JP3170059B2 - Calcium phosphate drug sustained-release body and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a calcium phosphate-based drug sustained-release body for continuously releasing a medical drug for hard tissue in a living body for a long period of time, and a method for producing the same.
The present invention relates to a calcium phosphate-based drug sustained-release body that can be firmly bonded and maintained in a living hard tissue and can control the drug release rate, and a method for producing the same.

[0002]

BACKGROUND ART [0002] Conventionally, a drug sustained-release body has been used as an effective means for long-term continuous administration of a drug to an affected part. And, as is well known, this drug sustained release body is composed of a predetermined drug and a base material holding the same, and is embedded in a hard tissue such as a bone in a living body, The drug is gradually released from the base material over a long period of time, so that an effective therapeutic effect on the affected area is improved.

[0003] Therefore, as such a drug sustained-release body, one having a high ability to retain a drug and an excellent sustained-release effect is required. A proposal has been made.

For example, JP-A-59-101145 discloses a chemical-impregnated porous ceramic in which a predetermined drug is impregnated in pores communicating with the outside. Discloses a method in which a ceramic fine powder and a drug powder are mixed and then molded at normal temperature under pressure. Further, in JP-A-3-294221, a hole is formed in a dense ceramic body, and a hole is formed in the hole. A liposome containing a drug therein has been proposed. And in those publications,
In any case, it is shown that the sustained-release drug disclosed therein has excellent sustained-release properties of the drug and can obtain a dosing effect over a long period of time.

[0005] However, since all of these drug sustained-release bodies are formed into a predetermined shape, when such drug sustained-release bodies are embedded in living body hard tissues having complicated shapes. It is necessary to precisely process to the shape to be embedded, so that it does not fall off from such living hard tissue, the processing work is,
It was very troublesome.

Moreover, as described above, they are only configured to release the drug in the living body for a long period of time, and therefore, they are relatively different depending on the application site in the living body, the type of disease, and the like. It is difficult to selectively control the release rate of a drug so that the drug can be released for a short period of time or for a longer period of time, and to obtain a more effective dosing effect. Was also inherent.

[0007]

The present invention has been made in view of the above-mentioned circumstances, and a problem to be solved by the present invention is to perform processing and the like on a living tissue having a complicated shape. Another object of the present invention is to provide a sustained-release drug substance that can be more firmly bonded and maintained without requiring a drug. Another object of the present invention is to easily control the release rate of a drug and to apply the drug to an application site in a living body. It is an object of the present invention to provide a method for producing a sustained-release drug that can obtain a more effective sustained-release effect depending on the type of a disease or a disease.

[0008]

In order to solve such a problem, the present invention provides a method for holding a drug as a base material, comprising tetracalcium phosphate and calcium hydrogen phosphate or a dihydrate thereof.
A calcium phosphate-based drug sustained-release body using a curable calcium phosphate-based cement composition prepared so that the Ca / P molar ratio becomes a hydroxyapatite composition,
This is the gist.

Further, the present invention relates to a method for converting tetracalcium phosphate and calcium hydrogenphosphate or a dihydrate thereof into Ca
/ As P molar ratio is hydroxyapatite composition, with respect to formulation and curable calcium phosphate cement composition comprising, allowed to cure by the addition of aqueous phosphoric acid solution, upon forming the substrate of the sustained drug release body Kneading by adding the concentration of the phosphoric acid aqueous solution to be added to 0.1 to 0.3 mmol / l and the addition amount thereof to 25 to 70% by weight,
The method for producing a calcium phosphate-based drug sustained-release body in which the porosity of the obtained cured body is controlled to 20 to 60% by curing and the release rate of the drug held in the cured body is controlled, This is the gist.

[0010]

In the meantime, in the calcium phosphate-based drug sustained-release body according to the present invention, the curable calcium phosphate-based cement composition used as a base material for holding the drug comprises tetracalcium phosphate (TeCP) and calcium hydrogen phosphate ( DCPA) or its dihydrate (DCPD)
Is a main component composition, and the main component compositions are mixed so that the Ca / P molar ratio becomes a hydroxyapatite composition. That is, in the written lapis phosphate calcium-based cement compositions, in an amount such as Ca / P molar ratio is 1.67, which TeCP and DCPA or DCP
D is blended with it,
After curing, such a composition will rapidly transform into hydroxyapatite crystals.

Here, as is well known, hydroxyapatite has excellent biocompatibility and is taken up as a part of bone in a living body.
Alternatively, it can be absorbed.

Accordingly, the calcium phosphate-based drug sustained-release body according to the present invention does not need to be taken out at all after the release of the drug. This has the advantage of serving as an alternative bone.

[0013] In the calcium phosphate-based drug sustained-release body, hydroxyapatite powder is preferably used as a seed crystal for accelerating the hardening of the calcium phosphate-based cement composition having the above composition. It will be added. The amount of the hydroxyapatite powder is preferably not more than 60% by weight.

The calcium phosphate-based drug sustained-release body according to the present invention is prepared by adding a phosphoric acid aqueous solution to a calcium phosphate-based cement composition having such a composition, as described later, kneading the mixture, and further mixing the same. That is, the drug is mixed or mixed.

That is, the calcium phosphate-based drug sustained-release body is prepared by adding a phosphoric acid aqueous solution to a calcium phosphate-based cement composition having a special composition,
While kneading them to advance the curing, while the slurry or clay-like state, the predetermined drug, in the form of a single powder or granules, or a mixed powder with a polymer compound that is not harmful to the living body It can be obtained by adding as a body or a porous granule containing a drug, and further kneading them, and such a drug powder or drug granule, or a mixed powder or drug with a polymer compound A molded product obtained by molding a drug or the like containing porous granules into a predetermined shape such as a tablet is obtained by adding a phosphoric acid aqueous solution, kneading, and forming a clay-like calcium phosphate cement composition.
Even if it covers so that the circumference | surroundings of such a molded object may be obtained.

In particular, when such a drug or the like is formed into a predetermined shape and is coated with a calcium phosphate cement composition, two or more drugs or the like having different types or concentrations are used. With the above, it is also possible that each of them is administered in a stepwise manner.
In other words, drugs and the like having different types and concentrations are positioned concentrically, and the entire surface of the inner layer is laminated so as to be covered with the outer layer. By coating with the cement composition to form a calcium phosphate-based drug sustained-release body, the drug can be sequentially eluted from the layer of the drug or the like immediately below the coating layer made of the cement composition. . Here, as a drug contained in such a drug sustained-release body, generally, a medical drug for a hard tissue such as a bone growth stimulating hormone, an antibiotic, an anti-inflammatory drug, an anti-cancer drug or the like is used.

[0017] Then, thus In the calcium phosphate sustained drug release body obtained, both are at the state of slurry or clayey before curing of-phosphate calcium <br/> um cement composition is completed For example, it is filled into the hard tissue of a living body such as a bone defect, so that it can be embedded in accordance with the complicated shape of the hard tissue of the living body without any troublesome processing or the like. Upon completion of curing, the implanted living hard tissue site can be more firmly joined to the implanted hard tissue site without falling off from the living hard tissue, and a stable medication effect can be ensured. is there.

Although the calcium phosphate cement composition is strongly acidic, it is immediately neutralized (pH 7.0 to 7.0) by adding an aqueous phosphoric acid solution and kneading the mixture.
In order to reach 4), such a sustained-release form of the drug is substantially neutral, and thus has little biostimulability, and the stability of the added drug can be advantageously ensured.

By the way, in the present invention, in the manufacture of such a calcium phosphate-based sustained drug release body, in particular, the phosphoric acid aqueous solution was added to 如-out-phosphate calcium-based cement composition as described above When the phosphoric acid aqueous solution is used at a concentration of 0.1 to 0.3 mmol / l and 25 to 7
It will be added in an amount of 0% by weight. If the concentration of the phosphoric acid aqueous solution is lower than 0.1 mmol / l, the concentration of phosphoric acid is too low, and the hydration hardening of the calcium phosphate cement composition does not proceed. If higher, the acidity is too high,
This is because such a cement composition dissolves and enhances the irritation to the living body.
If the amount is less than 5% by weight, the amount of the phosphoric acid aqueous solution added is too small, and a sufficient curing reaction does not proceed. Further, if the amount of the phosphoric acid aqueous solution exceeds 70% by weight, the obtained cured product becomes This is because not only is the hardness insufficient, but the elution rate of the drug becomes too high, so that an effective sustained release effect cannot be obtained.

The calcium phosphate cement composition to which the aqueous phosphoric acid solution has been added is cured by kneading. In the present invention, the porosity of the cured product obtained by the kneading is adjusted. But,
It is controlled at 20 to 60%. If the porosity is less than 20%, the cured product may be densified and the release of the drug through the voids of the cured product may be impaired. There is a problem that the ability to hold a drug is reduced and the sustained release effect is significantly reduced.

That is, in the calcium phosphate-based drug sustained-release body produced according to the present invention,
Brighter calcium phosphate cement composition is used as a base material for holding the drug, after curing, it has a predetermined gap,
In addition, the drug can be released through the voids, and the release rate of the retained drug largely depends on the porosity.

Further, in the present invention, the concentration and amount of aqueous phosphoric acid solution is caused to added to calcium phosphate cement composition, within such a range described above, by suitably changing, that obtained it is possible to control the porosity of the cured product of the-phosphate Cal <br/> Siumu cement composition.

Therefore, in the present invention, only by controlling the concentration and the amount of the phosphoric acid aqueous solution to be added, the release rate of the drug retained in the cured product of the calcium phosphate cement composition is extremely controlled. It can be done easily.

Therefore, according to the present invention, there is provided a calcium phosphate-based drug sustained-release body that can enjoy a more effective sustained-release effect according to the site to be applied in a living body, the type of disease, and the like. Can be obtained very easily.

[0025] In the present invention, TeCP and DCPA constituting the curable Li <br/> calcium phosphate cement composition, or by adjusting the particle size of the DCPD, the cured product obtained voids The rate can be varied, and thereby the rate of release of the drug from the cured product can be more broadly controlled. Furthermore,
In the drug to be mixed or mixed, the dissolution rate of the drug can be controlled by using drug powders having different particle diameters or granules coated with various polymer films on the surface of the drug, and the drug from the cured product can be controlled. It is effective in controlling the release rate.

[0026]

EXAMPLES Hereinafter, some examples of the present invention will be described to clarify the present invention more specifically. However, the present invention imposes some restrictions by the description of such examples. It goes without saying that you don't receive anything. Further, in addition to the following examples, the present invention may further include various changes and modifications based on the knowledge of those skilled in the art without departing from the spirit of the present invention, in addition to the above specific description. , Improvements and the like can be added.

Example 1 First, tetracalcium phosphate (TeCP) powder was prepared at 1.83.
g, 0.86 g of calcium hydrogen phosphate dihydrate (DCPD) powder, and synthetic hydroxyapatite (HA).
p) 1.794 g of powder were each weighed and mixed to obtain a mixed powder giving a curable calcium phosphate based cement composition. Next, 0.95 g of the mixed powder was weighed, and 0.25 mmol / l was added thereto.
After adding 0.36 ml of an aqueous phosphoric acid solution, the mixture was quickly kneaded to prepare a cement slurry. Thereafter, 0.05 g of indomethacin powder was added to the obtained cement slurry, kneaded, and poured into a mold having a diameter of 2 cm.
It was kept at 00% for 24 hours and was cured to obtain Sample 1 which was a sustained-release body of calcium phosphate-based drug containing indomethacin.

Then, for the sample 1 thus obtained, its X-ray powder diffraction (CuKα, 30 kv, 15 m
A) was performed with synthetic HAp, respectively. Each X-ray powder diffractogram is shown in FIGS.

As apparent from FIGS. 1 and 2,
The synthetic HAp and the sample 1 show the same peak position, the sample 1 has the same crystal structure as the synthetic HAp, and the peak intensity of the sample 1 is higher than the peak intensity of the synthetic HAp. Low, sample 1 is less than synthetic HAp,
The results show that the compound has a structure with a slightly lower crystallinity and a structure closer to HAp constituting a living body.

Next, to examine the drug release rate of the calcium phosphate-based drug sustained-release body obtained as described above,
In Sample 1, the amount of indomethacin eluted (released) at regular intervals was measured. The measurement results are excerpted and shown in Table 1. When measuring the amount of indomethacin eluted from the sample 1, a rotating disk method was used,
Using the dissolution tester of the revised Japanese Pharmacopoeia, the test was performed as follows. First, while exposing only one surface of the sample 1, the whole was solidified with wax and mounted on a sample fixing device. Then, using the dissolution tester, 1000 ml
50 ml of pH 7.4 phosphate buffer in a round bottom flask
Then, at a temperature of 37 ° C., sample 1 was rotated at 150 rpm to elute indomethacin. The eluted indomethacin was collected at regular intervals, and the total amount of the solvent was changed each time. Then, the amount of the collected indomethacin was measured at a wavelength of 264 nm using a spectrophotometer.

[0031]

[Table 1]

As is clear from Table 1, Sample 1
In, approximately all of indomethacin is eluted in about 2 weeks, and the calcium phosphate-based drug sustained-release form provides a dosing effect for about 2 weeks,
The results show that an excellent sustained release effect is exhibited.

[0033] mixed powder 1.0g of Example 1 and-phosphate calcium-based cement compositions obtained in the same manner, 0.25 mmol /
After adding 0.36 ml of an aqueous solution of 1 L of phosphoric acid, the mixture was quickly kneaded to prepare a cement slurry. Thus the resulting cementite Ntosurari, insulin powder was added 5 mg, after kneaded, poured into a mold having a diameter of 2 cm, in vivo conditions substantially the same temperature 37 ° C., and held for 24 hours at 100% relative humidity, curing At the very least, Sample 2 was obtained, which was a sustained-release form of insulin-containing calcium phosphate drug. Then, a dissolution test of insulin was performed on Sample 2 in the same manner as in Example 1. Table 2 shows the results. The insulin was quantified using a protein measurement kit: Bio-Rad at a wavelength of 595 nm with a spectrophotometer.

[0034]

[Table 2]

As is clear from Table 2, in sample 2, about 28% of insulin was eluted in about 3 weeks, and further after that, insulin can be expected to be eluted. Thus, it has been shown that such a calcium phosphate-based drug sustained-release body is more rich in insulin retention ability, and a more excellent sustained-release effect can be obtained.

Example 3 In the same manner as in Example 1, the TeCP powder and the DCPD powder were weighed, and further, the synthetic HAp was weighed so as to have a compounding ratio shown in Table 3 below. Each was mixed to obtain mixed powders of various calcium phosphate cement compositions having different synthetic HAp contents. Next, a 0.25 mmol / l aqueous solution of phosphoric acid was added in various amounts to each of the mixed powders so as to have a powder-liquid ratio as shown in Table 3 below. And kneaded quickly to prepare various cement slurries. Thereafter, each of the obtained cement slurries is poured into a mold having a diameter of 13 mm, and kept at a temperature of 37 ° C. and a relative humidity of 100%, which are almost the same conditions as those in a living body, for 24 hours. A system cement was obtained.

On the other hand, aspirin powder and 50% synthetic H
Ap powder was mixed with the resulting mixed powder, and 2t
And aspirin and 50% synthetic H
Ap and a tablet having a diameter of 13 mm were formed. Then, the tablet and the calcium phosphate-based cement hardened as described above are each laminated to form a two-layer tablet, and the two-layer tablets are further hardened with wax so as to cover the surfaces, respectively. By exposing only the surface of the calcium phosphate cement, Samples 3 to 8 which were sustained-release aspirin-containing calcium phosphate drugs were obtained.

Then, the thus obtained samples 3 to 3
The porosity of each sample No. 8 was determined. The result is
The results are shown in Table 3 below.

[0039]

[Table 3]

As is apparent from Table 3, the concentration was 0.25 with respect to the calcium phosphate cement composition.
It is recognized that the porosity of the obtained cured product increases as the amount of the added phosphoric acid aqueous solution of mmol / l increases, whereby the porosity of the obtained cured product depends on the added amount of the aqueous phosphoric acid solution. Is the result shown.

Next, a dissolution test of aspirin was performed in order to examine the drug release rate of each of Samples 3 to 8. FIG. 3 shows a graph of the results of the test. In addition, this dissolution test was performed by adopting the stationary disk method, and samples 3 to 8 were placed in 50 ml of 0.1 molar phosphate buffer maintained at 37 ° C. at pH 7.4.
Was immersed, and in this solution, a magnetic stirrer was rotated at 200 rpm to stir the solution to elute aspirin. The eluted aspirin was collected at regular intervals, and the entire amount of the solution was replaced each time.

As is apparent from FIG. 3, as the porosity increases, the elution rate of aspirin increases, and as a result, in the aspirin-containing calcium phosphate drug sustained-release body of this example, calcium phosphate It has been shown that the release rate of aspirin can be easily controlled by increasing or decreasing the amount of the phosphoric acid aqueous solution added to the system cement composition. In addition, when X-ray powder diffraction was performed on each of Samples 3 to 8, the X-ray powder diffraction chart showed that the transition to hydroxyapatite having excellent biocompatibility was observed.
confirmed.

[0043]

As is apparent from the above description, in the calcium phosphate-based drug sustained-release body according to the present invention, tetracalcium phosphate having a predetermined composition ratio and phosphorus Since it uses a hardenable calcium phosphate-based cement composition consisting of calcium hydrogen oxylate or its dihydrate, it is filled into the hard tissue of a living body during a slurry or clay-like state before the hardening is completed. by being, and of being brought hardening Te into a shape conforming to such a hard tissue, hence, as in the conventional sustained drug release body, when embedded in living hard in tissue, in line with the site to be embedded There is no need to precisely process the shape, and such processing can be firmly joined and maintained in the hard biological tissue of a complicated shape without any need. Te is the more stable dosage effect was decided that may be ensured.

Further, according to the method of the present invention, the concentration and the amount of the aqueous phosphoric acid solution added for hardening the calcium phosphate cement composition can be obtained only by appropriately changing the concentration and the addition amount within a predetermined range. The porosity of the cured product obtained can be very easily controlled, and the release rate of the drug retained in the cured product can be controlled efficiently, so that it can be applied in vivo. Depending on the site and the type of disease, a calcium phosphate-based drug sustained-release body that can enjoy a more effective sustained-release effect,
It was very easy to obtain.

[Brief description of the drawings]

FIG. 1 is an X-ray powder diffraction diagram of a sustained-release calcium phosphate-based drug obtained in Example 1, which is obtained in Example 1: Sample 1.

FIG. 2 is an X-ray powder diffraction diagram of synthetic hydroxyapatite.

FIG. 3 is a graph showing the measurement results of the elution amount of aspirin at regular intervals in various aspirin-containing calcium phosphate-based drug sustained-release products having different porosity, obtained in Example 3.

Claims (4)

(57) [Claims] Claims: 1. Curing by mixing tetracalcium phosphate and calcium hydrogen phosphate or a dihydrate thereof as a base material for holding a drug so that the molar ratio of Ca / P becomes a hydroxyapatite composition. A calcium phosphate-based drug sustained-release body characterized by using a possible calcium phosphate-based cement composition. 2. The calcium phosphate cement composition according to claim 1 .
Contains hydroxyapatite powder as seed crystal
2. The calcium phosphate drug sustained release according to claim 1,
body. 3. A hardened mixture of tetracalcium phosphate and calcium hydrogen phosphate or a dihydrate thereof such that the Ca / P molar ratio becomes a hydroxyapatite composition.
For a calcium phosphate-based cement composition that can be
When an aqueous solution of phosphoric acid is added and cured to form a substrate for a sustained-release drug, the concentration of the aqueous solution of phosphoric acid to be added is 0.1 to 0.3 mmol / l, and the amount of addition is 25 to 70% by weight, and kneading and curing, the porosity of the obtained cured product is controlled to 20 to 60%, and the release rate of the drug held in the cured product is controlled. For producing a sustained-release calcium phosphate drug. 4. The calcium phosphate cement composition
Contains hydroxyapatite powder as seed crystal
4. The calcium phosphate drug sustained release according to claim 3,
How to make the body.