JP4143705B2 - Method for producing drug release material - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing ceramics, and relates to the field of porous ceramics intended to be used as a bone filler or a DDS carrier.
[0002]
[Prior art]
Conventionally, calcium phosphate as a ceramic having excellent biocompatibility has been widely applied in the fields of bone filler and bone cement. Most of the shapes when applied are crushing irregular shapes, block bodies, porous bodies, self-curing cements and the like. In particular, some of the bone fillers are in the form of fractured irregular shapes and block shapes.
The application of this calcium phosphate to a DDS carrier has recently attracted attention as an application example. For example, in Japanese Patent Application Laid-Open No. 60-106459, combustible beads are coated with calcium phosphate, and the combustible beads are disappeared by firing this to produce calcium phosphate hollow beads, which are then filled with a drug. A method for producing a sustained-release drug carrier is disclosed. JP-A-59-101145 discloses a method for producing a carrier having the same effect by impregnating a porous calcium phosphate having open pores with a drug.
However, the above-described method complicates the manufacturing process such as injecting a drug into the hollow beads. In addition, it is difficult to appropriately control the sustained release rate of the drug. Similarly, in the method described later, there are concerns that the manufacturing process is complicated and it is difficult to control the sustained release rate.
On the other hand, spherical calcium phosphate is applied as a column packing material for liquid chromatographs. As a production method, a spray drying granulation method is common. The spray-drying granulation method is generally produced for particles having a particle diameter of 100 μm or less, and a large apparatus is required for producing particles larger than this. In addition, as a method for producing spherical calcium phosphate having a size of 100 μm or more, Japanese Patent Laid-Open No. 64-75030 injects a ceramic slurry into an oil phase, forms a W / O emulsion, and again injects it into an aqueous phase to solidify the oil phase. And the method of making this oil phase lose | disappear by baking and manufacturing spherical calcium phosphate is disclosed.
However, particles having a size of 100 μm or more are preferable for use as a bone filler, and equipment investment is required for production by the spray drying granulation method, resulting in an increase in cost. In addition, the method disclosed in Japanese Patent Application Laid-Open No. 64-75030 requires a manufacturing process such as oil phase adjustment, and there is a concern about an increase in cost.
[0003]
[Problems to be solved by the invention]
In order to apply to DDS, it is necessary to have excellent drug loading, biocompatibility, sustained drug release and bioabsorbability. Calcium phosphate is excellent in biocompatibility and bioabsorbability and has been actively studied for application to DDS, but has not yet been put into practical use.
One of the reasons is that it is difficult to process because it is ceramic. In order to carry a drug, it is necessary to make it porous, but it is difficult to change conditions such as size, strength, and pore distribution. In addition, in terms of improving the filling rate and operability of the affected area, the DDS carrier and the bone filler are preferably spherical, but have not yet been put into practical use because it is very difficult to process into a spherical shape.
[0004]
[Means for Solving the Problems]
In view of the above, the present invention provides a technique for easily processing a calcium phosphate ceramic, which is difficult to process, into a spherical shape. In addition, this spherical ceramic has optimal pores and bioabsorbability for DDS, and can be one of the effective treatments for cancer and bone tumors by impregnating the drug and administering it to the affected area. .
[0005]
DETAILED DESCRIPTION OF THE INVENTION
A detailed description of the present invention is given below.
Calcium phosphate synthesized by a known synthesis method, preferably wet synthesis or dry synthesis, preferably hydroxyapatite, tricalcium phosphate, dicalcium phosphate, tetracalcium phosphate, octacalcium phosphate, calcium phosphate glass, a mixture of these calcium phosphates More preferably, tricalcium phosphate is reduced to a powder, preferably 100 microns or less, using a crusher or a spray dryer. In this powder, a binder slurry, preferably a water-soluble cellulose derivative, polyvinyl alcohol, polyacrylic acid, polyacrylamide, polyvinyl pyrrolidone, polyethylene glycol, one or more aqueous solutions such as starch, more preferably polyvinyl alcohol, polyethylene glycol 3 ˜15 wt% aqueous solution is added 1 to 5 times, preferably 2 to 4 times the weight of the powder, and then stirred and mixed. At this time, similar results can be obtained even if a 10 to 50 wt% calcium phosphate slurry is used in addition to the powder.
Examples of the ceramic according to the present invention include alumina, zirconia, carbon and the like in addition to the above-described calcium phosphate ceramics.
[0006]
The above-described binder is an example, and other additives such as glycols may be added as stabilizers depending on the usage mode.
The obtained binder-containing calcium phosphate slurry is filled into a cylinder, and dropped into liquid nitrogen prepared in advance from a thin tube attached to the tip of the cylinder, preferably 0.3 to 2 mm in inner diameter.
The dropped binder-containing calcium phosphate slurry becomes spherical during dropping and on the liquid nitrogen liquid surface, and can be frozen while maintaining the spherical shape.
The resulting frozen product is lyophilized so as not to thaw, and the water is completely removed. Spherical ceramics is obtained by sintering the spherical calcium phosphate thus obtained at 800 to 1500 ° C., preferably 1000 to 1400 ° C., using an electric furnace.
The diameter of the ceramic powder obtained by the manufacturing method is 0.1 to 10 mm, but can be variously adjusted depending on the contact mode such as the dropping condition .
[0007]
In this spherical ceramic, fine small holes formed when the binder evaporates are formed in the entire spherical shape, and it is possible to impregnate a ceramic or the like into the ceramic from the small holes. The diameter of the small holes can be changed depending on the binder content. Furthermore, since the small pores can be blocked with a known calcium phosphate cement or other synthetic resin, the sustained release rate can be controlled.
The sustained release in the body can be sustained in the body fluid, for example, in units of several days or weeks, more specifically in one week to three weeks, and even in living tissue. Similar persistence is obtained.
By filling this bone-shaped ceramic into the bone defect portion, a small hole, which is one of the characteristics of the spherical ceramic, does not block the blood flow, so that the bone can be regenerated at an early stage. Further, it is more effective if the small pores are impregnated with drugs such as bone forming factor, collagen, antibiotics and the like .
As described above, good sustained-release products can be obtained by carrying various drugs, but due to excellent long-term sustained release properties, for example, penicillin antibiotics, tetracycline antibiotics, anticancer agents Five Syu, carboplatin, A drug such as cisplatin is preferably used.
[0008]
【Example】
Example 1
After mixing 1 g of calcium phosphate fine powder (# 400 mesh or less) of Ca / P = 1.48 synthesized by a known wet synthesis method into 3 g of a 10 wt% aqueous solution of polyvinyl alcohol, 0.5 g of ion exchange water was added and further mixed and stirred. The obtained slurry was filled in a Terumo syringe 10 ml and dropped onto liquid nitrogen using an injection needle 24G (inner diameter 0.47 mm). The obtained frozen product was dried using a vacuum freeze dryer and then sintered at 1400 ° C. for 5 hours to obtain 0.9 g of spherical ceramics. The obtained spherical ceramics had a diameter of 0.8 to 1.2 mm.
[0009]
Example 2
The spherical ceramics produced in Experimental Example 1 were observed with a scanning electron microscope (SEM). Two types of observation methods were used: the surface of the sample and the section of the sample.
As a result, it was confirmed that small pores of 1 to 4 micrometers were distributed over the entire surface of the sample. Then, it was confirmed from the SEM observation image of the split cross section that there was a hole of 100 to 200 micrometers inside the spherical ceramic, and the surrounding area was occupied by the calcium phosphate having a mosaic structure. (FIG. 1 (a) shows the bead surface (× 100) and FIG. 1 (b) shows the bead surface (× 1000). FIG. 2 (a) shows the bead split section (× 100) and FIG. b) shows a bead split section (× 1000).)
[0010]
Example 3
The spherical ceramic produced in Example 1 was immersed in red ink and then vacuum degassed for about 10 minutes. After returning to atmospheric pressure, it wipes the excess ink and dried by a vacuum lyophilizer. When this sample was cleaved at the center, it was confirmed that the red ink had penetrated into the ceramic. Therefore, it is possible to easily impregnate the drug only by vacuum degassing for a short time.
[0011]
[Effect of the present invention]
This production method is simple and can produce ceramics whose particle size and pore size are freely controlled in a short time. Therefore, when used as a bone filler, there is an effect of promoting bone regeneration without blocking the blood flow in the bone. Moreover, an ideal drug sustained-release carrier can be obtained by impregnating a bioabsorbable ceramic with a drug.
[Brief description of the drawings]
FIG. 1 is a scanning electron micrograph of the surface of a porous ceramic powder shown in the examples.
FIG. 2 is a scanning electron micrograph of a porous ceramic powder fractured section shown in the examples.

Claims (4)

After adding 2 to 4 times the weight of the powder to 3-15 wt% aqueous binder solution to ceramic powder of 100 microns or less, the aqueous solution obtained by stirring and mixing is dropped into liquid nitrogen and falling. Alternatively, the drug is released by forming a spherical frozen product on the surface of liquid nitrogen, freeze-drying the frozen product, and impregnating and drying the spherical ceramic particles obtained by sintering at 800 to 1500 degrees. A method of manufacturing the material . The method for producing a drug release material according to claim 1, wherein the spherical ceramic particles are impregnated with the chemical solution by vacuum degassing after being immersed in the chemical solution . The drug release according to claim 1, wherein the ceramic is calcium phosphate, preferably hydroxyapatite, tricalcium phosphate, dicalcium phosphate, tetracalcium phosphate, octacalcium phosphate, a mixture of these calcium phosphates , alumina, zirconia, or carbon. A method of manufacturing the material. Said binder is a water-soluble cellulose derivatives, polyvinyl alcohol, polyacrylic acid, polyacrylamide, polyvinyl pyrrolidone, polyethylene glycol, drug divided according to claim 1 in which selected from I one or two or more starch The production method of the release material.

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