphate crystals.

It is desirable that the initial protective layer should not be formed on the hydroxy apatite particles too slowly. Firstly of course if the process is too slow, preparation of the paste itself becomes a drawn out matter. In addition water deficient hydroxy apatite has a tendency to take up water from an aqueous environment to make up for its deficiency. Once the calcium phosphate protective layer has built up on the particles this does not happen. Thus the protective layer should be formed at a sufficient rate to prevent any appreciable gain of water.

The speed of formation of the initial calcium phosphate layer will depend upon several factors. Most particularly it will depend upon the degree of saturation of the aqueous calcium phosphate solution. The higher the degree of super saturation of the solution, then the faster will be the formation of the protective layer. Of course the higher the degree of super saturation, in addition the less stable will the aqueous solution itself be and it will have a tendency for calcium phosphate to precipitate out. Thus for practical purposes there is often a short concentration range which can be used bounded on one side by those solutions which are so highly concentrated that they are so metastable that they cannot practically be used and those solutions of lower concentration which have too slow a growth rate of dicalcium phosphate dihydrate crystals to be practical. Suitably the aqueous solution will contain F , the presence of F~ being desirable to ensure adequate speed of formation of the protective layer. On the other hand F should not be present in too great a quantity. At higher levels, the F~ may adversely affect the behaviour of the paste itself and impair the formation of the hydroxy apatite mineralising layer. Generally speaking the F concentration will be of the order of 5 to lOOppm, suitably 5 to 20ppm.

The pH of the starting aqueous calcium phosphate solution is also an important factor. It is preferred that the aqueous solution used be isotonic and has a pH of approximately 7.4. The tonality of this solution may be achieved by addition of sodium chloride, pH being adjusted with sodium hydroxide. The pH of the solution will be between 4.6 and 8.5. However this pH also affects the speed at which the calcium phosphate protective layer is formed. Below pH 4.6 the speed is too slow to be practical while above pH 8.5 the solution obtained is so unstable that again it is impractical.

In addition it may be desirable for the aqueous solution to contain an agent for preventing algal growth though of course that agent must not interfere with the dynamics of the mineralising solution. A suitable such agent is chloroform, preferably present at approximately 1.5% by weight concentration. The aqueous solution should preferably contain Ca and P in the hydroxy apatite stoichiometric ratio i.e. they should preferably be present in the ratio of approximately 1.67. Departure from this ratio may lead to a tendency for the mineralising hydroxy apatite layer formed using the paste to have for example calcium deficiency.

The amount of hydroxy apatite which is added to the calcium phosphate solution is not critical and excess liquid can be decanted off. Generally speaking 10 to 50% by weight of hydroxy apatite will be added to the solution. The hydroxy apatite is suitably used in the form of a fine powder having a particle size not exceeding 350 microns. Preferably the average particle size is approximately 100 microns.

Once the protective crystal layer has formed on the hydroxy apatite particles, there is reached an equilibrium within the paste which appears to provide its stability. While again it is not wished to be bound by any theory, when that paste is applied to dentine of higher pH (pH

7.4), the equilibrium within the paste becomes disturbed and it becomes unstable. The Ca 2+ and P0₄3- in the protective layer go into solution and subsequently those in the hydroxy apatite particles themselves and hydroxy apatite is deposited on the dentine. The presence of Ca 2+ and P0. ions in the stoichiometrically correct proportions ensures that the net flow is in stoichiometric proportions and accordingly that the deposited layer is not e.g. calcium deficient.

The behaviour of the paste according to the present invention is illustrated by way of example with reference to the accompanying Figure. In the accompanying Figure there is plotted the concentration of Ca 2+ in mM (the lower plot) and the pH (the upper plot) of the solution in equilibrium with paste at 25°C against time in minutes.

The plots fall into three parts. The first. Part I , represents the time after water deficient, highly crystalline hydroxy apatite powder has been added to an isotonic, stoichiometric aqueous calcium hydroxide solution. There is seen a drop in pH as the crystals of calcium phosphate form on the surface of the hydroxy apatite particles. When the protective layer has formed, there is formed a substantially stable composition and Part II of the plot shows the paste obtained when being stored at 25^βC. Part III shows the changes which occur when the paste is brought into contact with dentine. There is a rise in pH and, as will be seen, a loss of Ca 2+ from solution; the lost Ca 2+ having been deposited as hydroxy apatite mineralising layer on the dentine.

The invention is further illustrated in the following

Example:

EXAMPLE Preparation of hydroxy apatite powder

Industrial hydroxy apatite having particles of size between 2 and 150 microns was air dried and compacted in a

_2 sealed rubber sleeve at a pressure of 48824 kg. M

(10,000 psi) in oil. The compacting was carried out in a sturdy stainless steel cylinder with a heavy screw down gasketted top which was filled with oil and the pressure in the cylinder raised by means of a hydraulic pump. The resulting pellet was easy to handle being of similar consistency and strength as a stick of chalk. The pellets were then weighed and placed in a quartz boat which in turn was placed in a tube furnace having a fused silica liner and being flushed with atmospheric C0₂/steam. The heating cycle was as follows: When the quartz boat was introduced into the furnace the temperature was 500^βC. The temperature was raised at the rate of 35°C for 10 minutes to 1200^βC and then held at 1000°C overnight. Temperature was then reduced at the rate of 35°C per 10 minutes to 500^βC at which point the sintered material was withdrawn, over a period of the next hour.

There was obtained a sintered material having a highly crystalline structure which was subsequently ground to a fine powder of average particle size 100 microns.

X-ray crystallography of the dry powder showed it to have a highly crystalline and apatite structure with normal apatite dimensions except for one reduced dimension consistent with water-deficient hydroxy apatite. Preparation of mineralising solution Stock solutions were prepared as follows: Sodium chloride 35.lg sodium chloride was dissolved in 1000ml distilled water to give a 600mM solution. Sodium fluoride

2.2105g sodium chloride was dissolved in 100ml distiled water to give a 1% F solution. This solution was diluted to 100 times to give lOOppm F~^" solution, which was used as the stock solution. Calcium phosphate

2.961g stoichiometric hydroxy apatite was dissolved in 1M HC1, then it was made up to 1000ml with distilled water to give a 30mM calcium solution.

There were pipetted into a 100ml volumetric flask, 25ml sodium chloride stock solution, 10ml sodium fluoride stock solution and 10ml calcium phosphate stock solution and the whole was made up to 100ml with distilled water and the pH adjusted to 7.4 by addition of sodium hydroxide (about 2 drops). There was thus obtained an aqueous solution containing:

3mM Ca²⁺ lOppm F~^" 150mM NaCl

Preparation of paste The hydroxy apatite powder was then added to the mineralising solution. A protective layer of initially dicalcium phosphate dihydrate was deposited on the powder particles. After maturing the protective layer was found to contain predominantly octacalcium phosphate crystals and subsequently tricalcium phosphate crystals. Any excess liquid was then decanted off to leave a paste. use A cavity was cut into a patient's tooth through the enamel and into the dentine. The cavity was irrigated first as a precaution with a broad spectrum antibiotic or a non-irritant bactericide.

A thin layer (about 1mm) of paste was spread over the exposed dentine and over adjacent enamel. The remaining exposed enamel was etched and the tooth was then filled.

Claims

1. A storage stable paste comprising: (i) an aqueous phase containing Ca 2+ and P0.3- and having a pH between 5 and 7; and

(ii) dispersed in (i), particles of hydroxy apatite, the surfaces of which have thereon a protective layer comprising a calcium phosphate, the paste becoming unstable in the presence of dentine to deposit hydroxy apatite on the dentine.

2. A paste according to claim 1 wherein the particles of hydroxy apatite are particles of water deficient hydroxy apatite.

3. A paste according to claim 1 or 2 wherein the particles of hydroxy apatite are obtained by sintering hydroxy apatite at a temperature between 900°C and 1200°C such that water of crystallisation is lost and the sintered material is subsequently ground to a fine powder.

4. A paste according to any one of claims 1 to 3 wherein the protective layer comprises a mixture of octacalcium phosphate crystals and tricalcium phosphate crystals.

5. A paste according to any one of claims 1 to 4 wherein the aqueous phase also contains F .

6. A method of preparing a storage stable paste for use in dental treatment which method comprises contacting particles of hydroxy apatite with a saturated aqueous solution comprising a calcium phosphate having a pH of between 4.6 and 8.5 whereby a protective layer comprising a calcium phosphate forms on the surface of the particles and, after protective layer has formed, if desired, removing any excess liquid to give a paste.

7. A method according to claim 6 wherein the particles of hydroxy apatite are particles of water deficient hydroxy apatite.

8. A method according to claim 6 wherein the particles of hydroxy apatite are obtained by sintering hydroxy apatite at a temperature between 900'C and 1200^βC such that water of crystallisation is lost and the sintered material is subsequently ground to a fine powder.

9. A method according to any one of claims 6 to 8 wherein the saturated aqueous solution is an isotonic super saturated solution of calcium phosphate, which also contains F , and which comprises Ca and P approximately in the ratio 1.67.

10. A method according to any one of claims 6 to 9 wherein between 10% and 50% by weight hydroxy apatite powder is added to the aqueous solution.

11. A method of dental treatment which comprises applying to exposed dentine a storage stable paste which comprises: (i) an aqueous phase containing Ca 2+ and P0,3— and having a pH between 5 and 7; and

(ii) dispersed in (i), particles of hydroxy apatite, the surfaces of which have thereon a protective layer comprising a calcium phosphate, according to any one of claims 7 to 12 wherein the saturated aqueous solution also contains chloroform as algal growth preventing agent. the paste becoming unstable in the presence of dentine to deposit hydroxy apatite on the dentine, and applying dental filling material thereover.