WO2023216069A1 - Plastic orthopedic composition having erosion resistance - Google Patents

Plastic orthopedic composition having erosion resistance Download PDF

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Publication number
WO2023216069A1
WO2023216069A1 PCT/CN2022/091740 CN2022091740W WO2023216069A1 WO 2023216069 A1 WO2023216069 A1 WO 2023216069A1 CN 2022091740 W CN2022091740 W CN 2022091740W WO 2023216069 A1 WO2023216069 A1 WO 2023216069A1
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composition
calcium sulfate
orthopedic
bone
plastic
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PCT/CN2022/091740
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French (fr)
Chinese (zh)
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方旭伟
蒋孝鸿
苏真莹
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台北科技大学
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Priority to PCT/CN2022/091740 priority Critical patent/WO2023216069A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/02—Surgical adhesives or cements; Adhesives for colostomy devices containing inorganic materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/12—Phosphorus-containing materials, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/42—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix

Definitions

  • the present invention relates to a bone filling material, and in particular to a plastic orthopedic composition with erosion resistance.
  • Calcium sulfate has been used to help bone repair for a long time. Because of its good osteoconductivity and biocompatibility, it is mainly used as a cavity filler. It can help restore the shape and contour of the bone and prevent the invasion of soft tissue and its degradation. The rate can match the rate of new bone formation and aid vascular infiltration.
  • the dissociated calcium ions on the surface reach a specific concentration gradient and will combine with the phosphate ions normally present in the body to produce calcium phosphate precipitation.
  • phosphate precipitation produces secondary osteoconductivity, allowing osteoblasts to adhere.
  • Calcium sulfate can be divided into calcium sulfate dihydrate (CaSO 4 ⁇ 2H 2 O), calcium sulfate hemihydrate (CaSO 4 ⁇ 0.5H 2 O) and anhydrous calcium sulfate (Calcium sulfate hemihydrate, CaSO 4 ⁇ 0.5H 2 O) according to the amount of crystal water.
  • Calcium sulfate Dehydrate three kinds, calcium sulfate dihydrate can be called raw gypsum, calcium sulfate hemihydrate can also be called gypsum of paris. Both calcium sulfate dihydrate and calcium sulfate hemihydrate can be used in bone filling materials.
  • hydroxylapatite is the main inorganic component of human bones and has good biocompatibility. Its calcium-to-phosphorus ratio is 1.67, which is consistent with that of bones.
  • the mineral composition is very similar and can bond with the bone and become part of the bone.
  • the mechanical strength is too low. Therefore, when used as a composite material with calcium sulfate, increasing the proportion of calcium sulfate will increase the mechanical strength of the implant [4 ], and when calcium sulfate degrades, holes will also be created for new bone to grow in.
  • Calcium sulfate hemihydrate adds acellular bone matrix: In addition to providing biocompatibility and osteoconductivity, acellular bone matrix also has osteoinductivity and growth factors [7], but its main disadvantage is poor mechanical strength. , infection risks and sources of acquisition, etc. Therefore, composite aggregates adding calcium sulfate hemihydrate can provide initial mechanical strength and have the effect of initial vascular infiltration [8].
  • calcium sulfate products are mostly injection type. Calcium phosphate is available in tablet, sheet, columnar, injection and other dosage forms. There are also some bioglass (calcium silicate), polymer materials ( Polylactic acid, polyglycolic acid) are added to bone filling materials. Usually for injection-type or hydration-type materials, you need to mix powder and liquid into a paste before use, and then add it to the injection container or a thicker clay-like material that can match the shape of the affected area, mold it into the desired shape, and then fill it in. .
  • bioglass calcium silicate
  • polymer materials Polylactic acid, polyglycolic acid
  • the powder and water are not mixed evenly, which may cause changes in material properties, causing changes in the original curing time, injection properties, and mechanical properties.
  • the mixing methods of currently commercially available products are different.
  • Product A requires mixing the powder and water evenly within the specified time of one minute, and then waiting for three minutes before it can be filled into the affected area.
  • Product B needs to be soaked in powder and water for three minutes and mixed for one minute before it can be filled into the affected area.
  • premixed dosage forms are produced.
  • Premixed dosage forms generally refer to the fact that when doctors open the package, they can directly fill it without the complicated mixing of powder and water. The mixing time of powder and water can be omitted, which not only facilitates the doctor's Use can also reduce the risk of disease.
  • the inventor of the present invention has conducted relevant research and improvement on orthopedic compositions based on years of research experience; therefore, the main purpose of the present invention is to provide a plastic orthopedic composition with erosion resistance and its Preparation.
  • a plastic orthopedic composition with good erosion resistance is provided.
  • the present invention is about providing a plastic orthopedic composition, which includes: a powder composition, which includes calcium sulfate hemihydrate (CaSO 4 ⁇ 0.5H 2 O), tricalcium phosphate ( ⁇ -tricalcium phosphate ( ⁇ -TCP) and hydroxypropyl methylcellulose (HPMC); and a solvent including glycerol (Glycerol) and water.
  • a powder composition which includes calcium sulfate hemihydrate (CaSO 4 ⁇ 0.5H 2 O), tricalcium phosphate ( ⁇ -tricalcium phosphate ( ⁇ -TCP) and hydroxypropyl methylcellulose (HPMC); and a solvent including glycerol (Glycerol) and water.
  • the ratio of the calcium sulfate hemihydrate to the tricalcium phosphate is about 1:1 (g/g).
  • the weight percentage of hydroxypropyl methylcellulose is 1 to 6%.
  • the weight percentage of hydroxypropyl methylcellulose is 1 to 4%.
  • the volume percentage of glycerin is about 70-99%.
  • the volume percentage of glycerol is about 85%.
  • a bone filling kit which includes the moldable orthopedic composition according to the present invention stored in a separate container.
  • a plastic orthopedic composition is further provided for medical use in treating bone defects.
  • Figure 1 shows the washout percentage of orthopedic compositions that both contain 70% glycerol (Glycerol), but contain different proportions of hydroxypropyl methylcellulose (HPMC), immersed in simulated body fluids for 15 minutes or 1 hour.
  • **P ⁇ 0.01 is the difference between soaking for 15 minutes and 1 hour for the same formula.
  • Figure 2 shows the washout percentage of orthopedic compositions that both contain 85% glycerol (Glycerol), but contain different proportions of hydroxypropyl methylcellulose (HPMC), immersed in simulated body fluids for 15 minutes or 1 hour.
  • Glycerol 85% glycerol
  • HPMC hydroxypropyl methylcellulose
  • Figure 3 shows the erosion percentage of bone filling materials, which all contain 99% glycerol (Glycerol) but contain different proportions of hydroxypropyl methylcellulose (HPMC), soaked in simulated body fluids for 15 minutes or 1 hour. Using t test statistics, there is no statistical difference between soaking for 15 minutes and 1 hour.
  • Glycerol 99% glycerol
  • HPMC hydroxypropyl methylcellulose
  • the term "about” is used to indicate that a numerical value includes errors in material proportions, drug concentration values, or variations that exist between experimental subjects. Typically the term is intended to cover greater or less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14 %, 15%, 16%, 17%, 18%, 19% or 20% variability, as appropriate.
  • orthopedic composition include, but are not limited to, joint implants, spinal implants, craniofacial implants, dental implants, foot and ankle implants, or trauma implants. Objects (bone plates, bone nails), etc.
  • injected include the administration of any composition, such as injection, immersion or delivery to an individual via any delivery device .
  • the object of the present invention is to provide a plastic orthopedic composition, which includes: a powder composition, which includes calcium sulfate hemihydrate (CaSO 4 ⁇ 0.5H 2 O), tricalcium phosphate ( ⁇ -tricalcium phosphate, ⁇ -TCP) and hydroxypropyl methylcellulose (Hydroxypropyl Methylcellulose, HPMC); and a solvent including glycerol (Glycerol) and water.
  • a powder composition which includes calcium sulfate hemihydrate (CaSO 4 ⁇ 0.5H 2 O), tricalcium phosphate ( ⁇ -tricalcium phosphate, ⁇ -TCP) and hydroxypropyl methylcellulose (Hydroxypropyl Methylcellulose, HPMC); and a solvent including glycerol (Glycerol) and water.
  • the ratio of calcium sulfate hemihydrate to tricalcium phosphate is approximately 1:1 (g/g).
  • the weight percentage of hydroxypropyl methylcellulose in the powder composition is about 1 to 6%, preferably about 1 to 4%, and most preferably about 2 to 4%.
  • the weight percentage of hydroxypropyl methylcellulose exceeds 6%, the orthopedic composition of the present invention will be excessively sticky, resulting in poor operability and failure to become a plastic orthopedic composition.
  • the optimal liquid-to-powder ratio of the powder composition of the present invention and the solvent is about 0.35 ml/g.
  • the weight percentage of calcium sulfate hemihydrate in the powder composition of the present invention is about 47, 47.5, 48, 48.5, 49, 49.5%, preferably about 48, 48.5, 49, 49.5%, most preferably about 48, 48.5, 49%;
  • the weight percentage of tricalcium phosphate is about 47, 47.5, 48, 48.5, 49, 49.5%, preferably about 48, 48.5, 49, 49.5%, most preferably about 48, 48.5, 49%; hydroxyl
  • the weight percentage of propyl methylcellulose is about 1, 2, 3, 4, 5, 6%, preferably about 1, 2, 3, 4%, and most preferably about 2, 3, 4%.
  • the volume percentage of glycerin in the solvent is about 70% to 99%, preferably about 85%.
  • the volume percentage of glycerin is less than 70%, the orthopedic composition of the present invention is prone to disintegration and cannot be effectively formed, and will disintegrate within one day and cannot be formed.
  • the orthopedic composition of the present invention may need to further add a dispersant for uniformly dispersing the powder, a suspension stabilizer for maintaining the suspended state of the powder particles, and pharmaceutical agents (for example, bone cell formation/differentiation accelerator, angiogenesis accelerator, etc.), nutrients, antibacterial agents, antibiotics or additives (such as curing accelerator, curing retardant, etc.).
  • a dispersant for uniformly dispersing the powder for example, bone cell formation/differentiation accelerator, angiogenesis accelerator, etc.
  • pharmaceutical agents for example, bone cell formation/differentiation accelerator, angiogenesis accelerator, etc.
  • nutrients for example, antibacterial agents, antibiotics or additives (such as curing accelerator, curing retardant, etc.).
  • Another object of the present invention is to provide a bone filling kit, which includes the moldable orthopedic composition according to the present invention stored in a separate container.
  • the inner diameter of the injection port of a traditional bone filling syringe that is currently commonly used is about 3mm. Therefore, the particle size of the above-mentioned calcium sulfate hemihydrate, tricalcium phosphate and hydroxypropyl methylcellulose will also affect the injection of the orthopedic composition. of liquidity. In order to make the orthopedic composition of the present invention have better fluidity, it can be easily extruded.
  • the calcium sulfate hemihydrate that can be used in the present invention preferably has an average particle size of 20 to 40 ⁇ m
  • the tricalcium phosphate preferably has an average particle size of 20 to 40 ⁇ m
  • the hydroxypropyl methylcellulose preferably has an average particle size of 100 ⁇ 200 ⁇ m average particle size.
  • Another object of the present invention is to provide a plastic orthopedic composition for medical use in the treatment of bone defects.
  • the preparation method of the orthopedic composition is based on the weight percentage shown in Table 1, adding calcium sulfate hemihydrate (average particle size 20-40 ⁇ m), tricalcium phosphate (average particle size 20-40 ⁇ m) and hydroxypropyl methylcellulose After the powder (average particle size 100-200 ⁇ m) is fully mixed, mix glycerol and water thoroughly according to the volume percentage of the solvent shown in Table 1, and add it to the powder at room temperature, stir evenly with a spoon to form a Shapeable orthopedic composition with erosion resistance.
  • the moldable orthopedic composition was placed in a 304 stainless steel mold (diameter 6 mm, height 3 mm) to form a cylinder and weighed. It is then immersed in the center of the bottom of a cylinder containing simulated body fluids.
  • the cylinder has a diameter of 20 mm and a height of 20 mm, and is placed in an environment of 37 degrees Celsius.
  • the ratio of orthopedic composition and simulated body fluid is 0.2 g of bone filling material/1 ml of simulated body fluid.
  • the reason for using simulated body fluid is that its ion concentration is similar to that of human plasma [12].
  • the simulated body fluid is removed, 1 ml of 99.5% alcohol is added, and left at room temperature for 30 seconds. Then remove the alcohol, place the main body of the undisintegrated bone filling material (a cylinder with a diameter of 6 mm), and the disintegrated debris into an oven at 50 degrees Celsius for 3 days. Weigh the main body of the undisintegrated bone filling material to The weight loss is obtained by subtracting the weight of the main body of the undisintegrated bone filling material from the weight before the experiment, and then divided by the weight before the experiment to obtain the erosion percentage. Therefore, the lower the erosion percentage, the better the erosion resistance of the formula.
  • the orthopedic composition when the proportion of glycerol is less than 70%, that is, when the glycerol is 50% or 30%, the orthopedic composition cannot be stored for more than 1 day, that is, it will disintegrate within 1 day and cannot be formed.
  • the orthopedic composition When the glycerol ratio is higher than 70%, the orthopedic composition has the ability to be molded and can be stored at room temperature for at least 21 days.
  • the orthopedic composition of the present invention As shown in Table 7, compared with commercially available Gurai bone meal ( Compared with Bone Graft Substitute), the orthopedic composition of the present invention has slightly higher erosion resistance than Gurai bone powder. It shows that the orthopedic composition of the present invention has good erosion resistance and plasticity.
  • the present invention has a plastic orthopedic composition with erosion resistance, which is mainly composed of calcium sulfate and calcium phosphate (tetracalcium phosphate and dicalcium phosphate), and is added with citric acid and hydroxypropyl methyl fiber. After conditioning, it can achieve effective anti-erosion effect and have better repair function.

Abstract

The present invention relates to a plastic orthopedic composition having erosion resistance, comprising: a powder composition comprising calcium sulfate hemihydrate, tricalcium phosphate, and hydroxypropyl methylcellulose; and a solvent comprising glycerol and water. The orthopedic composition has good erosion resistance. The present invention also provides a method for preparing the orthopedic composition and a bone filler kit comprising the composition.

Description

抗冲刷能力的可塑型的骨科组合物Plastic orthopedic composition with erosion resistance 技术领域Technical field
本发明是关于一种骨填补材料，特别是关于一种有抗冲刷能力的可塑型的骨科组合物。The present invention relates to a bone filling material, and in particular to a plastic orthopedic composition with erosion resistance.
背景技术Background technique
硫酸钙已长久使用于帮助骨修复，因其具有良好的骨传导性与生物相容性，主要作为空腔的填补物，它能帮助恢复骨的形态轮廓，并阻止软组织的入侵，其降解的速率可以配合新骨生成的速率，并且帮助血管的浸润。当硫酸钙置于缺损处时，表面解离出的钙离子达到特定的浓度梯度会与体内正常存在的磷酸根离子结合，产生磷酸钙的沉淀。在骨骼修复的过程中，磷酸根沉淀产生二次的骨引导性，使成骨细胞可以贴附。硫酸钙开始降解时周围组织的pH值会呈现弱酸性，会造成周围骨骼组织的去矿物化(demineralisation)，而生长因子会伴随着去矿物化的现象而释放，产生骨诱导性，促使附近干细胞分化，细胞开始生长后矿化，产生新骨[1]。Calcium sulfate has been used to help bone repair for a long time. Because of its good osteoconductivity and biocompatibility, it is mainly used as a cavity filler. It can help restore the shape and contour of the bone and prevent the invasion of soft tissue and its degradation. The rate can match the rate of new bone formation and aid vascular infiltration. When calcium sulfate is placed in a defect, the dissociated calcium ions on the surface reach a specific concentration gradient and will combine with the phosphate ions normally present in the body to produce calcium phosphate precipitation. During the bone repair process, phosphate precipitation produces secondary osteoconductivity, allowing osteoblasts to adhere. When calcium sulfate begins to degrade, the pH value of the surrounding tissue will become slightly acidic, which will cause demineralization of the surrounding bone tissue. Growth factors will be released along with the demineralization phenomenon, resulting in osteoinductivity and promoting nearby stem cells. After differentiation, cells begin to grow and then mineralize to produce new bone [1].
硫酸钙依照结晶水多寡又可分为二水硫酸钙(Calcium Sulfate Dihydrate,CaSO 4·2H 2O)、半水硫酸钙(Calcium sulfate hemihydrate,CaSO 4·0.5H 2O)和无水硫酸钙(Calcium sulfate Dehydrate)三种，二水硫酸钙可称为生石膏，半水硫酸钙又可称为熟石膏。其中二水硫酸钙和半水硫酸钙皆可使用在骨填补材料中，但硫酸钙若没经过特殊处理或加入添加物，在体内很快就会被降解，无法提供缺损处初始支撑能力与细胞攀附，因此许多研究着重于开发硫酸钙复合材料，以使硫酸钙成为更良好的骨填补材。(1)硫酸钙添加α-三钙磷酸盐(α-tricalcium phosphate,α-TCP)：硫酸钙和α-TCP混合后，可变成稳定的结构，使得降解时间长达1-2年，而混合物中的硫酸钙降解后可产生孔洞，有助于新生骨长入[2-3]。(2)硫酸钙加入氢氧基磷灰石(hydroxylapatite,HAp):氢氧基磷灰石是人体骨骼中主要的无机成分，具有良好的生物相容性，其钙磷比为1.67与骨骼的矿物组成非常相似，可与骨骼产生键结，成 为骨的一部分，但限制是机械强度过低，故与硫酸钙为复合材料时，硫酸钙的比例提升会使植入物的机械强度增加[4]，而硫酸钙降解时，也会产生孔洞，使新成骨长入。(3)半水硫酸钙加入海藻酸钠、甲壳素、甲基纤维素或透明质酸:加入这些添加物都可使半水硫酸钙的降解时间增加，以及具有良好的操作性质，虽然有时机械强度会降低(例如添加海藻酸钠或甲壳素时)，但若比例调配得当，例如添加比例大于7.5％甲基纤维素或5％透明质酸，则可使抗压强度上升，使材料更加稳定[5-6]。(4)半水硫酸钙添加去细胞骨基质:去细胞骨基质是可以提供生物相容性与骨传导性外，还具有骨诱导性与生长因子[7]，但其主要缺点是机械强度差、传染风险与取得来源等问题，故添加半水硫酸钙的复合骨材可以提供初始的机械强度，具有初期血管浸润的效果[8]。 Calcium sulfate can be divided into calcium sulfate dihydrate (CaSO 4 ·2H 2 O), calcium sulfate hemihydrate (CaSO 4 ·0.5H 2 O) and anhydrous calcium sulfate (Calcium sulfate hemihydrate, CaSO 4 ·0.5H 2 O) according to the amount of crystal water. Calcium sulfate Dehydrate) three kinds, calcium sulfate dihydrate can be called raw gypsum, calcium sulfate hemihydrate can also be called gypsum of paris. Both calcium sulfate dihydrate and calcium sulfate hemihydrate can be used in bone filling materials. However, if calcium sulfate is not specially treated or added with additives, it will be degraded quickly in the body and cannot provide initial support and cells for the defect. Therefore, many studies focus on developing calcium sulfate composite materials to make calcium sulfate a better bone filling material. (1) Add α-tricalcium phosphate (α-TCP) to calcium sulfate: After mixing calcium sulfate and α-TCP, it can become a stable structure, making the degradation time as long as 1-2 years. The calcium sulfate in the mixture can create holes after degradation, which helps new bone grow in [2-3]. (2) Calcium sulfate added to hydroxylapatite (HAp): hydroxylapatite is the main inorganic component of human bones and has good biocompatibility. Its calcium-to-phosphorus ratio is 1.67, which is consistent with that of bones. The mineral composition is very similar and can bond with the bone and become part of the bone. However, the limitation is that the mechanical strength is too low. Therefore, when used as a composite material with calcium sulfate, increasing the proportion of calcium sulfate will increase the mechanical strength of the implant [4 ], and when calcium sulfate degrades, holes will also be created for new bone to grow in. (3) Add sodium alginate, chitin, methylcellulose or hyaluronic acid to calcium sulfate hemihydrate: adding these additives can increase the degradation time of calcium sulfate hemihydrate and have good operating properties, although sometimes mechanical The strength will decrease (for example, when sodium alginate or chitin is added), but if the proportion is properly formulated, for example, the addition proportion is greater than 7.5% methylcellulose or 5% hyaluronic acid, the compressive strength can be increased and the material will be more stable. [5-6]. (4) Calcium sulfate hemihydrate adds acellular bone matrix: In addition to providing biocompatibility and osteoconductivity, acellular bone matrix also has osteoinductivity and growth factors [7], but its main disadvantage is poor mechanical strength. , infection risks and sources of acquisition, etc. Therefore, composite aggregates adding calcium sulfate hemihydrate can provide initial mechanical strength and have the effect of initial vascular infiltration [8].
市售骨填补材料中，硫酸钙产品多以注射型占大多数，磷酸钙以锭状、片状、柱状、注射型等剂型皆有，也有一些生物玻璃(硅酸钙)、高分子材料(聚乳酸、聚羟基乙酸)被添加于骨填补材中。通常注射型或水合式的材料，在使用前需要将粉末与液体混合成糊状后，添加至注射容器或较为稠状像粘土的可以配合患部的形状，塑型成想要的形状后填入。Among commercially available bone filling materials, calcium sulfate products are mostly injection type. Calcium phosphate is available in tablet, sheet, columnar, injection and other dosage forms. There are also some bioglass (calcium silicate), polymer materials ( Polylactic acid, polyglycolic acid) are added to bone filling materials. Usually for injection-type or hydration-type materials, you need to mix powder and liquid into a paste before use, and then add it to the injection container or a thicker clay-like material that can match the shape of the affected area, mold it into the desired shape, and then fill it in. .
在混合的过程中，可能会遇到以下两个问题[9]：During the mixing process, the following two problems may be encountered [9]:
混合过程粉末与水没有混均匀的现象，此时可能会造成材料性质变化，使原定的固化时间、注射性质、机械性质有所改变。其中，目前市售产品的混合方法又有所不同，如：A产品是需要在规定时间一分钟内，将粉末与水混合均匀后，等待三分钟，才能够填充至患处。B产品需要将粉末与水浸泡三分钟后，在进行混合一分钟后，才能够填充至患处。市售产品并没有统一的混合规范，所以会造成容易医生的混淆。During the mixing process, the powder and water are not mixed evenly, which may cause changes in material properties, causing changes in the original curing time, injection properties, and mechanical properties. Among them, the mixing methods of currently commercially available products are different. For example: Product A requires mixing the powder and water evenly within the specified time of one minute, and then waiting for three minutes before it can be filled into the affected area. Product B needs to be soaked in powder and water for three minutes and mixed for one minute before it can be filled into the affected area. There are no uniform mixing specifications for commercially available products, which can lead to confusion among physicians.
医生必须在材料固化前植入病患体内，如果固化时间过快，会丧失注射性质；如果固化时间过慢，则会增加手术时间的进行，使病患添加手术时的风险。Doctors must implant the material into the patient before it solidifies. If the solidification time is too fast, the injectable properties will be lost; if the solidification time is too slow, the surgical time will be increased and the patient will be exposed to increased risks during surgery.
故有预混合的剂型产生，预混合剂型泛指医生在开起包装时，不需进行烦杂的粉末与水混合，便可直接进行填补，可以省略粉末与水的混合时间，不仅可以方便医生的使用，也可以降低病患的风险。Therefore, premixed dosage forms are produced. Premixed dosage forms generally refer to the fact that when doctors open the package, they can directly fill it without the complicated mixing of powder and water. The mixing time of powder and water can be omitted, which not only facilitates the doctor's Use can also reduce the risk of disease.
现今中国台湾市售骨填补材中，仅有吉莱骨粉有提供预混合的可塑型骨填补材，但在临床上发现此产品会引起病患的发炎反应，甚至在植入处会形成发炎囊肿[10-11]。目前推测是当吉莱骨粉中的硫酸钙降解后，会降低植入处的pH值，造成材料液化(liquefaction)后产生碎屑，进而引发发炎反应[11]。Among bone filling materials currently available on the market in Taiwan, China, only Gilai Bone Powder provides pre-mixed plastic bone filling materials. However, it has been clinically found that this product can cause inflammatory reactions in patients and even form inflammatory cysts at the implant site [ 10-11]. It is currently speculated that when the calcium sulfate in Gilai bone meal degrades, it will reduce the pH value of the implant site, causing the material to liquefy (liquefaction) and produce debris, which in turn triggers an inflammatory reaction [11].
因此开发出一种具有较长及较好的抗冲刷能力的可塑型的骨填补材料仍有其需要。Therefore, there is still a need to develop a plastic bone filling material with longer length and better erosion resistance.
发明内容Contents of the invention
有鉴于上述的问题，本发明人依据多年来的研究经验，针对骨科组合物进行相关研究与改进；因此，本发明的主要目的在于提供一种有抗冲刷能力的可塑型的骨科组合物及其制备方法。在本发明的部分实施例中，提供一种具有良好的抗冲刷性的可塑型的骨科组合物。In view of the above problems, the inventor of the present invention has conducted relevant research and improvement on orthopedic compositions based on years of research experience; therefore, the main purpose of the present invention is to provide a plastic orthopedic composition with erosion resistance and its Preparation. In some embodiments of the present invention, a plastic orthopedic composition with good erosion resistance is provided.
根据本发明的目的，本发明是关于提供一种可塑型的骨科组合物，其包括：一粉末组合物，其包括半水硫酸钙(CaSO 4·0.5H 2O)、三钙磷酸盐(β-tricalcium phosphate,β-TCP)和羟丙基甲基纤维素(Hydroxypropyl Methylcellulose,HPMC)；及一溶剂，其包括甘油(Glycerol)和水。 According to the purpose of the present invention, the present invention is about providing a plastic orthopedic composition, which includes: a powder composition, which includes calcium sulfate hemihydrate (CaSO 4 ·0.5H 2 O), tricalcium phosphate (β -tricalcium phosphate (β-TCP) and hydroxypropyl methylcellulose (HPMC); and a solvent including glycerol (Glycerol) and water.
较佳地，其中该半水硫酸钙与该三钙磷酸盐的比例约为1：1(克/克)。Preferably, the ratio of the calcium sulfate hemihydrate to the tricalcium phosphate is about 1:1 (g/g).
较佳地，其中该羟丙基甲基纤维素的重量百分比为1～6％。Preferably, the weight percentage of hydroxypropyl methylcellulose is 1 to 6%.
较佳地，其中该羟丙基甲基纤维素的重量百分比为1～4％。Preferably, the weight percentage of hydroxypropyl methylcellulose is 1 to 4%.
较佳地，其中该甘油的体积百分比约为70～99％。Preferably, the volume percentage of glycerin is about 70-99%.
较佳地，其中该甘油的体积百分比约为85％。Preferably, the volume percentage of glycerol is about 85%.
根据本发明的另一目的，进一步提供一种骨填补物套组，其包含储存于单独容器中如本发明所述的可塑型的骨科组合物。According to another object of the present invention, a bone filling kit is further provided, which includes the moldable orthopedic composition according to the present invention stored in a separate container.
根据本发明的另一目的，进一步提供一种可塑型的骨科组合物用于制备治疗骨缺损的医疗用途。According to another object of the present invention, a plastic orthopedic composition is further provided for medical use in treating bone defects.
附图说明Description of the drawings
为了更完整了解实施例及其优点，现参照结合所附附图所作的下 列描述，其中：For a more complete understanding of the embodiments and their advantages, reference is now made to the following description taken in conjunction with the accompanying drawings, in which:
图1所示为皆含70％甘油(Glycerol)的骨科组合物，但含不同比例的羟丙基甲基纤维素(HPMC)，浸泡在模拟体液中15分钟或1小时的冲刷百分比。使用t检定统计，**P<0.01为同样配方，浸泡15分钟和1小时相比的差异。Figure 1 shows the washout percentage of orthopedic compositions that both contain 70% glycerol (Glycerol), but contain different proportions of hydroxypropyl methylcellulose (HPMC), immersed in simulated body fluids for 15 minutes or 1 hour. Using t test statistics, **P<0.01 is the difference between soaking for 15 minutes and 1 hour for the same formula.
图2所示为皆含85％甘油(Glycerol)的骨科组合物，但含不同比例的羟丙基甲基纤维素(HPMC)，浸泡在模拟体液中15分钟或1小时的冲刷百分比。使用t检定统计，*P<0.05或**P<0.01为同样配方，浸泡15分钟和1小时相比的差异。Figure 2 shows the washout percentage of orthopedic compositions that both contain 85% glycerol (Glycerol), but contain different proportions of hydroxypropyl methylcellulose (HPMC), immersed in simulated body fluids for 15 minutes or 1 hour. Using t test statistics, *P<0.05 or **P<0.01 is the difference between soaking for 15 minutes and 1 hour for the same formula.
图3所示为骨填补材皆含99％甘油(Glycerol)，但含不同比例的羟丙基甲基纤维素(HPMC)，浸泡在模拟体液中15分钟或1小时的冲刷百分比。使用t检定统计，浸泡15分钟和1小时相比皆无统计上的差异。Figure 3 shows the erosion percentage of bone filling materials, which all contain 99% glycerol (Glycerol) but contain different proportions of hydroxypropyl methylcellulose (HPMC), soaked in simulated body fluids for 15 minutes or 1 hour. Using t test statistics, there is no statistical difference between soaking for 15 minutes and 1 hour.
具体实施方式Detailed ways
本发明将通过下列较佳实施例及配合的附图，作进一步的详细说明。需注意的是，以下各实施例所揭示的实验数据，是为便于解释本申请技术特征，并非用以限制其可实施的形式。The present invention will be further described in detail through the following preferred embodiments and accompanying drawings. It should be noted that the experimental data disclosed in the following examples are for the convenience of explaining the technical features of the present application and are not used to limit its implementable forms.
本说明书全文中，术语“约”用于指明一数值包括材料比例的误差、药物浓度值的误差、或者存在于实验对象之间的变异。典型地该用语是指涵盖大于或小于1％、2％、3％、4％、5％、6％、7％、8％、9％、10％、11％、12％、13％、14％、15％、16％、17％、18％、19％或20％的变异性，视情况而定。Throughout this specification, the term "about" is used to indicate that a numerical value includes errors in material proportions, drug concentration values, or variations that exist between experimental subjects. Typically the term is intended to cover greater or less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14 %, 15%, 16%, 17%, 18%, 19% or 20% variability, as appropriate.
本说明书全文中，所述“骨科组合物”的具体实施例如但不限于关节植入物、脊柱植入物、颅颌面植入物、牙齿植入物、足踝植入物或创伤植入物(骨板、骨钉)等。Throughout this specification, specific embodiments of the "orthopedic composition" include, but are not limited to, joint implants, spinal implants, craniofacial implants, dental implants, foot and ankle implants, or trauma implants. Objects (bone plates, bone nails), etc.
本说明书全文中，所述的“经注入(注射)”、“注入(注射)”或“可注射性”等用语包括任何组合物的投予，如注射、浸入或通过任何输送装置传送至个体。Throughout this specification, the terms "injected", "injected" or "injectable" include the administration of any composition, such as injection, immersion or delivery to an individual via any delivery device .
本发明的目的是提供一种可塑型的骨科组合物，其包括：一粉末组合物，其包括半水硫酸钙(CaSO 4·0.5H 2O)、三钙磷酸盐(β-tricalcium  phosphate,β-TCP)和羟丙基甲基纤维素(Hydroxypropyl Methylcellulose,HPMC)；及一溶剂，其包括甘油(Glycerol)和水。 The object of the present invention is to provide a plastic orthopedic composition, which includes: a powder composition, which includes calcium sulfate hemihydrate (CaSO 4 ·0.5H 2 O), tricalcium phosphate (β-tricalcium phosphate, β -TCP) and hydroxypropyl methylcellulose (Hydroxypropyl Methylcellulose, HPMC); and a solvent including glycerol (Glycerol) and water.
根据本发明的一具体实施例，其中半水硫酸钙与三钙磷酸盐的比例约为1：1(克/克)。According to a specific embodiment of the present invention, the ratio of calcium sulfate hemihydrate to tricalcium phosphate is approximately 1:1 (g/g).
根据本发明的一具体实施例，其中羟丙基甲基纤维素的重量百分比在粉末组合物中约为1～6％，较佳约为1～4％，最佳约为2～4％。当羟丙基甲基纤维素的重量百分比超过6％时，本发明的骨科组合物会过度黏腻，造成操作性差，无法成为可塑型的骨科组合物。According to a specific embodiment of the present invention, the weight percentage of hydroxypropyl methylcellulose in the powder composition is about 1 to 6%, preferably about 1 to 4%, and most preferably about 2 to 4%. When the weight percentage of hydroxypropyl methylcellulose exceeds 6%, the orthopedic composition of the present invention will be excessively sticky, resulting in poor operability and failure to become a plastic orthopedic composition.
根据本发明的一具体实施例，本发明的粉末组合物与溶剂的液粉比最佳约为0.35毫升/克。本发明的粉末组合物的半水硫酸钙的重量百分比约为47、47.5、48、48.5、49、49.5％，较佳约为48、48.5、49、49.5％、最佳约为48、48.5、49％；三钙磷酸盐的重量百分比约为47、47.5、48、48.5、49、49.5％，较佳约为48、48.5、49、49.5％、最佳约为48、48.5、49％；羟丙基甲基纤维素的重量百分比约为1、2、3、4、5、6％、较佳约为1、2、3、4％、最佳约为2、3、4％。According to a specific embodiment of the present invention, the optimal liquid-to-powder ratio of the powder composition of the present invention and the solvent is about 0.35 ml/g. The weight percentage of calcium sulfate hemihydrate in the powder composition of the present invention is about 47, 47.5, 48, 48.5, 49, 49.5%, preferably about 48, 48.5, 49, 49.5%, most preferably about 48, 48.5, 49%; the weight percentage of tricalcium phosphate is about 47, 47.5, 48, 48.5, 49, 49.5%, preferably about 48, 48.5, 49, 49.5%, most preferably about 48, 48.5, 49%; hydroxyl The weight percentage of propyl methylcellulose is about 1, 2, 3, 4, 5, 6%, preferably about 1, 2, 3, 4%, and most preferably about 2, 3, 4%.
根据本发明的一具体实施例，其中甘油的体积百分比在溶剂中约为70～99％，较佳约为85％。当甘油的体积百分比低于70％时，本发明的骨科组合物易于崩解无法有效成型，一天内会崩解无法成型。According to a specific embodiment of the present invention, the volume percentage of glycerin in the solvent is about 70% to 99%, preferably about 85%. When the volume percentage of glycerin is less than 70%, the orthopedic composition of the present invention is prone to disintegration and cannot be effectively formed, and will disintegrate within one day and cannot be formed.
本发明所述的骨科组合物，可是需要进一步加入用以使粉剂以均匀分散的分散剂、用以维持粉剂粒子悬浮状态的悬浮安定剂、药剂(例如，骨细胞成/分化促进剂、血管新生促进剂等)、营养剂、抗菌剂、抗生素或添加剂(例如固化促进剂、固化迟滞剂等)。The orthopedic composition of the present invention may need to further add a dispersant for uniformly dispersing the powder, a suspension stabilizer for maintaining the suspended state of the powder particles, and pharmaceutical agents (for example, bone cell formation/differentiation accelerator, angiogenesis accelerator, etc.), nutrients, antibacterial agents, antibiotics or additives (such as curing accelerator, curing retardant, etc.).
本发明的另一目的是提供一种骨填补物套组，其包含储存于单独容器中如本发明所述的可塑型的骨科组合物。传统的目前常用的骨填补注射器，其注射口的内径约3mm，故而上述半水硫酸钙、三钙磷酸盐和羟丙基甲基纤维素的粒径大小，亦会影响骨科组合物于注射时的流动性。为使本发明的骨科组合物具有较佳的流动性，使其易于被挤出。可应用于本发明的半水硫酸钙较佳为具有20～40μm的平均粒径、三钙磷酸盐较佳为具有20～40μm的平均粒径和羟丙基甲基纤维素较佳为具有100～200μm的平均粒径。Another object of the present invention is to provide a bone filling kit, which includes the moldable orthopedic composition according to the present invention stored in a separate container. The inner diameter of the injection port of a traditional bone filling syringe that is currently commonly used is about 3mm. Therefore, the particle size of the above-mentioned calcium sulfate hemihydrate, tricalcium phosphate and hydroxypropyl methylcellulose will also affect the injection of the orthopedic composition. of liquidity. In order to make the orthopedic composition of the present invention have better fluidity, it can be easily extruded. The calcium sulfate hemihydrate that can be used in the present invention preferably has an average particle size of 20 to 40 μm, the tricalcium phosphate preferably has an average particle size of 20 to 40 μm, and the hydroxypropyl methylcellulose preferably has an average particle size of 100 ~200μm average particle size.
本发明的另一目的是提供一种可塑型的骨科组合物用于制备治疗 骨缺损的医疗用途。Another object of the present invention is to provide a plastic orthopedic composition for medical use in the treatment of bone defects.
本发明将通过参考下列的实施例做进一步的说明，这些实施例并不限制本发明前面所揭示的内容。本领域的技术人员，可作些许的改良与修饰，但仍不脱离本发明的范畴。The invention will be further illustrated with reference to the following examples, which do not limit the foregoing disclosure of the invention. Those skilled in the art can make some improvements and modifications without departing from the scope of the present invention.
实施例Example
骨科组合物制备方法：Orthopedic composition preparation method:
依照表1所示的比例配制骨科组合物Prepare orthopedic composition according to the proportion shown in Table 1
表1Table 1
Figure PCTCN2022091740-appb-000001
Figure PCTCN2022091740-appb-000001
骨科组合物的配制方法为依据表1所示的重量百分比，将半水硫酸钙(平均粒径20～40μm)、三钙磷酸盐(平均粒径20～40μm)和羟丙基甲基纤维素(平均粒径100～200μm)的粉末充分混和后，依表1所示的溶剂的体积百分比，将甘油与水充分混和，并于室温下加入于粉末中，用药匙充分搅拌均匀，以形成一具有抗冲刷能力的可塑形的骨科组合物。The preparation method of the orthopedic composition is based on the weight percentage shown in Table 1, adding calcium sulfate hemihydrate (average particle size 20-40 μm), tricalcium phosphate (average particle size 20-40 μm) and hydroxypropyl methylcellulose After the powder (average particle size 100-200 μm) is fully mixed, mix glycerol and water thoroughly according to the volume percentage of the solvent shown in Table 1, and add it to the powder at room temperature, stir evenly with a spoon to form a Shapeable orthopedic composition with erosion resistance.
冲刷实验方法：Erosion test method:
可塑型骨科组合物放置在304不锈钢模具(直径6毫米，高度3毫米)中，以制成圆柱体状并秤重。之后浸泡在含模拟体液的圆筒底部中心，圆筒直径为20毫米，高度为20毫米，并放置在摄氏37度的环境。骨科组合物和模拟体液的比例为0.2克骨填补材/1毫升模拟体液，使用 模拟体液的原因是因其离子浓度和人类血浆相似[12]。骨科组合物浸泡了15分钟，1小时或4小时之后，移除模拟体液，加入1毫升的99.5％酒精，并放置在室温30秒。接着移除酒精，将未崩解的骨填补材主体(直径6毫米的圆柱体)，以及崩解的碎屑放入摄氏50度的烘箱3天，秤量未崩解的骨填补材主体，以实验前的重量扣除未崩解骨填补材主体的重量取得重量流失，再除以实验前的重量得到冲刷百分比，因此冲刷百分比越低，代表该配方的抗冲刷能力越好。The moldable orthopedic composition was placed in a 304 stainless steel mold (diameter 6 mm, height 3 mm) to form a cylinder and weighed. It is then immersed in the center of the bottom of a cylinder containing simulated body fluids. The cylinder has a diameter of 20 mm and a height of 20 mm, and is placed in an environment of 37 degrees Celsius. The ratio of orthopedic composition and simulated body fluid is 0.2 g of bone filling material/1 ml of simulated body fluid. The reason for using simulated body fluid is that its ion concentration is similar to that of human plasma [12]. After the orthopedic composition has been soaked for 15 minutes, 1 hour, or 4 hours, the simulated body fluid is removed, 1 ml of 99.5% alcohol is added, and left at room temperature for 30 seconds. Then remove the alcohol, place the main body of the undisintegrated bone filling material (a cylinder with a diameter of 6 mm), and the disintegrated debris into an oven at 50 degrees Celsius for 3 days. Weigh the main body of the undisintegrated bone filling material to The weight loss is obtained by subtracting the weight of the main body of the undisintegrated bone filling material from the weight before the experiment, and then divided by the weight before the experiment to obtain the erosion percentage. Therefore, the lower the erosion percentage, the better the erosion resistance of the formula.
实施例1Example 1
骨科组合物浸泡15分钟的结果如表2所示The results of soaking the orthopedic composition for 15 minutes are shown in Table 2
表2Table 2
Figure PCTCN2022091740-appb-000002
Figure PCTCN2022091740-appb-000002
骨科组合物浸泡1小时的结果如表3所示The results of soaking the orthopedic composition for 1 hour are shown in Table 3
表3table 3
Figure PCTCN2022091740-appb-000003
Figure PCTCN2022091740-appb-000003
由表1及表2的数据中可以看出，当加入羟丙基甲基纤维素(HPMC)后，在每个骨科组合物中皆能够有效降低骨科组合物的百分比，且随着羟丙基甲基纤维素的百分比增加，骨科组合物的抗冲刷能力越好。如图1、2、3所示，羟丙基甲基纤维素能够显著的提升骨科组合物长时间的抗冲刷能力，又以85％的甘油的组别中最具有显著的提升效果。It can be seen from the data in Table 1 and Table 2 that when hydroxypropyl methylcellulose (HPMC) is added, the percentage of orthopedic composition can be effectively reduced in each orthopedic composition, and as hydroxypropyl methylcellulose (HPMC) is added The greater the percentage of methylcellulose, the better the erosion resistance of the orthopedic composition. As shown in Figures 1, 2, and 3, hydroxypropyl methylcellulose can significantly improve the long-term erosion resistance of orthopedic compositions, and the 85% glycerol group has the most significant improvement effect.
实施例2Example 2
可塑型骨科组合物浸泡4小时的结果如表4所示。The results of soaking the plastic orthopedic composition for 4 hours are shown in Table 4.
表4Table 4
Figure PCTCN2022091740-appb-000004
Figure PCTCN2022091740-appb-000004
Figure PCTCN2022091740-appb-000005
Figure PCTCN2022091740-appb-000005
由表4中可以看出即使冲刷时间长达4小时，羟丙基甲基纤维素都能够有效的提升每个骨科组合物的抗冲刷能力，且随着甘油的比例的降低，更能有效的提升骨科组合物的抗冲刷能力。It can be seen from Table 4 that even if the erosion time is as long as 4 hours, hydroxypropyl methylcellulose can effectively improve the anti-erosion ability of each orthopedic composition, and as the proportion of glycerol decreases, it is more effective Improve the erosion resistance of orthopedic compositions.
实施例3Example 3
不同成分的骨科组合物的保存天数如表5所示。The storage days of orthopedic compositions with different components are shown in Table 5.
表5table 5
Figure PCTCN2022091740-appb-000006
Figure PCTCN2022091740-appb-000006
如表5所示，当甘油的比例低于70％时，即甘油为50％或30％时，骨科组合物没办法保存超过1天，即1天内会崩解而无法成型。而当甘油比例高于70％时，骨科组合物具有可塑型的能力，且能够保存于 常温中至少21天以上。As shown in Table 5, when the proportion of glycerol is less than 70%, that is, when the glycerol is 50% or 30%, the orthopedic composition cannot be stored for more than 1 day, that is, it will disintegrate within 1 day and cannot be formed. When the glycerol ratio is higher than 70%, the orthopedic composition has the ability to be molded and can be stored at room temperature for at least 21 days.
不同浓度的羟丙基甲基纤维素对骨科组合物的塑型能力的影响如表6所示。The effects of different concentrations of hydroxypropyl methylcellulose on the shaping ability of the orthopedic composition are shown in Table 6.
表6Table 6
Figure PCTCN2022091740-appb-000007
Figure PCTCN2022091740-appb-000007
如表6所示，随着羟丙基甲基纤维素的重量百分比的提升，骨科组合物的黏度也逐渐上升，造成可操作性下降。当羟丙基甲基纤维素的浓度达到6％时，骨科组合物会像口香糖一样粘着，造成骨科组合物不易塑型。As shown in Table 6, as the weight percentage of hydroxypropyl methylcellulose increases, the viscosity of the orthopedic composition gradually increases, resulting in a decrease in operability. When the concentration of hydroxypropyl methylcellulose reaches 6%, the orthopedic composition will stick like chewing gum, causing the orthopedic composition to be difficult to shape.
实施例4Example 4
本发明的骨科组合物与市售的骨科组合物的比较如表7所示。A comparison between the orthopedic composition of the present invention and commercially available orthopedic compositions is shown in Table 7.
表7Table 7
Figure PCTCN2022091740-appb-000008
Figure PCTCN2022091740-appb-000008
如表7所示，与市售的古莱骨粉(
Figure PCTCN2022091740-appb-000009
Bone Graft Substitute)相比，本发明的骨科组合物在抗冲刷能力上略高于古莱骨粉。显示本发明的骨科组合物具有良好的抗冲刷能力及可塑性。 As shown in Table 7, compared with commercially available Gurai bone meal (
Figure PCTCN2022091740-appb-000009
Compared with Bone Graft Substitute), the orthopedic composition of the present invention has slightly higher erosion resistance than Gurai bone powder. It shows that the orthopedic composition of the present invention has good erosion resistance and plasticity.
综上可知，硫酸钙已广泛使用于骨填补材料，其优点是有良好的生物相容性、无毒性、可被生物吸收与优良的骨传导特性。但硫酸钙在植入体内后，容易因血水冲刷而无法停留在需填补之处，则无法达到修复功能。因此本发明的一有抗冲刷能力的可塑型的骨科组合物，以硫酸钙与磷酸钙组合物(四钙磷酸盐与二钙磷酸盐)为主体，其添加柠檬酸与羟丙基甲基纤维素后，可达到有效的抗冲刷效果，具备更良好的修复功能。In summary, it can be seen that calcium sulfate has been widely used as bone filling materials. Its advantages are good biocompatibility, non-toxicity, bioabsorbability and excellent bone conduction properties. However, after calcium sulfate is implanted in the body, it is easily washed away by blood and cannot stay in the place where it needs to be filled, so it cannot achieve its repair function. Therefore, the present invention has a plastic orthopedic composition with erosion resistance, which is mainly composed of calcium sulfate and calcium phosphate (tetracalcium phosphate and dicalcium phosphate), and is added with citric acid and hydroxypropyl methyl fiber. After conditioning, it can achieve effective anti-erosion effect and have better repair function.
参考文献references
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[3]Bohner,M.New hydraulic cements based on-tricalcium phosphate-calcium sulfate dehydrate mixtures.Biomaterials.2004；25:741-749.[3]Bohner, M. New hydraulic cements based on-tricalcium phosphate-calcium sulfate dehydrate mixtures. Biomaterials. 2004; 25:741-749.
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[5]Ikenaga,M.,Hardouin,P.,Lemaitre,J.,Andrianjatovo,H.,Flautre,B.Biomechanical characterization of a biodegradable calcium phosphate hydraulic cement:A comparison with porous biphasic calcium phosphate ceramics.Journal of Biomedical Materials Research.1998；40:139-144.[5]Ikenaga,M.,Hardouin,P.,Lemaitre,J.,Andrianjatovo,H.,Flautre,B.Biomechanical characterization of a biodegradable calcium phosphate hydraulic cement:A comparison with porous biphasic calcium phosphate ceramics.Journal of Biomedical Materials Research.1998;40:139-144.
[6]d’Ayala,G.G.,Rosa,A.,Laurienzo,P.,Malinconico,M.Development of a new calcium sulphate-based composie using aliginate and chemically modified chitosan for bone regeneration.Journal of Biomedical Materials Research Part A.2007；81:811-820.[6]d'Ayala,G.G.,Rosa,A.,Laurienzo,P.,Malinconico,M.Development of a new calcium sulphate-based composie using aliginate and chemically modified chitosan for bone regeneration.Journal of Biomedical Materials Research Part A. 2007;81:811-820.
[7]Rougraff B.T.,Kling,T.J.Treatment of activie unicameral bone  cysts with percutaneous injection of demineralized bone matrix and autogenous bone marrow.The Journal of Bone Joint Surgery.2002；84:921-929.[7] Rougraff B.T.,Kling,T.J.Treatment of activie unicameral bone cysts with percutaneous injection of demineralized bone matrix and autogenous bone marrow.The Journal of Bone Joint Surgery.2002;84:921-929.
[8]Erdemli,O.,Captug,O.,Bilgili,H.,Orhan,D.,Tezcaner,A.,Keskin,D.In vitro and in vivo evaluation of the effects of demineralized bone matrix or calcium sulfate addition to polycaprolactone-bioglass composites.Journal of Materials Science:Materials in Medicine.2010；21:295-308.[8]Erdemli,O.,Captug,O.,Bilgili,H.,Orhan,D.,Tezcaner,A.,Keskin,D.In vitro and in vivo evaluation of the effects of demineralized bone matrix or calcium sulfate addition to polycaprolactone-bioglass composites.Journal of Materials Science:Materials in Medicine.2010;21:295-308.
[9]Carey,L.E.,Xu,H.H.,Simon,C.G.,Takagi,S.,Chow,L.C.Premixed rapid-setting calcium phosphate composites for bone repair.Biomaterials.2005；26(24):5002-5014.[9]Carey,L.E.,Xu,H.H.,Simon,C.G.,Takagi,S.,Chow,L.C.Premixed rapid-setting calcium phosphate compositions for bone repair.Biomaterials.2005;26(24):5002-5014.
[10]Friesenbichler,J.,Maurer-Ertl,W.,Sadoghi,P.,Pirker-Fruehauf,U.,Bodo,K.,Leithner,A.Adverse reactions of artificial bone graft substitutes:lessons learned from using tricalcium phosphate
Figure PCTCN2022091740-appb-000010
Clinical Orthopaedics and Related Research.2014；472:976-982. [10] Friesenbichler, J., Maurer-Ertl, W., Sadoghi, P., Pirker-Fruehauf, U., Bodo, K., Leithner, A. Adverse reactions of artificial bone graft substitutes: lessons learned from using tricalcium phosphate
Figure PCTCN2022091740-appb-000010
Clinical Orthopedics and Related Research. 2014;472:976-982.
[11]Friesenbichler,J.,Maurer-Ertl,W.,Sadoghi,P.,Pirker-Fruehauf,U.,Bodo,K.；Leithner,A.Adverse reactions of artificial bone graft substitutes:lessons learned from using tricalcium phosphate
Figure PCTCN2022091740-appb-000011
Clinical Orthopaedics and Related Research.2014；472:976-982. [11] Friesenbichler, J., Maurer-Ertl, W., Sadoghi, P., Pirker-Fruehauf, U., Bodo, K.; Leithner, A. Adverse reactions of artificial bone graft substitutes: lessons learned from using tricalcium phosphate
Figure PCTCN2022091740-appb-000011
Clinical Orthopedics and Related Research. 2014;472:976-982.
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Claims (9)

  1. 一种有抗冲刷能力的可塑型的骨科组合物，其包括：A plastic orthopedic composition with erosion resistance, which includes:
    一粉末组合物，其包括半水硫酸钙、三钙磷酸盐和羟丙基甲基纤维素；及a powder composition comprising calcium sulfate hemihydrate, tricalcium phosphate and hydroxypropyl methylcellulose; and
    一溶剂，其包括甘油和水。A solvent including glycerol and water.
  2. 如权利要求1所述的可塑型的骨科组合物，其中该半水硫酸钙与该三钙磷酸盐的比例约为1：1(克/克)。The plastic orthopedic composition of claim 1, wherein the ratio of the calcium sulfate hemihydrate to the tricalcium phosphate is approximately 1:1 (g/g).
  3. 如权利要求1所述的可塑型的骨科组合物，其中该羟丙基甲基纤维素的重量百分比为1～6％。The plastic orthopedic composition of claim 1, wherein the weight percentage of the hydroxypropyl methylcellulose is 1 to 6%.
  4. 如权利要求1所述的可塑型的骨科组合物，其中该羟丙基甲基纤维素的重量百分比约为1～4％。The plastic orthopedic composition of claim 1, wherein the weight percentage of the hydroxypropyl methylcellulose is about 1 to 4%.
  5. 如权利要求1所述的可塑型的骨科组合物，其中该甘油的体积百分比约为70～99％。The plastic orthopedic composition of claim 1, wherein the volume percentage of the glycerol is about 70 to 99%.
  6. 如权利要求1所述的可塑型的骨科组合物，其中该甘油的体积百分比约为85％。The plastic orthopedic composition of claim 1, wherein the volume percentage of glycerol is about 85%.
  7. 如权利要求1所述的可塑型的骨科组合物，其中该粉末组合物及溶剂的液粉比约为0.35毫升/克。The plastic orthopedic composition of claim 1, wherein the liquid-to-powder ratio of the powder composition and solvent is about 0.35 ml/g.
  8. 一种骨填补物套组，其包含储存于单独容器中如权利要求1～7所述的可塑型的骨科组合物。A bone filling kit, which includes the plastic orthopedic composition according to claims 1 to 7 stored in a separate container.
  9. 一种如权利要求1～6所述的可塑型的骨科组合物用于制备治疗骨缺损的医疗用途。A plastic orthopedic composition as claimed in claims 1 to 6 is used for medical purposes in treating bone defects.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6793725B2 (en) * 2001-01-24 2004-09-21 Ada Foundation Premixed calcium phosphate cement pastes
CN101366971A (en) * 2008-10-15 2009-02-18 苗军 Injectable water-proof calcium phosphate bone cement
CN101668550A (en) * 2007-04-20 2010-03-10 创新生物陶瓷公司 Premixed biological hydraulic cement paste composition and using the same
CN103349793A (en) * 2005-09-09 2013-10-16 阿格诺沃斯健康关爱公司 Composite bone graft substitute cement and articles produced therefrom
EP1622843B1 (en) * 2003-04-08 2015-06-03 Ada Foundation Premixed self-hardening bone graft pastes

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6793725B2 (en) * 2001-01-24 2004-09-21 Ada Foundation Premixed calcium phosphate cement pastes
EP1622843B1 (en) * 2003-04-08 2015-06-03 Ada Foundation Premixed self-hardening bone graft pastes
CN103349793A (en) * 2005-09-09 2013-10-16 阿格诺沃斯健康关爱公司 Composite bone graft substitute cement and articles produced therefrom
CN101668550A (en) * 2007-04-20 2010-03-10 创新生物陶瓷公司 Premixed biological hydraulic cement paste composition and using the same
CN101366971A (en) * 2008-10-15 2009-02-18 苗军 Injectable water-proof calcium phosphate bone cement

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