JPH0930988A - Sustained release porous ceramic molding for medicine and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject molding by impregnating a medicine into an open cells of a porous ceramic molded base, packing it into a bone, capable of locally administering the medicine for a long period of time and packing and restoring a deficient bone tissue simultaneously as an artificial bone. SOLUTION: A medicine (mainly an antibiotic or an anti-cancer medicine) is impregnated into an open cell of a porous ceramic molded base having the open. Hydroxyapatite as an inorganic component of bone tissue is preferably used as the material of the molded base. The molded base is preferably obtained by a method for blending a ceramic raw material with spherical particles such as a polymer material to be burnt down or the spherical particles and fibrous particles, press molding, heating and burning down the additive to form an open cell structure comprising a spherical cell and a fine communicating pipe connected to the cell. The porosity of the molding base is preferably 40-60% and the cell diameter is preferably 50-300μm.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a sustained drug release porous ceramics molded body and a method for producing the same. More specifically, the present invention provides continuous pores
For example, the present invention relates to a drug sustained release porous ceramics molded body capable of impregnating and holding a medical drug and gradually releasing the drug out of the pores, and a method for producing the same.

[0002]

2. Description of the Related Art Up to now, in the treatment of bone infections such as osteomyelitis, a closed graft is continuously washed with a drug after the curettage of a lesion, and a bone grafting operation for filling a dead space (bone defect portion) is performed after the inflammation is subsided. It was common practice. Further, in the infection after artificial joint replacement, cement beads (bone cement) impregnated with a drug are embedded in the lesion to kill bacteria, and after the infection disappears, the cement beads are taken out again to perform bone transplantation. However, these methods have drawbacks such as a large burden on the living body until the infection is completely eliminated, and the need for two operations of autologous bone transplantation. On the other hand, an anticancer agent is administered for the treatment of cancer such as malignant bone tumor, but it is often accompanied by significant systemic side effects, and in some cases, it is often associated with the life of the patient.

[0003]

DISCLOSURE OF THE INVENTION The present invention solves the above-mentioned problems of the prior art, safely and sufficiently administers a drug to the affected area after intraosseous filling, and at the same time, fills the defective bone tissue as artificial bone. It is intended to provide a drug sustained release porous ceramics molded body which can be repaired and a method for producing the same.

[0004]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present invention has excellent biocompatibility,
When the porous ceramic molded body having continuous pores and functioning as an artificial bone is used in which pores are preliminarily impregnated with a drug, the above-mentioned problems of the conventional technique can be largely or almost solved. Heading out, the present invention has been completed.

The drug sustained-release porous ceramics molded product of the present invention comprises a porous ceramics molded substrate having continuous pores and a drug impregnated in the continuous pores of the substrate. It is characterized in that it can be released slowly.

In one embodiment of the sustained-release drug-made porous ceramics molded article of the present invention, the porous ceramics molded substrate is molded into a shape adapted to a bone defect portion.

[0007] In one embodiment of the drug sustained-release porous ceramics molded article of the present invention, the drug is an antibiotic.

In one embodiment of the drug sustained-release porous ceramics molded article of the present invention, the drug is an anticancer agent.

In one embodiment of the sustained drug release porous ceramics molded article of the present invention, the porous ceramics molded substrate is formed of bioactive calcium phosphate-based ceramics.

In the method for producing a sustained-release drug-made porous ceramics molded article of the present invention, a liquid containing a drug is impregnated into the continuous pores of a porous ceramics molded substrate having continuous pores and dried. It is characterized by.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below. The porous ceramics-molded substrate of the present invention has excellent biocompatibility, can be molded in advance according to the shape of the dead space (bone defect part) after lesion curettage, and can be finely adjusted even during surgery. Since it can be easily processed, it has a function of filling and repairing the bone tissue that has been lost as artificial bone even after the filling into the bone.

The porous ceramics-molded substrate of the present invention has a large number of continuous pores, which are communicated with each other through fine capillary passages and are open to the outside at their ends. . When the continuous pores are impregnated with the drug, the drug in the continuous pores in vivo becomes
It is continuously released into the living body for a long time.

Therefore, by filling the dead space (bone defect) after the lesion curettage with the porous ceramics compact of the present invention in which the pores are previously impregnated with the drug, the lesion is locally and for a long time. A high-concentration drug can be administered over a long period of time, and after the sedation of the affected area is promoted, osteogenesis of the surrounding bone is promoted, and bone tissue penetrates into the continuous pores of the molded body and integrates with the surrounding bone to form a dead space (bone defect area). Is repaired.

In the present invention, alumina, zirconia, carbon, silicate glass, calcium silicate-based compound, calcium phosphate-based glass, calcium phosphate-based compound and the like are used as the material of the porous ceramics molded substrate, which has biocompatibility. It is not particularly limited as long as it has However, it is preferable to use a ceramic having bioactivity that directly binds to bone tissue, such as calcium phosphate-based glass, and a calcium phosphate-based compound, and among these, it is more preferable to use hydroxyapatite, which is an inorganic component of bone tissue. .

Here, the calcium phosphate-based compound such as hydroxyapatite is not particularly limited in its composition as long as it is a calcium phosphate-based compound having a Ca / P molar ratio of 1.00 to 2.00, and among these, Ca / P
A molar ratio of 1.30 to 1.70 is preferable, and Ca /
More preferably, the P molar ratio is 1.50 to 1.67. Therefore, for example, not only various apatites such as hydroxyapatite and carbonate apatite, but also tricalcium phosphate, octacalcium phosphate, dicalcium phosphate,
You may use monobasic calcium phosphate, tetracalcium phosphate, etc. individually or in mixture of 2 or more types. When the Ca / P molar ratio is 1.00 or less, tissue damage may occur, and when it exceeds 2.00, strong alkali stimulability is exhibited, and tissue damage may become a problem.

To produce the porous ceramics-molded substrate of the present invention, an additive for forming pores is prepared by using as a raw material one of the compounds having biocompatibility as described above or a mixture of two or more thereof. Are obtained by mixing and pressure-molding, and firing to burn off the additive. The method for forming continuous pores in the molded substrate and the shape of the pores are not particularly limited, and they can be produced by known methods. However, in order to achieve sustained drug release characteristics over a long period of time, and bone formation in the pores inside the molded body after sedation of the lesion, the base body and the spherical fine pores that connect the pores are connected. It is preferable to have a continuous pore structure composed of tubes. Such a continuous pore structure, for example, spherical particles such as a polymer material that is burned off by heating, or the spherical particles and fibrous particles are mixed with a ceramic material and pressure-molded, and this is heated to remove the additive. It can be formed by a method such as burning to form continuous pores.

The porosity of the porous ceramic molded substrate is 2
It is preferably from 0 to 80%, more preferably from 30 to 70%, even more preferably from 40 to 60%. If the porosity is below 20%, it may not be possible to impregnate a sufficient amount of drug, and it will
If it exceeds 0%, the strength of the molded substrate may be lowered and the function as an artificial bone may be lost. The pore size is
It is preferably 10 to 600 μm, and 30 to 500
More preferably, it is 50 μm to 300 μm. If the pore size is less than 10 μm, it may be difficult to impregnate the drug, and if it is larger than 600 μm, the drug may be rapidly released and a long-term sustained release property may not be obtained. Not only that, the strength of the molded product may be lowered and the molded product may not function as an artificial bone.

The firing temperature of the porous ceramics-molded substrate of the present invention is not particularly limited as long as it is within the temperature range in which the material used can be sintered, but when a calcium phosphate-based compound such as hydroxyapatite is used, Baking at temperature is preferred. That is, when the Ca / P molar ratio of the calcium phosphate-based compound is 1.67 or less, the firing temperature is preferably 800 to 1500 ° C.
More preferably, it is from 00 to 1200 ° C. The firing temperature is 800 ° C
If the amount is less than the range, not only the sinterability of the molded substrate is poor and the function as an artificial bone is not fulfilled, but also a foreign substance reaction may occur in the living body. Further, if the firing temperature is higher than 1500 ° C., the strength of the molded substrate will be reduced as in the above case. When the Ca / P molar ratio is 1.67 or more, the calcination temperature is preferably 1250 to 1600 ° C.
More preferably, it is from 00 to 1500 ° C. Firing temperature is 1250
If the temperature is lower than 0 ° C, the by-produced calcium oxide may cause an inflammatory reaction in the body, and if it is higher than 1600 ° C, the calcium oxide may be melted and the porous structure may be broken.

The porous ceramic molded substrate having continuous pores obtained in this manner is cut according to the purpose of use and the shape of the filling site to obtain a molded product having a function as artificial bone. If it is not necessary to cut out the details, the block body having a simple shape may be used as it is.

In the sustained-release pharmaceutical porous ceramics compact according to the present invention, a porous ceramics compact substrate having continuous pores as described above is sufficiently impregnated with a liquid containing a drug in advance to a deep portion of the compacted substrate, and this It is manufactured by drying.

The agents used in the present invention are, for example, mainly antibiotics and anticancer agents, but other agents can be used if necessary. The chemical impregnation method includes a suction method and a centrifugal precipitation method, and the impregnation method is not limited, but the centrifugal precipitation method is effective for sufficiently impregnating the chemical into a deep portion of the molded substrate. An ordinary centrifugal separator or the like can be used for the centrifugation operation. Since the spin-down time and the number of revolutions differ depending on the shape and size of the molded substrate, it is sufficient to select and set the conditions under which the drug-containing liquid can be sufficiently impregnated into the molded substrate. For example, centrifuge treatment for 10 to 30 minutes, 1000 to 2000 rp
It is preferable to apply at a rotation speed of m 3.

The drug-containing liquid thus impregnated is retained in the pores by, for example, drying. The drying method is not particularly limited, such as a heating method, a freeze-drying method and a critical point drying method, but the heating method is the easiest. However, since some drugs lose their potency by heating, it is preferable to dry at a temperature not higher than the specified temperature, and in some cases freeze-drying may be necessary. The above operation is preferably carried out under aseptic conditions using a previously sterilized drug and a ceramic porous body impregnated with the drug, but it may be sterilized after impregnation and drying operations in a clean environment. Good.

The sterilization method includes a dry heat sterilization method, a high pressure steam sterilization method, a gas sterilization method, a radiation sterilization method and the like, and there is no particular limitation. Among these methods, the dry heat sterilization method is the most preferable method because it can be easily dried and sterilized simultaneously with a simple device. The conditions for dry heat sterilization are 160 to 145 ° C. for 3 to 5 hours and 160 for 160 hours specified in the Japanese Pharmacopoeia.
~ 170 ° C for 2-4 hours, or 180-200 ° C for 0.
5 to 1 hour is preferable, but in the case of a drug which loses its efficacy by heating, it is more preferable to sterilize at 135 to 145 ° C. for 3 to 5 hours. The above-mentioned impregnation of the drug into the molded substrate and the sterilization operation are preferably performed before the operation, but may be performed during the operation, if necessary.

[0024]

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

Example 1 A porous hydroxyapatite compact having continuous pores for filling a tibial defect portion as a tibial spacer as shown in FIG. 1 was produced. Its dimensions are as shown. That is, 100 parts by weight of hydroxyapatite powder and 55 parts by weight of spherical PMMA (polymethylmethacrylate) beads (average diameter 300 μm) and 5
A weight part of acrylic fiber (diameter 20 μm, length 1 mm) was mixed, the mixture was compression-molded, and then fired at 1150 ° C. The obtained molded substrate had continuous pores and had a porosity of 50%. The iron dye solution was spun down on this porous molded substrate at 1500 rpm for 15 minutes, and dried at a temperature of 140 ° C. for 4 hours. As a result of observing the molded substrate obtained after drying in two, it was confirmed that the iron pigment was uniformly impregnated to the center of the molded body.

Comparative Example 1 A drug-impregnated molded article was produced under the same conditions as in Example 1 except that the pores were not continuous. As a result, the drug remained only in the pores on the surface of the hydroxyapatite compact, and was not impregnated into the interior. The discontinuous pore-forming substrate is 10
0 parts by weight of hydroxyapatite powder was mixed with 55 parts by weight of spherical PMMA (polymethylmethacrylate) beads (diameter of 30 μm or less), and compression molding was performed.
It was produced at 150 ° C.

Comparative Example 2 A drug-impregnated molded article was produced under the same conditions as in Example 1, except that immersion was performed instead of the centrifugation operation. As a result, the drug remained only in the pores on the surface of the hydroxyapatite compact, and was not impregnated into the interior.

Example 2 By the method described in Example 1, porosity 50%, size 10
A × 10 × 10 mm porous hydroxyapatite block having continuous pores was produced. To this, Gd-DT
A PA-containing phosphate buffer solution was used as a contrast agent and spun down at 1500 rpm for 15 minutes to enhance MRI (magnetic resonance
The image was observed. As a result, an MRI image showed a strong signal over the entire molded body, and it was confirmed that the contrast agent was uniformly impregnated to the center of the molded body.

Example 3 Porosity of 50% produced by the method described in Example 1,
An arbekacin sulfate solution, which is an antibiotic that is stable against heat treatment, was spun down at 1500 rpm for 15 minutes on a porous hydroxyapatite block having a size of 10 × 10 × 10 mm and having continuous pores, and then sterilized and dried at 160 ° C. 37 ° C
Was immersed in the phosphate buffer solution of No. 3, and the antibiotic concentration was measured over time by the total exchange method every other day, and the sustained release characteristics were examined. As a result, as shown in Fig. 2, it was confirmed that a sufficient sustained release amount was maintained over a long period of time.

Comparative Example 3 A drug-impregnated molded article was produced under the same conditions as in Example 3 except that sterilization drying at 160 ° C. was not performed. As a result, the same result as that of Example 3 shown in FIG. 2 was obtained, and no significant difference was observed between the two. This Comparative Example 3
Thus, in the drug sustained-release porous ceramics molded article of the present invention, by impregnating and encapsulating the drug before the operation and then drying, it becomes possible to prevent denaturation of the drug and preserve it for a long period of time, and it is not necessary to add a troublesome operation during the operation. It was also confirmed that the same sustained release effect as that obtained by impregnating the drug at the time of use was obtained.

Example 4 Produced by the method described in Example 1 and having a porosity of 50%,
An adriamycin solution, which is an anti-cancer agent, was spun down at 1500 rpm for 15 minutes on a porous hydroxyapatite block having continuous pores with dimensions of 10 × 10 × 10 mm.
Sterilized and dried at 160 ° C. It was immersed in a phosphate buffer solution at 37 ° C., and the anticancer agent concentration was measured over time by the total exchange method every day, and its sustained release characteristics were examined. It was confirmed that a sufficient sustained release amount was maintained over a long period of time when an anticancer agent was used, as in the case of using an antibiotic agent.

Example 5 Produced by the method described in Example 1 and having a porosity of 50%,
Arbekacin sulfate solution was added to a porous hydroxyapatite block with 2 x 2 x 2 mm dimensions and continuous pores.
The solution was spun down at 500 rpm for 15 minutes and then sterilized and dried at 160 ° C. This block was filled in the lesion of a rat that had osteomyelitis in the tibia in advance with Staphylococcus aureus, and after breeding for 3 months, the filling site was extracted to prepare a tissue sample, and the tissue around the lesion was observed. It was As a result, it was confirmed that the inflammation subsided, new bone was formed around the hydroxyapatite block and in the pores, and integrated with the surrounding bone to function as an artificial bone.

Example 6 The same molding substrate manufacturing process and iron dye impregnation test as in Example 1 were performed. However, the addition of acrylic fiber was omitted.
The obtained molded substrate had continuous pores with a porosity of about 50%, and the iron pigment could be uniformly impregnated into the central portion thereof. Further, the adriamycin solution was spun down on the porous hydroxyapatite block formed by the above method by the method described in Example 4, and a sustained release property test was conducted. The same result as in Example 4 was obtained.

[0034]

EFFECTS OF THE INVENTION According to the present invention, a drug sustained-release porous ceramics molded product can be easily produced, and the resulting molded product has a sustained drug sustained-release property for a long time. Therefore, it is possible to administer the drug locally for a long time after the lesion filling. In addition, since the molded body of the present invention also has a function as an artificial bone, it is not necessary to remove the molded body or transplant autologous bone by re-operation, which greatly reduces the burden on the patient. Further, since the drug sustained-release porous ceramics molded article of the present invention is impregnated with a drug and sealed and then dried,
It can be stored for a long period of time, and therefore can be prepared in advance before the operation, and it is not necessary to add a troublesome operation during the operation.

[Brief description of drawings]

FIG. 1 is a perspective explanatory view showing the shape and dimensions of an example of a drug sustained release porous ceramics molded article according to the present invention.

FIG. 2 is a graph showing the time-drug release amount relationship of the drug sustained-release porous ceramics compact of the present invention.

[Explanation of symbols]

 1 ... tibia spacer

Claims (6)

[Claims] 1. A controlled drug release, comprising a porous ceramics molded substrate having continuous pores and a drug impregnated into the continuous pores of the substrate, wherein the impregnated drug can be gradually released to the outside. Porous ceramics compact. 2. The drug sustained-release porous ceramics molded article according to claim 1, wherein the porous ceramics molded substrate is molded into a shape adapted to a bone defect portion. 3. The drug sustained-release porous ceramics molding according to claim 1, wherein the drug is an antibiotic. 4. The drug sustained release porous ceramics molded article according to claim 1, wherein the drug is an anticancer drug. 5. The drug sustained-release porous ceramics molded article according to claim 1, wherein the porous ceramics molded substrate is formed of bioactive calcium phosphate ceramics. 6. A method for producing a sustained-release porous ceramics molded article of a drug, characterized in that a liquid containing a drug is impregnated into the continuous pores of a porous ceramics molded substrate having continuous pores, and the liquid is dried. Method.