Title of Invention

AN APATITIC BONE CEMENT COMPOSITE WITH BIOACTIVE GLASS

Abstract

A calcium phosphate cement which self-hardens to hydroxyapatite-bloactive glass composite comprising a dry powder mix and an squeous solvent said dry powder mix having a cementing part containing a combination of calcium phosphate minerals such as herein described, present in molar proportion so that the net calcium-to-phosphorous ratio is 10:6, that of the apatitic phase and a filler part containing a bioactive glass in powdered form, said aqueous solvent comprising a solution of a physiologically acceptable phosphate compound (the cement setting manipulator) such as herein described is deionised, distilled water.

Full Text

FIELD OF INVENTION This invention relates to an apatitic bone cement composite with bioactive glass. BACKGROUND OF INVENTION Apatitic bone cements are formulations based on calcium phosphate minerals, used as implants for skeletal repair. The cement prove a workable material which self-harden to hdroxapatite, the mineral phase of bone. The unique combination of mouldability, bio-compatibilit and osteoconductivity (ie. the ability to promote bone formation on contact with hard tissue) make apatitic cements highly useful in filling and reconstructing bone defects. The requirement for grafting bones arises quite often in clinical practice, in circumstances like bone loss due to trauma or tumor removal and surgical correction of skeletal parts. Grafting can be done with live bone, incised from the same individual (autogenous) or from a donor (allogeneic). However, live bone grafting techniques encountered problems which limited their extensive application. The autogenous grafting involve more surgical procedures and related complications while the allogeneic grafts pose the risk of immunogenic response and infections. These factors prompted the search for snthetic materials suitable for bone grafts. Biocompatible and osteoconductive materials like calcium phosphate ceramics, bioactive (soda-calcia-phospho-silicate) glasses and apatite-wollastonite glass-ceramics had been developed for the purpose. These materials gained immediate popularity, and are now available commercially as granules, blocks and in preformed, intended for defect filling and reconstruction of bones. The ceramic bone grafts, despite their wide use in bone repair, are of limited help in certain applications (eg. fixation cases like hop arthroplasty, or filling of intricate cavities) where a cement consistency is required. Acrylic based cements are currently in use for the purpose. Even though acrlic cements offer good results initially, they ail from serious drawbacks like monomer toxicity, exothermic setting and shrinkage. Other similar materials like resin cements did not prove an alternative for fixation and filling, because of poor biodegradability and the presence of leachants. The invention of calcium phosphate based bone cements was considered as a breakthrough in skeletal repair. Apart from the mouldability and biocompatibility, these cements have an additional attraction that they get converted to hydroxyapatitey the bone mineral phase calcium phosphate. Generally, an apatitic cement formulation contains an intimate mix of acidic and basic calcium phosphate mineral particles in a net calcium-phosphorous ratio of 10:6. The aqueous solvent consists of distilled water along with physiologically acceptable additives to regulate the setting properties. On wetting the cement powder with the solvent in an appropriate liquid-to-powder ratio, a self-hardening putty with sufficient workability is obtained. The mechanism of setting is the dissolution of the ingredients in the solvent and their re-precipitation as hydroxyapatite. The growth of this phase as entangled crystallites helps the puttv to retain its strength and shape The calcium phosphate cements have several advantages over acrylic cements. As they are aqueous-based, there is no risk of toxic or allergic reactions. The self-setting nature of the cement putty makes curing steps unnecessary. They are observed, to be free from setting exotherm and shrinkage. A major advantage of the apatitic cements over the granular (apatitic) ceramics is that the cement adapts to the contours of the defect surfaces at microscopic level and gives optimum tissue contact necessary for the bone ingrowth. The apatitic cements are proved to be osteoinductive (i.e. materials that promote new bone formation at bone defect sites). In addition, they possess an interesting property termed as osteotransductivity. The cement initially shows fast osteo integration and later, gets resorbed in a rate comparable to that of the new bone growth. That is, the new bone replaces the implant simultaneously and gradually, leaving no gap in between. The osteotransduetive property of the apatitic cements is highlighted as a special advantage compared to other bone substitutes [4#3$- The subject invention originated out of the efforts to impart another important property to the cement, namely the osteoinduction(i.e. the ability of inducing bone formation at extraosseous sites). This property enhances the bone growth at the implant site and leads to a faster healing of the defect. f *J Prior Art The cementing reaction of calcium phosphate compounds was first demonstrated by Brown and Chow in 1983. They obtained mouldable and self-setting cements from tetracalcium phosphate-dicalcium phosphate mixtures. This marked a new era in the field of bone repair materials. However, scientists started pursuing calcium phosphate cements seriously only after 1992. A steady increase in the number of related publications can be observed during the recent years ££23. Most of the calcium and phosphorous containing compounds have been investigated in various combinations, along with biocompatible additives, in search of formulations capable of forming cement. Out of the cement-forming formulations identified, only a few have clinically relevant features. The composition of the precipitate will depend on the net calcium-to-phosphorous ratio in the mix. A ratio of 10:6 in the mix will give hydroxyapatite precipitate which is the basic bone mineral Various compositions of non-stoichiometric or defective apatites can also be precipitated as cement. Each of these possesses different in vivo properties (osteoconductivity, resorption etc.) and is useful in specific applications. Substituted phases (with Mg, Na, K, CO3, F, CI etc.) which are more close to the physiological apatites can also be precipitated by employing appropriate additives^}. A good amount of literature available on materials investigation, biological properties and clinical applications related to calcium phosphate cements. The material aspect of the cements includes the setting characteristics and the physical and mechanical properties. The chemical mechanism of cement setting and the structural and morphological features of the set cement have been studied. Al the calcium phosphate cements were found to possess inherent porosity (40 to 60 volume percent). Dimensional and temperature changes during setting, which are crucial factors in the clinical applications, were found to be negligible. The effects of ingredient particle size, seeding with apatite particles, additive incorporation etc on cement properties have also been investigated. Material modifications like injectable form and drug incorporation are under development, The studies on the biological properties of calcium phosphate cements mainly focus on the tissue and cellular reactions, both in vitro and in vivo. It has already been established that the calcium phosphates implanted in bone or dental tissues do not have any systemic defects. Several surgical and dental applications of calcium phosphate cements have been envisaged. The proposed clinical applications include filling of bone loss sites and tooth extraction sockets, reconstruction of alveolar ridge, dental root cancal filling and pulp capping. Uses in the form of luting cement in orthopedic and dental surgery, cement for implanting and replanting teeth, bone growth promoter at skeletal sites, liner for dental pulp etc. are also suggested. However, only very few of them were tried at the clinical level. OBJECTS OF THE INVENTION An object of this invention is to propose a composite apatitic cement with enhanced bone regeneration ability. Another object of this invention .Is to, propose a composite apatitic cement which imparts improved ' osteogenic property to the hydroxyapatite matrix of the set cement. Another object of this invention is to propose a composite apatitic cement which are are not biodegradable. Still another object of this invention is to propose a composite apatitic cement which provides an improved bone-bonding, enhanced bone formation and a consequent faster healing of the defect, and can successfully heal large bone defects or lesions and highly useful in periodontal and cranio-maxillofacial reconstruction. DESCRIPTION OF THE INVENTION According to this Invention, there is provided a calcium phoss-phate cement which self-hardens to hydroxyapatite-bioactive glass composite comprising a dry powder mix and an aqueous solvent, said dry powSer mix having a cementing part containing a combination of calcium phosphate minerals, and a filler part containing a bioactive glass in powdered form, said aqueous solvent comprising a solution of a physiologically acceptable phosphate compound (the cement setting manipulator) in deionised, distilled water. The cementing part of the subject cement formulation can be made out of different sets of ingredients, mixed in appropriate proportions to get a calcium-to-phosphorous ratio of 10:6. The ingredients include dicalcium phosphate CCaHPO^], discalcium phosphate dihydrate [CaHP0^.2H20] alpha/beta tricalcium phosphates [a/B-Ca3(POA)23 and tetracalcium phosphate CCa^PO^] and tetracalcium phosphate CCa^(PO^)203 alongwith compensators like calcium oxide CCaOl and solid phosphoric acid [H3PO4] and phase modifiers like calcium carbonate [CaCO-5] and calcium fluoride [CaF2]. They are crushed to different particle sizes ranging from 1 to 100 microns (as per the cement consistency required) and mixed. The filler part (for compositing) of the formulation is the bioactive glass. The glass particles (100-250 microns size) are added in percentages of the weight (l%-20% as per the bioactivity required) of the apatitic cement powder and dispersed well. The solvent is made by dissolving a physiologically acceptable phosphate compound [Na^PO^, NaH2P0^ or (NH^)H2P0^] in deionised, distilled water. Solutions of different concentrations can be made according to the setting time required. The wetting ratio is 0.4 ml-0.6 ml of the solutiuon per 1.0 gram of cement powder. The cement is prepared by taking the required amount (in weight) of the powder in a dish and pippetting out the aqueous solution in the prescribed wetting ratio into it. Then a thorough mixing is done using a spatula for 30 sec. The cement is ready for filling. The setting time will be 10-16 mins. according to the composition. After setting, the cement attains a composite structure with the glass particles embedded in a matrix of hydro-xyapatite, which is formed through the dissolution and recrys-tallisation of the cementing ingredients in the solvent. EXAMPLE The example relates to an unmodified hydroxyapatite phase with two calcium phosphate minerals as the ingredients. Dicalcium phosphate dihydrate ECaHP0A.2H20] was selected as the acidic compound and tetracalcium phosphate [Ca^PO^O] as the basic compound. No compensators were added because these compounds aione, in equimoiar ratio, can give a net caicium-to-pnospnorous ratio 10:6. The ingredients were milled to an average particle size of 100 microns and then mixed in equimoiar ratio to make the cementing powder, the calcium-phosphosilicate glass was powdered and sieved to get a particle sie of 150 microns. The glass particles were added to the cementing powder at a ratio of 5% by weight and mixed thoroughly. The solvent was prepared with disodium hydrogen phosphate [Na2HP0f A required quantity of cement powder was taken in a dish and the solvent is added using a pipette, with a solvent-to-powder ratio of 0.5 ml/gram. Mixing was done using a spatula for 30 sees, and the putty thus obtained was moulded into required shape. The setting time observed was 10 mins. The putty acquired sufficient hardness after 16 mins. The nature of the set cement was analysed. The scanning electron micrograph showed the microstructure with the glass particles embedded inside a porous matrix. The matrix was seen to be composed of crystalline particles of submicron size. The phase composition was identified to be apatitic through X-ray diffraction and Fourier Transform Infrared Spectroscopy analyses. The calcium-to-phosphorous ratio was identified through Electron Microprobe (EDAX) to be 1.69, which is close to the value for hydroxyapatite. The compressive strength of the cement, measured using universal mechanical testing machine was higher than that of trabecular bone (10 MPa). Neither any dimensional change nor any increase setting temperature was observed. The porosity was estimated to be -50% by volume. The set cement passed the preliminary in vitro toxicological screening (cytotoxicity and haemolysis) tests. An in vitro cell culture study using mouse fibroblast cell lines proved that the composite cement is more bioactive than the conventional cement. WE CLAIM: 1. A calcium phosphate cement which self-hardens to hydroxyapa- tite-bioactive glass composite comprising a dry powder mix and an aqueous solvent, said dry powder mix having a cementing part containing a combination of calcium phosphate minerals, and a filler part containing a bioactive glass in powdered form, said aqueous solvent comprising a solution of a physiologically acceptable phosphate compound (the cement setting manipulator) in deionised, distilled water. 2. A calcium phosphate cement as claimed in claim 1 wherein two or more minerals with differing calcium-to-phosphorous ratio are selected from one mineral from the set dicalcium phosphate [CaHPO^] and dical- cium phosphate dihydrate [Cahp0^.2H20]; one mineral from the set alpha/beta tricalcium phosphates [ Ca3(P0^)2] and tetracalcium phosphate CCa^CPO^O]; one or more compensator compound out of the set calcium oxide [CaO] and solid phosphoric acid [H-jPO^l, if required; one or more phase modifiers out of the set calcium carbonate [CaC033 and calcium fluoride [CaF2], if required. 3. A calcium phosphate cement as claim 2 wherein said minerals are present in molar proportions so that the net calcium-to-phosphorous ratio is 10:6, that of the apatitic phase. 4. A calcium phosphate cement as claimed in claim 1 wherein said cementing part has particle size of 1 to 100 microns. 5. A calcium phosphate cement as claimed in claim 1 wherein said filler comprises a calcium-phospho-silicate glass. 6. A calcium phosphate cement as claimed in claim 5 wherein said filler has particle size ranges of 100-250 microns. 7. A calcium phosphate cement as claimed in claims 5 & 6 wherein said filler is uniformly dispersed in said powder mix in weight ratios of 1%-10%. 8. A calcium phosphate cement as claimed in claim 1 comprising a cement setting manipulator selected from ^HPO^, Nah^PO^ and (NH^h^PO^, and dissolved in the aqueous medium in concen trations from 0.1 mol/litre to 0.5 mol/litre. 9. A calcium phosphate cement as claimed in claim 1 wherein said solvent and powder mix is present in wetting ratios 0.5 ml/gram to 0.6 ml/gram. 10. A calcium phosphate cement which self-hardens to hydroxy- apatite-bioactive glass composite substantially as herein described.

Documents:

0306-mas-2000 abstract-duplicate.pdf

0306-mas-2000 claims-duplicate.pdf

0306-mas-2000 description (complete)-duplicate.pdf

306-mas-2000-abstract.pdf

306-mas-2000-claims.pdf

306-mas-2000-correspondence others.pdf

306-mas-2000-correspondence po.pdf

306-mas-2000-description complete.pdf

306-mas-2000-form 1.pdf

306-mas-2000-form 19.pdf

306-mas-2000-form 3.pdf