JPH1053524A - Sustained release oral tablet of ibudilast and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an oral tablet capable of increasing compliance to patients and contributing to quality of life by including ibudilast as an active ingredient and sustainedly releasing ibudilast by a specific method. SOLUTION: This oral tablet contains ibudilast represented by the formula as an active ingredient and precisely controls the eluting property. The control of eluting property is carried out by subjecting, e.g. uniform mixture of ibudilast with an enteric polymer (e.g. cellulosic polymer or an acrylic polymer), a sustained release agent (e.g. a water-soluble polymer or waxes) and additive for tablets to compression molding. The sustained release oral tablet is further preferably coated with a coating agent (e.g. hydroxymethyl cellulose or hydroxypropyl methyl cellulose). Adverse effect such as nausea or vomiting action after oral administration can be suppressed by carrying out the treatment.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a pharmaceutical preparation using ibudilast as a sustained release oral tablet and a method for producing the same.

[0002]

2. Description of the Related Art Ibudilast (international generic name ibudi)
last, chemical name 3-isobutyryl-2-isopropylpyrazolo [1,5-a] pyridine) is a white crystalline powder having the following structural formula, a molecular weight of 230.0, and a melting point of 51 to 54 ° C. It is easily soluble in chloroform and ethanol but hardly soluble in water.

[0003]

Embedded image

[0004] Ibudilast has a cerebrovascular or bronchodilator action and is a very useful compound as a medicament. However, ibudilast has the side effect of developing nausea and vomiting after oral administration.

As a preparation having reduced side effects of ibudilast, a capsule containing sustained-release granules containing ibudilast (JP-A-60-193913) has been developed. Provided for medical treatment.

[0006]

DISCLOSURE OF THE INVENTION The present invention provides a tablet of ibudilast which is easy to take, and a sustained-release tablet in which the dissolution of ibudilast is precisely controlled in consideration of the therapeutic effect and side effects. The goal is to provide patients, increase patient compliance and contribute to the quality of life.

[0007]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have completed the present invention.

[0008] That is, the present invention relates to a sustained-release oral tablet of ibudilast and a method for producing the same as described in the following items (1) to (7).

(1) A sustained-release oral tablet comprising ibudilast as an active ingredient.

(2) The sustained release oral tablet according to the above (1), wherein a homogeneous mixture of ibudilast, an enteric polymer, a sustained release agent and a tablet additive is compression-molded.

(3) A sustained-release oral tablet formed by compression-molding a mixture of ibudilast, an enteric polymer, a sustained-release agent and an additive for tablets and superposed on two or more layers, wherein adjacent layers are different from each other. Ingredients containing the same or different components in the case of the same component, and the elution characteristics of the layer containing ibudilast are any of quick release, sustained release, enteric release, and enteric The sustained release oral tablet according to the above (1), which is characterized in that:

(4) A sustained-release agent and / or an additive for tablets, an enteric-coated sustained-release tablet comprising ibudilast and an enteric polymer may be prepared by adding one or more of ibudilast, a sustained-release agent and an additive for tablets. The sustained-release oral tablet according to the above (1), which is coated with at least two kinds of components and compression-molded.

(5) Ibudilast, a sustained-release component comprising a sustained-release component and an additive for tablets, and enteric-coated sustained-release particles comprising an ibudilast, a sustained-release component and an enteric polymer, are used to form ibudilast, sustained-release The sustained release oral tablet according to the above (1), wherein the tablet is mixed with at least one kind of tablet matrix selected from the group consisting of an agent and an additive for tablets and is compression-molded.

(6) A method for producing a sustained-release oral tablet of ibudilast, which comprises coating the sustained-release oral tablet described in the above items (2) to (5) with a coating material.

(7) The method according to the above (6), wherein the coating agent is at least one selected from hydroxymethylcellulose, hydroxypropylmethylcellulose, polyvinyl acetal diethylaminoacetate and aminoalkyl methacrylate copolymer.

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION The enteric polymer used in the present invention is a high-polymer having a function of gradually releasing a drug by reaching the intestine and dissolving the drug without causing the drug to be released in the stomach. It is a molecular compound and includes a cellulosic polymer and an acrylic polymer. As the cellulosic polymer, for example, hydroxypropyl methylcellulose phthalate (trade name “HPMCP HP-55, HP-55S, H
P-50 ", manufactured by Shin-Etsu Chemical Co., Ltd.), hydroxypropyl methyl cellulose acetate succinate (trade name" AQOAT LG, MG, LF, MF ", manufactured by Shin-Etsu Chemical Co., Ltd.), carboxymethyl ethyl cellulose (trade name" CMEC ", manufactured by Freund Corporation. Examples of the acrylic polymer include methacrylic acid copolymer L (trade name “Eudragit L”, manufactured by Rohm-Pharma), methacrylic acid copolymer S (trade name “Eudragit S”, R
ohm-Pharma).

The sustained-release agent used in the present invention is a compound having a function of gradually releasing a drug irrespective of the pH of digestive juice, and includes water-soluble polymers, waxes, and water-insoluble polymers. Can be

Examples of the water-soluble polymer used as a sustained-release agent include hydroxypropyl methylcellulose (trade name “Metroze”, manufactured by Shin-Etsu Chemical Co., Ltd.) and hydroxypropyl cellulose (trade name “HPC-M,
H "manufactured by Nippon Soda Co., Ltd.), low-substituted hydroxypropylcellulose (trade name" L-HPC ", manufactured by Shin-Etsu Chemical Co., Ltd.) and the like.

Examples of the wax used as a sustained release agent include, for example, hardened oil (trade name "Laburi Wax 10").
1 ", manufactured by Freund Corporation, paraffin, stearic acid, polyethylene glycol, sucrose fatty acid ester (trade name" Ryoto Sugar Ester ", manufactured by Mitsubishi Chemical Corporation), and the like.

Examples of the water-insoluble polymer used as the sustained-release agent include, for example, ethyl cellulose (trade name “Ethocel”, manufactured by Dow Chemical Co., Ltd.) and hydroxypropylmethylcellulose acetate succinate (trade name “AQOA”).
THG, HF ", Shin-Etsu Chemical Co., Ltd.), aminoalkyl methacrylate copolymer RS (trade name" Eudragit RS, manufactured by Rohm-Pharma ") and the like.

The tablet additives used in the present invention include excipients, binders, lubricants and the like. Examples of the excipient include lactose, sucrose, mannitol, crystalline cellulose, starches, calcium hydrogen phosphate (trade name “Fujicarin”, manufactured by Fuji Chemical Industry Co., Ltd.), and synthetic hydrotalcite (trade name “Alkamac”). , Kyowa Chemical Co., Ltd.)
Granulated product of synthetic aluminum silicate, hydroxypropyl starch and crystalline cellulose (trade name "Perfiller 10
1 ", manufactured by Freund Corporation).

Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol and the like.

Examples of the lubricant include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester and the like.

Hereinafter, embodiments of the sustained-release oral tablet of ibudilast described in the above items (2) to (5) will be described.

(A) Sustained-release oral tablets of ibudilast according to the above item (2) The sustained-release oral tablets of ibudilast according to the above item (2) include ibudilast, an additive for tablets, an enteric polymer, It is a compression-molded tablet in which a sustained-release agent is uniformly dispersed and mixed.

One example of the method for producing a sustained-release oral tablet of ibudilast according to the above item (2) is as follows. First, ibudilast, an excipient as an additive for tablets, an enteric polymer, a sustained-release agent , And the resulting mixed powder is directly compression-molded into a tablet, or the obtained mixed powder is mixed with water or methanol, ethanol, acetone, chloroform, methylene chloride, ethylene chloride, etc. A liquid dissolved in one or more of the organic solvents described above is added, kneaded well, dried at 40 to 50 ° C., and the dried product is sized using a sieve of an appropriate size. One or two or more lubricants may be mixed, and the mixed particles may be compression molded.

(B) The sustained-release oral tablet of ibudilast according to the above (3) is a compression-molded tablet having a multilayer structure of two or more layers. Adjacent layers are different components, or in the case of the same component, the component composition ratio is different, and the release characteristics of ibudilast in each layer are rapid release, sustained release, enteric release control, enteric release It is one of the features.

One example of the method for producing a sustained-release oral tablet of ibudilast described in the above item (3) is as follows. First, a part of ibudilast, an additive for tablets, an enteric polymer, and a sustained-release agent are prepared. Mixing well to obtain a mixed powder A of the tablet first layer component,
Alternatively, a liquid in which a binder is dissolved in water or one or more of organic solvents such as methanol, ethanol, acetone, chloroform, methylene chloride, and ethylene chloride in advance is added to the mixed powder, and the mixture is sufficiently kneaded.
After drying at 〜50 ° C. and sieving the dried product using a sieve of an appropriate size, a lubricant is mixed as necessary to obtain mixed particles A of the first layer component of the tablet.

Separately, the rest of ibudilast and an additive for tablets are mixed to obtain a mixed powder B of the second layer component of the tablet, or a binder is previously added to the mixed powder with water or methanol, ethanol, acetone, chloroform, methylene chloride. , A solution dissolved in one or more of organic solvents such as ethylene chloride and the like are added and sufficiently kneaded,
After the dried product is sized using a sieve of an appropriate size, a lubricant is mixed as needed to obtain mixed particles B of the tablet second layer component.

By compressing the mixed powders A and B or the mixed particles A and B into two layers, respectively,
A sustained release oral tablet of ibudilast having two layers of sustained release can be obtained.

(C) The sustained-release oral tablet of ibudilast according to the above (4), the sustained-release oral tablet of ibudilast according to the above-mentioned (4),
The tablet is an enteric-coated sustained-release tablet containing ibudilast, coated with at least one selected from ibudilast, a sustained-release releasing agent and an additive for tablets, and compression-molded.

One example of the method for producing an oral tablet for sustained release of ibudilast according to the above item (4) is as follows. First, ibudilast, an additive for tablets, and a sustained-release agent are sufficiently mixed. The mixed powder is compression-molded as it is to obtain a sustained-release tablet as a base, or the binder is added to water or one of organic solvents such as methanol, ethanol, acetone, chloroform, methylene chloride and ethylene chloride in advance. Alternatively, add a liquid dissolved in two or more types, knead well, dry to 40 to 50 ° C., size the dried product using a sieve of an appropriate size, and mix a lubricant if necessary. Then, the obtained mixed particles are compression-molded to obtain a sustained-release tablet as a base. The base sustained-release tablet thus obtained is coated with a solution in which the enteric polymer is dissolved in an organic solvent or a solution in which the enteric polymer is dispersed in water to obtain an enteric sustained-release agent.

Separately, ibudilast, an additive for tablets and a sustained release agent are sufficiently mixed to obtain a mixed powder of tablet coating components, or a binder is added to the mixed powder in advance with water or methanol, ethanol, acetone. , Chloroform,
A solution prepared by dissolving one or more of organic solvents such as methylene chloride and ethylene chloride is added, sufficiently kneaded, dried at 40 to 50 ° C, and sized using a sieve of an appropriate size. After that, if necessary, a lubricant is mixed to obtain mixed particles of the components for tablet coating. By coating the periphery of the previously prepared enteric-coated sustained-release tablet with the mixed powder or mixed particles of the tablet coating component and compression-molding, the enteric-coated sustained-release tablet containing ibudilast containing the ibudilast inside is released. Sustained-release oral tablets, including tablets, can be obtained.

(D) The sustained-release oral tablet of ibudilast according to the above (5), the sustained-release oral tablet of ibudilast according to the above-mentioned (5),
It is a compression-molded tablet in which sustained release particles containing ibudilast and enteric sustained release particles containing ibudilast are mixed in a tablet matrix.

One example of the method for producing a sustained-release oral tablet of ibudilast described in the above item (5) is as follows. First, one or more excipients are added to one of the excipients and one to the binder. The seed or two or more kinds are sufficiently kneaded with a solution obtained by dissolving in water or an organic solvent, granulated by an extrusion granulator equipped with a mesh of an appropriate size, and then granulated by a tumbling granulator. Dry at ℃ to prepare particles. The particles are coated with a solution prepared by dissolving ibudilast in an organic solvent such as methanol, ethanol, chloroform, ether, and ethyl acetate.
Obtain immediate-release particles coated with ibudilast. The ibudilast-coated particles are coated with a solution of a sustained-release agent dissolved in an organic solvent to obtain sustained-release particles.

Further, a solution obtained by dissolving an enteric polymer in an organic solvent is coated on a part of the obtained sustained release particles,
Enteric coated sustained release particles are obtained.

One or more components of ibudilast, a sustained release agent and an additive for tablets are added to one or more of the above-mentioned sustained release particles and enteric sustained release particles, and a lubricant. Is added, mixed and compression-molded to obtain a sustained-release oral tablet of ibudilast.

The sustained-release oral tablet of ibudilast of the above-mentioned items (2) to (5) can be prepared by using a suitable coating agent such as hydroxymethylcellulose, hydroxypropylmethylcellulose, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer and the like. May be coated.

[0039]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited to these Examples.

Embodiment 1

[0041]

[Table 1]

Ibudilast having the composition shown in Table 1 and each component of lactose, hydroxypropylmethylcellulose, and hydroxypropylmethylcellulose acetate succinate were thoroughly mixed, and 18.2 mg of ethanol was added per tablet to the resulting mixed powder. And knead well, 40 ~ 5
Dried at 0 ° C. The dried product was sized using a 850 μm sieve, and magnesium stearate was added.
The resulting mixture was compression-molded with a tablet molding punch of m to obtain tablets.

The dissolution rate of ibudilast in the obtained tablets was measured and is shown in FIG. The measurement of the elution rate of ibudilast was performed as follows.

(Dissolution test method) Apparatus: Japanese Pharmacopoeia 13, Dissolution test method, first method (rotating basket method) Rotational speed: 100 min ^-1 , temperature: 37 ± 0.5 ° C Test solution: Japanese Pharmacopoeia 13 for disintegration test First liquid 500ml, JP 1
(3) 500 ml of the second liquid for disintegration test Test time: 2 hours with the first liquid, then 5 hours with the second liquid Sample: 1 tablet As is clear from the results in FIG. It was almost the same as a commercially available ivudilast capsule (trade name “Ketas Capsule”).

Embodiment 2

[0046]

[Table 2]

The components from ibudilast to lactose in the first layer of the tablet shown in Table 2 were taken and thoroughly mixed, and 11.4 mg of ethanol per tablet was added and kneaded.
After drying at 0 ° C., it was sized with a 850 μm sieve to obtain granules. Separately, ibudilast and lactose of the second layer component of the tablet were taken and mixed, and 1.3 m of ethanol was added to each tablet.
g, kneaded and dried at 40-50 ° C.
The particles were sized with a sieve of μm to obtain granules. The granules were mixed with 0.14 mg of magnesium stearate per tablet. The granules of the first layer component are placed in a die having a diameter of 7 mm of a tableting machine.
08 mg was filled and compression molded to obtain a first layer tablet. Further, 20 mg of the granules of the second layer component are superimposed on the tablet of the first layer, filled and compression-molded again to obtain a 7 mm-diameter ibudilast sustained-release oral tablet containing 10 mg of ibudilast superimposed on the two layers. Obtained.

The dissolution rate of ibudilast from the obtained tablets was measured and is shown in FIG. As is clear from the results of FIG. 1, the dissolution characteristics of the obtained tablets were almost the same as those of the commercially available ibudilast capsules.

Embodiment 3

[0050]

[Table 3]

The enteric-coated sustained-release tablet components shown in Table 3 were mixed with lactose and below ibudilast and mixed well.
Of polyvinylpyrrolidone K-30 in ethanol
1.25 mg was added, kneaded and dried, and then sized with a 850 μm sieve to obtain granules. 0.8 per tablet
Mix 5mg of magnesium stearate, 6m in diameter
The tablets were compression-molded with a tableting punch of m to obtain 76.5 mg of sustained-release naked tablets per tablet. The sustained-release naked tablet is coated with an aqueous solution of hydroxypropylmethylcellulose 2910, and further coated with an ethanol solution of hydroxypropylmethylcellulose acetate succinate and a glycerin fatty acid ester to give 78.1 tablets.
mg of enteric-coated sustained-release tablet was obtained.

Separately, the tablet coating components shown in Table 3 were taken from ibudilast to lactose, and a 12% ethanol solution of polyvinylpyrrolidone K-30 was added and kneaded.
After drying, the particles were sized with a 850 μm sieve to obtain granules. Perfiller 101 (trade name) and magnesium stearate were mixed with the granules to obtain tablet coating granules having an immediate release property. The granules (160 mg) are filled in a die having a diameter of 9.5 mm, an enteric-coated sustained-release tablet having a diameter of 6 mm is arranged at the center thereof, and a component for a second tablet, 163.5 m, is further placed in the die.
g of the enteric-coated sustained-release tablet, coated with a tablet making punch having a diameter of 9.5 mm, and then the enteric-coated sustained-release tablet was coated with 10 mg of ibudilast contained in the immediate-release tablet. Oralized tablets were obtained.

The dissolution rate of ibudilast from the obtained tablets was measured and is shown in FIG. As is clear from the results of FIG. 1, the dissolution characteristics of the obtained tablets were almost the same as those of the commercially available ibudilast capsules.

Example 4 22.5 kg of lactose and 7.5 kg of crystalline cellulose were mixed, and a 2% aqueous solution of polyvinylpyrrolidone K-90 was added.
After adding 0 kg, kneading, granulating, and drying, the diameter is 0.5-0.
7 mm particles were obtained. 9 kg of an 8.3% ibudilast ethanol solution was sprayed on 12 kg of the particles with a fluidized bed coating apparatus to obtain quick-release particles coated with ibudilast. To 4000 g of these particles, 3.3% Eudragit R
3.2 kg of an ethanol solution of S (trade name) was spray-coated with a fluidized bed coating apparatus to obtain sustained-release particles of ibudilast. To 3 kg of the sustained-release particles, 4.2 kg of an ethanol solution of 3.3% Eudragit L (trade name) was spray-coated with a fluidized bed coating apparatus to obtain enteric sustained-release particles.

One part by weight of the sustained release particles and 3 parts by weight of the enteric sustained release particles were mixed, and 190 mg of the obtained particles, 258.4 mg of Perfiller 101 (trade name) and 1.6 mg of magnesium stearate were taken. Then, the mixture was subjected to compression molding to obtain a sustained-release oral tablet having a diameter of 9.5 mg containing sustained-release particles of ibudilast and enteric-sustained release particles in a tablet matrix.

The dissolution rate of ibudilast from the obtained tablets was measured and is shown in FIG. As is clear from the results of FIG. 1, the dissolution characteristics of the obtained tablets were almost the same as those of the commercially available ibudilast capsules.

[0057]

The present invention provides a tablet of ibudilast which is easier to take than a capsule, and provides a sustained-release preparation in which the dissolution of ibudilast is controlled in consideration of the therapeutic effect and side effects, and a method for producing the same. By doing so, it has the effect of increasing compliance with sick patients and contributing to quality of life.

[Brief description of the drawings]

FIG. 1 is a graph showing the relationship between the ibudilast elution rate and the elution time of the tablets prepared in Examples 1 to 4 and a commercially available ibudilast capsule (10 mg).

────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] June 24, 1997

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0020

[Correction method] Change

[Correction contents]

Examples of the water-insoluble polymer used as the sustained-release agent include, for example, ethyl cellulose (trade name “Ethocel”, manufactured by Dow Chemical Co., Ltd.) and hydroxypropylmethylcellulose acetate succinate (trade name “AQOA”).
THG, HF ", manufactured by Shin-Etsu Chemical Co., Ltd.), aminoalkyl methacrylate copolymer RS (trade name" Eudragit RS, manufactured by Rohm-Pharma ") ,
Ethyl acrylate / methyl methacrylate copolymer emulsion
(Product name "Eudragid NE, Rohm-Pha
rma) .

[Procedure amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0035

[Correction method] Change

[Correction contents]

One example of the method for producing a sustained-release oral tablet of ibudilast described in the above item (5) is as follows. First, one or more excipients are added to one of the excipients and one to the binder. The seed or two or more kinds are sufficiently kneaded with a solution obtained by dissolving in water or an organic solvent, granulated by an extrusion granulator equipped with a mesh of an appropriate size, and then granulated by a tumbling granulator. Dry at ℃ to prepare particles. The particles are coated with a solution prepared by dissolving ibudilast in an organic solvent such as methanol, ethanol, chloroform, ether, and ethyl acetate.
Obtain immediate-release particles coated with ibudilast. The ibudilast-coated particles are coated with a liquid in which a sustained-release agent is dissolved in an organic solvent or a liquid dispersed in water to obtain sustained-release particles.

[Procedure amendment 3]

[Document name to be amended] Statement

[Correction target item name] 0036

[Correction method] Change

[Correction contents]

Further, a solution of an enteric polymer in an organic solvent or a sustained-release agent is added to a part of the obtained sustained-release particles.
A solution dissolved in an organic solvent or a solution dispersed in water is coated to obtain enteric sustained-release particles or sustained-release particles .

Claims (7)

[Claims] A sustained-release oral tablet comprising ibudilast as an active ingredient. 2. The sustained release oral tablet according to claim 1, wherein a homogeneous mixture of ibudilast, an enteric polymer, a sustained release agent and a tablet additive is compression molded. 3. A sustained-release oral tablet obtained by compressing and molding a mixture of ibudilast, an enteric polymer, a sustained-release agent and an additive for tablets, wherein the tablet is composed of two or more layers. Or the same component, the composition ratio of the components is different, and the dissolution characteristics of the layer containing ibudilast are any of quick release, sustained release, enteric release, and enteric. The sustained release oral tablet according to claim 1, characterized in that: 4. A sustained release agent and / or an additive for tablets,
An enteric-coated sustained-release tablet comprising ibudilast and an enteric polymer is coated with a component comprising one or more of ibudilast, a sustained-release releasing agent and an additive for tablets, and compression molded. The sustained release oral tablet according to claim 1. 5. An extended release particle comprising ibudilast, a sustained release component and an additive for tablets, and an enteric sustained release particle comprising ibudilast, a sustained release component and an enteric polymer, wherein ibudilast, sustained release 2. The sustained-release oral tablet according to claim 1, wherein the tablet is mixed and compressed in at least one kind of tablet matrix selected from the group consisting of a preparation and a tablet additive. 6. A method for producing a sustained-release oral tablet of ibudilast, which comprises coating the sustained-release oral tablet according to claim 2 with a coating material. 7. The coating agent is hydroxymethyl cellulose,
At least one selected from hydroxypropyl methylcellulose, polyvinyl acetal diethylaminoacetate and aminoalkyl methacrylate copolymer
The method according to claim 6, which is a seed.