JPH03218310A - Sustained releasing granule of drug and its production - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Application The present invention relates to sustained release drug granules impregnated with a drug and a method for producing the same.

3- "Prior art and its problems" For chemotherapy, sustained-release drugs whose effects last as long as possible are desired. In particular, in recent years, transvascular chemotherapy has attracted attention as a treatment for liver tumors, etc., and sustained-release drugs effective for this therapy are being investigated.

Traditionally, sustained-release drugs used for this purpose include sponge-like particles of biologically derived substances such as gelatin impregnated with the drug, and drugs such as Lipiodol (trade name of iodinated poppy oil fatty acid ethyl ester manufactured by Kodama). Drug particles suspended in fats and oils are known.

However, with these drug particles, the particle size cannot be made constant, so the drug cannot be concentrated on the affected area, the effect is not sufficiently durable because it is easily diffused and absorbed into the living body, and it is difficult to contrast with X-rays or ultrasound. There are disadvantages such as the inability to capture the drug after administration.

Furthermore, in Japanese Patent Application Laid-Open No. 60-106459, beads of a flammable substance are coated with calcium phosphate, small holes are made in the resulting beads for filling antibiotics, and then the flammable substance is It is disclosed that a calcium phosphate filler containing an antibiotic can be manufactured by removing the pores to create hollow beads, filling the pores with the antibiotic, and then sealing the pores. However, with this method, small holes must be made in the beads, so beads with a diameter of 2 to 40 mm can only be produced, which is relatively large, and it requires extremely complicated operations such as filling the beads with antibiotics and sealing the small holes. I need.

``Object of the Invention'' The present invention provides sustained drug release granules that can control the sustained release effect by appropriately selecting porosity, pore diameter, specific surface area, etc., and that have good contrastability with X-rays and ultrasound. The purpose of the present invention is to provide a method for easily producing granules.

"Structure of the Invention" The sustained drug release granules of the present invention are baked at a temperature of 200 to 1400°C and have a Ca/P ratio of 1. 3 ~1. 8. Porosity 0. It is characterized by containing a drug in the pores of porous calcium phosphate compound granules with a specific surface area of 1 to 70%, a specific surface area of 0.1 to 50 bo/g, and a pore diameter of 1 nm to 10 μm.

Furthermore, the method for producing sustained drug release granules according to the present invention is characterized by impregnating the above porous calcium phosphate compound granules with a drug and drying them.

In the present invention, the calcium phosphate compound used as the granule Φ raw material is not particularly limited as long as it has a Ca/P ratio of 1.3 to 1.8.
The ratio is 1. 3 5 ~1. 7 5 is preferable,
More preferably, the Ca/P ratio is 1.4 to 1.7. For example, various abatites such as hydroxyapatite and fluoroapatite, tricalcium α- and β-monophosphate,
Examples include tetracalcium phosphate. The granules may contain one or more of the calcium phosphate compounds described above. The porous granules used in the present invention can be produced by methods known per se, such as a method using a blowing agent such as hydrogen peroxide, or a method in which the mixture is mixed with particles of a substance that disappears upon heating, granulated, and heated to make it porous. It can be manufactured by a method.

6 The porous granules used in the present invention have a temperature of 200 to 1400°C, preferably 500 to 1300°C, more preferably 700 to 1
It is fired at a temperature of 200"C. If the temperature is lower than 200"C, the bond between the particles will be weak and it will disintegrate in physiological saline or blood, making it unusable.On the other hand, if the firing temperature is 1
If the temperature exceeds 400°C, decomposition of calcium phosphate compounds such as hydroxy abatite occurs, which is not preferable.

The porous granules used in the present invention need to have a porosity of 0.1 to 70%. Porosity is 0. Less than 1%,
The content of the drug is too low to be practical, and if it exceeds 70%, the strength becomes weak and it becomes unusable. Granules with a porosity of 1 to 60% are preferred, and granules with a porosity of 10 to 50% are more preferred.

Furthermore, the specific surface area is 0. It needs to be 1 to 50 rrf/g. If the specific surface area is less than 0.1nf/g, the surface area to which the drug adheres is too small, resulting in a low drug content, making it impractical; if it exceeds 50n'f/g, the strength will be weakened, making it unsuitable for use. I can't stand it anymore. The specific surface area is preferably 1 to 40 rrf/g, more preferably 10 to 30 nf/g.

The porous granules used in the present invention preferably have a pore diameter of Inm to 10 μm, more preferably a pore diameter of 10 nm to 8 μm, and a pore diameter of 50 nm to 5 μm, from the viewpoint of drug retention ability. It is most preferable to have If the pore diameter is less than 1 nm, the drug cannot penetrate into the pores, and if it exceeds 10 μm, it becomes difficult for the drug to be retained in the pores, which is not preferable.

Furthermore, the particle size of the porous granules used in the present invention is lμm~
Preferably it is 10 mm. When the sustained drug release granules of the present invention are used for vascular embolization, the diameter of the capillary is 5 μm.
It is said that the inner diameter of the catheter is 1000 μm or more.
m, the granule diameter is preferably 5 to 1000 μm. Moreover, in reality, it is ideal for the granules to remain in blood vessels close to the tumor tissue, so the diameter is more preferably 5 to 500 μm, and most preferably 10 to 100 μm.

On the other hand, when the sustained drug release granules of the present invention are used as a filling material, if the particle size is less than 81 μm, it will easily diffuse in the living body and will not be eaten by macrophages etc., although it depends on the size of the defect. Cheap. In addition, the granule size is 10
When nwn is exceeded, the gaps between the granules become larger when the defect is filled, and bone regeneration occurs and the chicks form. Therefore, as a filling material, the granule diameter is preferably 1 μm to 10 mm, more preferably 5 llm to 5 rrlm, and 10 μm to 10 mm.
4 mm is most preferred. The particle size and particle size distribution can be appropriately adjusted by ceramic granulation technology.

The porous granules used in the present invention may be hollow, but the shells of the hollow granules need to have a thickness of 1/10 or more of the granule diameter. Such porous hollow granules are
It can be obtained by forming a layer of a porous calcium phosphate compound around beads of a burn-off material using a known method, and then removing the burn-off material by heating during the firing process.

The sustained drug release granules of the present invention can be produced by impregnating the above porous calcium phosphate compound granules with a drug and drying them.

In the case of liquid drugs, drug impregnation is carried out by immersing the drug as it is or in a diluent diluted with a diluent, and in the case of solid drugs, it is immersed in a drug solution dissolved or suspended in an appropriate solvent. It is done by doing. When immersing in a diluted solution or a drug solution, the concentration should be selected appropriately depending on the amount of drug that the granules are to be impregnated with, but in general, the solution should be as high as possible and the amount of drug impregnated into the granules should be controlled. It is preferable to use as many as possible.

In the present invention, the granules impregnated with the drug as described above are dried. Drying can be carried out by conventional methods, such as heating or freeze-drying. Heat drying can be performed by heating the impregnated granules in a high temperature dryer at 100° C. or lower. However, some drugs deteriorate at high temperatures, so freeze-drying is preferable. Freeze-drying can be performed by a method known per se.

For example, granules impregnated with a drug are frozen at -70°C or lower, and the frozen product is placed in a vacuum container at a temperature of 10-4 to 10-7T.
Freeze-drying can be carried out by dehydrating under reduced pressure to a vacuum degree of orr.

In the drug sustained release granules of the present invention, the drug sustained release effect can be controlled by appropriately selecting the porosity, specific surface area, and pore diameter.

Furthermore, by coating the sustained drug release granules of the present invention with a soluble organic polymer compound, the sustained drug release effect can be improved and the specific gravity of the granules can be controlled.

When drug sustained release granules are used for transvascular therapy, if their specific gravity is high, they will clog in the middle of the tube, making it difficult for them to reach the affected area where they are intended for administration. Since the calcium phosphate compound particles themselves have a higher specific gravity than water, the specific gravity of the sustained drug release granules is reduced by coating the particles with a substance that has a lower specific gravity than the calcium phosphate compound used. This makes it easier for the granules to reach the affected area.

Since it is desirable that the coated substance gradually dissolve in blood or body fluids, the organic polymer compound is preferably one that is soluble and harmless to living organisms. Examples of the organic polymer compound used include 111-albumin, dextran, coded poppy oil fatty acid ethyl ester, gelatin, carboxymethyl chitin, glycol chitin, and the like.

Coating can be performed by a method known per se.

For example, ■method by mixing dried granules and the above-mentioned organic polymer compound or its solution; ■method by spraying the organic polymer compound or its solution onto the granules; ■method by spraying the granules and their particle size. Coating can be carried out by a method such as mixing an organic polymer compound having a particle size of /10 or less, a binder and water if necessary, and then stirring at high speed. The thickness of the coating layer can be appropriately determined depending on the target specific gravity of the granules and the degree of sustained release effect.

In the present invention, the drug to be impregnated may be various kinds, such as anticancer drugs and antibiotics, and is not particularly limited.

In addition, in the administration method of the drug sustained release granules of the present invention,
Not limited to transvascular chemotherapy, local injections,
It can also be applied as an implant, filler, etc. For example, it can be applied to applications where it is desirable for the granules themselves to disappear by using a calcium phosphate-based compound with 12 higher solubility, such as tricalcium phosphate (Ca/P = 1.5),
In addition, calcium phosphate compounds with low solubility, such as hydroxyapatite (Ca/P-1.67)
If applied to bone defects, it can also function as a filling material.

"Examples of the Invention" Next, the present invention will be described in more detail based on Examples, but the present invention is not limited thereto.

Example 1 Ca/P ratio 1.67, average particle size 30 μm, porosity 50%, average pore size 90 nm, specific surface area 23. Onf/g porous hydroxyapatite granules were used. 100 mg of these granules were mixed with an aqueous solution in which 10 mg of Adriacin (an anticancer drug manufactured by Kyowa Hakko, trade name of doxorubicin sulfate, hereinafter abbreviated as ADH) was dissolved in water 2Id, and impregnated with this drug. The obtained impregnated granules were processed using MODULYO manufactured by Nippon Sanso Edwards Vacuum ■.
Freeze at a temperature of 70℃, vacuum degree 10-4 to 10-7
Freeze-dry the water by removing water with Torr, then crush the granules using an iodine-based contrast agent Conray (Daiichi Pharmaceutical ■).
A granule suspension in Lipiodol (hereinafter referred to as HAL granule (abbreviated as suspension) was produced.

Example 2 Calculated at 700°C, Ca/P ratio 1.67, average particle size 40
0μm (particle size range 300-500μm), porosity 40%
Porous hydroxyabatite granules having an average pore diameter of 80 nm and a specific surface area of 25%/g were impregnated with adriacin in the same manner as in Example 1, freeze-dried, and then crushed to obtain ADR-impregnated granules.

100 ml of a 10% dextran aqueous solution was sprayed onto 50 g of the granules while stirring in a stirrer at 30 rpm, and the mixture was dried at room temperature to a thickness of 20 to 100 μm.
Dextran-coated granules having a coating layer of m (dry state) were prepared.

Example 3 50 g of the ADR-impregnated granules prepared in Example 2 were dissolved at 70° C. under the same stirring conditions as in Example 2, and cooled to room temperature.
After spraying 100 mffi of % gelatin aqueous solution, it was dried at room temperature to produce gelatin-coated granules having a coating layer with a thickness of 50 to 200 μm (dry state).

Example 4 A mixture of 100 g of the ADH-impregnated granules prepared in Example 2 and 100 g of carboxymethyl chitin (average particle size 20 μm) was sprayed with 50 g of distilled water in a stirrer, stirred at high speed at 5000 rpm, and dried at room temperature to form a thick mixture. Sa100~300
Carboxymethyl chitin-coated granules having a coating layer of μm (dry state) were prepared.

Example 5 Calcined at 1100°C, Ca/P ratio 1.5, average particle size 20
Porous tricalcium phosphate granules of μm (particle size range 10-30 μm), porosity 40%, average pore diameter 500 nm, specific surface area 4.21'rf/15 g were impregnated with Adriacin in the same manner as in Example 1. After freeze-drying, crush A
DH-impregnated granules were obtained.

Add 50g of these granules to 10% 2% glycol chitin aqueous solution.
Mix with 0 mR, dry and crush to a thickness of 10-10
Glycol chitin-coated granules having a coating layer of 0 μm (dry state) were prepared.

Example 6 Spherical acrylic beads with an average particle diameter of 50 μm were
．． 8 μm hydroxyabatite powder with a Ca/P ratio of 1.67 was mixed in a stirrer, and then sprayed with distilled water.
Stir at high speed at 000 rpm to use acrylic beads as core,
Granules were prepared by coating this with hydroxyapatite powder and fired at 900°C to obtain hollow granules with an average particle size of 90 μm (particle size range 60 to 120 μm). These granules have a porosity of 50%, an average pore diameter of 200 nm, and a specific surface area of 14.5 r.
rf/g. ADH-impregnated granules were produced in the same manner as in Example 2 using these hollow granules.

50 g of these granules were sprayed with 100 ml of a 165% aqueous albumin solution under the same stirring conditions as in Example 2, and then dried at room temperature to produce dextran-coated granules having a coating layer with a thickness of 10 to 100 lm (dry state).

Test Example 1 The suspension of HAL granules produced in Example 1 was
g from the common hepatic artery of male Wistar rats to each rat.
．． Injected for 1 d each. Then, over time (immediately after injection,
After 6 hours, 24 hours, and 48 hours, the liver was removed.
High performance liquid chromatography (HP) was used to measure the amount of ADR in the liver.
The results were obtained as shown in Table 1 and FIG. 1. Note that there were 5 rats in each group. Further, the ADR amount is expressed as a residual rate, with the concentration of ADR in the liver taken as 100% from the value immediately after injection.

Test example 2 This example is a comparative example.

For comparison, a mixture of ADH 10■ and Conray IId (hereinafter abbreviated as ADH mixture) was injected in the same manner, and ADH 10■ suspended in Libiodol 1 relative and Conray 1D (hereinafter referred to as ADH mixture). (abbreviated as ALC)
The ADR amount was also measured in the case of injection, and the results are shown in Table 1 and Figure 1.

Table 1 ADR residual rate in liver tissue From the results shown in Table 1, the suspension of HAL granules has the highest residual rate of ADH in liver tissue, which is as high as 49.8% 6 hours after injection. It can be seen that the sustained release effect of the drug is significantly improved compared to the conventional method.

Test Example 3 This example shows that liver dysfunction is alleviated by using a suspension of HAL granules according to the present invention. For comparison, the ADH mixture and ALC used in Test Example 2 were used.

When the common hepatic artery of Wistar rats was ligated and each drug was injected, changes in serum GOT (aspartate aminotransferase) and GPT (alanine aminotransferase) over time were measured, and the results are shown in Figures 2 and 3, respectively. Shown in Table 2.

As a control, GOT and GPT are shown when only the hepatic artery was ligated and nothing was injected.

Table 2 Highest GOT and GPT values From the results in Table 2, when the suspension of HAL granules of the present invention is used, liver dysfunction is significantly milder than when conventional ALC is used. I understand that. This appears to be because the hydroxyabatite used as the material for the granules is a biocompatible substance 19 and because the particle size of the granules could be adjusted to be equal to or slightly larger than the blood vessel size.

Example 7 Calcined at 700°C, Ca/P ratio 1.67, particle size 300~
500μm, porosity 40%, average pore diameter 80nm, specific surface area 25n? /g of porous hydroxy abatite granules (used in Example 2) 50g in brown ink (Recorder ink manufactured by Chugai Kasei ■) 50m! After placing the granules in the container and impregnating them with a dye, water was removed in a constant temperature dryer at 50° C. to produce dye-impregnated granules (referred to as granules A).

These granules were coated with dextran in the same manner as in Example 2 to produce dextran-coated granules (referred to as granules B).

Example 8 Using 50 g of the dye-impregnated granules prepared in the same manner as in Example 7, gelatin-coated granules (referred to as granules C) were prepared in the same manner as in Example 3.

Example 9 Carboxymethyl chitin-coated granules (referred to as granules D) were prepared in the same manner as in Example 4 using 100 g of the dye-impregnated granules 20 prepared in the same manner as in Example 7.

Example 10 Dye-impregnated granules were obtained in the same manner as in Example 7 using the same tricalcium phosphate granules as used in Example 5. 50 g of these granules were coated with glycol chitin in the same manner as in Example 5 to produce glycol chitin-coated granules (referred to as granules E).

Example 11 Dye-impregnated granules were obtained in the same manner as in Example 7 using the hydroxyapatite hollow granules prepared in Example 6. These granules were coated with albumin in the same manner as in Example 6, resulting in albumin-coated granules (referred to as granules F).
was created.

Test Example 4 1 g of each of the granules A to F produced in Examples 7 to 11 was placed in a dialysis tube (Seamless Cellulose Tubing 8/32, manufactured by VISKASE SALES), and both ends of the tube were tied with thread and then closed. , distilled water 20
The mixture was placed in a beaker containing 0 mft and stirred with a stirrer. After 1 hour, the amount of ink dissolved in distilled water was
Measurements were taken after hours, 6 hours, 12 hours and 24 hours.

The amount of ink eluted from the granules can be determined by taking out the tube containing the granules after each period of time, evaporating the water in the beaker, and adding 10 d of distilled water to dissolve the ink in water again. The concentration of the ink was measured as the transmittance of light at a wavelength of 620 nm using a spectrophotometer (UV-10001 manufactured by Shimadzu Corporation). Note that the light transmittance of distilled water was set as 100%.

For comparison, dye 1, which is estimated to be impregnated per 1 g of granules, was put into a dialysis tube in the same way as the granules, and 2
The sample was placed in a beaker containing 0.0 ml of distilled water, stirred with a stirrer, and the amount of ink eluted into the water was measured in the same manner as described above, and this was used as a control.

The measurement results are shown in Figure 4.

The results show that the impregnated porous calcium phosphate granules slowly release the dye into the water, the dye concentration in the water gradually increases, and the light transmittance gradually decreases. That is, the drug-impregnated porous calcium phosphate granules of the present invention have a drug sustained release effect. Furthermore, it has been found that granules coated with an organic polymer compound have a more gradual drug sustained release effect, although this depends on the coating material and the structure of the granules.

In the above Examples and Test Examples, hydroxyabatite and tricalcium phosphate were used as calcium phosphate compounds, but it is clear that similar effects can be achieved using other calcium phosphate compounds.

"Effects of the Invention" The sustained drug release granules of the present invention can be easily produced by the method of the present invention, and have excellent sustained drug release properties because the pores of the porous granules are impregnated with the drug. ing. Since the particle size, particle size distribution, porosity, specific surface area, pore size, etc. can be controlled as necessary, the sustained release effect can be controlled. Furthermore, since granules of a calcium phosphate compound are used, they are harmless to living organisms, have excellent contrast properties with X-rays and ultrasound, and have the advantage of being easy to capture after administration. Furthermore, by coating with an organic polymer compound, the sustained release effect can be improved and the specific gravity can be adjusted, and it can also be suitably applied to transvascular embolization therapy.

In addition, the drug sustained release granules of the present invention can be impregnated with various drugs and administered in various administration methods, in addition to transvascular embolization therapy.If a highly soluble calcium phosphate compound is used, It is suitable for applications where it is desirable for the granules themselves to disappear, and if a calcium phosphate compound with low solubility is used and applied to bone defects, it can also function as a filler.

[Brief explanation of drawings]

Figure 1 is a graph showing changes over time in the residual rate of ADR in liver tissue, Figure 2 is a graph showing changes over time in serum GOT concentration, Figure 3 is a graph showing changes in serum GPTI level over time24, and Figure 4 is a graph showing changes in serum GPTI level over time. It is a graph showing the change over time in the light transmittance of an aqueous solution of a dye eluted from a dialysis tube. Explanation of symbols ○...HAL granules, ●...ALC, ▲...ADR
Mixture, ■... control

Claims (14)

[Claims] (1) Ca/P calcined at a temperature of 200 to 1400°C
Ratio 1.3-1.8, porosity 0.1-70%, specific surface area 0
．． A drug sustained release granule containing a drug in the pores of porous calcium phosphate compound granules with a pore size of 1 to 50 m^2/g and a pore diameter of 1 nm to 10 μm. (2) The sustained drug release granule according to claim 1, which has a particle size of 1 μm to 10 mm. (3) The sustained drug release granule according to claim 1, which is hollow and contains the drug also in the hollow space. (4) The sustained drug release granule according to claim 1 or 2, which has a coating layer made of a soluble organic polymer compound. (5) The organic polymer compound is albumin, dextran,
The drug sustained release granules according to claim 4, which are iodized poppy oil fatty acid ethyl ester, gelatin, carboxymethyl chitin, or glycol chitin. (6) Ca/P calcined at a temperature of 200 to 1400°C
Ratio 1.3-1.8, porosity 0.1-70%, specific surface area 0
．． Porous calcium phosphate compound granules with a size of 1 to 50 m^2/g and a pore size of 1 nm to 10 μm are impregnated with a drug,
A method for producing sustained drug release granules, characterized by drying. (7) freezing the impregnated granules at a temperature of -70°C or lower,
7. The method for producing sustained drug release granules according to claim 6, wherein the frozen product is lyophilized by dehydration at a reduced pressure of 10^-^4 to 10^-^7 Torr. (8) Produce granules with a hollow structure by coating beads of a burnable substance with porous calcium phosphate compound particles, heating the coated beads to remove the burnable substance, and impregnating the granules with a drug. 7. The method for producing sustained drug release granules according to claim 6. (9) Claim 6: Producing granules with a particle size of 1 μm to 10 mm.
A method for manufacturing the drug sustained release granules described above. (10) The method for producing sustained drug release granules according to claim 6, wherein the dried granules are coated with a soluble organic polymer compound. (11) The method for producing sustained drug release granules according to claim 10, wherein the coating is performed by mixing with a soluble organic polymer compound or an aqueous solution thereof. (12) The method for producing sustained drug release granules according to claim 10, wherein the coating is carried out by spraying a soluble organic polymer compound or an aqueous solution thereof. (13) A claim in which coating is performed by mixing dry granules, an organic polymer compound with a particle size of 1/10 or less of the particle size, and optionally a binder and water, and then stirring at high speed. Item 11. The method for producing sustained drug release granules according to item 10. (14) The method for producing sustained drug release granules according to claim 10, wherein albumin, dextran, iodized poppy oil fatty acid ethyl ester, gelatin, carboxymethyl chitin, or glycol chitin is used as the organic polymer compound.