JP2011122007A - Material for sustained release of physiologically active substance - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a material for the sustained release of a physiologically active substance, having excellent sustained releasability of a medicament, safety and bioaffinity at the tissue interface. <P>SOLUTION: The material for the sustained release of the physiologically active substance includes a copolymer using trimethylene carbonate and a saccharide containing at least one pyranose ring and/or furanose ring as constituent units, wherein the molar ratio of the monomers of the trimethylene carbonate to the saccharide is from 99:1 to 35:65. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

The present invention relates to a bioactive substance sustained-release material that can be suitably used in a drug delivery system (drug release control system).

Conventionally, in order to administer a drug to a living body effectively and while suppressing side effects, the drug release rate is set so that the blood concentration of the drug is between the lowest effective concentration and the side effect expression level for a certain period of time. Drug delivery systems have been proposed that control the amount of drug release and aim at continuous release from the formulation.
However, what is required for many diseases is that the drug is maintained in an effective concentration range in a specific tissue or site (target site) in the body, and the time during which the drug is maintained at a constant blood concentration Although the controlled drug delivery system achieves reduction in the number of administrations and sustained release at an arbitrary time, the administered drug also acts on normal cells, so there is room for improvement as a drug delivery system.
In other words, drug delivery systems are required not only to adjust temporally but also to target (target-directed), which is spatial adjustment, and it is necessary to achieve both of them and further reduce the side effects of drugs. It has been.

As a method for concentrating a drug on a target site, for example, a method using an antigen-antibody reaction using an antibody that specifically recognizes an antigen on a cell surface has been proposed. In this method, the drug is directly bound to the antibody, or the drug is contained in a liposome bound to the antibody.
Other methods include a method of inducing a drug containing a magnetic substance by applying a magnetic field to a target site, and a method of utilizing the property that fine particles containing a drug accumulate in a specific organ depending on the particle size. Proposed.
However, even if these methods show an effect in an in vitro test, there is a problem that an in vivo test in an animal does not show a sufficient effect or there is a large difference among animal species. The current situation is not progressing.

On the other hand, in order to achieve both temporal adjustment and targeting (target directivity), a method of locally administering a sustained-release drug has been proposed. In this method, since the drug comes into contact with the target site at a predetermined concentration, there is a possibility that side effects can be reduced while exhibiting a drug effect. Various polymeric materials have been proposed as compatible base materials for use as a locally-released sustained-release drug used for this purpose.

Specifically, for example, an ethylene-vinyl acetate copolymer, a silicone resin, and the like, which are non-degradable and insoluble materials in vivo, have been proposed as a base material.
However, when such a material is locally administered into a living body, the base material remains even after the drug is released, and it is necessary to remove this if the residue affects the living body. .

In addition, a method using a water-soluble polymer such as polyvinyl alcohol, hydroxypropyl cellulose, chitosan or the like as a base material has been proposed. However, since the base material containing the drug dissolves in a short time in a living body, it is difficult to adjust the release amount and speed of the drug.

It has also been proposed to use a natural material containing polysaccharides such as collagen, gelatin, albumin, fibrin, hyaluronic acid, alginic acid, and chitin, which are natural materials that are degradable in vivo, as a base material.
However, because these materials are natural materials, the composition, molecular weight, water retention, etc. are not constant, and substances having antigenicity, etc. are not completely removed in the course of the reaction / purification process. And may cause immunological problems during use. In addition, since these materials are highly hydrophilic, body fluids in vivo rapidly penetrate into the matrix, thereby causing a discontinuity in the drug release rate.

Furthermore, as a synthetic biodegradable material, an aliphatic polyester having a basic skeleton such as polylactic acid, polyglycolic acid, polyε-caprolactone, polytrimethylene carbonate, or a copolymer thereof, It has also been proposed to use a group polycarbonate (for example, see Non-Patent Document 1).
However, in sustained-release preparations composed of these aliphatic polyesters and the drug, the drug release rate controls the dissolution rate of the drug in water penetrating into the polymer, so that the drug is released from the matrix surface as the drug release proceeds. As the distance to the site of the drug increases, there is a problem that it is difficult to adjust the drug release amount and time.
Furthermore, the release amount is difficult to adjust, such as the initial protrusion of the drug from the surface of the sustained-release drug during release and the rapid drug release during decomposition into oligomers.

In addition, as a base material that stabilizes the release of a drug, a reaction product of glucose or fructose and a hydroxycarboxylic acid has been proposed. Such reaction products have been shown to be suitable for depot preparations due to the balance between the hydrophilicity and hydrophobicity of polyols such as glucose and polylactic acid (see, for example, Patent Document 1).
However, when an aliphatic polyester such as polylactic acid is present as a segment in the base material, the rigidity of the base material causes insufficient adhesion to the tissue interface of the base material, so that the drug is effectively guided to cells at the target site. It was not enough.

Patent Document 2 discloses a polymer containing 90 mol% or more of trimethylene carbonate as a physiologically active substance sustained release material.
In general, aliphatic polycarbonates such as aliphatic polyesters and trimethylene carbonate are known to have poor adhesion to the cell surface like polyethylene terephthalate and polytetrafluoroethylene, and are used for tissue engineering, for example. In the aliphatic polyester as a culture scaffold, a method of coating collagen on the scaffold surface is adopted in order to improve the low adhesion to the cell surface.
That is, the bioactive substance sustained release material comprising a polymer containing trimethylene carbonate in an amount of 90 mol% or more tended to be inferior in adhesion to the cell surface (easily adsorbed to cells or the like).

Japanese Patent Publication No. 8-19226 JP 2003-306543 A

A. J. Domb, J. Kost, D. M. Wiseman, “Handbook of Biodegradable Polymers”, CRC Press (USA), 1997, Vol. 7, p. 3-202

As described above, although many studies have been conducted on bioactive substance sustained release materials, sustained release of drugs, safety, and biocompatibility at the interface between sustained release preparations and tissues In view of the above, the present situation is that the characteristics required for the bioactive substance sustained release material are not sufficiently satisfied.

The present inventors have repeated intensive studies to solve the above problems, and as a result, found that a copolymer having trimethylene carbonate and a specific saccharide as a structural unit is extremely excellent as a physiologically active substance sustained release material, The present invention has been completed.

That is, the physiologically active substance sustained-release material of the present invention comprises a copolymer having trimethylene carbonate and a saccharide containing at least one pyranose ring and / or furanose ring as structural units, and the trimethylene carbonate and The molar ratio of the monomer to the saccharide is 99: 1 to 35:65.

Moreover, it is desirable that an anionic functional group is not bonded to the pyranose ring and furanose ring contained in the saccharide.
Moreover, it is desirable that the saccharide is a saccharide having no reducing property.

In the physiologically active substance sustained release material, the saccharide is preferably at least one selected from the group consisting of sucrose, sucrose monocaprate, sucrose monolaurate, and methyl α-D-glucoside. .
In the bioactive substance sustained release material, the metal content in the copolymer is preferably 0.5 ppm (weight ratio) or less.

The method for producing a physiologically active substance sustained-release material of the present invention is to add no metal catalyst and initiator when polymerizing trimethylene carbonate and a saccharide containing at least one pyranose ring and / or furanose ring. This is a featured manufacturing method.

In the method for producing a physiologically active substance sustained release material, it is desirable to polymerize a saccharide containing at least one pyranose ring and / or furanose ring and molten trimethylene carbonate under reduced pressure. In this case, the polymerization reaction is desirably performed under a pressure of 20 Pa or less and at a temperature of 120 ° C. or less.

In the method for producing a physiologically active substance sustained release material, trimethylene carbonate and a saccharide containing at least one pyranose ring and / or furanose ring are polymerized in a nitrogen atmosphere in the presence of water. It is also desirable that

Since the material for sustained release of the physiologically active substance of the present invention has the above-described configuration, it is excellent in sustained release property and safety of the drug and biocompatibility at the interface between the tissue and the sustained release preparation, and is used for a drug delivery system. It can be suitably used as a substrate.
Specifically, since it is a copolymer of trimethylene carbonate and a specific saccharide, it will be excellent in sustained release of the drug.
The reason for this is that the hydrophobic segment derived from trimethylene carbonate and the hydrophilic segment derived from saccharide are bonded, so that water in the living body penetrates not only to the surface but also to the inside by the hydrophilic group, and the drug is dispersed in the water. The volume of the diffusion layer becomes large. Therefore, it is considered that the region where the concentration gradient is kept constant increases, and the concentration gradient difference of the drug with the aqueous layer outside of the physiologically active substance sustained release material is kept constant.
In addition, since the trimethylene carbonate segment is present in the polymer chain, the above-mentioned copolymer has an appropriate softness for the bioactive substance sustained-release material itself, so that it easily corresponds to the surface shape of a living tissue. .

Further, the copolymer is a biodegradable copolymer and is excellent in safety. Along with the release of the drug, the bioactive substance sustained-release material decomposed in vivo is a compound that does not exhibit toxicity, and is characterized in that it is discharged from the metabolic system to the outside of the living body and does not remain in the living body.

In addition, since a specific saccharide, that is, a saccharide containing at least one pyranose ring and / or furanose ring is used as a structural unit, the biocompatibility is excellent.
A saccharide containing at least one pyranose ring and / or furanose ring has a high interaction with a sugar chain recognition receptor that functions as a specific recognition signal that exists as a membrane protein or glycolipid on the surface of a cell in a living body. This is because the affinity to living tissue and the adhesion at the cell interface are remarkably increased.
Moreover, the physiologically active substance sustained-release material is excellent in decomposition characteristics and sustained-release characteristics because it has moderate strength and many hydroxyl groups on the three-dimensional skeleton.

It is a graph which shows the result of the chemical | medical agent release test of the bioactive substance sustained release material manufactured in Examples 1-6. It is a graph which shows the result of the chemical | medical agent release test of the bioactive substance sustained release material manufactured by Comparative Examples 1-4.

Embodiments of the present invention will be described below.
The material for sustained release of the physiologically active substance of the present invention comprises a copolymer comprising trimethylene carbonate and a saccharide containing at least one pyranose ring and / or furanose ring as constituent units.

Examples of the saccharide containing at least one pyranose ring and / or furanose ring include sucrose, sucrose monocaprate, sucrose monolaurate, methyl α-D-glucoside, maltose, lactose, trehalose, neotrehalose, iso Examples include trehalose, raffinose, amylose, amylopectin, cyclodextrin, cellulose, lentinan, schizophyllan and UDP-galactose.
Of these, sucrose, sucrose monocaprate, sucrose monolaurate, and methyl α-D-glucoside are desirable. The reason is that the steric hindrance of the trimethylene carbonate chain extending from each hydroxyl group during the reaction of trimethylene carbonate and saccharide is reduced, so the trimethylene carbonate chain length tends to be constant, and the molecular weight of the resulting copolymer is reduced. It is because it becomes easy to adjust.

Saccharose, sucrose monocaprate, sucrose monolaurate, and methyl α-D-glucoside are desirable as the saccharide having no anionic functional group bonded to the pyranose ring or furanose ring. The reason is that if a saccharide having an anionic functional group bonded to the pyranose ring or furanose ring is used, a trimethylene carbonate homopolymer tends to be formed.

The saccharide containing at least one pyranose ring and / or furanose ring is preferably a saccharide having no reducing property.
The reason is that when a reducing sugar is used, a trimethylene carbonate homopolymer tends to be formed as described above.
Saccharose, sucrose monocaprate, sucrose monolaurate, and methyl α-D-glucoside are preferable as the saccharide having no reducing property.

In the copolymer, the molar ratio of the trimethylene carbonate and the saccharide monomer is 99: 1 to 35:65.
When the molar ratio of the trimethylene carbonate exceeds 99, the adhesiveness of the copolymer to the living body interface decreases, and further, the decomposition rate of the copolymer decreases.
When the degradation rate is reduced, the physiologically active substance sustained-release material remains in the living body for a long period of time after the drug is released when the physiologically active substance sustained-release material is used as a carrier for a sustained-release drug for local administration. Inconvenience arises.
On the other hand, in the above copolymer, the hydrophilicity of the copolymer becomes stronger when the proportion of trimethylene carbonate decreases. And when the molar ratio of trimethylene carbonate is less than 35,
Since the hydrophilicity of the copolymer becomes too strong, the shape collapses due to swelling during use, and the copolymer cannot be used as a carrier for sustained-release drugs for local administration.
In addition, during the polymerization, the number of saccharide molecules surrounding the trimethylene carbonate monomer molecule increases, and since the polymerization starts rapidly from the hydroxyl group, the reaction proceeds locally and stops, resulting in the product being It is easy to obtain a composition in which saccharides occupy main structural units, and it becomes difficult to obtain a material having a target composition.

Moreover, in the physiologically active substance sustained-release material of the present invention, the release rate of the contained drug can be adjusted by adjusting the molar ratio within the above range. The release rate can be increased by lowering the molar ratio, while the drug is gradually released over a long period of time (lowering the release rate) by increasing the molar ratio of trimethylene carbonate. Can do.

The molecular weight of the copolymer is preferably 600 to 50000 as a number average molecular weight, and more preferably 600 to 35000 from the viewpoint of miscibility with a drug, release property, and adhesion to tissue.
When the number average molecular weight is less than 600, the strength required as a material for sustained release of physiologically active substances cannot be ensured, and the base material becomes water-soluble, resulting in an increased drug release rate, and blood concentration Adjustment becomes difficult. On the other hand, if it exceeds 50000, the degradation rate becomes slow, the drug release rate decreases, and it becomes difficult to reach an effective blood concentration.

In the bioactive substance sustained release material, the metal content in the copolymer is preferably 0.5 ppm or less, and the metal content is preferably as small as possible.
This is because if the metal content in the copolymer exceeds 0.5 ppm, the metal remaining in the living body may be ionized in the living body and cause carcinogenesis, allergy, and the like.

In the physiologically active substance sustained release material, the desirable metal content in the copolymer is 0.5 ppm or less as described above, but such a metal content is the detection limit in the analysis by the “ICP emission analysis method”. It is desirable that the copolymer contains substantially no metal component.
Moreover, in order to make the metal content in the copolymer 0.5 ppm or less, for example, the production method of the present invention described later, that is, polymerization of monomer components without adding a metal catalyst or an initiator. Just do it.

In the copolymer, in addition to the trimethylene carbonate and the saccharide, other monomer components may be polymerized as necessary as long as the object of the present invention is not impaired.
Examples of the other monomer components include lactic acid, glycolic acid, β-hydroxybutyric acid, 4-hydroxyvaleric acid, hydroxycarboxylic acids such as 6-hydroxycaproic acid, lactide,
Examples thereof include lactones such as glycolide, ε-caprolactone, γ-butyrolactone, δ-valerolactone, and p-dioxanone. Among these, lactic acid, glycolic acid, lactide, and glycolide are desirable. The lactic acid may be D-form or L-form.
Moreover, when it contains the said other monomer component, it is desirable that the content is less than 10 mol% of all the monomer components.

The bioactive substance sustained release material of the present invention having such a configuration can be suitably used as a base material for a drug delivery system.
That is, a pharmacologically active agent such as a physiologically active substance can be contained, and can be suitably used as a base material that is localized in a target site while being stably released in vivo.
In this case, in order to stably release the pharmacologically active agent, it is desirable to appropriately adjust the composition ratio, molecular weight, etc. of the copolymer according to the type of the pharmacologically active agent to be contained.
Specifically, for example, in the case of containing a water-soluble and relatively low molecular weight drug, it is preferable to increase the trimethylene carbonate content and to increase the molecular weight, and to contain a lipophilic drug having low solubility in water. In some cases, it is preferable to increase the saccharide content and lower the molecular weight.
The method for incorporating a pharmacologically active agent into the physiologically active substance sustained release material will be described later.

Examples of the pharmacological activity suitable for using the physiologically active substance sustained-release material of the present invention include anti-inflammatory analgesic action, antibacterial action, antiviral action, antitumor action, immunoregulatory action and the like.
Examples of physiologically active substances having these actions include antibiotics, alkylating agents, anticancer agents, immunosuppressive agents, immunostimulants, antihypertensive agents, nerve growth factors, growth differentiation factors, cartilage-derived growth factors, pelvis Growth factor, epidermal growth factor, fibroblast-derived growth factor, platelet-derived growth factor, colony stimulating factor, erythropoietin, interleukins 1, 2, 3, interferon α, β, γ, transforming growth factor, insulin, calcitonin, immunity Globulin, prostaglandins and the like.
In addition to these, for example, genes such as antisense DNA, plasmid DNA, si-RNA and the like can be contained, and these genes may be contained alone or in combination of two or more. May be included.

The pharmacologically active agent is impregnated in advance with porous hydroxyapatite, biograss, therapy, tricalcium phosphate, tetracalcium phosphate, calcium aluminate, calcium carbonate or the like, or a fine powder thereof. And may be contained in the material for sustained release of the physiologically active substance in a premixed state.
In addition, the physiologically active substance sustained-release material containing the pharmacologically active agent may be a complex with water-soluble glycerin, triethyl citrate, polyethylene glycol, etc. Can be expressed in a complex manner.
Further, the physiologically active substance sustained release material containing the pharmacologically active agent can be combined with a living tissue such as periosteum.
The physiologically active substance sustained-release material of the present invention having such a structure can be produced, for example, by the production method of the present invention described later.

Next, the manufacturing method of this invention is demonstrated.
The production method of the present invention is a method for producing a material for sustained release of a physiologically active substance of the present invention, wherein when trimethylene carbonate and a saccharide containing at least one pyranose ring and / or furanose ring are polymerized, a metal It is characterized in that no catalyst and initiator are added.
In the production method of the present invention, the trimethylene carbonate and the saccharide are polymerized. Here, the trimethylene carbonate and the saccharide are as described above.

As a method for polymerizing the trimethylene carbonate and the saccharide, for example, a method (method (1)) in which the saccharide is added to molten trimethylene carbonate and then polymerized under reduced pressure can be used. Here, the polymerization reaction is desirably performed under a pressure of 20 Pa or less and at a temperature of 120 ° C. or less. The polymerization reaction may be performed in a nitrogen atmosphere.
Further, for example, a method of polymerizing trimethylene carbonate and the saccharide in the presence of water in a nitrogen atmosphere (method (2)) can also be used. In this method, trimethylene carbonate and the saccharide do not necessarily have to be completely dissolved in water, and both may coexist. In this case, it is considered that water acts as a catalyst and causes both to react. In order to cause both to react uniformly, it is preferable to polymerize them after completely dissolving them in water.
Furthermore, for example, a method (method (3)) of solution polymerization, suspension polymerization or emulsion polymerization in a solvent such as methylene chloride, chloroform, acetone, dimethyl sulfoxide, dimethylformamide, dioxane or the like can also be used.

Among these, the methods (1) and (2) are desirable.
The reason is as follows.
That is, when the method (1) is used, since only the compound to be reacted is present in the reaction system, there is no impurity to be contaminated, and it is advantageous in that the side reaction caused by that hardly occurs. . Further, when the method (2) is used, the use of water is advantageous in that a heterogeneous reaction hardly occurs in a reaction with a water-soluble material, and a yield reduction due to this can be prevented. .

The reaction temperature in the polymerization reaction is usually 30 to 150 ° C., and considering the fact that the reaction with saccharides that are easily thermally decomposed is carried out without a catalyst, the upper limit of the reaction temperature is preferably 120 ° C.
Further, a maximum reaction time of about 16 hours is sufficient. This is because, when the reaction temperature is 90 ° C., although it depends on the amount of the reaction raw material and the type of the reaction raw material (type of saccharide), the polymerization rate is usually about 99% in 8 hours.

After completion of the polymerization reaction, the reaction product (copolymer) is purified as necessary.
For example, the purification may be performed by reprecipitation by dissolving the reaction product in a solvent such as acetone or chloroform.
That is, after dissolving the reaction product in a solvent, unreacted saccharides are removed, and methanol, ethanol, ether, petroleum ether, hexane or the like is added 6 to 10 times the volume of the solution to precipitate the reaction product, and impurities The low molecular weight polymer, homopolymer, and unreacted raw material are removed.
Furthermore, when saccharides remain, extraction may be performed with water or a mixed solvent such as water-ethanol.

By performing such a process, the bioactive substance sustained-release material of the present invention can be suitably produced.
In the production method of the present invention, it is extremely important to carry out the polymerization reaction without adding a metal catalyst and an initiator. By carrying out the polymerization reaction by such a method, the metal content of the obtained copolymer is substantially 0.5 ppm or less and does not contain any metal without performing a complicated catalyst removal treatment after completion of the polymerization reaction. Can not be.
And since the copolymer which does not contain such a metal is excellent in safety | security, as above-mentioned, it is suitable as a bioactive substance sustained release material.

The bioactive substance sustained-release material of the present invention can be suitably used as a sustained-release preparation by containing the pharmacologically active agent.
As a method of incorporating the pharmacologically active agent into the physiologically active substance sustained release material, a conventionally known method can be used.
Specifically, for example, a method of dissolving or dispersing the physiologically active substance sustained-release material in a solvent, uniformly dispersing the pharmacologically active agent, and then removing the solvent can be used.
In this case, examples of the solvent to be used include acetone, methylene chloride, chloroform, ethanol and the like. These solvents may be used alone or in combination of two or more depending on the purpose.

In addition, a complex (sustained release preparation) containing the pharmacologically active agent in the material for sustained release of the physiologically active substance is used, for example, in the form of a film, a porous body, fine particles obtained by pulverizing these, etc. can do.
Further, when the sustained-release preparation contains a drug having high heat resistance as a pharmacologically active agent, it can be mixed under heating.

In addition, when the sustained-release preparation is a microsphere, the microsphere is an aqueous solution in which the pharmacologically active agent and the physiologically active substance sustained-release material are dispersed in a solvent and then polyvinyl alcohol is dissolved. It can be prepared by dropping and emulsifying to remove the solvent from the emulsion, and washing and filtering with water.

In addition, the physiologically active substance sustained-release material can be used in combination with a low molecular weight material with increased fluidity, and any dosage form can be prepared.

EXAMPLES Hereinafter, although an Example is hung up and demonstrated in more detail about this invention, this invention is not limited only to these Examples.

Example 1
To a reaction vessel having an internal volume of 100 ml equipped with a thermometer and an exhaust port, 20 g of trimethylene carbonate (manufactured by Tokyo Chemical Industry Co., Ltd., reagent) and 1.4 g of sucrose (manufactured by Aldrich Co., Ltd.) are added, and this is subjected to a pressure of 13 Pa. The reaction was performed at 90 ° C. for 8 hours. After the reaction, the obtained copolymer was dissolved in acetone so as to be about 10 w / v%, and purification treatment was performed by precipitating the copolymer in hexane equivalent to acetone. After the treatment, 13 g of a bioactive substance sustained release material was obtained.
As a result of obtaining the composition (molar ratio) of the obtained physiologically active substance sustained release material by ¹ H-NMR, the molar ratio of each structural unit of trimethylene carbonate and sucrose in the physiologically active substance sustained release material was: 95: 5.
Moreover, when the molecular weight of this bioactive substance sustained release material was determined by gel permeation chromatography (GPC), the number average molecular weight was 9,000.

(Example 2)
To the same reaction vessel as in Example 1, 20 g of trimethylene carbonate (manufactured by Tokyo Chemical Industry Co., Ltd., reagent) and 3.4 g of sucrose (manufactured by Aldrich Co., Ltd., reagent) were added, and this was stirred at 90 ° C. for 8 hours at a pressure of 13 Pa. Reaction was performed. After the reaction, the obtained copolymer was dissolved in acetone so as to be about 10 w / v%, and purification treatment was performed by precipitating the copolymer in hexane equivalent to acetone. After the treatment, 15 g of a bioactive substance sustained release material was obtained.
As a result of obtaining the composition (molar ratio) of the obtained physiologically active substance sustained release material by ¹ H-NMR, the molar ratio of each structural unit of trimethylene carbonate and sucrose in the physiologically active substance sustained release material was: 75:25.
Further, when the molecular weight of this physiologically active substance sustained-release material was determined by GPC, the number average molecular weight was 4,700.

(Example 3)
20 g of trimethylene carbonate (manufactured by Tokyo Chemical Industry Co., Ltd., reagent) and 8.4 g of sucrose (manufactured by Aldrich Co., Ltd., reagent) are added to the same reaction vessel as in Example 1, and this is heated at 90 ° C. for 6 hours under a pressure of 13 Pa. Reaction was performed. After the reaction, the obtained copolymer was dissolved in acetone so as to be about 10 w / v%, and purification treatment was performed by precipitating the copolymer in hexane equivalent to acetone. After the treatment, 15 g of a bioactive substance sustained release material was obtained.
As a result of obtaining the composition (molar ratio) of the obtained physiologically active substance sustained release material by ¹ H-NMR, the molar ratio of each structural unit of trimethylene carbonate and sucrose in the physiologically active substance sustained release material was: 55:45.
Further, when the molecular weight of this physiologically active substance sustained-release material was determined by GPC, the number average molecular weight was 1,700.

Example 4
To a reaction vessel similar to that in Example 1, 20 g of trimethylene carbonate (manufactured by Tokyo Chemical Industry Co., Ltd., reagent) and 4.3 g of sucrose (manufactured by Aldrich Co., Ltd., reagent) were added, and this was applied at 90 ° C. under a pressure of 13 Pa for 6 hours. Reaction was performed. After the reaction, the obtained copolymer was dissolved in acetone so as to be about 10 w / v%, and purification treatment was performed by precipitating the copolymer in hexane equivalent to acetone. After the treatment, 15 g of a bioactive substance sustained release material was obtained.
As a result of obtaining the composition (molar ratio) of the obtained physiologically active substance sustained release material by ¹ H-NMR, the molar ratio of each structural unit of trimethylene carbonate and sucrose in the physiologically active substance sustained release material was: 50:50.
Further, when the molecular weight of the bioactive substance sustained release material was determined by GPC, the number average molecular weight was 1940.

(Example 5)
To a reaction vessel similar to Example 1, 20 g of trimethylene carbonate (manufactured by Tokyo Chemical Industry Co., Ltd., reagent) and 3.4 g of sucrose (manufactured by Aldrich Co., Ltd., reagent) were added, and this was added at 90 ° C. under a pressure of 13 Pa for 1 hour. Reaction was performed. After the reaction, the obtained copolymer was dissolved in acetone so as to be about 10 w / v%, and purification treatment was performed by precipitating the copolymer in hexane equivalent to acetone. After the treatment, 14 g of a bioactive substance sustained release material was obtained.
As a result of obtaining the composition (molar ratio) of the obtained physiologically active substance sustained release material by ¹ H-NMR, the molar ratio of each structural unit of trimethylene carbonate and sucrose in the physiologically active substance sustained release material was: 35:65.
Further, when the molecular weight of this physiologically active substance sustained-release material was determined by GPC, the number average molecular weight was 1620.

(Example 6)
20 g of trimethylene carbonate (manufactured by Tokyo Chemical Industry Co., Ltd., reagent) and 5.8 g of methyl-α-D-glucoside (manufactured by Aldrich Co., Ltd.) are added to the same reaction vessel as in Example 1, and this is added under a pressure of 13 Pa. The reaction was performed at 90 ° C. for 10 hours. After the reaction, the obtained copolymer was dissolved in acetone so as to be about 10 w / v%, and purification treatment was performed by precipitating the copolymer in hexane equivalent to acetone. After the treatment, 17 g of a bioactive substance sustained release material was obtained.
As a result of obtaining the composition (molar ratio) of the obtained bioactive substance sustained release material by ¹ H-NMR, each constitution of trimethylene carbonate and methyl-α-D-glucoside in the bioactive substance sustained release material The molar ratio of units was 60:40.
Further, when the molecular weight of this physiologically active substance sustained release material was determined by GPC, the number average molecular weight was 1500.

<Drug release test>
1 g of each of the bioactive substance sustained release materials obtained in Examples 1 to 6 was dissolved in dichloromethane, and 0.004 g of tetracaine was mixed therewith. Next, the solvent was removed under reduced pressure to obtain a sustained-release preparation.
Next, the obtained sustained-release preparation was immersed in phosphate buffered saline, and the amount of tetracaine eluted into the physiological saline over time was measured with a spectrophotometer. The results are shown in Table 1 and FIG.
As a result, it became clear that the bioactive substance sustained-release materials of Examples 1 to 6 gradually decomposed to release the drug, and disappeared after the drug was released.

(Comparative Example 1)
To a reaction vessel similar to that in Example 1, 20 g of trimethylene carbonate (manufactured by Tokyo Chemical Industry Co., Ltd., reagent) and 3.1 g of sucrose (manufactured by Aldrich Co., Ltd.) were added, and this was added at 90 ° C. under a pressure of 13 Pa for 8 hours. Reaction was performed. After the reaction, the obtained copolymer was dissolved in acetone so as to be about 10 w / v%, and purification treatment was performed by precipitating the copolymer in hexane equivalent to acetone. After the treatment, 12 g of a bioactive substance sustained release material was obtained.
As a result of obtaining the composition (molar ratio) of the obtained physiologically active substance sustained release material by ¹ H-NMR, the molar ratio of each structural unit of trimethylene carbonate and sucrose in the physiologically active substance sustained release material was: 30:70.
Further, when the molecular weight of this physiologically active substance sustained-release material was determined by GPC, the number average molecular weight was 1,400.

(Comparative Example 2)
To the same reaction vessel as in Example 1, 40 g of trimethylene carbonate (manufactured by Tokyo Chemical Industry Co., Ltd., reagent) was added, and 7 g of water was added as a catalyst thereto. After reacting at 90 ° C. for 1 hour, the reaction was performed at 160 ° C. for 7 hours under a pressure of 13 Pa. After the reaction, the obtained copolymer was dissolved in chloroform so as to be about 10 w / v%, and purification treatment was performed by precipitating the copolymer in about 3 times methanol. After the treatment, 18 g of a bioactive substance sustained release material was obtained. When the molecular weight of this bioactive substance sustained release material was determined from gel permeation chromatography (GPC), the number average molecular weight was 3000.

(Comparative Example 3)
To the same reaction vessel as in Example 1, 40 g of trimethylene carbonate (manufactured by Tokyo Chemical Industry Co., Ltd., reagent) was added, and 7 g of water was added as a catalyst thereto. After reacting at 90 ° C. for 1 hour, the reaction was performed at 160 ° C. under a pressure of 13 Pa for 15 hours. After the reaction, the obtained copolymer was dissolved in chloroform so as to be about 10 w / v%, and purification treatment was performed by precipitating the copolymer in about 3 times methanol. After the treatment, 24 g of a bioactive substance sustained release material was obtained. When the molecular weight of this physiologically active substance sustained-release material was determined from gel permeation chromatography (GPC), the number average molecular weight was 6000.

(Comparative Example 4)
To the same reaction vessel as in Example 1, 40 g of trimethylene carbonate (manufactured by Tokyo Chemical Industry Co., Ltd., reagent) was added, and 7 g of water was added as a catalyst thereto. After performing the reaction at 90 ° C. for 1 hour, the reaction was performed at a pressure of 13 Pa at 160 ° C. for 23 hours. After the reaction, the obtained copolymer was dissolved in chloroform so as to be about 10 w / v%, and purification treatment was performed by precipitating the copolymer in about 3 times methanol. After the treatment, 31 g of a bioactive substance sustained release material was obtained. When the molecular weight of this physiologically active substance sustained-release material was determined from gel permeation chromatography (GPC), the number average molecular weight was 8,000.

<Drug release test>
1 g of each bioactive substance sustained release material obtained in Comparative Examples 1 to 4 was dissolved in dichloromethane, and 0.004 g of tetracaine was mixed therewith. Next, the solvent was removed under reduced pressure to obtain a sustained-release preparation.
Next, the obtained sustained-release preparation was immersed in phosphate buffered saline, and the amount of tetracaine eluted into the physiological saline over time was measured with a spectrophotometer. The results are shown in Table 2 and FIG.
As a result, it was revealed that the bioactive substance sustained release material of Comparative Example 1 was not suitable as a sustained release material because it swelled during the drug release test, collapsed in shape, and the drug eluted rapidly. .
Moreover, in the bioactive substance sustained release materials of Comparative Examples 2 to 4, it was revealed that the drug was released over a long period of time, and the release stopped when reaching a certain ratio.

From the results of Examples 1 to 6 and Comparative Examples 1 to 4, a physiological unit comprising trimethylene carbonate and a specific saccharide as a structural unit and a copolymer having a molar ratio of 99: 1 to 35:65 of both. It became clear that the active substance sustained-release material is suitable as the sustained-release material.

(Example 7)
500 mg of the physiologically active substance sustained-release material obtained in Example 3 was mixed at 37 ° C. with 10 μL of an adenovirus vector PBS dispersion encoding the β-galactosidase gene of Escherichia coli (LacZ) as a marker gene. Then it was transplanted to the back of nude mice. 72 hours later, the nude mouse dorsal tissue was stained with an X-gal staining solution (manufactured by Invitrogen, Beta Gal staining kit) and observed with a microscope. As a result, it was confirmed that the viral vector penetrated into the tissue and the LacZ gene was expressed.
This also revealed that the physiologically active substance sustained-release material of the present invention is suitable as a sustained-release material.

Claims (9)

It consists of a copolymer having trimethylene carbonate and a saccharide containing at least one pyranose ring and / or furanose ring as a structural unit, and the molar ratio of the trimethylene carbonate and the saccharide monomer is 99: 1. A material for sustained release of a physiologically active substance, characterized in that it is ˜35: 65. The material for sustained release of a physiologically active substance according to claim 1, wherein an anionic functional group is not bonded to the pyranose ring and furanose ring contained in the saccharide. The material for sustained release of a physiologically active substance according to claim 1 or 2, wherein the saccharide is a saccharide having no reducing property. 4. The saccharide according to claim 1, wherein the saccharide is at least one selected from the group consisting of sucrose, sucrose monocaprate, sucrose monolaurate, and methyl α-D-glucoside. Bioactive substance sustained release material. The bioactive substance sustained-release material according to any one of claims 1 to 4, wherein a metal content in the copolymer is 0.5 ppm or less. It is a manufacturing method of the bioactive substance sustained release material of any one of Claims 1-5,
A method for producing a material for sustained release of a physiologically active substance, wherein a metal catalyst and an initiator are not added when polymerizing trimethylene carbonate and a saccharide containing at least one pyranose ring and / or furanose ring. The method for producing a physiologically active substance sustained-release material according to claim 6, wherein a saccharide containing at least one pyranose ring and / or furanose ring and molten trimethylene carbonate are polymerized under reduced pressure. The method for producing a material for sustained release of a physiologically active substance according to claim 7, wherein the polymerization reaction is performed at a pressure of 20 Pa or less and at a temperature of 120 ° C or less. The method for producing a material for sustained release of a physiologically active substance according to claim 6, wherein trimethylene carbonate and a saccharide containing at least one pyranose ring and / or furanose ring are polymerized in a nitrogen atmosphere in the presence of water. .

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