FI68216B - OPALT ISOTROPISKT OCH POLYKRISTALLINT SINTRAT KERAMISKT MATERIAL OCH DETTA INNEHAOLLANDE PLOMBERINGSKOMPOSITION FOER TAENDER - Google Patents

Description

U ^ i ^ -1 NOTICE OF PUBLICATION, Q 0 *, B 11 utlAggningsskrift 6 8 2.1 6 C Patent granted 12 08 1985

Patent neddelat V (51) K ».ik.4 / int.a.4 C 04 B 35/00, A 61 K 6/06, 6/08 FINLAND — FINLAND (21) Patent application - Patentansöknlng 792164 (22) HikemispUvi - Ansöknlngsdtg 10.07.79 (EN) (23) Starting date - Glltighetsdag 31 .07.75 (41) Made public - Bllvlt offentllg 10.07.79

National Board of Patents and Registration (44) Date of publication and hearing publication - 30.04.85

Patents and Registration Cases 1 Ansökan utlagd ooh utl.skrlften publlcerad (32) (33) (31) Privilege claimed - Begird priomet 02.08.74 07.07.75 USA (US) 494240, 593303 (71) Sterling Drug Inc., 90 Park Avenue, New York, NY, USA (72) Michael Jarcho, Nassau, NY, USA (74) Oy Kolster Ab (54) Translucent, isotropic and polycrystalline sintered ceramic material and dental repair composition containing it - Opalt, The present invention relates to a transparent, isotropic, isotropic, isotropic, isotropic, isotropic, isotropic, isotropic, The new substance is especially suitable for use in dentistry and orthopedics.

The invention also relates to a dental replacement composition containing this substance.

Current dental research is largely focused on the manufacture of materials that can be used as a tooth and bone substitute, as a dental repair material for fillings, shells and crowns, and as a prosthetic filling material for bone. Dental research has also focused on preventing the formation of tooth rust in teeth, which is considered to be the cause of both dental caries and periodontal disease.

Fillers currently used in dental restorative compositions, such as quartz, alumina, silicates, glass beads, etc., resemble little tooth enamel chemically and physically. The actual weakness of these 2 68216 materials is the difference in the coefficients of linear thermal expansion of the filling material and the tooth, which can potentially cause cracks at the joints and new caries formation. Thus, in the treatment of teeth, a filling composition has long been desired, the physical properties of which closely correspond to those of natural teeth.

In addition, in the area of surgical prosthetic materials, which is currently dominated by strong, non-corrosive alloys, a need has been identified for a material that better resembles biological, hard tissues, as difficulties in tissue acceptance and attachment have not yet been completely eliminated / kulbert, et al., Material Science Research 5, 417 (1971) J.

In research to find effective anti-rust chemotherapeutic agents, there has been a need for a standard test material with a surface resembling a tooth in terms of both tooth rust formation and chemical action. Although natural tooth has been used for this purpose, it has the disadvantage of high variability, relatively difficult availability in large quantities, and the complex cleaning required before use. Therefore, other materials that form dental rust, such as powdered hydroxylapatite, acrylic teeth, glass, and metal wire, have been used. Although they may be suitable for studying the formation of dental fever per se, these materials bear little resemblance to the surface of a natural tooth and are thus not entirely suitable for finding an effective anti-rust agent. For example, it is known that chemicals that prevent rust from forming on teeth may not be effective with glass and metal (Turesky et al., J. Periodontology 43, 263 (1972)). Therefore, there is a need to obtain a cheap, readily available material that is chemically similar to tooth enamel, is hard, dense, and highly polishable.

Hydroxyl apatite, Ca 2 g (PO 2) g (OH) 2 r, also known as basic calcium orthophosphate, a tooth and bone mineral base, has been proposed for use in the various purposes set forth above, and in fact U.S. Patent 2,508,816 discloses a method for recovering hydroxyl apatite from tooth enamel and for use as a prosthetic dental composition mixed with a synthetic resin. This method is long and laborious and is limited to the preparation of finely divided hydroxylapatite. In addition, the method naturally depends on the availability of natural teeth.

ti 3 68216

Kutty / Indian J. Chem. 11, 695 (1973) / discloses mixtures of hydroxylapatite and whitlocyte formed by decomposing powdered hydroxylapatite at different temperatures.

Bett, et al. / J. Amer. Chem. Soc. 89, 5535 (1967)], discloses the preparation of finely divided hydroxylapatite with a stoichiometric Ca / P ratio ranging from 1.67 to 1.57. The materials thus prepared contain large internal pores of the crystals. It has also been mentioned that when heated to 1000 ° C, the calcium-deficient hydroxylapatites partially convert to the whitlocyte phase.

U.S. Patent 3,787,900 discloses a prosthetic bone and dental material containing a high melting material and a calcium phosphate compound, e.g., whitlocyte.

Several attempts have been made to obtain the macro form of hard, strong hydroxylapatite. However, no previously known form of hydroxylapatite has been completely satisfactory. Thus Roy and Linnehan / Mature. 247, 220 (1974) / have disclosed a complex hydrothermal exchange process in which the calcium carbonate backbone of sea coral was converted to hydroxylapatite. The material thus produced inevitably retains the very porous properties of the coral structure and, in addition, its tensile strength is relatively low, 2 about 19 to 33 kp / cm, which is a serious drawback in the prosthetic material.

Monroe, et al. (journal of Dental Research 50, 860 (1971)) has disclosed the preparation of a ceramic material by sintering compressed hydroxylapatite tablets. The material thus formed is in fact a mixture of hydroxylapatite with about 30% Of-whitloclite, Ca 3 (PO 4) 2 or tricalcium phosphate, as an ordered mosaic pattern of polyhedral crystals and proved to be too porous to be used as a dental material.

Rao and Boehm (Journal of Dental Research 53, 1351 (1974)) have reported that a polycrystalline form of hydroxylapatite is prepared by isostatically pressing powdered hydroxylapatite into a mold and sintering the formed body isothermally.

The ceramic body formed was porous and had a maximum compressive strength of about 1,200 kp / cm.

Bhaskar et al. / öral Surgery 32, 336 (1971) / discloses the use of a biodegradable calcium phosphate ceramic material to fill 4 6821 6 tooth cavities. The material is very porous, resorbed at its planting site and does not have the strength of a metal or non-dispersed ceramic spot.

Master Application No. 752194 of this application discloses a process for obtaining a polycrystalline sintered ceramic material, in which a calcium ion and a phosphate ion are reacted in an aqueous medium at a pH of 10-12 to form a gel-like calcium phosphate precipitate having a calcium and phosphorus content of 1. m - 1.72 at a molar ratio (between the approximate molar ratios of calcium and phosphorus in hydroxylapatite and whitlocyte), the precipitate is separated in solution, heated to at least 1 000 ° C but below the temperature at which significant decomposition of hydroxylapatite occurs and kept at this temperature for a sufficient time to sinter the formed product, whereby in order to achieve substantially maximum compaction, it is generally advantageous to prepare the ceramic material in macro form by sintering the entire mass formed by the precipitate, if desired in shape.

The present invention relates to a translucent, isotropic, polycrystalline, sintered ceramic material, characterized in that it is a substantially pure hydroxylapatite with an average crystal size of 0.2 to 3 μm and a density of about 3 ', 3.10 to 3.14. g / cm, which is essentially non - porous and splits along even curved surfaces. Chemically, it resembles a lot of tooth enamel. In addition, this material can be prepared relatively simply from inexpensive starting materials and is obtained in a uniform quality, thus avoiding the unfavorable variability inherent in a natural tooth.

The use of a new ceramic form of hydroxylapatite in dental restorative compositions provides a dense filling material with a coefficient of thermal expansion substantially equal to that of natural tooth enamel.

The dental and surgical implant material provided by the present invention is hard, strong and fully biocompatible and can be made into any desired shape without high pressures or other complicated procedures. In addition, as will be detailed later, this material can be given any desired degree of porosity, allowing tissues to adhere.

li 5 68216

As will be seen below, the features of the new article of manufacture disclosed herein, which is also subject to the claims, make it ideally suited for the manufacture of discs, plates or rods for testing anti-plaque agents.

The novel physical form of the hydroxylapatite object of the present invention, which differs from biological and geological forms and all previously known synthetic forms, as shown below, consists of a strong, hard, dense, isotropically transparent, polycrystalline ceramic material containing predominantly pure hydroxyl. the crystals have an average size of 0.2 to 3 μm, a density of 3.10 to 3.14 g / cm 3 and substantially no pores and which cleaves flat curves along the surfaces. In addition, when prepared in the usual manner, the above material 2 has a compressive strength of 2,500 to 8,500 kp / cm and a tensile strength of 210 to 2,100 kp / cm 2, a linear coefficient of thermal expansion of 10 to 12 ppm / ° C, a Knoop hardness of 470 to 500 and a modulus of elasticity 4. , 2 x 10 kbps / cm and does not have to be refracted in polarized light. Initial studies of the new hydroxylapatite showed that it is a strong, hard, dense, white, transparent ceramic material consisting mainly of pure microcrystalline hydroxylapatite in a random, isotropic order and having a compressive strength of 2,500 to 5,000 2 2 kp / cm, a tensile strength of 210 to 3,500 kp / cm, linear coefficient of thermal expansion 10-12 ppm / ° C, Knoop hardness 470-500 and modulus of elasticity 4.2 x 5 2 10 kp / cm and characterized by cleavage along flat curved surfaces and absence of birefringence (polarized light) .

The term dense, as used herein, refers to a very dense order of particles, with almost completely no gaps and distances between the particles.

In contrast to the form of hydroxylapatite described above, geological hydroxylapatite and synthetic hydroxylapatite prepared by the hydrothermal process are macrocrystalline, crack along planar surfaces, and are birefringent. Biological hydroxylapatite is characterized by the fact that it generally contains significant amounts of carbonate ions in the apatite structure and in its purest state, i. as a tooth enamel, it is anisotropically arranged into rotating radial rods so that it splits linearly along the joint surfaces of these enamels and has a relatively low tensile strength of 105 kp / cm.

In addition to the above-mentioned properties of the ceramic form of the novel hydroxylapatite prepared according to the present invention, it is also completely biologically suitable and thus excellently suitable as a dental and surgical prosthetic material. Thus, the ceramic material of the present invention can be cast or machined into dental crowns, artificial teeth, bone and bridge prostheses, cannulas for attachment to artificial body members that can be attached to bone and extends through the skin, and into the testicles, testicular gums. and to study other diseases that can affect the tooth and bone. Appropriately ground, the novel ceramic material of this invention can be used as a synthetic bone filler in bone defect repair, as an abrasive, and as a dental replacement composition combined with conventional resins, as described below.

As a test surface for testing anti-rust agents, the ceramic material of this invention can be machined into a body of any suitable shape and size, preferably a size and shape that can be easily placed in a normal test tube. This is conveniently done by cutting or machining a large plate-like piece of dried filter cake to a suitable size and then sintering. The sintered products can be polished to high gloss using standard patching procedures, and the formed bodies are then used as substrates in the study of anti-rust agents according to the procedure of Turesky, et al. supra. After use, the ceramic bodies are simply polished again to form a new moisture surface.

Conventionally made, the ceramic materials of this invention are not only dense but also non-porous, and although non-porous material is essential in dental applications, a certain degree of porosity in the implant material may be advantageous in allowing body fluids to circulate and tissue to grow. Various degrees of porosity can be formed in this ceramic material as disclosed by 7,68216

Monroe, et al. supra. In this case, an organic material such as starch, cellulose powder, cotton or collagen can be mixed in amounts of 5-25% by weight of the gelatinous precipitate of hydroxylapatite. In the next sintering process, the organic materials are removed by combustion, thus causing cavities and channels in the otherwise non-porous product. Alternatively, porosity can be achieved mechanically by drilling or machining holes or openings in the non-porous ceramic.

In this way, according to this aspect of the invention, a denture made of ceramics can be made porous at its implantation point and the bare tooth surface remains non-porous. Implantation can be performed as described by Hodosh, et al., Journal of the American Dental Association 70, 362 (1965). Alternatively, a polymerizable or polymerized bonding material may be added to the ceramics of the invention, as described below, and the resulting composition may be used as a coating for metallic implants, as disclosed in U.S. Patent 3,609,876.

The above-mentioned novel ceramic form of hydroxylapatite can be prepared by precipitating from an aqueous medium having a pH of 10 to 12 hydroxylapatite having a molar ratio of calcium to phosphorus of approximately 1.62 to 1.72, separating the precipitated hydroxylapatite from solution and heating the resulting hydroxylate. for a sufficient time at a sufficiently high temperature to sinter and maximally compact said hydroxylapatite without substantially decomposing it.

Thus, hydroxylapatite is precipitated from an aqueous medium by reacting calcium ions with phosphate ions at a pH of about 10-12. Any calcium- or phosphate-containing compound which forms calcium and phosphate ions in an aqueous medium is suitable provided that the corresponding counterions of said compounds can be readily separated from the hydroxylapatite product, are not themselves associated with the hydroxylapatite structure or otherwise adversely affect substantially pure and separation. Examples of compounds that donate calcium ions include calcium nitrate, calcium hydroxide and calcium carbonate. Phosphate ions are obtained from diammonium hydrogen phosphate, ammonium phosphate and phosphoric acid. In the present process, calcium nitrate and diammonium hydrogen phosphate are the preferred sources of calcium and phosphate ions, respectively.

The preparation of a new form of hydroxylapatite in which the ratio of reagents used is chosen so as to obtain a precipitate in which the molar ratio of calcium to phosphorus is substantially the same as in hydroxylapatite is suitably carried out as follows: First, at a molar ratio of calcium nitrate to diammonium hydrogen phosphate of 1.67: 1 12 hydroxylapatite to form a gelatinous precipitate. The procedure presented by Hayek, et al. Inorganic Syntheses 7, 63 (1963), is suitable for this purpose. The gel-like suspension of hydroxylapatite thus obtained is then allowed to come into contact with the initial solution for a time sufficient to allow the ratio of calcium and phosphorus in the suspended hydroxylapatite to reach 1.62 to 1.72. This is conveniently done by either stirring the suspension for 10-90 minutes and combining boiling and subsequent standing at room temperature. Preferably, the suspension is boiled for 10 minutes and then allowed to stand at room temperature for 15-20 hours. The hydroxylapatite is then separated from the solution in a suitable manner, for example by centrifugation and vacuum filtration. The gel-like product thus obtained contains a large amount of water, which can be largely removed by compression.

If desired, the wet clay-like material formed may be cut or shaped into a suitable shape or alternatively cast into a suitable mold. It should be noted that a shrinkage of about 25% usually occurs upon drying of wet hydroxylapatite and a further shrinkage of about 25% upon sintering is as follows. This must, of course, be taken into account when shaping or casting the material. The wet product can be slowly heated to a sintering temperature of 1,000 to 1,250 ° C, removing any remaining water. Maintaining the temperature at 1,000 to 1,250 ° C for 20 minutes to three hours will result in sintering and maximum compaction of the product. It is usually recommended to isolate the dried product before sintering. In this case, the moist product can be dried at a temperature of 90-900 ° C for 3-24 hours until the amount of water in it has decreased to 0 to about 2%. It is generally preferred to perform the drying at 90-95 ° C for about 15 hours, or until the water content is

II

9,68216 decreased to 1-2 percent. The hydroxylapatite obtained in this way is brittle and porous, but its mechanical strength is relatively good. Slight separation or cracking may occur in the clay-like material during drying, especially if a thick filter cake is used. However, pieces as large as 2 and 100 cm in area and 3 mm thick are easily obtained. Separation or cracking during drying can be reduced or completely prevented by adding 0.4 to 0.6% by weight of an organic binder such as collagen, powdered cellulose to the freshly precipitated hydroxylapatite suspension, about 0.5% collagen being preferred. The organic binder evaporates during sintering and the physical properties of the ceramic product appear to be substantially unchanged compared to a product made without such a binder. Naturally, larger amounts of organic binder cause a porous ceramic product, as discussed above. Other organic and inorganic binders known in the ceramics field may be used.

It is generally appropriate at this stage to cut or shape the dried precipitate approximately from the final product to the desired shape, taking into account the aforementioned shrinkage in sintering.

The pieces formed from the macroformat precipitate must be smooth and error-free before sintering. The presence of cracks and fissures causes the pieces to crack during sintering. The products are then sintered at a temperature of 1,000 to 1,250 ° C for 20 minutes to three hours, the temperature and time being inversely proportional to each other. The sintering is preferably carried out at a temperature of 1,100 to 1,200 ° C for 0.5 to 1 hour. The resulting hard, dense ceramic body can be polished or machined using conventional procedures.

In the above process, it is critical to prepare hydroxylapatite as a gel-like precipitate from an aqueous solution, because only in this cohesive gel-like state can hydroxylapatite be shaped or cast and then dried and sintered to obtain a macro-shaped ceramic body. Dry, finely divided or granular hydroxylapatite cannot be restored to this cohesive, gel-like form. For example, if powdered hydroxylapatite is suspended in water and filtered, a cohesive, finely divided filter cake is obtained which simply dries and crumbles and cannot be shaped, cast or turned into a ceramic body. In addition, although the powdered hydroxylapatite can be mechanically compressed into a shaped body, such as a tablet, the product obtained by sintering is highly porous and does not crack along flat surfaces, but merely crumbles into pieces.

Although the formation of hydroxylapatite in an aqueous medium is a complex and incompletely understood event, it is generally assumed that calcium and phosphate ions initially combine to form a calcium-deficient hydroxylapatite with a calcium to phosphorus ratio of about 1.5. In the presence of calcium ion, it then undergoes a slow conversion to hydroxylapatite, where the ratio of calcium to phosphorus is 1.67. / TEanes, et al. Nature 208, 365 (1965) and Bett et al. J. Amer. Chem. Soc. 89, 5535 (1967) ./. Thus, in order to obtain a ceramic containing substantially pure hydroxylapatite, it is necessary in the process of this invention that the initially formed hydroxylapatite gel precipitate be allowed to contact the initial solution for a sufficient time so that the ratio of calcium to phosphorus therein is about 1.62 to 1.72. A significant deviation from this range results in a less transparent ceramic product. For example, if hydroxylapatite is precipitated at room temperature and recovered within two hours of precipitation, the ratio of calcium to phosphorus is about 1.55 to 1.57 and the ceramic made therefrom is opaque and found to be a mixture of hydroxylapatite and whitlocyte in X-ray diffraction studies. In fact, as discussed in more detail below, a material having a calcium to phosphorus ratio of about 1.44 to 1.60 is useful in making the biphasic ceramic material described above. Thus, although the method disclosed herein provides a transparent ceramic material containing predominantly pure hydroxylapatite, due to the incompletely understood form of hydroxylapatite formation in an aqueous medium, it may be advantageous to control the formation of hydroxylapatite to determine that the desired calcium is present. pure hydroxylapatite. This is conveniently done by taking a sample of the hydroxylapatite suspension, separating the product, drying and sintering it as described above, and performing elemental and X-ray analysis on the ceramics thus formed.

11 6821 6

Sintering time and temperature are also critical in the disclosed method. In this case, the unsintered hydroxylapatite having the desired ratio of calcium to phosphorus, 1.62 to 1.72, is converted into the ceramic product of the present invention by heating at a temperature of at least 1,000 to 1,250 ° C. At 1000 ° C, sintering and maximum condensation may take 2-3 hours, while at 1200 ° C the process is complete in 20-30 minutes. It is recommended to perform sintering at a temperature of about 1100 ° C for about an hour. Temperatures well below 1,000 ° C cause incomplete sintering despite the length of the heating cycle, while heating above 1,250 ° C for more than an hour causes partial decomposition of hydroxylapatite to whitlocyte.

The invention also relates to a dental replacement composition comprising a dentally acceptable polymerizable or polymerized binder and an inorganic filler. The patch composition according to the invention is characterized in that said filler is substantially pure, finely ground hydroxylapatite having an average crystal size of 0.2 to 3 μm, a density of about 3.10 to 3.14 g / cm 3, which is substantially porous. -incomplete and splits along even curved surfaces, and that the filler content is about 10-90% by weight. The polymerization catalyst is, for example, an aliphatic ketone peroxide or benzoyl peroxide, the reactive diluent is, for example, di-, tri-, and tetraethylene glycol dimethacrylate, the hardener is, for example, -tonate tertiary amine such as Ν, Ν-bis- (2-hydroxyethyl) -p-toluidine and, for example, zinc oxide as a crosslinking agent; these substances together account for 0.01 to 45% of the total weight of the composition. Although not essential, a surfactant comonomer or blocking agent, such as the reaction product of N-phenylglycine and glycidyl methacrylate disclosed in U.S. Patent 3,200,142, methacryloxypropyltrimethoxysilane, 3,4-epoxycyclohexyltrinitrile or methoxysilane, may be added. to said composition in amounts of 0.05 to 10% of the total weight of the composition. The bonding or locking agent promotes the adhesion of the ceramic material to the resin and the adhesion of the tooth filling composition to the natural tooth. In this case, the ceramic hydroxylapatite of the present invention is reduced to a suitable particle size, e.g. Chemicals Co. 23 LS8275 and Pitssburgh Plate Glass under the name Selectron 580001, with styrene-modified unsaturated polyesters such as Glidien Glidpol 10Q8, G-136 and 4CS50, epoxy resins such as Ciba Araldite 6020, Union Carbide ERL2774 and glycidyl methacrylate A from bisphenol A and bisphenol in Patent 3,066,112. The resin may comprise a single monomer or a mixture of two or more comonomers. If desired, additives such as colorants, inorganic pigments and fluorinating agents may be added to the above composition according to principles known in the art of handling these materials. It is preferred to mix the resin, ceramic hydroxylapatite and any additives such as silane blockers, dyes, inorganic pigments or fluorinating agents before adding the catalyst, hardener, crosslinking agent, promoter or accelerator. However, the order of mixing of the ingredients is not critical and said ingredients may be mixed simultaneously. Using conventional procedures, the composition thus prepared can be used as a dental filling material, dental care cement, dental cavity liner, dental cortex shell material, or the composition can be molded into a suitable mold to make an artificial tooth or group of teeth.

It is, of course, very advantageous that the material used in the oral cavity is! caries resistant. This is readily accomplished using the present invention by adding 0.01 to 1% of fluoride ions, such as ammonium tannin fluoride, to a suspension of freshly precipitated hydroxylapatite. The ceramic material obtained by sintering the product formed withstands the action of lactic, acetic or citric acid very well, which is a normal in vitro method for determining caries resistance. Alternatively, the resistance to caries can be obtained in the final ceramic material by keeping it in a 0.5-5% aqueous solution of sodium fluoride for 12 hours to 5 days. Preferably, the ceramic body is allowed to remain in about 5% aqueous sodium fluoride for about 4 days.

It will, of course, be of interest to those skilled in the art of ceramics that in addition to organic and inorganic binders and fluoride ion, the ceramic material of the present invention may contain small amounts of other elements which, while not altering the essential nature of ceramic products, may provide useful properties. For example, it is known that barium and strontium can be associated with the crystal structure of apatite, and these elements transmit significantly less X-rays than calcium. Therefore, the addition of a small amount of barium or strontium ions to the calcium ions prior to reacting the latter with phosphate finally yields a ceramic of barium or strontium inoculated hydroxylapatite which, when used in dental replacement compositions as described above, has sufficient X-ray absorption for patched teeth. Magnesium is also involved in the crystal structure of apatite, however, it is known to retard the crystallization of hydroxylapatite while promoting the crystallization of whitlocyte (Eanes et al., Calc. Tiss. Res. 2, 32 (1968)).

The properties of the ceramic materials obtained as described above were determined by one or more of the following studies: Elemental analysis, density, X-ray diffraction, translucent electron microscopy, microscopy using polarized light, and mechanical properties.

The invention is illustrated by the following examples.

Example 1

To a stirred mixture of 130 mL of 1.63 M calcium nitrate (0.212 moles) and 125 mL of concentrated ammonia was added dropwise over about 20 minutes a mixture of 16.75 g (0.127 moles) of diammonium hydrogen phosphate, 400 mL of distilled water, and 150 ml of concentrated ammonia. The resulting suspension was boiled for 10 minutes, cooled in an ice bath and filtered. The filtrate cake was pressed onto a rubber sheet and then dried overnight at 95 ° C. A sample of the resulting hard, porous, brittle i4 6821 6 cake was heated in an electric oven for 115 minutes to a final temperature of 1230 ° C and then cooled to room temperature to give a strong, hard, white transparent ceramic product.

Conventional elemental analyzes performed on the final ceramic product and also on the dried hydroxyl apatate before sintering gave the following results calculated

According to Ca10 (PO4) 6 (° H) 2:

Calculated Dried, unsintered Ceramic hydroxylapatite product

Ca 39.89% 37.4% 39.6% P 18.5% 17.5% 18.9% h2o 0% 1%

Ca / P 1.667 1.65 1.62

When a thin ceramic plate was examined under a microscope using polarized light at 130 x 352 X magnifications, the material was found to be substantially free of whitlocyte. The absence of shrinkage refraction and observable structural properties such as crystal shape, orientation, interfaces, etc. indicated a microcrystalline structure. In comparison, Monroe et al. (supra), the two materials were found to be structurally similar in optical micrograph.

X-ray diffraction measurements were performed in the normal manner. The distances between the crystal planes were calculated and found to be substantially identical to hydroxylapatite in Doannay et al., Crystal Data, ACA Monogram No. 5,668 (1963). X-ray values further showed the absence of whitlocyte at least greater than 2-3%, which is the detection limit of the minimum concentration of the diffractometer.

Example 2

The pH of a solution containing 237.6 g (1.8 moles) of diammonium hydrogen phosphate in 1500 ml of distilled water was adjusted to 11-12 by the addition of about 2250 ml of concentrated ammonia. Distilled water was added to dissolve the precipitated ammonium phosphate to give a total volume of 9600 ml. If necessary, the pH was readjusted to 11-12. This solution was added dropwise over 30-40 minutes to a vigorously stirred solution of 3 moles of calcium-15 6821 6 nitrate in 2700 ml of distilled water, the pH of which was pre-adjusted to 12 with about 90 ml of concentrated aqueous ammonia solution, followed by dilution with distilled water. with water until the volume was 5400 ml. After the addition was complete, the resulting gel suspension was stirred for an additional 10 minutes and then boiled for 10 minutes, removed from the heater, covered and allowed to stand at room temperature for 15-20 hours. The clear supernatant was removed by decantation and the remaining suspension was centrifuged at 2000 rpm for 10 minutes.

The resulting slurry was resuspended in 2400 ml of distilled water and centrifuged again at 2000 rpm for 10 minutes. Sufficient distilled water was added to the solid residues to give a total volume of 2700 milliliters. Shaking vigorously gave a uniform suspension with substantially no larger particles or agglomerates. The entire suspension was poured into a Buchner funnel at the same time and filtered using a weak vacuum. As the filter cake began to crumble, a rubber plate was placed on it and the vacuum was increased. After 1 hour, the rubber plate was removed and the uncracked, intact filter cake was transferred to a flat surface and dried for 15 hours at 90-95 ° C to give 304 g of white, porous, brittle hydroxylapatite pieces.

Sintering at 1100 ° C for one hour gave dense, non-porous, white, transparent ceramic bodies with a density of 0.0 3.10 g / cm 3. X-ray diffraction showed that the material was homogeneous hydroxylapatite.

Two-stage sample protrusions were prepared by shading the surface of the sample with a colloid ion protrusion with chromium and then coating with carbon. Penetration examination of the replicas by electron microscopy showed a relatively uniform grain size (0.7–3 μm) without pores or second phase precipitation at the granule interfaces or in the granules themselves in amounts greater than about 0.5%, which is the minimum sensitivity of the electron microscope to concentration. A sample of the ceramic material was then polished with SiC paper to 600 mesh and then with a 3 μm diamond paste on a metallographic plate coated with a thin nylon cloth. The sample was then etched with 4% hydrofluoric acid for 30 seconds. Copies of the polished and etched surface were then taken and examined by electron microscopy. In this case, a second phase of 6821 6 16 was also observed at the interfaces of the granules.

Porosity was determined qualitatively by immersing the sample material in magenta color for 15 minutes, washing it with water, drying, and then examining the sample material for color residues. This experiment was performed simultaneously on the non-porous form of the ceramic material of the present invention, a sintered compressed tablet of hydroxylapatite, and a natural tooth. The sintered compressed tablet showed considerable color retention, while no color residue was observed in the novel ceramic material and natural tooth of the present invention. According to the second method, the test material was immersed in a 6 N aqueous ammonia solution for 15 minutes, washed with water, dried and wrapped in moist litmus paper. Any ammonia left in the surface pores will cause the surrounding litmus paper to turn blue. When this experiment was performed simultaneously on the mechanical material of the present invention, a sintered compressed tablet of hydroxylapatite, and a natural tooth, the litmus paper in contact with the sintered compressed tablet turned blue, thus indicating the presence of ammonia in the tablet. No discoloration was observed in the plaque paper in contact with either the ceramic material of the present invention or the natural tooth.

Example 3 A. The procedure of Example 2 was followed except that 1/6 of the amounts shown therein were used, whereby approximately 50 g of hydroxylapatite precipitated from aqueous solution. After centrifugation and decantation, the mineral slurry obtained was re-extracted into water to a total volume of 1 liter and homogenized in a Waring mixer for 2 minutes.

B. The mixture containing 0.5 g of powdered cellulose (<0.5 μια) in 200 ml of water was stirred in a Waring mixer for 3 minutes. An aliquot of 100 ml of a homogeneous suspension of hydroxylapatite was then added and the resulting mixture was further stirred for 5 minutes. The suspension was then filtered and the filter cake was dried and sintered according to Example 2. After drying, the filter cake showed very few cracks and the ceramic product obtained by sintering was slightly porous as defined above.

II

17 6821 6 using the magenta color test.

C. A mixture of 0.5 g of shredded surgical cotton in 200 ml of water was stirred in a Waring mixer for 45 minutes or until a nearly homogeneous suspension was obtained. An aliquot of 100 ml of the homogeneous aqueous suspension of hydroxylapatite shown in Example 3A was then added and stirring was continued for another 15 minutes. The resulting suspension was filtered and the filter cake was dried and sintered as described in Example 2. The ceramic product remained intact and was visibly porous.

Example 4 A. A mixture containing 5 g of collagen (bovine Achilles tendon) in 300 ml of water was stirred in a Waring mixer for 5 minutes. Collagen absorbed large amounts of water to form a thick gel-like mass. A small amount of finely divided collagen (20-30 mg) remained in the suspension.

B. A suspension of finely divided collagen (250 mL) was decanted and mixed in a Waring mixer for 5 minutes with a subset of 100 mL of the homogeneous aqueous suspension of hydroxylapatite shown in Example 3A. The resulting mixture was filtered and the filter cake was dried and sintered according to Example 2. The ceramic product formed remained intact and almost non-porous.

C. About 20% of the thick gel-like collagen was mixed in a Waring mixer for 6 minutes with 150 ml of the homogeneous aqueous suspension of hydroxylapatite shown in Example 3A. The resulting mixture was filtered and the filter cake was dried and sintered according to Example 2. The filter cake remained intact before Sint scraping and had relatively good mechanical strength. The ceramic product obtained in the sintering was hard, strong and visibly porous.

Example 5

Samples of the ceramic product prepared according to Example 2 were allowed to remain in a 1% aqueous solution of sodium fluoride for 12 hours. These materials, together with the untreated ceramic material and the natural tooth, were then exposed to 1C lactic acid. After three days, the effect of lactic acid was significantly less observed in ceramics treated with fluoride than in untreated ceramics or natural tooth enamel. If the ceramic was allowed to stand in 18 6821 6 in 1% aqueous sodium fluoride solution for 3 days, there was no detectable effect of lactic acid after 3 days and only slight degradation had occurred after 1 month, whereas the untreated samples had significantly degraded.

Example 6

The procedure of Example 2 was followed except that 1/6 of the amounts present were used to precipitate about 50 g of hydroxylapatite from aqueous solution. After centrifugation, the mineral slurry was suspended in sufficient water to achieve a total volume of 500 milliliters. The suspension was divided into ten equal portions, each diluted with 50 ml of water and treated with ammonium fluoride as follows: To samples 1, 2, 3, 4 and 5, 0, 0.1, 0.5, 1.0 and 2.0 ml of aqueous ammonium fluoride solution were added, respectively. containing 0.00085 g F / ml. Samples 6, 7 and 8 were treated with 0.5, 1.0 and 10.0 ml of aqueous ammonium fluoride solution containing 0.0085 g F / ml, respectively. To samples 9 and 10, 2.0 and 4.0 ml of an aqueous ammonium fluoride solution containing 0.045 g F / ml were added, respectively. The suspensions were then shaken on a rotary shaker for 1.5 hours and then filtered. The filter cakes were pressed for 15 minutes with a rubber plate, dried for 2 days at 95 ° C and then heated in an electric oven to 1200 ° C. The resulting ceramic bodies were ground to a fine powder and sieved through a 325 mesh screen (ASTM standard). 80 mg of each powder sample was mixed with 80 ml of sodium lactate buffer solution (0.4-m) at pH 4.1 at 23 ° C and the mixtures were shaken on a Burrel joint shaker. An aliquot of 3 ml was removed from each sample mixture at 2.9, 25 and 40 minutes after mixing, immediately filtered to remove an insoluble sample, and the amount of dissolved ceramic was determined by a chlorimetric analysis procedure. The results are given in Table A. For comparison, the sintered portion of Sample 1 was allowed to stand for 4 days in 1 ml of 5% sodium fluoride. The solids were removed, washed thoroughly with water, dried and then subjected to the above-mentioned solvent analysis according to Sample IA. It should, of course, be appreciated that the experimental conditions described above do not correspond to in vivo conditions. They have been selected to ensure sufficient dissolution of the sample within a reasonable time to accurately assess the relative effect of the fluoride ion content.

Thus, the in vivo dissolution rates of ceramic hydroxylapatite are expected to be significantly lower than the rates observed above in strong lactate buffer.

Table A

Relative dissolution rates of fluorinated ceramic hydroxylapatite Sample Fluoride content (ppm) Dissolved% no. added observed 2 min 9 min 25 min 4Q min 10 - 9.2 18.5 32.0 39.7

2 17 19 9.2 18.8 29.3 39, Q

3 85 190a 8.9 17.6 30.0 38.3 4 170 190 10.3 18.3 3Q, 5 37.5 5 340 216 9.9 18.1 29.7 35.2 6 850 226 8, 8 17.1 27.7 33.0 7 1700 470 7.9 18.1 25.7 29.8 8 17000 1460 6.7 12.1 19.7 23.3 9 18000 1700 6.3 11.5 19 , 7 23.3 10 36000 2307 5.9 11.3 17.6 21.0 IA - - 3.7 7.1 13.7 18.7 a. Apparently erroneous analysis.

Example 7

Large pieces of dried filter cake about 3-4 mm thick, prepared according to Example 2 and with a Ca / P ratio of 1.64-1.66, were grooved and broken into rectangular sheets about 14-15 mm long and 7-8 mm wide and a small the hole was drilled through the other end. One thousand such plates were then sintered according to Example 2 and polished to high gloss using standard patching procedures. The formed ceramic bodies had a density of 3.12-3.14 and were rectangular pieces about 10-11 mm long, 4-5 mm wide and 2-3 mm thick and had a hole at one end through which a metal was placed. 2 1 6 lilanka. Plates, which could thus be placed to the desired depth in the test tube, were used as test surfaces in the development of anti-rust agents, as described above.

The liver-shaped ceramic articles prepared according to Examples 1, 2, 4B and 5-7 are hard, strong, dense, white, transparent ceramic bodies containing mainly pure, non-porous, isotropic polycrystalline hydroxylapatite and having a compressive strength of approximately 2 2 2500-9000 kp / cm, tensile strength in the range of approximately 210-210Q kp / cm, coefficient of linear thermal expansion in the range of approximately 10-12 ppm / ° C,

Knoop hardness in the range of approximately 470-50Q and a kimin modulus of about 5 2 4.2 x 10 kp / cm and characterized by cleavage along flat, curved surfaces and the absence of birefringence in polarized light.

Macro-shaped ceramic products made according to Examples 3 and 4, although containing the same material as those made in Examples 1, 2, 4B and 5-7, have formed openings and pores of varying number and size. It is, of course, apparent that the formation of pores in said articles alters their physical properties, for example by lowering the compressive strength, tensile strength, resilience and hardness. Example 8

A composition suitable as a dental filling cement and filler was prepared as follows: A. To a solution of 20 mg of the condensation product of N-phenylglycine and glycidyl methacrylate (disclosed in U.S. Patent 3,200,142; referred to therein as NPG-GMA) in 7 ml of ethanol was added 2, 0 g of ground ceramic hydroxylapatite. After stirring for 5 minutes, the ethanol was evaporated off in vacuo at room temperature and the solid residue was dried for 2 hours at 1 mm Hg.

B. An 80 mg sample of the above material was mixed with 0.4 g of benzoyl peroxide and 30 mg of the reaction product of hydroxyethyl methacrylate and bisphenol A and glycidyl methacrylate (disclosed in U.S. Patent 3,066,112; referred to in the art as Bis). -GMA) mixture in a ratio of 1: 2. The resulting mixture was placed in a cylindrical steel mold where it cured in 3-5 minutes.

ii.

21 6821 6

The compressive strength was determined by means of four cylindrical 2 pins thus prepared. The mean value was 12QQ kp / cm.

Example 9

A mixture of 60 parts of ground ceramic hydroxylapatite, 13 parts of hydroxyethyl methacrylate, 27 parts of the condensation product of bis-phenol A and glycidyl meracrylate, 0.3 part of Ν, Ν-bis- (2-hydroxyethyl) -p-toluidine and 0, 8 parts of benzoyl peroxide was mixed thoroughly to give a thin, free-flowing preparation useful as a cover for dental cavities and cracks. The mixture was poured into a cylindrical steel mold where it cured for about 3 minutes. The compressive strength was determined by means of seven cylindrical rods 2 thus prepared. The average value was 1400 kp / cm.

Example 10

The following is an example of a preparation suitable as a dental filling material.

To 5 ml of 2-propanol was added 0.5 g of ground ceramic hydroxylapatite. The 2-propanol was then evaporated in vacuo at room temperature to remove any water of hydration from the surface of the ceramic material. To 120 milligrams of the hydroxylapatite thus treated was added 0.3 mg of benzoyl peroxide and then 40 mg of a mixture containing the condensation product of bisphenol A and glycidyl methacrylate triethylene glycol dimethacrylate and Ν, Ν-bis- (2-hydroxyethyl) p-toluidine Pharmaceuticlas under the trade name Epoksylite Hl-72. The mixture was kneaded with a spatula to a uniform paste and placed in cylindrical steel molds and allowed to cure for 4 hours. The cylindrical pins were removed from the molds and 3 pieces were examined and their 2 average compressive strength was found to be 1600 kp / cm.

Example 11

To a solution of 30 mg of the condensation product of N-phenylglycine and glycidyl methacrylate in 7 ml of ethanol was added with stirring 1 g of ground ceramic hydroxylapatite. The ethanol was evaporated in vacuo at room temperature. To a mixture of 180 mg of the thus treated ground ceramic hydroxylapatite and 3.0 mg of benzoyl peroxide was added 74 mg of a mixture of 60 parts of the condensation product of bisphenol A glycidyl methacrylate 22 6 8 2 1 6 and 40 parts of triethylene glycol dimethacrylate which was placed in cylindrical steel molds and allowed to cure for 3 hours. The cylindrical bars were removed from the molds and the examination of 4 individuals 2 gave an average compressive strength of 1600 kp / cm.

Example 12

A composition suitable as a dental or orthodontic cement or temporary dental filling was prepared by mixing together 100 mg of ground ceramic hydroxylapatite, 300 mg of zinc oxide and 300 mg of a 40% aqueous solution of polyacrylic acid. The resulting mixture was placed in cylindrical steel molds where it cured in about 3-5 minutes. The cylindrical pins were removed from the molds and 4 individuals were examined to give an average compressive strength of 870 kp / cm.

The average diametrical tensile strength 2 of the other 5 individuals was 110 kp / cm. 40% polyacrylic acid and zinc oxide were obtained as a liquid and solid component, respectively, in a commercial polycarboxylate cement sold by ESPE G.m.b.H, West Germany, under the trade name DURELOI ^.

Example 13

A composition suitable as a dental cement and dental filler was prepared by mixing together 6 parts by weight of a 40% aqueous solution of polyacrylic acid and a mixture containing 6 parts by weight of ground ceramic hydroxylapatite and 4 parts by weight of zinc oxide. The settling time of the formed composition was about 5-10 minutes. A 40% aqueous solution of polyacrylic acid and zinc oxide were obtained as ingredients of commercial polycarboxylate cement, respectively, sold by ESPE G.m.b.H. West Germany, under the trade name DURELcW®.

Example 14

The following is an example of a dental filling composition:

Ingredient Percent by weight

Styrene modified polyester resin (Glidden Glidpol G-136) 29.2

Benzoyl peroxide 0.7

Styrene 0.6

Methacryloxypropyltrimethoxysilane 1.5

Ceramic hydroxylapatite 68.0

II

23 6821 6

Example 15

The following is an example of a composition suitable as a dental cement, cavity liner and peel material:

Ingredient Percent by weight

Epoxy resin (Union Carbide ERL2774) 67 N-3-oxo-1,1-dimethylbutylacrylamide 23

Ceramic hydroxylapatite 10

Example 16

The following is an example of a composition suitable for making an artificial tooth or group of teeth.

A mixture of 60 parts by weight of ceramic hydroxylapatite having a mesh number of about 150-200 and 40 parts by weight of ground polymethyl methacrylate is mixed with about 15 parts by weight of liquid monomeric methyl methacrylate and the resulting mixture is allowed to stand. in a closed container at room temperature until the material no longer adheres to the walls of the container and its composition is pasty and shaped. The material is placed in an appropriate mold and the mold and its contents are immersed in water, which is heated to boiling for about an hour and this temperature is maintained for 30 minutes. The mold is then allowed to cool in air for about 15 minutes and finally cooled with cold tap water.

The biocompatibility of the novel ceramic form of hydroxylapatite according to the present invention was established by implantation studies, which showed that no inflammatory effect was obtained if the ceramic bodies prepared according to Example 1 were implanted intraperitoneally in rats or placed subcutaneously in rabbits.

Ceramic hydroxylapatite pellets prepared as described in Example 3 were surgically implanted in the femurs of dogs. Implanted objects were monitored in vivo from time to time by X-rays. After one month and six months, respectively, the animals were sacrificed and the thighs containing the implanted objects were removed. Samples were excised from the femur at the implantation sites and examined using both optical and scanning electron microscopy. Both the one-month and six-month 24 6821 6 implants were characterized by normal healing, strong adherence of new bone to the implant surface without interstitial fibrous tissue, no signs of inflammation or foreign body rejection, and no resorption of the implanted material was observed.

Claims (5)

25 6821 6 A translucent, isotropic, polycrystalline, sintered ceramic material, characterized in that it is substantially pure hydroxylapatite with an average crystal size of 3 to 0.2 to 3 μm and a density of about 3.10 to 3.14 g / cm 3. which is substantially non-porous and cleaves along flat curved surfaces. Ceramic material according to claim 1, characterized in that an amount of fluoride ions is included which is able to substantially reduce the decomposition of said ceramic material by the action of lactic acid. 3. A dental restorative composition comprising a dentally acceptable polymerizable or polymerized binder and an inorganic filler, characterized in that said filler is substantially pure, finely ground hydroxylapatite having a crystal size of 0.3 to 3 μm in chimera with a density of 0.2 to 3 μm. about 3.10 to 3.14 g / cm 3, which is substantially non-porous and cleaves along flat curved surfaces, and that the filler content is about 10 to 90% by weight. Composition according to Claim 3, characterized in that the dentistically acceptable binder is polyacrylic acid. Composition according to Claim 3, characterized in that the dentistry-acceptable binder is a condensation product of bis-phenol A and glycidyl methacrylate.