JP7116277B2 - Granules, tablets and manufacturing method thereof - Google Patents

Description

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

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

The dutasteride is widely known as a so-called highly pharmacologically active compound that exhibits the above-mentioned pharmacological activity at a small dose and as a sparingly soluble drug with low solubility in water. Due to such characteristics, when the drug is to be made into an oral formulation, it is difficult to protect the manufacturing workers from exposure to the scattering of drug powder during the manufacturing process and to prevent contamination of the environment. Developing into tablets was not easy. From such a point of view, Patent Document 2 refers to a soft capsule formulation containing dutasteride as an active ingredient. We are about to offer a capsule formulation.

Japanese Patent No. 2904310 Japanese Patent No. 6051334

Including the techniques disclosed in Patent Documents 1 and 2, at present, only capsule formulations containing dutasteride as an active ingredient are distributed on the market. However, in addition to the problems of general soft capsules, the soft capsule has a large size of "about 19.3 mm in total length and about 6.6 mm in thickness", which makes it difficult to take. In particular, many of the prostate cancer patients who use this agent are elderly patients who have difficulty swallowing, and from the viewpoint of ease of administration, etc., there has been a strong demand for the development of an easy-to-take tablet.
A main object of the present invention is to provide granules and tablets containing dutasteride as an active ingredient and a method for producing the same.

For the dutasteride-containing tablet of the present invention for solving the above problems, the production method is important from the above properties of the active ingredient, and the method is
dissolving dutasteride in a solubilizer to prepare a solution;
A step of adding an adsorbent to the solution and pulverizing to prepare a powder;
a step of adding a binder, a first excipient and a kneading liquid to the powder, kneading and drying to prepare granules;
a step of adding a disintegrant, a second excipient and optionally a lubricant to the granules and mixing them to prepare a powder for tableting;
a step of compressing the tableting powder to produce a tablet;
contains.
By this method, the desired tablet can be produced, and the structure of the tablet largely depends on the production method.

In addition, the tablet of the present invention is characterized by containing (i) dutasteride as the main drug and (ii) granules containing an adsorbent and a solubilizer as formulation additives, and (2) a disintegrant. and

Further, the granules of the present invention are characterized by containing (i) dutasteride as a principal drug and (ii) an adsorbent and a solubilizer as formulation additives.

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 workers during the manufacturing process and contamination of the manufacturing site, and is smaller and easier to take than the soft capsules currently provided to the medical field. can provide. In addition, the granules of the present invention are extremely important intermediate preparations in the manufacture of the tablets of the present invention, and can be administered to patients as granules as they are or in the form of hard capsules. is.

[Granule, tablet and manufacturing method thereof]
The present invention provides a tablet containing dutasteride as an active ingredient and a method for producing the same.
In the method for producing such a tablet, a first step of dissolving dutasteride in a solubilizer to prepare a solution, a second step of adding an adsorbent to the solution and pulverizing it to prepare a powder, and a binder added to the powder , a third step of adding a first excipient and a kneading liquid, kneading and drying to prepare granules, and adding a disintegrant, a second excipient and, if necessary, a lubricant to the granules A fourth step of adding and mixing agents to prepare a powder for tableting, and a fifth step of tableting the powder for tableting to produce tablets. Each step will be described below, and the granules and tablets of the present invention will also be described.

[First step]
In the first step, dutasteride is dissolved in a solubilizer 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. The solubilizer may be used singly or in combination of two or more of these compounds. The solubilizer is preferably a mono-diglyceride of fatty acids.
The amount of the solubilizer to be added is preferably 50 to 300 parts by weight per 1 part by weight of dutasteride.
In the dissolution step of this step, the addition of ethanol to the solubilizing agent and the main agent allows the dissolution to be carried out more efficiently.

[Second step]
In the second step, an adsorbent is added to the solution prepared in the first step, stirred and mixed, and pulverized. Specifically, a certain amount of adsorbent is weighed, a solution is added thereto, and the mixture is mixed until powdery.
Examples of adsorbents include silicon dioxide (light anhydrous silicic acid, hydrated silicon dioxide, fine silicon dioxide), calcium silicate, anhydrous calcium hydrogen phosphate, magnesium aluminometasilicate, and the like. The adsorbent may be used alone among these compounds, or two or more of them may be mixed and used. The adsorbent is preferably silicon dioxide or magnesium aluminometasilicate.
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 with the first excipient and kneading liquid, and optionally with a binder added. The combined product is dried to prepare granules (sometimes referred to as "granules"). Preferably, the powder is added with a binder, a first excipient and a kneading liquid and kneaded, the kneaded product is granulated, dried at a constant temperature for a certain time, and the dried product is granulated again. Then, granules that can be used for tableting can be produced.
Examples of binders include conventional 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, more preferably 0.005 to 0.03 parts by weight, per 1 part by weight of the granulated portion.
Examples of the first excipient include commonly used ones such as lactose and its hydrates, corn starch, potato starch, and microcrystalline cellulose. As the first excipient, one of these compounds may be used alone, or two or more of these compounds may be used in combination. The amount of the first excipient used is not particularly limited, and an appropriate amount may be blended according to the target weight of the tablet.
Examples of the kneading liquid include ethanol and water, preferably 30-99.5% aqueous ethanol solution, more preferably 50-95% aqueous ethanol solution.
The amount of the kneading liquid to be used is not particularly limited, and may be used in such an amount that an appropriate viscosity can be obtained in the kneading process.
The granules thus obtained, that is, the granular composition, are important as an intermediate composition in the manufacturing process of the intended tablet, and are also used as they are, for example, as granules or fine granules, or as hardened granules. It can also be filled into capsules and taken as hard capsules.

[Fourth step]
In the fourth step, the granules prepared in the third step, i.e., granules, are mixed with a disintegrant, a second excipient and, if necessary, a lubricant to prepare a powder for tableting. . Preferably, the disintegrant and the second excipient are added to the granules and mixed, and the mixture is optionally added with a lubricant and mixed.
Examples of disintegrants include low-substituted hydroxypropylcellulose, carmellose calcium, sodium starch glycolate, partially pregelatinized starch, croscarmellose sodium, povidone, crospovidone, and the like. Disintegrants may be used singly or in combination of two or more of these compounds.
Examples of the second excipient preferably include mannitol, hydrogenated maltose starch syrup, and the like. As the second excipient, one of these compounds may be used alone, or two or more thereof may be mixed and used. Also, the second excipient may be the same as the first excipient, or may be different. A second excipient may be used as appropriate depending on 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 the same amounts as those normally used in the production of tablets are sufficient.

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

[Tablet and application]
According to this production method, a tablet containing at least dutasteride, a solubilizer, an adsorbent and a disintegrant can be produced, and if desired, the tablet can be additionally compounded with a binder, an excipient, and a lubricant. can be manufactured by
The tablet of the present invention produced by such a manufacturing method is smaller than conventional soft capsules and is easier to take, has a drug elution effect equivalent to that of soft capsules, and is suitable for benign prostatic hyperplasia, prostatic cancer or men. It has a therapeutic effect on pattern baldness.

Furthermore, the tablet of the present invention has sufficient stability under long-term storage, can be manufactured with general manufacturing equipment, and is manufactured at a lower cost than conventional soft capsules.
In general, many solid formulations that adsorb liquid solubilizers are unstable due to heat (temperature), and when they are made into tablets, it is difficult to maintain the quality of formulations due to large fluctuations in disintegration time and hardness in disintegration tests. . In this respect, according to the present tablet manufacturing method, by specifically selecting the kneading liquid in the third step and the external additives (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 by no means limited to the following examples.

In addition to being easy to take, the tablet preferably satisfies the following conditions.
(1) The tablet disintegration time is 2 to 10 minutes in order to make the dissolution behavior similar to existing soft capsules.
(2) A tablet that satisfies the above disintegration time can be compressed at a compression pressure of 2000 kgf or less.
(3) Changes in disintegration time and dissolution properties are as small as possible in a heat test (closed at 50°C for 1 week).

[Preparation of sample]
(1) Example 1
Dutasteride tablets were manufactured according to the procedures (1.1) to (1.9) below.
(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 solution A1.
(1.2) 2 g of hydroxypropyl cellulose (NISSO HPC-L manufactured by Nippon Soda Co., Ltd.) was dissolved in 38 g of a 95% aqueous ethanol solution with stirring to obtain a solution B1.
(1.3) 35 g of light silicic anhydride (Adsolider 101 manufactured by Freund Corporation) was weighed in a mortar, and solution A1 was added thereto and mixed with a pestle until powdery to obtain a mixture C1.
(1.4) Mixed powder D1 was obtained by adding solution B1 to mixture C1 and mixing with a pestle until the whole was homogeneous.
(1.5) To mixed powder D1, 45.5 g of lactose hydrate (DFE Pharma Pharmatose 200M) and 122 g of crystalline cellulose (Seolus UF711, Asahi Kasei Chemicals) were added and mixed with a pestle, followed by 95% aqueous ethanol solution. 100 g was added and kneaded to obtain granulated powder E1.
(1.6) After the granulated powder E1 was sieved through a sieve with 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 F1.
(1.7) The dried material F1 was sieved through a 500 μm sieve to obtain granules G1 (sieved powder).
(1.8) 207 g of granules G1 were 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 (Pearitol 100SD manufactured by Rocket Japan) were added. After adding and mixing for 2 minutes in a plastic bag, 2.7 g of magnesium stearate (Magnesium stearate S manufactured by NOF Corporation) was added and mixed for another 1 minute. got
(1.9) Tableting powder H1 was tableted using a rotary tableting machine (HT-AP18SS-II, manufactured by Hata Iron Works Co., Ltd.). In the tableting process, a punch with a diameter of 9 mm and a radius of curvature of 10 mm is used, and the parameters of the tableting machine are set so that each tablet is 305 mg at 30 revolutions per minute and the hardness is about 110 N. Tablets (size: diameter 9 mm, thickness 4.84 mm) was obtained.

(2) Example 2
Dutasteride tablets were manufactured according to the procedures (2.1) and (2.2) below.
(2.1) To 207 g of granules G1 (sieved 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 syrup (Amalty MR manufactured by Mitsubishi Shoji Foodtech Co., Ltd.) were added. -50) was added and mixed for 2 minutes in a plastic bag, then 2.7 g of magnesium stearate (Magnesium stearate S manufactured by NOF Corporation) was added and mixed for 1 minute. A powder for 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 punch 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 each tablet was 340 mg at 30 revolutions per minute and the hardness was about 105 N. Tablets (size: diameter 9 mm, thickness 5.16 mm) was obtained.

(3) Example 3
Dutasteride tablets were manufactured according to the procedures (3.1) to (3.9) below.
(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 solution A3.
(3.2) 2 g of hydroxypropylcellulose (NISSO HPC-L manufactured by Nippon Soda Co., Ltd.) was dissolved in 38 g of a 95% ethanol aqueous solution with stirring to obtain a solution B3.
(3.3) 40 g of magnesium aluminometasilicate (Neusilin UFL2 manufactured by Fuji Kagaku Kogyo Co., Ltd.) was weighed in a mortar, and solution A3 was added thereto and mixed with a pestle until powdery to obtain mixed powder C3.
(3.4) Mixed powder D3 was obtained by adding solution B3 to mixed powder C3 and mixing with a pestle until the whole was homogeneous.
(3.5) To mixed powder D3, 45.5 g of lactose hydrate (DFE Pharma Pharmatose 200M) and 122 g of crystalline cellulose (Seolus UF711, Asahi Kasei Chemicals) were added and mixed with a pestle, followed by 95% aqueous ethanol solution. 80 g was added and kneaded to obtain granulated powder E3.
(3.6) After the granulated powder E3 was sieved through a sieve with 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 F3.
(3.7) The dried product F3 was sieved through a 500 μm sieve to obtain granules G3 (sieved powder).
(3.8) 211.5 g of granules G3 are weighed, and 13.5 g of sodium starch glycolate (Glycolith, manufactured by Rocket Japan) and 24.3 g of D-mannitol (Pearitol 100SD, manufactured by Rocket Japan) are added and placed in a plastic bag. After mixing for 2 minutes inside, 2.7 g of magnesium stearate (Magnesium stearate S manufactured by NOF CORPORATION) was added and further mixed for 1 minute.
(3.9) Tableting powder H3 was tableted with a rotary tableting machine (Model HT-AP18SS-II manufactured by Hata Iron Works). In the tableting process, a punch 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 each tablet was 280 mg at 30 revolutions per minute and the hardness was about 190 N. Tablets (size: diameter 9 mm, thickness 4.17 mm) was obtained.

(4) Example 4
Dutasteride tablets were manufactured according to the procedures (4.1) to (4.9) below.
(4.1) 0.5 g of dutasteride was added to 50 g of medium-chain fatty acid mono/diglyceride (Sunsoft No. 707 manufactured by Taiyo Kagaku Co., Ltd.) and dissolved to obtain solution A4.
(4.2) 3 g of hydroxypropyl cellulose (NISSO HPC-L manufactured by Nippon Soda Co., Ltd.) was dissolved in 57 g of a 50% aqueous ethanol solution with stirring to obtain a solution B4.
(4.3) 75 g of light silicic anhydride (Adsolider 101 manufactured by Freund Corporation) was weighed in a mortar, and solution A4 was added thereto and mixed with a pestle until powdery to obtain a mixture C4.
(4.4) Solution B4 was added to mixture C4 and mixed with a pestle until the whole was homogeneous to obtain mixed powder D4.
(4.5) To mixed powder D4, 44.5 g of lactose hydrate (DFE Pharma Pharmatose 200M) and 122 g of crystalline cellulose (Seolus UF711, Asahi Kasei Chemicals) were added and mixed with a pestle, followed by 50% aqueous ethanol solution. 120 g was added and kneaded to obtain granulated powder E4.
(4.6) The granulated powder E4 was sieved through a sieve with an opening of 500 µm, transferred to a stainless steel tray and dried at 70°C for 60 minutes to obtain a dried product F4.
(4.7) The dried material F4 was sieved through a 500 μm sieve to obtain granules G4 (sieved powder).
(4.8) 265.5 g of granules G4 were 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 (Pearitol 100SD manufactured by Rocket Japan) were added. After adding and mixing for 2 minutes in a plastic bag, 2.7 g of magnesium stearate (Magnesium stearate S manufactured by NOF Corporation) was added and mixed for another 1 minute. 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 punch 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 each tablet was 385 mg at 30 revolutions per minute and the hardness was about 90 N. Tablets (size: diameter 10 mm, thickness 4.85 mm) was obtained.

(5) Example 5
Dutasteride tablets were manufactured according to the procedures (5.1) to (5.9) below.
(5.1) 1 g of dutasteride was added to 80 g of medium-chain fatty acid mono/diglyceride (CAPMUL MCM EP/NF manufactured by ABITEC) and 144 g of a 95% aqueous ethanol solution to obtain solution A5.
(5.2) 6 g of hydroxypropyl cellulose (NISSO HPC-L manufactured by Nippon Soda Co., Ltd.) was dissolved in 114 g of a 95% ethanol aqueous solution with stirring to obtain a solution B5.
(5.3) Put 140 g of light silicic anhydride (Adsolider 101 manufactured by Freund Corporation) into a high-speed stirring granulator (NMG-5L manufactured by Nara Machinery Co., Ltd.), add solution A5, and mix until powdery. A mixture C5 was obtained.
(5.4) To the mixture C5, 39 g of lactose hydrate (DFE Pharma Pharmatose 200M) and 164 g of crystalline cellulose (Seolus UF711, Asahi Kasei Chemicals) were added 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 sieved with a sizing machine (Comil 197S manufactured by Powrex), 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 (Comil 197S manufactured by Powrex) to obtain granules G5 (sizing powder).
(5.8) 387 g of granules G5 were weighed, and 99 g of low-substituted hydroxypropyl cellulose (L-HPC manufactured by Shin-Etsu Chemical Co., Ltd.) and 54 g of D-mannitol (Pearitol 100SD manufactured by Rocket Japan) were added and placed in a plastic bag. for 2 minutes to obtain a powder for tableting 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, a punch with a diameter of 9 mm and a radius of curvature of 13 mm is used, and the parameters of the tableting machine are set so that each tablet is 300 mg at 30 revolutions per minute and the hardness is about 90 N. Tablets (size: diameter 9 mm, thickness 4.58 mm) was obtained.

(6) Example 6
Dutasteride tablets were manufactured according to the procedures (6.1) to (6.9) below.
(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 to obtain solution A6.
(6.2) 2 g of hydroxypropyl cellulose (NISSO HPC-L manufactured by Nippon Soda Co., Ltd.) was dissolved in 38 g of purified water with stirring to obtain a solution B6.
(6.3) 25 g of light anhydrous silicic acid (Adsolider 101 manufactured by Freund Corporation) was weighed in a mortar, and solution A5 was added thereto and mixed with a pestle until powdery to obtain a mixture C6.
(6.4) Solution B6 was added to mixture C6 and mixed with a pestle until the whole was homogeneous to obtain mixed powder D6.
(6.5) To mixed powder D6, 57.5 g of lactose hydrate (DFE Pharma Pharmatose 200M) and 125 g of crystalline cellulose (Seolus UF711, Asahi Kasei Chemicals) were added and mixed with a pestle, and then 80 g of purified water was added. In addition, they were kneaded to obtain granulated powder E6.
(6.6) After the granulated powder E6 was sieved through a sieve with 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 F6.
(6.7) The dried product F5 was sieved through a 500 μm sieve to obtain granules G6 (sieved powder).
(6.8) Weigh 211.5 g of granules G6, add 3.15 g of sodium starch glycolate (Glycolith manufactured by Rocket Japan Co., Ltd.) and mix by hand in a plastic bag for 2 minutes, then magnesium stearate (manufactured by NOF Corporation) After adding 2.25 g of magnesium stearate S) and further mixing for 1 minute, the mixture was sieved through a sieve with an opening of 500 μm to obtain powder for tableting H6.
(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 punch 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 each tablet was 241 mg at 30 revolutions per minute and the hardness was about 125 N. Tablets (size: diameter 8 mm, thickness 4.44 mm) was obtained.

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

The formulations for Examples 1-7 are shown in Table 1.

[Sample evaluation]
The tablets of Examples 1-7 were subjected to the following measurements and tests.
(1) Measurement of tableting pressure The actual pressure at the time of tableting five tablets was measured, and the average value of each measured value was calculated.
(2) Measurement of tablet hardness 5 tablets were sampled, hardness was measured, and the average value of each measured value was calculated. A tablet hardness tester (Model PC-30 manufactured by Okada Seiki Co., Ltd.) was used to measure the hardness.
(3) Disintegration test A disintegration test was performed by sampling 6 tablets (disintegration time was measured), and the average value of each measured value was calculated. The disintegration test was carried out according to the disintegration test method of the Japanese Pharmacopoeia, and a disintegration tester (NTR-6300A manufactured by Toyama Sangyo Co., Ltd.) was used in the disintegration test.
After that, the tablets were subjected to a heat resistance test, and the tablets were again subjected to a disintegration test. In the heat resistance test, the tablets were placed in a 9 cc screw tube made of glass, sealed with a lid made of polypropylene, and allowed to stand in a constant temperature machine at 50° C. for one week.
(4) Dissolution test A dissolution test was performed by sampling 6 tablets (the dissolution rate was measured), and the average value of each measured value at the test time of 60 minutes was calculated. A dissolution tester (NTR-6300A model manufactured by Toyama Sangyo Co., Ltd.) was used in the dissolution test. 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 paddle speed was set to 50 revolutions.
After that, the tablets were subjected to the same heat resistance test as the heat resistance test in the disintegration test, and the tablets were again subjected to the dissolution test.

Table 2 shows the evaluation results of Examples 1 to 7.

[summary]
As shown in Table 2, in any of Examples 1 to 7, a tableting pressure of 2000 kgf or less was able to produce tablets having a certain hardness and an easy-to-take size.
In Examples 1 to 5, the collapse time was within 2 to 10 minutes before and after the heat resistance test, whereas in Examples 6 and 7, the collapse time exceeded 10 minutes after the heat resistance test.
Further, as shown in Table 2, among the examples, in Examples 1 to 5, the decrease in the dissolution rate before and after the heat resistance test fell within 10%, whereas in Examples 6 and 7, dissolution after the heat resistance test. The drop in rate exceeded 10%.
In particular, from a comparison between Examples 1-5 and Examples 6-7, when the kneading liquid was changed from 50% ethanol aqueous solution or 95% ethanol aqueous solution to purified water, heat resistance test: delay in disintegration time and dissolution rate in 1 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 be high. By selecting sodium starch glycolate, D-mannitol, and powdered hydrogenated maltose starch syrup as the second excipients, respectively, the moldability is successfully improved, and heat (temperature) resistant tablets are produced. I was able to

Claims (10)

dissolving dutasteride in a solubilizer to prepare a solution;
A step of adding an adsorbent to the solution and pulverizing to prepare a powder;
A binder, a first excipient and a kneading liquid are added to the powder, kneaded and dried. and
including
The solubilizer is at least one selected from fatty acid monoglycerides, fatty acid diglycerides, fatty acid mono/diglycerides, fatty acid triglycerides, and propylene glycol fatty acid esters,
The adsorbent is at least one selected from silicon dioxide, calcium silicate, anhydrous calcium hydrogen phosphate, and magnesium aluminometasilicate,
the binder is at least one selected from hydroxypropylcellulose, hypromellose, povidone, carboxyvinyl polymer, and gum arabic;
The first excipient is at least one selected from lactose, lactose hydrate, corn starch, potato starch, and crystalline cellulose,
The kneading liquid is an ethanol aqueous solution
A method for producing granules, characterized by: Claim 1granulesIn the manufacturing method of the agent,
Granules, wherein the amount of the solubilizer added is 50 to 300 parts by weight with respect to 1 part by weight of the dutasteride A method of manufacturing the agent. Claim 1 or 2granulesIn the manufacturing method of the agent,
Granules, wherein the amount of the adsorbent added is 0.5 to 3.0 parts by weight with respect to 1 part by weight of the solubilizer. A method for producing the agent. According to any one of claims 1 to 3granulesIn the manufacturing method of the agent,
Granules, wherein the kneading liquid is a 30 to 99.5% ethanol aqueous solution A method for producing the agent. According to any one of claims 1 to 4granulesIn the manufacturing method of the agent,
Granules, wherein the amount of the binder is 0.005 to 0.1 parts by weight in 1 part by weight of the granules agentmanufacturing method. According to any one of claims 1 to 5granulesAgent manufacturing method A step of adding and mixing a disintegrant, a second excipient and, if necessary, a lubricant to the granules obtained in , to prepare a powder for tableting;
a step of compressing the tableting powder to produce a tablet;
including
The disintegrant is at least one selected from low-substituted hydroxypropylcellulose, carmellose calcium, sodium starch glycolate, partially pregelatinized starch, croscarmellose sodium, povidone, and crospovidone,
The second excipient is at least one selected from mannitol, reduced maltose starch syrup, lactose, lactose hydrate, corn starch, potato starch, and crystalline cellulose.
A method for producing a tablet, characterized by: (i) dutasteride as the main drug and (ii) an adsorbent as the formulation additive,solubilizer, a binder, and a first excipient(1) granules containing
(2) disintegrantand a second excipienttablet containing and
The adsorbent is at least one selected from silicon dioxide, calcium silicate, anhydrous calcium hydrogen phosphate, and magnesium aluminometasilicate,
The solubilizer is at least one selected from fatty acid monoglycerides, fatty acid diglycerides, fatty acid mono/diglycerides, fatty acid triglycerides, and propylene glycol fatty acid esters,
the binder is at least one selected from hydroxypropylcellulose, hypromellose, povidone, carboxyvinyl polymer, and gum arabic;
The first excipient is at least one selected from lactose, lactose hydrate, corn starch, potato starch, and crystalline cellulose,
The disintegrant is at least one selected from low-substituted hydroxypropylcellulose, carmellose calcium, sodium starch glycolate, partially pregelatinized starch, croscarmellose sodium, povidone, and crospovidone,
The second excipient is at least one selected from mannitol, reduced maltose starch syrup, lactose, lactose hydrate, corn starch, and potato starch.
A tablet characterized by: The tablet according to claim 7, wherein the amount of said adsorbent is 0.5 to 3.0 parts by weight with respect to 1 part by weight of said solubilizer. The tablet according to any one of claims 7 to 8, wherein the amount of said binder is 0.005 to 1 part by weight per 1 part by weight of said granules. The tablet according to any one of claims 7 to 9, wherein said granules do not contain a disintegrant.