KR20240006013A - Composition for bone defect and preparation method of the same and kit for the same - Google Patents

Abstract

The present invention relates to a bone graft material composition, and more specifically, includes a porous bone graft material and hydroxypropyl methylcellulose.

Description

Bone graft material composition, manufacturing method thereof, and bone graft material composition kit {COMPOSITION FOR BONE DEFECT AND PREPARATION METHOD OF THE SAME AND KIT FOR THE SAME}

The present invention relates to a bone graft material composition, a method for producing the same, and a bone graft material composition kit.

For the reconstruction of missing bone, various materials and various methods can be used. For example, bone graft materials such as bone powder, bone chips, and bone blocks can be used, or autograft, allograft, and allograft can be used to reconstruct missing bone. Methods such as transplantation may be used.

Bone graft materials used to reconstruct missing bones can be used in orthopedics, neurosurgery, and dentistry. For example, they can be used in bone defects during disc surgery to induce bone regeneration, and can be used in implant procedures and oral jaw surgery. It can also be used to repair bone defects.

Meanwhile, Korean Patent No. 10-0401941 discloses a technology related to bone graft material and its manufacturing method. When using mesh bone composed of bioceramic powder and having a three-dimensionally connected pore structure, There may be limitations to the effectiveness of bone grafting in terms of biocompatibility, mechanical properties, toxicity, etc.

No. 10-0401941

One object of the present invention is to provide a bone graft material composition, a method for producing the same, or a bone graft material composition kit that has excellent bone formation activation, biocompatibility, and ease of use effects.

1. A bone graft material composition containing a porous bone graft material and hydroxypropyl methylcellulose.

2. In 1 above,

The porous bone graft material is a bone graft material of natural origin.

3. In 1 above,

A bone graft material composition in which the content of the hydroxypropyl methylcellulose is 0.15 to 6 parts by weight relative to 1 part by weight of the porous bone graft material.

4. In 1 above,

A bone graft material composition comprising a sponge form containing a porous structure.

5. A bone graft material composition kit, comprising the bone graft material composition of any one of items 1 to 4 above and a syringe for mounting the bone graft material composition.

6. Preparing a bone morphogenetic protein solution by adding bone morphogenetic protein to a solvent or dissolving the bone morphogenetic protein in the solvent;

Adsorbing the bone morphogenetic protein to the graft powder by immersing the graft powder in the bone morphogenetic protein solution by flowing the bone morphogenetic protein solution into a previously prepared graft powder or dropping the graft powder into the bone morphogenetic protein solution;

Forming a viscous gel by mixing and stirring the graft material powder to which the bone morphogenetic protein is adsorbed and the hydroxypropyl methylcellulose powder; and

Preparation of a bone graft material composition comprising the step of drying the mixed and stirred mixture of the graft material powder and the hydroxypropyl methylcellulose powder while freezing at a low temperature in a vacuum to form a sponge shape including a structure including a plurality of pores. method.

7. In 6 above,

The bone morphogenetic proteins include BMP-2, BMP-3, BMP-3b, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, BMP-10, BMP-11, and BMP. -12, BMP-13, BMP-14, BMP-15, BMP-16, BMP-17, BMP-18, at least one bone morphogenetic protein selected from the group consisting of their recombinant bone morphogenetic proteins and bone morphogenetic proteins equivalent thereto, Method for producing a transplant material composition.

8. In 6 above,

A method for producing a bone graft material composition, wherein the bone morphogenetic protein solution has a concentration of 0.05 to 0.15 mg/ml.

9. In 8 above,

A method for producing a bone graft material composition, wherein the acidity is adjusted using phosphate buffer saline.

10. In 6 above,

A method of producing a bone graft material composition, wherein the step of adsorbing the bone morphogenetic protein to the graft material powder includes adsorbing the bone morphogenetic protein using a refrigerated centrifuge.

11. In 10 above,

A method for producing a bone graft material composition, wherein the rotation speed of the refrigerated centrifuge is 4000 rpm or more.

12. In 6 above,

A method for producing a bone graft material composition, wherein the adsorption step using a refrigerated centrifuge is performed at a refrigerated temperature of 5°C or lower.

13. In 6 above,

A method for producing a bone graft material composition, wherein the volume ratio of the bone morphogenetic protein-adsorbed graft powder and hydroxypropyl methylcellulose powder is 1:0.2 to 1:0.6.

14. In 6 above,

A method for producing a bone graft material composition, further comprising mounting the prepared bone graft material composition including a sponge form including a structure including a plurality of pores on a snap tube of a size that can be inserted into a syringe.

15. In 14 above,

A method for producing a bone graft material composition, further comprising placing the bone graft material composition including a sponge form including a structure including the plurality of pores mounted on the snap tube into a syringe and sealing it.

16. In 6 above,

A method for producing a bone graft material composition, further comprising the step of sterilizing the bone graft material composition including the sponge form including the structure including the plurality of pores through ethylene oxide gas or gamma ray irradiation.

17. In 16 above,

A method for producing a bone graft material composition, wherein the Ethylene Oxide Gas concentration is 450 to 1200 mg/l, or the gamma ray irradiation amount is 10 to 25 kGy.

The bone graft material composition, its manufacturing method, or bone graft material composition kit according to the present invention may have excellent bone formation activation, biocompatibility, and ease of use effects.

Figure 1 is a diagram schematically showing the procedure for manufacturing a bone graft material composition according to an embodiment of the present invention.

Examples of one embodiment of the present invention relate to a bone graft material composition that includes a porous bone graft material and hydroxypropyl methylcellulose, and thus has excellent bone formation activation, biocompatibility, and ease of use effects.

However, in the description of this embodiment, parts that overlap with other embodiments are omitted for clearer and concise description, and the omission of the description does not mean that the part is excluded from the present invention, and the scope of rights is limited to other embodiments. It must be recognized as the same as the form.

In describing the present invention, if it is determined that a detailed description of the known technology related to the present invention may unnecessarily obscure the gist of the present invention, the detailed description will be omitted. In addition, the terms described below are terms defined in consideration of functions in the present invention, and may vary depending on the intention or custom of the user or operator. Therefore, the definition should be made based on the contents throughout this specification.

The technical idea of the present invention is determined by the claims, and the following examples are only a means to efficiently explain the technical idea of the present invention to those skilled in the art in the technical field to which the present invention pertains.

In the present invention, when a repeating unit, compound or resin represented by a chemical formula has isomers thereof, the chemical formula representing the repeating unit, compound or resin means a representative chemical formula including the isomers.

Hereinafter, specific embodiments of the present invention will be described. However, this is only an example and the present invention is not limited thereto.

The bone graft material composition of the present invention includes a porous bone graft material and hydroxypropyl methylcellulose. The bone graft material composition can be used to repair the bone defect by implanting it into the bone defect and filling it.

The bone graft material may be naturally derived bone, for example, autogenous bone, allogeneic bone, or xenograft bone. By using bone of natural origin, it has excellent biocompatibility, and in addition, by containing a large number of pores, it has good wettability and hygroscopicity, so the bone formation effect can be excellent. Additionally, it can be used to reconstruct missing bones and can also be used in orthopedics, neurosurgery, and dentistry.

The bone graft material composition may have adhesion to the bone defect by containing hydroxypropyl methylcellulose. If the adhesion is excellent, the bone graft material composition may not fall off even if applied to the maxilla, and it can help prevent the bone graft material composition from being separated from the bone defect even if there is impact due to masticatory movements, etc.

The content of hydroxypropyl methylcellulose in the bone graft material composition according to an embodiment of the present invention may be 0.15 to 6 parts by weight, preferably 0.2 to 0.4, based on 1 part by weight of the porous bone graft material. If the content of hydroxypropyl methylcellulose is less than 0.15 parts by weight compared to 1 part by weight of the porous bone graft material, the adhesion to the bone defect is insufficient and there is a high possibility that it will fall from the bone defect when used, and if the content of hydroxypropyl methylcellulose exceeds 6 parts by weight compared to 1 part by weight of the porous bone graft material. In this case, bone formation may be hindered by interfering with the hygroscopicity and wettability of the heterogeneous bone.

A bone graft material composition kit according to another embodiment of the present invention includes the bone graft material composition described above and a syringe for mounting the same. By providing a syringe that directly contains the bone graft material composition, convenience of use can be ensured, and the possibility of contamination that may occur during use can be dramatically reduced.

However, in the description of this embodiment, parts that overlap with other embodiments are omitted for clearer and concise description, and the omission of the description does not mean that the part is excluded from the present invention, and the scope of rights is limited to other embodiments. It must be recognized as the same as the form.

A method for producing a bone graft material composition according to another embodiment of the present invention includes the steps of adding bone morphogenetic protein to a solvent or adding bone morphogenetic protein to a solvent to dissolve the bone morphogenetic protein in the solvent to prepare a bone morphogenetic protein solution;

Adsorbing the bone morphogenetic protein to the graft powder by immersing the graft powder in the bone morphogenetic protein solution by flowing the bone morphogenetic protein solution into a previously prepared graft powder or dropping the graft powder into the bone morphogenetic protein solution;

Forming a viscous gel by mixing and stirring the graft material powder to which the bone morphogenetic protein is adsorbed and the hydroxypropyl methylcellulose powder; and

A step of drying the mixed and stirred mixture of the graft material powder and the hydroxypropyl methylcellulose powder while freezing at a low temperature in a vacuum to form a sponge shape including a structure containing a plurality of pores, thereby activating bone formation and bioactivity. The suitability and ease of use effects can be excellent.

However, in the description of this embodiment, parts that overlap with the above-described embodiment will be omitted for clearer and concise description. The omission of the description does not exclude the part from the present invention, and the scope of rights is limited to the above. It should be recognized as the same as one embodiment.

Figure 1 is a diagram schematically showing the procedure for manufacturing a bone graft material composition according to an embodiment of the present invention.

First, prepare a bone morphogenetic protein solution by dissolving the bone morphogenetic protein in a solvent. A bone forming protein solution can be prepared by adding bone forming protein to a solvent or dissolving the bone forming protein in the solvent by adding bone forming protein to the solvent.

Bone morphogenetic proteins are BMP-2, BMP-3, BMP-3b, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, BMP-10, BMP-11, BMP- 12, BMP-13, BMP-14, BMP-15, BMP-16, BMP-17, BMP-18, recombinant bone morphogenetic proteins thereof, and bone morphogenetic proteins equivalent thereto, In terms of the bone formation effect of the present invention, rhBMP-2 may be preferable.

The bone morphogenetic protein concentration of the bone morphogenetic protein solution according to an embodiment of the present invention may be 0.05 to 0.15 mg/ml, and preferably 0.08 to 0.12 mg/ml. By satisfying the above concentration range, bone formation of bone morphogenetic protein can be activated. If the concentration of bone morphogenetic protein is less than 0.05, the ability to form new bone may be reduced, and if it is more than 0.15, side effects may occur.

Additionally, the acidity of the bone morphogenetic protein solution according to an embodiment of the present invention may be, for example, pH 4.6 to 5. By satisfying the above acidity range, the bone formation of the bone morphogenetic protein can be activated. If the pH of the bone morphogenetic protein solution is less than 4.6, the new bone formation ability may be reduced, and if the pH is more than 5, the expression of the new bone formation ability may be reduced. For example, acidity can be adjusted using phosphate buffer saline. Adjusting acidity with phosphate buffer saline may have an effect on new bone formation.

Next, the graft powder is immersed in the bone morphogenetic protein solution to adsorb the bone morphogenetic protein to the graft powder. By flowing the bone morphogenetic protein solution into a previously prepared graft powder or dropping the graft powder into the bone morphogenetic protein solution, the graft powder can be immersed in the bone morphogenetic protein solution and the bone morphogenetic protein can be adsorbed onto the graft powder.

The graft material powder may be autologous bone, allogeneic bone, or xenograft bone. For example, implant powder can be prepared by injecting it into a snap tube.

The average particle diameter (D50) of the transplant material powder may be 200 to 5,000 ㎛, preferably 250 to 1,000 ㎛. If the average particle diameter of the powder is less than 200㎛, the graft material is absorbed quickly and bone conduction necessary for bone formation may be insufficient, and if it is more than 5,000㎛, precise processing may be difficult when applied to patients.

The step of adsorbing the bone morphogenetic protein to the implant powder according to an embodiment of the present invention may include adsorbing the bone morphogenetic protein using a refrigerated centrifuge.

In some cases, the bone morphogenetic protein may be suspended in the solution, and when adsorbed by rapidly rotating it using a centrifuge, the bone morphogenetic protein can be prevented from floating in the solution and thus within the surface or pores of the graft powder. Bone morphogenetic proteins can be well absorbed. It must be adsorbed while rotating rapidly to prevent bone morphogenetic proteins from falling off from the graft powder and re-suspending. If it is slow, bone morphogenetic proteins may float and adsorption may be poor. Bone morphogenetic proteins can be quickly adsorbed on the surface or in the pores of the implant powder.

The rotation speed of the refrigerated centrifuge according to an embodiment of the present invention may be 4000 rpm or more. When adsorbing using a centrifuge, the higher the rotation speed, the better the adsorption. For example, the rotation speed of the centrifuge may be 4000 rpm or more, and if the above-mentioned range is satisfied, the bone formation protein is suspended in the solution. can be prevented.

The adsorption step using a refrigerated centrifuge according to an embodiment of the present invention may be performed at a refrigeration temperature of 5°C or lower. By performing the adsorption step using a refrigerated centrifuge at a refrigerated temperature of 5℃ or lower, the temperature of the solution is prevented from rising due to rotation, thereby preventing deformation of the heat-vulnerable bone morphogenetic protein and the surface of the bone morphogenetic protein graft powder through rotation. Alternatively, the adsorption effect within the pores can be maximized. The refrigeration may be at a temperature at which the solution does not freeze, for example, 5°C or lower, and preferably 0.5 to 1.5°C.

Next, the graft powder adsorbed with bone morphogenetic protein and the hydroxypropyl methylcellulose powder are mixed and stirred to form a gel. This can form a viscous gel, and the formed gel can improve the adhesion of the implant powder. For example, the stirring can be performed with a mixer. By mixing the transplant material powder with hydroxypropyl methylcellulose in powder form, a result with uniform quality can be obtained.

The volume ratio of the graft powder adsorbed with bone morphogenetic protein and the hydroxypropyl methylcellulose powder according to an embodiment of the present invention may be 1:0.2 to 1:0.6. If the volume ratio of the hydroxypropyl methylcellulose powder is less than 0.2, it is difficult to form a gel, and if it is more than 0.6, the volume of the gel becomes larger than the volume of the graft powder, making it difficult to form an effective bone graft material composition. In terms of the effectiveness of the invention, the volume ratio of the graft material powder adsorbed with bone morphogenetic protein and the hydroxypropyl methylcellulose powder may preferably be 1:0.25 to 1:0.35.

Next, the mixed and stirred graft material powder and hydroxypropyl methylcellulose powder mixture is vacuum freeze-dried to form a sponge shape containing a porous structure. The mixed and stirred mixture of the implant powder and the hydroxypropyl methylcellulose powder can be dried while being frozen at a low temperature in a vacuum to form a sponge shape containing a structure containing a plurality of pores.

By vacuum freeze-drying, a sponge shape containing a porous structure can be formed. As the gel is absorbed into the implant powder, a sponge shape with a porous structure can be formed, and it is believed that vacuum treatment mainly contributes to the formation of a sponge shape with a porous structure.

The method for producing a bone graft material composition according to an embodiment of the present invention may further include a packaging step.

The method for manufacturing a bone graft material composition according to an embodiment of the present invention includes the step of mounting the manufactured bone graft material composition including a sponge form including a structure including a plurality of pores on a snap tube of a size that can be inserted into a syringe. More may be included. By further including the step of mounting on a snap tube of a size that can be inserted into a syringe, it can be directly inserted into the syringe without a separate process by having a size that can be inserted into a syringe, making it easy to work in the process of manufacturing the bone graft material composition. can do.

The method for manufacturing a bone graft material composition according to an embodiment of the present invention may further include the step of placing a bone graft material composition in the form of a sponge including a structure including a plurality of pores mounted on a snap tube into a syringe and sealing it. . By providing the bone graft material composition in a syringe, convenience of use can be ensured, and the possibility of contamination that may occur during use can be dramatically reduced.

The method for producing a bone graft material composition according to an embodiment of the present invention may further include the step of sterilizing the bone graft material composition.

One embodiment of the present invention can sterilize a bone graft material composition including a sponge-type structure including a plurality of pores through ethylene oxide gas. For example, the Ethylene Oxide Gas concentration may be 450 to 1200 mg/l. If the Ethylene Oxide Gas concentration is less than 450 mg/l, sterilization may be insufficient, and if it is more than 1200 mg/l, deformation of bone formation proteins may occur.

In one embodiment of the present invention, a bone graft material composition including a sponge-like structure including a structure including a plurality of pores may be sterilized through gamma ray irradiation. For example, the irradiation dose of gamma rays may be 10 to 25 kGy. When the gamma ray irradiation amount is less than 10 kGy, sterilization may be insufficient, and when it is more than 25 kGy, deformation of bone morphogenetic proteins may occur.

Hereinafter, preferred embodiments are presented to aid understanding of the present invention, but these examples are only illustrative of the present invention and do not limit the scope of the appended claims, and are examples within the scope and technical idea of the present invention. It is obvious to those skilled in the art that various changes and modifications are possible, and it is natural that such changes and modifications fall within the scope of the appended patent claims.

Experiment example

1. Wetability of the graft material

0.1ml, 0.2ml, and 0.3ml of blood was dropped on the edge of allogeneic bone, xenogeneic bone, and synthetic bone to observe whether the graft material absorbed the blood well. The results are shown in Table 1 below.

- ○○: Excellent, ○: Good, △: Average

- Each experiment is performed 10 times for each blood amount.

All graft materials have good blood absorption, but in the case of synthetic bone, blood cannot be trapped in the graft material, so bone formation ability is reduced. Blood plays an important role in bone formation, and it was confirmed that the wettability of the graft material improves the bone formation effect.

2. Wetability according to the ratio of bone graft material and hydroxypropyl methylcellulose

Bone graft material compositions were prepared by varying the ratio of hydroxypropyl methylcellulose to allogeneic bone, xenogeneic bone, and synthetic bone (each experiment was performed 100 times for each ratio), and the contents and results for each are shown in Tables 2 to 4. .

The hydroxypropyl methylcellulose was suitably formed in Putty type at a weight of 0.05 g or more, and the ratio that maximizes the wettability of the implant material was confirmed to be in the range of 0.05 to 0.13 g. The blood wettability of the graft material may be important in relation to new bone formation in bone defect areas.

3. Adhesion of transplant material

A dental maxillary model frame was prepared, and the molar area was selected as the missing area. After transplanting (adhering) the Putty type graft material to the defect area, blood (20 cc/hr) was allowed to affect the defect area through the feeding bag supply container. Experiments were conducted on allogeneic bone, xenograft bone, and synthetic bone (each experiment was performed 100 times for each ratio), and the contents and results for each are shown in Tables 5 to 7.

- The adhesion of the graft material was tested for each example, considering that in actual clinical practice, it takes 2 to 5 minutes for the operator to suture the graft material after implantation. As a result of all experiments on the putty-type graft material, all tests were 5 for over 0.05 g of HPMC. Adhesion of more than 10 minutes was confirmed.

In addition, it was confirmed that a desirable effect was achieved when the ratio of the putty-type graft material was 0.2 to 0.4 parts by weight compared to 1 part by weight of the porous bone graft material.

Claims (4)

Contains porous bone graft material and hydroxypropyl methylcellulose,
The hydroxypropyl methylcellulose allows the bone graft material composition to have adhesion to the bone defect,
A bone graft material composition in which the content of the hydroxypropyl methylcellulose is 0.15 to 6 parts by weight relative to 1 part by weight of the porous bone graft material.
In claim 1,
The porous bone graft material is a bone graft material of natural origin.
In claim 1,
A bone graft material composition comprising a sponge form containing a porous structure.
A bone graft material composition kit, comprising the bone graft material composition of any one of claims 1 to 4 and a syringe for mounting the bone graft material composition.