JP3107488B2 - Sustained-release preparation and embolic agent using cross-linked hyaluronic acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to crosslinked hyaluronic acid, sustained-release preparations and embolizing agents using the same, and more particularly to an improvement in the crosslinking mechanism thereof.

[0002]

2. Description of the Related Art Hyaluronic acid is a high-molecular-weight in-vivo component and, of course, has high biocompatibility and, of course, has excellent functions such as water retention, and is itself used in the field of cosmetics and the like. It is also expected to be used as a carrier for drug delivery systems due to its complex with components. On the other hand, in recent anticancer therapies, studies on administration methods and dosage forms that distribute anticancer drugs only around the affected area of the cancer to prevent side effects on normal cells and at the same time maintain the efficacy by using polymer carriers such as resins. Is being actively conducted. As a so-called sustained-release local administration method in which an effective concentration of a drug is continuously supplied only for a long time around the affected area, for example, an anticancer drug is placed in a capsule, or a tablet-formed preparation is embedded around the affected area of the cancer. A method of injecting a drug-containing microsphere into a muscle or a blood vessel, embolizing a local blood vessel, and leaching the drug only into the occluded local blood vessel can be used.

[0003] Conventionally, a polymer film or matrix formed into microspheres to provide a sustained release of a drug has been formulated with ethylcellulose or wax (JP-A-54-163).
808) and microencapsulated preparations of polylactic acid (JP-A-54-55717, JP-A-59-33214). Even in the case where hyaluronic acid is used as a drug carrier, for example, Japanese Patent Application Laid-Open No. Sho 62-129226.
And JP-A-1-156912 are known. In addition, in the combination of hyaluronic acid and an anticancer drug, a covalent conjugate of hyaluronic acid and adriamycin (doxorubicin hydrochloride) is used in POLYMER PREPRINTS, JAPAN VOL142, No. 3, 898 (1993).
Etc. are reported.

[0004]

However, for example, when a microsphere-formed preparation is administered to an affected area, the drug release rate in the initial stage of administration tends to be extremely high, causing side effects or sustained release over a long period of time. For example, it was difficult to obtain a sustained release effect of supplying a drug at a constant concentration, for example, because it was not possible to obtain the desired properties. Also, the drug release rate is sensitive to the shape and size distribution of the particles, and a uniform shape and a uniform particle size have been required. However, it is difficult to form such fine and uniform particles per se, which makes it difficult to control the drug release rate well. Further, even in a sustained-release preparation using hyaluronic acid as a carrier, hyaluronic acid is only water-soluble if the drug is chemically or physically adsorbed to the hyaluronic acid, so that hyaluronic acid in vivo The drug was rapidly released with the dissolution of the acid, and it was difficult to properly obtain the sustained release effect of the drug.

Further, in the case of a covalent conjugate of hyaluronic acid and adriamycin, although there is an advantage that the drug is retained until the hyaluronic acid is enzymatically decomposed, several steps are required for the synthesis, and the production is complicated. And the yield was low. As described above, various difficulties remain in sustained-release preparations of microspheres or sustained-release preparations utilizing hyaluronic acid, and there has been a long-felt need for a device for an appropriate preparation that brings out a more favorable pharmacological effect. Was. To solve such a problem, for example, Japanese Patent Application Laid-Open No. Sho 60-1306
01, JP-A-61-138601 and the like can be used. However, since the substance used for crosslinking is generally not an in-vivo component, attention must also be paid to the safety of the cross-linked substance in vivo. In this regard, a substance using an epoxy compound is preferable ((Polymer Preprints) , Japan Vol.142, No3,938,199
3).

As the cross-linked hyaluronic acid using an epoxy compound as a cross-linking agent, those described in JP-A-60-233101 or JP-A-61-164558 are mentioned. There was a problem that the rate was extremely large. That is, when a crosslinked hyaluronic acid is embedded in a living body, particularly,
For example, when applied as an embolic agent to a blood vessel as described in -281660, although a certain degree of swelling is required, if the swelling rate is too large, there is a possibility that the tissue around the applied portion may be pressed. In this respect, the conventional crosslinked hyaluronic acid with an epoxy compound is not very suitable for in vivo application. The present invention has been made in view of the problems of the prior art, and its purpose is to examine the crosslinked state of hyaluronic acid, adjust the water solubility and swelling degree, and further use the crosslinked hyaluronic acid for a long time. An object of the present invention is to provide a sustained-release preparation capable of supplying a drug at a constant concentration.

[0007]

Means for Solving the Problems As a result of intensive studies by the present inventors to achieve the above object, it was found that cross-linking between carboxyl groups of hyaluronic acid affects the basic structure of hyaluronic acid. However, the present inventors have found that the solubility in water and the sustained release when complexed with a drug can be adjusted, and the present invention has been completed. That is, sustained-release preparation according to claim 1 of the present application, the carboxyl group of the carboxyl group of hyaluronic acid residues of hyaluronic acid residues are crosslinked by both terminal epoxy compound-based crosslinking agent, the following general formalized
Consists of a complex of cross-linked hyaluronic acid and drug shown in 3
In sustained release formulations, the drug is
Cancer that can form a complex by interacting ionically with
It is characterized by being an agent .

[0008]

Embedded image In the above chemical formula 3 , R is a residue of the crosslinking of the epoxy compound-based crosslinking agent. Further, sustained-release preparation according to claim 2, the
The cross-linked hyaluronic acid is characterized in that the cross-linked carboxyl group is 0.3% or more of the total carboxyl groups of the hyaluronic acid and is water-insoluble and low swelling. The embolic agent according to claim 3 is a carboxyl group of a hyaluronic acid residue.
Group was cross-linked by a cross-linking agent at both ends epoxy compound,
In the embolizing agent comprising cross-linked hyaluronic acid represented by the following general formula 4 , the cross-linked hyaluronic acid is the total amount of hyaluronic acid.
The crosslinked carboxyl group is 0.1 to the ruboxyl group.
It is characterized by being insoluble in water and having a low swellability of 3% or more .

Embedded image In the above chemical formula 4, R represents the crosslinking of the epoxy compound-based crosslinking agent.
The rest. The embolic agent according to claim 4 is characterized in that a drug that interacts ionically with the carboxyl group of hyaluronic acid is complexed.

The present inventors have found that if the carboxyl groups of hyaluronic acid are crosslinked with an epoxy compound, the solubility of hyaluronic acid in water can be adjusted, and the swelling ratio can be appropriately controlled. It has been found that the above-mentioned problems can be solved by forming a complex with a crosslinked hyaluronic acid that has been insolubilized with water, as long as the drug can form a complex by interacting ionically with the crosslinked hyaluronic acid. That is, the present invention comprises a complex of a water-insoluble crosslinked hyaluronic acid and a drug, and the drug is released as the hyaluronic acid skeleton is enzymatically decomposed, whereby a granular or microparticle sustained-release preparation is characterized. Or an embolic agent.

Hereinafter, the present invention will be described in detail. Hyaluronic acid used as a starting material of the present invention is usually a sodium salt, but the kind of the salt is not particularly limited. Also,
The molecular weight is likewise not limited. However, if the molecular weight is too low, the following crosslinking reaction does not proceed well, so that the molecular weight is preferably 200,000 or more. The cross-linking reaction is carried out with hyaluronic acid,
After dissolving the epoxy compound at both ends as a cross-linking agent and a neutral to weakly acidic catalyst in pure water, the reaction is terminated by evaporating and drying the water by heating. The crosslinking mechanism is shown in FIG. As is apparent from the figure, the carboxyl groups of hyaluronic acid are cross-linked by epoxy compounds at both ends under weak acidity. The concentration of the hyaluronic acid at this time is usually 1 to 3% because a too high viscosity makes it difficult to form a uniform solution. The amount of the cross-linking agent may be added so as to obtain a desired cross-linking rate, and the rate of decomposition in the living body is determined by controlling the cross-linking rate. That is, the higher the crosslinking ratio, the slower the enzymatic degradation in vivo.

In this reaction, the carboxyl group of hyaluronic acid and the epoxy group of the cross-linking agent undergo a cross-linking reaction. However, since the reaction proceeds as the water evaporates to dryness, the cross-linking reaction proceeds efficiently with an extremely short intermolecular distance. . Further, the carboxyl group having electrostatic repulsion participates in the crosslinking point, whereby the repulsion is blocked, the water swelling is almost lost, and the water becomes insoluble.
For example, assuming that the cross-linking rate is 100% when all the carboxyl groups are at the cross-linking points, the cross-linking rate becomes 0.3% or more, and the water becomes insoluble. On the other hand, conventional hyaluronic acid crosslinking methods (JP-A-60-233101, JP-A-61-13860)
In the case of 1), water is soluble at such a degree of crosslinking. In the conventional method, a hydroxyl group is cross-linked in a basic aqueous solution, so that the cross-linking is performed with a long distance between the polymer chains participating in the cross-linking, and the carboxyl group causing electrostatic repulsion remains intact. . Therefore, it becomes water-soluble or water-swellable.

As the epoxy compound at both ends used in the crosslinking method, diglycidyl compounds such as diglycidyl ether, diglycidyl ester, diglycidylamine, and diglycidyl ammonium salt are preferable. Of course, three or more glycidyl groups may be used. Of these, glycidyl ether compounds are the most readily available and inexpensive, but specific examples include ethylene glycol diglycidyl ether, propylene glycol diglycidyl ether, polypropylene diglycidyl ether, glycerin diglycidyl ether, and the like. . Also, as described above, it has been reported that these epoxy-based cross-linking agents have higher in vivo safety than other cross-linking agents. Suitable catalysts for the reaction between the carboxyl group of hyaluronic acid and the epoxy compound at both ends include quaternary ammonium salts, tertiary amines, phosphates, imidazole compounds and the like. However, considering the toxicity of the catalyst itself and the fact that the hyaluronic acid chain is easily decomposed even under weak basicity, it is preferable to use a neutral to weakly acidic safe inorganic catalyst.

For example, aqueous solutions of p-ammonium phosphate, sodium phosphate monobasic, potassium phosphate monobasic, etc.
Phosphates with 4 to 7 H are preferred. The concentration of the catalyst may be 2 mg or more per 100 ml of pure water as a solvent. Usually, about 20 mg is sufficient. The cross-linking reaction proceeds while evaporating and drying the water by heating.The film-shaped cross-linked hyaluronic acid thus obtained is then pulverized to an average particle size of 1 mm or less, and is used for complexing with the drug in the next step. Moved. At this time, it is not necessary to particularly limit the average particle size, but a smaller particle size is preferable because the compounding with the drug in the next step can be completed in a short time. The drug to be complexed can be any drug that interacts ionically with the carboxyl group of the cross-linked hyaluronic acid to form a complex. ,
Since a significant improvement in pharmacological effect can be expected, the sustained-release preparation of the present invention, which releases a drug in response to enzymatic degradation, is effective.

The anticancer agent which forms a complex by interacting ionically needs to have a basic ion in its chemical structure. Specific examples thereof include nimustine hydrochloride, ancitabine hydrochloride, daunorubicin hydrochloride, Doxorubicin hydrochloride, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, aclarubicin hydrochloride, epirubicin hydrochloride, vinblastine sulfate, vincristine sulfate, vindesine sulfate and the like. Complexation of the anticancer drug and the crosslinked hyaluronic acid powder is essentially due to chemisorption by ionic interaction. Therefore, the ratio of amounts that can be complexed is directly related to the amount of chemisorption, and differs depending on the type of anticancer agent.

In order to prepare a complex, first, crosslinked hyaluronic acid is dispersed in an aqueous solution of an anticancer drug, and when the chemical adsorption reaches an equilibrium, the complex is allowed to stand. The precipitated complex is separated by filtration, dried, and crushed. To obtain a granular or particulate composite. In use, it is necessary to satisfy the conditions required for ordinary injections. Although it depends on the stability of the complexed anticancer agent, a time-dispersion type preparation which is used by dispersing it in an isotonic solution such as a physiological saline solution is preferable. The release of the anticancer drug depends on its complexation rate (= amount of anticancer drug / amount of cross-linked hyaluronic acid). The conjugation takes place in pure, but the release takes place under physiological conditions.
Therefore, the adsorption equilibrium under pure water conditions shifts to the adsorption equilibrium under physiological conditions.If the chemisorbed amount of the anticancer drug in pure water is less than the equilibrium adsorption amount under physiological conditions, the release of the anticancer drug is complex. If the rate is equal to the rate of enzymatic degradation of hyaluronic acid in the body, and conversely, if the rate is high, the anticancer drug corresponding to the rate is temporarily released, and then the anticancer drug is released at a rate corresponding to the rate of enzymatic degradation. Such a temporary release is used as an effective means to quickly raise the blood concentration to an effective drug concentration.

The preparation may be administered at any location where hyaluronan degrading enzyme is present, and can be administered as a sustained-release safe bioabsorbable preparation. In fact, hyaluronan degrading enzyme is widely distributed in living bodies such as liver, testis, lung, kidney, and synovial fluid, so that it can be effectively used in these organs. Thus, this formulation
Since it is a preparation that releases a drug using the decomposition reaction of hyaluronic acid by an enzyme, it is not affected by the particle size or particle size unlike conventional capsule-type preparations.

Further, the sustained-release preparation of the present invention is effective as an embolic agent also having a sustained release of an anticancer drug depending on the particle size.
Embolization therapy is widely known as a therapy that blocks nutrition by administering an intravascular embolic agent to the artery of its unresectable tumor. It has also been reported that good results have been obtained by maintaining a high concentration of an anticancer drug in a tumor in combination with an anticancer drug (Nichigaikai, '92, 187, 1).
991). If the sustained release preparation of the present invention is used for the same purpose, it is possible to simultaneously perform sustained release and embolization with one preparation. Moreover, since the sustained-release preparation of the present invention is bioabsorbable, there is no need to remove it postoperatively unlike the therapy using a balloon that is partially performed as an embolization therapy. Embolization therapy is not particularly limited as long as it is a tumor in which a catheter can be inserted into a dominant artery. However, the most frequently used tumor for embolization therapy is unresectable liver cancer. However, it is possible to insert catheters into arteries of most organs with the current advanced medical technology, and it is expected that the application of this therapy will be further expanded in the future.

[0018]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, specific embodiments of the present invention will be described in detail. Note that the present invention is not limited by these examples. Example 1 0.4% 10% ammonium phosphate solution in 200 ml of pure water
Four liquids were prepared by adding ml, and 2% aqueous glycerin diglycidyl ether solution was added to each of 20, 5, 1.67,
After adding 0.62 g, 2 g of hyaluronic acid having a molecular weight of about 2,000,000 was dissolved in each aqueous solution. Next, the solutions were transferred to a petri dish and placed in an air-circulating constant temperature bath at 80 ° C.
After leaving for a time, a crosslinking reaction was performed. The thus obtained crosslinked hyaluronic acid film was washed with a 50% ethanol solution, dried, pulverized, and sieved to 100 μm or less. These were all water-insoluble, and almost no swelling in water was observed. In addition, the crosslinking rate of these crosslinked hyaluronic acid fine powders was calculated on the assumption that the entire amount of the added crosslinking agent reacted with the carboxyl group of hyaluronic acid.
A crosslinking degree of 100% means that all carboxyl groups are at crosslinking points. In the case of the above addition amounts, the crosslinking rates correspond to 59.3, 14.8, 4.9 and 1.8%, respectively.

Four types of the crosslinked hyaluronic acid fine powders of Example 1 having different crosslinking rates were placed in test tubes of 10 mg each, and 4 ml of an acetate buffer having a pH of 6.0 containing 100 units of hyaluronidase (Amano Pharmaceutical) was added thereto. Add and stir 50
C. was maintained. In order to examine the change over time in the amount of free hyaluronic acid (decomposition rate), sampling was performed while filtering over time with a 0.45 μm membrane filter, and the amount of hyaluronic acid dissolved therein was colorimetrically determined by the carbazole / sulfuric acid method. Table 1 shows the results. From Table 1, it is understood that the higher the cross-linking rate, the more difficult the enzymatic degradation. It is also suggested that controlling the crosslinking rate can control the decomposition rate.

Table 1 率 Crosslinking rate 59.3 14.8 4.9 1.8 後 0.5 hours later 1.0 1.5 2 2.2 2.3 1 1.6 2.8 4.5 4.5 4.8 22.5 6.0 12.2 13.0 4 3.6 12.1 25.6 27.0 7 4.5 19. 7 45.1 40.3 10 5.9 31.3 64.6 60.9 24 12.5 56.0 81.3 91.5 36 17.9 63.5 86.7 90.3 48 26.2 72.5 96.3 98.7 ───────────────────────────────────

Of the crosslinked hyaluronic acid fine powders according to the present embodiment, transplantation tests using rabbits were performed on two samples having a crosslink rate of 59.3% and 1.8%. Each sample was dispersed in a 10-fold amount of physiological saline, and 0.5 ml of each dispersion was subcutaneously injected at three points on both sides of the spine of a healthy male rabbit weighing 2.5 kg. One week later, after the rabbit was anesthetized and bled,
The tissue surrounding the sample was examined using a magnifying glass. as a result,
In the case of the sample having a cross-linking rate of 59.3%, the injected cross-linked hyaluronic acid fine powder almost remained, but the cross-linking rate was 1.8%.
In the case of, no trace was observed, and it was absorbed into the living body. In addition, neither bleeding nor encapsulation formation was observed in both samples. From this, it is understood that the present crosslinked hyaluronic acid fine powder has high safety and excellent bioabsorbability.

Example 2 5 mg of the crosslinked hyaluronic acid fine powder of Example 1 was added to 2 ml of an aqueous solution having a doxorubicin hydrochloride concentration of 200 to 5000 ppm, followed by incubation at 25 ° C. for 3 hours. After centrifugation, the amount of doxorubicin hydrochloride in the supernatant was reduced to 479 nm.
And the amount of adsorption on the crosslinked hyaluronic acid fine powder was determined from the difference from the initial concentration. The adsorption isotherm is shown in FIG. The figure suggests that doxorubicin hydrochloride chemisorbs to cross-linked hyaluronic acid regardless of the cross-linking rate. Further, it was confirmed that the doxorubicin hydrochloride thus chemisorbed was desorbed again when the surrounding environment was adjusted to pH 3 or less.

Example 3 10 mg of doxorubicin hydrochloride was dissolved in 10 cc of pure water, and 50 mg of the hyaluronic acid fine powder having a cross-linking ratio of 4.9% prepared in Example 1 was dispersed therein. Was discarded and dried under vacuum. The dried product was pulverized again and sieved to reduce the average particle size to 100 μm or less. Doxorubicin hydrochloride / crosslinked hyaluronic acid complex fine powder 5 thus prepared
0 mg was dispersed in 20 ml of physiological saline and shaken at 37 ° C. at 100 strokes / min. The amount of doxorubicin hydrochloride released at this time was quantified by absorbance measurement. FIG. 3 shows the time course of the concentration of released doxorubicin hydrochloride. About 1
After 30 minutes, equilibrium was reached, but when 1000 units of hyaluronidase (Amano Pharmaceutical) were added, release started again, and the total amount was released after 220 minutes.

Example 4 A crosslinked hyaluronic acid prepared by adding ethylene glycol diglycidyl ether so as to have a crosslinking ratio of 2, 5, 10% was made into a fine powder in the same manner as in Example 1. Part 10
Each of 00 mg was dispersed in an aqueous solution containing 10 mg of doxorubicin hydrochloride, followed by centrifugation and vacuum drying. 100μ
After pulverizing to below, 50 mg thereof was dispersed in 10 ml of physiological saline containing 500 units of hyaluronidase,
Shake at 100 strokes / min. At this time, the amount of doxorubicin hydrochloride released into the supernatant was quantified over time by absorbance measurement. FIG. 4 shows the result. The released doxorubicin hydrochloride is released at one time to an effective concentration at an initial stage, and thereafter maintains a constant release rate. Moreover,
The release rate is slower with higher crosslink rates. In the control test containing no hyaluronidase, only a temporary release of the drug was observed at the initial stage, but no release was made thereafter.

Example 5 A test was conducted in the same manner as in Example 7 except that bleomycin hydrochloride was used instead of doxorubicin hydrochloride of Example 7. The results showed almost the same behavior.

Example 6 0.2 ml of 10% ammonium monophosphate solution in 50 ml of pure water
Eight liquids were prepared, and 2% aqueous solution of ethylene glycol diglycidyl ether was added to each of 1.76, 0.
88, 0.35, 0.15, 0.060, 0.030,
After adding 0.015 and 0.008 g, 0.5 g of hyaluronic acid having a molecular weight of about 1.6 million was dissolved in each aqueous solution.
Next, these solutions were transferred to a Petri dish, left in a 100 ° C. air-circulating thermostat for 5 hours to allow a crosslinking reaction, and
After washing with a 10% aqueous ethanol solution, the film was dried to obtain a crosslinked hyaluronic acid film. The cross-linking rate of the hyaluronic acid film thus obtained was 59, 30, 12, 4.9,
2.0, 1.0, 0.5, and 0.25%, except for the film with a cross-linking ratio of 0.25%, all of which were water-insoluble. It was used for measurement. The measurement method is as follows.
cm, cut out using a scanning microscope (Olympus) and a thickness gauge (Tokyo Seimitsu), measure length x width x thickness, and then measure at 25 ° C.
In pure water or physiological saline until the swelling equilibrium was reached. Next, the film which reached the swelling equilibrium was taken out of the liquid, and water droplets on the surface were cut off. Based on this result, the volume swelling ratio before and after immersion was calculated and plotted in FIG. The swelling ratio in pure water and physiological saline is not much different, and the swelling ratio increases as the crosslinking rate decreases. However, even in a film having a water-insoluble property and a cross-linking rate of 0.5%, the swelling ratio does not exceed 4, and it is understood that the swelling ability is remarkably low. As described above, the crosslinked hyaluronic acid according to the present invention is not only water-insoluble, but also has a low degree of water swelling. There is nothing to do.

Example 7 Crosslinked hyaluronic acid fine powders having a crosslinking ratio of 1.8% and 100% prepared according to Example 1 were examined for hot springs such as adsorption of doxorubicin hydrochloride in the same manner as in Example 2. FIG. 6 shows the results. Doxorubicin hydrochloride chemisorbs to a crosslinked hyaluronic acid powder having a crosslinking rate of 1.8%, but has a crosslinking rate of 10%.
0% powder does not chemisorb, only physisorption is observed. This difference is due to the fact that the crosslinking reaction according to the present invention is a crosslinking between carboxyl groups of hyaluronic acid.
That is, in the case of a powder having a cross-linking rate of 100%, all carboxyl groups are at cross-linking points, so that free carboxyl groups do not remain. As a result, doxorubicin hydrochloride cannot be chemically adsorbed, and only physical adsorption is observed. It is thought that it was done.

[0027]

As described above, the cross-linked hyaluronic acid according to the present invention can be made to be water-insoluble and low swelling because carboxyl groups are cross-linked.
When a drug is compounded with the cross-linked hyaluronic acid to form a sustained-release preparation, the drug can be gradually released when administered in vivo with enzymatic degradation of hyaluronic acid. Furthermore, when the crosslinked hyaluronic acid according to the present invention is used as an embolic agent, unnecessary pressure is not applied to other tissues.

[Brief description of the drawings]

FIG. 1 is an explanatory diagram of a cross-linked state of a cross-linked hyaluronic acid according to the present invention.

FIG. 2 shows a cross-linked hyaluronic acid powder of adriamycin (doxorubicin hydrochloride) in pure water,
It is an adsorption isotherm at 25 degreeC.

FIG. 3 is an explanatory diagram showing the time-dependent change in the amount of adriamycin released from the sustained-release preparation according to Example 3.

FIG. 4 is an explanatory diagram showing the time-dependent change in the amount of adriamycin released from the sustained-release preparation according to Example 4.

FIG. 5 is an explanatory diagram showing the dependency of the cross-linking ratio on the volume swelling ratio of the cross-linked hyaluronic acid film prepared in Example 6 in pure water and physiological saline at 25 ° C.

FIG. 6 shows a crosslinked hyaluronic acid powder of doxorubicin hydrochloride measured in Example 7 (crosslinking ratio 1.8%: ：, 100%:
It is an adsorption isotherm at 25 ° C with pure water for ●).

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Kimio Ohno 262-2-5-306 Kamigo-cho, Sakae-ku, Yokohama-shi, Kanagawa (72) Inventor Ken Uchida 4-39-21-104, Hikawadai, Nerima-ku, Tokyo (56) References Tokuyo Sho 63-503551 (JP, A) Tokuyo Sho 61-502729 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C08B 37/08 A61K 9/00 A61K 47 / 36 C08B 37/00 CA (STN)

Claims (4)

(57) [Claims] (1) a carboxyl group of a hyaluronic acid residue
The following one cross-linked by a terminal epoxy compound-based cross-linking agent
Is a complex of cross-linked hyaluronic acid and a drug represented by general formula 1
A sustained-release preparation, comprising a carcinostatic agent, wherein the drug ionically interacts with a carboxyl group of hyaluronic acid to form a complex. . Embedded image In the above chemical formula 1, R represents the crosslinking of the epoxy compound-based crosslinking agent.
The rest. (2) The sustained-release preparation according to claim 1, wherein
Bridge hyaluronic acid binds to all carboxyl groups of hyaluronic acid
Water containing 0.3% or more of cross-linked carboxyl groups
Sustained release product characterized by insolubility and low swelling
Agent. 3. The carboxyl group of a hyaluronic acid residue has both
The following one cross-linked by a terminal epoxy compound- based cross-linking agent
The embolic agent comprising a crosslinked hyaluronic acid represented by the general formula of 2
In this case, the cross-linked hyaluronic acid
0.3% or less of cross-linked carboxyl group to sil group
The above embolic agent, which is water-insoluble and low swelling . Embedded image In the above chemical formula 2, R represents the crosslinking of the epoxy compound-based crosslinking agent.
The rest. 4. The embolic agent according to claim 3 , wherein an agent that ionically interacts with the carboxyl group of hyaluronic acid is complexed.