JP5404407B2 - Curable composition - Google Patents

Description

  The present invention claims priority based on US Provisional Application No. 60 / 960,218 filed on September 20, 2007, the contents of which are hereby incorporated by reference. . In addition, all documents, patent publications, and published patent publications mentioned in this specification are incorporated herein by reference.

  The present invention relates to a novel curable composition, a process for its production, its use, and a method of therapeutic treatment using it. Specifically, the curable composition of the present invention may be a medical curable composition, or a filling material composition, a filling material composition, or a hemostatic composition. More specifically, the hard tissue composition of the present invention can prosthetic the function of the defect void in the living hard tissue and induce the generation of new hard tissue.

  In the medical field, the curable composition is mainly used as a bone defect filling material or a bone bonding material, and in the dental field, a bonding material, a heat insulating material for a metal restoration, a temporary or permanent filling material, and a root canal filling material. Or it is used as a capping material. Bone cement, which is a medically curable composition currently used, is kneaded, for example, by mixing a powder part containing methyl methacrylate polymer as a main component and a kneading liquid part containing methyl methacrylate monomer. It is a curable methyl methacrylate polymer obtained by this. The dental curable composition is obtained from, for example, a zinc phosphate cement obtained from a powder containing zinc oxide and a kneading liquid containing an aqueous phosphoric acid solution, or a kneading liquid containing a powder containing zinc oxide and an aqueous polycarboxylic acid solution. Examples thereof include a carboxylate cement, a Eugenol cement obtained from a powder containing zinc oxide and a kneading liquid containing Eugenol, and all of them obtain a desired curable composition by kneading the powder part with a kneading liquid. These current curable compositions for medical use can obtain a curable composition of a desired form by kneading the powder part with a kneading liquid, but the curable composition to be produced is different from biological tissue. Therefore, these curable compositions do not exhibit biocompatibility. Moreover, in the case of bone cement, inflammation occurs in the surrounding tissue due to residual monomers and / or heat generation during polymerization.

  On the other hand, living hard tissues such as bones or teeth are calcium phosphates mainly composed of apatite, and apatite is known to exhibit excellent biocompatibility and osteoconductivity. Therefore, apatite cement that hardens to become apatite has been developed (Non-Patent Document 1, Patent Documents 1 and 2), and clinical application has begun. Apatite cement is clinically applied as a biological cement that exhibits excellent tissue affinity and osteoconductivity, but its mechanical strength is limited, and the development of apatite cement that exhibits greater mechanical strength is expected. ing. The characteristics of apatite as a biomaterial are excellent tissue affinity and osteoconductivity. However, if the tissue affinity and osteoconductivity are improved, the treatment period can be shortened. Therefore, the development of apatite cement that is more excellent in tissue affinity and osteoconductivity is expected. Furthermore, faster bone formation is required in the clinical setting. Some trace essential elements are known to be effective for bone formation. For example, silicon (Si), which is one of the essential elements, is localized in an active site of bone formation in higher animals, so that early bone It is known to play an important role in formation (Non-Patent Document 2). It has also been reported that in some bioceramics, the addition of silicon promotes the differentiation of mesenchymal cells and osteoblasts, thereby promoting bioactivity (Non-patent Documents 3 and 4). Therefore, it is considered that introduction of silicon into apatite improves the osteoconductivity of apatite.

Medical curable compositions generally have multiple properties of 1) exhibiting curability, 2) exhibiting excellent tissue affinity, 3) exhibiting excellent osteoconductivity, and 4) exhibiting excellent mechanical properties. It is desirable to have both. Showing curability is an essential requirement of a medical curable composition, and is determined by whether or not it is actually cured. Tissue affinity and osteoconductivity are determined by implanting into a bone defect formed in a laboratory animal and conducting a histopathological search. However, calcium phosphate-based materials are excellent as long as they do not release powder. It is known to show tissue affinity and excellent osteoconductivity. Therefore, a necessary condition for a curable composition comprising calcium phosphate to exhibit excellent tissue affinity and excellent osteoconductivity is whether or not it breaks down before curing to release the powder. In addition, cell adhesion and proliferation may be examined to further confirm tissue affinity. Excellent mechanical properties are determined by measuring the mechanical properties of the cured body.
Japanese Patent No. 2537121 Japanese Patent No. 2808410 H. Monma and T. Kanazawa: Yogyo-Kyokai-shi Vol. 84 (1976), p209 EM Carlisle: Science Vol. 167 (1970), p. 279 S. Langstaff, M. Sayer, TJN Smith and SM Pugh: Biomaterials Vol. 22 (2001), p. 135 C. L Camire, SJ Saint-Jean, C. Mochales, P. Nevsten, JSL Lidgren and M. Ginebra: J. Biomed. Mater. Res. Part B: Appl Biomater. Vol. 76B (2006), p. 424

  Accordingly, an object of the present invention is to provide a curable composition excellent in 1) sclerosis, 2) tissue affinity, 3) osteoconductivity, and 4) mechanical properties.

  As a result of various studies, the present inventor has found that a calcium phosphate-containing cement containing calcium silicate is excellent in the above properties, and has completed the present invention.

  Accordingly, in the first aspect, the present invention provides a curable composition (the curable composition of the present invention) comprising calcium silicate and calcium phosphate.

  In the second aspect, the present invention provides a curable composition characterized in that the powder part contains calcium phosphate and calcium silicate. Here, in the present specification, the powder part may be in the form of a mixture containing both calcium phosphate and calcium silicate, or the first powder part containing calcium phosphate and the second powder part containing calcium silicate. It may be in the form of a combination comprising Preferably, the powder part is in the form of a mixture containing both calcium phosphate and calcium silicate.

  In a further aspect, the present invention provides a method for producing a curable composition comprising the step of mixing a powder part containing calcium phosphate and calcium silicate and a kneading liquid part.

  In another aspect, the present invention relates to defects and / or voids in living hard tissue caused by pathological or external causes such as fractures; osteogenesis imperfecta, osteoporosis, rickets, osteomalacia, hyperparathyroidism Bone defects caused by allergic diseases, all types of osteomyelitis, Paget's disease, tumors (eg including osteoma, osteoid osteoma, osteoblastoma, primary and secondary osteosarcoma), epilepsy or other diseases Relates to the use of calcium silicate for the manufacture of a curable composition for the treatment of voids; or bone-joint voids due to age, artificial joint implantation, etc .; or root canal filling in dental care; .

  In yet another aspect, the present invention relates to a defect and / or void in a living hard tissue caused by a pathological or external cause, such as fracture; osteogenesis imperfecta, osteoporosis, rickets, osteomalacia, parathyroid function Bone defects caused by hypertension, all types of osteomyelitis, Paget's disease, tumors (including osteoma, osteoid osteoma, osteoblastoma, primary and secondary osteosarcoma), epilepsy or other diseases Or a void; or any element, such as age, bone-to-joint void due to artificial joint implantation, etc .; or root canal filling in dental treatment, wherein the subject is cured according to the present invention. A method comprising applying a sex composition is provided.

  In another aspect, the invention also includes 1) a powder part comprising calcium phosphate and calcium silicate, 2) a kneading liquid part, and optionally 3) instructions for use of the curable composition of the invention. A kit consisting of

  Thus, for example, the present invention is a method of mixing the powder part and the kneading liquid part containing calcium phosphate and calcium silicate, for example, in the form of a mixture or combination, immediately before application to the subject, and before the mixture is completely cured. The curable composition is applied to a target portion requiring the curable composition, for example, an affected part, the curable composition of the present invention is formed into an appropriate shape, and the curable composition of the present invention is cured to be used. Or, for example, after obtaining the form of the curable composition of the present invention that the subject needs (individually or generally) in advance, and then a powder part containing calcium phosphate and calcium silicate in the form of a mixture or combination The kneading liquid part is mixed, formed into a desired shape, and cured to obtain the curable composition of the present invention. Alternatively, for example, the curable composition of the present invention can be used as a part of an artificial hard tissue such as an artificial bone.

  The present invention provides a medical curable composition comprising calcium phosphate and calcium silicate, and 1) exhibits sclerosis by the curable composition, and 2) has excellent tissue affinity. A medical curable composition satisfying all the characteristics of 3) excellent osteoconductivity and 4) excellent mechanical properties could be realized for the first time.

It is a powder state (0h) of the tricalcium phosphate cement which does not contain tricalcium silicate, and is an X-ray diffraction image after hardening for 3 hours, 6 hours, 12 hours, 24 hours and 168 hours. It is an X-ray-diffraction image after hardening for 3 hours, 6 hours, 12 hours, 24 hours, and 168 hours of the tricalcium phosphate cement containing 2.5% by weight of tricalcium silicate. It is an X-ray-diffraction image after hardening for 3 hours, 6 hours, 12 hours, 24 hours and 168 hours of the tricalcium phosphate cement containing 5% by weight of tricalcium silicate. It is an X-ray-diffraction image after hardening for 3 hours, 6 hours, 12 hours, 24 hours, and 168 hours of the tricalcium phosphate cement containing 10% by weight of tricalcium silicate. It is an X-ray-diffraction image after hardening for 3 hours, 6 hours, 12 hours, 24 hours, and 168 hours of the tricalcium phosphate cement containing 20% by weight of tricalcium silicate. It is the initial setting time of a tricalcium phosphate cement containing 0-20% by weight of tricalcium silicate. It is a time-dependent change of the indirect tensile strength (DTS, unit: MPa) of the tricalcium phosphate cement containing 0-20 weight% of tricalcium silicate. Cell adhesion of tricalcium phosphate cement containing 0-10 wt% tricalcium silicate. Cell proliferation of tricalcium phosphate cement containing 0-10 wt% tricalcium silicate. It is an X-ray-diffraction image after hardening for 3 hours, 6 hours, 12 hours, 24 hours, and 168 hours of the calcium hydrogenphosphate cement which does not contain tricalcium silicate. It is an X-ray-diffraction image after hardening for 3 hours, 6 hours, 12 hours, 24 hours, and 168 hours of calcium hydrogenphosphate cement containing 10% by weight of tricalcium silicate. It is an X-ray-diffraction image after hardening for 3 hours, 6 hours, 12 hours, 24 hours, and 168 hours of the calcium hydrogenphosphate cement containing 20% by weight of tricalcium silicate. It is an X-ray-diffraction image after hardening for 3 hours, 6 hours, 12 hours, 24 hours, and 168 hours of the calcium hydrogenphosphate cement containing 30% by weight of tricalcium silicate. It is an X-ray-diffraction image after hardening for 3 hours, 6 hours, 12 hours, 24 hours, and 168 hours of calcium hydrogenphosphate cement containing 40% by weight of tricalcium silicate. It is an X-ray-diffraction image after hardening for 3 hours, 6 hours, 12 hours, 24 hours, and 168 hours of calcium hydrogenphosphate cement containing 50% by weight of tricalcium silicate. It is a time-dependent change of the indirect tensile strength (DTS, unit: MPa) of calcium hydrogenphosphate cement containing 0-50 weight% of tricalcium silicate.

  In general, a certain compound and a solvate such as a salt or hydrate thereof have a close relationship and are known to exhibit similar properties. Where appropriate, it is understood that reference is made not only to the compound but also to solvates such as salts and hydrates of the compound as well.

  The term “subject” as used in the present invention means vertebrates, particularly mammals including humans. Preferred subjects include, but are not limited to, humans, dogs, cows, pigs, horses, sheep and the like. Particularly preferred subjects are biological hard tissue defects and / or voids caused by pathological or external causes such as fractures; osteogenesis imperfecta, osteoporosis, rickets, osteomalacia, hyperparathyroidism, any Bone defects or voids caused by types of osteomyelitis, Paget's disease, tumors (including osteoma, osteoid osteoma, osteoblastoma, primary and secondary osteosarcoma), epilepsy or other diseases; or It refers to subjects, especially vertebrates, especially mammals including humans, having any element, for example, bone-to-joint voids due to age, artificial joint implantation, etc .; or root canal filling in dental care.

  In one aspect, the present invention provides a curable composition comprising calcium silicate and calcium phosphate. The weight ratio of calcium silicate to calcium phosphate can be easily determined by those skilled in the art as appropriate by known experiments, for example, experiments as shown in the Examples.

The term “calcium phosphate” as used herein is used in a broad sense to refer to compounds having Ca and PO ₄ , monocalcium phosphate, dicalcium phosphate, tricalcium phosphate (TCP, Ca ₃ (PO ₄ ) ₂ ). , Tetracalcium phosphate (TTCP, Ca ₄ (PO ₄ ) ₂ O), octacalcium phosphate (Ca ₈ H ₂ (PO ₄ ) ₆ ), calcium hydrogen phosphate (DCPA, CaHPO ₄ ), calcium dihydrogen phosphate (DCPD, Ca (H ₂ PO ₄ ) ₂ ), hydroxyapatite (HAP), or a mixture thereof is exemplified. A particularly preferred calcium phosphate is tricalcium phosphate. The calcium phosphate may be crystalline or amorphous, and the amorphous calcium phosphate can be synthesized by a known method such as mixing a solution containing a calcium component and a solution containing a phosphate component at a low temperature. In the present invention, calcium phosphate containing amorphous calcium phosphate as a main component and containing, for example, a relative weight ratio of 51% or more is preferable, and amorphous calcium phosphate also contains magnesium or carbonate ions.

  Calcium phosphate is obtained by methods known to those skilled in the art or, for example, in the desired molar ratio of calcium source to phosphate source, for example in the case of tetracalcium phosphate, a 2: 1 molar ratio of calcium source to phosphate source. And can be produced by baking at an appropriate temperature and optionally under an inert atmosphere such as nitrogen, or can be purchased as a chemical. Alternatively, for example, to obtain a mixture of tetracalcium phosphate and tricalcium phosphate, the molar ratio of calcium to phosphoric acid can be less than 2: 1.

Alternatively, calcium phosphate such as calcium hydrogen phosphate (CaHPO ₄ ) is mixed with the phosphate source or calcium phosphate source in a desired molar ratio and calcined at an appropriate temperature and optionally in an inert atmosphere such as nitrogen. Thus, other calcium phosphates such as tricalcium phosphate (Ca ₃ (PO ₄ ) ₂ ) can be obtained.

Examples of the calcium source include calcium oxide (CaO), calcium hydroxide (Ca (OH) ₂ ), calcium carbonate (CaCO ₃ ) and the like, all of which can be purchased as chemicals. Examples of the phosphoric acid source include phosphoric acid, (NH ₄ ) ₃ PO ₄ , (NH ₄ ) ₂ HPO ₄ , NH ₄ H ₂ PO ₄ , Na ₃ PO ₄ , Na ₂ HPO ₄ , NaH ₂ PO ₄ , K Examples include phosphoric compounds such as ₃ PO ₄ , K ₂ HPO ₄ , KH ₂ PO ₄ , and zinc phosphate, all of which can be purchased as chemicals. Preferably, calcium hydrogen phosphate or ammonium phosphate ((NH ₄ ) ₃ PO ₄ , (NH ₄ ) ₂ HPO ₄ , NH ₄ H ₂ PO ₄ ) is used. In particular, ammonium phosphate is preferable because ammonium is volatilized by baking and no salt remains.

Tricalcium phosphate may include α-Ca ₃ (PO ₄ ) ₂ and β-Ca ₃ (PO ₄ ) _{2 which} are different crystal forms. α-Ca ₃ (PO ₄ ) ₂ is preferred because it provides a more rapid curing reaction. Tricalcium phosphate can be produced by methods known to those skilled in the art or, for example, by mixing and heating a calcium source and a phosphate source in a molar ratio of 3: 2. It is known that α-type tricalcium phosphate is mainly generated when heated at 1200 ° C. or higher, and β-type tricalcium phosphate is mainly generated when heated at 1000 ° C. or lower. Preferred curable compositions comprising α-Ca ₃ (PO ₄ ) ₂ are, for example, Biopex (Biopex or Biopex-R, registered trademark, manufactured by Pentax), Sementech (registered trademark, manufactured by Teknimed) or Mimix, It is commercially available under the trade name of registered trademark, Walter Lorenz Surgical.

Hydroxyapatite refers to one having a basic structure of Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ . Ca-deficient apatite Ca _10-x (HPO ₄ ) _y (PO ₄ ) _6-y (OH) _2-z and carbonate-containing apatite Ca _10-x (HPO ₄ ) _y (PO ₄ ) _6-y (CO ₃ ) _a (OH) _{2-z and the} like (where x is 1-2, preferably 1, y is 0-6, preferably 1, z is 0-2, preferably 1, a is 1 to 5.) Alternatively, Ca ₈ Ba ₂ (PO ₄ ) ₆ (OH) ₂ or the like in which Ca is partially or completely substituted with another metal is also included in hydroxyapatite. For example, Ca ₉ (HPO ₄ ) (PO ₄ ) ₅ OH can be obtained from α-TCP and water.

  The calcium phosphate used in the curable composition of the present invention is tricalcium phosphate, especially α-tricalcium phosphate and calcium hydrogen phosphate. For example, when using tricalcium phosphate, especially α-tricalcium phosphate, the curable composition of the present invention is preferably about 0.1 to 20% by weight, for example about 0.00, based on the weight of tricalcium phosphate. 5 to 18 wt%, preferably 2.5 to 10 wt%, most preferably 2.5 to 5 wt% calcium silicate. In this case, a curable composition containing 20% by weight or more of calcium silicate is not preferable because the initial curing time is delayed and the mechanical strength is lowered. Moreover, in the curable composition containing less than 0.1% by weight of calcium silicate, the promotion of bone formation by silicon may be insufficient.

  For example, when calcium hydrogen phosphate is used as the calcium phosphate, the curable composition of the present invention is preferably about 10 to 50% by weight, for example, about 20 to 50% by weight, most preferably based on the weight of calcium hydrogen phosphate. Preferably it contains 30-40% by weight of calcium silicate.

The term “calcium silicate” in this specification is used in a broad sense to refer to a compound corresponding to a composition in which calcium oxide and silicon dioxide are combined, and includes dicalcium silicate (belite, 2CaO · SiO ₂ ), Examples include tricalcium acid (Alite, 3CaO · SiO ₂ ), or a mixture thereof. A preferred calcium phosphate is tricalcium phosphate.

  Calcium silicate can be obtained by methods known to those skilled in the art or, for example, in a desired molar ratio of calcium source to silicate source, eg, 3: 1 molar ratio of calcium source to silicate source in the case of tricalcium silicate. Can be produced by, for example, the method described in the Examples, by firing at an appropriate temperature, and optionally firing in an inert atmosphere such as nitrogen.

Examples of calcium sources include, but are not limited to, calcium oxide (CaO), calcium hydroxide (Ca (OH) ₂ ), and calcium carbonate (CaCO ₃ ), all of which can be purchased as chemicals. The silicic acid source includes, for example, but is not limited to, silicon dioxide (SiO ₂ ) and tetraethoxysilane (Si (OC ₂ H ₅ ) ₄ ), both of which can be purchased as chemicals. A preferred silicic acid source is silicon dioxide (SiO ₂ ).

  In a further embodiment, the curable composition of the present invention has a powder part containing calcium silicate and calcium phosphate and a kneading liquid part.

The kneading liquid as used in the present invention includes all kneading liquids that can be used in the technical field, and medically acceptable non-toxic kneading liquids are particularly preferable. Examples of preferable kneading liquids include distilled water, carbonyl acid salt (carboxylic acid or carbonate) aqueous solution, phosphate salt (eg (NH ₄ ) ₃ PO ₄ , (NH ₄ ) ₂ HPO ₄ , NH ₄ H ₂ PO ₄ , Na ₃ PO ₄ , Na ₂ HPO ₄ , NaH ₂ PO ₄ , K ₃ PO ₄ , K ₂ HPO ₄ , KH ₂ PO ₄ ) aqueous solution, or a mixture thereof, in particular, sodium hydrogen phosphate aqueous solution , Aqueous disodium hydrogen phosphate solution, or a mixture thereof is preferred.

  In order to adjust the pH of the kneading liquid, a plurality of salts can be mixed, or a pH adjusting agent can be added. The pH of the preferred kneading liquid is generally about 4 to 10, preferably about 5 to 8, and most preferably about 6.5 to 7.5. For example, when the pH is lowered, the powder part and the kneading liquid part Is not sufficiently cured, and as a result, the mechanical strength of the cured body may be lowered. Further, in the case of a kneading liquid having a high pH, tissue damage can be caused. However, a pH other than the above range may be selected depending on the site to which the curable composition of the present invention is applied. For example, when used as a dental pulp protecting material, a high pH is preferred, and for example, calcium hydroxide can be added to the kneading liquid part.

  Preferably, the kneading liquid of the curable composition of the present invention is 0.05 to 1.0 mol / L, preferably 0.1 to 0.5 mol / L, more preferably 0.25 mol / L phosphate. Or a carbonyl salt aqueous solution.

  Moreover, the curable composition of this invention can be sterilized. Sterilization may be performed on the powder part and the kneaded liquid part before mixing, or on the cured body after mixing. Preferably, the powder part and the kneading liquid part before mixing can be sterilized by a conventional method.

  The curable composition of this invention can be shape | molded by mixing the powder part and kneading | mixing liquid part containing a calcium phosphate and a calcium silicate, and making it harden | cure. The weight ratio between the powder part to be mixed and the kneading liquid part can be appropriately determined or predicted by a person who performs molding, typically a doctor or veterinarian, based on ordinary knowledge techniques, but typically For example, 2 parts by weight or less of the kneading liquid part with respect to 1 part by weight of the powder part, preferably 0.1 to 1 part by weight of the kneading liquid part with respect to 1 part by weight of the powder part, most preferably 1 part by weight of the powder part. On the other hand, it can mix in the range of 0.5 weight part of kneading | mixing liquid parts. The mixing is performed by a method commonly used by those skilled in the art. For example, the stirring can be performed manually using a stirring bar, or can be performed using a stirring device equipped with a stirring bar, a stirring fan, or the like, for example, a stirrer.

  Curing is typically under conditions of about 15-40 ° C. and a relative humidity of about 20-100%, such as physiological conditions, eg, about 37 ° C., relative humidity of about 100%, or in vivo. In particular, in the affected area of the subject to which the curable composition of the present invention is applied, or under external conditions, for example, at about 25 ° C. and relative humidity of about 50%, and optionally in the presence of body fluids such as blood, saliva, lymph, etc. And you can do it.

  Curability is typically determined by the initial cure time of the curable composition. The initial cure time can be measured by any method available to those skilled in the art, such as the Vicat needle method as defined in ISO 1566 (which is hereby incorporated by reference). The Vicat needle method is simply explained. After 3 minutes from the start of mixing the powder part and the kneading liquid part, the kneaded product is transferred into a thermostat having a temperature of 37 ° C. and a relative humidity of about 100%, and a Vicat needle having a mass of 300 g. Is gently dropped on the surface of the kneaded product, and it is examined whether or not needle marks are formed, and the initial curing time is calculated from the start of mixing when no needle marks are left. The initial curing time of the curable composition of the present invention by the Vicat needle method is preferably, for example, within 180 minutes, preferably within 30 minutes, and more preferably within 20 minutes. If the initial curing time is short, it is preferable that the treatment can be completed quickly because it adheres to the application site immediately after the curable composition of the present invention is applied to the target. As will be understood by those skilled in the art, even after the initial curing time has elapsed, the curing of the curable composition proceeds and the mechanical strength further increases.

  Calcium phosphate cement is hardened by entanglement of acicular crystal apatite formed by dissolution and precipitation reaction of calcium phosphate. Without being bound by theory, it is believed that the added calcium silicate plays two roles in the hardening reaction of the calcium phosphate cement. The first role is to delay the setting time of the calcium phosphate cement. This is because when calcium silicate comes into contact with water, dissolution of calcium phosphate is suppressed due to an alkaline environment. On the other hand, the second role is to increase the mechanical strength of the calcium phosphate cement. This is because dissolution of calcium silicate promotes nucleation of apatite and forms silicate ions that polymerize as a calcium silicate gel. Therefore, in order to obtain a curable composition having excellent curability and mechanical properties, it is preferable to add an appropriate amount of, for example, calcium silicate as described above.

  Tissue affinity and osteoconductivity are usually determined by implanting a curable composition into a bone defect formed in a laboratory animal and searching histopathologically. However, a material based on calcium phosphate is a powder. It is known that it exhibits excellent tissue affinity and excellent osteoconductivity unless it is released. Therefore, the curable composition containing calcium phosphate like the curable composition of the present invention exhibits excellent tissue affinity and excellent osteoconductivity after mixing the powder part and the kneading liquid part, for example, at 37 ° C. It can be easily determined by observing with the naked eye that the powder does not break apart before curing under the condition of 100% relative humidity. A preferable curable composition of the present invention is a mixture of a powder part and a kneading liquid part, which is cured under the conditions of 37 ° C. and a relative humidity of 100% and does not release the powder. Can have conductivity. In order to further confirm tissue affinity, cell adhesion and proliferation can also be examined, for example, by cell experiments, as described in the Examples.

  Mechanical properties are determined by measuring the mechanical properties of the cured body, such as crush resistance, compressive strength, shear strength or indirect tensile strength. The crushing resistance can be measured, for example, according to the crushing resistance test of zinc phosphate cement of Japanese Industrial Standard T6602 (part of which is incorporated herein by reference). The indirect tensile strength is calculated by crushing the cured body with a universal testing machine and substituting the load P required for crushing, the diameter d and thickness l of the cured body into indirect tensile strength = 2P / (πdl). Or, for example, the curable composition of the present invention is preferably 0.5 to 10 MPa after 6 hours of mixing, preferably 0.5 to 15 MPa after 12 hours of mixing, more preferably Has an indirect tensile strength of 1 to 12 MPa, more preferably 6 to 12 MPa, or preferably 0.5 to 20 MPa after 24 hours of mixing, more preferably 1 to 16 MPa, and most preferably 10 to 15 MPa.

  In another embodiment, the curable composition of the present invention combines further other components with the powder part and / or the kneading liquid part, in the form of a mixture, or as another powder part or kneading liquid part. It may be included in the form. The form of the combination is, for example, a form of a curable composition comprising a first powder part containing calcium phosphate and calcium silicate, a second powder part containing further other components, and a kneading liquid part, or It can be in the form of a curable composition comprising a first powder part comprising calcium phosphate, a second powder part comprising calcium silicate and further other ingredients, and a kneading liquid part.

  Such other ingredients include, but are not limited to, excipients, organic or inorganic carriers, preservatives, antioxidants, lubricants, dispersants, wetting agents, solubilizers, pH adjusters, vitamins, amino acids , Proteins, silicon-containing compounds such as silicic acid, magnesium oxide, calcium oxide, iron oxide, phosphorus oxide, potassium oxide, metal oxides such as sodium oxide, metal salts such as calcium hydroxide, analgesics / anti-inflammatory agents Bone formation promoters, osteoporosis therapeutic agents, bone metabolism promoters, anticancer agents, hemostatic agents, gout therapeutic agents, antibiotics and antibacterial agents, and the like. In particular, in a medical curable composition, a component that is medically acceptable as the other component, that is, a component that is not toxic to a living body is preferable. Examples of medically acceptable ingredients are described in, for example, Pharmaceutical Additive Standards (Pharmaceutical Daily, 2003, which is hereby incorporated by reference).

  Examples of analgesic / anti-inflammatory agents include salicylic acid anti-inflammatory agents such as acetylsalicylic acid and sodium salicylate, fenamic acid anti-inflammatory agents, aryl acid anti-inflammatory agents such as diclofenac sodium, sulindac, indomethacin and acemetacin, propionic acid Anti-inflammatory agents such as ibuprofen, ketoprofen, flurbiprofen, oxicam anti-inflammatory agents, and aspirin and acetaminophen are included.

  Examples of osteogenesis promoters, osteoporosis therapeutic agents, and bone metabolism promoters include alphacalcidol, calcitriol, menatetrenone, elcatonin, salmon calcitonin, etidronate, alendronate, risedronate, pamidronate, incadronate, ipriflavone, etc. .

  The present invention will be explained by the following examples, but the technical scope of the present invention and claims is not limited by the examples.

Production of Curable Composition Containing α-Tricalcium Phosphate and Tricalcium Silicate Tricalcium silicate was prepared from calcium carbonate (CaCO ₃ ) and silicon dioxide (SiO ₂ ). 75 g of calcium carbonate (CaCO ₃ ) and 15 g of silicon dioxide (SiO ₂ ) were mixed (molar ratio 3: 1), calcined at 1000 ° C. for 2 hours, rapidly cooled in the air, and pulverized. The pulverized powder was reacted at 1500 ° C. for 24 hours and quenched in the air. 30 g of α-tricalcium phosphate (α-TCP B, manufactured by Taihei Chemical Co., Ltd.) and the obtained tricalcium silicate were mixed in the following weight ratio to prepare powder parts of each sample composition.

1 g of the powder part was mixed with a kneading liquid (0.25 mol / L NaH ₂ PO ₄ aqueous solution, 0.5 ml), placed in a stainless steel split mold, and cured under conditions of a relative humidity of 100% and 37 ° C. After the specified curing time, all samples were immersed in acetone and the curing reaction was stopped by drying at 60 ° C.

  The obtained 24-hour cured product was observed with a scanning electron microscope (measured at an acceleration voltage of 15 kV after coating a gold thin film by a scanning electron microscope JSM-5400LV (JEOL Ltd.) sputtering method). In the control case and in samples 1 and 2, a leaf-like crystal structure typical of hydroxyapatite was observed (photos not shown). On the other hand, in the case of samples 3 and 4, crystals having a diameter of about 5 microns covered with fine crystals were observed (photos not shown).

  Moreover, X-ray diffraction analysis (RINT 2500V (Rigaku Co., Ltd.) and 40 kV, 100 mA CuKα rays were used as the X-ray source for the powder part before mixing of each sample and the cured product for 3, 6, 12, 24 and 168 hours. , Measured at a scanning speed of 2 ° / min). The results are shown in FIGS. In the figure, h means time, and 0h means the powder part before mixing. A peak attributed to tricalcium phosphate (typically, for example, a peak of about 30.8 degrees / 2θ) is observed in the powder before mixing. In the case of the control, the peak attributed to tricalcium phosphate decreases with time, and a broad peak attributed to apatite (typically, for example, a broad peak of about 31 to 33 degrees / 2θ) increases. That is, the composition conversion reaction from tricalcium phosphate to apatite gradually proceeds and is completed in about 168 hours. On the other hand, in the case of sample 2, the same composition conversion reaction was observed. However, in the case of sample 2, it is noted that the similar composition conversion reaction proceeds significantly faster than that of the control. That is, in sample 2, the composition conversion reaction to apatite occurs rapidly in 6-12 hours and is completed in 24 hours, but in the control, tricalcium phosphate remains unreacted at 24 hours. In the case of sample 3, tricalcium phosphate remains unreacted even after 168 hours, and it is understood that the composition conversion reaction is extremely slow. In the case of sample 4, no change in the peak intensity of tricalcium phosphate was observed even after 168 hours.

Measurement of initial curing time of curable composition The initial curing time of the control and each sample was measured by the Vicat needle method (triple). Each kneaded sample is filled in a Teflon (registered trademark) mold, and a Vicat needle (load 300 g) is gently dropped onto the sample in an atmosphere of 37 ° C. and 100% relative humidity, and the needle enters the paste. The time until the traces of the needles were not taken was defined as the initial curing time. The results are shown in FIG. The initial curing time for the control is about 7 minutes. The initial curing time was delayed by the addition of tricalcium silicate, and the initial curing times for Samples 1-3 were 11-16 minutes. On the other hand, the curing time of Sample 4 was greatly delayed and was about 180 minutes.

Indirect Tensile Strength Measurement of Curable Composition Indirect tensile strength was measured for the control and 3, 6, 12, 24 and 168 hour cured bodies of each sample (triple). A sample with a diameter of 6 mm and a thickness of 3 mm was crushed by a universal testing machine (SV-301 type tensile compression testing machine, Imada Seisakusho Co., Ltd.), and the load P required for crushing, the diameter d and thickness l of the hardened cement were indirectly The tensile strength was calculated by substituting for 2P / (πdl). The results are shown in FIG. In the control case, the indirect tensile strength increased 3 hours after mixing and reached the final strength after 6 hours. The initial indirect tensile strength of Samples 1 and 2 is small after 3-6 hours compared to the control, but then a sharp increase in indirect tensile strength is observed. As a result, the final indirect tensile strength of the curable composition obtained after 24 hours is 12 to 15 MPa. This is significantly greater than the control of 9 MPa. In the case of samples 3 and 4, the increase in indirect tensile strength was completed in 6 hours, and the indirect tensile strength was maintained. Therefore, the final indirect tensile strength was smaller than the other samples.

In vitro cell experiment ・ Primary culture of bone marrow cells Bone marrow cells were collected from 4 weeks old male SD rat tibia, 20% fetal bovine serum (FBS); Biowest, France and 1% antibiotic (Pennicillin-Streptomycin) Invitrogen Co., NY, USA) was cultured in α-MEM (SIGMA-Aldrich Co., UK) at 37 ° C., 5% CO ₂ , saturated water vapor atmosphere for 5 days.

・ Evaluation of cell adhesion and proliferation The cells cultured for 5 days were washed 3 times with phosphate buffered saline (PBS), the floating cells were removed, and the cells attached to the cell culture dish were detached with 0.25% trypsin EDTA. 168 hours of sample 5 which is the same as sample 1-4 except that it contains 5000% by weight of control or samples 1-3 and tricalcium silicate to give 5000 cells / cm ² in a 48-well culture plate It seed | inoculated on the hardening body and was culture | cultivated. Regarding initial cell adhesion, after 7 hours of culture after seeding, the cells attached to the sample were detached with 0.25% trypsin EDTA, the number of adherent cells was counted using a hemocytometer, and the cell adhesion rate was calculated. The results are shown in FIG. Samples 1, 2 and 5 showed an improved cell adhesion rate over the control.

  As for cell proliferation, the cells attached to the sample were detached after culturing for 3, 5 and 7 days after seeding, and the number of adherent cells was counted using a hemocytometer to calculate the cell proliferation rate. The results are shown in FIG. There is no significant difference in the number of cells between the control and each sample in the 3-day culture, but significantly more cells are measured in any of samples 1-3 than the control in the 5-day culture. Also, in 7 days culture, significantly more cells are measured in samples 2 and 5 than in the control.

Preparation of a curable composition comprising calcium hydrogen phosphate and tricalcium silicate Tricalcium silicate was prepared as described in Example 1. 30 g of calcium hydrogen phosphate (manufactured by Taihei Chemical Co., Ltd.) and the obtained tricalcium silicate were mixed at the following weight ratio to prepare powder parts of each sample composition.

1 g of the powder part was mixed with a kneading liquid (0.25 mol / L NaH ₂ PO ₄ aqueous solution, 0.5 ml), placed in a stainless steel split mold, and cured under conditions of a relative humidity of 100% and 37 ° C. After the specified curing time, all samples were immersed in acetone and the curing reaction was stopped by drying at 60 ° C.

  X-ray diffraction analysis was performed as described in Example 1 for the control and the pre-mixing powder portion of each sample and the 3, 6, 12, 24 and 168 hour cured bodies. The results are shown in FIGS. In the figure, h means time, 0h means powder part before mixing, DCPA means calcium hydrogen phosphate, HAp means hydroxyapatite, and Alite is tricalcium silicate. Meaning,% means the weight percent of tricalcium silicate to the weight of calcium hydrogen phosphate. A peak attributed to tricalcium phosphate (typically, for example, a peak of about 30.8 degrees / 2θ) is observed in the powder before mixing. In the case of the control and sample 6, it can be understood that the peak attributed to calcium hydrogen phosphate hardly changed over time, and hydroxyapatite was not formed. On the other hand, in the case of samples 7 to 10, the peak attributed to calcium hydrogen phosphate decreases with time, and instead a wide peak attributed to hydroxyapatite (typically, for example, about 31 to 33 degrees / 2θ). Broad peaks). That is, the composition conversion reaction from tricalcium phosphate to apatite proceeds gradually and is completed in about 168 hours. Therefore, it can be understood that when calcium hydrogen phosphate is used as the calcium phosphate, it does not harden unless about 10% by weight or more of tricalcium silicate is added to the tricalcium phosphate.

Measurement of Indirect Tensile Strength of Curable Composition As described in Example 1, the indirect tensile strength of each sample was measured for 3, 6, 12, 24 and 168 hours. The results are shown in FIG. In the case of the control, the indirect tensile strength does not change at all over time and does not cure. In the case of sample 6, the indirect tensile strength increased 3 hours after mixing, reached the final strength 24 hours later, and then the indirect tensile strength decreased with time. Regarding the initial indirect tensile strength of Samples 7 to 10, an increase in indirect tensile strength over time is observed. As a result, the final indirect tensile strength of the curable composition obtained after 168 hours is 1.5 to 3 MPa.

Claims (9)

  α-tricalcium phosphate, a powder part containing 2.5 to 7.5% by weight of tricalcium silicate based on the weight of α-tricalcium phosphate, and 0.1 to 0.5 mol / L phosphate A curable composition having a kneading liquid part which is an aqueous solution.   The curable composition according to claim 1, comprising 2.5 to 5% by weight of tricalcium silicate based on the weight of α-tricalcium phosphate.   The curable composition of Claim 1 or 2 whose kneading | mixing liquid part is a 0.25 mol / L phosphate aqueous solution.   The curable composition in any one of Claims 1-3 containing 0.1-1 weight part of kneading | mixing liquid parts with respect to 1 weight part of powder parts.   The curable composition of Claim 4 containing 0.5-1 weight part of kneading | mixing liquid parts with respect to 1 weight part of powder parts.   The manufacturing method of the curable composition in any one of Claims 1-5 including the process of mixing a powder part and a kneading | mixing liquid part. The curable composition according to any one of claims 1 to 5 for treatment of defects and / or voids in living hard tissue, wherein the defects and / or voids are
(A) A tumor selected from the group consisting of osteoma, osteoid osteoma, osteoblastoma, primary and secondary osteosarcoma, osteogenesis imperfecta, osteoporosis, rickets, osteomalacia, parathyroid function Bone defects resulting from diseases selected from the group consisting of hypertension, osteomyelitis, Paget's disease and epilepsy,
(B) bone defects resulting from fractures, and
(C) Bone-joint gap due to artificial joint implantation,
A curable composition selected from the group consisting of:   The curable composition according to any one of claims 1 to 5, which is used for root canal filling in dental treatment. 1) Powder part containing α-tricalcium phosphate and 2.5 to 7.5% by weight of tricalcium silicate based on the weight of α-tricalcium phosphate,
2) A curable resin composition preparation kit comprising a kneading liquid part that is a 0.1-0.5 mol / L phosphate aqueous solution.

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