WO1997034601A1

WO1997034601A1 - Drug compositions improved in solubility

Info

Publication number: WO1997034601A1
Application number: PCT/JP1997/000853
Authority: WO
Inventors: Hisao Furitsu; Yukiko Inoue; Akira Kato; Hidenobu Ando
Original assignee: Eisai Co., Ltd.
Priority date: 1996-03-18
Filing date: 1997-03-18
Publication date: 1997-09-25

Abstract

Drug compositions improved in solubility and controlled in dissolving out. A drug composition prepared by dissolving or dispersing 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl)benzothiazole and a polymeric substance in a solvent and distilling the resulting solution or dispersion to remove the solvent; another drug composition prepared by shaping 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl)benzothiazole and a polymeric substance together by the use of an extruding granulator of agitation and compression type; and other drug compositions prepared by adding water-soluble polymeric substances to these compositions.

Description

Itoda · Pharmaceutical composition with improved dissolution Background of the invention

Technical field:

The present invention relates to a pharmaceutical composition containing 6-hydroxy-5,7-dimethyl-2-methylamino-4- (3-pyridylmethyl) benzothiazole, which has improved solubility and which can be controlled in release.

Conventional technology:

6-Hydroxy-1,5,7-dimethyl-12-methylamino 4- (3-pyridylmethyl) benzothiazole (hereinafter sometimes referred to as the compound of the present invention) is a drug for treating ulcerative colitis and Crohn's disease It is a compound under development. However, the compounds according to the invention have a very low solubility, especially in the alkaline region. In general, to improve the solubility of poorly soluble drugs, fine powdering of the drug, formation of solvates, increase of surface area by solid surface adsorption, polymorphism, mixing and grinding with excipients, solid dispersion, etc. Methods are known and are disclosed, for example, in JP-B-59-144446, JP-A-58-183636. Pharmaceutical products, on the other hand, are required to have efficacy and safety, as well as various properties depending on the purpose of use. Above all, there is a growing need for a system (called D-DSS) that delivers the required amount of drug to the target site for the required amount of time by devising the dosage form. A sustained-release formulation that regulates the release rate of a drug from a drug product and provides a sustained effect has already been put to practical use, but recently a drug product that controls the time until drug release starts has been developed. . For example, when the water-swellable substance expands, the film is destroyed and the drug is released, and as a film of a preparation that provides a lag time until the release starts, water-repellent salts such as metal salts of fatty acids and acrylic acid-based polymers And those utilizing the interaction between Eudragit RS (trade name) and organic acids.

6-hydroxy-5,7-dimethyl-2-methylamino-4- (3-pyridyl T-methyl) benzothiazol does not substantially dissolve in neutral to alkaline water depending on the usual formulation, so its absorption rate when administered to a living body may be low and its fluctuation may be large. Among the techniques for improving solubility, the method based on pulverization has a limited effect, and the use of surfactants has problems in terms of safety.

Furthermore, when controlled release is imparted to these absorption-improved preparations, there is a problem that the absorption-improving effect is lost.

As a result of intensive studies to solve the above problems, the present inventors have found that the following method can solve the problems, and have completed the present invention. DISCLOSURE OF THE INVENTION The present invention comprises dissolving or dispersing 6-hydroxy-1,5,7-dimethyl-12-methylamino-4- (3-1-pyridylmethyl) benzothiazole and a polymer substance in a solvent, and then distilling off the solvent. It is a pharmaceutical composition. Further, it is a pharmaceutical composition obtained by molding 6-hydroxy-5,7-dimethyl-12-methylamino-14- (3-pyridylmethyl) benzothiazole and a polymer substance by a stirring compression type extrusion granulator. . The present invention is a drug composition obtained by further adding a water-soluble polymer substance to the above-mentioned drug composition.

DETAILED DESCRIPTION OF THE INVENTION: 6-Hydroxy-1,5,7-dimethyl-1-methylamino-4- (3-pyridylmethyl) benzothiazole has the following structural formula:

The high molecular substance in the present invention means a high molecular substance dissolved or dispersed in water, and specifically, hydroxypropyl methylcellulose phthalate, hydroxypropynolemethinolecinolate, and canoleboxymethinoletinolate. Senorelose, methinoresenorelose, hydroxypropylcellulose, polyvinylpyrrolidone, methacrylic acid 'methyl acrylate' copolymer, methyl methacrylate · methyl butyl methacrylate · dimethylaminoethyl methacrylate 'copolymer or methacrylic The term “ethyl acrylate” means a copolymer, and preferred examples thereof include hydroxypropylmethylcellulose phthalate and canoleboxymethylethylcellulose. Preferred as the water-soluble polymer substance to be further added to the drug composition are hydroxypropyl senorelose, hydroxyl butylmethylcellulose, carboxymethinolethynolacese / rerose, methizoresenorelose, and polyvinyl acetate. Norepyrrolidone, methacrylic acid 'methyl acrylate' copolymer, methyl methacrylate It means phthalate and the like, and is preferably hydroxypropylcellulose, hydroxypropylmethylcellulose, or carboxymethylethylcellulose.

The solvent in the present invention means a solvent capable of dissolving or dispersing 6-hydroxy-1,5,7-dimethyl-12-methylamino41- (3-pyridylmethyl) benzothiazole and a polymer substance, for example, water, Examples include ethanol, methanol, dichloromethane, and chloroform. Further, these solvents can be used in combination. For example, the mixing ratio of the water-Z ethanol mixed solvent is usually 1 to 90% of water, and the ethanol is 99 to: L0 <½. More preferably, it is 1 to 30% of water and 99 to 70% of ethanol. In the case of other mixed solvents, the mixing ratio in which the compound according to the present invention and the high molecular substance are both dissolved can be appropriately selected. The compound of the present invention and the water-soluble polymer substance are usually dissolved at room temperature, but may be cooled or heated as needed.

Further, the agitation compression type extrusion granulator in the present invention refers to a screen or a nozzle while stirring and mixing the compound of the present invention and a water-soluble polymer substance with a screw or the like installed in the granulator. With a machine that extrudes under pressure and performs granulation molding Some preferred examples include a twin-screw extruder. During granulation and molding, the temperature is usually raised to 30 to 180 ° C.

It is believed that in the pharmaceutical composition of the present invention, the compound of the present invention may be a solid dispersion. The solid dispersion refers to a state in which the compound according to the present invention is dispersed in a polymer material that is a medium, and means that the compound is in a molecular state or an amorphous state. When it is not a body, that is, for example, even if it is dispersed in a crystalline state, the effects of the present invention can be obtained.

Further, in the present invention, for the purpose of controlling the release, a drug composition formed by adding a powder of a water-soluble polymer to the above-mentioned drug composition, or a water-soluble polymer dissolved in a solvent is used. The above-mentioned drug composition can be made into a drug composition which is formed into granules. The release of 6-hydroxy-1,5,7-dimethyl-2-methylamino-4- (3-pyridylmethyl) benzothiazole is freely controlled by the type and amount of water-soluble polymer added, and the absorption improvement effect does not decrease. As a result, the drug can be delivered to the target site in a required amount for a required time, and an excellent drug effect can be obtained.

The method for producing 6-hydroxy-5,7-dimethyl-12-methylamino41- (3-pyridylmethyl) benzothiazole, which is a compound according to the present invention, is described, for example, in JP-A-5-178788555. Can be performed by the method disclosed in

6-Hydroxy-1,5,7-dimethyl-1-methylamino-1 in the present invention

The mixing ratio of (3-pyridylmethyl) benzothiazole and the polymer substance is 6-hydroxy-5,7-dimethyl-2-methylamino-1- (3-pyridylmethyl) benzothiazole per 1 part by weight of polymer The substance is at least 1 part by weight, preferably at least 4 parts by weight. The upper limit of the mixing ratio of the polymer substance is usually 20 parts by weight or less.

The production method of the composition according to the present invention is obtained, for example, by dissolving the compound according to the present invention and hydroxypropylmethylcellulose phthalate in a mixed solvent of 85% ethanol / water and evaporating the solvent to dryness. Can be. The obtained composition can be pulverized and sieved, and if necessary, mixed with other substances to prepare granules, tablets and the like. Further, for example, a compound according to the present invention and a hydroxypropylcellulose acetate lid The composition according to the present invention can be obtained by mixing the rates and granulating with a biaxial extruder. In this case, the mixture is 40-120. C can be heated and plasticizers such as Lovely wax, sugar ester, and stearic acid can be added. The obtained composition can be pulverized and sieved, and if necessary, mixed with other substances to prepare a preparation such as a granule or a tablet.

The ratio of the case where the water-soluble polymer substance is further added to the 6-hydroxy-1,5,7-dimethyl-2-methylamino-4- (3-pyridylmethyl) benzothiazol-containing drug composition in the present invention is as follows. The water-soluble polymer is used in an amount of 0.01 to 10 parts by weight, preferably 0.02 to 5 parts by weight, more preferably 0.05 to 0.5 part by weight, based on 1 part by weight of the drug composition. 5 parts by weight. It is appropriately selected depending on the purpose of the release control. In these drug compositions, a water-soluble polymer substance is added to the above-mentioned drug composition and then mixed and tableted, or the composition is formed into granules by using a water-soluble polymer substance dissolved in a solvent. It can be manufactured by doing. In the case of tablets and granules, formulation aids such as commonly used disintegrants and lubricants can be used. Action:

According to the present invention, 6-hydroxy-1,5,7-dimethyl-12-methylamino-14- (3-pyridylmethyl) benzothiazole is not decomposed, its crystal structure is changed, and the original crystal form is exhibited. The solubility is transiently higher than the solubility. During this time, the compound according to the present invention is absorbed from the digestive tract, and the effect can be more reliably exhibited. Additionally _v type of water soluble polymer and the amount by 6-arsenide Dorokishi one 5, 7-dimethyl one 2 - Mechiruamino one 4 one (3-pyridylmethyl) release of benzothiazole Ichiru is freely controlled, and improved absorption The effect does not decrease. This makes it possible to deliver a required amount of a drug to a target site for a required time, thereby achieving an excellent drug effect.

BRIEF DESCRIPTION OF THE DRAWINGS:

FIG. 1 is a diagram showing the elution of the compound according to the present invention when various polymer substances are blended.

FIG. 2 is a diagram showing elution when a substance according to the present invention is mixed with carboxymethylethylcellulose at various ratios and produced by a biaxial extruder. FIG. 3 is a graph showing changes in the blood glucose level of the substance of the present invention when the substance of the present invention and carboxymethylethyl cellulose mixture are produced by a biaxial extruder and administered to a beagle dog. is there.

FIG. 4 is a diagram showing the elution of the compound according to the present invention from tablets obtained by tableting after adding various types of polymer substances to powder.

FIG. 5 is a diagram showing the dissolution of the compound according to the present invention from tablets obtained by tableting after adding powder of hydroxymethyl pill methyl cellulose.

FIG. 6 is a diagram showing the dissolution of the compound according to the present invention from a tablet obtained by tableting after adding powder of carboxymethylethylcellulose.

FIG. 7 is a diagram showing the elution of the compound according to the present invention from granules produced by dissolving methacrylic acid / methyl acrylate / copolymer in ethanol. EXAMPLES Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto. Example 1

Mix 1 g of 6-hydroxy-5,7-dimethyl-2-methylamino-1- (3-pyridylmethyl) benzothiazol with 5 g of hydroxypropinolemethinoresenolellose phthalate and mix with 85% ethanol / water After mixing with the solvent, the solvent was evaporated to dryness to produce the composition according to the present invention.

Example 2

10 g of polypyrrolidone is mixed with 2 g of 6-hydroxy-1,5,7-dimethyl-12-methylamino-4- (3-pyridylmethyl) benzothiazol, dissolved in ethanol, and then the solvent is evaporated. After drying, a composition according to the present invention was produced.

Example 3

A mixture of 100 g of hydroxypropynolemethinolecellulose phthalate and 200 g of 6-hydroxy-5,7-dimethyl-2-methylamino-141- (3-pyridylmethyl) benzothiazole is mixed with 200 g to form a biaxial type. using Ekusutoru one da one, sieved and crushed ₃ the composition prepared a composition according to the present invention warmed to 8 0 C in Jietsu Bok mill, A powder was produced.

Example 4

Kano levo carboxymethyl methylcarbamoyl Honoré ethyl Se Honoré port one scan l OOO g 6-arsenide Dorokishi 5, 7-di methyl one 2- Mechiruamino one ⁴ one (3-pyridylmethyl) benzothiazole one Honoré 20 0 g mixed biaxial type Ekusutoru The composition according to the present invention was heated to 70 ° C. using a die, and was then pulverized with a hammer mill and sieved to prepare granules.

Example 5

To 10 g of the composition obtained in Example 1, 2.5 g of powder of carboxymethylethylcellulose, hydroxypropylmethylcellulose, polybutylpyrrolidone, methylcellulose or hydroxy-5-hydroxypropylcellulose was added. A post-lubricating agent was added, and the mixture was compressed at a pressure of 600 kg to produce a tablet having a diameter of 9 mm and a tablet of 300 mg.

Example 6

Hydroxypropyl methylcellulose was added to 10 g of the composition obtained in Example 2 after adding 5%, 12.5% or 25% powder, and the mixture was compressed at a pressure of 800 kg to give a tablet having a diameter of 9 mm and 1 tablet. 30 Omg tablets were produced.

Example 7

5 g of carboxymethylethyl cellulose was added to 10 g of the composition obtained in Example 3. After adding ₀ /25% or 25% powder, a lubricant was added, and the mixture was compressed under a pressure of 600 kg to produce tablets each having a diameter of 9 mm and a tablet size of 30 Omg.

Example 8

10 g of the composition obtained in Example 4 was dissolved in 100% ethanol so as to have a weight ratio of 5 <½, 10% or 15% in 10 g of the composition obtained in Example 4. The mixture was dried, dried and sieved to produce granules.

Effect:

Hydroxypropyl cellulose acetate phthalate, hydroxypropylmethyl methylenololose, carboxymethylinoethyl cellulose or methacrylic acid / methyl acrylate / copolymer was used per 1 part by weight of the compound of the present invention. 5 parts by weight were mixed, and the composition according to the present invention was produced using a biaxial extruder. The results of the elution of the compound of the present invention with respect to 900 mL of the Japanese Pharmacopoeia at 37 ³ C in the paddle method at 100 rpm are shown in FIG. 1. As a control, only the compound according to the present invention was used as a control. Using. Each of the compositions according to the present invention exhibited higher solubility and a higher dissolution rate than the control.- 1 to 1 part by weight of the compound of the present invention was mixed with 3 to 10 parts by weight of carboxymethylethylcellulose to obtain a biaxial type. Using the composition according to the present invention manufactured by an extruder, the results of measuring the elution (37 ° C, 900 mi, paddle method, 100 rpm) of the compound of the present invention in two solutions of S station, and Figure 2 shows.

From FIG. 2, it can be seen that, at any mixing ratio, only the compound of the present invention shows a higher solubility and a higher dissolution rate than the compound according to the present invention. Is evident.

Blood drug after oral administration of 50 mg as 6-hydroxy-5,7-dimethyl-2-methylamino 4- (3-pyridylmethyl) benzothiazole to beagle dogs using the composition obtained in Example 3 Figure 3 shows the change in concentration. The test was carried out by a crossover method using, as a control, tablets prepared by a conventional method from a compound crystal of the present invention which was not a solid dispersion. As is apparent from FIG. 3, the composition according to the present invention significantly improved the absorption amount and the dispersion of the absorption as compared with the control.

6-Hydroxy-1,5,7-dimethyl-2-methylamino-41- (3-pyridylmethyl) -benzothiazol of the tablet obtained in Example 5 against 90 Om ^ of the first and second liquids of S department FIG. 4 shows the results obtained by measuring the elution of the compound with the paddle method at 100 rpm. As a control, only the solid dispersion according to the present invention was used. It is clear that the solid composition according to the present invention can control the release in one Japanese Pharmacopoeia by the added water-soluble polymer substance while maintaining the solubility in the two Japanese Pharmacopoeia.

Dissolution of 6-hydroxy-5,7-dimethyl-1-methylamino-41- (3-pyridylmethyl) benzothiazol into 900 mf of JP 1st and 2nd liquids of the tablets obtained in Example 6 FIG. 5 shows the results of the measurement using the paddle method at 100 rpm. As a control, only the solid dispersion according to the present invention was used.- The solid composition according to the present invention was released in 1st JP by the added hydroxypropylmethyl cellulose while maintaining the solubility in 2nd PS. It is clear that the control of is possible. ⁶ -Hydroxy-5,7-dimethyl_2-methylamino-4- (3-pyridylmethyl) benzothiazol of the tablet obtained in Example 7 with respect to 90 Omf of the first and second liquids of the Pharmacopoeia The results of the elution measured with the paddle method at 100 rpm are shown in FIG. 6: Only the solid dispersion according to the invention was used as a control. It is clear that the release of the solid composition according to the present invention can be controlled by adding the amount of carboxymethylethylcellulose in the first and second liquids.

6-Hydroxy-5,7-dimethyl-12-methylamino-14- (3-pyridylmethyl) benzothiazol of the granules obtained in Example 8 against 90 Om of the first and second liquids of JP FIG. 7 shows the results of measuring the elution of the compound by the paddle method at 100 rpm. As a control, only the solid dispersion according to the present invention was used. It is clear that the solid composition according to the present invention can control the release in one Japanese Pharmacopoeia by the addition amount of methacrylic acid / methyl acrylate / copolymer while maintaining the solubility in two Japanese Pharmacopoeia. is there.

Claims

Scope of word blue

1.6-Hydroxy-5,7-dimethyl-2-methylamino-1- (3-pyridylmethyl) benzothiazole and a drug substance obtained by dissolving or dispersing a polymer substance in a solvent and distilling off the solvent.

2.6—Hydroxy-5,7-dimethyl-1-methylamino-4- (3-pyridylmethyl) benzothiazole and a pharmaceutical composition obtained by molding a high molecular weight substance with a stirring compression type extrusion granulator.

3. High molecular substances are hydroxypropyl methylcellulose phthalate, hydroxypropizolemethinoresenolerose, canolepo'ximetinoleethylsenolate, methinoresulose, hydroxypropylcellulose, polyvinylpyrrolidone, and methanol. 3. A polymer substance selected from the group consisting of copolymers of acrylic acid 'methyl acrylate', copolymers of methyl methacrylate, butyl methacrylate 'dimethylaminoethyl methacrylate' and copolymers of ethyl methacrylate and ethyl methacrylate. A pharmaceutical composition as described.

4. The pharmaceutical composition according to claim 1, further comprising a water-soluble polymer substance.

5. The pharmaceutical composition according to claim 2, further comprising a water-soluble polymer substance.

6. The water-soluble polymer substance is hydroxypropylmethylcellulose, carboxymethylethylcellulose, methinoresolesol, hydroxypropinoresolenor, polybutylpyrrolidone, methacrylic acid 'methyl acrylate' copolymer 6. The drug according to claim 4 or 5, wherein the drug is selected from methyl methacrylate 'butyl methacrylate' dimethylaminoethyl methacrylate. A copolymer and a copolymer of methacrylic acid, ethyl acrylate and copolymer. Composition.