WO2009096709A2

WO2009096709A2 - Bone cement with anion

Info

Publication number: WO2009096709A2
Application number: PCT/KR2009/000426
Authority: WO
Inventors: Kug Sun Hong; Hyun Seung Yu; Jeong Seop Lee; Dong Wook Kim; In Sun Cho; Shin Tae Bae; Hyun Suk Jung
Original assignee: Snu R & Db Foundation
Priority date: 2008-01-30
Filing date: 2009-01-29
Publication date: 2009-08-06
Also published as: WO2009096709A3; KR20090083806A; KR100981961B1

Abstract

Disclosed is bone cement including dry ingredients as a calcium source and a phosphate source containing at least one type of compound, a hardening solution obtained by dissolving a phosphate and an emulsifying agent in water, and anion added to at least one of the dry ingredients and the hardening solution. The bone cement of the present invention can be used in an injector that allows the setting time and the injection time to be easily and simultaneously adjusted such that sufficient surgical operating time can be provided to a user during operation.

Description

Anion-substituted bone cement

The present invention relates to anion-substituted bone cement, and more particularly, it is easy to simultaneously adjust the setting time and injection time, which are the most basic characteristics of bone cement that can be used in a syringe, so that users have sufficient procedure time during surgery. It relates to bone cement substituted with an anion.

Bone cement is a substance that can form artificial bones that can replace human bones, and is also referred to as calcium phosphate cement because it mainly contains phosphoric acid and calcium. The bone cement is composed of dry ingredients, which are compounds containing calcium and phosphate sources, and mixed with a hardening solution to form a paste in a state similar to toothpaste. It is to use the process of fixing to hydroxyapatite.

One of the most important conditions for bone cement is to have the proper injection time and setting time along with the property that can be injected through the syringe, that is, injection property.

For bone cement, the easiest way to control the injection time and setting time is to control the amount of curing liquid used. However, in this case, if the curing liquid is not enough, not only the problem of injection property, but also the injection time and setting time is too short, there is a limit to use as a structural material in orthopedic and dental. To solve this problem, consider adding a hardening accelerator additive to the curing liquid to provide an injection time and proper setting time to allow sufficient procedure time while maintaining the amount of curing liquid to have sufficient injectability. can see.

In other words, although the amount of the curing liquid is increased or an cellulose-based additive is added to secure the injection property, if the amount is too large, an appropriate setting time cannot be obtained. Of course, at this time, by increasing the amount of the curing acceleration additives added to the curing liquid to obtain an appropriate injection time and setting time, another problem occurs, such as precipitation of the added curing acceleration additives when the temperature is lowered.

Accordingly, the present invention provides a sufficient amount through the method of adding an anion to the dry component or the curing liquid, in addition to selecting the amount of the curing liquid, the cellulose-based additives, and the curing accelerator additive within the range which does not cause the above-mentioned problems. The object is to provide bone cement that is injectable, has sufficient injection time, and can be adjusted to set the time appropriately.

In order to achieve the above object, according to the present invention, a dry component which is a compound containing a calcium source and a phosphate source, a curing liquid obtained by dissolving a soluble phosphate and an emulsifier, and further added to at least one of the dry component and the curing liquid Provided is a bone cement containing anion, characterized in that it comprises anion.

According to the present invention, it is possible to inject through the needle of the syringe by giving an adequate flowability by adjusting the rate of the curing reaction by adding an anion to the dry components or phosphate ions containing a compound containing a calcium source and a phosphate source This provides bone cement that is capable of injecting time (injection time) is sufficient and the setting time can be properly adjusted.

The dry ingredient (s), which is a compound comprising a calcium source and a phosphate source to which the anion is added, typically has a particle size in the range of about 0.1 to 1000 μm, which may be a single calcium phosphate compound or two or more compounds. May exist.

Examples of the compound including a calcium source and a phosphate source include MCPM (monium phosphate monohydrate, Ca (H ₂ PO ₄ ) ₂ H ₂ O), MCPA (monium calcium phosphate, Ca (H ₂ PO ₄ ) ₂ ), DCPD (dicalcium phosphate dihydrate, blushite or CaHPO ₄ · 2H ₂ O), ACP (amorphous calcium phosphate or Ca ₃ (PO ₄ ) ₂ · H ₂ O), DCPA (dicalcium phosphate, monite or CaHPO ₄ ), α-TCP and β-TCP (tricalcium phosphate or Ca ₃ (PO ₄ ) ₂ ), TTCP (tetracalcium phosphate or Ca ₄ (PO ₄ ) _2O ), calcium hydroxide (Ca (OH) ₂ ), oxidation Examples include, but are not limited to, calcium (CaO), HA (hydroxy apatite or Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ ), and the like.

In addition, as a compound capable of supplying anions added to the compound including the calcium source and the phosphate source, calcium carbonate (CaCO ₃ ), calcium sulfate (CaSO ₄ ), barium sulfate (BaSO ₄ ), sodium fluoride (NaF), and the like. Likewise, it is a compound containing anions such as CO ₃ ^2- , SO ₄ ^2- , F ⁻ , PO ₄ ^3- , and HPO ₄ ^2- . The addition amount of such a compound is good for 0.1-30 weight part with respect to 100 weight part of dry components.

And the curing solution containing the phosphate ion of the present invention means an aqueous solution in which soluble phosphate and emulsifier dissolved in distilled water.

Soluble phosphates include diammonium hydrogen phosphate (NH ₄ ) ₂ HPO ₄ ), ammonium dihydrogen phosphate (NH ₄ H ₂ PO ₄ ), sodium phosphate monobasic (NaH) ₂ PO ₄ ), sodium hydrogen phosphate (Na ₂ HPO ₄ ), sodium phosphate tribasic (Na ₃ PO ₄ ), potassium phosphate dibasic (K ₂ HPO ₄ ), phosphoric acid Potassium phosphate monobasic (KH ₂ PO ₄ ), dimethyl phosphate (C ₂ H ₇ PO ₄ ), monomagnesium phosphate (Mg (H ₂ PO ₄ ) ₂ ), magnesium phosphate dibasic (magnesium phosphate dibasic, MgHPO ₄ ), lithium dihydrogen phosphate (LiH ₂ PO ₄ ), lithium phosphate (Lithim phosphate, LiPO ₄ ), calcium hydrogen orthophosphate hydrate (CaHPO ₄ · 2H ₂ O ), Calcium hydrogen orthopho sphate, CaHPO ₄ ), Calcium metaphosphate (CaP ₂ O ₆ ), amorphous calcium phosphate (Ca ₃ (PO ₄ ) ₂ ), etc. Among these, sodium phosphate monobasic , NaH2PO4), sodium phosphate (Na ₂ HPO ₄ ), sodium phosphate tribasic (Na ₃ PO ₄ ), potassium phosphate dibasic (K ₂ HPO ₄ ), potassium phosphate Monobasic (potassium phosphate monobasic, KH ₂ PO ₄ ) is preferred because of high solubility in the curing liquid.

The emulsifier increases the viscosity of the paste when the paste is mixed with the dry ingredients and the curing solution. If the emulsifier does not enter the cured liquid, the dry ingredient and the cured liquid are mixed and injected into the human body, and the viscosity may be too low, causing the paste to be released by the blood and roam along the blood vessel. In addition, when injected into the human body is the best when the viscosity of the toothpaste, without the emulsifier it is difficult to obtain that viscosity.

Emulsifiers include polyoxyethylene or polyoxypropylene polymers or copolymers thereof, such as polyethylene glycol and polypropylene glycol; Various natural polymers such as gum arabic, guar gum, carrageenan, tragacanth gum, pectin, starch, gelatin, casein, dextrin, cellulose; Nonionic cellulose ethers such as methyl cellulose, ethyl cellulose, hydroxy methyl cellulose, hydroxy ethyl cellulose, carboxy methyl cellulose, carboxy ethyl cellulose and hydroxy propyl cellulose, further celluloses such as carboxy methyl cellulose sodium , Carboxy methyl cellulose calcium, carboxymethyl starch and the like.

That is, in the present invention, as a method of adding an anion to a dry component that is a calcium source or a phosphate source, the compound of the dry component and a feed material of an anion such as calcium carbonate may be mixed. In this case, the calcium carbonate is dissolved in the curing liquid to serve as a source material for providing CO ₃ ^2- ions.

In addition, a method of adding an anion feed material to the curing liquid may be considered, in which an amount of CO ₂ gas is added to the curing liquid as an anion feed material for supplying a gaseous anion feed material, for example, CO ₃ ^2- ions. There is a way to infuse. Another method is to add a soluble anion feeder in the form of a compound to the curing liquid.

On the other hand, the reason for adding anion in the present invention is added for the purpose of delaying the curing of bone cement, depending on the actual use case may be added to promote the curing of bone cement.

In addition, the amount of anion added to the bone cement of the present invention should be considered in order to secure sufficient injectable time and appropriate control of the setting time. When the amount is too small, it is difficult to substantially expect the effect of adding anion, If the amount is too large, it causes a problem of excessive delay of bone cement hardening time.

When the soluble anion feed material is added to the cured liquid in the form of a compound, the amount of addition is preferably 0.1 to 30 g when the volume of distilled water which is a solvent of the cured liquid is 100 ml.

Considering the injectable time of the bone cement and the total setting time, the injectable start time should exceed 4 minutes, and the longer the injectable last time is better. However, if the last possible injection time is too long, it will adversely affect the setting time, so the time interval between the initial setting time and the last setting time is about 5 minutes is sufficient, so it is desirable to properly control the last injection time within this range. .

According to the experiments of the present inventors, in order to add CO ₃ ^2- ions, pH 8.3 to pH 6.0 are preferred based on the pH change amount of the curing liquid.

The anion is further dissolved by further dissolving compounds containing anions such as CO ₃ ^2- , SO ₄ ^2- , F ⁻ , PO ₄ ^3- , and HPO ₄ ^2- in the cured solution containing the phosphate ions thus prepared, or Blow the gas that can add anion into the curing solution.

As described above, the present invention is sufficient to inject the injection time (injection time) by delaying the curing rate of bone cement through the addition of anion to the dry components or phosphate ions containing a compound containing a calcium source and a phosphate source It is useful to secure the setting time and to adjust the setting time appropriately.

1 is an X-ray diffraction graph according to the curing time of bone cement cured using a curing liquid to which TTCP and DCPD are used as dry components of bone cement and CO ₃ ^2- anion is added thereto.

FIG. 2 is a graph obtained by infrared spectroscopy of bone cement according to the amount of CO ₃ ^2- anion added. (A) shows that when the pH of the cured solution is 7.5 due to the low addition of CO ₃ ^2- anion, (b) is cured. It shows the case where CO ₃ ^2- anion was added until the pH of the liquid no longer decreased.

3 is an electron micrograph before (a) and after curing (b) of the present invention bone cement curing.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the scope of the present invention is not limited to the following examples.

Basically, a compound including a calcium source and a phosphate source, that is, a dry ingredient, is mixed with TTCP and DCPD in a molar ratio of 1: 1, milled for 1 to 7 days using anhydrous ethanol, and then used by freeze drying. This powder is 0.1 to 1000 mu m in size and uses completely dried.

The cured solution was thoroughly stirred with 1 g of Na ₂ HPO _{4 in} 100 g of distilled water, 1 g of carboxymethyl cellulose was added thereto, dissolved by heating, and used after cooling completely. And exemplary clerical script anion is added in a stylized way that blowing CO ₂ gas into the hardening liquid, the by measuring the pH of, measuring the amount of the added CO ₂ gas produced in the hardening liquid is not possible to add CO ₃ ^2- anions We indirectly know the amount of.

For all comparative examples and examples, the setting time and the injection time were measured in the following manner. That is, the setting time was measured by a gilmore needle by mixing 1 g of dry ingredients and 1.8 ml of a curing liquid in a beaker in a thermostat of 37 degrees and 30% relative humidity in a beaker, and then evenly stirring for 30 seconds with a spatula. The time measurement was taken as the start time when the dry component and the curing liquid were mixed. Injection time was measured by cooling the dry ingredients 3g and 3ml of the curing liquid to 20 degrees similar to the operating room temperature, thoroughly stirred with a spatula for 30 seconds, and then squeezed with a syringe to squeeze directly.

(Comparative Example)

Using the above dry component and a hardening liquid are not blown into the CO ₂ gas were measured setting time and the injection time. In this case, the pH of the curing liquid was 8.6 to 9.0, and the details of the setting time and the injection time are shown in Table 1.

(Examples 1 to 5)

In order to add CO ₃ ^2- anion to the curing liquid, the amount of CO ₂ gas was blown in different amounts, and the pH was measured in real time, thereby preparing a curing liquid having a pH of 8.0, 7.5, 7.0, 6.5, and fully saturated pH, respectively. It was. Detailed setting time and injection time are shown in Table 1.

As shown in Table 1, in the comparative example in which CO ₃ ^2- ions were not added, injection was possible after 4 minutes, and the last possible injection time was 8.5 minutes, which was about 4.5 minutes. On the contrary, in Examples 1 to 5 of the present invention, it can be seen that as the amount of CO ₃ ^2- ions increases, the start time of injectable starts to be delayed to 4.5 minutes and is delayed up to 9 minutes. In addition, the last possible injection time is also gradually delayed up to 21 minutes can be seen that.

From these results, it can be seen that according to the present invention, by sufficiently securing the time required for injection, it is possible to prevent mistakes in the hasty procedure and to perform precise procedures with time.

In addition, even in the setting time, in the embodiments of the present invention, the total setting time is approximately 5 to 6 minutes, and the initial time required for the setting as a whole, while maintaining almost the same level as that of the comparative example without CO ₃ ^2- ions being added. It can be seen that a sufficient delay of the last time can be obtained, thus ensuring sufficient time for the procedure.

Referring to the accompanying drawings, in all cases, as shown in Figure 1, as the bone cement hardened it could be seen that the mixture of TTCP and DCPD turned into hydroxyapatite. 2 shows that the hydroxyapatite substituted with CO ₃ ^2- anion is formed as a cured product. In addition, it can be seen from FIG. 3 that in all cases, as hardening proceeds, needle-like hydroxyapatite is formed, and bone cement is hardened by crosslinking.

Table 1

	Curing solution pH	Setting time (minutes)		Injection time (minutes)
	Curing solution pH	Initial setting time	Last setting time	Injectable Start Time	Last time to inject
Comparative example	8.6-9.0	8	13.5	4	8.5
Example 1	8.0	8.5	14	4.5	8.5
2	7.5	9	14.5	5.5	10.5
3	7.0	10	15	6	14
4	6.5	12	17	7.5	17.5
5	6.1-6.4	15	21	9	21

In the above, the present invention has been illustrated and described with reference to specific preferred embodiments, but the present invention is not limited to the above-described embodiments and the general knowledge in the technical field to which the present invention pertains without departing from the spirit of the present invention. Various changes and modifications will be made by those who possess.

Claims

A dry ingredient comprising at least one compound as a calcium source and a phosphate source, respectively

A curing liquid obtained by dissolving a soluble phosphate and an emulsifier in water, and

Bone cement containing anion, characterized in that it comprises an anion further added to at least one of the dry component and the curing liquid.
The method of claim 1,

Bone cement containing anion, characterized in that the anion is selected from CO 3 2- , SO 4 2- , F − , PO 4 3- , HPO 4 2- .
The method according to claim 1 or 2,

When the anion is added to the dry ingredient bone cement containing anion, it is added in the form of a powdered compound.
The method of claim 3,

The powdery compound includes an anion comprising calcium carbonate (CaCO 3 ), sodium carbonate (Na 2 CO 3 ), calcium sulfate (CaSO 4 ), barium sulfate (BaSO 4 ), and sodium fluoride (NaF). Bone cement.
The method of claim 3,

The amount of the compound is bone cement containing anion, characterized in that 0.1 to 30 parts by weight based on 100 parts by weight of the dry ingredient.
The method of claim 1,

When the anion is added to the curing liquid, the bone cement containing anion, characterized in that it is added in the form of a gas (gas) or in the form of a compound dissolved in the curing liquid.
The method of claim 6,

The compound is selected from calcium carbonate (CaCO 3 ), sodium carbonate (Na 2 CO 3 ), calcium sulfate (CaSO 4 ), barium sulfate (BaSO 4 ), sodium fluoride (NaF), and the addition amount thereof is a solvent of the curing liquid. Bone cement containing anion, characterized in that when the volume of distilled water to 100 ml to 0.1 to 30g.
The method of claim 6,

The gas is bone cement containing anion, characterized in that the CO 2 gas.
The method of claim 8,

The addition amount of the CO 2 gas bone cement containing anion, characterized in that to have a value of pH 8.3 to pH 6.0 based on the pH change amount of the curing liquid.