BRPI1005577A2 - bioceramic material of bovine hydroxyapatite and bio-glass niobosphate, use and process of obtaining - Google Patents

Abstract

BIOCERAMIC MATERIAL OF BOVINE HYDROXIAPATHY AND BIOVIDRO NIOBO PHOSPHATE, USE AND OBTAINING PROCESS. The present invention provides a biocompatible, bioactive, partially synthetic bioceramic material comprising a sintered body of a hydroxyapatite mixture of bovine origin with biohydro-phosphate (CaO-CaF ~ 2 ~ P ~ 2 ~ 0 ~ 5 ~ -Nb ~ 2 ~ O ~ 5 ~). In a preferred embodiment, said bioceramic material comprises hydroxyapatite and more soluble phases comprising?: -TCP; <225> -TCP with magnesium; calcium niobates, or combinations thereof. The ceramic material of the invention is particularly useful in the preparation of synthetic bone substitutes. Said bone substitutes have the advantage of being biocompatible and properly degraded by the body, presenting strong chemical bond to bone tissue. Also disclosed is a process for obtaining such ceramic materials, comprising the mixture of hydroxyapatite of bovine origin and biohydro-phosphate (CaO-CaF-2-P-2-O-5--Nb-2-O-5 ~) followed by sintering.

Description

Patent Invention Descriptive Report

Bioceramic Material of Bovine Hydroxyapatite ε Bio-Glass Niobo Phosphate, Use ε Obtaining Process

Field of the Invention

The present invention belongs to the field of graft and implant related dentistry and orthopedics. More specifically, the invention provides a process for the production of bioceramic material and a bioceramic material of bovine hydroxyapatite and bio-glass phosphate. The invention is especially directed to the production of a partially synthetic, biocompatible and bioactive bioceramic material produced from hydroxyapatite of bovine origin and bio glass niobo phosphate (CaO-CaF2-P2O5-Nb2O5).

Background of the Invention

There is a worldwide trend in the use of synthetic bone grafts in place of the traditional autogenous bone graft when it is necessary to repair or regenerate extensive bone lesions of traumatic, pathological or inflammatory origin.

One of the important requirements of synthetic bone grafts is the solubility in the medium and through cells present in bone tissue, which allow them to act as temporary materials that will be gradually exchanged for new bone produced by the body.

The bone taken from the patient himself (autogenous) is considered as the "gold standard" among the materials of choice, as it adds the presence of viable cells and bone growth inducing proteins, but its use is limited by local and systemic complications, limited availability. , uncontrolled resorption and pronounced loss of grafted bone volume (EWERS, 2006).

These disadvantages have led many surgeons to choose materials of synthetic origin such as calcium phosphate bioceramics and bioactive glasses. By 2005, the number of orthopedic surgical procedures performed in the United States using synthetic bone grafts had already surpassed those in which autogenous bone grafts were employed. In Europe, a similar trend is observed, especially when new regulatory guidelines imposed by the European Community affect the practice and routine of bone banks (VALIMAKI1 2006).

Calcium phosphate ceramics and bioactive glass are bone defect fillers, already widely used in orthopedics and dentistry due to their high biocompatibility, mainly based on their ability to chemically bind to bone tissue and their ability to undergo bone dissolution and reabsorption. Among calcium phosphates, hydroxyapatite has a close chemical and structural similarity with the mineral phase of bone tissue and its use as a synthetic bone substitute has grown significantly (SHORS, 1993). The main sources of hydroxyapatite in the preparation of these products are analytical chemical reagents, bovine bone and corals.

Among the commercial products of bovine origin, we highlight Bio-Oss®, Osteohealth Company - Switzerland, with clinical behavior reported in almost two decades of scientific work. Its benefit seems to be related to the chemical process of removal of the organic part keeping unchanged the size and shape of the nano crystals and the high macro and microscopic porosity of the bone (LUSSI, 1992), as well as the low crystallinity, which implies a resorbable material. .

Removal of organic compounds from bovine bone by volatilization at elevated temperatures increases the crystallinity of the hydroxyapatite present impairing the bone resorption process in vivo.

Bioglass is normally used in situations where high tensile, compressive or flexural strength values are not required. However, bio-glazing can be used in composites such as bio-glass reinforced hydroxyapatite (HA), known as "glass-reinforced hydroxyapatite - GR-HA", which have been the subject of extensive studies. The sintering of HA with the addition of bioglass usually occurs with the presence of liquid phase. In previous studies, it was observed that these bio-glasses induce the decomposition of part of hydroxyapatite in tricalcium phosphate (TCP). Depending on the added bioglass content and the sintering temperature, the product may be HA + β-TCP or HA + α-TCP + β-TCP. The purpose of the HA + TCP association is to produce a partially resorbable material.

Recently, it has been shown that niobo-phosphate glasses induced the degradation of synthetic and stoichiometric hydroxyapatite with α and β TCP phase formation after sintering. Such glasses also showed absence of cytotoxicity (PRADO da SILVA, 2008). The addition of bioactive glasses to stoichiometric hydroxyapatite prior to sintering has also been shown to be effective in increasing degradation in vivo and in enhancing bone-implant bond strength in vivo compared to pure hydroxyapatite (SO, 2006).

In the patent area, some documents describe processes for the production of bioceramic material. References which circumscribe the invention, without however anticipating or even suggesting it, are listed below.

Document P0506242-0 discloses a process for obtaining hydroxyapatite via fish bone calcination. The present invention is in no way confused with that of the above document by reporting a different step process which results in a different product using bovine feedstock which comprises a bio glass and has better implant and graft characteristics.

Document P 0601447-0 describes the production of niobium phosphate-containing hydroxyapatite composite. The present invention differs from that document, among other technical reasons, in that it uses bovine hydroxyapatite, while the one described is synthesized in the laboratory. Additionally the invention uses a glass to reinforce bovine hydroxyapatite, while that of Pl 0601447-0 uses a niobium phosphate. Document P 0605628-8 discloses a product and process for obtaining a bioactive porous ceramic matrix composed of alumina, hydroxyapatite and bioglass. The process of the present invention is not to be confused with that disclosed and the product is a bioceramic material of bovine hydroxyapatite and bio glass niobosphate, not even hinted in above.

Pl 8903641-7 shows a process for obtaining bioceramic material (hydroxyapatite) obtained by sintering commercial tricalcium phosphate. Pl 9104220-8 discloses a process for obtaining a ceramic material, hydroxyapatite, for use in grafts. The present invention differs from these documents, among other technical reasons, in that it presents an improved material for implants and grafts using natural raw material of bovine origin and comprising a bio-glass.

Pl 9307825-0 describes a calcium phosphate-containing composition, an improved process for preparing it, and a calcium phosphate cement. The present invention differs from this document, among other technical reasons, in that it presents a bioceramic material of bovine hydroxyapatite and bio glass niobo phosphate for implants and grafts.

Pl 9608344-1 discloses a biocompatible hydroxyapatite formulation, where such formulation is administered to a plant or animal. The present invention is not to be confused with that of the document, among other technical reasons, for presenting a process and a bioceramic material of bovine hydroxyapatite and bio glass niophosphate for implants and grafts.

Document P 0202117-0 discloses a process for obtaining nanocrystalline hydroxyapatite by high energy milling. Said process adds a high energy milling step to the process, and such fact is in no way confused with the process steps of the present invention.

Pl 0204440-4 describes a low temperature preparation process of calcium phosphate bioceramics giving a product in the form of granules and blocks with bone regeneration properties for use in implants, such a process consists of preparing pastes of various compositions to be from calcium phosphates using tricalcium phosphate as a solid phase and using a sodium monohydrogen phosphate solution as a liquid phase. The present invention differs from these documents, among other technical reasons, in that it presents an improved material for implants and grafts using hydroxyapatite of bovine origin and which comprises a bio glass niobo phosphate.

Document P 0208800-2 demonstrates improved bioactive glass with niobium addition. This document does not at any time anticipate or suggest the process and bioceramic material of the present invention using hydroxyapatite of bovine origin and a bio glass niobo phosphate. The present document presents as starting material the bone of bovine origin, which is modified by the addition of the niobo phosphate glass. Said bioglass is the subject of co-pending patent application Pl 0901317-2, by the same inventor. The addition of said bioglass induces the decomposition of bovine bone hydroxyapatite when heated to high temperatures in resorbable crystalline phases. One of the main advantages of the present invention over all bovine bone products is that it provides heat treatment at temperatures above 1100 ° C, without prejudice to the resorption rate.

WO 01/94274 discloses a method for producing a glass reinforced ceramic foam comprising hydroxyapatite and a biocompatible glass. The present invention differs from this document, among other technical reasons, in that it presents an improved material for implants and grafts using natural bovine feedstock and comprises a bio-glass phosphate.

WO 2009/126054 reports a bone substitute based on silicon, biocompatible glass and hydroxyapatite. The present invention relates to a naturally occurring bovine hydroxyapatite ceramic material with the addition of a niobo phosphate bioglass.

US 5,071,434 shows a biologically active ceramic as a hard tissue substitute comprising a dense calcium phosphate ceramic body having a surface layer comprising hydroxyapatite and tertiary calcium β-phosphate. The product of this document at no time suggests the product of the present invention which is a bioceramic material of bovine hydroxyapatite and biohydro-phosphate.

WO 2007/121457 describes a bioactive glass and a composition of such glass with a calcium source, which may be a hydroxyapatite. Said glass contains in its composition the silicon (SiO2) 1 phosphorus (P2O5) 1 calcium (CaO) 1 sodium (Na2O) and magnesium (MgO) oxides. The invention reported herein provides a bioceramic bovine hydroxyapatite bioceramic material containing bioaviolous phosphate.

From what can be inferred from the researched literature, no documents were found anticipating or suggesting the teachings of the present invention, so that the solution proposed here, in the eyes of the inventors, has novelty and inventive activity in the state of the art.

Thus, there is still a need for a cost-effective bone graft material that has at least the same characteristics as similar products on the market. To this end, the present invention describes the process of producing a partially synthetic, biocompatible and bioactive bioceramic material produced from hydroxyapatite of bovine origin and biohydro-phosphate (CaO-CaF2-P2O5-Nb2O5).

Summary of the Invention

This invention provides a process for producing a bioceramic material and a bioceramic material of bovine hydroxyapatite and bio glass niobosphate.

It is therefore an object of the present invention a process for the production of bioceramic material of bovine hydroxyapatite (HA) and bio glass niobosphate (BIOVIDRO) comprising the following steps:

a) obtaining hydroxyapatite from bovine bone;

b) preparation of niobo phosphate glass;

c) mixing the products of a) with b); d) obtaining green bodies; and

e) sintering said bodies.

Preferably, step a) uses fresh raw material. In step a) the volatilization of the organic compounds preferably occurs by slow heating, starting at room temperature up to 550 ° C at a rate of 0.5 ° C per minute with abundant air supply and staying at 550 ° C. for 2 hours.

In a preferred embodiment, the percentage of bio glass added to bovine hydroxyapatite, as per step c), is in the range of 2% to 50%.

In step d) the obtained bodies are preferably sintered in a temperature range which may vary from 100 ° C to 1400 ° C depending on the desired final composition.

It is a further object of the present invention the bioceramic material of bovine hydroxyapatite and bio glass niobosphate obtained from the process described above, characterized by having optimal biocompatibility.

A further object of the present invention is a partially synthetic, biocompatible and bioactive bioceramic material comprising a sintered body of a hydroxyapatite mixture of bovine origin with biohydro-phosphate (Ca0-CaF2-P205-Nb205). In a preferred embodiment, said bioceramic material comprises hydroxyapatite and more soluble phases comprising β-TCP; β-TCP with magnesium; calcium niobates, or combinations thereof.

It is a further object of the invention to use the ceramic material of the invention in the preparation of synthetic bone substitutes. Said bone substitutes have the advantage of being biocompatible and properly degraded by the body, presenting strong chemical bond to bone tissue.

These and other objects of the invention will be immediately appreciated by those skilled in the art and companies having an interest in the segment, and will be described in sufficient detail for their reproduction in the following description. Brief Description of the Figures

Figure 1 shows the X-ray diffractogram of calcined bone at 900 ° C.

Figure 2 shows the X-ray diffractogram of the control sample at 1400 ° C.

Figure 3 shows the X-ray diffractogram of the HA-BIOVIDRO sample.

4% at 1400 ° C.

Figure 4 shows scanning electron micrographs of the surface of a 4% sintered bioglass hydroxyapatite sample at 1400 ° C.

Detailed Description of the Invention

This invention relates to a partially synthetic, biocompatible and bioactive bioceramic material, as well as its use and process for obtaining it. Said material is obtained by a process comprising the use of hydroxyapatite of bovine origin in admixture with biohydro-phosphate (CaO-CaF2-PaO5-NbaO5). The resulting mixture is sintered and the material obtained is composed of hydroxyapatite and more soluble phases such as β-TCP, β-TCP with magnesium and calcium niobates, depending on bioglass concentrations. Thus, we have the incorporation of bioactive glasses to hydroxyapatite of bovine origin as an alternative route, to the production of a synthetic bone substitute that can be properly degraded by the body and show strong chemical bond to bone tissue.

Among the main advantages of this bone graft production process is the unlimited availability and low cost of bovine bones combined with the simplified and inexpensive hydroxyapatite extraction process described herein. The present invention also provides a bioceramic product.

Bio-glass reinforced for use in dental grafts, orthopedic, ceramic denture, orthopedic metallic coatings, ceramic, maxillofacial, aesthetic etc., with low cost and optimum biocompatibility. The process of the present invention for producing bioceramic material of bovine hydroxyapatite (HA) and bio glass niobo phosphate (BIOVIDRO) comprises the following steps:

a) obtaining hydroxyapatite from bovine bone;

b) preparation of niobo phosphate glass;

c) mixing the products of a) with b);

d) obtaining green bodies;

e) sintering of the material obtained in d).

HA-BIOVIDRQ bioceramic material production process

In the following, a preferred embodiment of the invention is described in detail.

a) Obtaining hydroxyapatite from bovine bone

The hydroxyapatite used comes from the processing of bovine bones. The bones, preferably the large bovine bones, preferably the femur, are cut into transverse slices approximately 10mm thick. Preferably, the bones used are fresh. Initially, they are cleaned in boiling water to remove soft and fatty tissues from the trabecular spaces and medullary cavities. After initial cleaning, the slices are cut into blocks of approximately 10mm X 10mm dimensions. Then, the portion of organic compounds intrinsically bound to the hydroxyapatite crystals is volatilized in a sintering furnace. The volatilization of the organic portion is by slow heating starting from room temperature to approximately 550 ° C at a preferred rate of 0.5 ° C per minute, with abundant air supply and staying at 550 ° C of 1.5 to 2, 5 hours, preferably 2 hours.

After this time, the oven is turned off and the samples remain inside until fully cooled. Then the bone blocks are ground and sieved. For milling the blocks preferably ball mills are used. The particle size employed is in a preferred particle size range between 35 pm and 20 μιτι.

Alternatively, the bone blocks are not ground remaining as a porous block of mineral bone because the organic part has been volatilized. Preferably, these unground blocks have a size of up to 20mm χ 20mm χ 20mm, preferably up to 10mm χ 10mm χ 10mm.

(b) Preparation of niobophosphate glass

The bioactive glass was prepared from analytical chemical reagents and has a composition of 30% P2O5; 30% Nb 2 O 5; 20% CaO and 20% CaF2 by weight.

The source of P2O5 used is the result of the decomposition of phosphoric acid into phosphoric anhydride and water according to the equation below:

2 H3PO4 = P2O5 + 3 H2O

The source of CaO used is the result of the decomposition of calcium carbonate in calcium oxide and carbon dioxide, according to the equation below:

CaCO3 = CaO + CO2

However, any form of obtaining P2O5 and CaO may be used for the preparation of the niobo phosphate bioglass of the present invention.

Nb2O5 and CaF2 are obtained from analytical chemical reagents Nb2O5 and CaF2 respectively. In the production of bioactive glass, the reagents are homogenized for up to 30 hours, preferably 24 hours, in a magnetic stir plate, followed by oven drying at 60 ° C for up to 10 hours, preferably 6 hours. The mixture is melted at a temperature ranging from 1200 to 1400 ° C, preferably 1300 ° C remaining at this temperature for up to 1 hour. The compound is removed from the oven and immediately cooled in cold water, preferably distilled, demineralized or deionized.

The glass obtained in this way is milled and sieved, preferably milled in ball mills. The size of the glass particles employed is within a submicron particle size range.

c) Mixing of the product from a) with b)

The HA-BIOVIDRO composite was obtained by adding 1% to 50% by weight of bioactive niobophosphate glass to hydroxyapatite obtained from bovine bone processing. The mixtures of bioglass and hydroxyapatite are homogenized under magnetic stirring for up to 10 hours, preferably 8 hours, in ethanol suspension and then oven dried at 60 ° C for up to 24 hours. The powders are then deagglomerated, for example, into alumina grit and pistil.

In the alternative case for the use of blocks, such blocks are then impregnated with bio glass phosphate.

d) Get the green bodies

The green bodies are preferably produced in the form of tablets. To this end, up to 10 g of HA-BIOVIDRO composite, preferably 7 g, preferably 5 g, preferably 2 g, is weighed and then placed in a suitable size metal pressing matrix for the chosen amount of HA-BIOVIDRO composite. For example, for the case of 2 g HA-BIOVIDRO composite, the metal press matrix used was 12 mm in diameter.

The pressing of the obtained material may be performed by any means of the prior art, such as isostatic pressing and / or isostatic hot pressing. In a preferred embodiment the pressing of the obtained material is uniaxial. In pressing the pellets a preferential load of up to 1,500 kg, preferably 1,000 kg (strain 87 MPa) is employed for approximately 2 minutes.

In alternative embodiments of the invention, the ceramic material is produced with porous scaffolds through porous ceramic production techniques such as: addition of pore forming agents, gelcasting, impregnation of polymeric sponges, among others. The frames thus produced are sintered for the consolidation of the porous ceramic body, e) Sinter the material obtained in d)

The pellet-shaped green bodies are sintered in a sintering furnace over a temperature range of from 100 ° C to 1400 ° C depending on the desired final composition. Higher temperatures induce a higher percentage of resorbable phases.

The tablets are heated from room temperature to 550 ° C at a rate of 0.5 ° C per minute. They are kept at this level for 2 hours and then heated to the desired final temperature between 1000 ° C and 1400 ° C at a rate of 5 ° C per minute, kept at this level for 1h and then cooled naturally in the oven. HA-BIOVIDRO bioceramic material and its use

The bioceramic material of the present invention is partially synthetic, biocompatible, and bioactive, comprising a sintered body of a hydroxyapatite mixture of bovine origin with bio glass hydroxy phosphate (CaO-CaF2-P2O5-Nb2O5). In a preferred embodiment, said bioceramic material comprises hydroxyapatite and more soluble phases comprising β-TCP; β- TCP with magnesium; calcium niobates, or combinations thereof.

The ceramic material of the invention is particularly useful in the preparation of synthetic bone substitutes. Said bone substitutes have the advantage of being biocompatible and properly degraded by the body, presenting strong chemical bond to bone tissue. Results Fig 1 shows the X-ray diffractogram of bone after calcination at 900 ° C, demonstrating pure hydroxyapatite. Figure 2 shows the diffractogram of a sintered bovine hydroxyapatite sample at 1400 ° C. The result shows that hydroxyapatite did not degrade despite the high temperature of the sintering reaction. In Figure 3, the diffractogram of a sample of bovine hydroxyapatite mixed with 4% niobo-phosphate biomass and sintered at 1400 ° C indicates that the addition of a small fraction of bioglass was able to induce hydroxyapatite degradation and the emergence of soluble phases β-TCP and β-TCP with magnesium. Figure 4 shows the surface scanning electron micrographs of a 4% bio-sintered hydroxyapatite sample at 1400 ° C.

Obtaining the diffractograms of the tablets containing well-defined percentages of glass provided a basis for querying the percentages of glass contained in samples prepared by another route: 10mmxl Ommxl Omm1 crouton-like bone blocks were immersed in a ground glass suspension. The blocks were sintered, giving rise to a block with original trabecular bone architecture and containing more resorbable phases. Subsequent X-ray diffraction analyzes allowed to infer the percentage of glass incorporated.

One of the advantages of this production route is that it obtains porous blocks without the need for conformation from dust. The blocks are biocompatible, bioresorbable and heat treated at temperatures above 100 ° C, which eliminates any question of the animal origin of the samples.

In one embodiment of the invention, the architecture of the porous bone blocks is utilized: the blocks undergo the same chemical and thermal treatments described above to obtain bovine hydroxyapatite. The difference lies in the absence of the milling step: the material is not reduced to dust, remaining as a porous block of mineral bone because the organic part has been volatilized. The block of mineral bone is then impregnated with bio glass Niobophosphate and sintered in the same way as the pressed pellets are.

In the process presented in the present invention, despite the high crystallinity of the resulting phases, a bioreabsorbable ceramic material is obtained due to the presence of soluble phases β TCP and β TMCP.

The addition of small fractions of bioactive glasses to hydroxyapatite as a sintering additive has been shown to be effective in increasing mechanical strength in general and in increasing solubility of the final product against pure hydroxyapatite. This result seems to be related to the degradation of part of hydroxyapatite with formation of known and more soluble TCP phases and the inhibition of grain growth exerted by glass.

The bio-glass reinforced composite reported herein is intended for the prevention and treatment of vertebrate tissue damage, more specifically in cases where the tissue is bone or tooth requiring an increase in hydroxyapatite deposition. Thus, these materials can be used as bone grafts or implants in periodontitis, bone fractures, vertebroplasty, dental caries or demineralization or dentin hypersensitivity restorations. They can also be used as a covering for materials to be implanted in mineralized tissues, such as prostheses and implant pins.

The examples shown herein are intended solely to exemplify one of the numerous ways of carrying out the invention, but without limiting the scope thereof.

Those skilled in the art will appreciate the knowledge presented herein and may reproduce the invention in the embodiments presented and in other embodiments within the scope of the appended claims.

Claims (13)

Bioceramic Material of Bovine Hydroxyapatite ε Bio-Glass Niobo Phosphate, Use ε Obtaining Process 1. Partially synthetic, biocompatible and bioactive bioceramic material comprising a sintered body of a hydroxyapatite mixture of bovine origin with bio-glass niobo phosphate (CaO-CaF2-P2O5-Nb2O5). Bioceramic material according to claim 1, characterized in that it comprises hydroxyapatite and more soluble phases comprising β-TCP; β-TCP with magnesium; calcium niobates, or combinations thereof. 3. Partially synthetic, biocompatible and bioactive bioceramic material characterized in that it is obtained by a process comprising the following steps: (a) obtaining hydroxyapatite from bone; b) preparation of niobo phosphate glass; c) mixing the product from a) with b); and d) sintering the material obtained in c). Process for the production of bioceramic material comprising the steps of: a) obtaining hydroxyapatite from bovine bone; b) preparation of niobo phosphate glass; c) mixing the products of a) with b); d) obtaining green bodies; and e) sintering said bodies. Process according to claim 4, characterized in that the hydroxyapatite is obtained from fresh bovine bone, cleaned in boiling water, cut into blocks up to 20mm χ 20mm χ 20mm. Process according to claim 4 or 5, characterized in that the organic compounds of said hydroxyapatite are volatilized with slow heating, starting at room temperature up to 550 ° C at a rate of 0.5 ° C per minute, with supply. plenty of air and stay at 550 ° C for 2 hours. Process according to Claim 4, 5 or 6, characterized in that the bone material is further ground and sieved to obtain particles in the particle size range between 35 pm and 20 pm. Process according to any one of claims 4-7, characterized in that the percentage of bio-glass added to bovine hydroxyapatite is in the range of 2% to 50%. Process according to any one of claims 4-8, characterized in that the step of preparing the niobophosphate glass comprises the homogenization of P2O5; NbaO5; CaO and CaF2 for up to 30 hours, drying at 60 ° C for up to 10 hours, and casting at a temperature between 1200 and 1400 ° C, remaining at this temperature for up to 1 hour and then immediately cooled. Process according to any one of claims 4-9, characterized in that the glass is further ground and sieved to obtain particles in the submicron particle size range. A process according to any one of claims 4-10, characterized in that the sintering is conducted in a temperature range ranging from 1000 ° C to 1400 ° C. Use of biocompatible and bioactive partially synthetic bioceramic material, comprising a sintered body of a hydroxyapatite mixture of bovine origin with bio glass niobosphate (CaO-CaF2-P2O5-Nb2O5), characterized for the preparation of synthetic bone substitutes. Use according to claim 12, characterized in that said bioceramic material comprises hydroxyapatite and more soluble phases comprising β-TCP; β-TCP with magnesium; calcium niobates, or combinations thereof.