JP3104043B2 - Heterogeneous structure drug release device - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a drug release device having a heterogeneous structure for releasing a drug over a long period of time. The present invention also relates to a heterogeneous structure drug release device capable of controlling the blood concentration of a drug in response to a change in disease symptoms, that is, releasing a drug in response to a change in disease symptoms such as inflammation.

[0002]

2. Description of the Related Art Conventionally, a drug release device in which a biodegradable polymer material is used as a carrier (matrix) and a drug is dispersed in the carrier is known. In a conventional drug release device, a polymer material is decomposed by hydrolysis in a living body to release a drug. The polymer materials are all hydrophobic because it is necessary to control the rate of water intrusion in controlling the rate of hydrolysis.
However, the decomposition of the hydrophobic polymer material is a so-called bulk decomposition that proceeds throughout the polymer material, and cracks and destruction occur at the same time as the decomposition, and there is a disadvantage that the surface area changes significantly. However, it was impossible to release a drug based on the biodegradation of a polymer material. Therefore, it has been difficult to release the drug for a long time and in a controlled manner based on its degradability after implantation in a living body.

[0003] Drug delivery systems that control the drug concentration in the blood in response to changes in disease symptoms have also been known. As one method, use of a substance having a property of degrading in vivo in response to a signal emitted by a living body based on a symptom, as a carrier, and releasing a drug in accordance with the decomposition has been studied. Until now, various polymeric substances have been studied as substances that control drug release in response to temperature, hydrogen ion concentration (pH), etc. as in vivo stimuli.
All of these drug release controls are intended to change the diffusion or solubility of a drug by a polymer substance. However, in general, these biodegradable polymer substances are all degradable by hydrolysis, as described above, and thus it is impossible to control the degradability in the living body ON-OFF. Furthermore, such a biodegradable polymer substance has a very slow hydrolysis rate as compared to the rate of water intrusion into the polymer substance material. Therefore, it is extremely difficult to control the amount of drug release, because of the influence of the change in the surface area due to the change in the shape (crack formation, breakage, etc.) accompanying the above. Therefore, control of stimulus-responsive drug release by a biodegradable polymer substance was practically impossible.

[0004]

DISCLOSURE OF THE INVENTION The present invention relates to a drug capable of releasing a drug over a long period of time in a controlled manner based on the degradability of the polymer material after implantation in a living body using the polymer material as a carrier. It is another object of the present invention to provide a release device having a function of controlling release of a drug in response to a stimulus.

[0005]

Means for Solving the Problems The biodegradable polymer substances used in conventional drug carriers are all hydrophobic as described above. Various studies were conducted on the use of polymer materials that decompose by a mechanism other than bulk decomposition, in which the whole proceeds in a uniform manner, and came up with the idea of using a hydrophilic polymer gel, which decomposes only from the surface, as a carrier. Using a molecular gel as a carrier, a drug is contained in microspheres, stabilized and then dispersed to form an inhomogeneous structure, so that the drug can be released over a long period of time, and the drug is released due to surface degradation of the polymer material. The product of the present invention in which the release can be rate-controlled has been completed.

Further, the present inventors, as a hydrophilic polymer gel used for the above carrier, decompose only from the surface by the action of hydroxyl radicals, which are active oxygens that are generated temporarily during inflammation as biospecific signals. When a hydrophilic polymer gel is used, the decomposition of the hydrophilic polymer gel is performed in response to inflammation, so that the release of the drug can be controlled in accordance with the decomposition, that is, the release of the drug is controlled by the amount of hydroxyl radicals generated. Knowing that it is possible, the present invention has been completed.

That is, the present invention is a drug release device having a heterogeneous structure, characterized in that a hydrophilic polymer hydrogel which decomposes from the surface is used as a carrier and a drug-containing microsphere is dispersed in the carrier (claim 1). In addition, there is provided a drug release device with a heterogeneous structure in which the hydrophilic polymer hydrogel decomposed from the surface is a hydrophilic polymer hydrogel decomposed from the surface by the action of hydroxyl radical (Claim 2).

The present invention will be described in more detail. In general, biodegradation of a polymer material is known to be a bulk decomposition system in which the decomposition of the entire polymer material proceeds uniformly, a surface decomposition system in which the decomposition proceeds only from the surface of the polymer material, and a mixed system of both. ing. In order to quantitatively and temporally control the biodegradability of a polymer material in vivo, the surface degradability of the material is indispensable.
Therefore, in the device of the present invention for releasing a drug having a heterogeneous structure, a surface-degradable polymer material in which the decomposition proceeds only from the surface is used. Thus, if the drug-containing microspheres are dispersed in a hydrophilic polymer hydrogel whose decomposition proceeds from this surface to form a so-called heterogeneous structure, the carrier is synchronized with the decomposition of the hydrophilic polymer hydrogel from the surface. Thus, the drug can be released at a rate. Therefore, by controlling the surface degradation of the hydrophilic polymer hydrogel, the release of the drug can be controlled.

Thus, in the heterogeneous structure drug release device of the present invention, a hydrophilic polymer hydrogel whose surface is decomposed over a long period of time is selected, or its surface is decomposed over a long period of time. , A drug release device capable of releasing a drug over a long period of time is obtained. Also, when a hydrogel whose surface degradation is performed in response to a certain stimulus is selected as the hydrophilic polymer hydrogel, a drug release device that releases a drug in response to the stimulus is obtained. For example,
In inflammation, it is already known that active oxygen is transiently generated from leukocytes and macrophages, and this is a cause of various tissue disorders, but it shows surface degradability by the action of active oxygen. That is, when a polymer hydrogel that specifically exhibits surface degradability due to the action of hydroxyl radical is used as a carrier, a drug release device that releases a drug in response to inflammation can be obtained.

[0010] The hydrophilic polymer hydrogel which decomposes from the surface used in the present invention may be a water-soluble polysaccharide such as cross-linked hyaluronic acid, dextran or carboxymethyl chitin, or a hydrophilic polymer such as polyethylene glycol or polyvinyl alcohol. It is a polymer. Here, the crosslinking agent used for crosslinking is
For example, polyethylene glycol diglycidyl ether,
Polyfunctional glycidyl ethers such as polyglycerol polyglycidyl ether; and polyfunctional isocyanates such as triisocyanate. All of these hydrophilic polymer hydrogels are those in which the surface is decomposed in vivo by enzymes or the like over a long period of time, and are specifically decomposed in a short time by hydroxyl radicals. The hydrophilic polymer hydrogel has a gel water content of about 30 to 99.9%, preferably 50 to 9%.
9.8%.

[0011] In addition, when a drug is released by decomposition from the surface of the hydrophilic polymer hydrogel, the drug release is controlled quantitatively and temporally. In consideration of prevention, it is desirable that the drug is not uniformly dissolved in the gel and a domain containing a high concentration of the drug is formed. It is desirable that the drug-containing domain be rapidly absorbed or decomposed after being released into a living body. Therefore, in the present invention, the drug is made into a microsphere-containing form and dispersed in the hydrophilic polymer hydrogel.

In the present invention, the drug-containing microsphere dispersed in the hydrophilic polymer hydrogel is a particle having hydrophilicity-hydrophobicity, stability, and biocompatibility necessary for supporting the drug therein, For example, a bio-absorbable polymer bead is conceivable, but lipid-soluble drugs such as lipid microspheres and water-soluble drugs such as ribosomes are desirable. The size (particle size) of the microspheres distributed in the hydrophilic polymer hydrogel varies depending on the drug release pattern, but is usually from 0.1 μm to 10 mm, preferably from 1.0 μm to 10 μm. It is about 100 μm. Although the microsphere concentration depends on the particle size, it is 1 to 5
It is about 0%, preferably about 5 to 10%. And
It is possible to change the drug release pattern depending on the size of the microsphere.

In the present invention, various methods can be employed to disperse the drug-containing microspheres in the polymer hydrogel that decomposes from the surface. A water-soluble polysaccharide such as hyaluronic acid, dextran, carboxymethyl chitin or a hydrophilic polymer such as polyethylene glycol and polyvinyl alcohol is dissolved in water to prepare an aqueous solution, and the drug-containing microspheres are contained in the aqueous solution. Is added and dispersed well, and then a crosslinking agent as described above is added to cause a crosslinking reaction of the water-soluble polymer to form a hydrogel.

FIG. 1 shows a heterogeneous structure drug release device of the present invention in which a hydrophilic polymer hydrogel which is specifically surface-degradable by hydroxyl radicals is used as the hydrophilic polymer hydrogel. It is a schematic diagram for explaining the operation of the discharge device. 1 is a device for drug release with a heterogeneous structure of the present invention. Reference numeral 2 denotes a hydrophilic polymer hydrogel that specifically exhibits surface degradability by hydroxyl radicals, and 2 ′ denotes a decomposition product thereof. 3 is a microsphere containing a drug. Now, when inflammation occurs in a living body, active oxygen is temporarily generated from leukocytes and macrophages. This active oxygen comes into contact with one surface 4 of the heterogeneous structure drug release device 1 administered in the living body (FIG. 1,
a) and the action of this active oxygen causes the hydrophilic polymer hydrogel constituting the drug release device 1 having a heterogeneous structure to decompose from the surface. Then, with the decomposition, the drug-containing microspheres are released from the hydrophilic polymer hydrogel and released (FIG. 1, b).

As described above, in the present invention, when the hydrophilic polymer hydrogel is decomposed from the surface, the dispersed drug-containing microspheres are released at a rate synchronized with the decomposition. This is because the drug is not simply dissolved or dispersed in the hydrophilic polymer hydrogel, but is contained in microspheres and dispersed in the gel to form a heterogeneous device. Drug release corresponding to the time of non-decomposition becomes possible. In addition, the use of the heterogeneous drug release device of the present invention is expected to eliminate cell damage caused by active oxygen generated during inflammation and to exert anti-inflammatory action by steroid hormones released in synchronization with degradation. it can.

In the conventional biodegradable drug release system, the drug release is greatly affected by drug solubility such as water solubility and fat solubility. In the present invention, however, the drug is contained in microspheres. Since it is dispersed in the surface-degradable hydrophilic polymer hydrogel afterwards, the drug release rate can be regulated without being affected by drug properties such as drug solubility. Furthermore, conventionally, the degradation mechanism of a biodegradable material is by hydrolysis, and the rate is lower than the rate of water infiltration into the material. Is contained in microspheres and then dispersed in a biodegradable material to maintain drug activity until released. Also in the present invention, since the drug is contained in the microsphere and dispersed in the surface-degradable hydrophilic polymer hydrogel, the drug activity can be maintained until the drug is released by hydrogel decomposition.

[0017]

Next, the present invention will be described in more detail with reference to Examples and Examples. Reference Example 1 (Production of Hydrophilic Polymer Hydrogel) 1.0 g of hyaluronic acid (estimated molecular weight of about 1 million) was dissolved in 4.5 ml of a 1 N aqueous sodium hydroxide solution, and sufficiently degassed with an aspirator. 0.22 g of ethylene glycol diglycidyl ether was dissolved in 0.5 ml of ethanol, and this was quickly mixed with a hyaluronic acid solution and quickly injected into a 2 mm thick spacer. This is 6
The mixture was allowed to stand in an oven heated to 0 ° C. for 15 minutes to cause a crosslinking reaction. The crosslinked gel was immediately transferred to a 50% aqueous ethanol solution and neutralized by dropwise addition of hydrochloric acid. The gel was further replaced three times with fresh ethanol aqueous solution. The obtained gel was colorless and transparent, and its water content was 99.85% (HA1).

Reference Example 2 (Production of Hydrophilic Polymer Hydrogel) 1.0 g of hyaluronic acid (estimated molecular weight: about 1 million) was dissolved in 4.5 ml of a 1 N aqueous solution of sodium hydroxide and sufficiently degassed with an aspirator. did. 0.65 g of ethylene glycol diglycidyl ether was dissolved in 0.5 ml of ethanol, and this was quickly mixed with a hyaluronic acid solution and quickly injected into a 2 mm thick spacer. This is 6
The mixture was allowed to stand in an oven heated to 0 ° C. for 15 minutes to cause a crosslinking reaction. The crosslinked gel was immediately transferred to a 50% aqueous ethanol solution, and neutralized by dropwise addition of hydrochloric acid. The gel was further replaced three times with fresh ethanol aqueous solution. The obtained gel was colorless and transparent, and its water content was 99.48% (HA
3).

Reference Example 3 (Production of Hydrophilic Hydrogel) 1.0 g of hyalonic acid (estimated molecular weight: about 1 million) was dissolved in 5.0 ml of a 1N aqueous solution of sodium hydroxide to give an aspirate.
It was sufficiently degassed by a tar. The polyglycerol polyglycidyl ether was quickly mixed with the hyaluronic acid solution, degassed, and then quickly injected into a 2 mm thick spacer. This was left standing in an oven heated to 60 ° C. for 15 minutes to cause a crosslinking reaction. The crosslinked gel was immediately transferred to a 50% aqueous ethanol solution, and neutralized by dropwise addition of hydrochloric acid. The gel was further replaced three times with fresh ethanol aqueous solution. The resulting gel was pale white and had a water content of 99.54% (HA9).

Reference Example 4 (Production of Hydrophilic Polymer Hydrogel) 4.0 g of dextran (estimated molecular weight: about 200,000) was dissolved in 18.0 ml of 1N aqueous sodium hydroxide solution, and sufficiently degassed with an aspirator. . 1.92 g of ethylene glycol diglycidyl ether was added to 2.0 m of ethanol.
dextran solution, and mix it quickly with the dextran solution.
It was quickly injected into a 2 mm thick spacer. This was left standing in an oven heated to 60 ° C. for 15 minutes to cause a crosslinking reaction. The crosslinked gel was immediately transferred to a 50% aqueous ethanol solution, and neutralized by dropwise addition of hydrochloric acid. The gel was further replaced three times with fresh ethanol aqueous solution. The obtained gel was further replaced three times with a new aqueous ethanol solution. The resulting gel is colorless and translucent and has a water content of 85.40%.
(DEl).

EXAMPLE 0.45 g of hyaluronic acid (estimated molecular weight of about one million) was added to 0.1 g of hyaluronic acid.
Dissolve in 2.25 ml of 5N aqueous sodium hydroxide solution,
It was sufficiently degassed by an aspirator. In addition, a lipid preparation for intravenous injection (Otsuka Pharmaceutical, trade name: Intralipid, concentration 20% by weight) 400 as a lipid microsphere
μl was added and mixed well. Further, 0.61 g of polyglycerol polyglycidyl ether was added, and the mixture was quickly mixed and degassed. Then, the mixture was quickly poured into a spacer having a thickness of 2 mm. This was left standing in an oven heated to 60 ° C. for 15 minutes to cause a crosslinking reaction. The crosslinked gel is then immediately
The mixture was transferred to a 0% aqueous ethanol solution, and neutralized by dropwise addition of hydrochloric acid. The gel was further replaced three times with fresh ethanol aqueous solution. The resulting gel is pale white and has a water content of 99.
69% (HA10).

(Physical Property Test of Hydrophilic Polymer Hydrogel and Product of the Present Invention) The hydrophilic polymer hydrogels (HA1, HA3) obtained in Reference Examples 1 and 2 were cut into cubes each having a size of 7 × 7 × 7 mm to prepare samples. Each of these was immersed in a 5 mM aqueous solution of FeSO ₄ for 2 days,
Each of the solution was placed in 100 ml of an aqueous solution of H ₂ O _{2 of} 500 μM or 500 μM, and stirred with a stirrer.
Was analyzed over time. The hydrophilic polymer hydrogel decomposed in several minutes to several tens of hours, and as can be seen from FIGS. 2 and 3, the decomposition was consistent with the rate equation assuming surface decomposition. Also this rate of degradation, based on the rate equation was calculated to ^{10 ~ 5 ~10 ~ 4 cm /} sec about (see Table 1). These hydrophilic polymer hydrogels are Fe Fe
The hydrophilic polymer hydrogel was not decomposed unless pre-treated with an aqueous solution of SO ₄ , indicating that the surface of the hydrophilic polymer hydrogel was decomposed by hydroxyl radicals.

[0023]

[Table 1]

2. The hydrophilic polymer hydrogel (HA3) obtained in Reference Example 2 was cut into a size of 20 × 20 × 6 mm to prepare three samples. 5 mM FeSO each
₄ Dipped in the aqueous solution for 2 days. One of these samples was
First, the operation of immersing in 100 ml of purified water for 3 minutes and then immersing in 100 ml of a 1 mM H ₂ O ₂ aqueous solution for 3 minutes was repeated several times, and the weight change of the gel during this operation was measured. The other two samples were operated in the same manner except that 100 ml of a ₂ mM and 10 mM H ₂ O ₂ aqueous solution was used instead of the 1 mM H ₂ O ₂ aqueous solution, and the weight change of each gel was measured. FIG. 4 shows the results. Crosslinked gels show significant weight loss only in aqueous H ₂ O ₂ , and the weight loss is affected by H ₂ O ₂ concentration. This crosslinked gel is FeSO ₄
Since it does not decompose unless pre-treated with an aqueous solution, ON-OFF of decomposition in response to the generation of hydroxyl radicals
Is controlled.

3. The hydrophilic polymer hydrogel (HA3) obtained in Reference Example 2 was cut into a size of 7 × 7 × 7 mm,
Further, the product of the present invention (HA10) obtained in the above example was 20 × 1
A sample was prepared by cutting into a size of 0 × 1.8 mm. Each of these samples was placed in a 0.14 M phosphate buffer (pH 7.4) of bovine testicular hyaluronidase at a predetermined concentration, and the mixture was stirred with a stirrer at 37 ° C. Was analyzed. Table 2 shows the results. The gel is decomposed over several hours to several tens of days, and it can be confirmed that the decomposition is surface decomposition, and the decomposition rate is 10 to ⁶ to 10
It was calculated to be ~ ⁸ cm / sec. Under the same conditions, it was also confirmed that uncrosslinked hyaluronic acid was decomposed within a few minutes, indicating that the hyaluronic acid crosslinked gel (HA) had high resistance to hyaluronidase. Furthermore,
Comparing the hyaluronidase degradability of HA3 and HA10, the degradation rate of HA10 was low under the same conditions, indicating that the crosslinker of the crosslinker had the same water content and the same amount of hyaluronic acid even under the same conditions. It was found that the hyaluronidase resistance in vivo could be improved by controlling the crosslinked structure of the gel by the structure.

[0026]

[Table 2]

4. The hydrophilic polymer hydrogel (DE1) obtained in Reference Example 4 was cut into a cube having a size of 7 × 7 × 7 mm, and dextranase at a predetermined concentration in a 0.14 M phosphate buffer (pH 7.4). The mixture was stirred at 37 ° C. with a stirrer, and the change in gel weight was analyzed over time. The crosslinked gel degraded over several days to tens of days depending on the dextranase concentration. FIG. 5 shows the results of the dextran crosslinked gel decomposition. This result was in good agreement with the theoretical formula assuming that the degradation was surface-degradable, which confirmed the surface-degradability of the dextran crosslinked gel. FIG. 6 illustrates this. The decomposition rate was 2.6 × 10 to ⁸ and 8.8 × 10 to ⁸ cm at dextranase concentrations of 1.5 and 15 unit / ml, respectively.
/ Sec. In addition, under the same conditions, it was confirmed that uncrosslinked dextran decomposed within a short time,
Dextran cross-linked gel was shown to have high resistance to dextranase. This indicates that the dextran cross-linked gel is a polymer hydrogel that degrades from the surface in vivo over a long period of time, and is useful as a microsphere-containing heterogeneous device.

5. The product of the present invention (HA1
0) was cut into a plate having a size of 20 × 10 × 1.8 mm, and 0.14 M phosphate buffer solution of bovine testicular hyaluronidase at a predetermined concentration (2.4 u / ml, 23 u / ml) ( p
H7.4), the mixture was stirred with a stirrer at 37 ° C., and the gel degradability and microsphere release at that time were analyzed over time by measuring the weight change of the gel and measuring the turbidity of the solution. As shown in FIG. 7, the gel decomposes at a constant rate over several hours to several tens of hours depending on the concentration of hyalonidase, and as shown in FIG. 8, the microsphere release at that time also proceeds at a constant rate in synchronization with the decomposition. Was done. This indicates that the microspheres in the product of the present invention were released at a rate limited by the surface decomposition of the gel.

6. The hydrophilic polymer hydrogel (HA3) obtained in Reference Example 2 was cut into a cube having a size of 7 × 7 × 7 mm, and this was put into rabbit platelet poor platelet plasma and stirred at 37 ° C. with a stirrer. The change in gel weight was analyzed over time. Immediately after immersion (at least one hour later)
% Weight loss, after which the weight did not change until after 160 hours. The crosslinked gel of hyaluronic acid is an electrolyte gel and contracts due to ionic strength, but the weight loss in this case is considered to be due to this. Therefore, it is understood that this hyaluronic acid crosslinked gel has high resistance to plasma components.

7. The hydrophilic polymer hydrogels (HA3, HA9) obtained in Reference Examples 2 and 3 were cut into a size of 20 × 10 × 2 mm, wet-sterilized at 120 ° C. for 60 minutes, and measured for gel weight and carbazole for each. Hyaluronic acid was determined by the method. In the case of HA3, the weight increase and the decrease in the amount of hyaluronic acid were observed by the above sterilization.
% Of hyaluronic acid was decomposed, whereas HA
In No. 10, no significant difference was observed in both the weight and the amount of hyaluronic acid from before sterilization. This indicates that even when the crosslinked gels have the same water content and hyaluronic acid content, the behavior during sterilization differs depending on the type of the crosslinking agent used for crosslinking.

8. The hydrophilic polymer hydrogel (HA9) obtained in Reference Example 3 was implanted subcutaneously in the back of a healthy rat, and the in vivo stability was examined. Under anesthesia by intraperitoneal injection of pentobarbital, the back of a male Wistar rat (5 weeks old) was incised, and a 20 × 10 × 1.8 mm crosslinked gel (HA10) was inserted therein. No. silk suture. Although the insertion gel was not particularly fixed, the connective tissue between the incision site and the gel was sutured at two places with nylon 5 thread so that the gel did not move to the incision suture site, and then the incision site was sutured. After a certain period of the implantation, the rats were euthanized by intraperitoneal injection of a large amount of pentobarbital, and then the implanted gel was excised from the subcutaneous area, and the amount of the remaining gel was immediately determined by the carbazole method. Further, after a certain period of time, the skin adjacent to the buried site was surgically incised, a wound caused by surgical invasion was applied to cause inflammation, and one week later, the skin was excised from the skin and the amount of the remaining gel was similarly quantified.

About 20% of the hyaluronic acid crosslinked gel was decomposed in about one week after the operation, but thereafter, it was relatively stable for a long period of time, and about 70% of the gel remained in each case. In any case, no effect on connective tissue around the gel implant was observed at all by visual observation. In addition, by injecting the rat with the wound, the implanted gel can be further reduced to about 20%.
% Decomposed (FIG. 9). This indicates that about 20% of the cross-linked hyaluronic acid gel was decomposed immediately after implantation in response to wound healing at the back incision site, and about 20% was further decomposed due to external inflammation. confirmed. From the above, it is considered that this crosslinked gel of hyaluronic acid is extremely stable under normal conditions and decomposes for a long period of time, but is decomposed immediately in response to hydroxyl radicals generated during inflammation.

[0033]

The drug release device of the present invention has a hydrophilic polymer hydrogel that decomposes from the surface as a carrier, and a drug-containing microsphere dispersed in the carrier to form a heterogeneous structure. The release of the drug can be rate-controlled in synchronization with the decomposition from the surface of the polymer hydrogel.
Therefore, by controlling the surface degradation of the hydrophilic polymer hydrogel, the release of the drug can be controlled. That is, when a hydrophilic polymer hydrogel whose surface degradation is performed over a long period of time is selected, or when the surface decomposition is controlled to be performed over a long period of time, drug release that can release a drug over a long period of time is performed. Device is obtained. In addition, when a polymer hydrogel that specifically exhibits surface degradability due to the action of hydroxyl radicals generated temporarily in inflammation is used as a carrier, a drug that releases a drug in response to inflammation An emission device is obtained.

Therefore, the heterogeneous structure drug release device of the present invention can release a drug over a long period of time, and can control the amount of drug release in response to the degree of symptoms such as inflammation. Furthermore, it has high resistance to plasma components, has good in vivo stability, can be implanted for a long time, can maintain the activity of the bioactive drug high until the time of release, and at the time of biological signal generation-non-generation The drug release can be controlled ON-OFF in response to the limited surface degradation of the gel. Further, since the amount of drug release due to the decomposition of the polymer hydrogel can be regulated by the surface area of the gel, the amount of drug release can be predicted as a function of the surface area from the initial stage to the end stage of the degradation.
Thus, the heterogeneous structure drug release device of the present invention is extremely useful.

[Brief description of the drawings]

FIG. 1 is a model diagram showing the action of a device for drug release with a heterogeneous structure of the present invention.

FIG. 2 is a graph showing the degradability of a hyaluronic acid crosslinked gel by hydroxyl radicals.

FIG. 3 is a graph showing a decomposition rate of a hyaluronic acid crosslinked gel by a hydroxyl radical.

FIG. 4 is a graph showing the hydroxyl radical-responsive surface degradability of a crosslinked gel of hyaluronic acid.

FIG. 5 is a graph showing the degradability of a dextran cross-linked gel by dextranase.

FIG. 6 is a graph showing the rate of degradation of dextran cross-linked gel by dextranase.

FIG. 7 is a graph showing the surface degradability of a crosslinked gel of hyaluronic acid by hyaluronidase.

FIG. 8 is a graph showing the microsphere release behavior of a hyaluronic acid crosslinked gel that is rate-limited by surface decomposition.

FIG. 9 is a graph showing the biodegradability of the implanted rat hyaluronic acid crosslinked gel and its inflammatory response.

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 1 Heterogeneous structure drug release device 2 Hydrophilic polymer hydrogel 3 Drug-containing microsphere

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ identification code FI A61K 47/36 A61K 47/36 (58) Fields investigated (Int.Cl. ⁷ , DB name) A61K 9/00 A61K 9/127 A61K 9/16 A61K 9/51 A61K 47/30 A61K 47/36

Claims (2)

(57) [Claims] An inhomogeneous structure drug release device characterized in that a hydrophilic polymer hydrogel that decomposes from the surface is used as a carrier and drug-containing microspheres are dispersed in the carrier. 2. The device of claim 1, wherein the hydrophilic polymer hydrogel that decomposes from the surface is a hydrophilic polymer hydrogel that decomposes from the surface by the action of hydroxyl radicals.