WO2018230504A1

WO2018230504A1 - Granules, tablets and method for producing same

Info

Publication number: WO2018230504A1
Application number: PCT/JP2018/022242
Authority: WO
Inventors: 満二稲垣; 健太杉坂; 晴樹小山
Original assignee: 富士化学工業株式会社
Priority date: 2017-06-12
Filing date: 2018-06-11
Publication date: 2018-12-20
Also published as: JP7116277B2; JPWO2018230504A1

Abstract

A method for producing tablets, said method comprising: a step for dissolving dutasteride in a solubilizing agent to give a solution; a step for adding to the solution an adsorbent and powdering the resultant mixture to give a powder; a step for adding to the powder a binder, a first excipient and a kneading liquid, kneading the resultant mixture and then drying to give granules; a step for adding to the granules a disintegrating agent and a second excipient, optionally together with a lubricant agent, and mixing to give a powder for tableting; and a step for tableting the powder for tableting to thereby produce tablets.

Description

Granules, tablets and method for producing the same

The present invention relates to granules, tablets containing dutasteride as an active ingredient and a method for producing the same.

Dutasteride (chemical formula: 17β-N- (2,5-bis (trifluoromethyl)) phenylcarbamoyl-4-aza-5-α-androst-1-en-3-one represented by the following formula (I) )) Is a dual 5-α reductase inhibitor that suppresses the conversion of testosterone to dihydrotestosterone (DHT). Dutasteride is known to be useful for the treatment of benign prostatic hypertrophy, prostate cancer, androgenetic alopecia (Patent Document 1).

The dutasteride is a so-called highly pharmacologically active compound that exhibits the above pharmacological activity in a small dose, and is widely known as a poorly soluble drug with low solubility in water. Due to such characteristics, when an attempt is made to make the drug into an oral formulation, the compound is exposed to the properties of the compound due to its properties such as exposure to manufacturing workers due to scattering of drug powder, prevention of environmental pollution, and poor water solubility. Development into tablets has not been easy. From such a viewpoint, Patent Document 2 refers to a soft capsule preparation containing dutasteride as an active ingredient. In particular, the soft capsule formulation is optimized for the dissolution of dutasteride regardless of storage or packaging conditions and has excellent consistent dissolution stability. Trying to provide a capsule formulation.

Japanese Patent No. 2904310 Japanese Patent No. 6051334

Including the techniques of Patent Documents 1 and 2, at present, only capsule preparations are distributed in the market as preparations containing dutasteride as an active ingredient. However, in addition to the problems of general soft capsules, the soft capsules have a difficulty that they are difficult to take due to their large size of “total length of about 19.3 mm and thickness of about 6.6 mm”. In particular, there are many elderly patients who have difficulty swallowing prostate cancer patients using this drug, and from the viewpoint of ease of administration, development of tablets that are easy to take has been strongly desired.
A main object of the present invention is to provide a granule, a tablet containing dutasteride as an active ingredient, and a method for producing the same.

The dutasteride-containing tablet of the present invention for solving the above problems is important for its production method due to the above characteristics of the active ingredient.
Dissolving dutasteride in a solubilizing agent to prepare a solution;
Adding an adsorbent to the solution to prepare a powder;
Adding a binder, a first excipient and a kneading liquid to the powder, kneading and drying to prepare granules;
A step of preparing a tableting powder by adding a disintegrant, a second excipient and, if necessary, a lubricant to the granules and mixing them;
Tableting the tableting powder to produce a tablet;
Is included.
By this method, the target tablet can be produced, and the composition of the tablet largely depends on the production method.

In addition, the tablet of the present invention is characterized in that it contains (i) dutasteride as an active ingredient and (ii) an adsorbent and a solubilizer as a formulation additive, (1) a granule, and (2) a disintegrant. And

Further, the granule of the present invention is characterized by containing (i) dutasteride as a main agent and (ii) an adsorbent and a solubilizer as a formulation additive.

According to the present invention, it is possible to provide granules and tablets containing dutasteride as an active ingredient. The tablet of the present invention can minimize problems such as exposure to manufacturing workers and contamination at the manufacturing site in the manufacturing process, and is a small preparation that is easy to take compared to the soft capsule currently provided in the medical field. Can be provided. Further, the granule of the present invention is a production intermediate preparation that is extremely important for producing the tablet of the present invention, and can be administered to a patient as it is as a granule or as a hard capsule. It is.

[Granule, tablet and method for producing the same]
The present invention provides a tablet containing dutasteride as an active ingredient and a method for producing the tablet.
In such a tablet production method, a first step of preparing a solution by dissolving dutasteride in a solubilizer, a second step of preparing a powder by adding an adsorbent to the solution, and a binder in the powder A third step of adding a first excipient and a kneading liquid, kneading and drying to prepare a granule, a disintegrant in the granule, a second excipient and, if necessary, a lubricant A fourth step of preparing a tableting powder by adding an agent and mixing, and a fifth step of tableting the tableting powder to produce a tablet. Hereinafter, while explaining each process, the granule and tablet of this invention are also demonstrated collectively.

[First step]
In the first step, dutasteride is dissolved in a solubilizing agent to prepare a solution.
Examples of solubilizers include fatty acid monoglycerides, fatty acid diglycerides, fatty acid mono-diglycerides, fatty acid triglycerides, propylene glycol fatty acid esters, and the like. A solubilizer may be used individually by 1 type among these compounds, and 2 or more types may be mixed and used for it. The solubilizer is preferably a mono-diglyceride of a fatty acid.
The amount of solubilizer added is preferably 50 to 300 parts by weight per 1 part by weight of dutasteride.
In the dissolution step of this step, dissolution can be performed more efficiently by adding ethanol to the solubilizer and the main agent.

[Second step]
In the second step, an adsorbent is added to the solution prepared in the first step, and the mixture is stirred and mixed to be powdered. Specifically, a certain amount of adsorbent is weighed, and a solution is added to the adsorbent and mixed until powdered.
Examples of the adsorbent include silicon dioxide (light anhydrous silicic acid, hydrous silicon dioxide, fine silicon dioxide), calcium silicate, anhydrous calcium hydrogen phosphate, magnesium aluminate metasilicate, and the like. An adsorbent may be used individually by 1 type among these compounds, and 2 or more types may be mixed and used for it. The adsorbent is preferably silicon dioxide or magnesium aluminate metasilicate.
The amount of adsorbent added is preferably 0.5 to 3.0 parts by weight, more preferably 1.2 to 2.0 parts by weight, per 1 part by weight of the solubilizer.

[Third step]
In the third step, the powder prepared in the second step is kneaded by adding the first excipient and kneading liquid, and optionally a binder. The association product is dried to prepare granules (sometimes referred to as “granule”). Preferably, the binder, the first excipient, and the kneading liquid are added to the powder and kneaded. After the kneaded product is sized, it is dried at a constant temperature for a certain period of time, and the dried product is sized again. Thus, a granular material that can be used for tableting, that is, a granule can be produced.
Examples of the binder include ordinary ones such as hydroxypropylcellulose, hypromellose, povidone, carboxyvinyl polymer, gum arabic and the like. The amount of the binder used is preferably 0.005 to 0.1 parts by weight and more preferably 0.005 to 0.03 parts by weight in 1 part by weight of the granulated part.
Examples of the first excipient include those commonly used such as lactose and hydrates thereof, corn starch, potato starch, and crystalline cellulose. A 1st excipient | filler may be used individually by 1 type among these compounds, and 2 or more types may be mixed and used for it. The amount of the first excipient used is not particularly limited, and an appropriate amount may be blended according to the target mass of the tablet.
Examples of the kneading liquid include ethanol, water, etc., preferably 30 to 99.5% ethanol aqueous solution is used, and more preferably 50 to 95% ethanol aqueous solution is used.
The amount of the kneading liquid used is not particularly limited, and may be an amount used so that an appropriate viscosity can be obtained in the kneading step.
The granules thus obtained, that is, the granular composition, is important as an intermediate composition in the production process of the target tablet, and in this form, for example, as a granule or a fine granule or harden the granule. It is also possible to fill capsules and take them as hard capsules.

[Fourth step]
In the fourth step, a powder for tableting is prepared by adding a disintegrant, a second excipient and, if necessary, a lubricant to the granules prepared in the third step, that is, granules. . Preferably, the disintegrant and the second excipient are added to the granule and mixed, and if necessary, a lubricant is added to the mixture and mixed.
Examples of the disintegrant include low-substituted hydroxypropyl cellulose, carmellose calcium, sodium starch glycolate, partially pregelatinized starch, croscarmellose sodium, povidone, crospovidone and the like. A disintegrating agent may be used individually by 1 type among these compounds, and 2 or more types may be mixed and used for it.
Examples of the second excipient preferably include mannitol, reduced maltose water candy and the like. A 2nd excipient | filler may be used individually by 1 type among these compounds, and 2 or more types may be mixed and used for it. The second excipient may be the same as the first excipient, or a different one may be used. The second excipient may be used as appropriate according to the purpose.
Examples of lubricants include magnesium stearate, calcium stearate, talc, sodium stearyl fumarate, sucrose fatty acid ester and the like.
The amount of the disintegrant, the second excipient, and the lubricant used is not particularly limited, and may be about the same as the amount usually used in tablet production.

[Fifth step]
In the fifth step, the tableting powder prepared in the fourth step is tableted to produce tablets.
A general-purpose tableting machine can be used as the tableting machine. For example, a rotary tableting machine is used. The tableting conditions (such as the size of the punch, the tableting pressure, the number of rotations, etc.) may be appropriately set according to the size and hardness of the tablet to be produced.

[Tablets and uses]
According to such a production method, a tablet containing at least dutasteride, a solubilizer, an adsorbent, and a disintegrant can be produced, and the tablet additionally contains a binder, an excipient, and a lubricant as required. Can be manufactured.
The tablet of the present invention by such a production method is smaller and easier to take than conventional soft capsules, has a drug-eluting effect equivalent to that of soft capsules, and is sufficiently benign prostatic hypertrophy, prostate cancer or male It has a therapeutic effect on alopecia areata.

Furthermore, the tablet of the present invention has sufficient stability under long-term storage and can be produced by a general production facility, and the production cost is lower than that of a conventional soft capsule.
In general, many solid preparations adsorbing liquid solubilizers are unstable due to heat (temperature), and when they are made into tablets, the disintegration time and hardness of the disintegration test vary greatly, making it difficult to maintain the preparation quality. . In this regard, according to the manufacturing method of the present tablet, by specifically selecting the kneading liquid in the third step and the external additive (disintegrant, second excipient) in the fourth step, Tablets that can withstand (temperature) can be produced.

Examples of the present invention will be described below.
However, the scope of the present invention is not limited to the following examples.

In addition to ease of administration, the tablet preferably satisfies the following conditions.
(1) Since the dissolution behavior is similar to that of existing soft capsules, the tablet disintegration time is 2 to 10 minutes.
(2) Tablets satisfying the disintegration time can be tableted with a tableting pressure of 2000 kgf or less.
(3) In the heat resistance test (sealed at 50 ° C., 1 week), the disintegration time and dissolution change are as small as possible.

[Preparation of sample]
(1) Example 1
Dutasteride tablets were produced according to the following procedures (1.1) to (1.9).
(1.1) 0.5 g of dutasteride was added to 25 g of medium chain fatty acid mono-diglyceride (Sunsoft No.707 manufactured by Taiyo Kagaku Co., Ltd.) and dissolved to obtain a solution A1.
(1.2) 2 g of hydroxypropyl cellulose (NISSO HPC-L manufactured by Nippon Soda Co., Ltd.) was stirred and dissolved in 38 g of 95% aqueous ethanol solution to obtain a solution B1.
(1.3) 35 g of light anhydrous silicic acid (Adsolider 101 manufactured by Freund Sangyo Co., Ltd.) was weighed in a mortar, and the solution A1 was added thereto and mixed with a pestle until powdered to obtain a mixture C1.
(1.4) The solution B1 was added to the mixture C1 and mixed with a pestle until the whole became uniform to obtain a mixed powder D1.
(1.5) 45.5 g of lactose hydrate (Pharmatose 200M manufactured by DFE Pharma Co., Ltd.) and 122 g of crystalline cellulose (Theolas UF711 manufactured by Asahi Kasei Chemicals Co., Ltd.) 122 g were added to the mixed powder D1 and mixed with a pestle, and then 95% aqueous ethanol solution 100 g was added and kneaded to obtain granulated powder E1.
(1.6) The granulated powder E1 was sieved with a sieve having an opening of 500 μm, and then transferred to a stainless steel tray and dried at 70 ° C. for 60 minutes to obtain a dried product F1.
(1.7) The dried product F1 was sieved with a sieve having an opening of 500 μm to give granules G1 (sized powder).
(1.8) 207 g of granule G1 was weighed, and 40.5 g of low-substituted hydroxypropyl cellulose (L-HPC manufactured by Shin-Etsu Chemical Co., Ltd.) and 24.3 g of D-mannitol (Pairitol 100SD manufactured by Rocket Japan) were added to this. In addition, after mixing for 2 minutes in a plastic bag, 2.7 g of magnesium stearate (magnesium stearate S manufactured by NOF Corporation) was added and further mixed for 1 minute, followed by sieving with a sieve having an opening of 500 μm. Got.
(1.9) Tableting powder H1 was tableted with a rotary tableting machine (HT-AP18SS-II, manufactured by Hata Iron Works). In the tableting process, a tablet having a diameter of 9 mm and a radius of curvature of 10 mm was used, and the parameters of the tableting machine were set so that one tablet was 305 mg at a rotation speed of 30 revolutions per minute and the hardness was about 110 N (size: diameter 9 mm, thickness 4.84 mm).

(2) Example 2
Dutasteride tablets were produced according to the following procedures (2.1) and (2.2).
(2.1) 207 g of granules G1 (sized powder) prepared in the same manner as in Example 1, 40.5 g of carmellose calcium (ECG505 manufactured by Nichirin Chemical Industry Co., Ltd.) and reduced maltose water candy (Amalty MR manufactured by Mitsubishi Corporation Foodtech) -50) After adding 55.8 g and mixing in a plastic bag for 2 minutes, add 2.7 g of magnesium stearate (magnesium stearate S manufactured by NOF Corporation), mix for another 1 minute, and press through a sieve with an opening of 500 μm. Powder H2 was obtained.
(2.2) Tableting powder H2 was tableted with a rotary tableting machine (HT-AP18SS-II, manufactured by Hata Iron Works). In the tableting process, a tablet with a diameter of 9 mm and a radius of curvature of 10 mm was used, and the parameters of the tableting machine were set so that one tablet was 340 mg and the hardness was about 105 N at a rotation speed of 30 revolutions per minute. 5.16 mm).

(3) Example 3
Dutasteride tablets were produced according to the following procedures (3.1) to (3.9).
(3.1) 0.5 g of dutasteride was added to 25 g of medium-chain fatty acid mono-diglyceride (Sunsoft No.707 manufactured by Taiyo Kagaku Co., Ltd.) and dissolved to obtain a solution A3.
(3.2) 2 g of hydroxypropyl cellulose (NISSO HPC-L manufactured by Nippon Soda Co., Ltd.) was stirred and dissolved in 38 g of 95% aqueous ethanol solution to obtain a solution B3.
(3.3) Magnesium aluminate metasilicate (Neusilin UFL2 manufactured by Fuji Chemical Industry Co., Ltd.) was weighed in a mortar, and solution A3 was added thereto and mixed with a pestle until powdered to obtain mixed powder C3.
(3.4) The mixed powder C3 was mixed with the solution B3 and mixed with a pestle until the whole became uniform to obtain a mixed powder D3.
(3.5) 45.5 g of lactose hydrate (Pharmatose 200M manufactured by DFE Pharma Co., Ltd.) and 122 g of crystalline cellulose (Theoras UF711 manufactured by Asahi Kasei Chemicals Co., Ltd.) are added to the mixed powder D3 and mixed with a pestle. 80 g was added and kneaded to obtain granulated powder E3.
(3.6) The granulated powder E3 was sieved with a sieve having an opening of 500 μm, and then transferred to a stainless steel tray and dried at 70 ° C. for 60 minutes to obtain a dried product F3.
(3.7) The dried product F3 was sieved with a sieve having an opening of 500 μm to obtain granules G3 (size-regulated powder).
(3.8) 211.5 g of granule G3 was weighed, and 13.5 g of sodium starch glycolate (Glycolith manufactured by Rocket Japan) and 24.3 g of D-mannitol (Pearlitol 100SD manufactured by Rocket Japan) were added to this and a plastic bag. After mixing for 2 minutes, 2.7 g of magnesium stearate (magnesium stearate S manufactured by NOF Corporation) was added and further mixed for 1 minute, and then sieved with a sieve having an opening of 500 μm to obtain powder H3 for tableting.
(3.9) Tableting powder H3 was tableted with a rotary tableting machine (HT-AP18SS-II, manufactured by Hata Iron Works). In the tableting process, a tablet with a diameter of 9 mm and a radius of curvature of 10 mm was used, and the parameters of the tableting machine were set so that one tablet was 280 mg at a rotation speed of 30 revolutions per minute and the hardness was about 190 N (size: diameter 9 mm, thickness 4.17 mm).

(4) Example 4
Dutasteride tablets were produced according to the following procedures (4.1) to (4.9).
(4.1) 0.5 g of dutasteride was added and dissolved in 50 g of medium chain fatty acid mono-diglyceride (Sunsoft No.707 manufactured by Taiyo Kagaku Co., Ltd.) to obtain a solution A4.
(4.2) 3 g of hydroxypropyl cellulose (NISSO HPC-L manufactured by Nippon Soda Co., Ltd.) was stirred and dissolved in 57 g of 50% ethanol aqueous solution to obtain a solution B4.
(4.3) 75 g of light anhydrous silicic acid (Freund Sangyo Co., Ltd. Adsolider 101) was weighed in a mortar, and the solution A4 was added thereto and mixed with a pestle until powdered to obtain a mixture C4.
(4.4) The solution B4 was added to the mixture C4 and mixed with a pestle until the whole became uniform to obtain a mixed powder D4.
(4.5) 44.5 g of lactose hydrate (Pharmatose 200M manufactured by DFE Pharma Co., Ltd.) and 122 g of crystalline cellulose (Theolas UF711 manufactured by Asahi Kasei Chemicals Co., Ltd.) 122 g were added to the mixed powder D4 and mixed with a pestle, followed by 50% aqueous ethanol solution. 120 g was added and kneaded to obtain granulated powder E4.
(4.6) After the granulated powder E4 was sieved with a sieve having an opening of 500 μm, it was transferred to a stainless steel tray and dried at 70 ° C. for 60 minutes to obtain a dried product F4.
(4.7) The dried product F4 was sieved with a sieve having an opening of 500 μm to obtain granules G4 (size-regulated powder).
(4.8) 265.5 g of granule G4 was weighed, and 54 g of low-substituted hydroxypropyl cellulose (L-HPC manufactured by Shin-Etsu Chemical Co., Ltd.) and 24.3 g of D-mannitol (Pairitol 100SD manufactured by Rocket Japan) were added thereto. In addition, after mixing for 2 minutes in a plastic bag, 2.7 g of magnesium stearate (magnesium stearate S manufactured by NOF Corporation) was added and further mixed for 1 minute, followed by sieving with a sieve having an opening of 500 μm. Got.
(4.9) Tableting powder H4 was tableted with a rotary tableting machine (HT-AP18SS-II, manufactured by Hata Iron Works). In the tableting process, a tablet with a diameter of 10 mm and a radius of curvature of 13 mm was used, and the parameters of the tableting machine were set so that one tablet was 385 mg and the hardness was about 90 N at a rotation speed of 30 revolutions per minute. 4.85 mm).

(5) Example 5
Dutasteride tablets were produced according to the following procedures (5.1) to (5.9).
(5.1) 1 g of dutasteride was dissolved in 80 g of medium-chain fatty acid mono-diglyceride (CAPMUL MCM EP / NF manufactured by ABITEC) and 144 g of 95% aqueous ethanol solution to obtain a solution A5.
(5.2) 6 g of hydroxypropyl cellulose (NISSO HPC-L manufactured by Nippon Soda Co., Ltd.) was stirred and dissolved in 114 g of 95% aqueous ethanol solution to obtain a solution B5.
(5.3) 140 g of light anhydrous silicic acid (Freund Sangyo Co., Ltd. Adsolider 101) is put into a high-speed stirring granulator (NMG-5L made by Nara Machinery Co., Ltd.), and the solution A5 is added thereto and mixed until it becomes powdery. Mixture C5 was obtained.
(5.4) 39 g of lactose hydrate (Pharmatose 200M manufactured by DFE Pharma Co., Ltd.) and 164 g of crystalline cellulose (Ceorus UF711 manufactured by Asahi Kasei Chemicals Co., Ltd.) were added to the mixture C5 and mixed to obtain a mixed powder D5.
(5.5) Solution B5 was added to mixed powder D5 and kneaded to obtain granulated powder E5.
(5.6) The granulated powder E5 was sized with a sizing machine (Cormil 197S manufactured by POWREC), then transferred to a stainless steel tray and dried at 60 ° C. for 90 minutes to obtain a dried product F5.
(5.7) The dried product F5 was sized with a sizing machine (Cormil 197S manufactured by POWREC Co., Ltd.) to obtain Granule G5 (sized sizing powder).
(5.8) 387 g of granule G5 was weighed, and 99 g of low-substituted hydroxypropyl cellulose (L-HPC manufactured by Shin-Etsu Chemical Co., Ltd.) and 54 g of D-mannitol (Pairitol 100SD manufactured by Rocket Japan Co., Ltd.) were added to this. Was mixed for 2 minutes to obtain tableting powder H5.
(5.9) Tableting powder H4 was tableted with a rotary tableting machine (HT-AP18SS-II, manufactured by Hata Iron Works). In the tableting process, using a punch with a diameter of 9 mm and a curvature radius of 13 mm, the parameters of the tableting machine were set so that one tablet was 300 mg at a rotation speed of 30 revolutions per minute and the hardness was about 90 N (size: diameter 9 mm, thickness 4.58 mm).

(6) Example 6
Dutasteride tablets were produced according to the following procedures (6.1) to (6.9).
(6.1) 0.5 g of dutasteride was added to 25 g of propylene glycol fatty acid ester (NIKKOL Sefsol-218 manufactured by Nikko Chemicals) and dissolved therein to obtain a solution A6.
(6.2) 2 g of hydroxypropyl cellulose (NISSO HPC-L manufactured by Nippon Soda Co., Ltd.) was stirred and dissolved in 38 g of purified water to obtain a solution B6.
(6.3) 25 g of light anhydrous silicic acid (Freund Sangyo Co., Ltd. Adsolider 101) was weighed in a mortar, and the solution A5 was added thereto and mixed with a pestle until powdered to obtain a mixture C6.
(6.4) Solution B6 was added to mixture C6 and mixed with a pestle until the entire mixture became uniform to obtain mixed powder D6.
(6.5) After adding 57.5 g of lactose hydrate (Pharmatose 200M manufactured by DFE Pharma Co., Ltd.) and 125 g of crystalline cellulose (Theoras UF711 manufactured by Asahi Kasei Chemicals Co., Ltd.) to the mixed powder D6 and mixing with a pestle, 80 g of purified water was added. In addition, kneading was carried out to obtain granulated powder E6.
(6.6) The granulated powder E6 was sieved with a sieve having an opening of 500 μm, then transferred to a stainless steel tray and dried at 70 ° C. for 60 minutes to obtain a dried product F6.
(6.7) The dried product F5 was sieved with a sieve having an opening of 500 μm to give granules G6 (sized powder).
(6.8) 211.5 g of granule G6 was weighed, 3.15 g of sodium starch glycolate (Glycolith manufactured by Rocket Japan) was added thereto, and after manual mixing for 2 minutes in a plastic bag, magnesium stearate (manufactured by NOF Corporation) 2.25 g of magnesium stearate S) was added, and the mixture was further mixed for 1 minute, and then sieved with a sieve having an opening of 500 μm to obtain powder H6 for tableting.
(6.9) Tableting powder H6 was tableted with a rotary tableting machine (HT-AP18SS-II, manufactured by Hata Iron Works). In the tableting process, a tablet with a diameter of 8 mm and a radius of curvature of 9 mm was used, and the parameters of the tableting machine were set so that one tablet 241 mg at a rotation speed of 30 revolutions per minute and a hardness of about 125 N were set (size: diameter 8 mm, thickness 4.44 mm).

(7) Example 7
The propylene glycol fatty acid ester of Example 6 (NIKKOL Sefsol-218 manufactured by Nikko Chemicals) was changed to a medium chain fatty acid mono-diglyceride (Sunsoft No. 707 manufactured by Taiyo Kagaku). Others were prepared in the same manner as in Example 6 to obtain tablets (size: diameter 8 mm, thickness 4.58 mm).

Table 1 shows the formulations of Examples 1-7.

[Sample Evaluation]
The following measurements and tests were performed on the tablets of Examples 1 to 7.
(1) Measurement of tableting pressure The main pressure at the time of tableting of 5 tablets was measured, and the average value of each measured value was calculated.
(2) Measurement of tablet hardness Five tablets were sampled, the hardness was measured, and the average value of each measured value was calculated. A tablet hardness meter (Okada Seiki PC-30 type) was used to measure the hardness.
(3) Disintegration test Six tablets were sampled and a disintegration test was performed (disintegration time was measured), and the average value of each measurement value was calculated. The disintegration test was conducted according to the Japanese disintegration test method. In the disintegration test, a disintegration tester (NTR-6300A type manufactured by Toyama Sangyo) was used.
Thereafter, the tablets were subjected to a heat resistance test, and the disintegration test was performed again on the tablets. In the heat resistance test, the tablet was placed in a glass 9 cc screw tube, which was sealed with a polypropylene lid and allowed to stand in a thermostat at 50 ° C. for 1 week.
(4) Dissolution test Six tablets were sampled and a dissolution test was performed (dissolution rate was measured), and an average value of each measurement value at a test time of 60 minutes was calculated. In the dissolution test, a dissolution tester (NTR-6300A type manufactured by Toyama Sangyo) was used. In the dissolution test, the tablets were immersed in 900 ml of pH 4.0 McIlvaine buffer supplemented with 0.5% (W / V) polysorbate 80, and the rotation speed of the paddle was set to 50 revolutions.
Thereafter, the tablets were subjected to a heat test similar to the heat test in the disintegration test, and the dissolution test was performed again on the tablets.

The evaluation results of Examples 1 to 7 are shown in Table 2.

[Summary]
As shown in Table 2, in any of Examples 1 to 7, a tablet having a certain hardness and easy to take could be produced at a tableting pressure of 2000 kgf or less.
In Examples 1 to 5, the disintegration time was within 2 to 10 minutes before and after the heat test, while in Examples 6 to 7, the disintegration time exceeded 10 minutes after the heat test.
Also, as shown in Table 2, among the examples, in Examples 1 to 5, the decrease in dissolution rate was within 10% before and after the heat test, while in Examples 6 to 7, elution was performed after the heat test. The rate drop exceeded 10%.
In particular, from the comparison between Examples 1 to 5 and Examples 6 to 7, when the kneading solution was changed from 50% ethanol aqueous solution or 95% ethanol aqueous solution to purified water, the heat resistance test: delay of disintegration time and dissolution rate in one week A decline occurred. In Examples 1 to 5, since a 50% ethanol aqueous solution or a 95% ethanol aqueous solution is used as the kneading liquid, the tableting pressure tends to increase. However, as the disintegrant, low-substituted hydroxypropylcellulose, carmellose calcium, By selecting sodium starch glycolate, D-mannitol as the second excipient, and powdered reduced maltose water candy, the moldability was successfully improved and a tablet that can withstand heat (temperature) is produced. I was able to.

Claims

Dissolving dutasteride in a solubilizing agent to prepare a solution;
Adding an adsorbent to the solution to prepare a powder;
Adding a binder, a first excipient and a kneading liquid to the powder, kneading and drying to prepare granules;
A step of preparing a tableting powder by adding a disintegrant, a second excipient and, if necessary, a lubricant to the granules and mixing them;
Tableting the tableting powder to produce a tablet;
The manufacturing method of the tablet containing this.
In the manufacturing method of the tablet of Claim 1,
A method for producing a tablet, wherein the solubilizer is at least one selected from the group consisting of fatty acid monoglycerides, fatty acid diglycerides, fatty acid mono-diglycerides, fatty acid triglycerides, and propylene glycol fatty acid esters.
In the manufacturing method of the tablet of Claim 1 or 2,
A method for producing a tablet, wherein the solubilizer is added in an amount of 50 to 300 parts by weight per 1 part by weight of the dutasteride.
In the method for producing a tablet according to any one of claims 1 to 3,
The tablet production method, wherein the adsorbent is at least one selected from the group consisting of silicon dioxide, calcium silicate, anhydrous calcium hydrogen phosphate, and magnesium aluminate metasilicate.
In the method for producing a tablet according to any one of claims 1 to 4,
A method for producing a tablet, wherein the adsorbent is added in an amount of 0.5 to 3.0 parts by weight per 1 part by weight of the solubilizer.
In the method for producing a tablet according to any one of claims 1 to 5,
A method for producing a tablet, wherein the kneaded solution is a 30-99.5% ethanol aqueous solution.
(I) Dutasteride as the active ingredient and (ii) tablets containing an adsorbent and solubilizer as formulation additives, (1) granules, and (2) tablets containing a disintegrant.
The tablet according to claim 7, wherein the solubilizer is at least one selected from the group consisting of a fatty acid monoglyceride, a fatty acid diglyceride, a fatty acid mono-diglyceride, a fatty acid triglyceride, and a propylene glycol fatty acid ester.
The tablet according to claim 8 or 9, wherein the adsorbent is at least one selected from the group consisting of silicon dioxide, calcium silicate, anhydrous calcium hydrogen phosphate, and magnesium aluminate metasilicate.
(I) Dutasteride as the active ingredient and (ii) granules containing adsorbent and solubilizer as formulation additives.