WO2013147135A1

WO2013147135A1 - Controlled-release pharmaceutical composition

Info

Publication number: WO2013147135A1
Application number: PCT/JP2013/059487
Authority: WO
Inventors: 宏行小島; 誓詞 ▲高▼江; 毅彦保地; 敦司櫻井; 里美池内; 迫　和博
Original assignee: アステラス製薬株式会社
Priority date: 2012-03-30
Filing date: 2013-03-29
Publication date: 2013-10-03
Also published as: JP6123795B2; JPWO2013147135A1

Abstract

Provided is a controlled-release pharmaceutical composition which contains 4-{[(1R,2s,3S,5s,7s)-5-hydroxy-2-adamantyl]- amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide, which is a compound of which the solubility in an acidic pH region is extremely different from that in a neutral pH region, as a medicinal agent, wherein the solubility of the medicinal agent can be maintained in a neutral pH region in the digestive tract after gastric emptying (e.g., the small intestine) and the controlled-release pharmaceutical composition exhibits a good oral absorption property and has high bioavailability. The controlled-release pharmaceutical composition comprises 4-{[(1R,2s,3S,5s,7s)-5-hydroxy-2-adamantyl]amino}-1H- pyrrolo[2,3-b]pyridine-5-carboxamide or a pharmaceutically acceptable salt thereof, an acidic substance, a persaturation-maintaining agent, and a controlled-release base ingredient.

Description

Controlled release pharmaceutical composition

The present invention relates to 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide or pharmaceutics thereof The present invention relates to a controlled-release pharmaceutical composition comprising a pharmaceutically acceptable salt, an acidic substance, a supersaturation maintaining agent, and a controlled-release base. Specifically, the present invention relates to 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide. Or a pharmaceutically acceptable salt thereof, an acidic substance, a supersaturation maintaining agent, and a release-controlling base, and 4-{[(1R, 2s, 3S, 5s, 7s ) -5-Hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide or its pharmaceutically acceptable salts, maintaining solubility in pharmacokinetics The present invention relates to a controlled-release pharmaceutical composition that suppresses the difference.

4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide (hereinafter abbreviated as Compound A) Has an excellent JAK3 inhibitory activity and is known to be useful as an active ingredient of a therapeutic and / or prophylactic agent for various immune diseases including autoimmune diseases, inflammatory diseases and allergic diseases. (Patent Document 1).

A hydrogel sustained-release preparation that enables good drug release in the colon of the lower gastrointestinal tract has been disclosed (Patent Document 2). It is disclosed that when a drug is a poorly soluble drug, a solid dispersion can be formed with a polymer such as hypromellose (HPMC) to improve the solubility.

Since the drug elution rate depends on the solubility of the drug in the digestive juice, sustained-release preparations containing basic drugs have the problem that the elution rate increases in gastric juice and the elution rate decreases in intestinal fluid, or acidic drugs Since the dissolution rate of gastric juice decreases in the gastric juice, the sustained-release preparation containing a drug, a buffer, and a hydrophobic substance Matrix tablets containing molecules or gel-forming polymers are disclosed.

In addition, the buffer is retained in the matrix pores for a long time despite being easily soluble, so that the pH in the pores is kept constant. It is known that the elution rate of the drug can be arbitrarily changed by changing the composition of the added buffering agent (Patent Document 3).

In order to provide a highly safe and stable drug-releasing and absorbable taglandin I derivative sustained-release preparation, a prostaglandin I derivative and a hydrogel base and a buffer agent excluding carboxyvinyl polymer as a release controlling component Sustained-release preparations containing sulfur are disclosed (Patent Document 4).

However, there is no specific disclosure of a controlled-release preparation containing Compound A, and in order to provide a controlled-release pharmaceutical composition for Compound A that suppresses fluctuations in PK parameters caused by pH fluctuations in the digestive tract. There is room for technological improvement.

International Publication No. 2007/077949 Pamphlet Japanese Patent No. 3140465 Japanese Examined Patent Publication No. 7-76172 Japanese Patent No. 3744441

The subject of the present invention is a digestion after excretion from the stomach (such as the small intestine) when orally administered in a pharmaceutical composition containing Compound A having extremely different solubility in acidic pH range and neutral pH range. An object of the present invention is to maintain the solubility of Compound A even in the neutral pH range of the tube, to exhibit good oral absorption, or to provide a pharmaceutical composition with high bioavailability.

Under such circumstances, the inventors have intensively studied to solve the above problems.
The solubility of Compound A is determined in the acidic pH range (approximately 8,600 μg / mL in the Japanese Pharmacopoeia Dissolution Test Solution No. 1 (JP1 (pH 1.2))) and the neutral pH range (Japanese Pharmacopoeia Dissolution Test Solution No. 2 In the liquid (JP2 (pH 6.8)), there was a 1000-fold difference, and it was found that the solubility was particularly low in a neutral pH environment such as JP2 (about 12, 1 in water). 500 μg / mL).

With the goal of achieving sustained drug absorption throughout the gastrointestinal tract where the pH in the gastrointestinal tract is different, focusing on maintaining the solubility (eg, supersaturation) of Compound A even in the neutral pH region of the gastrointestinal tract. As a result, a controlled-release pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt thereof, an acidic substance, a substance that maintains solubility (for example, supersaturation), and a controlled-release base has been found in the digestive tract. It has been found that a pharmaceutical composition that maintains the solubility (for example, supersaturation) of Compound A even in a neutral pH range, has a high bioavailability, and has a good and sustained drug absorbability. It came to be completed.

That is, the present invention
[1] 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide or a pharmaceutical thereof A controlled release pharmaceutical composition comprising an acceptable salt, an acidic substance, a supersaturation maintaining agent, and a controlled release base,
[2] The controlled-release pharmaceutical composition according to [1], wherein the acidic substance is citric acid, malic acid, tartaric acid, fumaric acid, ascorbic acid, succinic acid, or maleic acid,
[3] The addition amount of the acidic substance is 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5 -The controlled-release pharmaceutical composition according to [1] or [2], which is 10% by weight or more and 200% by weight based on the weight of carboxamide or a pharmaceutically acceptable salt thereof,
[4] The supersaturation maintaining agent is one or more substances selected from the group consisting of hypromellose, hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate, and vinylpyrrolidone-vinylacetate copolymer, [1]-[ 3] any controlled-release pharmaceutical composition,
[5] The amount of supersaturation maintaining agent is 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine- The controlled-release pharmaceutical composition according to any one of [1] to [4], which is 10% by weight or more and 200% by weight based on the weight of 5-carboxamide or a pharmaceutically acceptable salt thereof,
[6] The controlled-release pharmaceutical composition according to any one of [1] to [5], wherein the release-controlling base is a substance having a viscosity average molecular weight of 2 million or more or a viscosity of 1% aqueous solution at 25 ° C. of 1000 cps or more.
[7] The controlled-release pharmaceutical composition according to any one of [1] to [6], further comprising a hydrophilic base,
[8] The controlled release pharmaceutical composition according to [7], wherein the hydrophilic base has an amount of water required to dissolve 1 g of the base at 5 ± 5 ° C. at 5 ± 5 ° C.,
[9] 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2] when the dissolution test was conducted with a pH 6.8 phosphate buffer , 3-b] pyridine-5-carboxamide concentration of 8.6 μg / mL or more, controlled release pharmaceutical composition of any of [1]-[8],
About.

According to the controlled-release pharmaceutical composition of the present invention, compound A can be recrystallized / precipitated by maintaining the solubility (particularly supersaturation) of compound A even in the neutral pH region in the digestive tract (after gastric emptying). It can be avoided. In addition, according to the controlled-release pharmaceutical composition of the present invention, the drug is continuously released (elution while maintaining the dissolved state) regardless of the pH environment in the digestive tract, and the entire digestive tract becomes an absorption site. Furthermore, according to the controlled-release pharmaceutical composition of the present invention, inter-individual variation or intra-individual variation (for example, pharmacokinetics (PK) parameter variation due to pH variation in the gastrointestinal tract) is suppressed, and the bioavailability Can be provided.

For the preparations of Reference Examples 1 to 6 and Comparative Example 1 (control preparation), dissolution using pH 6.8 test liquid (for control preparation, pH 6.8 test liquid and 0.1N hydrochloric acid) It is a graph which shows the result (elution profile) of a test. It is a graph which shows the result (elution profile) of the dissolution test which used 0.1N hydrochloric acid as a test liquid about the formulation of the comparative examples 2 and 3 and Example 1. FIG. It is a graph which shows the result (elution profile) of the elution test which used pH6.8 phosphate buffer as a test liquid about the formulation of Comparative Examples 2, 3, 4, and Example 1. FIG. It is a graph which shows the result (plasma drug concentration pattern, ie, PK profile) of the test examples 5, 6, 7, and 9 implemented using the dog which controlled gastric pH to acidic or neutral. It is a graph which shows the result (plasma drug concentration pattern, ie, PK profile) of the test examples 13, 14, and 15 implemented using the dog which controlled the gastric pH to acidity forcibly. It is a graph which shows the result (elution profile) of the elution test which used pH6.8 phosphate buffer as a test liquid about the formulation of Example 5,22,23.

Hereinafter, embodiments of the present invention will be described in detail.
In the present specification, “solubility” or “solubility” means the degree of dissolution of compound A by the method in the 16th revision Japanese Pharmacopoeia and the like. For example, as a certain aspect, within the range of 30 minutes when compound A is powdered and then placed in a solvent and shaken every 5 minutes at 20 ± 5 ° C. for 30 seconds as “solubility” or “solubility” of compound A It is defined as the degree to which it dissolves. “Practically insoluble, or insoluble” means that the amount of solvent required to dissolve 1 g or 1 mL of compound A is 10,000 mL or more, and “Very slightly soluble” means 1 g of compound A or The amount of solvent required to dissolve 1 mL refers to properties of 1,000 mL or more and less than 10,000 mL. As another embodiment, the solubility (test tube shaking method) after putting the powder of Compound A with a solvent in a test tube and shaking for 10 minutes at 23 ± 5 ° C. (330 strokes / minute, 4 cm / stroke) is also included. . When measured by this method, the solubility of Compound A in JP1 is about 8,600 μg / mL, about 8.6 μg / mL for JP2, and about 12,500 μg / mL for water. . In another embodiment, the solubility (test tube shaking method) after the powder of Compound A is placed in a test tube together with a solvent and shaken at 37 ° C. for 14 hours is also included. When measured by this method, the solubility of Compound A in the United States Pharmacopeia (USP) pH 6.8 phosphate buffer is 10.9 μg / mL.

In the present specification, “supersaturated” means that a solute (compound A) having a solubility or higher is contained.
In the present specification, “supersaturated solution” means a solution containing a solute (compound A) having a solubility or higher.
In the present specification, “maintaining supersaturation” means, as one embodiment, solubility of Compound A at pH 6.8 (8.6 μg / mL (23 ° C. in the case of a test tube shaking method), 10.9 μg / mL (37 ° C)) and maintaining the above solubility.

In the present specification, “improvement of bioavailability (rate)” or “improvement of bioavailability” means that “relative bioavailability” for a composition not including the composition of the present invention is higher. means. For example, it is defined that “Bioavailability” is high for a pharmaceutical composition not containing an “acidic substance” used in the present invention.
In the present specification, “reducing PK parameter fluctuation” means the ratio of the same parameter when the gastric pH is administered at neutral to the Cmax and AUC when the gastric pH is administered at acidic, for example, It is defined as 0.5 times or more as one aspect, 0.6 times or more as another aspect, and 0.7 times or more as another aspect.
In this specification, “release control” means, for example, USP pH 6.8 phosphate buffer 900 mL or USP pH 6.8 phosphate buffer as a test solution according to the Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method). When the dissolution test was conducted under the condition of paddle rotation speed of 100 rpm using 900 mL of a test solution in which 1% of sodium lauryl sulfate was added to the solution, the dissolution rate of Compound A for 30 minutes after the start of the test was less than 80%. In another aspect, it means controlling to less than 50%, and in another aspect, controlling to less than 30%.

Formula (I):

4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide or a pharmaceutical thereof Salts acceptable in the above can be easily obtained by the production method described in Patent Document 1 or according thereto.

The known compound A represented by the formula (I) may form an addition salt with an acid or a base. Such a salt may be a pharmaceutically acceptable salt. Specifically, in one embodiment, an inorganic acid (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid) or an organic acid (for example, And acid addition salts with succinic acid, fumaric acid, L-malic acid, L-tartaric acid, mesylic acid, and tosylic acid. Another embodiment is an acid addition salt with hydrobromic acid.

Furthermore, various hydrates, solvates and crystal polymorphs of the compound represented by the formula (I) or a salt thereof may be used.
The known compound A or a pharmaceutically acceptable salt thereof can be used alone or in combination of two or more.

The known compound A or a pharmaceutically acceptable salt thereof has an inhibitory activity against JAK3 and is caused by unwanted cytokine signaling (for example, rejection in living transplants, autoimmune diseases, asthma, atopic) Dermatitis, Alzheimer's disease, atherosclerosis), or useful as an active ingredient of a therapeutic or prophylactic agent for diseases (for example, cancer, leukemia) caused by abnormal cytokine signaling.

The dose of the known compound A or a pharmaceutically acceptable salt thereof is appropriately determined according to individual cases in consideration of the administration route, the symptoms of the disease, the age, race, sex, etc. of the administration subject. In the case of oral administration, the daily dose of the known compound A or a pharmaceutically acceptable salt thereof is about 0.001 to about 100 mg / kg in one embodiment, about 0.1 to about 100 mg / kg in another embodiment. From about 30 mg / kg to about 0.1 to about 10 mg / kg is suitable, and this is administered once or divided into multiple doses such as 2 to 4 times. In the case of intravenous administration, the daily dose is suitably about 0.0001 to about 10 mg / kg per body weight, and is administered once to several times a day. In addition, as a transmucosal agent, about 0.001 to about 100 mg / kg per body weight is administered once to several times a day.

The addition amount of the known compound A or a pharmaceutically acceptable salt thereof is 10 mg or more and 200 mg or less as a certain embodiment and 15 mg or more and 150 mg or less as another embodiment per unit preparation. The addition amount of the known compound A or a pharmaceutically acceptable salt thereof is 5% by weight or more and 70% by weight or less as a certain embodiment and 7% by weight or more and 50% by weight or less as another embodiment per unit preparation.

The “acidic substance” used in the present invention is not limited as long as it is pharmaceutically acceptable and maintains the solubility of Compound A in a neutral pH range. Moreover, as another aspect, if the supersaturated state of the compound A is maintained, it will not be restrict | limited.
For example, as an aspect, citric acid, malic acid, tartaric acid, fumaric acid, ascorbic acid, succinic acid, maleic acid and the like can be mentioned. Other embodiments include citric acid, tartaric acid, malic acid, and ascorbic acid. Yet another embodiment is citric acid or tartaric acid, and another embodiment is tartaric acid.
In the controlled-release pharmaceutical composition of the present invention, acidic substances can be used alone or in combination of two or more.

The addition amount of the acidic substance is not limited as long as it is an amount that maintains the solubility of Compound A in the neutral pH range. Specifically, for example, with respect to the weight of the compound A, it is 10% by weight or more and 200% by weight or less as one aspect, 50% or more and 150% by weight or less as another aspect, and 100 as another aspect. % By weight or more and 120% by weight or less. In another embodiment, it is 5% by weight or more and 50% by weight or less per unit preparation, in another embodiment, it is 10% by weight or more and 40% by weight or less, and in another embodiment, it is 20% by weight or more and 40% by weight or less. .

The “supersaturation maintaining agent” used in the present invention is a “substance that maintains the solubility of Compound A (dissolution maintenance agent)” as one embodiment, and the “substance that maintains the supersaturation of Compound A (supersaturation maintenance) as another embodiment. As long as it is a substance that is pharmaceutically acceptable and maintains the solubility of Compound A, it is not limited. Alternatively, the substance is not limited as long as it is pharmaceutically acceptable and maintains the supersaturation of Compound A. Another embodiment is a pharmaceutically acceptable water-soluble polymer.

Specifically, for example, hypromellose, hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate, polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer and the like can be mentioned as an embodiment. Other embodiments include hypromellose, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate. Another embodiment is hypromellose.

Specifically, for example, as hypromellose, trade names TC-5E (viscosity: 3 mPa · s (2% aqueous solution 20 ° C.)), TC-5M (viscosity: 4.5 mPa · s (2% aqueous solution 20 ° C.)) TC-5R (viscosity: 6 mPa · s (2% aqueous solution 20 ° C.)) and TC-5S (viscosity: 15 mPa · s (2% aqueous solution 20 ° C.)). (All are Shin-Etsu Chemical)
Hydroxypropyl cellulose can be obtained under the trade names HPC-L (Nippon Soda), KLUCEL LF (Hercules), KLUCEL JF (Hercules).
Further, hydroxypropylmethylcellulose acetate succinate can be obtained as a trade name AQOAT (Shin-Etsu Chemical Co., Ltd.).
In the controlled release pharmaceutical composition of the present invention, “solubility maintenance agent” or “supersaturation maintenance agent” can be used alone or in combination of two or more.

The addition amount of the “solubility maintenance agent” or the “supersaturation maintenance agent” is not limited as long as the solubility of the compound A is maintained. Or it will not restrict | limit if it is the quantity which maintains the supersaturation of the compound A. With respect to the weight of the known compound A, for example, in one embodiment, it is 10 wt% or more and 200 wt% or less, in another embodiment, 20 wt% or more and 200 wt% or less, and in another embodiment, 40 wt% or more and 150 wt% or less. It is 50 weight% or less and as a further aspect, it is 50 weight% or more and 120 weight% or less. Per unit preparation, it is 5% by weight or more and 50% by weight or less as one embodiment, 10% by weight or more and 40% by weight or less in another embodiment, and 10% by weight or more and 30% by weight or less in another embodiment. Moreover, as another aspect, it is 20 to 30 weight%.

The “release control base” used in the present invention is not limited as long as it is a polymer that forms a hydrogel (hydrogel-forming polymer). Moreover, as another aspect, if it is a base which controls the discharge | release of the compound A, it will not restrict | limit.
As another embodiment, examples of the “release controlling base” include those having a high viscosity at the time of gelation. For example, in one embodiment, the viscosity of a 1% aqueous solution (25 ° C.) is 1000 cps or more. As another aspect, the molecular weight of the polymer material forming the hydrogel is, for example, 100,000 or more, and as another aspect, 100,000 or more and 7 million or less. Further, the properties of the polymer substance depend on its molecular weight, and higher molecular weight is preferable. One embodiment includes a viscosity average molecular weight of 2 million or more, and another embodiment includes a viscosity average molecular weight of 4 million or more.

As such a “release controlling base”, for example, as one embodiment, polyethylene oxide (PEO) (for example, trade name Polyox WSR-303 (average molecular weight: 7 million, viscosity: 7500-10000 cps (1% aqueous solution 25 ° C.)) )), Polyox WSR Coagulant (average molecular weight 5 million, viscosity: 5500-7500 cps (same)), Polyox WSR-301 (average molecular weight: 4 million, viscosity: 1650-5500 cps (same)), Polyox WSR-N-60K ( Average molecular weight: 2 million, viscosity: 2000-4000 cps (2% aqueous solution at 25 ° C.), Polyox WSR-N-12K (average molecular weight: 1 million, viscosity: 400-800 cps (2% aqueous solution at 25 ° C.)), Polyox WSR- 1105 (average Amount: 900,000, Viscosity: 8800-17600 cps (5% aqueous solution 25 ° C.), Polyox WSR-205 (Average molecular weight: 600,000, Viscosity: 4500-8800 cps (5% aqueous solution 25 ° C.)), Polyox WSR-N-750 (Average molecular weight: 300,000, viscosity: 600-1200 cps (5% aqueous solution, 25 ° C.)), Polyox WSR-N-80 (average molecular weight: 200,000, viscosity: 55-90 cps (5% aqueous solution, 25 ° C.)), Polyox WSR -N-10 (average molecular weight: 100,000, viscosity: 12-50 cps (5% aqueous solution 25 ° C.)); Hypromellose (HPMC) (for example, trade name Metroise 90SH100000 (viscosity: 4100-5600 cps (1 % Aqueous solution 20 ° C.), Metroise 90SH50000 (viscosity: 290) -3900 cps (same)), Metrolose 90SH30000 (viscosity: 25000-35000 cps (2% aqueous solution 20 ° C.)); Shin-Etsu Chemical Co., Ltd.), sodium carboxymethylcellulose (CMC-Na) (for example, trade name Sunrose F-150MC ( Average molecular weight: 200,000, viscosity 1200-1800 cps (1% aqueous solution 25 ° C.), Sunrose F-1000MC (average molecular weight: 420,000, viscosity 8000-12000 cps (same)), Sunrose F-300MC (average molecular weight: 30 10,000, viscosity 2500-3000 cps (same) manufactured by Nippon Paper Industries Co., Ltd.), hydroxyethyl cellulose (HEC) (for example, trade name HC Daicel SE850 (average molecular weight: 1,480,000, viscosity 2400-3000 cps (1% aqueous solution 25 ° C.)), HEC Daicel SE900 (average Molecular weight: 156,000, viscosity: 4000-5000 cps (same) manufactured by Daicel Chemical Industries, Ltd.), or carboxyvinyl polymer (for example, trade name Carbopol 940 (average molecular weight of about 2.5 million); F. Goodrich (manufactured by Chemical) and the like. Another embodiment includes PEO having an average molecular weight of 2 million or more. When it is necessary to maintain the release for a long period of time, for example, 12 hours or more, a higher molecular weight, in one embodiment, an average molecular weight of 4 million or higher or higher viscosity, preferably a viscosity of 1% aqueous solution at 25 ° C. is 3000 cps or higher. The polymer which is is preferable. These polymer substances forming the hydrogel can be used alone or in combination of two or more. Also, a mixture comprising two or more kinds of polymer substances and having properties suitable for the present invention as a whole can be suitably used as the polymer substance forming the hydrogel of the present invention.

Another embodiment is a hydrogel-forming polymer having a viscosity average molecular weight of 2 million to 7 million.
For example, polyethylene oxide, hypromellose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, carboxyvinyl polymer and the like can be mentioned as certain embodiments. Other embodiments include polyethylene oxide.

The addition amount of the hydrogel-forming polymer is 5% by weight or more and 500% by weight or less as an aspect with respect to the weight of the known compound A, and 10% by weight or more and 80% by weight or less as another aspect. As another aspect, it is 10 to 60 weight%. Per unit preparation, it is 3% by weight or more and 60% by weight or less as an aspect, in another aspect, it is 5% by weight or more and 30% by weight or less, and in another aspect, it is 5% by weight or more and 20% by weight or less. .

If desired, a hydrophilic base may be further added to the controlled-release pharmaceutical composition of the present invention.
As the “hydrophilic base” used in the present invention, the amount of water necessary for dissolving 1 g of the hydrophilic base in one embodiment is 5 mL or less at 20 ± 5 ° C., and in another embodiment, 4 mL or less. belongs to. The higher the solubility in water, the higher the effect of allowing water to enter the preparation. Specifically, for example, as one embodiment, polyethylene glycol (PEG; for example, trade names PEG400, PEG1500, PEG4000, PEG6000, PEG20000; manufactured by NOF Corporation), polyvinylpyrrolidone (PVP; for example, trade name PVP K30 manufactured by BASF Corporation) ), Water-soluble polymers, sugar alcohols such as D-sorbitol and xylitol, sucrose, anhydrous maltose, D-fructose, dextran (eg, dextran 40), sugars such as glucose and sucrose, polyoxyethylene Surfactants such as polyoxypropylene glycol (for example, Pluronic F68; manufactured by Asahi Denka Co., Ltd.), salts such as sodium chloride and magnesium chloride, organic acids such as citric acid and tartaric acid, glycine, β-alanine, lysine hydrochloride and the like Ami Examples include amino acids such as noic acids and meglumine. Other embodiments include PEG6000, PVP, D-sorbitol and the like.
As another aspect, Preferably PEG8000, a citric acid, sucrose, etc. are mentioned.
In addition, the aspect which considers a part of citric acid and tartaric acid as a part of the hydrophilic base of this invention among the acidic substances used for this invention can also be taken.
A hydrophilic base can be used 1 type or in combination of 2 or more types.

The addition amount of the hydrophilic base is 5% by weight or more and 100% by weight or less as an aspect with respect to the weight of the known compound A, and is 10% by weight or more and 80% by weight or less as another aspect. As another certain aspect, they are 100 weight% or more and 120 weight% or less. In one embodiment, it is 3% by weight or more and 50% by weight or less per unit preparation, and in another embodiment, it is 5% by weight or more and 30% by weight or less. *

In the controlled-release pharmaceutical composition of the present invention, various pharmaceutical additives are appropriately used as necessary, and formulated. Such a pharmaceutical additive is not particularly limited as long as it is pharmaceutically acceptable and pharmacologically acceptable. For example, excipients, binders, disintegrants, acidulants, foaming agents, artificial sweeteners, fragrances, lubricants, colorants, buffers, antioxidants, surfactants, fluidizing agents, etc. are used. .

Examples of the excipient include D-mannitol and lactose hydrate.
Examples of the binder include gum arabic, hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose and the like.
Examples of the disintegrant include corn starch, potato starch, carmellose calcium, carmellose sodium, and low-substituted hydroxypropylcellulose.
Examples of the sour agent include citric acid, tartaric acid, malic acid and the like.

Examples of the foaming agent include baking soda.
Examples of the artificial sweetener include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia and thaumatin.
Examples of the fragrances include lemon, lemon lime, orange and menthol.
Examples of the lubricant include light anhydrous silicic acid, magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid, sodium lauryl sulfate and the like.

Examples of the colorant include yellow ferric oxide, red ferric oxide, black iron oxide, edible yellow No. 4, No. 5, edible red No. 3, No. 102, edible blue No. 3, and the like.
Buffers include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or salts thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid , Boric acid or its salts.
Examples of the antioxidant include ascorbic acid, dibutylhydroxytoluene, propyl gallate and the like.
Examples of the surfactant include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, and the like.
Examples of the fluidizing agent include light anhydrous silicic acid.
As a pharmaceutical additive, an appropriate amount can be appropriately added by combining one or more kinds.
As for the addition amount, any excipient is used in an amount within the range in which the desired effect of the present invention is achieved.

As a dosage form of the controlled-release pharmaceutical composition of the present invention, a preferable dosage form is an oral solid preparation that can be easily taken by a patient and is convenient for storage and carrying. For example, as an aspect, it is a tablet, a capsule, a powder, a granule, a fine granule, a dry syrup, etc., and it is a tablet as another aspect.

Although the manufacturing method of the controlled release pharmaceutical composition of this invention is demonstrated below, these do not limit this invention.
The controlled-release pharmaceutical composition of the present invention can be produced by a known method such as pulverization, mixing, granulation, molding (tablet), film coating and the like.

The method for pulverizing the pulverizing step is not particularly limited as long as it can be pharmaceutically pulverized. Examples of the pulverizer include a hammer mill, a ball mill, a jet mill, and a pin mill. The grinding conditions are not particularly limited as long as they are appropriately selected.

As a method of mixing in the mixing step , there is no particular limitation on the apparatus and means as long as it is a method that can generally mix each component uniformly pharmaceutically. Examples of the mixing apparatus include a V-type mixer, a ribbon-type mixer, a container mixer, and a high-speed stirring mixer. The mixing conditions are not particularly limited as long as they are appropriately selected.

Examples of the granulating step granulator include a high speed stirring granulator and the like. Examples of the granulation method include, for example, a fluidized bed granulation method, a melt granulation method, a high-speed stirring granulation method, a crushing (pulverization) granulation method, an extrusion granulation method, a rolling granulation method, and a spray granulation method. Examples thereof include a granulation method and a dry granulation method. Another embodiment is a high-speed stirring granulation method.
The binder solution is prepared by dissolving or dispersing in a solvent such as water, ethanol or methanol. Further, these solvents can be appropriately mixed and used.
The conditions for preparing the binder solution are not particularly limited as long as they are appropriately selected.

It can also be dried after granulation. The drying method is not particularly limited as long as it is usually a pharmaceutically drying method, and examples thereof include ventilation drying and drying under reduced pressure. After drying, sizing may be performed to remove coarse particles having a certain size or more.
A solid dispersion containing Compound A and a supersaturation maintaining agent may be prepared before granulation, and an acidic substance and various additives may be mixed into the solid dispersion for granulation.

Molding process In the molding process, a granulated product or a mixture of granulated products mixed with various pharmaceutical additives is filled into capsules to make capsules, or compressed into tablets using a rotary tableting machine. be able to.
The compression step is not particularly limited as long as it is a method for molding the controlled-release pharmaceutical composition of the present invention. Examples thereof include a direct tableting method in which a drug and an appropriate pharmaceutical additive are mixed and then compression-molded to obtain a tablet, and a method in which a lubricant is further mixed with the granulated product and then compression-molded to produce a tablet.
Examples of the tableting device include a rotary tableting machine, a single tableting machine, and an oil press. Tableting conditions such as tableting pressure are not particularly limited as long as the tablet can be molded and the tableting pressure does not damage the tablet during the production process.

Film coating step Film coating may be applied to the tablet surface after tableting as appropriate.
The method is not particularly limited as long as it is usually a pharmaceutically film coating method. Examples thereof include pan coating and dip coating.
Examples of the film coating agent include hypromellose, polyvinyl alcohol, polyvinyl alcohol copolymer, polyvinyl pyrrolidone, iron sesquioxide (red, yellow), titanium oxide, polyethylene glycol, triethyl citrate and the like. The film coating agent can be appropriately added in an appropriate amount by combining one kind or two or more kinds.
A film coating rate will not be restrict | limited especially if it is a rate which forms a film coat in a tablet.
You may dry after film coating. The method is not particularly limited as long as it can be usually pharmaceutically dried. The drying conditions are not particularly limited as long as they are appropriately set in consideration of, for example, the stability of the preparation.

EXAMPLES Hereinafter, although an Example, a comparative example, a reference example, and a test example are given and this invention is demonstrated further in detail, this invention is not limitedly interpreted by these.
Compound A hydrobromide used was prepared by the method described in Patent Document 1 (WO2007 / 077949).

Reference Examples 1-6
Based on the formulation shown in Table 1, Compound A hydrobromide (manufactured by Astellas Pharma, the same applies hereinafter), acidic substance (anhydrous citric acid: manufactured by Komatsuya Co., Ltd., malic acid: manufactured by Kanto Chemical Co., Inc., tartaric acid: manufactured by Komatsuya Co., Ltd.) , Fumaric acid: manufactured by Kanto Chemical Co., Inc., ascorbic acid: manufactured by Kanto Chemical Co., Ltd., succinic acid: manufactured by Wako Pure Chemical Industries, Ltd., hereinafter the same unless otherwise specified, polyethylene oxide (molecular weight: 7 million, Polyox WSR-303, Dow Made by Chemical Co., unless otherwise noted, and magnesium stearate (Parteck (registered trademark) LUB MST, Merck Co., Ltd.) were mixed using a mortar pestle and compression molded using an oil press tableting machine. And tablets (diameter 9 mm) were produced.

Comparative Example 1
In order to make the size of the preparations the same without adding the acidic substance in the present invention, polyethylene glycol (PEG 8000 (Polyglycol 8000, manufactured by Clariant Co., Ltd., hereinafter the same unless otherwise specified)) was added for comparison. A pharmaceutical composition (tablet) was prepared.

Examples 1 to 4 and Comparative Examples 2 to 4
Based on the formulation shown in Table 2, various additives were mixed using a mortar pestle. The mixture was compression-molded using an oil press tableting machine to produce a controlled release pharmaceutical composition (tablet) of the present invention and a comparative pharmaceutical composition (tablet). The polyethylene oxide having a molecular weight of 2 million is Polyox WSR N-60K manufactured by Dow Chemical Co. (hereinafter, unless otherwise specified), and the hypromellose is manufactured by TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd. Hereinafter the same unless otherwise specified), as the crystalline cellulose, Ceolus PH101, manufactured by Asahi Kasei (hereinafter, the same unless otherwise specified), as sodium lauryl sulfate, NIKKOL SLS, manufactured by Nikko Chemicals (hereinafter, The same applies hereinafter unless otherwise specified.

Examples 5-8
Based on the formulation shown in Table 3, 299.7 g of Compound A hydrobromide, 320.0 g of anhydrous citric acid (manufactured by Mallinckrodt Baker), 129.1 g of crystalline cellulose (Ceolous PH101), 304. hypromellose (TC-5E). After mixing 0 g using a high-speed stirring granulator (PMA 1 High Shear Granulator, manufactured by GEA), purified water was added and wet granulation was performed. After drying using a fluidized bed granulator (Niro Aerodynamic Fluid bed S-2, manufactured by Niro), and using a granulator (Quadro mill 197S, manufactured by Quadro Engineering), the required amount of polyethylene is obtained. Oxide (Polyox WSR-303), magnesium stearate, sodium lauryl sulfate (manufactured by Stepan) were mixed using a mixer (4-QT. V-shell blender, manufactured by O'Hara technologies), and rotary tableting machine (PICCOLA, manufactured by RIVA) was compression-molded to produce a controlled release pharmaceutical composition (uncoated tablet) of the present invention (

tablet diameter

6, 7, 9, 12 mm). Using a film coating machine (Labcoat, manufactured by O'Hara technologies), 3% by weight film coating (Opadry 03F42192, manufactured by Colorcon) with respect to the tablet weight, the controlled release pharmaceutical composition of the present invention (film coating) Tablet).

Examples 9-14 and 16-18
Based on Tables 4 and 5, Compound A hydrobromide, anhydrous citric acid, crystalline cellulose (Ceolus PH101), hypromellose (TC-5E) were mixed at a high speed agitation granulator (VG) on a scale of 990 g. -05, manufactured by POWREC Co., Ltd.), then purified water was added and wet granulation was performed. The granulated product is dried by using a fluidized bed granulator (Multiplex MP-01, manufactured by Paulek) and then granulated by using a granulator (Power Mill P-04S, manufactured by Dalton). Got. Polyethylene oxide (molecular weight: 7 million or molecular weight: 2 million), magnesium stearate, sodium lauryl sulfate (manufactured by Stepan), light anhydrous silicic acid (AEROSIL 200, manufactured by Evonik, etc.) unless otherwise specified. ) Were mixed and compression-molded using a rotary tableting machine (HT-X18SS-IIW, manufactured by Hata Iron Works Co., Ltd.) to produce a controlled-release pharmaceutical composition (tablet) of the present invention.

Examples 15, 19 and 20
In the same manner as in Examples 9 to 14 and 16 to 18, based on Tables 4 and 5, Compound A hydrobromide, anhydrous citric acid, crystalline cellulose (Ceolous PH101), hypromellose (TC-5E) were stirred at high speed. After mixing using a granulator, purified water was added to perform wet granulation. This granulated product was dried using a fluidized bed granulator, and then granulated using a granulator to obtain a granulated product. Hypromellose (Methocel K100LV, manufactured by Dow Chemical), polyethylene oxide (molecular weight: 7 million or molecular weight: 2 million), magnesium stearate, sodium lauryl sulfate (manufactured by Stepan), and light anhydrous silicic acid (AEROSIL 200) It mixed and compression-molded using the rotary tableting machine, and manufactured the controlled release pharmaceutical composition (tablet) of this invention.

Examples 21-25
Based on the formulation shown in Table 6, various additives were mixed using a mortar pestle. The mixture was compression-molded using an oil press tableting machine to produce a controlled release pharmaceutical composition (tablet) of the present invention.

Test example 1
The drug dissolution properties of the preparations of Reference Examples 1 to 6 and the control preparation (preparation of Comparative Example 1) were evaluated. Using 900 mL (37 ° C.) of a test solution obtained by adding 1% sodium lauryl sulfate to a USP pH 6.8 phosphate buffer as a test solution, an elution test was performed according to the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle rotation speed: 100 rpm) ). After starting the dissolution test, the dissolution rate was calculated by sampling over time and measuring the absorbance using a spectrophotometer. In addition, about the control formulation, 0.1N hydrochloric acid was used as a test solution, and the drug dissolution property was similarly evaluated.

The dissolution rate in the test solution in which 1% of sodium lauryl sulfate was added to the pH 6.8 phosphate buffer of the control preparation was significantly delayed compared to 0.1N hydrochloric acid (FIG. 1). This is because the solubility of the known compound A hydrobromide is high in acidity, whereas in the test solution in which 1% sodium lauryl sulfate is added to the pH 6.8 phosphate buffer, the drug solubility is low, the formulation (tablet) It was thought that the dissolution rate of the drug inside decreased. In contrast, the preparations of Reference Examples 1 to 6 to which an acidic substance was added improved the dissolution rate at pH 6.8 compared to the control preparation. Among them, especially when citric anhydride, ascorbic acid, malic acid, and tartaric acid were added, the dissolution was greatly improved.

Test example 2
Regarding the supersaturation maintaining agent, hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda Co., Ltd., unless otherwise specified), hypromellose (TC-5E), and a mixture of hydroxypropylcellulose and hypromellose, Compound A bromide The supersaturation ability of hydrates was evaluated. USP pH 6.8 phosphate buffer 488 mL (37 ° C.) was used as a test solution, and hydroxypropylcellulose and hypromellose in the amounts shown in Table 7 were added to the dissolution tester vessel and completely dissolved. 12 mL of Compound A hydrobromide aqueous solution (free body concentration of 10 mg / mL) was added dropwise to the vessel, and the paddle was rotated at 100 rpm. Sampling was performed over time until 1 hour later, and the absorbance of the solution was measured using a spectrophotometer to calculate the drug concentration of Compound A (Table 7).

As a result, in the case where the supersaturation maintenance agent was not added (known compound A hydrobromide alone), the drug concentration 10 minutes after addition of the drug solution was 169.7 μg / mL, whereas after 60 minutes, 36.4 μg. / ML, and recrystallization of the known compound A hydrobromide was observed. In contrast, hydroxypropylcellulose, hypromellose, and a mixture of both showed high drug concentrations after 10 minutes and 60 minutes.

Test example 3
Dissolution (supersaturation) was evaluated using a dissolution test method (paddle method). The test solution system was subjected to a dissolution test in accordance with the Japanese Pharmacopoeia dissolution test method 2 under the same conditions as in Test Example 2. Various additives shown in Table 8 (polyvinyl alcohol: PVA, manufactured by Nippon Synthetic Chemical Co., Ltd., hydroxypropyl cellulose: HPC-L, hypromellose: TC-5E, hydroxypropyl methylcellulose acetate succinate: HPMC-AS, manufactured by Shin-Etsu Chemical Co., Ltd.) 120 mg was added to the dissolution tester vessel and completely dissolved. 12 mL of Compound A hydrobromide aqueous solution (free body concentration: 10 mg / mL) was added dropwise to the vessel, and the paddle was rotated at 100 rpm. The sample was sampled after 14 hours, and the absorbance of the solution was measured using a spectrophotometer to calculate the drug concentration of Compound A.

As a result, the drug concentrations when hydroxypropylcellulose, hypromellose, and hydroxypropylmethylcellulose acetate succinate were added were 85.1 μg / mL, 80.5 μg / mL, and 78.5 μg / mL, respectively, and no supersaturation maintenance agent was added. The drug concentration of the product was significantly higher than the drug concentration of 20.3 μg / mL, and it was revealed that the supersaturation was maintained even after 14 hours (Table 8). On the other hand, when polyvinyl alcohol was added, the drug concentration was 23.7 μg / mL, which was similar to that of the product without the addition of the supersaturation maintenance agent.

Test example 4
The tablets of Comparative Examples 2, 3, 4, and Example 1 were evaluated for drug dissolution. As a test solution, 900 mL (37 ° C.) of 0.1N hydrochloric acid or pH 6.8 phosphate buffer was used, 5 tablets were added per vessel, and a dissolution test was conducted according to the second method of the Japanese Pharmacopoeia Dissolution Test Method. In addition, the vertical axis | shaft 100% in a figure corresponds to 133.3 microgram / mL as a well-known compound A density | concentration.
In 0.1N hydrochloric acid solution, all tablets showed sustained drug dissolution and released 85-100% of the drug in 5 hours (FIG. 2). On the other hand, in pH 6.8, the tablet of Comparative Example 2 remained below 7% (drug concentration: 9.3 μg / mL) even after 5 hours (FIG. 3). In the tablet of Comparative Example 3 to which citric acid anhydride was added as an acidic substance, although the dissolution rate was improved immediately after the start of the dissolution test, no continuous dissolution was observed thereafter, and 10% (drug concentration 13.3 μg) after 5 hours. / ML). This is considered to be because the drug solubility of the known compound A hydrobromide is low at pH 6.8. In the tablet of Comparative Example 4 to which hypromellose was added, the dissolution rate was improved 2 hours after the start of the dissolution test compared to Comparative Example 3, but 22% after 5 hours (drug concentration 29.3 μg / mL). Elution rate. On the other hand, the tablet of Example 1 formulated with tartaric acid and hypromellose showed a stable dissolution property until 3 hours after the start of the dissolution test, and has a lower solubility than Comparative Example 2, Comparative Example 3 and Comparative Example 4. The drug dissolution property at .8 was greatly improved. The drug elution rate is 40% (drug concentration 53.3 μg / mL) or more even at 5 hours from the start of the test, greatly improves the drug solubility at pH 6.8, and can maintain the supersaturation of the solubility even after 5 hours. It became clear.

Test Example 5
The oral absorbability of the tablet of Comparative Example 2 was evaluated. As an evaluation system, a dog fasted for 18 hours or more after administration was used. In order to forcibly control the dog's gastric pH to be acidic, treatment with pentagastrin (intra thigh muscle administration; 30 minutes before tablet administration, 30 minutes after tablet administration, 90 minutes after administration) is performed before tablet administration. did.
Six tablets of Comparative Example 2 (150 mg as known compound A hydrobromide) were orally administered together with 50 mL of water to dogs whose gastric pH was acidified by treatment with pentagastrin, and the plasma drug concentration was measured.
As a result, a continuous plasma drug concentration pattern was shown (FIG. 4). The maximum plasma drug concentration (Cmax) and the area under the plasma drug concentration transition curve (AUC) up to 24 hours after administration were 1346 ng / mL and 11102 ng · h / mL, respectively.

Test Example 6
The oral absorbability of the tablet of Comparative Example 2 was evaluated. As an evaluation system, a dog fasted for 18 hours or more after administration was used. In order to force the canine gastric pH to be neutrally controlled, famotidine (intramuscular thigh administration; 90 minutes before tablet administration, 30 minutes before administration) was administered before tablet administration.
Six tablets of Comparative Example 2 (150 mg as known compound A hydrobromide) were orally administered together with 50 mL of water to dogs with neutral gastric pH by famotidine treatment, and the plasma drug concentration was measured.
As a result, the plasma drug concentration was remarkably low (FIG. 4), and Cmax and AUC were 268 ng / mL and 3096 ng · h / mL, respectively. They were 0.20 times and 0.28 times lower than Cmax and AUC, respectively, when administered to the dogs subjected to the pentagastrin treatment evaluated in Test Example 5.

Test Example 7
The oral absorbability of the tablet of Comparative Example 3 was evaluated. The same evaluation system as in Test Example 6 was used. Six tablets of Comparative Example 3 (150 mg as known compound A hydrobromide) were orally administered together with 50 mL of water to dogs with neutral gastric pH by famotidine treatment, and the plasma drug concentration was measured.
As a result, the plasma drug concentration transition up to 1 hour after administration showed a pattern similar to that during the pentagastrin treatment in Test Example 5, but did not continue thereafter (FIG. 4). Cmax and AUC were 464 ng / mL and 3377 ng · h / mL, respectively, which were 0.34 times and 0.30 times lower than those of the pentagastrin treatment of Comparative Example 2 evaluated in Test Example 5, respectively.

Test Example 8
The oral absorbability of the tablet of Example 1 was evaluated. The same evaluation system as in Test Example 5 was used. Six tablets of Example 1 (150 mg as known compound A hydrobromide) were orally administered with 50 mL of water to dogs whose gastric pH was acidified by treatment with pentagastrin, and the drug concentration in plasma was measured.
As a result, a sustained plasma drug concentration pattern was shown, and Cmax and AUC were 2326 ng / mL and 15285 ng · h / mL, respectively.

Test Example 9
The oral absorbability of the tablet of Example 1 was evaluated. The same evaluation system as in Test Example 6 was used. Six tablets of Example 1 (150 mg as known compound A hydrobromide) were orally administered together with 50 mL of water to dogs with neutral gastric pH by famotidine treatment, and the plasma drug concentration was measured.
As a result, a continuous increase in plasma drug concentration was observed (FIG. 4), Cmax and AUC were 1746 ng / mL and 14879 ng · h / mL, respectively, and during the pentagastrin treatment of Example 1 evaluated in Test Example 8. They were 0.75 times and 0.97 times, respectively.

Test Example 10
The oral absorbability of the tablet of Example 2 was evaluated. The same evaluation system as in Test Example 5 was used. Eight tablets of Example 2 (150 mg as known compound A hydrobromide) were orally administered with 50 mL of water to dogs whose gastric pH was acidified by treatment with pentagastrin, and the drug concentration in plasma was measured.
The results showed a sustained plasma drug concentration profile, with Cmax and AUC being 1942 ng / mL and 12927 ng · h / mL, respectively.

Test Example 11
The oral absorbability of the tablet of Example 3 was evaluated. The same evaluation system as in Test Example 5 was used. One tablet of Example 3 (150 mg as known compound A hydrobromide) was orally administered with 50 mL of water to a dog whose gastric pH was acidified by treatment with pentagastrin, and the drug concentration in plasma was measured.
The results showed a sustained plasma drug concentration profile, with Cmax and AUC being 2232 ng / mL and 16452 ng · h / mL, respectively.

Test Example 12
The oral absorbability of the tablet of Example 4 was evaluated. The same evaluation system as in Test Example 5 was used. As a result of oral administration of one tablet of Example 4 (150 mg as known compound A hydrobromide) with 50 mL of water to a dog whose stomach pH was acidified by pentagastrin treatment, a sustained plasma drug concentration profile was obtained. The indicated Cmax and AUC were 2091 ng / mL and 16081 ng · h / mL, respectively.

From the results of Test Examples 5 and 6, in the tablet of Comparative Example 2 that does not contain an acidic substance and a supersaturation maintenance agent, the PK parameter fluctuates greatly when the gastric pH is acidic and neutral (0.20 for Cmax and AUC). And 0.28 times). Moreover, in the prescription of the comparative example 3 which mix | blended the acidic substance from the test example 7, although the oral absorptivity immediately after administration improved, the effect was a short time.
On the other hand, in the formulation containing an acidic substance and a supersaturation maintenance agent (polymer), from the results of Test Examples 8 and 9, the PK parameter fluctuation range when the gastric pH is acidic and neutral is small (Cmax and AUC). 0.75 times and 0.97 times). As described above, by adding an acidic substance and a supersaturation maintaining agent to maintain the supersaturation of the known compound A hydrobromide in the controlled release preparation, the drug can be continuously maintained even in the neutral pH environment of the digestive tract. It is considered that the PK parameter variation due to the release and the pH variation in the digestive tract was reduced.

Test Example 13
The oral absorbability of the tablet of Example 5 was evaluated. The same evaluation system as in Test Example 5 was used. As a result of orally administering 8 tablets (150 mg as known compound A hydrobromide) of Example 5 together with 50 mL of water to dogs whose gastric pH was acidified by treatment with pentagastrin, a sustained plasma drug concentration profile was obtained. Cmax and AUC shown were 1942 ng / mL and 12927 ng · h / mL, respectively (FIG. 5).

Test Example 14
The oral absorbability of the tablet of Example 22 was evaluated. The same evaluation system as in Test Example 5 was used. One tablet of Example 22 (150 mg as known compound A hydrobromide) was orally administered together with 50 mL of water to a dog whose stomach pH was acidified by treatment with pentagastrin, resulting in a sustained plasma drug concentration profile. Cmax and AUC shown were 2332 ng / mL and 16452 ng · h / mL, respectively (FIG. 5).

Test Example 15
The oral absorbability of the tablet of Example 23 was evaluated. The same evaluation system as in Test Example 5 was used. One tablet of Example 23 (150 mg as known compound A hydrobromide) was orally administered with 50 mL of water to a dog whose stomach pH was acidified by treatment with pentagastrin, resulting in a sustained plasma drug concentration profile. The indicated Cmax and AUC were 2091 ng / mL and 16081 ng · h / mL, respectively (FIG. 5).

Test Example 16
The oral absorbability of the tablet of Example 6 was evaluated. The same evaluation system as in Test Example 5 was used. Four tablets of Example 6 (150 mg as known compound A hydrobromide) were orally administered together with 50 mL of water to dogs whose gastric pH was acidified by treatment with pentagastrin, resulting in a sustained plasma drug concentration profile. Cmax and AUC shown were 1329 ng / mL and 9749 ng · h / mL, respectively.

Test Example 17
The oral absorbability of the tablet of Example 17 was evaluated. The same evaluation system as in Test Example 5 was used. One tablet of Example 17 (150 mg as known compound A hydrobromide) was orally administered with 50 mL of water to a dog that had been treated with pentagastrin for acidification of the gastric pH. As a result, a sustained plasma drug concentration profile was obtained. Cmax and AUC shown were 1635 ng / mL and 11439 ng · h / mL, respectively.

Test Example 18
For the tablets of Example 5, Examples 22 and 23, drug dissolution was evaluated. In addition, about the tablet of Example 5, 8 tablets were injected | thrown-in per 1 vessel. Using 900 mL (37 ° C.) of USP pH 6.8 phosphate buffer as a test solution, an elution test was conducted according to the second method of the Japanese Pharmacopoeia Elution Test (paddle rotation speed: 100 rpm). After starting the dissolution test, the dissolution rate was calculated by sampling over time and measuring the absorbance using a spectrophotometer. In addition, the vertical axis | shaft 100% in a figure corresponds to 133.3 microgram / mL as a well-known compound A density | concentration (FIG. 6).

In Test Example 18, both the tablets of Example 5, Examples 22 and 23 showed sustained and stable dissolution up to 6 hours from the start of the dissolution test, and the dissolution rate was 60% (drug concentration 80.0 μg / The elution rate was 30% (drug concentration 40.0 μg / mL) or more at 14 hours. Compared with the drug solubility (10.9 μg / mL) at pH 6.8, it showed a very high value, and it was revealed that supersaturation can be maintained for a long time.

According to the present invention, Compound A has excellent JAK3 inhibitory activity and is useful as an active ingredient of a therapeutic and / or prophylactic agent for various immune diseases including autoimmune diseases, inflammatory diseases, and allergic diseases. Alternatively, high bioavailability can be imparted to a controlled-release pharmaceutical composition containing a pharmaceutically acceptable salt thereof.

Claims

4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide or a pharmaceutically acceptable salt thereof A controlled release pharmaceutical composition comprising a salt, an acidic substance, a supersaturation maintaining agent, and a controlled release base.
The controlled-release pharmaceutical composition according to claim 1, wherein the acidic substance is citric acid, malic acid, tartaric acid, fumaric acid, ascorbic acid, succinic acid, or maleic acid.
The amount of acidic substance added is 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide or The controlled-release pharmaceutical composition according to claim 1 or 2, which is 10 wt% or more and 200 wt% based on the weight of the pharmaceutically acceptable salt.
The supersaturation maintaining agent is one or more substances selected from the group consisting of hypromellose, hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate, and vinylpyrrolidone-vinylacetate copolymer. A controlled release pharmaceutical composition according to claim 1.
The amount of the supersaturation maintaining agent is 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide. Or the controlled release pharmaceutical composition as described in any one of Claim 1 to 4 which is 10 to 200 weight% with respect to the weight of the pharmaceutically acceptable salt.
6. The controlled-release pharmaceutical composition according to any one of claims 1 to 5, wherein the controlled-release base is a substance having a viscosity average molecular weight of 2 million or more or a viscosity of 1% aqueous solution at 25 ° C of 1000 cps or more.
The controlled-release pharmaceutical composition according to any one of claims 1 to 6, further comprising a hydrophilic base.
8. The controlled release pharmaceutical composition according to claim 7, wherein the hydrophilic base has an amount of water required to dissolve 1 g of the base at 5 ± 5 ° C. at 5 ± 5 ° C.
4-{[((1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3- when the dissolution test was performed with a pH 6.8 phosphate buffer. b] The controlled-release pharmaceutical composition according to any one of claims 1 to 8, wherein the concentration of pyridine-5-carboxamide is 8.6 μg / mL or more.