JP2014201606A - Slow-release compact and production method of the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a production method of slow-release compact that includes an agent and a polyglycolic acid based resin and expresses agent slow-release under the existence of moisture.SOLUTION: A production method of a slow-release compact includes: a pretreatment in which a polyglycolic acid based resin in which a calorie ΔHat a crystallization temperature Tc measured by a differential scan calorimeter under the nitrogen atmosphere, and in a temperature rising process of a rate of temperature rise of 20°C/minute is at least 1 J/g is prepared; a mixing process in which the polyglycolic acid based resin obtained by the pretreatment and an agent are mixed; and a molding process in which a mixture obtained from the mixing process is performed by compression molding at a temperature T that satisfies a condition represented by the following formula(1): Tg≤T<Tm (1) (in the formula, T denotes a molding temperature, Tg denotes a glass transformation temperature of the polyglycolic acid based resin, Tm denotes a melt temperature of the polyglycolic acid based resin, and units each denote [°C]).

Description

  The present invention relates to a sustained-release molded article and a method for producing the same, and more particularly to a sustained-release molded article containing a polyglycolic acid resin and a method for producing the same.

  A technique for gradually releasing a drug component is known as a technique for exerting the effect (medicine effect) of a drug component such as a fragrance, insect repellent, agricultural chemical, and fertilizer stably for a long time. As a sustained-release preparation using such a technique, for example, a sustained-release preparation in which a container is filled with a kneaded product of a volatile drug, a fatty acid triglyceride that is liquid at normal temperature, and a hydrophobic substance that is solid at normal temperature is proposed. (Japanese Patent Laid-Open No. 2005-75762 (Patent Document 1)).

  Also, preparations containing biodegradable polymers have attracted attention as sustained release preparations. For example, Japanese Patent Application Laid-Open No. 11-286439 (Patent Document 2) discloses a method for producing a biodegradable polymer type drug release system in which a mixture of polylactic acid and a biologically active ingredient is compression molded to a specific bulk density. Has been. Japanese Patent Application Laid-Open No. 2001-187749 (Patent Document 3) discloses a long-term sustained-release compression molding containing biodegradable α-hydroxycarboxylic acid polymer microparticles whose terminal carboxyl group is esterified with an alcohol and a drug. A formulation is disclosed, and polylactic acid, polyglycolic acid, and lactic acid-glycolic acid copolymer are described as the biodegradable α-hydroxycarboxylic acid polymer. Furthermore, Japanese translations of PCT publication No. 2004-534765 (patent document 4) discloses a tablet in which a lubricant is mixed in a mixture of a chemical substance and a dissolution regulator or a soluble polymer and a diluent, and compression-molded. As the diluent, polyglycolide, poly-L-lactide and the like are described.

JP 2005-75762 A Japanese Patent Laid-Open No. 11-286439 Japanese Patent Laid-Open No. 2001-187749 JP-T-2004-534765

  However, conventional sustained-release preparations do not necessarily have sufficient drug-releasing properties. For example, in a preparation containing a polyglycolic acid resin, the drug is released immediately in the presence of moisture. Some of them did not show sustained drug release.

  The present invention has been made in view of the above-described problems of the prior art, contains a drug and a polyglycolic acid resin, and exhibits a sustained release molded article exhibiting excellent drug sustained release in the presence of moisture, and It aims at providing the manufacturing method.

  As a result of intensive studies to achieve the above object, the present inventors used an amorphous polyglycolic acid resin when producing a molded product containing a drug and a polyglycolic acid resin. Furthermore, by molding at a specific molding temperature, it was found that the resulting molded product exhibits excellent drug sustained release in the presence of moisture, and the present invention has been completed.

That is, the method for producing the sustained-release molded article of the present invention includes:
Before preparing a polyglycolic acid-based resin having a calorific value ΔH _Tc of 1 J / g or more at a crystallization temperature Tc measured by a differential scanning calorimeter in a nitrogen atmosphere under a temperature rising process of 20 ° C./min. Processing steps;
A mixing step in which the polyglycolic acid resin obtained in the pretreatment step and the drug are mixed;
The mixture obtained in the mixing step is represented by the following formula (1):
Tg ≦ T <Tm (1)
(In the above formula, T represents the molding temperature, Tg represents the glass transition temperature of the polyglycolic acid resin, Tm represents the melting temperature of the polyglycolic acid resin, and the unit is [° C.].)
A molding step of compression molding at a temperature T that satisfies the condition represented by
It is characterized by including.

In the pretreatment step, as the polyglycolic acid resin, the following formula (2):
Crystallinity (%) = (ΔH _Tm + ΔH _Tc ) / ΔH _Tm0 × 100 (2)
(In the above formula, ΔH _Tm and ΔH _Tc represent the amount of heat at the melting temperature Tm and the crystallization temperature Tc, respectively, measured by a differential scanning calorimeter in the temperature rising process at a temperature rising rate of 20 ° C./min. ΔH _Tm0 is This represents the amount of heat at a melting temperature Tm ₀ of a glycolic acid homopolymer having a crystallinity of 100%, and the unit is [J / g])
It is preferable to prepare a glycolic acid homopolymer having a degree of crystallinity of 35% or less obtained in (1).

  In the mixing step, it is preferable that the polyglycolic acid resin obtained in the pretreatment step is pulverized while being maintained at a temperature not higher than the glass transition temperature of the polyglycolic acid resin, and then mixed with the drug. .

Furthermore, in the molding step, the following formula (1a):
Tg ≦ T <Tc (1a)
(In the above formula, T represents the molding temperature, Tg represents the glass transition temperature of the polyglycolic acid resin, Tc represents the crystallization temperature in the temperature rising process of the polyglycolic acid resin, and the unit is [° C. ]
It is preferable to perform compression molding at a temperature T that satisfies the condition represented by:

  The sustained-release molded article of the present invention is obtained by the production method of the present invention, and exhibits excellent drug sustained-release in the presence of moisture.

The reason why the sustained-release molded product obtained by the production method of the present invention exhibits excellent drug sustained-release in the presence of moisture is not necessarily clear, but the present inventors speculate as follows. That is, in the method for producing a sustained-release shaped article of the present invention, a polyglycolic acid resin having a calorific value ΔH _{Tc at} a crystallization temperature Tc of 1 J / g or more and a drug are mixed, and the resulting mixture is polyglycolic acid. Compression molding is performed at a temperature not lower than the glass transition temperature of the resin and lower than the melting temperature (preferably lower than the crystallization temperature). The polyglycolic acid resin having a calorific value ΔH _{Tc at the} crystallization temperature Tc of 1 J / g or more is an amorphous polyglycolic acid resin having a relatively low crystallinity, and such an amorphous polyglycolic acid is used. When a mixture containing a resin is compression-molded under the above temperature conditions, the resin is blocked due to stickiness of the amorphous part, so that it is presumed that a molded article having a low porosity can be obtained. In the molded product thus obtained, the drug is sealed in a polyglycolic acid resin and is protected from moisture. When moisture comes into contact with such a molded article having a low porosity, moisture hardly penetrates into the molded body, and therefore hydrolysis of the polyglycolic acid resin hardly occurs inside the molded body. And it is assumed that it occurs gradually from the outer edge. Since the drug encapsulated in the polyglycolic acid resin is released when the polyglycolic acid resin is hydrolyzed, in the molded article of the present invention, the drug is not released from the inside, and the outer surface and the outer edge. It is assumed that excellent drug sustained-release properties can be obtained as a result.

On the other hand, a polyglycolic acid resin having a heat quantity ΔH _Tc of less than 1 J / g at the crystallization temperature Tc is a crystalline polyglycolic acid resin having a relatively high degree of crystallinity. Even if the resin is compression-molded under the above temperature conditions, it is presumed that there are many voids in the obtained molded article because the resin is hardly blocked. When moisture comes into contact with such a molded body having many voids, moisture penetrates into the molded body. Therefore, it is assumed that the drug in the molded body easily comes into contact with moisture and is quickly released. For this reason, it is presumed that such a molded article cannot provide sustained drug release.

  In addition, even when a mixture containing an amorphous polyglycolic acid resin is compression molded at a temperature lower than the glass transition temperature of the polyglycolic acid resin, resin blocking is unlikely to occur. Therefore, it is assumed that moisture penetrates into the molded body and the sustained drug release property cannot be obtained.

  On the other hand, when a mixture containing an amorphous polyglycolic acid resin is compression molded at a temperature equal to or higher than the melting temperature of the polyglycolic acid resin, the deactivation of the drug due to the high melting temperature, There is a possibility that the polyglycolic acid resin is decomposed by the reaction with the polyglycolic acid resin.

  ADVANTAGE OF THE INVENTION According to this invention, it becomes possible to obtain the sustained release molded object which contains a chemical | medical agent and polyglycolic acid type-resin, and shows the chemical | medical agent sustained release in presence of a water | moisture content.

It is a graph which shows the influence of the crystallinity degree of polyglycolic acid resin and molding temperature which give to KBr sustained release property. It is a graph which shows the influence of the crystallinity degree of the polyglycolic acid resin which gives to tartrazine sustained release property. It is a graph which shows the influence of the pressure at the time of compression molding which gives to drug sustained release property.

  Hereinafter, the present invention will be described in detail with reference to preferred embodiments thereof. First, the components used in the present invention will be described.

(Polyglycolic acid resin)
A polyglycolic acid resin (hereinafter also referred to as “PGA resin”) used as a raw material in the present invention is represented by the following formula (1):
_{- [O-CH 2 -C (} = O)] - (1)
A glycolic acid homopolymer consisting only of glycolic acid repeating units represented by the formula (hereinafter referred to as “PGA homopolymer”, including a ring-opened polymer of glycolide which is a bimolecular cyclic ester of glycolic acid). And a polyglycolic acid copolymer containing glycolic acid repeating units (hereinafter referred to as “PGA copolymer”). Such PGA-type resin may be used individually by 1 type, or may use 2 or more types together.

  The PGA homopolymer can be synthesized by dehydration polycondensation of glycolic acid, dealcoholization polycondensation of glycolic acid alkyl ester, ring-opening polymerization of glycolide, etc., among which it is preferable to synthesize by ring-opening polymerization of glycolide. . Such ring-opening polymerization can be carried out by either bulk polymerization or solution polymerization.

  The PGA copolymer can be synthesized by using a comonomer in combination in such a polycondensation reaction or ring-opening polymerization reaction. Such comonomers include ethylene oxalate (ie, 1,4-dioxane-2,3-dione), lactides, lactones (eg, β-propiolactone, β-butyrolactone, β-pivalolactone, γ- Butyrolactone, δ-valerolactone, β-methyl-δ-valerolactone, ε-caprolactone, etc.), carbonates (eg, trimethylene carbonate, etc.), ethers (eg, 1,3-dioxane, etc.), ether esters ( For example, cyclic monomers such as dioxanone), amides (such as ε-caprolactam); hydroxycarboxylic acids such as lactic acid, 3-hydroxypropanoic acid, 3-hydroxybutanoic acid, 4-hydroxybutanoic acid, 6-hydroxycaproic acid or Its alkyl ester; ethylene glycol, 1 Aliphatic diols such as 1,4-butanediol, succinic acid, and substantially equimolar mixture of an aliphatic dicarboxylic acid or its alkyl esters such as adipic acid. These comonomers may be used individually by 1 type, or may use 2 or more types together.

  Catalysts used when the PGA resin is produced by ring-opening polymerization of glycolide include tin compounds such as tin halides and tin organic carboxylates; titanium compounds such as alkoxy titanates; aluminum compounds such as alkoxy aluminums Known ring-opening polymerization catalysts such as zirconium compounds such as zirconium acetylacetone; antimony compounds such as antimony halides and antimony oxides;

  The PGA resin can be produced by a conventionally known polymerization method, and the polymerization temperature is preferably 120 to 300 ° C, more preferably 130 to 250 ° C, particularly preferably 140 to 220 ° C, and 150 to 200. C is most preferred. When the polymerization temperature is less than the lower limit, the polymerization tends not to proceed sufficiently. On the other hand, when the polymerization temperature exceeds the upper limit, the produced resin tends to be thermally decomposed.

  The polymerization time of the PGA resin is preferably 2 minutes to 50 hours, more preferably 3 minutes to 30 hours, and particularly preferably 5 minutes to 18 hours. When the polymerization time is less than the lower limit, the polymerization tends not to proceed sufficiently. On the other hand, when the polymerization time exceeds the upper limit, the generated resin tends to be colored.

In the PGA resin used in the present invention, the content of the glycolic acid repeating unit represented by the formula (1) is preferably 70% by mass or more, more preferably 80% by mass or more, and further preferably 90% by mass or more. 100 mass% is particularly preferable. When the content of the glycolic acid repeating unit is less than the lower limit, the properties as a PGA-based resin tend to be impaired.

  The weight average molecular weight of such a PGA resin is preferably 30,000 to 800,000, more preferably 50,000 to 500,000, and particularly preferably 80,000 to 300,000. The weight average molecular weight is a polymethylmethacrylate conversion value measured by gel permeation chromatography (GPC).

(Drug)
There is no restriction | limiting in particular as a chemical | medical agent used for this invention, For example, the well-known chemical | medical agent used in various fields, such as a civil engineering related field | area (for example, bioremediation) and an agricultural field | area (for example, insecticide / bactericidal / herbicide) is mentioned. .

  Examples of chemicals used in civil engineering-related fields include alkali metal salts such as sodium nitrate, potassium nitrate, potassium monohydrogen phosphate and potassium dihydrogen phosphate, and alkaline earth metal salts such as magnesium sulfate and calcium acetate; ferrous sulfate Transition metal salts such as manganese chloride; alkaline earth metal peroxides such as calcium peroxide and magnesium peroxide; inorganic ammonium salts such as ammonium sulfate, ammonium chloride and ammonium phosphate; vitamins, amino acids, nucleic acids, etc. Can be mentioned.

  Examples of drugs used in the agricultural field include organophosphorus, organochlorine, synthetic pyrethroids, carbamates, oxadiazoles, nereistoxins, amidinohydrazones, chloronicotyl neonicotinoids, and furnicotyl neonicotis. Various insecticides such as noids, thianicotyl neonicotinoids, phenylpyrazoles, and maclaroids; inorganic sulfurs, organic sulfurs, inorganic coppers, organic coppers, organic chlorines, organic phosphoruss, carboxamides, benzimidazoles , Triazoles, strobilurins, ergosterols, guanidines and other fungicides; phenoxys, bipyridiniums, ureas, sulfonylureas, fatty acids, acid amides, inorganics, triazines, nitriles, uracils , Carbamate, aniline, organic System, and a variety of herbicides, such as amino acid-based.

<Method for producing sustained-release molded article>
Next, the manufacturing method of the sustained-release molded object of this invention is demonstrated. The method for producing a sustained-release molded article of the present invention comprises a pretreatment step of preparing an amorphous PGA resin from a raw PGA resin, and an amorphous PGA resin obtained in the pretreatment step. It is a method including a mixing step of mixing a drug and a molding step of compression-molding the mixture obtained in this mixing step at a predetermined temperature.

(Pretreatment process)
In the method for producing a sustained-release molded article of the present invention, first, an amorphous PGA-based resin is prepared from a raw material PGA-based resin. In the present invention, the amorphous PGA-based resin is a crystallization temperature Tc [unit: ° C.] measured by a differential scanning calorimeter in a temperature rising process at a temperature rising rate of 20 ° C./min in a nitrogen atmosphere. This means a PGA resin having a calorific value ΔH _Tc of 1 J / g or more, and has a relatively low crystallinity. The amount of heat ΔH _{Tc at the} crystallization temperature Tc is obtained by using a differential scanning calorimeter (DSC) and heating the PGA resin from 0 ° C. to 300 ° C. at a temperature rising rate of 20 ° C./min in a nitrogen atmosphere. It can be determined from the DSC spectrum. That is, since the DSC spectrum of the amorphous PGA-based resin has an exothermic peak accompanying crystallization, the amount of heat ΔH _Tc at the crystallization temperature Tc can be obtained from the area of this exothermic peak. On the other hand, the DSC spectrum of the highly crystallized PGA resin does not show an exothermic peak due to crystallization, and the heat quantity ΔH _{Tc at the} crystallization temperature _Tc is 0 J / g.

The amount of heat ΔH _Tc at the crystallization temperature Tc is the amount of heat generated when the amorphous PGA-based resin is crystallized. Therefore, the PGA-based resin with a larger amount of amorphous portion is a PGA-based resin with a larger amount of heat ΔH _Tc. It means that there is. Accordingly, since the PGA resin having a calorific value ΔH _Tc of less than 1 J / g has few amorphous parts, blocking of the PGA resin is difficult to occur, and the encapsulation of the drug due to blocking of the PGA resin does not sufficiently function, It is difficult to form a molded article exhibiting a good drug sustained release property. In the present specification, the PGA resin having a calorific value ΔH _Tc of less than 1 J / g is referred to as “crystalline PGA resin”. On the other hand, since the PGA resin having a heat quantity ΔH _Tc of 1 J / g or more has many amorphous parts, the PGA resin is often blocked by compression molding at a glass transition temperature or higher, and a molded article having a low porosity is obtained. It is done. Moreover, in such a molded body, the chemical | medical agent is enclosed with PGA-type resin, and will be in the state protected from the water | moisture content. And, when moisture comes into contact with such a molded body, hydrolysis of the PGA resin gradually occurs from the outer surface and outer edge of the molded body, and the drug contained in the hydrolyzed PGA resin is released. Thus, since the drug is gradually released from the outer surface and the outer edge of the molded article, excellent drug sustained release can be obtained. And, in order to form a molded article exhibiting more excellent drug sustained release properties, PGA-based resin having more amorphous parts is preferable. Therefore, the heat quantity ΔH _Tc is preferably 5 J / g or more, 10 J / g or more is more preferable, and 15 J / g or more is particularly preferable.

As a specific pretreatment method, for example, a raw material PGA-based resin is heated and melted, and the obtained PGA-based resin melt is rapidly cooled. Thereby, an amorphous PGA resin having a heat quantity ΔH _{Tc in the} above range can be obtained. In the pretreatment method, the heating temperature is preferably 200 to 300 ° C, more preferably 230 to 280 ° C, and particularly preferably 240 to 270 ° C. When the heating temperature is less than the lower limit, the raw material PGA resin is insufficiently melted, and it tends to be difficult to obtain an amorphous PGA resin after extrusion quenching. Tend to pyrolyze. Moreover, as a cooling rate at the time of rapid cooling, -50 degreeC / min or more is preferable and -150 degreeC / min or more is more preferable. When cooled at a rate slower than the above range, a crystalline PGA resin tends to be obtained. As a specific method of rapid cooling at the cooling rate, the PGA resin melt is kept at 40 ° C. or lower (more preferably 10 ° C. or lower) within 1 second (more preferably within 0.5 second) after the end of heating. And a method of charging the refrigerant (for example, water).

In the pretreatment step, the PGA-based resin has a glycolic acid weight of 35% or less (more preferably 30% or less, still more preferably 25% or less, particularly preferably 20% or less). It is preferable to prepare a coalescence (hereinafter also referred to as “PGA resin”). When the crystallinity of the PGA resin exceeds the upper limit, blocking of the PGA resin is difficult to occur, and the encapsulation of the drug due to the blocking of the PGA resin does not sufficiently act, and sufficient drug sustained release tends to be not obtained. The crystallinity is expressed by the following formula (2):
Crystallinity (%) = (ΔH _Tm + ΔH _Tc ) / ΔH _Tm0 × 100 (2)
Is required.

In the above formula (2), ΔH _Tm and ΔH _Tc are respectively measured by a differential scanning calorimeter (DSC) during the temperature rising process at a temperature rising rate of 20 ° C./minute, and the heat amounts at the melting temperature Tm and the crystallization temperature Tc [units] : J / g], and ΔH _Tm0 represents the amount of heat [unit: J / g] at the melting temperature Tm ₀ of the PGA resin having a crystallinity of 100%. The amount of heat ΔH _{Tm at the} melting temperature Tm can be obtained from the DSC spectrum obtained by heating the PGA resin from 0 ° C. to 300 ° C. at a rate of temperature increase of 20 ° C./min in a nitrogen atmosphere using DSC. it can. That is, since an endothermic peak accompanying melting of the PGA resin exists in the DSC spectrum of the PGA resin, the amount of heat ΔH _Tm at the melting temperature Tm can be obtained from the area of the endothermic peak.

  As a pretreatment method for preparing the PGA resin having the crystallinity, the raw PGA resin is melted by heating at 240 to 270 ° C., and the obtained PGA resin melt is −150 ° C./min or more. A method of quenching at a cooling rate of is preferable. As a specific method for rapidly cooling at the cooling rate, a method of charging a PGA resin melt into a refrigerant (for example, water) of 10 ° C. or less within 0.5 seconds after the completion of heating may be mentioned. .

(Mixing process)
Next, the amorphous PGA resin obtained in the pretreatment step and the drug are mixed. At this time, the amorphous PGA resin is preferably pulverized in advance. The average particle size of the amorphous PGA resin pulverized product (amorphous PGA resin particles) is preferably 1 mm or less, more preferably 500 μm or less, further preferably 250 μm or less, and particularly preferably 150 μm or less. When the average particle diameter of the amorphous PGA resin particles exceeds the upper limit, it becomes difficult to uniformly mix the amorphous PGA resin particles and the drug, and blocking of the amorphous PGA resin particles. Encapsulation of the drug by this does not work sufficiently, and there is a tendency that sufficient drug sustained release cannot be obtained. The lower limit of the average particle diameter of the amorphous PGA resin particles is not particularly limited, but PGA resin particles having a small average particle diameter are likely to be crystallized due to an increase in the temperature of the PGA resin during pulverization. Therefore, 50 μm or more is preferable.

  The amorphous PGA-based resin is preferably pulverized while maintaining the glass transition temperature Tg or lower. When the temperature of the PGA resin exceeds the Tg, the resin tends to soften and become difficult to pulverize. Examples of the method of pulverizing the PGA resin while maintaining the temperature below the glass transition temperature Tg include a method of pulverizing the PGA resin with dry ice or liquid nitrogen.

  The mixing method of the amorphous PGA resin and the drug is not particularly limited as long as the amorphous PGA resin is not heated and mixed. For example, dry blending, mixer blending, manual plastic bag And the like. When the PGA-based resin is heated and mixed in the mixing step, the amorphous PGA-based resin is easily crystallized, and it becomes difficult to obtain sufficient drug sustained release properties.

  The compounding ratio of the amorphous PGA resin and the drug is not particularly limited, but the amorphous PGA resin is 99 to 10% with respect to the total amount of the amorphous PGA resin and the drug. % By weight and 1 to 90% by weight of drug (more preferably 99 to 30% by weight of amorphous PGA resin and 1 to 70% by weight of drug, particularly preferably 99% of amorphous PGA resin). -50 mass% and 1-50 mass% of the drug) are preferably mixed. When the amount of the drug is less than the lower limit, the amount of the drug released is small and the effect of the drug itself tends not to be sufficiently obtained. On the other hand, when the upper limit is exceeded, the amorphous PGA resin is blocked. Encapsulation of the drug becomes difficult, and it tends to be difficult to produce a molded article exhibiting desired drug sustained release properties.

(Molding process)
Next, the mixture obtained in the mixing step is represented by the following formula (1):
Tg ≦ T <Tm (1)
Compression molding is performed at a temperature T that satisfies the condition expressed by:

  In the formula (1), T represents the molding temperature [° C.], Tg represents the glass transition temperature [° C.] of the PGA resin, and Tm represents the melting temperature [° C.] of the PGA resin. Tg and Tm can be determined from the DSC spectrum obtained by heating the PGA resin from 0 ° C. to 300 ° C. at a temperature rising rate of 20 ° C./min in a nitrogen atmosphere using DSC.

  By molding a mixture of an amorphous PGA resin and a drug at a temperature that satisfies the condition represented by the above formula (1), a molded article exhibiting excellent drug sustained release can be obtained. On the other hand, when T <Tg, blocking of the PGA resin hardly occurs, the encapsulation of the drug due to the blocking of the PGA resin does not sufficiently act, and sufficient drug sustained release cannot be obtained, while T ≧ Tm. In this case, the polyglycolic acid resin may be decomposed due to the deactivation of the encapsulated drug or the reaction between the drug and the polyglycolic acid resin due to the high temperature.

The molding temperature T is expressed by the following formula (1a):
Tg ≦ T <Tc (1a)
It is preferable that the condition represented by

  In the formula (1a), T represents a molding temperature [° C.], Tg represents a glass transition temperature [° C.] of the PGA resin, and Tc represents a crystallization temperature [° C.] in the temperature rising process of the PGA resin. . Tg and Tc can be obtained from a DSC spectrum obtained by heating a PGA resin from 0 ° C. to 300 ° C. at a temperature rising rate of 20 ° C./min using a DSC in a nitrogen atmosphere.

  By compression molding of a mixture of an amorphous PGA resin and a drug at a temperature that satisfies the condition represented by the formula (1a), the PGA resin blocking is reliably generated during the compression molding, thereby ensuring the drug. It is possible to encapsulate the molded body in a stable manner and to obtain a molded article exhibiting more excellent drug sustained release properties. On the other hand, when the molding temperature T becomes T <Tg, the amorphous PGA-based resin is not softened, blocking is difficult to occur, and drug encapsulation is insufficient, so that sufficient drug sustained release cannot be obtained. On the other hand, when T ≧ Tc, the amorphous PGA resin is crystallized at the time of compression molding, and blocking is difficult to occur. Encapsulation of the drug due to blocking of the PGA resin does not work sufficiently, and is sufficient. There is a tendency that sustained drug release cannot be obtained.

  Furthermore, the molding temperature T is preferably less than the decomposition temperature of the drug, that is, T <Td (Td represents the drug decomposition temperature [° C.]). When T ≧ Td, the drug is decomposed during compression molding, and the effect of the drug itself tends not to be sufficiently obtained.

  Although there is no restriction | limiting in particular as compression molding pressure, 0.1-100 Mpa is preferable, 1-80 Mpa is more preferable, and 5-50 Mpa is especially preferable. When the compression molding pressure is less than the lower limit, blocking of the PGA resin is unlikely to occur, the encapsulation of the drug due to blocking of the PGA resin does not sufficiently function, and sufficient drug sustained release tends not to be obtained, If the upper limit is exceeded, the amorphous PGA resin powder escapes, and it is difficult to apply a pressure higher than that.

  Although there is no restriction | limiting in particular as compression molding time, 0.5 minute or more is preferable and 1 minute or more is especially preferable. When the compression molding time is less than the lower limit, the encapsulation of the drug due to blocking of the PGA resin does not sufficiently act, and sufficient drug sustained release tends to be not obtained.

  In the sustained-release molded article of the present invention thus obtained, in the absence of moisture, the amorphous PGA-based resin restricts the movement of the drug, so that the drug is released from the molded article. In addition, it has excellent storage properties. On the other hand, in the presence of moisture, the amorphous PGA-based resin on the surface of the molded body is gradually hydrolyzed, so that the drug encapsulated by the hydrolyzed PGA-based resin is gradually released and is excellent. Sustained drug release is obtained.

  EXAMPLES Hereinafter, although this invention is demonstrated more concretely based on an Example and a comparative example, this invention is not limited to a following example. The PGA resin used in Examples and Comparative Examples was synthesized by the following method. Moreover, the average particle diameter of particle | grains, the physical property of PGA resin, and the characteristic of the molded object were measured with the following method.

(Synthesis example)
A SUS container (capacity: 56 L) having a steam jacket structure equipped with a stirrer was charged with 22500 g of glycolide and 0.68 g (30 mass ppm) of dichloride dihydrate, and the total proton concentration in the container was 0.13. Water 1.49g was added so that it might become mol%. Note that all protons in the container include protons of moisture (humidity) in the atmosphere in the container, and the amount of water added takes into account the amount of water (0.11 g) in the atmosphere in the container. Decided. Thereafter, the container was sealed, and steam was circulated through the jacket while stirring, and the mixture was heated until the temperature of the mixture in the container reached 100 ° C. to melt the mixture to obtain a uniform liquid mixture.

  Next, a reactor comprising a jacket-structured main body provided with a reaction tube (made of SUS304) having an inner diameter of 24 mm and two jacket-structured metal plates (made of SUS304) was prepared. After attaching one of the metal plates (hereinafter referred to as “lower plate”) to the lower opening of the reaction tube, the temperature of the liquid mixture is maintained at 100 ° C. from the upper opening of the reaction tube. It was transferred as it was. Immediately after the transfer, the other metal plate (hereinafter referred to as “upper plate”) was attached and the reaction tube was sealed. Thereafter, a heat medium oil at 170 ° C. was circulated through the main body and a jacket of two metal plates and held for 7 hours to synthesize a polyglycolic acid resin (PGA resin).

  Next, the heat medium oil circulating in the jacket was cooled to cool the reaction apparatus to near room temperature. Thereafter, the lower plate was removed, and the PGA resin mass was taken out from the lower opening of the reaction tube. In addition, when a PGA resin is synthesized by this method, the yield is almost 100%. The obtained PGA resin block was pulverized by a pulverizer.

<Average particle size>
The PGA resin composition particles are dispersed in water containing a surfactant ("SN Dispersant 7347-c diluted solution" manufactured by San Nopco Co., Ltd.), and a laser diffraction particle size distribution analyzer (Co., Ltd.) is used for the particle dispersion. The particle size distribution was determined using “SALADA-3000S” manufactured by Shimadzu Corporation, and the particle size at which the cumulative mass was 50% from the small particle size side was defined as the average particle size d50.

<Physical properties of PGA resin>
10 mg of PGA resin is weighed in an aluminum pan, and this is mounted on a differential scanning calorimeter (“DSC60-A” manufactured by Shimadzu Corporation), and the temperature rising rate is 20 ° C./min from 0 ° C. to 300 ° C. in a nitrogen atmosphere. And heated. Based on the obtained DSC spectrum, the glass transition temperature Tg of the PGA resin is obtained from the second-order transition start temperature of the calorie in the second-order transition region corresponding to the transition region from the glass state to the rubber state, and the exothermic peak accompanying crystallization The crystallization temperature Tc and its heat quantity ΔH _Tc in the temperature rising process were obtained from the above, and the melting temperature Tm and its heat quantity ΔH _Tm were obtained from the endothermic peak accompanying melting. The crystallization temperature Tc in the temperature rising process is found in the DSC spectrum of the amorphous PGA resin, but not in the crystallized PGA resin.

From these calorific values ΔH _Tc and ΔH _Tm , the crystallinity of the PGA resin was determined using the following formula (2).
Crystallinity (%) = (ΔH _Tm + ΔH _Tc ) / ΔH _Tm0 × 100 (2)
In the above formula, ΔH _Tm0 is the amount of heat (−200 J / g) at the melting temperature Tm ₀ of a PGA resin having a crystallinity of 100%.

<Formability evaluation>
The moldability of the molded body was determined according to the following criteria.
A: The molded body did not collapse even when pressed with a finger, and the molded body was translucent. In addition, when the crimping | compression-bonding of resin by blocking of an amorphous part occurs, the part will become translucent.
B: The molded body did not collapse even when pressed with a finger, but there was a translucent portion in the molded body.
C: The molded body collapsed when pressed with a finger.

<Hardness of molded body>
For the hardness of the molded body, the molded body was cut out to produce a test piece (20 mm × 20 mm × 1 mm), and this test piece was subjected to a tensile / compression tester (“RTC-1210A” manufactured by Orientec Co., Ltd., load: 1 kN). Was used to measure the compression test.

(Example 1-1)
About 100 parts by mass of the PGA resin pulverized product obtained in the above synthesis example, an approximately equimolar mixture of mono and distearyl acid phosphates (“ADEKA STAB AX-71” manufactured by ADEKA) 0.030 as a heat stabilizer Part by mass was added and mixed. The temperature of the 10 sections and the die provided with the mixture from the supply unit to the discharge unit is 200 ° C, 230 ° C, 260 ° C, 270 ° C, 270 ° C, 270 ° C, 270 ° C, 250 ° C in order from the supply unit. , 240 ° C., 230 ° C., and 230 ° C., and a twin-screw kneading extruder (“TEM-41SS” manufactured by Toshiba Machine Co., Ltd.) was melt-kneaded. This melt-kneaded product was extruded into a strand shape and immediately cooled in water at 10 ° C. to produce a PGA resin strand. This strand was pulverized with a pelletizer to obtain a pellet-like PGA resin composition. The obtained pellet-like PGA resin composition was pulverized twice at a temperature of −50 ° C. and a peripheral speed of 187 m / s using a pulverizer to obtain PGA resin composition particles.

When the average particle diameter d50 of the obtained PGA resin composition particles was determined according to the above method, it was 100 μm. Further, the glass transition temperature Tg of the PGA resin in the PGA resin composition particles, the crystallization temperature Tc at the time of temperature rise and its calorie ΔH _Tc , the melting temperature Tm and its calorie ΔH _Tm , and the crystallinity were determined according to the above method. . The results are shown in Table 1. As is clear from the results shown in Table 1, this PGA resin was confirmed to be amorphous.

Next, the PGA resin composition particles are sandwiched between an aluminum sheet together with a sheet molding die (set film thickness: 1 mm), further sandwiched between ferrotype plates, and placed on a heat press at 80 ° C. to 110 kgf / cm ² (10 .8 MPa) for 1 minute. The appearance of the obtained PGA resin sheet (50 mm × 50 mm × 1 mm) (molded body) was visually observed, and the moldability was evaluated based on the above criteria. The results are shown in Table 1.

(Example 1-2)
After heating (annealing) the PGA resin composition particles obtained in the same manner as in Example 1 at 80 ° C. for 30 seconds, the glass transition temperature Tg of the PGA resin in the PGA resin composition particles, the crystallization temperature at the time of temperature increase Tc and its calorific value ΔH _Tc , melting temperature Tm and calorie ΔH _Tm , and crystallinity were determined according to the above methods. The results are shown in Table 1. As is clear from the results shown in Table 1, this PGA resin was confirmed to be amorphous. Next, a PGA resin sheet (50 mm × 50 mm × 1 mm) (molded body) was produced in the same manner as in Example 1, and the moldability was evaluated. The results are shown in Table 1.

(Comparative Example 1-1)
After heating (annealing) the PGA resin composition particles obtained in the same manner as in Example 1 at 80 ° C. for 5 minutes, the glass transition temperature Tg of the PGA resin in the PGA resin composition particles, the crystallization temperature at the time of temperature increase Tc and its calorific value ΔH _Tc , melting temperature Tm and calorie ΔH _Tm , and crystallinity were determined according to the above methods. The results are shown in Table 1. As is clear from the results shown in Table 1, this PGA resin was confirmed to be crystalline. Next, a PGA resin sheet (50 mm × 50 mm × 1 mm) (molded body) was produced in the same manner as in Example 1, and the moldability was evaluated. The results are shown in Table 1.

(Comparative Example 1-2)
After heating (annealing) the PGA resin composition particles obtained in the same manner as in Example 1 at 80 ° C. for 20 minutes, the glass transition temperature Tg of the PGA resin in the PGA resin composition particles, the crystallization temperature at the time of temperature increase Tc and its calorific value ΔH _Tc , melting temperature Tm and calorie ΔH _Tm , and crystallinity were determined according to the above methods. The results are shown in Table 1. As is clear from the results shown in Table 1, this PGA resin was confirmed to be crystalline. Next, a PGA resin sheet (50 mm × 50 mm × 1 mm) (molded body) was produced in the same manner as in Example 1, and the moldability was evaluated. The results are shown in Table 1.

As is clear from the results shown in Table 1, a PGA resin (amorphous PGA resin) having a heat quantity ΔH _Tc of 1 J / g or more (preferably a crystallinity of 35% or less) at the crystallization temperature Tc was used. In the case (Examples 1-1 to 1-2), a PGA resin having a heat quantity ΔH _Tc of 0 J / g (crystallinity of 40% or more) at the crystallization temperature Tc was used (Comparative Examples 1-1 to 1-1). Compared with 1-2), it was confirmed that the PGA resin sheet (molded body) can be molded well.

(Example 2-1)
95 mass parts of PGA resin composition particles containing amorphous PGA resin obtained in the same manner as in Example 1-1 and 5 mass of potassium bromide (KBr, molecular weight 119.02, density 2.75 g / cm ³ ) The resulting mixture was sandwiched with an aluminum sheet together with a sheet molding die (set film thickness: 1 mm), further sandwiched between ferrotype plates and placed on a heat press at 60 ° C. to 110 kgf / cm ^2. Pressurization was performed at (10.8 MPa) for 1 minute. It was 600 N when the hardness of the obtained mixture sheet (50 mm x 50 mm x 1 mm) (molded article) was measured according to the above method.

(Comparative Example 2-1)
A mixture sheet (50 mm × 50 mm × 1 mm) in the same manner as in Example 2-1, except that the temperature of the heat press was changed to room temperature (25 ° C.) and the press pressure was changed to 169 kgf / cm ² (16.6 MPa). Was made. The hardness of the mixture sheet (molded product) was measured in accordance with the above method and found to be 77N.

(Comparative Example 2-2)
The PGA resin composition particles were prepared in the same manner as in Example 1-1, except that the melt-kneaded product was extruded into a strand shape and then gradually cooled to room temperature instead of rapid cooling (cooling rate: equivalent to −49 ° C./min). did. It was 96 micrometers when the average particle diameter d50 of this PGA resin composition particle | grain was calculated | required according to the said method. Further, when the glass transition temperature Tg of the PGA resin in the PGA resin composition particles, the crystallization temperature Tc at the time of temperature rise and the heat quantity ΔH _Tc , the melting temperature Tm, and the crystallinity were determined according to the above method, Tg: 49 0.7 ° C, Tc: not detected, ΔH _Tc : 0 J / g, Tm: 221.21 ° C, crystallinity: 43.0%. Therefore, it was confirmed that this PGA resin was crystalline. Next, a mixture sheet (50 mm × 50 mm × 1 mm) was produced in the same manner as in Example 2-1, except that 95 parts by mass of the PGA resin composition particles were used. When this mixture sheet (molded body) was pressed with a finger, no collapse was observed, and it was confirmed that the hardness was 30 N or more.

(Comparative Example 2-3)
A mixture sheet (50 mm × 50 mm × 1 mm) was produced in the same manner as in Comparative Example 2-2 except that the temperature of the heat press was changed to room temperature (25 ° C.). When this mixture sheet (molded body) was pressed with a finger, collapse occurred and it was confirmed that the hardness was less than 30N.

(Comparative Example 2-4)
Except that the temperature of the heat press machine was changed to 250 ° C., an attempt was made to prepare a mixture sheet in the same manner as in Example 2-1, but KBr and the PGA resin composition reacted during press molding, and the PGA resin composition was It decomposed to a low molecular weight, and the desired mixture sheet (molded product) could not be obtained.

(Example 3-1)
Instead of potassium bromide the following formula:

In the same manner as in Example 2-1, except that 5 parts by mass of tartrazine represented by the formula (Yellow No. 4, molecular weight: 534.37) was used and the temperature of the heat press machine was changed to 80 ° C., a mixture sheet (50 mm × 50 mm × 1 mm). It was 600 N when the hardness of this mixture sheet (molded body) was measured according to the above method.

(Example 3-2)
A mixture sheet (50 mm × 50 mm × 1 mm) was produced in the same manner as in Example 3-1, except that the pressing pressure was changed to 450 kgf / cm ² (44.1 MPa). The hardness of the mixture sheet was measured according to the above method and found to be 600N.

(Comparative Example 3-1)
A mixture sheet (50 mm × 50 mm × 1 mm) as in Example 3-1 except that 95 parts by mass of PGA resin composition particles containing a crystalline PGA resin obtained in the same manner as in Comparative Example 2-2 were used. Was made. When this mixture sheet (molded body) was pressed with a finger, no collapse was observed, and it was confirmed that the hardness was 30 N or more.

<Slow release test>
The test piece (20 mm × 20 mm × 1 mm) was cut by cutting the mixture sheet prepared in Example 2-1, Examples 3-1 to 3-2, Comparative Examples 2-1 to 2-4, and Comparative Example 3-1. Produced. This test piece was immersed in 300 ml of water and allowed to stand at a temperature of 25 ° C. The concentration of the drug (potassium bromide or tartrazine) in water was measured every predetermined time by the following method, and the amount of the drug released from the mixed sheet (molded body) was determined. The results are shown in FIGS.

(Potassium bromide concentration)
The potassium bromide concentration was calculated from the bromide ion concentration measured using a bromide ion electrode (“8005-10C” manufactured by Horiba, Ltd.).

(Tartrazine concentration)
The concentration of tartrazine was determined by measuring the absorbance from the transmittance at a wavelength of 427 nm using a visible ultraviolet spectrophotometer (“UV-260” manufactured by Shimadzu Corporation), and calculating the concentration of tartrazine in water from a calibration curve prepared in advance. . The calibration curve was obtained by measuring the transmittance at a wavelength of 427 nm of a concentration-adjusted tartrazine aqueous solution whose concentration was adjusted to 8, 12, 16, 20, 24 × 10 ⁻⁶ mol / L, and calculating the absorbance (−log ( The transmittance / 100)) was calculated, and the absorbance was plotted against the concentration.

  As is clear from the results shown in FIG. 1, when an amorphous PGA resin having a crystallinity of 35% or less is used and molded at a temperature (60 ° C.) of Tg to Tm of the PGA resin (Example) In 2-1), a molded article exhibiting excellent KBr sustained release property was obtained. On the other hand, when the amorphous PGA resin is used and molded at a temperature (room temperature) lower than the Tg of the PGA resin (Comparative Example 2-1), about 90% in one day after the start of the sustained release test. Thus, a molded product having a KBr sustained release property was not obtained. When a crystalline PGA resin having a crystallinity of 40% is used (Comparative Examples 2-2 and 2-3), potassium bromide is released immediately after the start of the sustained release test, and the KBr sustained release property A molded product having the following was not obtained.

  As is clear from the results shown in FIG. 2, even when tartrazine (Yellow No. 4) is used as a drug, the amorphous PGA resin is used, and the temperature (Tg to Tm) of the PGA resin ( When molded at 80 ° C., a molded product exhibiting excellent tartrazine sustained release was obtained (Example 3-1), but when the crystalline PGA resin was used, tartrazine was released immediately after the start of the sustained release test. Thus, a molded article having a tartrazine sustained release property was not obtained (Comparative Example 3-1).

  Furthermore, as is clear from the results shown in FIG. 3, it was found that the tartrazine sustained-release property is improved by increasing the pressure during molding.

  As described above, according to the present invention, it is possible to obtain a molded article that contains a drug and a polyglycolic acid resin and exhibits excellent drug sustained release in the presence of moisture.

  Therefore, the method for producing a sustained-release molded article of the present invention is useful as a method for producing a sustained-release preparation used in an environment where moisture exists, such as civil engineering-related fields and agricultural fields.

Claims (5)

Before preparing a polyglycolic acid-based resin having a calorific value ΔH _Tc of 1 J / g or more at a crystallization temperature Tc measured by a differential scanning calorimeter in a nitrogen atmosphere under a temperature rising process of 20 ° C./min. Processing steps;
A mixing step in which the polyglycolic acid resin obtained in the pretreatment step and the drug are mixed;
The mixture obtained in the mixing step is represented by the following formula (1):
Tg ≦ T <Tm (1)
(In the above formula, T represents the molding temperature, Tg represents the glass transition temperature of the polyglycolic acid resin, Tm represents the melting temperature of the polyglycolic acid resin, and the unit is [° C.].)
A molding step of compression molding at a temperature T that satisfies the condition represented by
A method for producing a sustained-release shaped article comprising: In the pretreatment step, as the polyglycolic acid resin, the following formula (2):
Crystallinity (%) = (ΔH _Tm + ΔH _Tc ) / ΔH _Tm0 × 100 (2)
(In the above formula, ΔH _Tm and ΔH _Tc represent the amount of heat at the melting temperature Tm and the crystallization temperature Tc, respectively, measured by a differential scanning calorimeter in the temperature rising process at a temperature rising rate of 20 ° C./min. ΔH _Tm0 is This represents the amount of heat at a melting temperature Tm ₀ of a glycolic acid homopolymer having a crystallinity of 100%, and the unit is [J / g])
A method for producing a sustained-release molded article according to claim 1, wherein a glycolic acid homopolymer having a crystallinity of 35% or less is prepared.   In the mixing step, the polyglycolic acid resin obtained in the pretreatment step is pulverized while being maintained at a temperature not higher than the glass transition temperature of the polyglycolic acid resin, and then mixed with the drug. Item 3. A method for producing a sustained-release molded article according to Item 1 or 2. In the molding step, the following formula (1a):
Tg ≦ T <Tc (1a)
(In the above formula, T represents the molding temperature, Tg represents the glass transition temperature of the polyglycolic acid resin, Tc represents the crystallization temperature in the temperature rising process of the polyglycolic acid resin, and the unit is [° C. ]
The method for producing a sustained-release molded article according to any one of claims 1 to 3, wherein the molding is performed at a temperature T that satisfies the condition represented by:   A sustained-release shaped article obtained by the production method according to any one of claims 1 to 4.

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