JP3000718B2 - Drug sustained release calcium phosphate cement - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a sustained-release drug cement based on calcium phosphate cement.

[0002]

2. Description of the Related Art Conventionally, as a drug sustained-release material having good biocompatibility, for example, JP-A-59-101145 and JP-A-60-106459 disclose an antibiotic or an anticancer agent with a porous material. Combinations with ceramics have been proposed. However, the drug sustained-release material is a ceramic material having a certain shape as a base material,
There is a problem that processing must be performed before or during the operation in accordance with the implantation site.

On the other hand, calcium phosphate cement has been developed as the drug sustained release material. The calcium phosphate cement is very easy to handle because the paste is mixed with a powder and a liquid before or during the operation, and the mixture is allowed to inject into the site to be implanted and hardened. However, most of the calcium phosphate-based cement uses a considerably high concentration of acid as a liquid agent as disclosed in, for example, JP-A-60-253454. However, there is a problem in that the pH is lowered due to the elution of unreacted acid even after curing, thereby stimulating the living body and further reducing the drug efficacy. Further, the calcium phosphate cement has a problem that its strength decreases with time in a living body.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide excellent biocompatibility, there is no need to remove the drug from the body even after all of the drug has been released, and since it cures at a pH near neutrality, it is biostimulable. It is an object of the present invention to provide a drug sustained-release calcium phosphate cement which has a low drug content and does not impair the efficacy of the mixed drug.

Another object of the present invention is to provide a drug sustained-release calcium phosphate cement which has excellent operability, can be filled in any place, and which is stably present in a living body without deterioration in strength for a long period of time. It is in.

[0006]

According to the present invention, there is provided a calcium phosphate cement comprising a powder and a liquid and containing a drug, wherein the main component of the calcium phosphate cement has a Ca / P molar ratio of 1. A mixture of tribasic calcium phosphate and dibasic calcium phosphate mixed to be 40 to 1.498, and the tribasic calcium phosphate is a mixture of α-type tribasic calcium phosphate and β-type tribasic calcium phosphate. Drug sustained release calcium phosphate cement is provided.

Hereinafter, the present invention will be described in detail.

[0008] The drug sustained-release calcium phosphate cement of the present invention contains, as a main component, a powder obtained by mixing dibasic calcium phosphate and specific tribasic calcium phosphate at a specific Ca / P molar ratio.

In the sustained-release calcium phosphate cement of the present invention, the tribasic calcium phosphate used as the powder component is a mixture of α-type tribasic calcium phosphate and β-type tribasic calcium phosphate. The α-type tricalcium phosphate in the mixture reacts with the dibasic calcium phosphate to form and harden the octacalcium phosphate so as to exert the initial strength of the obtained cement hardened body, Β-type tribasic calcium phosphate, whose reaction rate is much slower than that of calcium triphosphate, is a component that reacts with time so as to gradually exert the strength of the obtained cement hardened body. Type 3
By using a mixture with calcium phosphate, it is possible to prevent the strength of the obtained hardened cement from deteriorating. The reaction proceeds most rapidly at pH 6-8.

The α-type tribasic calcium phosphate and the β-type tribasic
The mixing ratio with calcium phosphate is 97: 3 by weight ratio.
It is preferred to be in the range of 50:50. When the mixing ratio of the β-type tribasic calcium phosphate is less than 3, the effect of preventing the deterioration of the strength cannot be obtained, and when the mixing ratio is more than 50, the initial strength decreases, which is not preferable.

In order to prepare the α-type tribasic calcium phosphate and the β-type tribasic calcium phosphate, for example, an equimolar mixture of calcium pyrophosphate and calcium carbonate is used. In addition, in the case of β-type tricalcium phosphate, a calcination temperature is preferably 900 ° C. to 1100 ° C., and a dry method in which a solid phase reaction is performed, or a tertiary calcium phosphate slurry synthesized by, for example, dropping phosphoric acid into slaked lime, is dried, It can be obtained by a wet method of baking at preferably 1200 ° C. or more for α-type calcium phosphate and preferably at 900 to 1100 ° C. for β-type calcium triphosphate.

[0012] The tribasic calcium phosphate synthesized by the wet method has a higher hydration activity than the tribasic calcium phosphate synthesized by the dry method, can shorten the hardening time of the cement, and further has the strength. Since it becomes high, it can be preferably used. At this time, both the α-type tricalcium phosphate and the β-type tricalcium phosphate can be synthesized by a wet method.
It is preferable to use at least α-type tribasic calcium phosphate synthesized by a wet method.

In the present invention, the second component used as a dust component
Although it does not specifically limit as a calcium phosphate, Commercially available dibasic calcium phosphate dihydrate etc. can be mentioned preferably.

In the present invention, the Ca / P molar ratio when mixing the tribasic calcium phosphate used as the powder component and the dibasic calcium phosphate is 1.400.
It is necessary to mix so as to be 1.498. Said C
When the a / P molar ratio is less than 1.400, a large amount of unreacted dibasic calcium phosphate remains after kneading and the strength decreases, and when it exceeds 1.498, it takes a long time to cure. Therefore, it is necessary to set the above range.

Further, as the powder, only the above-mentioned tribasic calcium phosphate and dibasic calcium phosphate are sufficient, but if necessary, an X-ray contrast agent such as hydroxyapatite or barium sulfate having high biocompatibility may be added. May be used.

As the liquid agent used in the present invention, water alone is sufficient, but in order to further improve the operability,
Mucopolysaccharides such as sodium chondroitin sulfate and sodium hyaluronate, and water-soluble sodium salts such as sodium succinate and sodium lactate for shortening the curing time may be used.

The mixing ratio of the powder and the liquid is preferably in the range of 300 to 50: 100 by weight. If the mixing ratio of the powder is less than 50, it takes a long time to cure, and if it exceeds 300, the operability during kneading deteriorates, which is not preferable.

As the drug used in the drug sustained-release calcium phosphate cement of the present invention, antibiotics, anticancer materials, proteins having a special action such as bone morphogenetic factor (BMP), and the like can be preferably mentioned. The antibiotics are further penicillin-based, due to differences in chemical structure and activity.
It can be classified into cephem type, aminoglycomide type, tetracycline type, macrolite type, monobactam type and the like. Specific examples of the drugs include tetracycline hydrochloride, doxycycline hydrochloride, erythromycin, josamycin, sulbenicillin sodium, cefazolin sodium, and mitomycin C.

The compounding ratio of the drug is not particularly limited as long as it is not less than the effective concentration of the drug to be used and is an amount that does not harm the animals to be filled.

The pH at the time of preparing the drug sustained-release calcium phosphate cement of the present invention is usually determined by the p.
H6-8 is best exhibited near neutrality, becomes unstable in an acidic or alkaline environment, and rapidly loses its efficacy (for example, tetracycline hydrochloride and doxycycline hydrochloride are strong against acids but weak against alkali, Further, erythromycin and josamycin are weak to acids, and sulbenicillin sodium, cefazolin sodium, mitomycin C and the like are stable in neutral but unstable in acidic and alkaline environments.) And the reaction of dibasic calcium phosphate is p
Since the best progress is made at H6 to 8, the pH is preferably adjusted to 6 to 8.

In preparing the drug sustained-release calcium phosphate cement of the present invention, when the drug is in a powder form, it is preliminarily mixed with the powder of the calcium phosphate cement, and the obtained powder and liquid are mixed with water. When a readily soluble drug, such as tetracycline hydrochloride or cefazolin sodium, is used, it can be obtained by dissolving it in a liquid agent in advance and blending the resulting mixture, and mixing the obtained liquid agent and powder.

The drug sustained release calcium phosphate cement of the present invention can be used by filling a paste or a hardened cement obtained by kneading the powder and liquid with an implanted site. At this time, the drug sustained-release calcium phosphate cement of the present invention uses calcium phosphate cement having good biocompatibility as a main component of the powder, and thus does not need to be taken out from the body even after it is recognized that the drug effect has been lost.

As an extremely effective method of using the drug sustained-release calcium phosphate cement of the present invention, for example, an operation is performed by using the drug sustained-release calcium phosphate cement of the present invention in combination with an artificial joint replacement operation and releasing a drug such as an antibiotic. It is possible to use a biocement that is rich in biocompatibility as well as preventing the subsequent infection, that is, a method of inducing new bone around and joining the artificial joint and the bone.

[0024]

Industrial Applicability The drug sustained-release calcium phosphate cement of the present invention is excellent in operability since it is based on a calcium phosphate cement having a specific composition rich in biocompatibility, and can be filled in any place. Since it cures at a pH around the property, there is no risk of impairing the efficacy of the drug, and biostimulation is low. Furthermore, since it has excellent biocompatibility and does not deteriorate in strength for a long period of time, it does not need to be taken out of the living body after all the drug has been released, and is useful as a drug sustained-release cement.

[0025]

The present invention will be described below in more detail with reference to Examples and Comparative Examples, but the present invention is not limited thereto.

[0026]

Reference Example 1 The mixing ratio of α-type tribasic calcium phosphate synthesized by a wet method using slaked lime and phosphoric acid, and β-type tribasic calcium phosphate synthesized by a dry method using calcium pyrophosphate and calcium carbonate was determined by weight. At 80:
Tricalcium phosphate and dibasic calcium phosphate dihydrate (special grade, manufactured by Wako Pure Chemical Industries, Ltd.) of 20
/ P molar ratio is 1.40, 1.45, 1.48, 1.4
The mixture was adjusted to 98 to prepare a calcium phosphate cement for living body. Next, 100 parts by weight of water as a hardening liquid was added to 200 parts by weight of the obtained calcium phosphate cement for living body and kneaded, and the hardening time and compressive strength of the hardened cement were measured. At this time, the curing time is J
The compressive strength was measured according to IS T6604, and the compressive strength was measured by removing cement (diameter 7 mm,
(Length: 14 mm) was measured while applying pressure at a load rate of 1 mm / min per minute while wet. In the measurement, a universal testing machine “1125 type” manufactured by Instron was used. Table 1 shows the results. In addition, when the pH of the cement paste at the time of hardening was measured using litmus test paper, all were within the range of pH 6 to 8.

[0027]

Reference Example 2 Reference Example 1 was repeated except that the tribasic calcium phosphate and dibasic calcium phosphate dihydrate obtained in Reference Example 1 were mixed at a Ca / P molar ratio of 1.35 and 1.499. The curing time and compressive strength were measured in the same manner.
Table 1 shows the results.

[0028]

[Table 1]

[0029]

Reference Examples 3 and 4 Both α-type and third-type calcium phosphates were synthesized by a wet method using slaked lime and phosphoric acid. Next, the mixing ratio of β-type tribasic calcium phosphate in the third calcium phosphate was adjusted to 3% by weight, 10% by weight, 20% by weight, 40% by weight, and 50% by weight.
(Reference Example 3), 0% by weight (Reference Example 4), and a mixture of the third calcium phosphate and the second calcium phosphate so that the Ca / P molar ratio was 1.48. Sodium succinate hexahydrate (manufactured by Wako Pure Chemical Industries, Ltd.) was added to 100 parts by weight of the obtained hydraulic calcium phosphate cement.
60 parts by weight of a 0% by weight aqueous solution was added and kneaded, and the curing time and the compressive strength in the days shown in Table 2 were measured. Table 2 shows the results.

[0030]

[Table 2]

[0031]

Example 1 A tribasic calcium phosphate in which the mixing ratio of α-type tribasic calcium phosphate and β-type tribasic calcium phosphate is 80:20 in weight ratio, and dibasic calcium phosphate,
1.6 g of a commercially available aqueous solution of cefazolin sodium for injection (manufactured by Fujisawa Pharmaceutical Co., Ltd.) was mixed with 3 g of the cement powder mixed so that the Ca / P molar ratio was 1.48, and the resulting mixture (hereinafter, cement mixture) was mixed. A), five disks of 5 mmφ and 3 mmL were prepared. The obtained disc was placed in 100 ml of physiological saline, and the elution state of the drug was examined using an ultraviolet absorption method. As a result, about 50% by weight was eluted in one day, and about 70% by weight was eluted in three days. It decreased and almost all eluted after 2 weeks. In other words, the drug effect seems to last for two weeks.

[0032]

Example 2 Using the cement mixture A prepared in Example 1, a granular hardened product having a maximum diameter of 1 to 2 mmφ was prepared. On the other hand, osteomyelitis was artificially generated in the femur of the dog, the cortical bone was excised, the inflamed area was scraped, and then the defective area was filled with the granules. In addition, the cement mixture A as it was in a paste state was injected and filled into the deficient portion of another dog that had been subjected to the same treatment.

Three months after the operation, the affected part was incised to confirm the condition. After three months, the hardened cement was surrounded by a large amount of new bone in any case, and the bone defect was completely healed. Was recognized. In any case, no recurrence of osteomyelitis was observed. Further, all of the hardened cement was stably present, and no deterioration was observed.

Continuation of front page (58) Field surveyed (Int.Cl. ⁷ , DB name) A61L 27/00 A61K 6/00-6/06

Claims (1)

(57) [Claims] 1. A calcium phosphate cement comprising a powder and a liquid and containing a drug, wherein the main component of the calcium phosphate cement has a Ca / P molar ratio of 1.
A mixture of tribasic calcium phosphate and dibasic calcium phosphate mixed to be 40 to 1.498, and the tribasic calcium phosphate is a mixture of α-type tribasic calcium phosphate and β-type tribasic calcium phosphate. Drug sustained release calcium phosphate cement.