JPH0959159A - Drug composition with improved absorption - Google Patents

Abstract

(57) [Summary] [Objective] To provide a pharmaceutical composition with improved absorption. [Structure] 2- (4-carboxypiperidino) -4-
A pharmaceutical composition obtained by dissolving (3,4-methylenedioxybenzyl) amino-6-chloroquinazoline sodium and a polymeric substance in ethanol or a water / ethanol mixed solvent, and then distilling the solvent off, and 2- (4 -Carboxypiperidino) -4- (3,4-methylenedioxybenzyl) amino-6-chloroquinazoline sodium and a polymer composition molded by a stirring compression-type extrusion granulator.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a solid dispersion of 2- (4-carboxypiperidino) -4- (3,4-methylenedioxybenzyl) amino-6-chloroquinazoline sodium.

[0002]

2. Description of the Related Art 2- (4-Carboxypiperidino) -4-
(3,4-Methylenedioxybenzyl) amino-6-chloroquinazoline sodium (hereinafter sometimes referred to as the compound according to the present invention) is a therapeutic agent under development as a therapeutic agent for chronic heart failure and pulmonary hypertension. However, since the compound according to the present invention has remarkably low solubility in a wide pH range, there is a concern that it will not be sufficiently absorbed from the digestive tract or that the absorption will vary. On the other hand, in order to improve the absorbability of poorly soluble drugs, fine powdering of the drug, formation of solvate, increase of surface area by solid surface adsorption, crystalline polymorphism, mixing and grinding with excipients, solid dispersion, etc. The method is known.

[0003]

2- (4-Carboxypiperidino) -4- (3,4-methylenedioxybenzyl) amino-6-chloroquinazoline sodium is used as a commonly used pharmaceutical excipient. It has high reactivity and is easily converted from the sodium salt to the free form, resulting in lower solubility than the sodium salt. On the other hand, if the surface area is increased by pulverization or the like in order to increase the solubility and improve the absorbability, the conversion to the free form is increased, and sufficient effect cannot be obtained for the increase in the solubility. It was The present inventor has conducted extensive studies to solve the above problems, and as a result, has found that the problems can be solved by the following method, and completed the present invention.

[0004]

DISCLOSURE OF THE INVENTION The present invention relates to sodium 2- (4-carboxypiperidino) -4- (3,4-methylenedioxybenzyl) amino-6-chloroquinazoline and a polymeric substance as ethanol. Alternatively, it is a pharmaceutical composition obtained by dissolving in a water / ethanol mixed solvent and then distilling off the solvent. In addition, the present invention molds 2- (4-carboxypiperidino) -4- (3,4-methylenedioxybenzyl) amino-6-chloroquinazoline sodium and a polymeric substance by a stirring compression type extrusion granulator. A pharmaceutical composition comprising:

The polymer substance in the present invention means a polymer substance which is dissolved or dispersed in water. Dissolving or dispersing in water is insoluble at low pH, and includes cases where it is dissolved or dispersed at high pH. Specifically, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose, carboxymethyl ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, polyvinyl. It means pyrrolidone or methacrylic acid / acrylic acid copolymer, and preferred examples thereof include hydroxypropyl cellulose acetate and carboxymethyl ethyl cellulose.

The mixing ratio of the water / ethanol mixed solvent is not particularly limited, but a mixing ratio in which both the compound according to the present invention and the polymer substance are dissolved is preferable, and usually 1 to 9 of water.
0%, ethanol 99 to 10%, more preferably water 1 to 30%, ethanol 99 to 70%. The compound according to the present invention and the water-soluble polymer substance are usually dissolved at room temperature, but may be cooled or heated if necessary.

Further, the stirring compression type extrusion granulator in the present invention means that the compound according to the present invention and the water-soluble polymer substance are stirred and mixed by a blade or the like installed in the granulator,
It is a machine for performing granulation molding by applying pressure from a screen or a nozzle, and a machine such as a twin-screw extruder can be used. In the pharmaceutical composition of the present invention, the compound of the present invention is considered to be a solid dispersion. The solid dispersion is a state in which the compound according to the present invention is dispersed in a polymer substance as a medium, and it is most preferable that the compound is dispersed in a molecular state,
Alternatively, it is desirable that the material is made amorphous, but it is not limited to these dispersed states and may be dispersed in a crystalline state, for example.

A method for producing sodium 2- (4-carboxypiperidino) -4- (3,4-methylenedioxybenzyl) amino-6-chloroquinazoline, which is a compound according to the present invention, is described in, for example, the Patent Cooperation Treaty. It is disclosed in the international application WO93 / 07124 published on the basis of the above. An example of a specific manufacturing method is shown below. A mixture of 3.6 g of 2,4,6-trichloroquinazoline, 2.4 g of piperonylamine, 1.6 g of triethylamine and 50 ml of isopropyl alcohol was added.
The mixture was refluxed for 1.5 hours. When hot, the precipitate is filtered off,
5.2 g of 6-dichloro-4- (3,4-methylenedioxybenzyl) aminoquinazoline was obtained.

Next, 2,6-dichloro-4- (3,4-
To 1 g of methylenedioxybenzyl) aminoquinazoline, 3.61 g of methyl isonipecotate, 2.32 g of triethylamine and 5 ml of 2-propanol were added, and the mixture was refluxed for 100 minutes. The mixture was extracted twice with chloroform, and the combined organic layers were washed with water and dried over magnesium sulfate. After distilling off the solvent, the residue was recrystallized from ethanol-water to obtain 1.31 g of 2- (4-ethoxycarbonylpiperidino) -4- (3,4-methylenedioxybenzyl) amino-6-chloroquinazoline. It was 2- (4-ethoxycarbonylpiperidino) -4
-(3,4-Methylenedioxybenzyl) amino-6-
To 1 g of chloroquinazoline, 10 ml of ethanol, 5 ml of water and 820 mg of sodium hydroxide were added, and the mixture was refluxed for 20 minutes. The solvent was concentrated under reduced pressure, 1N hydrochloric acid was added for neutralization, and the precipitated crystals were collected by filtration, and 2- (4-carboxypiperidino) -4-
920 mg of (3,4-methylenedioxybenzyl) amino-6-chloroquinazoline was obtained. To this compound, 12 ml of 1N sodium hydroxide aqueous solution and 40 ml of water were added, dissolved by heating, and dried under reduced pressure in the presence of phosphorus pentoxide to give 2- (4-carboxypiperidino) -4- (3,4-methylenediene). Oxybenzyl) amino-6-chloroquinazoline sodium was obtained.

2- (4-carboxypiperidino) -4- (3,4-methylenedioxybenzyl) in the present invention
The mixing ratio of amino-6-chloroquinazoline sodium and the water-soluble polymer is 1- (2- (4-carboxypiperidino) -4- (3,4-methylenedioxybenzyl) amino-6-chloroquinazoline sodium). The amount of the water-soluble polymer substance is 1 part by weight or more, preferably 4 parts by weight.
It is more than part by weight. The method for producing a solid dispersion according to the present invention is carried out, for example, by adding the compound according to the present invention and hydroxypropyl cellulose acetate phthalate to 85% ethanol /
It can be obtained by dissolving in a water mixed solvent and evaporating the solvent to dryness. The obtained solid dispersion can be crushed, sieved, and optionally mixed with other substances to prepare a preparation such as granules and tablets. Further, for example, the compound according to the present invention and hydroxypropyl cellulose acetate phthalate can be mixed and granulated with a biaxial extruder to obtain the solid dispersion according to the present invention. The obtained solid dispersion can be crushed, sieved, and optionally mixed with other substances to prepare a preparation such as granules and tablets.

[0011]

When the solid dispersion according to the present invention is used, the compound according to the present invention is not decomposed, the crystal structure is changed, and the solubility is transiently higher than that of the original crystal form. During this period, the compound according to the present invention is absorbed from the digestive tract and can more reliably exhibit the effect.

[0012]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited thereto. Example 1 2- (4-Carboxypiperidino) -4 in 5 g of hydroxypropyl cellulose acetate phthalate
-(3,4-Methylenedioxybenzyl) amino-6-
1 g of sodium chloroquinazoline was mixed and mixed with an 85% ethanol / water mixed solvent, and then the solvent was evaporated to dryness to prepare a composition according to the present invention. Example 2 2 g of 2- (4-carboxypiperidino) -4- (3,4-methylenedioxybenzyl) amino-6-chloroquinazoline sodium was mixed with 10 g of polyvinylpyrrolidone, dissolved in ethanol, and then the solvent was added. The composition according to the present invention was produced by evaporation to dryness.

Example 3 2- (4-Carboxypiperidino) -4- (3,4-methylenedioxybenzyl) amino-6-chloroquinazoline sodium 200 per 1000 g of hydroxypropyl cellulose acetate phthalate
g was mixed and treated with an extruder to prepare a composition according to the present invention. This composition was crushed with a jet mill and sieved to produce granules. Example 4 10 g of hydroxypropyl methylcellulose
2- (4-carboxypiperidino) -4- (3,4-
2 g of methylenedioxybenzyl) amino-6-chloroquinazoline sodium were mixed and dissolved in an 85% ethanol / water mixed solvent, and the solvent was evaporated to dryness to prepare a composition according to the present invention.

EXAMPLE 5 2- (4-Carboxypiperidino) was added to 1000 g of hydroxypropylmethylcellulose.
-4- (3,4-methylenedioxybenzyl) amino-
200 g of 6-chloroquinazoline sodium was mixed and treated with an extruder to produce a composition according to the present invention,
Further, it was crushed with a hammer mill and sieved to produce granules. Example 6 Polyvinylpyrrolidone (PVP K-30) 1000
2- (4-carboxypiperidino) -4- (3,4)
-Methylenedioxybenzyl) amino-6-chloroquinazoline sodium (200 g) was mixed, heated and melted at 120 ° C, cooled, and pulverized to produce a composition according to the present invention.

[0015]

[Effect] To 1 part by weight of the compound of the present invention, 5 parts by weight of hydroxypropylcellulose acetate phthalate, hydroxypyropyrmethylcellulose, carboxymethylethylcellulose or polyvinylpyrrolidone are mixed, dissolved in an ethanol / water mixed solvent, and the solvent is distilled off. FIG. 1 shows the results obtained by measuring the elution of the compound of the present invention in 900 ml of Japanese Pharmacopoeia solution 2 at 37 ° C. using the composition obtained by the paddle method and 100 prm. As a control, only the compound according to the present invention was used. All the compositions according to the present invention showed higher solubility and faster dissolution rate than the control.

A composition obtained by mixing 1 to 5 parts by weight of hydroxypropylcellulose acetate phthalate with 1 part by weight of the compound according to the present invention, dissolving the mixture in an ethanol / water mixed solvent, and distilling the solvent off, The results of measuring the elution (37 ° C., 900 ml, paddle method, 100 rpm) of the compound of the present invention with JP-2 solution are shown in FIG. At all mixing ratios, higher solubility and faster dissolution rate than the compound of the present invention alone were exhibited, and particularly at a mixing ratio of 4 parts by weight or more, remarkable improvements in solubility and dissolution rate were observed.

3 to 5 parts by weight of hydroxypropyl cellulose acetate phthalate is mixed with 1 part by weight of the compound according to the present invention, and an extruder is used to obtain a composition according to the present invention. The results of measuring elution of the compound (37 ° C., 900 ml, paddle method, 100 rpm) are shown in FIG. At all mixing ratios, the composition according to the present invention was found to have a markedly improved solubility and dissolution rate.

Using the solid dispersion obtained in Example 3, 2
FIG. 4 shows changes in blood drug concentration after oral administration of 15 mg of-(4-carboxypiperidino) -4- (3,4-methylenedioxybenzyl) amino-6-chloroquinazoline sodium to beagle dogs. It was The test was carried out by a crossover method using as a control a tablet prepared by a conventional method of the compound crystal according to the present invention, which is not a solid dispersion. As is clear from FIG. 4, the solid dispersion according to the present invention was remarkably improved in both absorption amount and variation in absorption as compared with the control.

Using the solid dispersion obtained in Example 2, 2
FIG. 5 shows changes in blood drug concentration after oral administration of 15 mg of sodium- (4-carboxypiperidino) -4- (3,4-methylenedioxybenzyl) amino-6-chloroquinazoline to beagle dogs. It was The test was carried out by a crossover method using as a control a tablet prepared by a conventional method of the compound crystal according to the present invention, which is not a solid dispersion. As is clear from FIG. 5, the solid dispersion according to the present invention was remarkably improved in both absorption amount and absorption variation as compared with the control.

[0020]

[Brief description of drawings]

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

FIG. 2 is a diagram showing elution when hydroxypropylmethylcellulose phthalate was added to the substance according to the present invention in various proportions.

FIG. 3 is a diagram showing that the substance according to the present invention is blended with hydroxypropylmethylcellulose phthalate in various proportions,
It is a figure which shows elution when a composition is obtained by an extruder.

FIG. 4 is a graph showing changes in blood concentration of the substance according to the present invention when a composition comprising the substance according to the present invention and hydroxypropylmethylcellulose phthalate is administered to beagle dogs.

FIG. 5 is a graph showing changes in blood concentration of the substance according to the present invention when a composition comprising the substance according to the present invention and polyvinylpyrrolidone is administered to beagle dogs.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 47/32 A61K 47/38 B 47/38 C07D 405/14 211 C07D 405/14 211 A61K 9 / 14 L // (C07D 405/14 C 211: 62 239: 95 317: 48)

Claims (3)

[Claims] 1. 2- (4-Carboxypiperidino) -4-
(3,4-Methylenedioxybenzyl) amino-6-chloroquinazoline sodium and a polymeric substance are dissolved in ethanol or a water / ethanol mixed solvent, and then the solvent is distilled off. 2. 2- (4-Carboxypiperidino) -4-
A pharmaceutical composition obtained by molding (3,4-methylenedioxybenzyl) amino-6-chloroquinazoline sodium and a polymeric substance by a stirring compression type extrusion granulator. 3. The polymer substance is hydroxypropylcellulose acetate phthalate, hydroxypropylmethylcellulose, carboxymethylethylcellulose, methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone or a methacrylic acid / acrylic acid copolymer. Pharmaceutical composition. [0001]