KR20100037979A - Premixed cement paste and method for forming a cementitious mass - Google Patents

Abstract

PURPOSE: Premixed cement paste and a production method of cementitious materials are provided to obtain high mechanical strength, controllable clotting time, low hydration heat, excellent resistance to decomposition, high biocompatibility, and excellent resistance to corrosion. CONSTITUTION: Premixed cement paste comprises: calcium silicate compound of one or more kinds; and anhydrous liquid carrier which is mixed with the calcium silicate compound and is exchanged with physiological solution to hydrate and harden the cement paste. The calcium silicate compound is calcium silicate(CS), C_2S, C_3S, or the mixture of calcium silicate. The anhydrous liquid carrier is ethylene glycol, polyethylene glycol, liquid glycerol, glycerine, ethyl alcohol, plant oil, animal oil, silicon oil, hydroxypropylmethyl cellulose, or their mixture.

Description

PRE-MIXED CEMENT PASTE AND METHOD FOR FORMING A CEMENTITIOUS MASS}

FIELD OF THE INVENTION The present invention relates to biomedical hydraulic cements, and more particularly, to a premixed paste composition of dental and orthopedic biological hydroponic cements.

Calcium silicates (calcium silicate (CS), dicalcium silicate (C2S) and tricalcium silicate (C3S)) are mixed with water to form calcium silicate hydrate (Ca-Si-H ₂ O gel) (CSH). It is known to hydrate, solidify, and cure through precipitation, usually similar to Portland Cement (OPC).

The publications point out that hydroxyapatite nuclei can form and grow between hydrated calcium silicate particles and that hydrated calcium silicate is a potential candidate for biocompatible materials for hard tissue recovery [Gou et al., " Synthesis and in vitro bioactivity of dicalcium silicate powders , "Journal of the European Ceramic Society 24 (2004) 93-99. Also, Ni et al." Comparison of Osteoblast-Like Cell Responses to Calcium Silicate and Tricalcium Phosphate Ceramics In Vitro "( J Biomed Mater Res Part B: Appl Biomater 80B: 174183, 2007 ). The results suggest that calcium silicate ceramics have biocompatibility and bioactivity and thus are suitable as biocompatible materials for new bone repair.

Recently, certain Portland cement-based materials (MTA) have also been used for dental applications such as root canal treatment and core retention [Vargus et al., " A Comparison of the In vitro Retentive Strength of Glass- Ionomer Cement, Zinc-Phosphate Cement, and Mineral Trioxide Aggregate for the Retention of Prefabricated Posts in Bovine Incisors ”J. Endodont. 30 (11) 2004, 775-777 "]. MTA is a material similar to Portland cement, which is composed mainly of tricalcium silicate, tricalcium oxide, and tricalcium aluminate [Torabinejad et al.," Physical and chemical properties of a new root - end filling material , "J Endodont 21 (1995), 349-253]. MTAs are used in numerous surgical and non-surgical applications and have the necessary biocompatibility and sealing capabilities for perforated materials (Lee et al.," Sealing. ability of a mineral trioxide aggregate for repair of lateral root perforations , "J Endod 1993; 19: 541-4). MTA can be used as a non-absorbent barrier material and a non-absorbent restorative material for treating root perforation. MTA is hydrophilic and requires moisture when it solidifies. Because of this, MTA is difficult to select if there is a potential for water contamination or if there are constraints on technical access and visibility.

The physical and chemical properties of the MTA were tested and the initial pH at mixing was 10.2 and increased to 12.5 after 3 hours. MTA also has good compressive strength after solidification. MTA has proven to be significantly less toxic than other near-end filling materials when mixed freshly, and this toxicity is negligible when fully coagulated for 24 hours (Mitchell et al., " Osteoblast biocompatibility of mineral trioxide aggregate, " Biomaterials 20 (1999), 167-173).

Torabinejad et al. (US Pat. Nos. 5,415,547 and 5,769,638) disclose an improved method of filling and sealing the root cavity, which includes the use of MTA cement compositions, including the ability to cure in an aqueous environment. do. This cement composition includes a modification to Portland cement or a composition thereof, which shows good physical properties sufficient to form an effective sealant against the reflow of infectious organics. However, this cement is gray in color, which is unsuitable for many dental applications.

Primus (US Patent Application No. 2003/0159618) discloses a process for producing white dental materials that are substantially free of iron based on Portland cement compositions. This material can be used as dental cement, dental restoratives and the like. However, this process only reduced the iron content, but did not improve the biological properties of these materials.

LU et al. (PCT / CS2006 / 001761) disclose a medical hydraulic cement composition comprising calcium silicate and calcium phosphate, referred to as calcium silicate phosphate cement (CPSC), using in situ fixing and curing. This composition is claimed to be suitable for dental, implants, bone fixation, and bone repair. CPSCs have high mechanical strength, adequate settling time, low heat of hydration, resistance to biodegradation, high bioactivity and biocompatibility, and stability to corrosive environments. This cement forms in situ hydroxyapatite (HAP) / calcium silicate hydrate gel complex at room temperature or near room temperature and pressure, accompanied by removal of calcium hydroxide [Ca (OH) ₂ ], referred to as CH during the cement hydration step New chemical processes are employed. This process involves in situ reacting CH with phosphate ions to precipitate hydroxyapatite (HAP) intimately mixed with CSH gels resulting from the hydration of much more powerful and chemically resistant calcium phosphates, especially calcium silicates. Is performed through. As a result of this in situ chemical precipitation process, the composite cement has high mechanical strength, but also has biocompatibility, bioactivity, and proper settling time. These properties do not require the application of pressure-assisted molding or hydrothermal treatment of the components. However, like the MTA and calcium phosphate cement (CPC), CPSC powder must be mixed with water to initiate the hydration and fixation process.

Mixing and handling of cements is an important aspect of any particular use. For clinical use, it is very important to properly mix the cement with a liquid such as water and then place this cement paste within the defined time in the defect, which is an important factor in achieving optimal results. One of the major problems associated with the mixing process is an inadequate and non-uniform mixing of solids and liquids or an inappropriate ratio of cement solids to water, thereby impairing implant placement, fixation process, fixation properties, and performance. Thus, the cements are preferably mixed in advance under well-controlled conditions. Premixing is widely practiced in construction, for example premixed concrete is delivered by truck, but hydraulic cements premixed with water have rather shorter working times and must be delivered immediately to the application site. Another problem specific to medical cements is that all of the individual components of the cement material and equipment need to be sterilized and the mixing step needs to be performed in a sterile environment. In addition, the mixing time can be increased to understand the overall surgical placement time. Thus, it may be desirable to have a premixed cement paste that is stable in a sterile package for an extended period of time, easy to implant after the package is opened, and cures only after being placed in the defect.

Takagi et al. ( J Biomed Mater Res Part B : Appl Biomater 67B: 689-696, 2003) reported the findings associated with premixed calcium phosphate cement (CPC) pastes. The premixed pastes were prepared by mixing anhydrous glycerol and calcium phosphate cement powder to form a stable paste. Calcium phosphate cement hardened only after delivery to the defect site when glycerol-tissue fluid exchange occurred. However, fixed calcium phosphate cements are biodegradable, have relatively low mechanical strength and are therefore not suitable for many medical or dental applications [Xu et al., " Premixed calcium phosphate cements : Synthesis , physical properties, and cell cytotoxicity "dental materials 23 (2007) 433-441].

It is an object of the present invention to solve the above problems and to provide a premixed calcium silicate cement paste for dental, orthopedic and other biomedical applications.

More specifically, an object of the present invention is a premixed calcium silicate cement having high post-solidification mechanical strength, adjustable solidification time, low heat of hydration, good degradation resistance, high bioactivity and biocompatibility, and stability to corrosive environments. To provide a paste.

This premixed biocement paste (PBP) hydrates when the paste liquid is replaced with water-based body fluids and coagulates with a biodegradable high strength C-S-H gel.

This novel PBP comprises at least one calcium silicate and at least one substantially anhydrous liquid. PBP paste is prepared by mixing substantially anhydrous liquid and calcium silicate. This paste does not cure in a sealed package because calcium silicate cement only hydrates and hardens when exposed to an aqueous environment. After this PBP paste has contacted the physiological solution, the exchange of the non-aqueous liquid carrier with the physiological solution leads to cement hydration and hardening. This reaction involves the hydration of calcium silicate composites such as C2S or C3S to produce anhydrous calcium silicate gel C-S-H and calcium hydroxide.

Calcium silicate is the main component of cement and provides cement with biocompatible and bioactive properties. Calcium monosulfate (CaSiO ₃ ), dicalcium silicate (Ca ₂ SiO ₄ ) and tricalcium silicate (Ca ₃ SiO ₅ ) powders were synthesized by sol-gel process and hydrothermal synthesis. In vitro bioactivity of dicalcium silicate (Ca ₂ SiO ₄ ) and tricalcium silicate (Ca ₃ SiO ₅ ) is similar to the hydrated powder for various periods to analyze the nucleation and growth of hydroxyapatite (HAP) on the surface of the powder. Proven by soaking in simulated body fluid (SBF).

In dental and any orthopedic applications, radiopaque materials may be included in the composition of PBP pastes for enhancing X-ray absorption and thus for improved X-ray imaging. Such radiopaque materials include, but are not limited to, barium sulfate, zirconium oxide, bismuth oxide, tantalum oxide, and mixtures thereof. Radiation impermeability is important for filling and sealing teeth using cement. However, some dental applications do not require having a high radiopacity for example for pulp capping and rot treatment.

Premixed pastes include secondary additives suitable for any particular biological application, including chemical (reaction) modifiers such as phosphates, or non-reactive modifiers such as fibers and fillers to improve the microstructure and mechanical properties of the hardened cement. do. For example, the bioactive agent can be incorporated into PBP for controlled release. Such bioactive agents include, but are not limited to, anti-inflammatory agents, antibiotics, anticancer agents, proteins and DNA. Various types of filler materials (particles or fibers, reactive or non-reactive) may also be incorporated into the composition of the novel paste PBP to improve mechanical and biological properties such as polymeric materials, powders, and metals. In particular, if the premixed cement paste contains phosphate, the paste is hydrated and cured with biodegradable high strength C-S-H gel / HAp nanocomposites when the paste liquid is exchanged with aqueous body fluids.

As mentioned above, the premixed calcium silicate cement paste provided according to the present invention is characterized by high post-solidification mechanical strength, adjustable solidification time, low heat of hydration, good resistance to decomposition, high bioactivity and biocompatibility, and corrosion environment. Has stability.

Various features and advantages of the invention will be more fully understood and appreciated by reading the following detailed description with reference to the accompanying drawings.

The present invention relates to novel premixed pastes for biomedical applications, specifically for dental and orthopedic biological hydroponic cements. The paste herein is referred to as premixed biocement paste, or PBP for short. PBP comprises at least one calcium silicate and at least one substantially anhydrous liquid. PBP has high post-solidification mechanical strength, adjustable solidification time, low heat of hydration, good degradation resistance, high bioactivity and biocompatibility, and stability to corrosive environments. PBP is formed by mixing substantially anhydrous liquid (s) and calcium silicate (s).

As used herein for a liquid carrier, the term "substantially anhydrous" means that there is no water, or that the paste contains a small enough amount of water to not hydrate or solidify when kept under airtight conditions. For the use of the preferred compositions described herein, it is preferred that water is present in the carrier in an amount of at least about 20% by weight percent of the paste.

Other additives (having functional and non-functional or medical functionality such as pharmaceuticals, proteins or DNA) can be included in the base PBP composition as desired or necessary for a particular biomedical use. The injectable cement paste PBP obtained does not solidify or harden in a sealed package because the final calcium silicate cement is hydrated only when exposed to an aqueous environment. After the PBP paste is in contact with the physiological solution, the exchange of the non-aqueous carrier with the aqueous solution results in PBP coagulation-curing. These reactions involve the hydration of the calcium silicate composite to produce calcium silicate hydrogel and calcium hydroxide.

As mentioned above, the main component of PBP comprises at least one calcium silicate compound and at least one substantially anhydrous liquid compound. Examples of calcium silicate composites that can be used include, but are not limited to, calcium monosulfate (CS: CaO · SiO ₂ ), dicalcium silicate (C2S: 2CaO · SiO ₂ ) and tricalcium silicate (C3S: 3CaO · SiO ₂ ) and mixtures thereof. It is not limited. Examples of suitable substantially anhydrous liquids include, but are not limited to, ethyl alcohol, ethylene glycol, polyethylene glycol (PEG), glycerol liquids, glycerin, liquid organic acids, vegetable oils, animal oils, fish oils, and mixtures thereof. The water content of the substantially anhydrous liquid is preferably less than 20 wt%.

Calcium silicate may be included in the paste composition in the range of about 20 wt% to 90 wt%, preferably in the range of 30 wt% to 70 wt%. The total solid component in the PBP may range from about 30 wt% to 95 wt%, preferably from about 60 wt% to 90 wt% with respect to the paste composition. The liquid component of the PBP may range from about 5 wt% to 70 wt%, preferably from about 10 wt% to 40 wt% with respect to the paste composition.

Other calcium compounds that may be included in the PBP paste composition include, but are not limited to, calcium oxide, calcium carbonate, calcium hydroxide, calcium sulfate, calcium phosphate, and mixtures thereof. Phosphoric acid compounds can be incorporated into the PBP paste composition, which contains calcium phosphate, magnesium phosphate, sodium phosphate, zinc phosphate, iron phosphate, potassium phosphate, nickel phosphate, zirconium phosphate, phosphoric acid, organometallic phosphates and mixtures thereof. Including but not limited to. Phosphates used in PBP may contain hydrated water. More complex (pre-reacted) phosphates can also be used. Calcium phosphates usable in PBP include, but are not limited to, calcium monophosphate, dicalcium phosphate, tricalcium phosphate, tetracalcium phosphate and mixtures thereof. Calcium phosphate may contain hydrated water.

In another embodiment of the present invention, PBP included a secondary phase to improve the physical, mechanical, chemical and biological properties of the cured PBP cement paste. In general, ceramic matrix composites (CMS) combine reinforcing ceramic phases with a ceramic matrix to form materials with new and superior properties that overcome the disadvantages of brittle ceramics. If the (tragic) brittle fracture is replaced by a stable fiber failure, the ceramic composite can be reliably used as an engineering material for structural applications and other high performance applications. The breakdown of the fiber reinforced composite is mainly determined by the interface between the reinforcing fibers and the surrounding matrix. As the complexes crack, the fibers are pulled out of the matrix, absorbing energy and creating high toughness. Thus, low interfacial stress and resistance are required to ensure fiber breakage. If strong interfacial bonds are present, the crack cuts the fibers without pulling the fibers, resulting in insignificant fracture behavior with unreinforced single (monolithic) ceramics. For hydraulic cements based on calcium silicate, as a brittle ceramic material, the tensile strength is significantly lower (by a factor of about 10) compared to the compressive strength, which is structurally related to the low fracture toughness of the brittle material. In nature, brittle inorganic (calcium phosphate) phases are combined with fibrous collagen nanodispersed phases to solve this "problem" in bone. In the present invention, secondary phases such as fibers or second particles are introduced into the premixed cement phase PBP.

Multiphase complexes are utilized, for example, when it is necessary to adjust the stiffness of an implant to the stiffness of adjacent bone tissue. This avoids the "stress shield" effect where very strong implants carry much greater stress than adjacent bones which are less tough. In the long run, such "stressless" bones are more likely to be absorbed again and lose the structural integrity between the implant and the bone. (For example, rigid metal implants are known to cause such effects.) In the present invention, the stiffness of the PBP cement paste is characterized by the fact that the premixed paste has a less rigid organic phase (eg PLA (polylactic acid biopolymer)) or rigidity. The stiffness of the PBP cement paste can be controlled by combining with this smaller porous inorganic phase (such as calcium carbonate or calcium phosphate). The aforementioned materials are biocompatible and are reabsorbed to provide enough space for new bone to grow and penetrate into the coagulated PBP implant volume. In such capacity, these fillers do not act to control the initial stiffness of the implant but provide large pores (in the range of 1 μm to 1 mm) for the non-absorbable coagulation PBP implant to integrate with the newly grown bone tissue.

Thus, in the present invention, the bioabsorbable secondary phase material (s) is introduced into a premixed PBP paste to (i) adjust the stiffness of the coagulated complex to the stiffness of adjacent tissues, and (ii) bisphosphonate for accelerating bone growth. ) Or reabsorb and release biological agents such as antibiotics to cause transient-local infections, and (iii) allow bones to grow into the spaces (voids) created during reabsorption of the second phase. Secondary particles may be fibrous and may be either isotropic (non-fibrous) materials such as PLA or PLGA, calcium carbonate or calcium sulfate. In the fibrous form, the second phases are primarily intended to increase the fracture toughness and tensile strength of the coagulated PBP based fibrous composite.

Another aspect of the invention is the use of PBP cement as an injectable scaffold for tissue engineering. Currently, supports for bone tissue engineering are prefabricated 3D porous matrices with relatively low mechanical strength. The support shape and size must be designed and machined (machined) according to the defect geometry, which can be very complex. This is a relatively long time, expensive procedure and somewhat inconvenient for surgery. For example, complex shaped prefabricated supports may be difficult or impossible to insert into the bone cavity due to difficult accessibility. This is often the case in cases of vertebral fractures or loss of bone in the skull or jaw.

In the present invention, PBP (or PBP based composite) cement is used as a liquid support that solidifies and cures in situ to form a high initial strength 3D matrix support without the need for predesign and assembly processes. The new concept of PBP-based "liquid supports" is expected to shorten surgical and patient recovery time, save support costs, and ultimately have better performance when compared to predesigned supports. The aqueous and biodegradable second phases are preferably mixed in a premixed bio cement paste PBP that decomposes and disintegrates in the human body to provide sufficient porosity of the support. For example, bioglass, water soluble salts, water soluble metal oxides, calcium phosphate, carbonates and sulfates, biodegradable biopolymer sodium phosphate, magnesium phosphate, bioglass, sodium silicate and mixtures thereof. Such phases may also contain medically active ingredients that can be used for specific clinical uses. For example, bisphosphonates can be included to progressively release from the degradable second phase into adjacent bone tissue to promote growth of new bone into the resulting cavity. The biocompatible and bioactive calcium silicate based porous supports thus obtained are extremely useful for bone tissue engineering.

Another aspect of the present invention includes a second phase having the effect of removing calcium hydroxide, which is a by-product of hydration of calcium silicate. During the solidification-curing of calcium silicate cement, the hydration of calcium silicate produces nanosize calcium silicate hydrate gel and calcium hydroxide, resulting in high pH (pH = 10-12) (although in some dental applications, This may damage adjacent tissues in some applications, even if high pH is beneficial if the same long-term sterile environment is required. To treat this tissue, various reactive calcium phosphates of different acidity are included in the PBP composition to react with calcium hydroxide to produce amorphous calcium nitrate (ACP) and / or hydroxyapatite (HAP). This reduces the pH of the cement to about 8-10 (depending on the amount of nitric acid added) and increases the mechanical strength and chemical stability of the solidified PBP cement. Precipitated phosphates such as ACP and HAP are engineered to determine the absorption of phosphate phase components of PBP cement in a biological environment. Suitable compounds for reaction with calcium hydroxide include, but are not limited to, phosphate, phosphoric acid, calcium phosphate, sodium phosphate, magnesium phosphate and organic acids.

Depending on the application, the second phase of the PBP cement may include metals, metal salts, metal oxides, hydroxide compounds, non-oxide ceramics, biopolymers, and mixtures thereof. Metal salts include calcium salts, sodium salts, iron salts, magnesium salts, barium salts, strontium salts, potassium salts, zinc salts, phosphates, carbonates, sulfates, silicates, aluminates, hydroxides and combinations and / or mixtures thereof. But it is not limited thereto. Metal oxides include calcium oxide, sodium oxide, iron oxide, magnesium oxide, barium oxide, strontium oxide, potassium oxide, zinc oxide, zirconium oxide, titanium oxide, tantalum oxide, aluminum oxide, tungsten oxide, bismuth oxide, nickel oxide, cobalt oxide, Hafnium oxide, yttrium oxide, silver oxide, include but are not limited to gold oxide and mixtures thereof. Non-oxides in PBP include, but are not limited to, silicon carbide, silicon nitride, borate silicon, titanium nitride, titanium nitride-oxide titanium, and mixtures thereof. Biopolymers include, but are not limited to, biodegradable biopolymers and biodegradable polymers. Also for dental use, PBP cement may include gutta percha powder to improve suture and healing capabilities.

Additional incidental compounds that may be included in the PBP paste composition of the present invention include: less than 30% of the weight of cement in the PBP paste composition, tricalcium aluminate (3CaOAl ₂ O ₃ ), tetracalcium aluminoferrite (4CaO). Al ₂ O ₃ Fe ₂ O ₃ ), calcium oxide, ferrite oxide, calcium sulfate dihydrate (CaSO ₄ 2H ₂ O), sodium salt, magnesium salt, strontium salt and mixtures thereof, but not limited thereto . The paste also contains a number of impurity oxides from the raw materials, preferably in an amount less than 5% by weight of the paste in the cement composition, which oxides are iron oxide, magnesia (MgO), potassium oxide, sodium oxide, sulfur oxide, Carbon dioxide, water and mixtures thereof, including but not limited to.

For dental and orthopedic use, radiopaque materials may be added to the PBP paste composition to improve the absorption of X-rays and to improve the visibility of the implants in the X-ray image. Radiopaque materials that can be used include, but are not limited to, metals, metal oxides, salts, nonoxides, and mixtures thereof. Examples of additive materials include, but are not limited to, barium sulfide, zirconium oxide, bismuth oxide, tantalum oxide, tantalum, titanium, stainless steel, alloys, and mixtures thereof, wherein the additive material is less than about 70% of the weight of the PBP paste composition. It is preferable if it is comprised.

Another aspect of the present invention is the use of pastes for medical materials and devices, such as prostheses, implants, coatings, and surgical procedures. For example, premixed PBP pastes are useful for the treatment of damage, breakage and disease of the musculoskeletal system such as the spine, joints and ligaments. Treatment conditions include bone deformity due to cerebral palsy osteoarthritis, bone loss due to trauma or disease, scoliosis, implants (hips, knees, shoulders, etc.) and the like.

As noted above, the injectable PBP cement paste of the present invention does not solidify and cure in hermetic packages because the calcium silicate cement starts to hydrate and cure only when exposed to an aqueous environment. However, after the paste is in contact with the physiological solution, the non-aqueous carrier is exchanged with the aqueous solution in a diffusion manner, exposing the cement to water and thus causing hydration and curing. This reaction involves hydration of calcium silicate hydrate gel (CSH) and calcium silicate to produce calcium hydroxide (CH). Biocompatible and bioactive calcium silicate hydrate gel is a major structural component of cement and contributes to its mechanical strength. As mentioned above, in some embodiments, a calcium phosphate composite is added to the PBP paste composition, so that during solidification of the cement, the phosphate ions are added to the calcium silicate paste, dicalcium silicate (2CaO.SiO ₂ ) and tricalcium silicate (3CaO.SiO). _It reacts with the extra calcium hydrate obtained by hydration of the main component of ₂ ). Without phosphate ions, calcium hydroxide forms the contents of the main gel (expressed as CaO-SiO ₂ -H ₂ O, CSH) structure of variable size and shape. These calcium hydroxide contents are structurally-chemically fragile points and do not contribute to the strength of the solidified calcium silicate cement and are sensitive to environmental influences. However, when CH is reacted with phosphate ions, various calcium phosphate contents are produced, the most stable and strong being hydroxyapatite (HAP). The formation of the CSH / HAP composite is carried out by the reduction of the CH content in the solidified cement, where CH is the structural-chemically weakest component of the solidified cement. The material obtained has a reduced CH content, significantly increased mechanical strength, calcium phosphate and hydroxyapatite act as reinforcing phases and calcium silicate hydrate gel is the matrix in the composite structure. At the same time, the solidification pH of the cement is reduced, which is advantageous for most medical and dental applications.

The strength of the solidified PBP cement is such that it can be used for load and unloaded applications. PBP cement is resistant to decay loss when PBP cement is in contact with blood and is perfectly suited to the living environment, so when injected into the wound, it lessens the surrounding tissue. Thus, examples of suitable biomedical applications include percutaneous spinal surgery, craniofacial surgery, alveolar augmentation, fusion cage / implant, treatment of radial fractures, treatment of jaw joint disorders, plastic surgery, cosmetic enhancement, bone graft replacement, Applications, support, dosing, dental applications, apoxification, pulp reconstruction, root canal filling and recovery, pulp cutting, endodontics, and combinations thereof.

Another aspect of the present invention is the drug separation capability of a PBP-based implant dental device, combining release control of the drug with other functions of the prosthetic implant (such as a load support function and a support function). This represents a multifaceted improvement over implant devices. Prosthetic and dental implants are used to treat bone defects caused, for example, in diseases, trauma, surgical procedures or congenital defects. Each year, millions of prosthetic implants are placed to functionally replace or completely replace tissue (eg, total joint replacement) to secure and strengthen broken bones that are being repaired. Bone-implant fusion (ie, direct bone-implant binding) and long-term stability are common clinical problems including infection, bone resorption, implant loosening, slow recovery or non-union. According to this aspect of the invention, the bioactive agent is included in a premixed bio cement paste PBP for controlled release, promoting and accelerating bone angiogenesis, more reliable treatment and functional tissue replacement, and preventing infection. Drug-separated PBP cements have the ability to improve device performance and the quality of life of patients associated with it. In addition, multiple bioactive agents can be incorporated into premixed pastes such as combinations of antibiotics for short-term release (two to three weeks) to treat possible short-term infections, and as long-term release as inhibitors of osteoclast absorption in the treatment of osteoporosis. Can be incorporated into premixed pastes such as bisphosphonates. Bioactive agents that may be included in PBP cement include, but are not limited to, antibiotics, anticancer drugs, bisphosphonates, anti-inflammatory drugs, protein drugs, DNA, stem cells, bone growth factors, vitamin drugs, and mixtures thereof.

According to another aspect of the present invention, microspheres of PBP bio cement paste can be designed for administering a medicament, protein, DNA or other type of medically active substance to the corresponding area of the body. The bioactive agent is encapsulated into microspheres processed into PBP paste, which is released into a controlled profile and comes into contact with blood once the microspheres are placed in the tissue area. The release profile of the bioactive agent is designed according to specific clinical requirements and is controlled by engineering the composition of the PBP paste and the microstructure of the solidified PBP cement. According to one variant, the bioactive agent is encapsulated into biopolymer capsules, liposomes, bovine-cells, emulsions or core-shell spheres, and then these intermediate carriers are incorporated into a premixed PBP paste for controlled release. Including such intermediate carriers adds flexibility to predesign multiple drug degradation profiles to meet specific clinical requirements.

According to another aspect of the present invention, controlling the particle size distribution of the solid component in the paste improves the flowability and injectability of the PBP paste. The particle size of the cement solids is suitably in the range of about 0.01 μm to about 1000 μm, and preferably in the range of about 0.1 μm to about 50 μm. In addition, an organic dispersant (binder) may be added to the paste to improve the stability and injectability of the paste, such as citric acid, sodium citrate, cellulose, hydroxypropyl methylcellulose, polyacrylic acid, carbonylmethyl cellulose, bio Polymers, organic acids, and mixtures thereof, including but not limited to.

Premixed PBP pastes according to the invention can be prepared by physical mixing processes (non-reactive), chemical processes (reactive), biological processes and combinations thereof. For example, a ball-mill process may be used to mix the solid phase and the anhydrous liquid to prepare a premixed PBP paste. The binder is adsorbed on the solid powder surface by physical-chemical adsorption, improving the stability of the premixed paste. The coated solid particles are mixed with anhydrous liquid by an ultrasonic mixer to produce a uniform paste.

<Examples>

Example  1: calcium silicate cement PBP  Preparation of the paste

This example describes the treatment of pure PBP calcium silicate paste for biomedical use. Calcium silicate was prepared by mixing 151 g of calcium oxide and 60 g of silica and ball milling for 24 hours in an alcohol solution. The mixed powder was dried at 110 ° C. and calcined at 1600 ° C. As a result, a uniform mixed powder of 30 wt% dicalcium silicate and 70 wt% tricalcium silicate was obtained, and further ball milled to achieve an average particle size of about 10 μm. In this example, 100 g of the calcium silicate powder and 21 ml of ethylene glycol thus obtained were mixed in a planetary ball mill to prepare a premixed bio cement paste PBP in a 45 min time until complete homogenization was achieved. The homogenized calcium silicate PBP paste was filled into syringes to test the injectability and to evaluate the solidification properties and the solidified cement properties. This calcium silicate PBP paste was determined to be injectable and white. It is also suitable for dental applications such as root canal filling, proximal filling, recursive filling, pulp capping, root canal shaping and perforation closure.

Example  2: phosphate-containing calcium silicate cement PBP  Preparation of the paste

In this example, a silicate phosphate paste was prepared using well specified pure chemicals (as opposed to insufficiently specified minerals utilized in the manufacture of conventional commercial Portland cement). The raw materials used to prepare the calcium silicate phosphate powder were colloidal silica (50wt% Ludox, 3M) for SiO ₂ , calcium hydroxide (99.9%, Sigma-Aldrich) for CaO, Ca ₄ (PO ₄ ) ₂ O) And anhydrous dicalcium phosphate (CaHPO ₄ H ₂ O, Fisher). In contrast, without affecting the final properties of the paste, colloidal silica is derived from pyrolysis of hydrated silicon alkoxides such as tetra-eth-oxide silicate or TEOS, or as purified pure silica powder. Can be added. The cement composition prepared was 65 wt% tricalcium silicate, 20 wt% dicalcium silicate, 10 wt% tetracalcium phosphate, and 5 wt% dicalcium phosphate. 96.32 g of colloidal silica, 160.98 g of calcium hydroxide and 300 g of distilled water were mixed in an alumina pot and ball milled for 24 hours to prepare a 200 g batch. The slurry mixture was dried using a spray dryer and then fired in a high temperature furnace at 1550 ° C. for 1 hour to form a mixture of tricalcium silicate and dicalcium silicate. It was then naturally cooled to room temperature.

The resulting cement clinker was ground to a standard particle size (particle size less than 45 μm) of −325 so that the average particle size was about 10 μm. 11.25 g of anhydrous dicalcium phosphate was dried in a furnace at 140 ° C. for 24 hours and then ball milled for 24 hours by mixing with 20 g of tetracalcium phosphate and calcined cement powder (168 g) in an alcohol solution. The slurry obtained was spray dried. The average particle size of the cement powder was about 10 μm. A paste was prepared by mixing 200 g calcium silicate phosphate powder, 30 g polyethylene glycol (molecular weight 400, Sigma) and 5 g hydroxypropyl methylcellulose in an oily ball for 10 minutes. Hydroxypropyl methylcellulose is a gelling agent for improving the viscosity and flowability of phosphate containing PBP pastes. The solidification time of the PBP paste thus prepared was about 10 hours at 37 ° C. in a 100% humidity environment. The average compressive strength after solidification at 37 ° C. and 100% humidity for 7 days was 101 MPa, with a standard deviation of about 8 MPa. This PBP cement paste is injectable and suitable for dental and orthopedic use.

Example  3: PBP  Bioactivity of Paste Cement In vitro  exam

This example illustrates the bioactivity of calcium silicate phosphate PBP paste. The paste was prepared by the procedure described in Example 2. Cement paste was filled into a cylinder mold 1 inch in diameter and 2 inches in height. Samples were incubated at 100% humidity without using organics and pH was adjusted to 7.4 with 7.5% NaHCO ₃ solution. All samples were immersed in SBF solution for 10 days at 37 ° C., then washed with distilled water and dried for SEM observation. It was found that a typical hydroxyapatite structural layer was formed on the surface of the cement as shown in FIG. These results demonstrate that the PBP cement of the present invention has excellent bioactivity, osteoinductive and osteogenicity.

Example  4: dental radiation Non-transmissive  Having ingredients PBP  Paste composition

This example describes a process for preparing a calcium silicate PBP dental paste comprising a radiopaque material. Calcined cement powders were prepared as described above in Example 2. Zirconia (ZrO ₂ , Zircoa, USA) is biocompatible and used in orthopedic implants, so it was selected as a dental radiopaque material. Alternatively, radiopaque materials can be derived from tantalum oxide (TaO ₂ ), without affecting the final properties of the paste. A paste was prepared by mixing 7 g cement powder, 30 g zirconia and 10 g ethylene glycol in a ball mill for 20 minutes. X-ray tests indicate the clear transparency of the modified paste and are evidence that dental cements containing radiopaque zirconia are suitable for dental use. The radiopacity of the paste was specified according to ISO standards (ANSI / ADA No. 57: 2000 Endodontic Sealing Materials, ISO 3665 Photography-Oral Dental Radiation Graphics Film-Specification and ISO 6876: 2001 Root Canal Sutures). The radiopacity of the cement was greater than the aluminum wedge 4 mm thick.

Example  5: dental PBP  Paste composition

The procedure for preparing a pure high strength PBP paste for bioactivity and biocompatibility is described below. The raw materials used in the examples were colloidal silica (50 wt% Ludox, 3M) for SiO 2, calcium hydroxide (99.9%, Sigma-Aldrich) for CaO, boehmite (AlOOH) for Al ₂ O ₃ , iron oxide (Fe ₂ O). ₃ , 99%, Fisher), dehydrated calcium sulfate (CaSO ₄ .H ₂ O, 99%, Fisher) and calcium monophosphate [Ca (H ₂ PO ₄ ) ₂ , 99%, Sigma]. Alternatively, without affecting the final properties of the paste, colloidal silkys can be derived from pyrolysis of hydrated silicon alkoxides such as TEOS. The composition of the present invention is 58wt% tricalcium silicate (3CaOSiO ₂ ), 11wt% dicalcium silicate (2CaOSiO ₂ ), 6wt% tricalcium aluminate (3CaOAl ₂ O ₃ ), 7wt% tetracalcium aluminoferrite (4CaO. Al ₂ O ₃ · Fe ₂ O ₃ ), 4 wt% dehydrated calcium sulfate (CaSO ₄ 2H ₂ O), 4 wt% calcium oxide and 10 wt% calcium monophosphate [Ca (H ₂ PO ₄ ) ₂ ]. 78 g colloidal silica, 156.9 g calcium hydroxide, 10.57 g boehmite, 4.61 g ferrite oxide, and 300 g distilled water were mixed in an alumina pot and ball milled for 24 hours to prepare a 200 g batch. The slurry mixture was dried using a spray dryer, calcined in a high temperature furnace at 1550 ° C. for 1 hour and then naturally cooled to room temperature. Thereafter, polishing was carried out to an average particle size of 10 mu m. 20 g of calcium monophosphate, 8 g of calcium hydroxide and 8 g of dehydrated calcium sulfate were mixed for 5 minutes by calcined cement powder and 35 g of polyethylene glycol 600 with an oily ball mill. The paste was filled into a syringe for evaluation. This cement PBP paste was gray as an injectable. It is also suitable for dental applications such as near-end filler, retrofill, dimensional demodulation, root-induced shaping and perforation closure. In order to produce specific dental white PBP cements requiring color control, the entire cement preparation process was repeated exactly except for the iron oxides in the cement composition. The characteristics of such a white variant of PBP were essentially the same as that of the brown variant of PBP as shown in FIGS. 3, 4 (a) and 5.

Example  6: for drug administration PBP  Paste composition

This example illustrates the incorporation of a bioactive agent into the PBP paste to control subsequent release into the biological environment. A paste was prepared as described in Example 1, but additionally contained antibiotic vancomycin at 1 wt% and 5 wt%, respectively. The PBP paste was injected into the bone voids and then placed in aqueous phosphate buffer solution to immediately initiate curing through exchange of PEG with water in the paste. At the same time, antibiotics were released from the paste into the PBS solution. PBP cement paste # 2 contained 5 wt% vancomycin and the amount of other components was reduced proportionally. Vancomycin was released within 2 weeks from PBP paste # 1 (containing 1% vancomycin) and within 5 weeks from PBP paste # 2 containing high content (5% vancomycin). In both cases, the released concentrations were higher than the effective concentrations for different forms of Staphylococcus aureus resistant to Meticilin-Cefem (MRSA). The drug release rate depends on the composition of the paste, but was independent of the two periods investigated with up to 80% of the antibiotic, as shown in FIG.

Example  7: premixed silicate PBP  Biological Evaluation of Pastes

This example describes the biological properties of a medically premixed PBP paste. Samples were prepared as described in Example 2. Sensitization tests were selected to determine whether the PBP cement of the present invention interacts with the body's immune system so as to cause local or systemic side effects after repeated or prolonged exposure. Such sensitization (allergic) or hypersensitivity reactions to biocompatible materials were dermal cell mediated rather than humoral or antigen-antibody forms, and the skin of the experimental animals was used for sensitivity testing. Dermal sensitization in laboratory animals is characterized by redness and edema. Guinea pigs were used because they are known to respond to dermal sensitizers similarly to humans. The guinea pig sensitization test (Magnusson-Kligman technique) is the most sensitive test for delayed type hypersensitivity and is recommended for test devices, chemicals and materials that are externally or internally contacted by the body or body fluids. In this study, test materials were mixed with complete Freund's adjuvant (CFA) to enhance skin sensitization. This test is considered more sensitive than the repeated patch model, and the sensitization test is used for device materials that will come into contact with areas other than skin. The test results show that the premixed cement PBP paste of the present invention did not cause significant dermal reactions. Results for the infusion, induction and provoke phases showed no erythema or edema after 24 hours. Satisfactory weight gain was shown when the weight of the animals treated during each stage was compared with the weight of the control animals. The premixed cement pastes of the present invention not only caused delayed contact dermatitis (Type IV sensitization) but also did not cause potential allergies after multiple use. The negative results of such sensitivity analyzes provide significant safety margins with regard to potential risks to humans.

Genotoxicity testing was chosen because it provides an in vitro method for detecting mutagens, which are substances that can cause gene damage directly or indirectly through various mechanisms. Microbial Reverse Mutation Assay or Ames test employs several species of bacterial Salmonella typhimurium to detect point mutations, which are susceptible to mutagenic factors and various DNA actives. Because it was chosen. Potential mutagenesis in the presence / absence of mammalian liver S-9 activity was assessed. Mammalian liver S-9 activity systems assess the activity of enzyme activation, mutant precursors, or direct action mutagenesis. The test results indicate that premixed cement PBP did not induce mutagenic activation in the microbial reverse mutation test (Ames test) with or without S-9 enzyme activation. Positive control of the test elicited the predicted mutagenesis response, demonstrating the results for the premixed cement of the present invention.

The transplantation test was chosen because local pathological tissue effects and responses around the surgically implanted cement according to the present invention in contact with living tissue are evaluated at both global and microscopic levels. Histopathological analysis assesses the biochemical exchange of tissues and the dynamics of cellular and immunological responses in transplantation trials. Implantation techniques evaluate both absorbent and nonabsorbent materials. This test for the substance is identical to the subchronic toxicity test for the substance.

Since the premixed PBP cement of the present invention is designed to be used internally for a long time, implanting samples into the body of an experimental animal is the most direct means of assessing the potential impact of medical device material on surrounding living tissue. Therefore, the pre-mixed PBP cement of the present invention was surgically implanted into the sebum of the mice, and the mice were susceptible to systemic dermal toxic action of most substances and easy access for transplantation. It was therefore chosen as the species for transplantation testing. Transplantation in the subcutaneous tissue of rats was performed for two periods, 15 days and 3 months. In each period, three mice were each implanted with premixed cement. Through the test, the rats gained weight well, especially the rats subject to the 3 month test. Macro and micro histological analysis led to the conclusion that the premixed cement of the present invention was well received by subcutaneous tissue.

Example  8: Pre-mixed Silicate PBP  Of paste Root canal Sealer ( sealer ) Applications

This example demonstrates the availability of a premixed PBP paste to effectively seal the root canal during root canal treatment. PBP paste was prepared as described in Example 4. Pulled teeth were used to perform root canal filling with PBP cement and gutta-percha. The solidification time of PBP cement in the root canal depends on the availability of water for the hydration reaction of calcium silicate in the paste. Teeth were filled using PBP paste and taper 0.02 ISO standard Gutta Percha Point (GPP). Lateral condensation technique was used for side filling. The end of the syringe containing the PBP paste was inserted into the deepest part of the root canal. The PBP paste was gently and smoothly injected into the upper end of the root canal by pressing the syringe piston. The syringe was withdrawn gradually while injecting the PBP paste into the root canal. Accordingly, the root canal was filled in a conventional manner using GPP. After filling, the excess (excess) PBP paste was removed with a wet cotton ball and the coronary pores of the root canal were closed with nail polish solution. To compare different dosing systems, PBP paste was also used to fill the root canal without GPP. The filled teeth were placed in an incubator at 100% humidity and 37 ° C for 7 days. After coagulation for 7 days, radiographs of randomly selected teeth were taken to assess the quality of PBP cement filling with or without gutta percha (GP). The result is shown in FIG. A close examination of the X-rays shows that PBP cement almost completely fills the root canal volume for both presence / absence of GP. However, in order to evaluate the suture quality at a micro level, it is necessary to perform a scanning electron microscope (SEM) examination on the cross sections of the teeth. In addition, in order to evaluate the progress of hydration and coagulation, the cross-sectional area should be evaluated with a Vicat probe. Thus, the teeth were cut with a diamond saw so that the cross sections of the coronal 1/3, middle 1/3 and top 1/3 portions of the teeth were opened, respectively. The cross section of the upper third portion was observed by SEM and the results are shown in FIG. 4 (middle magnification: size bar = 500 µm) and FIG. 5 (high magnification: size bar = 50 µm). No gaps were found at either interface (ie dentin / PBP interface and GP / PBP interface) at both medium and high magnifications. Thus, SEM results show that PBP cement forms a tight bond with both dentin and GPP. The high magnification SEM shown in FIG. 5A shows that PBP cement diffused into the dentin tubule. Such a tightly bonded interface between cement and dentin provides good root canal closure, effectively preventing bacterial leakage. In addition to SEM observations, in order to set the time with a Vicat needle, the coronal one-third portion of the sutured root was examined with a probe according to the standard test method of dental aqueous cement (ISO9917: 1991). The set time was determined to be 10 hours.

1 is a scanning electron microscope (SEM) image showing the results of a bioactivity test on a modified substance of the PBP calcium silicate paste of the present invention, wherein the modified substance contains about 10% calcium phosphate co-precipitated with a CSH gel. It was then immersed in analogous fluid (SBF) at 37 ° C. for 10 days, showing that a typical hydroxyapatite structure layer was formed on the surface of the cement, thereby demonstrating that the PBP cement had a high bioactivity.

FIG. 2 is a graph showing the profile of in vitro vancomycin (antibiotic) eluting from PBP cement paste according to the invention containing 1 wt% and 5 wt% vancomycin.

Figure 3 is an X-ray micrograph of two teeth with filler material formed using cement according to the present invention, showing that these filler materials were made with or without gutta percha points.

FIG. 4 (a) is an enlarged intermediate section of the tooth of FIG. 3 in which the filling material is formed without gutta percha points, showing that complete filling and absence of the gap was achieved using the cement of the present invention. .

Figure 4 (b) is an enlarged medium cross-sectional view of the tooth of Figure 3, in which the filler material comprises guttaperca points, again showing the complete filling with the cement of the present invention.

Figure 5 (a) is a high magnification of the cross section of Figure 4 (a), showing in more detail the interface between the cement filler and the dentin of the tooth.

Figure 5 (b) is a high magnification of the cross section of Figure 4 (b), showing in more detail the interface between the cement-filled material and all gutta-percha points.

Claims (21)

Pre-mixed cement paste for use in medical or dental applications, At least one calcium silicate compound; And A premixed cement paste comprising: at least one substantially anhydrous liquid carrier mixed with the at least one calcium silicate compound and exchanged with a physiological solution to hydrate and cure when the cement paste is in a physiological environment . The method of claim 1, The at least one calcium silicate composite is Calcium silicate, Dicalcium silicate, Tricalcium silicate, and A premixed cement paste selected from the group consisting of mixtures thereof. The method of claim 1, The at least one substantially anhydrous liquid carrier, Ethylene glycol, Polyethylene glycol, Liquid glycerol, glycerin, Ethyl alcohol, vegetable oil, Animal Oil, Silicone oil, Hydroxypropylmethylcellulose, and A premixed cement paste selected from the group consisting of mixtures thereof. The method of claim 1, Wherein said at least one substantially dry liquid carrier is about 20% by weight of said paste. The method of claim 1, Wherein said at least one calcium silicate is in an amount ranging from about 20% to about 95% by weight of said paste. The method of claim 5, Wherein said at least one calcium silicate is in an amount ranging from about 30% to about 70% by weight of said paste. The method of claim 1, And said at least one substantially dry liquid carrier is in an amount in the range of from about 5% to about 70% by weight of said paste. The method of claim 7, wherein And said at least one substantially dry liquid carrier is in an amount in the range of from about 10% to about 40% by weight of said paste. The method of claim 1, Premixed cement paste further comprising at least one secondary phase for enhanced efficacy when the paste is cured in a physiological environment. 10. The method of claim 9, Wherein said secondary phase is a fiber material for improved material properties of said hardened cement paste. 10. The method of claim 9, Wherein said secondary phase is guttaperca for improved sealing of said hardened cement paste. The method of claim 11, Wherein said secondary phase is at least one material eroded from said hardened cement in said physiological environment for improved internal growth of bone in said cement. The method of claim 12, At least one material that is eroded from the cured cement, Biodegradable Material, Soluble material, and A premixed cement paste selected from the group consisting of mixtures thereof. 10. The method of claim 9, Wherein said secondary phase is at least one radiopaque material for enhanced x-ray imaging of said hardened cement. The method of claim 14, Wherein said radiopaque material is in an amount of up to about 70% by weight of said paste. 10. The method of claim 9, The secondary phase is at least one bioactive agent for elution from the cured cement into the physiological environment. The method of claim 16, The bioactive agent, antibiotic, Anticancer drugs, Bisphosphonates, Anti-inflammatory drugs, DNA, Stem Cells, Bone growth factor, Vitamin pharmaceutical, and A premixed cement paste selected from the group consisting of mixtures thereof. Pre-mixed cement paste for use in medical or dental applications, At least one calcium silicate composite in an amount ranging from about 30% to about 70% by weight of the paste; And Exchange with the physiological solution in an amount ranging from about 30% to about 70% by weight of the paste so as to hydrate and cure when the cement paste is present in a physiological environment. At least one substantially dry liquid carrier in an amount of about 20% or less by weight of the paste; The calcium silicate composite is selected from the group consisting of calcium silicate, dicalcium silicate, tricalcium silicate, and mixtures thereof, And said anhydrous liquid carrier is selected from the group consisting of ethylene glycol, polyethylene glycol, ethyl alcohol, vegetable oils, animal oils, silicone oils, hydroxypropylmethylcellulose, and mixtures thereof. A method of preparing cement-specific materials for preparing cement-specific materials in medical or dental applications, Providing a premixed cement paste comprising at least one calcium silicate compound and at least one substantially anhydrous liquid carrier mixed with the at least one calcium silicate compound; And Disposing the premixed cement paste in a physiological environment such that the at least one substantially anhydrous liquid carrier exchanges with a physiological solution to hydrate the cement paste in the physiological environment. Way. The method of claim 19, Providing the pre-mixed paste, Calcium silicate, Dicalcium silicate, Tricalcium silicate, and A method for producing a cement characteristic material, wherein said at least one calcium silicate compound is selected from the group consisting of a mixture thereof. The method of claim 19, Providing the pre-mixed paste, Ethylene glycol, Polyethylene glycol, Liquid glycerol, glycerin, Ethyl alcohol, vegetable oil, Animal Oil, Silicone oil, Hydroxypropylmethylcellulose, and A method of producing a cementitious material, wherein said substantially anhydrous liquid carrier is selected from the group consisting of mixtures thereof.

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