JP2000072692A - Controlled release base and controlled release film- forming agent, and their production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prepare a controlled release base and a controlled release film- forming agent both capable of releasing drug at a stable releasing speed for a releasing period by irradiating ultraviolet rays to of a specific polyester, its copolymer or their blended polymer. SOLUTION: This controlled release base and the controlled release film- forming agent are prepared by irradiating ultraviolet rays to a polyester having 300-50,000 (pref. 900-30,000) weight average molecular weight and mainly comprising (usually >=70 mol%, pref. >= 80 mol%, more pref. >=90 mol%) aliphatic structural units, its copolymer or their blended polymer. The polyester cited is (A) the one mainly comprising aliphatic hydroxycarboxylic acid units, (B) the one mainly comprising aliphatic hydroxycarboxylic acid units, aliphatic polybasic carboxylic acid units and aliphatic polyhydric alcohol units, or the like.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a sustained release base and a sustained release coating, and a method for producing the same. The present invention also relates to a method for producing a sustained-release drug composition using the sustained-release base or the sustained-release coating agent, and a sustained-release drug composition.

[0002] A technique for releasing a drug at a constant release rate over a certain period of time is useful in the fields of medicine, agricultural chemicals, veterinary medicine, toiletry medicine, sanitary medicine and the like.
These drugs are practically used in various forms such as granules, pills, powders, tablets, capsules, and microcapsules. In addition, as an implantable drug in a living body, it is processed into a form such as a sphere, a rod, a needle, or a film and put to practical use.

[0003] The sustained-release base or the sustained-release coating of the present invention can be used as an excipient, a binder, a coating, a disintegrant, a capsule, a microcapsule, etc., when producing a pharmaceutical composition in these forms. Is used as In the case of a drug to be administered to humans or animals, the base or the coating agent is required to have biocompatibility and biodegradability.

[0004]

2. Description of the Related Art Conventionally, various proposals have been made for a drug release control technique. For example, Tokuho 4-2
No. 8020 discloses a method in which an aluminum salt of a higher fatty acid is added to polylactide or polyglycolide having a molecular weight of 500 to 15,000 to form pores in a polymer to form a matrix of a sustained-release base. However, in this case, since it is difficult to control the pore diameter and the number of the pores, it is difficult to control the release rate of the drug, and the operation itself of forming the pores requires man-hours, which is inconvenient and cost-effective. There is a problem of disadvantage.

JP-A-5-112468 discloses a base for a sustained-release preparation comprising a mixture of a copolymer of polylactic acid and glycolic acid having a peak molecular weight of about 5,000 to 30,000 and another hydroxycarboxylic acid. Is disclosed. JP 9
JP-316008 discloses a sustained-release drug composition using a mixture of a biodegradable polymer and an amino acid polymer as a sustained-release base. Also, Japanese Patent Application Laid-Open No. 9-3159
No. 04 discloses a resin having a biodegradable polymer having a molecular weight of about 2000 to 300,000 and an olefin copolymer as main components.
A time-disintegrable pesticide granule coated with a water-swellable substance and a pesticide is disclosed.

In these prior arts, by changing the synthesis conditions or synthesis formula of a polymer to be a sustained-release base or a sustained-release coating, that is, by changing the monomer composition and molecular weight of the polymer, You are trying to control the timing or rate of release of a drug. However, there is a problem in that the release rate of the drug becomes too large at the time when the polymer serving as the matrix disintegrates. In addition, there is a problem in that the operation itself of changing the synthesis conditions or the synthesis prescription requires man-hours, which is inconvenient and disadvantageous in terms of cost.

[0007] Conventionally, attempts have been made to control the timing or rate of drug release by changing the thickness of the coating film. However, it is difficult to control the thickness itself of the coating film. Also,
When the thickness of the coating film is large, the use amount of the coating agent increases, which is not economical. Conversely, if the thickness of the coating film is small, voids are easily generated in the coating film, and a sufficient coating effect cannot be obtained. These problems limit the range of controllable drug release times and rates. Furthermore, in this case as well, there is a problem that the release rate of the drug becomes too high at the time when the matrix polymer disintegrates.

[0008]

In general, a sustained-release drug is required to release a drug at a constant rate during a specific period. However, in the prior art, as described above, the initial drug release amount is too large, the late drug release amount is too large, or the drug release amount at other times in relation to the time when the matrix polymer disintegrates. Is too large.

Accordingly, an object of the present invention is to solve the above-mentioned problems of the prior art, to easily control the release rate and release period of a drug, and to release a drug at a stable release rate during a required drug release period. An object of the present invention is to provide a sustained-release base and a sustained-release coating agent that can be used, and a method for producing the same. Another object of the present invention is to provide a method for producing a sustained-release drug composition using the sustained-release base or the sustained-release coating agent, and a sustained-release drug composition.

[0010]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and as a result, obtained by irradiating an aliphatic polyester having a weight average molecular weight in a specific range with ultraviolet rays. By using a release base or a sustained release coating agent, it is possible to easily control the release rate and release period of the drug, and to release the drug at a stable release rate during the release period, The present invention has been completed.

[0011] That is, the present invention provides a method for producing a polymer having a weight average molecular weight of 30.
A sustained release base or a sustained release coating obtained by irradiating a polyester or a copolymer thereof mainly composed of an aliphatic structural unit of 0 to 50,000, or a blend polymer containing the polyester or the copolymer thereof with ultraviolet light. Agent.

As the polyester, for example, (1)
Polyester mainly composed of aliphatic hydroxycarboxylic acid units, (2) polyester mainly composed of aliphatic hydroxycarboxylic acid units, aliphatic polycarboxylic acid units and aliphatic polyhydric alcohol units, (3) mainly aliphatic polycarboxylic acid And a polyester comprising an aliphatic polyhydric alcohol unit. Type (1) and (2) above
In the above, it is effective that the aliphatic hydroxycarboxylic acid unit is at least one selected from a lactic acid unit and a glycolic acid unit.

[0013] The present invention also relates to the present invention.
50,000 polyesters or copolymers mainly composed of aliphatic structural units, or a blend polymer containing the polyesters or copolymers thereof, which are irradiated with ultraviolet rays, wherein a sustained release base or a sustained release coating is applied. It is a manufacturing method of the agent. In this method, the polymer is dried before UV irradiation, and the water content of the polymer is reduced to 20%.
It is preferably at most 00 ppm.

[0014] The present invention also relates to the present invention.
The drug is coated with a polyester or a copolymer thereof comprising 50,000 predominantly aliphatic constituent units, or a blend polymer containing the polyester or the copolymer thereof, or a predominantly aliphatic constitution having a weight average molecular weight of 300 to 50,000. A sustained release, comprising: encapsulating the drug in a microcapsule consisting of a polyester comprising a unit or a copolymer thereof, or a blend polymer containing the polyester or the copolymer thereof, and thereafter irradiating the polymer with ultraviolet rays. This is a method for producing a pharmaceutical composition. In this method, it is also preferable to coat the drug in advance with a substance that blocks ultraviolet rays. further,
The present invention is a sustained-release drug composition produced by this method.

Hereinafter, the present invention will be described in detail. The polyester used in the present invention has a weight average molecular weight of 30.
It mainly consists of 0 to 50,000 aliphatic structural units.
Here, “mainly composed of aliphatic structural units” means
Usually, about 70 mol% or more, preferably about 80 mol% or more, more preferably about 90 mol% or more is meant to be composed of an aliphatic structural unit. And polyesters having the formula:

The polyester used in the present invention has a weight average molecular weight of 300 to 50,000, preferably 900 to 3,000.
0000. If the weight-average molecular weight is less than 300, the rate of hydrolysis or biodegradation is too high, so that there is a problem that the release time of the drug is too early or the release rate is too fast. On the other hand, when the weight average molecular weight is 500
If it exceeds 00, the rate of hydrolysis or biodegradation is too slow, so that there is a problem that the release time of the drug is too late or the release rate is too slow.

The polyester used in the present invention is not particularly limited, but includes, for example, the following three types. (1) Polyester mainly composed of aliphatic hydroxycarboxylic acid units. (2) Polyesters mainly comprising aliphatic hydroxycarboxylic acid units, aliphatic polycarboxylic acid units and aliphatic polyhydric alcohol units. (3) Polyester mainly composed of aliphatic polycarboxylic acid units and aliphatic polyhydric alcohol units.

Examples of the aliphatic hydroxycarboxylic acid include, but are not limited to, glycolic acid, lactic acid, hydroacrylic acid, 2-hydroxybutyric acid, 3-hydroxybutyric acid, 4-hydroxybutyric acid, 3-hydroxyvaleric acid, and 4-hydroxyvaleric acid. , 5-hydroxyvaleric acid, ε-hydroxycaproic acid, malic acid, tartaric acid, citric acid and the like.

Also included are cyclic monoesters of hydroxycarboxylic acids (lactones) such as propiolactone, butyrolactone, valerolactone and caprolactone, and cyclic diesters (lactides) of hydroxycarboxylic acids such as glycolide and lactide.

Hydroxycarboxylic acids having optical isomers such as lactic acid, 2-hydroxybutyric acid, 3-hydroxybutyric acid, and 3-hydroxyvaleric acid may be in D-form or L-form alone or in a mixture of D-form and L-form. There may be. One or more of these hydroxycarboxylic acids may be used in the polyester.

Of these hydroxycarboxylic acids, L
By using a polyester oligomer consisting of -lactic acid, D-lactic acid or 3-hydroxybutyric acid, the release rate of a drug in the presence of water of the obtained sustained-release base or sustained-release coating can be reduced. . This is considered to be due to the fact that the obtained polyester has high crystallinity and a high glass transition point, so that hydrolysis is slow.

By using a polyester comprising glycolic acid or ε-hydroxycaproic acid among these hydroxycarboxylic acids, the resulting sustained-release base or sustained-release coating can be used in the presence of water. Release speed can be increased. This is considered to be due to the fact that the obtained polyester has low crystallinity and a low glass transition point, so that hydrolysis is slow.

As described above, when at least one selected from lactic acid and glycolic acid is contained as the aliphatic hydroxycarboxylic acid, it is effective in controlling the release rate of the drug in the presence of water.

Further, by using a polyester comprising ε-hydroxycaproic acid and 3-hydroxyvaleric acid, the release rate of the drug in the natural environment of the obtained sustained release base or sustained release coating can be increased. can do. this is,
It is considered that the polyester oligomer composed of ε-hydroxycaproic acid and 3-hydroxyvaleric acid has high biodegradability.

Examples of the aliphatic polycarboxylic acid include, but are not limited to, succinic acid, malonic acid, adipic acid, azelaic acid, sebacic acid, suberic acid, dodecanedioic acid, propanetricarboxylic acid, and the like; Anhydrides and the like. One or more of these polycarboxylic acids may be used in the polyester.

In addition to these aliphatic polycarboxylic acids, depending on the purpose, aromatic polycarboxylic acids such as phthalic acid, naphthalenedicarboxylic acid, trimellitic acid, and pyromellitic acid; An anhydride of a polycarboxylic acid may be used. By using these aromatic polycarboxylic acids, the rate of release of the drug from the obtained sustained release base and sustained release coating in the presence of water can be reduced. This is considered because the hydrolysis of the obtained polyester oligomer is slowed down. This release rate delay effect increases as the proportion of the aromatic polycarboxylic acid used increases. The usage ratio of the aromatic polycarboxylic acid in the polyester is usually up to about 30 mol%.

The aliphatic polyhydric alcohol includes, but is not limited to, ethylene glycol, propylene glycol,
Polypropylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol, polypropylene glycol, polytrimethylene glycol,
Examples include dihydric alcohols such as butanediol, pentanediol, hexanediol, and cyclohexanediol, and trihydric or higher polyhydric alcohols such as glycerin, trimethylolpropane, pentaerythritol, polyethylenetriol, and polypropylenetriol.

By using a trihydric or higher polyhydric alcohol among these polyhydric alcohols, the release rate of the drug in the presence of water of the obtained sustained-release base or sustained-release coating can be reduced. can do. This is considered because the hydrolysis of the obtained polyester oligomer is slow.
This release rate delay effect also appears in accordance with the proportion of tri- or higher-valent alcohol when a dihydric alcohol and a tri- or higher polyhydric alcohol are used in combination.

The polyester used in the present invention is:
It can be manufactured by a known method. For example, (1)
The polyhydroxycarboxylic acid can be obtained by a method of subjecting at least one kind of the above-mentioned hydroxycarboxylic acid or an aqueous solution thereof to condensation polymerization by heating, reducing pressure, or the like, a method of subjecting at least one kind of lactones or lactides to ring-opening polymerization and the like. . Further, a polyester having a desired molecular weight can be obtained by methanolysis and hydrolysis of a high molecular weight polyoxycarboxylic acid. Furthermore, poly-3-hydroxybutyric acid, poly-4-hydroxybutyric acid, poly-3-hydroxyvaleric acid and the like can also be obtained by extracting and purifying bacterial energy storage substances. It is not limited to these manufacturing methods.

(2) The polyhydroxycarboxylic acid-polycarboxylic acid-polyhydric alcohol includes at least one kind of the hydroxycarboxylic acid, at least one kind of the polyvalent carboxylic acid, and at least one kind of the polyhydric alcohol. Or a method in which an aqueous solution thereof is subjected to polycondensation by heating, reducing pressure, or the like, a method in which at least one lactone or at least one lactide is subjected to ring-opening polymerization in the presence of a polyhydric carboxylic acid and a polyhydric alcohol. Can be obtained by Also,
A polyester having a desired molecular weight can be obtained by methanolysis and hydrolysis of a high molecular weight polyhydroxycarboxylic acid-polycarboxylic acid-polyhydric alcohol.
It is not limited to these manufacturing methods.

(3) The poly-polycarboxylic acid-polyhydric alcohol is subjected to polycondensation of at least one kind of the polyvalent carboxylic acid and at least one kind of the polyhydric alcohol or an aqueous solution thereof by heating, depressurizing, or the like. It can be obtained by a method. It is not limited to this manufacturing method.

The above manufacturing method will be described in more detail below. (Details of Polyester Production Method by Polycondensation) To obtain a polyester by polycondensation, usually 100 ° C. to 250 ° C.
At a pressure of from normal pressure to 1 mmHg, in the absence of a catalyst or in the presence of a catalyst, for dehydration and condensation polymerization. The catalyst in this case is not limited, but is usually a group IA, a group IIA, a group IIA of the periodic table.
Group B, Group IIIB, Group IVA, Group IVB, Group VB metals, oxides, hydroxides, chlorides, other inorganic compounds,
Organic compounds or acids or acids may be used alone or in combination.

Examples of the group IA catalyst include sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium oxide, potassium oxide, lithium oxide, sodium methoxide, and potassium ethoxide.

The group IIA catalyst includes magnesium hydroxide, calcium hydroxide, barium hydroxide, magnesium oxide, calcium oxide, barium oxide and the like.

Examples of the group IIIB catalyst include aluminum oxide, aluminum triethoxide, and aluminum octylate.

Examples of the group IVA catalyst include titanium oxide, tetramethyl titanate, tetrabutyl titanate, zirconium, zirconium oxide, zirconium tetramethoxide, and zirconium tetrabutoxide.

Examples of the group IVB catalyst include germanium, germanium oxide, tin, tin oxide, tin chloride, tin oxalate, tin octylate, dibutyltin dilaurate, dibutyltin oxide, butyltin chlorooxide, lead oxide, and silicon oxide. Is mentioned.

Examples of the VB group catalyst include antimony trioxide, antimony triacetate, and triphenylantimony. Acid catalysts include sulfuric acid, hydrochloric acid,
Examples include nitric acid, phosphoric acid, toluenesulfonic acid, and cation exchange resin.

(Details of Method for Producing Polyester by Ring-Opening Polymerization) To obtain a polyester by ring-opening polymerization, usually,
A lactone or lactide is subjected to ring-opening polymerization in the presence of a catalyst at a temperature of 80 ° C to 300 ° C under an inert gas stream. The catalyst in this case is not limited, but is usually in the periodic table III.
Group B, IVA, IVB and VB metals, oxides,
Hydroxides, chlorides, other inorganic compounds, organic compounds and the like and acids are used alone or in combination. IIIB, IV
Specific examples of the group A, group IVB, and group VB catalysts are the same as those described above.

(Details of Method for Producing Polyester by Methanolysis and Hydrolysis) In order to obtain a polyester by methanolysis and hydrolysis, it is usually from 80 ° C to 20 ° C.
A polyester having a high molecular weight (for example, about 50,000 to 500,000) is reacted with water or an alcohol such as methanol or ethanol at a temperature of 0 ° C. in the absence or presence of a catalyst to obtain a polyester having a desired molecular weight.

The catalyst in this case is not limited, but is usually a group IA, IIA, IIB, IIIB, or IB of the periodic table.
A single element, an oxide, a hydroxide, a chloride, another inorganic compound, an organic compound, or the like, or an acid of a group IVA, IVB, or VB metal is used alone or in combination. IA, IIA, I
Specific examples of the group IIB, IVA, IVB, and VB group catalysts are the same as those described above.

(Details of Method for Producing Polyester by Bacteria, etc.) In this case, poly-3-hydroxybutyric acid, poly-4-hydroxybutyric acid, poly-3-hydroxyvaleric acid, etc. are obtained by extracting and purifying bacterial energy storage substances. . In this case, Alcaligenes europhus, Alcaligenes
Bacteria such as latus are provided with a carbon source such as sugars and organic acids to accumulate polyester as an energy storage substance in the cells. The accumulated polyester is extracted with an organic solvent or the like, and further purified by a method such as reprecipitation to obtain a polyester.

In the present invention, a copolymer of the polyester having a weight average molecular weight of 300 to 50,000, instead of or together with the polyester,
Alternatively, a blend polymer containing the polyester or a copolymer thereof can also be used.

The polyester copolymer means a copolymer of the polyester and another oligomer or polymer. The copolymerization ratio is not particularly limited, but the copolymerization ratio at which the effects of the present invention are sufficiently exhibited, that is, the copolymerization ratio of the polyester is preferably 30% by weight or more, more preferably 60% by weight or more. .

The other oligomer or polymer copolymerized with the polyester is not particularly limited.
Polyethylene glycol, polypropylene glycol,
Polyalkylene polyols such as polyethylene glycol propylene glycol copolymers and polytetramethylene glycol; polycarbonates such as polypropylene carbonate and polybutylene carbonate; and synthetic polymers such as polyvinyl alcohol, polyamide, polyurea, polyurethane, polyisocyanate, and polyorganosiloxane. And natural polymers such as starch, cellulose, chitin and chitosan.

The polymer or oligomer blended with the polyester or a copolymer thereof is not particularly limited, but may be polyethylene glycol, polypropylene glycol, polyethylene glycol-propylene glycol copolymer, polyalkylene polyol such as polytetramethylene glycol, or polypropylene. Examples include synthetic polymers such as polycarbonate, polyvinyl alcohol, polyamide, polyurea, polyurethane, and polyorganosiloxane, such as carbonate and polybutylene carbonate, and natural polymers, such as starch, cellulose, chitin, and chitosan.

The mixing ratio is not particularly limited, but the mixing ratio at which the effect of the present invention is sufficiently exhibited, that is, the mixing ratio of the polyester is preferably 30% by weight or more, more preferably 60% by weight or more. .

Further, the terminal of the polyester or the copolymer thereof may be modified by chemical modification. That is, the terminal hydroxy group and carboxyl group of the obtained oligomer or polymer may be modified by esterification with monohydric carboxylic acid or monohydric alcohol, respectively. By such chemical modification, the effect of reducing the viscosity of the oligomer or polymer, the effect of reducing hydrophilicity, and the improvement of hydrolysis resistance are obtained, and the processability in the production process of the sustained release base and the sustained release coating agent is obtained. Or the release characteristics of the drug.

The carboxyl group at the terminal of the obtained oligomer or polymer may be used as a metal salt. By using a metal salt, the hydrolysis resistance of the oligomer or polymer can be improved, and the release characteristics of the drug can be improved.

The sustained-release base or the sustained-release coating of the present invention comprises:
It can be obtained by irradiating a polyester comprising the aliphatic structural unit or a copolymer thereof, or a blend polymer containing the polyester or the copolymer thereof with ultraviolet rays.

The method for irradiating ultraviolet rays is not particularly limited. The ultraviolet light to be applied is 400 nm or less and 1 nm.
Those having the above wavelengths are used, and those having a wavelength of 360 nm or less and 200 nm or more are preferably used.

The type of the light source is not particularly limited. For example, a hydrogen discharge tube, a xenon discharge tube, a low-pressure mercury lamp, a high-pressure mercury lamp, a metal halide lamp, a ruby laser, a YAG laser, an excimer laser, and the like are used.

When infrared light is included in the light emitted from these light sources, the heat generated by the infrared light may cause decomposition or deformation of the polymer. Therefore, in order to prevent heat generation, it is effective to irradiate only ultraviolet rays by using a filter or the like, or to irradiate while performing cooling such as air cooling or water cooling.

In the case of a light source that emits ultraviolet light in a wide wavelength range, it is preferable to irradiate only ultraviolet light having a required wavelength using a filter or the like in order to prevent unnecessary degradation reaction of the polymer.

Among the excimer lasers, an F ₂ excimer laser (wavelength 157 nm), an ArF excimer laser (wavelength 193 nm), a KrCl excimer laser (wavelength 222 nm), and a KrF excimer laser (wavelength 2
48 nm) is effective because it is excellent in monochromaticity, efficiency and high energy.

As described above, by irradiating the polymer with ultraviolet rays, a partial crosslinked structure is generated in the polyester, and the molecular weight is increased. Therefore, when the sustained release base or the sustained release coating of the present invention undergoes decomposition in the presence of water, it is considered that rapid physical disintegration of the polyester is prevented, and the sustained release base or It becomes excellent as a sustained release coating agent.

By increasing the amount of UV irradiation on the polymer, partial crosslinking of the polyester proceeds more,
The molecular weight tends to increase. Therefore, the release rate of the drug can be reduced by increasing the amount of ultraviolet irradiation.

In the above-described ultraviolet irradiation method, it is preferable that the polymer is dried before the ultraviolet irradiation, so that the water content of the polymer is 2,000 ppm or less.
More preferably, it is 0 ppm or less. If the moisture content of the polyester is high during ultraviolet irradiation, deterioration such as a decrease in the molecular weight of the polyester is likely to occur. For this reason, it is preferable to dry the polymer by a conventional method before irradiation with ultraviolet rays. For example, room temperature to 70 ° C., 10 to 0.01 Torr
r. Drying for about 0.1 to 20 hours may be sufficient.

The sustained-release base or sustained-release coating of the present invention thus obtained may be used in the form of granules, pills, powders, tablets, capsules, microcapsules, bioimplantable drugs and the like. When preparing a pharmaceutical composition in a form, excipients, binders,
It is used as a base or coating material such as a coating agent, disintegrant, capsule, microcapsule, etc.

The drugs used include, but are not limited to, drugs, veterinary drugs, pesticides, fertilizers, toiletry drugs, sanitary drugs, and the like. Pharmaceuticals include, for example, parasympathomimetics, parasympathomimetics, muscle relaxants, antihistamines, antiallergics, antiepileptics, psychotropics, analgesics, anti-inflammatory drugs, antirheumatic drugs, antiarrhythmic drugs , Antihypertensives, hyperlipidemias, diuretics,
Antitussives, expectorants, corticosteroids, hemostats, bactericides, antibacterials, antituberculosis drugs, antibiotics, antifungals, antitumor drugs, antiulcer drugs, and the like.

Examples of the veterinary drug include the same drugs as those described above for the medicinal use. Pesticides include insecticides, fungicides,
Herbicides, growth promoters and the like can be mentioned. Fertilizers include nitrogen fertilizer, phosphorus fertilizer, potassium fertilizer, calcium fertilizer,
Magnesium fertilizer, sulfur fertilizer, trace element fertilizer, and the like. Examples of the toiletry medicine and the sanitary medicine include cleaning agents for toilets, baths, sinks, etc., disinfectants, antibacterial agents and the like.

The excipients, binders, coatings, disintegrants, capsules, and the like in which the sustained-release base or sustained-release coating of the present invention is used.
Details of the microcapsules and the like will be described.

(Excipient) The excipient is added to give a certain size and weight when the amount of the drug is too small to be suitable for granulation. In addition to the polyester described in the present invention, lactose, sucrose, glucose, starch, crystalline cellulose and the like which have been conventionally used can be used at the same time.

(Binder) The binder is added to give a binding force to the drug and to make the drug stable. In addition to the polyester described in the present invention, conventionally used starch paste, hydroxypropyl cellulose solution, carboxymethyl cellulose solution, gum arabic solution, gelatin solution, glucose solution, sucrose solution, sodium polyalginate, crystalline cellulose Etc. can be used simultaneously.

(Disintegrant) A disintegrant is added to impart disintegration to a drug in water or gastric juice. In addition to the polyester described in the present invention, conventionally used starch, carboxymethylcellulose, calcium carbonate and the like can be used.

(Coating agent) The coating agent (coating agent)
It is used to form a coating for the purpose of controlling disintegration, controlling solubility, improving taste, and preventing moisture. In addition to the polyester described in the present invention, conventionally used sucrose, gelatin, gum arabic, casein, shellac,
Methylcellulose, hydroxyethylcellulose, vinylpyridine, alkylvinylpyridine, hydroxypropylmethylcellulose phthalate, precipitated calcium carbonate, kaolin, talc and the like can be used.

(Capsules) Capsules are used for masking taste and odor and for imparting enteric properties and sustained action to powdered or granular drugs. In addition to the polyester described in the present invention, conventionally used gelatin, sucrose, glycerin, gum arabic and the like can be used simultaneously.

(Microcapsules) Microcapsules are used for the purpose of controlling the release rate and release time of a drug. In addition to the polyesters described in the present invention, natural polymers such as gelatin, casein, rubber, sodium polyalginate, waxes, waxes, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, and polyvinyl alcohol which have been conventionally used. And synthetic polymers can be used simultaneously.

(Lubricant) In addition to the above, a lubricant may be used. The lubricant is added to prevent the drug from adhering to the device at the time of tableting and to make the surface of the obtained tablet beautiful. Purified talc, magnesium stearate, calcium stearate, stearic acid and the like are used.

Using the sustained-release base or sustained-release coating of the present invention as a base, a pharmaceutical composition can be produced by various known methods.

(Examples of Manufacturing Methods of Granules, Powders, Pills, and Tablets) For example, the following methods are used to granulate drug granules, powders, pills, and tablets. a. After the liquid or solution base of the present invention as an excipient or a binder is mixed with the drug, the mixture is extruded and granulated using a cylindrical granulator, a marmalizer, a pelletizer or the like. b. After the liquid or solution base of the present invention as an excipient or a binder is mixed with the drug, the mixture is crushed and granulated using a speed mill, a power mill or the like. c. After mixing the drug with the powdered base of the present invention as an excipient or binder, the mixture is granulated using a compressor. d. By spraying the liquid or solution base of the present invention as a binder onto a drug in a fluidized state by an air stream using a fluidized bed granulator, drug particles are condensed and granulated.

The granules, powders, and granules thus granulated
Pills and tablets can be coated with a coating agent using a coating pan, a film coating machine, a dry coating machine or the like.

(Example of Manufacturing Method of Capsule) For example, the following method is used for manufacturing a drug capsule. A mixture of the base of the present invention, gelatin, water, sucrose, glycerin, gum arabic and the like is placed in a mold and dried and molded to obtain capsules.
This capsule is filled with the drug itself or the granulated drug.

(Example of Manufacturing Method of Microcapsules) For example, the following method is used for manufacturing drug microcapsules. a. After the organic solvent is removed from the emulsion of water and the organic solvent solution of the base polymer and the drug of the present invention by evaporation, the obtained microspheres are dried by filtration (drying in liquid). b. A coacervating agent is gradually added to a W / O emulsion of an organic solvent solution of the base polymer of the present invention and an aqueous solution of a drug under stirring, and the obtained microspheres are filtered and dried (layer separation method). c. The W / O emulsion of the organic solvent solution of the base polymer of the present invention and the aqueous solution of the drug is dried with a spray dryer or the like to obtain microspheres (spray drying method).

(Example of Manufacturing Method of Implantable Biomedical Agent) For example, the following method is used to manufacture an implantable biomedical agent. a. A mixture of a drug and the base polymer of the present invention,
It is plasticized by adding a solvent or heating, and is put into a mold and molded. b. The drug microcapsules are placed in a mold and compressed and molded.

In the present invention, as described above, a polymer is irradiated with ultraviolet rays to obtain a sustained-release base or a sustained-release coating, and various sustained-release drug compositions are produced using the same. be able to.

In the present invention, a sustained-release pharmaceutical composition can be produced by the following alternative method. That is, when a drug is coated, a weight average molecular weight of 300
The drug is coated with a polyester or a copolymer thereof mainly composed of aliphatic structural units of up to 50,000 or a blend polymer containing the polyester or the copolymer thereof, and thereafter, the polymer is irradiated with ultraviolet rays to obtain a sustained-release property. A pharmaceutical composition is manufactured.

In the case of obtaining drug microcapsules, a polyester or a copolymer thereof mainly composed of an aliphatic structural unit having a weight average molecular weight of 300 to 50,000 or a blend polymer containing the polyester or a copolymer thereof is used. Encapsulating the drug in microcapsules, then irradiating the polymer with ultraviolet light,
Produce a sustained release drug composition.

Irradiation with ultraviolet rays can be performed in the same manner as described above. Also in this case, it is preferable that the water content of the polymer is set to 2000 ppm or less before the ultraviolet irradiation. If the irradiation light has a possibility of adversely affecting the drug, such as deterioration, it is preferable to coat the drug in advance with a substance that substantially blocks ultraviolet rays.
The deterioration of the drug can be prevented.

As a substance that substantially blocks ultraviolet rays,
Although not particularly limited, for example, precipitated calcium carbonate, kaolin, talc, bentonite and other inorganic substances, starch, sucrose, gelatin, gum arabic, casein, shellac, methylcellulose, hydroxyethylcellulose,
A mixture with an organic substance such as vinylpyridine, alkylvinylpyridine, hydroxypropylmethylcellulose phthalate, carboxymethylcellulose, sodium alginate, and crystalline cellulose is used.

[0081]

EXAMPLES The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to these examples. [Synthesis example 1 of copolymer] L-lactic acid (90%) 100.0
g and 14.7 g of glycolic acid (70%),
The mixture was charged into a 300 ml separable flask equipped with a stirrer, a condenser, a decompression device, and a heater. First, the mixture was heated at normal pressure and 130 ° C. for 2 hours, then under reduced pressure at 130 ° C. for 2 hours, and further under reduced pressure at 150 ° C. for 2 hours to obtain a poly-L-lactic acid-glycolic acid copolymer having a weight average molecular weight of 1350. . The weight average molecular weight was measured by GPC. This copolymer was pulverized into fine powder by a hammer crusher mill. The pulverized copolymer is added at 20 ° C. and 0.2 Torr for 1 hour.
Dried for 0 hours. The water content of the dried poly-L-lactic acid-glycolic acid copolymer measured by the Karl Fischer method was 340 ppm.

[Synthesis Example 2 of Copolymer] L-lactic acid (90
%) And 72.9 g of glycolic acid (70%) were charged into a separable flask having a capacity of 300 ml equipped with a thermometer, a stirrer, a condenser, a decompression device, and a heater. First at normal pressure, 130 ° C for 2 hours, then under reduced pressure
The mixture was heated at 30 ° C. for 2 hours, further under reduced pressure at 150 ° C. for 2 hours, and further under reduced pressure at 170 ° C. for 4 hours to obtain a weight average molecular weight of 4830.
Of poly-L-lactic acid-glycolic acid copolymer was obtained. The weight average molecular weight was measured by GPC. This copolymer was pulverized into fine powder by a hammer crusher mill. The pulverized copolymer was dried at 20 ° C. and 0.2 Torr for 10 hours. The water content of the dried poly-L-lactic acid-glycolic acid copolymer measured by the Karl Fischer method is 310.
ppm.

[Synthesis Example 3 of Copolymer] L-lactic acid (90
%), 100.0 g, succinic acid (100%) 6.6 g, and ethylene glycol (100%) 3.4 g,
The mixture was charged into a 300 ml separable flask equipped with a stirrer, a condenser, a decompression device, and a heater. First, normal pressure at 130 ° C for 2 hours, then under reduced pressure at 130 ° C for 2 hours, further under reduced pressure at 150 ° C for 2 hours, and further under reduced pressure at 170 ° C
For 4 hours to obtain a poly-L- having a weight average molecular weight of 4510.
A lactic acid-succinic acid-ethylene glycol copolymer was obtained.
The weight average molecular weight was measured by GPC. This copolymer was pulverized into fine powder by a hammer crusher mill. The pulverized copolymer was dried at 20 ° C. and 0.2 Torr for 10 hours. The water content of the dried poly-L-lactic acid-succinic acid-ethylene glycol copolymer measured by the Karl Fischer method was 370 ppm.

[Example 1] (Manufacture of drug) Sodium salicylate 5.0 as drug
g and microcrystalline cellulose 45.0 as excipient and binder
g., and the mixture is molded with a tablet machine, about 0.3 g /
A spherical tablet was obtained. The obtained tablets were coated with a 10% by weight chloroform solution of the poly-L-lactic acid-glycolic acid copolymer obtained in Synthesis Example 1 using a coating pan. Further, it was blow-dried for 2 hours using the same coating pan, and about 0.1 g / tablet in weight after drying was applied.

Next, 4 μm was added to the coated tablets.
Ultraviolet rays were irradiated for 30 seconds at an irradiation distance (distance between an object to be irradiated and a light source) of about 40 cm using a 100 W / cm metal halide lamp having a light emission length of 200 mm equipped with a filter for removing light having a wavelength of 00 nm or more. The irradiation was performed while rolling the tablet with a shaker so that the entire surface of the tablet was uniformly irradiated with ultraviolet rays. A tablet coated in this way was produced.

(Evaluation of Drug Release Characteristics) The coated tablets were placed in a pH 7.0 phosphate buffer maintained at 37 ° C. and shaken with a shaker, and the released sodium salicylate was quantitatively determined periodically by liquid chromatography. Then, the release characteristics of the drug were evaluated. Table 1 shows the results. Further, the copolymer of the coating layer of the tablet after the irradiation of the ultraviolet rays was collected and dissolved in chloroform. As a result, about 7% by weight of a solvent-insoluble content was found. The weight average molecular weight of the copolymer dissolved in the solvent by GPC is 2
090.

Example 2 A coated tablet was produced and the drug release characteristics were evaluated in the same manner as in Example 1 except that the irradiation time of the ultraviolet rays was changed to 90 seconds in the production of the drug. Table 1 shows the results. Further, the copolymer of the coating layer of the tablet after the irradiation of the ultraviolet rays was collected and dissolved in chloroform, so that about 23% by weight of a solvent-insoluble matter was found. The weight average molecular weight by GPC of the copolymer dissolved in the solvent was 3570.
Met.

[Comparative Example 1] In the same manner as in Example 1 except that ultraviolet irradiation was not performed in the production of the drug,
Coated tablets were prepared and the release characteristics of the drug were evaluated.
Table 1 shows the results.

[0089]

[Table 1]

As shown in Table 1, in Examples 1 and 2, sodium salicylate was released at a stable release rate during the release period, and the drug was excellent in sustained release. In addition, it can be seen that the release rate of the drug becomes slower when the amount of ultraviolet irradiation on the polymer is increased. In Comparative Example 1, there is no sustained release of the drug. In this case, it is considered that a partial crosslinked structure was not formed in the polyester, and sudden physical collapse of the polyester occurred.

Example 3 5.0 g of sodium salicylate as a drug and 45.0 g of crystalline cellulose as an excipient and a binder were mixed, and the mixture was molded with a tableting machine to give about 0.3 g / tablet. A spherical tablet was obtained. The obtained tablets were coated with a 10% by weight chloroform solution of the poly-L-lactic acid-glycolic acid copolymer obtained in Synthesis Example 2 using a coating pan. Further, it was blow-dried for 2 hours using the same coating pan, and about 0.1 g / tablet in weight after drying was applied.

Next, in the same manner as in Example 1, ultraviolet irradiation was performed to produce a coated tablet, and the release characteristics of the drug were evaluated. Table 2 shows the results. Further, the copolymer of the coating layer of the tablet after the irradiation of the ultraviolet rays was collected and dissolved in chloroform, whereby about 9% by weight of a solvent-insoluble content was found. The weight average molecular weight by GPC of the copolymer dissolved in the solvent was 6,720.
Met.

Example 4 A coated tablet was prepared and the release characteristics of the drug were evaluated in the same manner as in Example 3, except that the irradiation time of the ultraviolet rays was changed to 90 seconds. Table 2 shows the results. When the copolymer of the coating layer of the tablet after irradiation with ultraviolet rays was collected and dissolved in chloroform, a solvent insoluble content of about 28% by weight was found. The weight average molecular weight by GPC of the copolymer dissolved in the solvent was 1193.
It was 0.

[Comparative Example 2] In the same manner as in Example 3 except that ultraviolet irradiation was not performed in the production of the drug,
Coated tablets were prepared and the release characteristics of the drug were evaluated.
Table 2 shows the results.

[0095]

[Table 2]

As shown in Table 2, in Examples 3 and 4, sodium salicylate was released at a stable release rate during the release period, and the drug was excellent in sustained release. In addition, it can be seen that the release rate of the drug becomes slower when the amount of ultraviolet irradiation on the polymer is increased. In Comparative Example 2, the initial burst phenomenon was observed, and the sustained release of the drug was considerably poor.

Example 5 5.0 g of sodium salicylate as a drug and 45.0 g of crystalline cellulose as an excipient and a binder were mixed, and the mixture was molded using a tableting machine. A spherical tablet was obtained. The obtained tablets were coated with a 10% by weight chloroform solution of the poly-L-lactic acid-succinic acid-ethylene glycol copolymer obtained in Synthesis Example 3 using a coating pan. Further, it was blow-dried for 2 hours using the same coating pan, and about 0.1 g / tablet in weight after drying was applied.

Next, in the same manner as in Example 1, ultraviolet irradiation was performed to produce a coated tablet, and the release characteristics of the drug were evaluated. Table 3 shows the results. Further, the copolymer of the coating layer of the tablet after the irradiation of the ultraviolet rays was collected and dissolved in chloroform, whereby about 11% by weight of a solvent-insoluble content was found. The weight average molecular weight by GPC of the copolymer dissolved in the solvent was 638.
It was 0.

Example 6 A coated tablet was produced in the same manner as in Example 5 except that the irradiation time of the ultraviolet ray was changed to 90 seconds in the production of the drug, and the release characteristics of the drug were evaluated. Table 3 shows the results. Further, the copolymer of the coating layer of the tablet after the irradiation of the ultraviolet rays was collected and dissolved in chloroform, whereby about 32% by weight of a solvent-insoluble content was found. The weight average molecular weight by GPC of the copolymer dissolved in the solvent is 1005.
It was 0.

[Example 7] (Manufacture of drug) The pulverized product of poly-L-lactic acid-succinic acid-ethylene glycol copolymer obtained in Synthesis Example 3 was added with 40
Using a 100 W / cm metal halide lamp with a light emission length of 200 mm equipped with a filter for removing light having a wavelength of 0 nm or more, the irradiation distance (distance between the irradiation object and the light source) is about 4
Ultraviolet irradiation was performed at 0 cm for 15 seconds. Irradiation was performed while rolling the ground material with a vibrator so that the entire surface of the ground material was uniformly irradiated with ultraviolet rays. When the poly-L-lactic acid-succinic acid-ethylene glycol copolymer after irradiation with ultraviolet rays was dissolved in chloroform, there was a solvent insoluble content of about 5% by weight. The weight average molecular weight by GPC of the copolymer dissolved in the solvent was 5,570.

Next, 5.0 g of sodium salicylate as a drug and crystalline cellulose 4 as an excipient and a binder were used.
5.0 g, and the mixture is molded with a tablet machine, about 0.
A spherical tablet of 3 g / tablet was obtained.

The obtained tablet was treated with poly-L after ultraviolet irradiation.
-Lactic acid-succinic acid-ethylene glycol copolymer 10
The coating was performed using a coating pan with a weight% chloroform solution. Further, it was blow-dried for 2 hours using the same coating pan, and about 0.1 g / tablet in weight after drying was applied. (The obtained poly-L-lactic acid-succinic acid-
An insoluble component was present in the chloroform solution of the ethylene glycol copolymer, which was used without particular removal. 2.) The tablets coated in this way were produced and the release characteristics of the drug were evaluated. Table 3 shows the results.

[Comparative Example 3] In the same manner as in Example 5 except that ultraviolet irradiation was not performed in the production of the drug,
Coated tablets were prepared and the release characteristics of the drug were evaluated.
Table 3 shows the results.

[0104]

[Table 3]

As shown in Table 3, in Examples 5 and 6, sodium salicylate was released at a stable release rate during the release period, and the drug was excellent in sustained release. In addition, it can be seen that the release rate of the drug becomes slower when the amount of ultraviolet irradiation on the polymer is increased. In Comparative Example 3, the release amount was as high as 58% over 4 to 5 days, and the sustained release of the drug was considerably poor. From Tables 1, 2 and 3, the release characteristics of the drug can be adjusted by adjusting the molecular weight and type of the polymer used and the amount of ultraviolet irradiation on the polymer.

The present invention may be embodied in various other forms without departing from its spirit or essential characteristics. Therefore, the above-described embodiment is merely an example in every aspect, and should not be construed as limiting. Furthermore, all modifications belonging to the equivalent scope of the claims are within the scope of the present invention.

[0107]

According to the present invention, as described above, the drug release rate and the release period can be easily controlled, and the drug can be released at a stable release rate during the required drug release period. A sustained release base and a sustained release coating are provided. Further, according to the present invention, there is provided a sustained-release pharmaceutical composition using the sustained-release base or the sustained-release coating agent.

 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Kenshi Kanamori 1F, Nishinokyo Kuwaharacho, Nakagyo-ku, Kyoto, Kyoto Prefecture F-term (reference) 4C076 AA38 CC01 EE24H EE24M EE31A EE46H EE46M EE48H EE48M FF31 GG50

Claims (10)

[Claims] 1. A sustained release obtained by irradiating a polyester or a copolymer thereof mainly composed of an aliphatic structural unit having a weight average molecular weight of 300 to 50,000, or a blend polymer containing the polyester or a copolymer thereof, with ultraviolet light. Base or sustained-release coating. 2. The sustained-release base or the sustained-release coating according to claim 1, wherein the polyester mainly comprises aliphatic hydroxycarboxylic acid units. 3. The sustained release base or the sustained release coating according to claim 1, wherein the polyester mainly comprises aliphatic hydroxycarboxylic acid units, aliphatic polycarboxylic acid units and aliphatic polyhydric alcohol units. . 4. The method according to claim 1, wherein the aliphatic hydroxycarboxylic acid unit is at least one selected from a lactic acid unit and a glycolic acid unit.
The sustained release base or the sustained release coating according to claim 2 or 3, which is a seed. 5. The polyester mainly comprises aliphatic polycarboxylic acid units and aliphatic polyhydric alcohol units,
The sustained-release base or sustained-release coating according to claim 1. 6. A method of irradiating a polyester or a copolymer thereof mainly composed of an aliphatic structural unit having a weight average molecular weight of 300 to 50,000 or a blend polymer containing the polyester or the copolymer with ultraviolet rays. A method for producing a sustained release base or a sustained release coating. 7. Prior to irradiation with ultraviolet light, a weight average molecular weight of 30
The polyester or copolymer thereof mainly composed of an aliphatic structural unit of 0 to 50,000 or a blend polymer containing the polyester or copolymer thereof is dried to make the water content of the polymer 2000 ppm or less. A method for producing the sustained release base or the sustained release coating according to the above. 8. A drug coated with a polyester or a copolymer thereof mainly composed of an aliphatic structural unit having a weight average molecular weight of 300 to 50,000, or a blend polymer containing the polyester or the copolymer thereof, or Polyester or copolymer thereof mainly composed of aliphatic structural units having a molecular weight of 300 to 50,000,
Alternatively, a method for producing a sustained-release drug composition, comprising encapsulating a drug in a microcapsule made of a blended polymer containing the polyester or a copolymer thereof, and thereafter irradiating the polymer with ultraviolet rays. 9. The method for producing a sustained-release drug composition according to claim 8, wherein the drug is coated in advance with a substance that blocks ultraviolet rays. 10. A sustained-release pharmaceutical composition produced by the method according to claim 8 or 9.