JPH06298639A - Sustained release pharmaceutical preparation - Google Patents

Abstract

PURPOSE:To obtain a sustained release pharmaceutical preparation capable of releasing a definite amount of medicine over a long period. CONSTITUTION:This sustained release pharmaceutical preparation has plural layers containing a complex of a medicine and a biodegradable organic substance, e.g. a polymer of lactic acid, glycolic acid or lactone or a copolymer thereof or collagen and ceramics and all layers except outermost layer of the plural layers are covered by the outside layer and in a ratio of the complex in each layer of the plural layers to ceramic, the ratio of the outside layer is smaller than that of the inner layer. As the ceramics, a material having biological affinity, e.g. calcium phosphate-based compound, CaO.P2O5-based glass, alumina or zirconia is preferably used. Since a ratio of the complex is small in the outside layer having large contact area with the biological tissue, decomposition of an organic substance occurs slowly. Since a ratio of the complex is large regardless of small contact area with biological tissue also in the inner layer, the organic substance is readily decomposed and as a result, release amount of the medicine becomes definite in each layer.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a drug sustained-release preparation.

[0002]

2. Description of the Related Art A drug sustained-release preparation containing a drug and a carrier, in which the carrier is gradually decomposed in the living body to release the drug, is widely used in the medical field. For example,
For various diseases such as cancer, a drug sustained-release preparation is implanted near the affected area. In the drug sustained-release preparation, the carrier is gradually decomposed to release the drug slowly. As a result, the locally effective drug concentration is maintained, so that side effects can be significantly reduced as compared with the treatment method by systemic administration of the drug.

As a carrier used in the above-mentioned drug sustained-release preparation, a biodegradable organic substance such as polylactic acid is used. The biodegradable organic substance has a property that it is gradually decomposed in the living body and is eventually absorbed by the living body and disappears.

Conventional drug sustained-release preparations are produced by mixing such a biodegradable organic substance and a desired drug and molding the mixture into a desired shape.

[0005]

However, the drug sustained-release preparation using the above-mentioned biodegradable organic substance as a carrier is
The release characteristics of the drug depend on the degradability of the carrier. That is, the carrier is decomposed on the surface of the drug sustained-release preparation which is in contact with the living tissue, and therefore when the surface area of the drug sustained-release preparation at the initial stage of implantation is large, the amount of carrier decomposed is large and a large amount of the drug is released. However, after a long period of time after implantation, the drug sustained-release preparation is decomposed and its surface area is reduced, so that the decomposition of the carrier is reduced as compared to the initial stage of implantation and the amount of drug released is also reduced.

[0006] As described above, the conventional drug sustained-release preparations in which a biodegradable organic substance and a drug are simply combined with each other are correlated with the decomposition characteristics of the biodegradable organic substance, and the drug from the initial stage of implantation to the disappearance of the drug. The release amount of is uneven. For this reason, it is impossible to constantly release the drug in an appropriate amount that does not easily cause side effects.

The present invention has been made in view of the above points, and provides a drug sustained-release preparation capable of releasing a fixed amount of drug over a long period of time.

[0008]

The present invention has a plurality of layers containing a complex of a drug and a biodegradable organic substance and ceramics, and all layers except the outermost layer of the plurality of layers are concerned. A drug sustained-release preparation coated on one outer layer, wherein the ratio of the composite to ceramics in each of the plurality of layers is smaller in the outer layer than in the inner layer. Disclosed is a drug sustained-release preparation.

The present invention will be described in more detail below.

The biodegradable organic substance used in the drug sustained-release preparation of the present invention is, for example, a polymer of lactic acid, glycolic acid, a lactone or a copolymer thereof or collagen.

The drug is not particularly limited, but antibiotics such as gentamicin can be used. Such a drug is complexed with the above-mentioned biodegradable organic substance to form a complex.

[0012] The other component, ceramics, is, for example, a calcium phosphate compound (for example,
Hydroxyapatite, β-tricalcium phosphate), CaO
· P ₂ O ₅ based glass, alumina, those good biocompatibility of zirconia desired.

Each layer of the drug sustained-release preparation of the present invention contains a composite of the above-mentioned drug and a biodegradable organic substance and ceramics. More specifically, even if the powder or granules of ceramics are dispersed in the layer made of a composite, the powdered or granular composite is dispersed in the layer made of ceramics. It may be.

In the drug sustained-release preparation of the present invention, the layers having the above constitution are laminated. The peripheral surfaces of all layers except the outermost layer are covered with the outer layer.

The number of layers of the drug sustained-release preparation of the present invention is at least 2 or more, preferably 3 or more.

The ratio of the above-mentioned complex to the ceramics in each layer of the drug sustained-release preparation of the present invention (hereinafter, also simply referred to as occupancy rate) is smaller in the outer layer than in the inner layer.
Preferably, the occupancy rate of the complex in each layer is such that, when the drug sustained-release preparation of the present invention is implanted in a living body, the biodegradable organic substance has any value in the area in which the layer comes into contact with living tissue. Is set so that the decomposition of is almost constant between each layer.

More specifically, when the drug sustained-release preparation of the present invention is molded into a relatively simple shape such as a sphere, the relationship between the biodegradable organic substance decomposition rate in vivo and time is parabolic. Changes to. This indicates that the degradation rate depends on the change in the surface area of the drug sustained release preparation. A spherical drug sustained-release preparation having a radius R, and in the case of being composed of a central part to an n-th layer, when n is a sufficiently large numerical value, biodegradation in an arbitrary m-th layer (1 <m ≦ n) Occupancy of Organic Organic Substances v
And the distance r from the center to the m-th layer is made to satisfy the relationship shown in the following formula (1), even if the decomposition of the drug sustained-release preparation proceeds and the surface area of the drug sustained-release preparation decreases, the composite Since there is no change in the contact area between the body and the biological tissue (surface area at that time xv), the decomposition of the biodegradable organic substance is kept substantially constant.

1 / v ∝ r ² ··· (1) Therefore, in order to maintain the decomposition rate of the biodegradable organic substance, that is, the drug release amount more accurately and constant, the total number of layers n is increased. In addition, a drug sustained-release preparation satisfying the relationship of the above formula (1) may be prepared.

The shape and size of the drug sustained-release preparation of the present invention are not particularly limited, but for example, the diameter is 3 to 15 mm.
Is a substantially spherical shape. In particular, the spherical shape is preferable from the viewpoint of keeping the drug release amount constant as described above.

As described above, according to the drug sustained-release preparation of the present invention, by changing the occupancy rate of the complex in each layer, the amount of drug released when each layer comes into contact with living tissue can be easily controlled.

Next, a method for producing the above-mentioned drug sustained-release preparation of the present invention will be described. The first method first prepares a complex of drug and biodegradable organic material. For example, when polylactic acid is used as the biodegradable organic substance, the melted complex can be obtained by heating and melting polylactic acid and adding a drug thereto to dissolve or disperse it. Also,
The lactic acid-glycolic acid copolymer powder and the drug powder can be mixed at a predetermined ratio to form a powdery complex.
The latter is effective when the drug or biodegradable organic substance has low thermal stability.

Next, such a composite is mixed with powdery or granular ceramics (hereinafter simply referred to as ceramics) at a predetermined ratio and then molded into a desired shape to obtain an inner layer portion. That is, in the case of the above-mentioned melted composite, the inner layer portion can be obtained by mixing the ceramic particles with the melted composite and then casting the obtained mixture. On the other hand, in the case of the powdery composite described above, the inner layer portion can be obtained by mixing the powdery composite with the ceramic particles and then compression-molding the obtained mixture.

Thereafter, a mixture is prepared by mixing the composite and the ceramic so that the ratio of the composite to the ceramic is reduced, and the mixture is molded in the same manner as described above so as to coat the periphery of the inner layer portion. Get the outer layer.
By repeating this step a plurality of times, it is possible to obtain the drug sustained-release preparation of the present invention which has a multilayer structure and in which the ratio of the above-mentioned complex in each layer to the ceramic is smaller in the outer layer than in the inner layer.

In the second method for producing a drug sustained-release preparation of the present invention, first, a ceramic porous body having a multi-layer structure and each layer having a different porosity is produced. That is, the ceramic raw material is molded to obtain the inner layer portion having a predetermined porosity.
Then, the ceramic raw material is molded so as to cover the peripheral surface of the inner layer portion to obtain an outer layer portion having a porosity lower than that of the inner layer portion. The same operation is repeated to obtain a multilayer ceramic porous body in which the porosity decreases toward the outermost layer.

Here, for forming each layer, for example, water, a foaming agent and a bubble stabilizer are added to ceramic powder to prepare a slurry, which is cast in a predetermined mold, dried and then fired. Alternatively, a urethane foam having pores communicating with each other may be prepared, and a slurry of ceramic powder may be soaked in the urethane foam, followed by drying and firing to burn out the urethane foam. However, the method is not limited to these methods, and it is possible to apply an ordinary method for manufacturing a porous ceramic body.

The ceramic porous body obtained as described above is impregnated with a complex of a drug and a biodegradable organic substance. For example, by immersing the ceramic porous body in a molten composite of the above-mentioned drug and polylactic acid and then leaving it under reduced pressure conditions, the molten composite is soaked in the pores of the ceramic porous body, and cooled. It is possible to obtain the drug sustained-release preparation of the present invention which has a multilayer structure and in which the ratio of the above-mentioned complex in each layer to the ceramic is smaller in the outer layer than in the inner layer.

[0027]

In each layer of the drug sustained-release preparation of the present invention, a composite of a drug and a biodegradable organic substance and ceramics are combined. Therefore, when the drug sustained-release preparation is implanted in a living body, the biodegradable organic substance is gradually decomposed from the outermost layer toward the center. Since the contact area of the biological tissue is smaller than that of the complex alone, the biodegradable organic substance is less likely to be decomposed.

Further, since the outer layer has a small ratio of the composite to the ceramics, the biodegradable organic substance is decomposed slowly even though the contact area of the whole layer with the living tissue is large. On the other hand, when the inner layer comes into contact with the biological tissue, the ratio of the composite to the ceramics is larger than that of the outer layer, so the contact area of the entire layer with the biological tissue is small, but Degradation of biodegradable substances is more likely to occur than in the layer. As a result, the amount of drug released in each layer of the drug sustained-release preparation becomes substantially constant.

[0029]

The present invention will be described in detail with reference to the drawings.

Example 1 FIG. 1 is a sectional view showing an example of the drug sustained-release preparation of the present invention. In the figure, 11 is a substantially spherical first layer having a diameter of 5 mm.
The first layer 11 is composed of β-tricalcium phosphate (hereinafter referred to as β-TCP) granules 13 dispersed in a complex 12 of gentamicin which is one kind of antibiotics and poly-DL-lactic acid.
The volume occupancy rate of the composite in the first layer 11 is 80%. The mixing ratio of gentamicin and polylactic acid in the complex 12 is 1 :.
It is 1. The particle size of β-TCP granules 13 is 100.
Is about 500 μm.

A second layer 14 having a substantially spherical surface and a thickness of 3 mm is provided on the peripheral surface of the first layer 11. Second layer 1
4 is β-TCP in the composite 12 as in the first layer 11.
The granules 13 are dispersed, and the volume occupancy rate of the composite 12 is 40%.

Further, the peripheral surface of the second layer 14 has a thickness of 2 mm.
Is provided with a third layer 15 having a substantially spherical surface.
Similar to the first layer 11, the third layer 15 has β in the composite 12.
-TCP granules 13 are dispersed. The volume occupancy rate of the composite 12 in the third layer 15 is 20%.

Drug sustained-release preparation 1 having the above constitution
0 means that the volume occupancy of the composite 12 in the innermost first layer 11 to the outermost third layer 15 is 80, 40, 2 respectively.
It is 0%. Therefore, at the beginning of implantation in a living body, the outermost third layer 15 comes into contact with living tissue, but
Since the volume occupancy of the composite 12 in the layer 15 is small,
The contact area of the entire third layer with the living tissue is large, but the area of the complex 12 in the third layer 15 with the living tissue is relatively small. Therefore, poly-DL-lactic acid is slowly decomposed, and gentamicin is also released little by little.

As time elapses after the drug sustained-release preparation 10 is implanted in the living body, the inner second layer 14 comes into contact with the living tissue, but since the inner layer has a smaller surface area, the second layer The contact area between the entire layer 14 and the living tissue is small. However, since the second layer 14 has a larger volume occupancy rate of the composite 12 than the third layer 15, the area in which the composite 12 comes into contact with the living tissue is larger than that of the third layer 15, and thus the poly DL lactic acid Decomposition is likely to occur. As a result, the amount of gentamicin released in the second layer 14 becomes substantially equal to that in the third layer 15.

Also in the first layer 11, the above-mentioned second layer 14 is used.
Similarly, since the volume occupancy rate of the complex 12 is larger than that of the second layer 14 and the third layer 15, the decomposition of poly-DL-lactic acid is more likely to occur, and as a result, the release amount of gentamicin is less than that of the second layer 14 and the third layer 15. It is substantially equal to the second layer 14 and the third layer 15.

In this way, the amount of gentamicin released is kept substantially constant for a long period of time from the outermost third layer 15 to the second layer 14 to the first layer 11.

The β-TCP granules 13 left after the DL polylactic acid is decomposed and disappeared as described above are excellent in biocompatibility and are less likely to adversely affect the living body. It is absorbed by living tissues.

Next, the above-mentioned drug sustained-release preparation 10 was produced as follows. First, gentamicin was mixed with poly DL lactic acid heated and dissolved at 120 ° C. in a weight ratio of 1: 1 to obtain a molten composite.

Next, β-TCP was applied to this molten composite.
Granules (100-500 μm) were added to 20 vol% and mixed well at 120 ° C. The obtained mixture was cast into a Teflon-made split mold in which a spherical cavity having an inner diameter of 5 mm was formed. By cooling the molten composite to solidify it, a substantially spherical first layer 11 was produced.

Next, β-TCP granules were added to the molten composite so as to be 60 vol%, and well mixed at 120 ° C. to obtain a mixture. As shown in FIG. 2, the split mold 2
A small excess amount of the mixture 2 is formed in each of the hemispherical cavities 21a and 22a having a diameter of 8 mm formed on the abutting surfaces of 1 and 22, respectively.
3,24 was filled. Next, as shown in FIG. 3, the split molds 21 and 22 were butted so that the first layer 11 was located substantially in the center of the mixture 31. Then, the mixture is cooled and solidified, and the excess amount of the mixture 31a is removed, so that the second layer 15 becomes the first layer 1.
1 was molded on the peripheral surface.

Further, β-TCP granules were added to the melted composite so as to be 80 vol% and well mixed at 120 ° C. to obtain a mixture. This mixture is cast-molded on the peripheral surface of the second layer 15 using a split mold in which a spherical cavity having a diameter of 10 mm is formed in the same manner as the second layer. The third layer 1 so as to cover the peripheral surface of the layer 15.
6 was provided.

According to the method for producing the drug sustained-release preparation 10 as described above, since a predetermined amount of gentamicin is added to heat-dissolved poly-DL-lactic acid, gentamicin is added to poly-D-lactic acid.
It can be uniformly dispersed in L-lactic acid.

Example 2 FIG. 4 is a sectional view showing a second example of the drug sustained-release preparation of the present invention.

Reference numeral 40 in the figure is a drug sustained-release preparation having a substantially spherical shape with a diameter of 15 mm and having a multilayer structure. Innermost first
From the layer 41 toward the outside, the second layer 42 and the third layer 43
The fourth layer 44, which is the outermost layer, is sequentially stacked.
Each of the first to fourth layers 41 to 44 is composed of a complex 45 containing gentamicin and an L-lactic acid-glycolic acid copolymer and β-TCP granules 46. The volume occupancy of the composite 45 in each layer is 80% for the first layer and 2% for the second layer.
The layer is 50%, the third layer is 30%, and the fourth layer is 20%.

The four-layered drug sustained-release preparation 40 having such a structure has the same effect as the drug sustained-release preparation 10 of the first embodiment. Particularly, in the case of the present embodiment, since it has a four-layer structure, the drug release amount can be more accurately made constant than in the case of the three-layer structure of the first embodiment.

The above-mentioned drug sustained-release preparation 40 was manufactured as follows. First, dibekacin powder was mixed with powder of L-lactic acid-glycolic acid copolymer at a weight ratio of 1: 1 to obtain a powdery composite. To this powdery complex, β-TCP granules (100 to 300 μm) were added to the powdery complex in an amount of 20 vo
It was added so as to be 1% and further mixed well.

The mixture thus obtained was filled into a heat-resistant rubber mold having a spherical cavity with an inner diameter of 8 mm formed therein, and isotropic pressure of 1000 kg / cm ² was applied to the rubber mold. While heating at 80 ℃, compression molding,
After cooling, it was taken out from the rubber mold to obtain the first layer 41.

Next, β-TCP granules were added to the above powdery complex so as to be 50 vol% and mixed well.
The mixture was filled in a heat-resistant rubber mold having a spherical cavity having an inner diameter of 11 mm formed therein, with the first layer 41 arranged in the center thereof. After this, add 100 to this rubber mold.
While applying an isotropic pressure of 0 kg / cm ² , it is heated at 80 ° C. to form a compression film, and the second layer having a thickness of 3 mm is formed on the peripheral surface of the first layer 41.
Layer 42 was provided.

Then, following the same procedure as for the second layer 42,
70 vol% of β-TCP granules to each of the above powdery composites
And 80 vol% of the mixture were sequentially compression-molded on the second layer 42 using a heat-resistant rubber mold in which spherical cavities having inner diameters of 13 mm and 15 mm were formed. A drug sustained-release preparation 40 having a layered structure was obtained.

According to the production method of this example, it is not necessary to heat and melt the biodegradable organic substance, and the compression molding is also carried out under relatively low temperature conditions. Biodegradable organic substances having a low melting point and a high melting point can also be used.

Example 3 FIG. 5 is a sectional view showing a third example of the drug sustained-release preparation of the present invention. In the figure, reference numeral 50 denotes a drug sustained-release preparation having a substantially spherical shape with a diameter of 14 mm and having a multilayer structure. A second layer 52 and a third layer 53 are sequentially stacked from the innermost first layer 51 toward the outside. In each of the layers 51 to 53, a hydroxyapatite (hereinafter referred to as HAP) porous body 54 is impregnated with a complex 55 containing gentamicin and polylactic acid. The volume occupancy of the composite 54 in each layer is 80% for the first layer 51, 50% for the second layer 52, and 30 for the third layer 53.
%. The first layer 51 to the third layer 53 have an integrated structure.

Drug sustained-release preparation 50 having such a constitution
Has the same effect as the drug sustained-release preparation 10 of Example 1. Particularly, in the case of this example, since the HAP porous body having a multi-layer structure is integrated, even after the polylactic acid of the first layer 51 is decomposed, the HAP porous body is integrated into the living tissue. Since it remains, the drug sustained-release preparation 5 of this example is particularly used.
When 0 is used by embedding it in bone tissue, it is excellent in that HAP is self-ossified after the drug is released and good bone formation can be obtained at the implantation site.

The above-mentioned drug sustained-release preparation 50 was produced as follows. First, to 30 g of HAP powder, 15 ml of water, 3 ml of a foaming agent (polyoxyethylnonylphenol type) and 15 ml of a foam stabilizer (ammonium polyacrylate type) were added, mixed and foamed to prepare a first foaming slurry. The first foamed slurry is cast into a silicone rubber mold having a spherical cavity having an inner diameter of 7 mm and is dried and taken out from the mold, corresponding to the first layer 51. A first preform was obtained.

Next, to 30 g of HAP powder, 10 ml of water, 2 ml of a foaming agent, and 10 ml of a foam stabilizer were added and mixed to form a second foaming slurry. As shown in FIG. 6, a diameter of 11 mm formed on the abutting surfaces of the split molds 61 and 62, respectively.
The second foaming slurries 23 and 24 were filled in the hemispherical cavities 61a and 62a, respectively. Then, as shown in FIG. 7, the split molds 61 and 62 were butted so that the first preform 72 was located substantially at the center of the second foamed slurry 71. After drying, an excess amount of the dried product 7 of the second foaming slurry 7
1a was removed, and a portion corresponding to the second layer 52 was molded on the peripheral surface of the first preform 72 to obtain a second preform.

Further, to 30 g of HAP powder, 6 ml of water, 1 ml of a foaming agent and 6 ml of a foam stabilizer were added and mixed to form a third foaming slurry. This third foaming slurry is used to form a 14 mm diameter on the abutting surface of a split mold.
The third foam slurry was filled in each of the hemispherical cavities. Then, the second preform obtained in the previous step was placed at approximately the center of the third foamed slurry, and the split molds were butted. After drying, an excessive amount of the dried material of the third foamed slurry is removed, and a portion corresponding to the third layer 53 is molded on the peripheral surface of the second preformed body 72 to form a third preformed body. Got

The third preform thus obtained was calcined at 1200 ° C. for 1 hour to sinter the HAP and eliminate the foaming agent and cell stabilizer components to obtain a HAP porous body having a three-layer structure. The porosity of each layer of the HAP porous body thus produced was 80% for the first layer, 50% for the second layer, and 3 for the third layer.
It was 0%.

Next, gentamicin was heated to 120 ° C. and mixed with the dissolved polylactic acid at a weight ratio of 1: 1 to obtain a molten composite. The above HAP was added to this molten composite.
The porous body was dipped, a container containing these was housed in a closed container, and the inside of the closed container was depressurized to impregnate the molten composite in the pores of the HAP porous body. After that, the molten complex was solidified by cooling to obtain the above drug sustained-release preparation 50.

Example 4 The case where the method for producing the HAP porous body in the method for producing the drug sustained-release preparation of Example 3 was changed will be described.

First, three types of urethane foam having pores communicating with each other and having porosities of 80%, 60% and 40% respectively were prepared. By processing these urethane foams, a urethane foam processed body 81 having a three-layer structure with a diameter of 14 mm as shown in FIG. 8 was produced. Processed body 81
Is a first layer 81 having a porosity of 80%, a second layer 82 having a porosity of 60%, and a third layer 83 having a porosity of 40%.
It is composed of.

Next, 10% by weight of a deflocculant was added to the HAP powder, and then water was added and mixed to prepare a slurry having a concentration of 20% by weight. This slurry is used as a urethane foam processed body 8
Absorbed to 0. As a result, the slurry permeated into the pores 84 of the urethane foam that communicate with each other. After drying, it is baked at 1200 ° C for 1 hour to sinter the HAP and extinguish the urethane foam.
A porous body was obtained. The porosity of each layer of this HAP porous body was 80% for the first layer in the innermost layer, 60% for the second layer, and 40% for the third layer in the outermost layer.

The obtained HAP porous body was impregnated with the molten complex prepared in the same manner as in Example 3 according to the same procedure and then cooled and solidified to obtain a drug sustained-release preparation having a three-layer structure. It was In the obtained drug sustained-release preparation, the volume occupancy of the complex was 80% for the first layer, 60% for the second layer, and 40% for the third layer in the outermost layer.

The drug sustained-release preparation thus obtained is
The same effect as that of the fourth embodiment is obtained.

[0063]

INDUSTRIAL APPLICABILITY Since the ratio of the complex containing the drug and the biodegradable organic substance to the ceramics in each layer of the drug sustained-release preparation of the present invention is smaller in the outer layer than in the inner layer, it can be used in vivo. When implanted, the biodegradable organic substance decomposes almost uniformly even if the contact area between the biological tissue and the drug sustained-release preparation in the outer and inner layers is different. The release amount of the drug can be kept constant until it is released.

[Brief description of drawings]

FIG. 1 is a cross-sectional view showing a first embodiment of a drug sustained-release preparation of the present invention.

FIG. 2 is an explanatory view showing one step of a method for producing a drug sustained release preparation of the same example.

FIG. 3 is an explanatory view showing one step of the method for producing a drug sustained-release preparation of the same example.

FIG. 4 is a sectional view showing a second embodiment of the drug sustained-release preparation of the present invention.

FIG. 5 is a sectional view showing a third embodiment of the drug sustained-release preparation of the present invention.

FIG. 6 is an explanatory view showing one step of a method for producing a drug sustained release preparation of the same example.

FIG. 7 is an explanatory view showing one step of the method for producing the drug sustained release preparation of the same Example.

FIG. 8 is a cross-sectional view showing a urethane foam processed body used in another example of the method for producing a drug sustained-release preparation of the present invention.

[Explanation of symbols]

10 ... Drug sustained-release preparation, 11 ... First layer, 12 ... Complex, 1
3 ... β-TCP granules, 14 ... second layer, 15 ... third layer, 2
1, 22 ... Split mold, 23, 24 ... Mixture.

Claims (1)

[Claims] 1. A plurality of layers including a complex of a drug and a biodegradable organic substance and ceramics, and all layers other than the outermost layer of the plurality of layers are one outer layer of the layer. A coated drug sustained-release preparation, characterized in that the ratio of the composite to ceramics in each of the plurality of layers is smaller in the outer layer than in the inner layer. Formulation.