JPH03215417A - Long-acting article and its production - Google Patents

Abstract

PURPOSE:To obtain a novel long-acting article capable of gradually releasing a drug by incorporating a miotic agent or proteolytic enzyme-inhibiting agent into a polyvinyl alcohol-containing gel containing at least one kind of compound selected from among hyaluronic acid and salts thereof. CONSTITUTION:An aqueous solution of polyvinyl alcohol containing hyaluronic acid which is one kind of mucopolysaccharides or salt thereof is irradiated with ionized radiation to form a water-containing gel, which is then dipped into an aqueous solution containing miotic agent or proteolytic enzyme inhibitor to provide a long acting article. The novel long-acting article gradually releases drug and the effects are retained over a long time.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel long-lasting active substance and a method for producing the same. More specifically, the present invention provides a long-acting agent including a miotic agent or an anti-pupillary enzyme inhibitor that can gradually release the drug and maintain its effect over a long period of time; often! This relates to a method of making two.

Conventional technology In recent years, in the field of clinical medicine, active agents that gradually release drugs over a long period of time and maintain their effects have attracted attention, and various such long-lasting active agents and their production methods have been proposed. has been done. However, the reality is that a long-lasting active substance that satisfactorily satisfies all of the requirements of biocompatibility, drug release properties, and handling properties has not yet been found. The present inventors previously proposed a method for producing a long-lasting active substance by impregnating a polyvinyl alcohol hydrogel with a drug (Japanese Patent Publication No. 52-3297
1, Japanese Patent Publication No. 56-20284), and a long-lasting high-viscosity eye drop a (Japanese Patent Publication No. 56-48484) comprising a crosslinked polyvinyl alcohol hydrogel containing an eye disease therapeutic agent. However, these long-acting substances have not always been fully satisfactory in terms of biocompatibility and drug release properties.

On the other hand, the present inventors have prepared polyvinyl alcohol gel containing acidic polysaccharides and modified products by irradiating ionizing radiation to an aqueous solution containing polyvinyl alcohol and acidic polysaccharides and modified products thereof. It has been found that it is possible to obtain an artificial living tissue containing a good biocompatibility (4% Publication No. 5T11139).

Problems to be solved by the invention The present invention was made with the aim of providing a long-acting substance that has excellent biocompatibility, maintains its effect for a long period of time, and is easy to handle. It is.

Means for Solving the Problems As a result of intensive research to develop a long-lasting active substance having the above-mentioned preferable properties, the present inventors have developed a polyvinyl containing hyaluronic acid, which is a type of mucopolysaccharide, and its salts. Compared to hydrogels made only of polyvinyl alcohol, alcohol-containing hydrogels have superior biocompatibility, contain large amounts of specific drugs, release the drugs gradually over a long period of time, maintain their effects, and are easier to handle. The present inventors have found that the properties are good, and have completed the present invention based on this knowledge.

That is, the present invention provides a long-lasting active substance comprising a polyvinyl alcohol hydrogel containing at least one selected from hyaluronic acid and its salts, which contains a miotic agent or a proteinaceous enzyme inhibitor. It provides:

According to the present invention, the long-lasting active substance is obtained by irradiating an aqueous polyvinyl alcohol solution containing at least one selected from hyaluronic acid and its salts with ionizing radiation to form a hydrogel. It can be produced by immersing it in an aqueous solution containing a pupil agent or a proteolytic enzyme inhibitor to incorporate the aphrodisiac or the proteolytic enzyme inhibitor into a hydrogel.

The present invention will be explained in detail below.

The hyaluronic acid used in the present invention is a type of mucopolysaccharide, and has excellent water absorption and biocompatibility, and is a substance that has attracted attention as a pharmaceutical, medical material, and cosmetic material. It used to be expensive because it was extracted from the fibers of animals such as chicken combs and skin, but in recent years it has become possible to obtain it from microorganisms and at a relatively low price due to new biotechnology. became.

In the present invention, there is no particular restriction on the molecular weight of hyaluronic acid, and hyaluronic acid having a molecular weight of 11 million or more is usually used. Further, this hyaluronic acid may be used in a free form, a salt form such as a sodium salt or a potassium salt, or a mixture of these may be used.

Regarding the polyvinyl alcohol used to form the polyvinyl alcohol hydrogel in the present invention,
Any material that does not inhibit the reaction during crosslinking treatment by irradiation with ionizing radiation is not particularly limited, and either completely saponified or partially saponified materials can be used. Further, there is no particular restriction on the degree of polymerization, but from the viewpoint of reaction efficiency during crosslinking treatment, an average degree of polymerization of 1000 or more is preferred.

In the present invention, a polyvinyl alcohol aqueous solution containing the hyaluronic acid or its salts is irradiated with ionizing radiation to form a hydrogel, but there is no particular restriction on the concentration of the hyaluronic acid or its salts used at this time. The concentration may be such that an aqueous solution can be formed in coexistence with polyvinyl alcohol, but it is generally selected within a range that is equal to or lower than the concentration of polyvinyl alcohol. Further, as the ionizing radiation, any of gamma rays, electron beams, etc. can be used, but it is advantageous to use gamma rays because they can form a homogeneous gel in a glass container.

In the present invention, a polyvinyl alcohol aqueous solution containing hyaluronic acid or its [1] is irradiated with ionizing radiation to form crosslinks between polyvinyl alcohol molecules,
A hydrogel is formed by forming a three-dimensional network structure. The equilibrium weight swelling ratio of this hydrogel depends on the ionizing radiation dose and the concentration of hyaluronic acid and its salts; as the ionizing radiation dose increases, the equilibrium weight swelling ratio decreases; The higher the concentration of or its salts, the more balanced! The ffi swelling ratio increases.

The drug is trapped in the network structure of the hydrogel thus formed, and is gradually released to the outside through this network. The capture power and release rate of this drug depend on the concentration of hyaluronic acid and its salts and the irradiation ffi (crosslinking density) of ionizing radiation.At the same crosslinking density, the higher the concentration of hyaluronic acid and its salts, the more shrinkage The trapping power of the protease inhibitor is high, and on the other hand, when the concentration of hyaluronic acid or its salts is the same, the higher the crosslinking density, the lower the rate of release of the drug. Therefore, the duration of the effect of the drug can be controlled by the concentration of hyaluronic acid or its salts and the dose of ionizing radiation.

In the present invention, a miotic agent and a protease inhibitor are used as the drugs included in the hydrogel. These drugs do not deteriorate over a long period of time,
A water-soluble one is preferable. As a miotic agent, pilocarpine hydrochloride is preferable, and as a protein enzyme inhibitor, nafamosnotate is preferable. These drugs have an affinity for hyaluronic acid and its salts,
A large amount of hyaluronic acid and its salts are captured by the polyvinyl alcohol hydrogel, and the effects of the present invention are more effectively exhibited.

In the method of the present invention, in order to incorporate the drug into the hydrogel, the hydrogel obtained as described above is directly used.
Alternatively, after partially or completely drying, the material is immersed in an aqueous solution containing the drug for several hours to several tens of hours.

At this time, if the drug is to be rapidly captured, it is advantageous to freeze-dry the hydrogel and immerse it in an aqueous solution containing the drug. The concentration of the aqueous solution containing this drug is not particularly limited, and is appropriately selected within the saturation concentration, preferably within the range of 0.05 to 5% by weight.

In this way, it is possible to efficiently produce the long-lasting active substance of the present invention, which comprises a polyvinyl alcohol-containing hydrogel containing hyaluronic acid or its salts, which contains a miotic agent or a protein fraction q enzyme inhibitor. can.

As a method for producing this long-acting substance, a method other than the above-mentioned method of the present invention may be used, for example, a miotic agent or a protease inhibitor is added in advance to a polyvinyl alcohol aqueous solution containing hyaluronic acid or its salts, and ionizing radiation is A method of producing the long-lasting active substance by irradiation with ionizing radiation can also be used in some cases, but this method is not preferable if the drug to be used is susceptible to alteration or decomposition by irradiation with ionizing radiation. .

Since the long-lasting active substance of the present invention obtained in this way is a drug encapsulated in a hydrogel of polyvinyl alcohol, it can be in the form of a film, a sheet, a block, a granule, etc.
It can be molded into any shape such as a contact lens shape.

Effects of the Invention The long-lasting active substance of the present invention is a polyvinyl alcohol-containing hydrogel containing hyaluronic acid or its salts, which contains a miotic agent or a protease inhibitor. Due to the action of the salts, a large amount of the drug is included, and the drug is gradually released to the outside by the three-dimensional network structure of the hydrogel, so that its effect lasts for a long time. Moreover, the sustainability of this effect is
It can be easily controlled by the position of hyaluronic acid or its salts included in the hydrogel and the crosslinking density of the hydrogel. Since the long-lasting active substance of the present invention has such excellent characteristics, it is extremely useful in the ophthalmology field and the clinical medical field.

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples in any way.

The amount of drug incorporated into the hydrogel was determined from the decrease in the amount of drug in the aqueous drug solution, and the amount of drug released from the hydrogel into water was determined from the amount of drug in the aqueous solution from which the drug was released. . In addition, the drug position in the aqueous solution was measured using an ultraviolet spectrophotometer.

Reference Example: An aqueous solution containing 7% by weight of fully saponified polyvinyl alcohol (PVA) with an average degree of polymerization of about 2000, and the PVA
An aqueous solution containing 7% by weight and sodium hyalanate (HANa) with a molecular weight of about 1.2 million at each t14 degree was rA1.
After 2 hours, 5 mil of each aqueous solution was put into an ampoule and sealed under slightly reduced pressure, which was then irradiated with cobalt 607 radiation at various doses to form a hydrogel.

Next, this hydrous gel was taken out from the ampoule and poured into distilled water at 23° C. to swell, and the equilibrium weight swelling ratio was determined according to the following formula. The results are shown graphically in FIG.

Weight equilibrium weight swelling ratio of the swollen gel = Solid weight in the gel As can be seen from Figure 1, at the same γ-ray irradiation dose,
As the concentration of sodium hyaluronate increases, the equilibrium weight swelling ratio increases; on the other hand, at the same sodium hyaluronate concentration, as the γ-ray irradiation dose increases, that is, as the crosslinking density of the gel increases, the equilibrium weight swelling ratio decreases. .

Example 1 After preparing an aqueous solution containing 7'ffl% of completely saponified PVA with an average degree of polymerization of about 2000, and an aqueous solution containing 7% by weight of the PVA and 1% by weight of sodium hyaluronate with a molecular weight of about 1.2 million, respectively. ,? Similarly to the example,
A hydrogel with an equilibrium weight swelling ratio of about 30 was formed.

On the other hand, the miotic agent pilocarpine hydrochloride, the proteolytic enzyme inhibitor nafamostat mesylate [hereinafter referred to as 7san (trade name)], the antibiotic chloramphenicol, and the antiviral agent 5-iododeso-uridine were used as
Each aqueous solution was prepared containing 0mg/g concentration. Next, about 0.7 g of each of the above gels was added to about 1.4 g of each drug aqueous solution.
The drug was immersed in the gel until an equilibrium state was reached to obtain a long-lasting active substance, and the drug concentration in the gel was determined. The results are shown in FIG.

As can be seen from FIG. 2, in the gel containing only PVA without sodium hyaluronate, the drug concentration in the gel was about 400 mg per gel II2. On the other hand, a gel containing 1% by weight of PVA7i and 1% by weight of sodium hyaluronate contains a large amount of fusan and vilocarpine hydrochloride, with fusan at 1800 mg/L, which is 4.5 times more, and pilocarpine hydrochloride at 700 mg/II, which is about twice as much. there were. However, the concentrations of chloramphenyfur and 5-iododeso-cyuridine were almost the same as in the case of the PVA-only gel, and it is assumed that there is almost no interaction between these drugs and sodium hyaluronate.

Example 2 7% by weight of completely saponified PVA with an average degree of polymerization of about 2000, and 7% by weight of the PVA and 0.2% by weight, 0.5% by weight, 1.0% by weight of sodium hyaluronate with a molecular weight of about 1.2 million.
After preparing m aqueous solutions containing each of these, a hydrogel having an equilibrium weight swelling ratio of about 30 was formed in the same manner as in the reference example.

Approximately 0.7 g of each gel was then added to a concentration of 500 m. -g
The gel was immersed in about 1.4 g of a 7-san aqueous solution of No. 11 until an equilibrium state was reached to incorporate Fusan into the gel to obtain each long-lasting active substance.

Next, each of the long-lasting active substances containing fusan thus obtained was put into 20 g of water, and the release curve of fusan was determined. The results are shown graphically in FIG. In FIG. 3, the vertical axis represents the ratio of the amount of fusan released into the water to the amount of fusan contained in the gel, and the horizontal axis represents the elapsed time.

As can be seen from FIG. 3, in the case of a gel containing only PVA, the release reaches equilibrium in a very short time after immersion, and there is almost no sustained release effect. On the other hand, in PVA gel containing sodium hyaluronate, a sustained release effect was observed in correlation with the amount of sodium hyaluronate included in the gel, and in gel containing 1% by weight of sodium hyaluronate, after 600 hours (25 days) but,
It still showed sustained release effect.

Example 3 An aqueous solution containing 71% completely saponified PVA with an average degree of polymerization of about 2000, and 7% superposition of the PVA and 0.5% by weight of sodium hyaluronate with a molecular weight of about 1.2 million was prepared as follows. A hydrous gel was formed in the same manner as in the reference example, changing the amount of γ-ray irradiation as shown in the table.

Next, about 0.7 g of each gel was added to a concentration of 500 mg
The gel was immersed in about 1.4 g of an aqueous solution of Fusan of /R until an equilibrium state was reached to incorporate Fusan into the gel to obtain each long-lasting active substance, and the amount of Fusan contained therein was determined.

Next, each of the long-lasting active substances containing fusan thus obtained was put into 20 g of water, and the amount of fusan released after 5 days was determined. These results are shown in the table.

As you can see from the table, sodium hyaluronate 0.51f
The gel containing fi% has much more fusan inclusion and significantly less fusan release than the PVA only gel at the same irradiation dose. In addition, sodium hyaluronate o. The gel containing 5fold ffi% was irradiated with gamma rays.
As the irradiation amount increases, the amount of fusan included increases and the amount of fusan released decreases, and as a result, the ratio of the amount of fusan released to the amount of fusan included decreases rapidly as the irradiation dose increases.

From the above results, the active substance of the present invention, which is a polyvinyl alcohol-containing gel containing hyaluronic acid or its salts, containing a 11-fold agent or a protease inhibitor, can be used to release the drug gradually and for a long period of time. It can be seen that the effect can be maintained over a period of time.

[Brief explanation of drawings]

Figure 1 is a graph showing an example of the relationship between the γ-ray irradiation dose and the equilibrium weight swelling ratio for polyvinyl alcohol hydrogels containing sodium hyaluronate at various concentrations. Figure 3 is a graph showing the IN of various drug concentrations contained in the polyvinyl alcohol hydrogel containing sodium hyaluronate. It is a graph showing an example of a relationship.

Claims (1)

[Scope of Claims] 1. A long-lasting active substance comprising a miotic agent contained in a polyvinyl alcohol hydrogel containing at least one selected from hyaluronic acid and its salts. 2. The long-acting substance according to claim 1, wherein the miotic agent is pilocarpine hydrochloride. 3. A polyvinyl alcohol aqueous solution containing at least one selected from hyaluronic acid and its salts is irradiated with ionizing radiation to form a hydrogel, and then immersed in an aqueous solution containing a miotic agent to form a hydrogel. 2. The method for producing a long-lasting active substance according to claim 1, characterized in that the miotic agent is included in a gel. 4. A long-lasting active substance comprising a protease inhibitor contained in a polyvinyl alcohol hydrogel containing at least one selected from hyaluronic acid and its salts. 5. The long-acting product according to claim 4, wherein the protease inhibitor is nafamostat mesylate. 6. After irradiating an aqueous polyvinyl alcohol solution containing at least one selected from hyaluronic acid and its salts with ionizing radiation to form a hydrogel, the aqueous solution containing a proteolytic enzyme inhibitor and miotic agent is applied. 5. The method for producing a long-lasting active substance according to claim 4, wherein the protease inhibitor is incorporated into the hydrogel by soaking.