JP2018172288A - Method for producing ground product and tablet - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a ground product with suppressed attachment of powder to a crushing machine and excellent elution of a medicine.SOLUTION: A method for producing a ground product has the step of applying crushing treatment to a mixture containing following (A) component and (B) component. In the mixture, the mass percentage of the (B) component, represented by the (B) component/(the (A) component+the (B) component)×100, is 5-25 mass%. (A) component: a poorly water-soluble medicine with a melting point of 250°C or lower and (B) component: water at 0°C or lower.SELECTED DRAWING: None

Description

  The present invention relates to a method for producing a pulverized product and a tablet.

  It is known that poorly water-soluble drugs such as ibuprofen have a low dissolution property and are poor in immediate effect. In order to improve the dissolution property of a poorly water-soluble drug, it is useful to grind the poorly water-soluble drug to reduce the particle size. The types of grinders used to grind poorly water-soluble drugs include impact mills such as hammer mills, sample mills, disk mills and pin mills; dry fine mills such as jet mills, cylinder mills, and roller mills. Although a large amount of pulverization is possible at one time, an impact pulverizer is often used.

  The impact-type pulverizer has a high processing capability, but has a problem that a poorly water-soluble drug tends to adhere to the inside of the pulverizer. When the adhesion to the pulverizer occurs, the energy efficiency is lowered, and the yield with respect to the charged powder before pulverization is also lowered. When the pulverizer is continuously operated for a long time, heat is generated due to friction between the pulverizer and the powder. Due to this heat, a low-melting poorly water-soluble drug such as ibuprofen is melted and the melt adheres to the grinder, so that it is difficult to grind continuously.

  As a method for suppressing the adhesion of the powder to the pulverizer, Patent Document 1 proposes a method in which a poorly water-soluble drug, an excipient, and water are mixed at a predetermined ratio and the mixture is co-ground. .

JP 2012-193177 A

However, in the method of Patent Document 1, the content of the excipient and water with respect to the content of the poorly water-soluble drug is large, and the content of the active ingredient in the preparation may be small. When the amount of the active ingredient contained in the preparation is small, the tablet per tablet becomes large, or the number of tablets at the time of taking once increases, and the burden at the time of taking increases. For this reason, there has been a demand for a method for producing a drug with good dissolution of an active ingredient even if the contents of excipient and water are small.
Accordingly, an object of the present invention is to provide a method for producing a pulverized product that suppresses the adhesion of powder to a pulverizer and has good drug elution.

The present invention has the following aspects.
[1] A step of pulverizing a mixture containing the following component (A) and component (B), wherein the mixture is the component (B) / (the component (A) + the component (B)) The manufacturing method of the ground material whose mass percentage of the said (B) component represented by x100 is 5-25 mass%. Component (A): a poorly water-soluble drug having a melting point of 250 ° C. or lower. (B) Component: Water of 0 ° C. or less.
[2] The method for producing a pulverized product according to [1], wherein the pulverization is performed using a pin disk rotary impact pulverizer.
[3] In the mixture, the content of the components excluding the component (A) and the component (B) is 2% by mass or less based on the total mass of the mixture, according to [1] or [2]. Of manufacturing pulverized material.
[4] The method for producing a pulverized product according to any one of [1] to [3], wherein the component (A) is at least one selected from ibuprofen and ketoprofen.
[5] A step of obtaining a pulverized product by the method for producing a pulverized product according to any one of [1] to [4], and a step of producing a tablet using the powder composition containing the obtained pulverized product. A method for producing a tablet, comprising:
[6] The method for producing a pulverized product according to any one of [1] to [4], wherein the average particle size of the component (A) after the pulverization treatment is 1 to 20 μm.

  According to the method for producing a pulverized product of the present invention, since the average particle size of a poorly water-soluble drug is 20 μm or less while suppressing adhesion of powder to a pulverizer, the drug dissolution property can be improved.

≪Production method of pulverized product≫
The method for producing a pulverized product of the present invention includes a step of subjecting a mixture containing the following components (A) and (B) to a pulverization treatment.
Component (A) is a poorly water-soluble drug having a melting point of 250 ° C. or lower, and component (B) is water at 0 ° C. or lower.
In the method for producing a pulverized product of the present invention, the mixture has a mass percentage of the component (B) represented by the component (B) / (the component (A) + the component (B)) × 100. 5 to 25% by mass.
The method for producing a pulverized product of the present invention includes, for example, a first mixing step for preparing the mixture, and a pulverizing step for subjecting the mixture to a pulverization process.
Hereinafter, each process will be described in more detail.

<First mixing step>
The first mixing step is a step of preparing a mixture by mixing the component (A) and the component (B).
The manufacturing method of the ground material of this invention has a 1st mixing process, and it is easy to make the volume average particle diameter of (A) component after a grinding | pulverization process smaller.
In the present invention, the mixture is preferably powdered, granular or the like.

((A) component)
Component (A) is a poorly water-soluble drug having a melting point of 250 ° C. or lower. In the present specification, the “poorly water-soluble drug” refers to a drug having a solubility in water at 20 ° C. (hereinafter sometimes simply referred to as “solubility”) of 0 to 30 mg / mL. The solubility of the component (A) is preferably 0.01 to 10 mg / mL, more preferably 0.01 to 5 mg / mL, and further preferably 0.1 to 1 mg / mL. When the solubility is equal to or higher than the lower limit, it has an affinity for water and an adhesion suppressing effect can be easily obtained. When the solubility is less than or equal to the above upper limit, the component (A) is suppressed from being dissolved in water and the viscosity is suppressed, and pulverization is facilitated.

(A) Melting | fusing point of a component is 250 degrees C or less, 40-250 degreeC is preferable, 50-120 degreeC is more preferable, 65-80 degreeC is further more preferable. When the melting point of the component (A) is equal to or higher than the lower limit, the adhesion of the powder to the pulverizer tends to be reduced, and when the melting point is equal to or lower than the upper limit, the volume average particle diameter after the pulverization process becomes smaller. Cheap.
As the component (A), a powdery one is usually used. The volume average particle size of the component (A) used for preparing the mixture (volume average particle size before pulverization) is not particularly limited as long as it is larger than the volume average particle size of the pulverized product to be produced. Within the range of ~ 100 μm.
In the present specification, “volume average particle diameter” (hereinafter, also simply referred to as “average particle diameter”) is a value measured by a laser diffraction method. For example, LS13 320 manufactured by Beckman Coulter (product) Name) etc. and can be measured by using a dry powder module.

The type of component (A) is not particularly limited as long as it is a poorly water-soluble drug having a melting point of 250 ° C. or lower. Specifically, ibuprofen (solubility 0.19 mg / mL, melting point 76 ° C.), naproxen (solubility 0.04 mg) / ML, melting point 157 ° C.), ketoprofen (solubility 0.24 mg / mL, melting point 94 ° C.), indomethacin (solubility 0.01 mg / mL, melting point 158 ° C.), aspirin (solubility 3.3 mg / mL, melting point 135 ° C.), Antipyretic analgesics such as non-steroidal anti-inflammatory agents such as etodolac (solubility 0.11 mg / mL, melting point 145 ° C.); hypnotic / sedatives such as nitrazepam (solubility 0.04 mg / mL, melting point 227 ° C.); carbamazepine (solubility 0) Antiepileptic agents such as 14 mg / mL, melting point 189 ° C.); Haloperidol (solubility 0.01 mg / mL, melting point 149 ° C.), Psychiatric and neurological agents such as pyrido (solubility 0.55 mg / mL, melting point 178 ° C.); Arrhythmic agents such as disopyramide (solubility 1.6 mg / mL, melting point 85 ° C.); Atenolol (solubility 20 mg / mL, melting point 154 ° C.), etc. Anti-hypertensive agents; antitussives such as nifedipine (solubility 0.01 mg / mL, melting point 173 ° C.), noscapine (solubility 0.01 mg / mL, melting point 176 ° C.); bromhexine hydrochloride (solubility 1.1 mg / mL, melting point 239 ° C.) Such as expectorants; These may be used alone or in combination of two or more.
As the component (A), among the above, at least one selected from antipyretic analgesics is preferable, and at least one selected from ibuprofen and ketoprofen is more preferable because the effects of the present invention can be obtained particularly remarkably. Ibuprofen is particularly preferred.

  In the mixture, the content of the component (A) is preferably 70 to 95% by mass, more preferably 75 to 90% by mass, and still more preferably 80 to 85% by mass with respect to the total mass of the mixture. When the content of the component (A) is equal to or greater than the lower limit, the volume average particle size of the component (A) after the pulverization process tends to be smaller. When the content of the component (A) is not more than the above upper limit value, the adhesion suppressing effect is easily improved.

((B) component)
(B) A component is 0 degrees C or less water. Under normal atmospheric pressure (1 atm), component (B) is ice.
By containing the component (B), the component (A) and the component (B) come into contact with each other, and the adhesion suppressing effect of the mixture (mixed powder) can be enhanced.
(B) The kind of component is not specifically limited, Purified water, ion-exchange water, distilled water, ultrafiltration water, these ice, etc. are mentioned. From the viewpoint of suppressing the adhesion to the apparatus by shortening the residence time in the apparatus by making the volume average particle diameter of the component (A) easier to reduce and increasing the fluidity of the powder, the component (B) Is preferably ice.

  The temperature of (B) component should just be 0 degrees C or less just before a grinding | pulverization, -20--2 degreeC is preferable, and -10-5 degreeC is more preferable. When the temperature of the component (B) is equal to or higher than the lower limit value, it is easy to reduce the time and power consumption required for cooling, and when it is equal to or lower than the upper limit value, the adhesion suppressing effect is likely to be improved.

  In the mixture, the mass percentage of the component (B) represented by (B) component / ((A) component + (B) component) × 100 is 5 to 25% by mass, preferably 10 to 25% by mass, 12.5-22.5 mass% is more preferable, and 15-20 mass% is further more preferable. When the mass percentage of the component (B) is equal to or greater than the lower limit value, the adhesion suppressing effect is easily improved, and when the mass percentage is equal to or less than the upper limit value, the volume average particle diameter of the component (A) after the pulverization process tends to be smaller. .

  In the first mixing step, other components other than the component (A) and the component (B) may be mixed. The content of other components is preferably 2% by mass or less, more preferably 1% by mass or less, and may be 0% by mass with respect to the total mass of the first mixture. If the content of the other components is not more than the above upper limit value, the grinding efficiency can be increased and the size of the final preparation can be reduced, so that the dosing property is improved.

In the first mixing step, the component (A) and the component (B) respectively prepared may be mixed, or the component (A) and water above 0 ° C. are mixed in advance (primary mixing), (A) You may obtain a mixture by putting the primary mixture of a component and water over 0 degreeC in the environment below 0 degreeC.
From the viewpoint that the component (A) and the component (B) can be uniformly mixed and the adhesion suppressing effect is enhanced, the primary mixture of the component (A) and water above 0 ° C. is placed in an environment of 0 ° C. or less, and the mixture Is preferably prepared.
The first mixing step can be carried out using a known mixing device such as a ribbon mixer, a Boule container mixer, a V-type mixer, a double cone mixer, a high speed mixer, or the like.

<Crushing process>
In the pulverization step, the mixture prepared in the first mixing step is pulverized. Thereby, the pulverized material of the component (A) is obtained.
The type of pulverizer used in the pulverization process is not particularly limited. Impact pulverizers such as hammer mills, sample mills, disk mills and pin mills (pin disk rotary impact pulverizers); A crusher, a cylinder grinder, a roller grinder, etc. are mentioned. Among these, an impact pulverizer is preferable, and a pin disk rotary impact pulverizer is more preferable.

The pin disk rotary impact pulverizer is a pulverizer that uses the pin impact pulverization method. A large number of pins are installed on the disk. When rotating the disk at high speed in the pulverization chamber and passing the powder, The pin and powder collide with each other to be crushed. Usually, it is an apparatus used in continuous operation, and is a pulverizer that is widely used and has a high production efficiency.
As a model of the pin disk rotary impact crusher, Coroplex (manufactured by Hosokawa Micron Co., Ltd.), sample mill (manufactured by Nara Machinery Co., Ltd.), impact mill (manufactured by Dalton Co., Ltd.), etc. can be used. it can.

  Although it does not specifically limit as a rotational speed of the disk of a pin disk rotary impact type crusher, 2500-10000 m / s is preferable, 5000-9000 m / s is more preferable, 6300-7500 m / s is further more preferable. When the rotation speed is equal to or higher than the lower limit, the average particle diameter after pulverization can be easily reduced. When the rotation speed is equal to or lower than the upper limit value, it is easy to suppress adhesion of powder.

  The temperature of the mixture when pulverizing is preferably 0 ° C. or lower, more preferably −20 to −2 ° C., and further preferably −10 to −5 ° C. When the pulverization temperature is equal to or higher than the lower limit value, it is easy to reduce the time and power consumption required for cooling, and when the temperature is equal to or lower than the upper limit value, the adhesion suppressing effect is likely to be improved.

1-20 micrometers is preferable, as for the average particle diameter of (A) component after a grinding | pulverization process, 3-17.5 micrometers is more preferable, and 7-15 micrometers is further more preferable. When the average particle diameter of the component (A) after the pulverization treatment is equal to or larger than the lower limit, the handling (handling) of the powder tends to be favorable, and when the average particle size is equal to or smaller than the upper limit, the elution of the component (A) is It tends to be good.
The average particle size of the pulverized product can be adjusted by pulverization processing conditions (such as pulverization time, processing amount, and pulverizer rotational speed).

The pulverized product after pulverization may be subjected to a drying operation or may be granulated as it is without performing the drying operation. By performing the drying operation, moisture in the pulverized product can be removed, and the drug concentration (content of component (A)) in the pulverized product can be increased. From the viewpoint of increasing the drug concentration, reducing the size of the final preparation, and improving the dosage, it is preferable to perform a drying operation.
The method for the drying operation is not particularly limited, and a known method can be used. For example, the pulverized product is put into a dry oven set to a temperature equal to or lower than the melting point of the component (A) and dried for an arbitrary time, or the use of a fluidized bed dryer.
The drying operation may be performed during any process such as a granulation process, a second mixing process, and a tableting process, which will be described later, and the drying operation may be performed by providing a drying process between these processes.

In the present invention, adhesion of the powder to the pulverizer can be reduced by co-grinding a specific amount of the component (A) and the component (B). Therefore, the burden of collecting the pulverized material adhering to the inside of the pulverizer with a spatula or a brush is reduced, and the operability and safety in actual production can be improved.
In addition, since the average particle diameter of the pulverized product obtained by the method for producing the pulverized product of the present invention is 20 μm or less, the granulated particles and tablets are excellent in the elution of the component (A), and the granulated particles Useful for production or tablet production.

The pulverized product is preferably used for a solid preparation for internal use.
The dosage form of the internal solid preparation is not particularly limited, and examples thereof include granules, tablets and capsules. Of these, tablets are preferred.
In this invention, since there are few addition amounts of another component, it is possible to increase the content rate of (A) component in a ground material. For this reason, since the size of the tablet per tablet when it is used as a preparation can be reduced, or the number of tablets at the time of taking once can be reduced, the burden at the time of taking can be reduced.

≪Tablet manufacturing method≫
The manufacturing method of the tablet of this invention has the process of obtaining a pulverized material with the manufacturing method of the said pulverized material, and the process of manufacturing a tablet using the powder composition containing the obtained pulverized material.

(Powder composition)
The powder composition contains a pulverized product obtained by the method for producing a pulverized product of the present invention.
The powder composition may be a pulverized product alone or may contain other components (hereinafter also referred to as “optional components for tablets”).

(Optional ingredients for tablets)
The optional ingredients for tablets are not particularly limited, and the ingredients blended in tablets can be usually contained. Examples of optional components for tablets include excipients such as binders and disintegrants; lubricants; flavors; and flavoring agents such as sweeteners and acidulants.
Examples of the binder include starch, pregelatinized starch, sucrose, gelatin, gum arabic powder, methylcellulose, carmellose, carmellose calcium, carmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, pullulan, dextrin and the like. .
Examples of the disintegrant include crospovidone, carboxymethylcellulose calcium, and low-substituted hydroxypropylcellulose.
Examples of other excipients include lactose, fructose, corn starch, talc, crystalline cellulose (such as Avicel), powdered sugar, mannitol, erythritol, sorbitol, calcium carbonate, L-cysteine, and the like.
Examples of the lubricant include sodium lauryl sulfate, magnesium stearate, calcium stearate, polyethylene glycol, talc, stearic acid, and sucrose fatty acid ester.
Examples of the fragrances include menthol, limonene, plant essential oil (mint oil, mint oil, lychee oil, orange oil, lemon oil, etc.) and the like.
Examples of the sweetener include saccharin sodium, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, sucralose and the like.
Examples of the acidulant include citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, and salts thereof.
The arbitrary component for tablets may be used individually by 1 type, and may be used in combination of 2 or more type.

  Although content of the arbitrary component for tablets is not particularly limited, it is preferably 0 to 70% by mass with respect to the total mass of the tablet.

In the powder composition, all or a part of the constituent materials may be granulated or may not be granulated. Since the component (A) in the powder composition is granulated, the dissolution rate is improved and the fluidity is improved. Therefore, all or part of the powder composition of the present invention is granulated. It is preferable.
When a part of the powder composition is granulated, the granulated product (hereinafter also referred to as granulated particles) preferably contains the pulverized product.

The step of producing a tablet includes, for example, a granulation step of granulating the pulverized product to obtain granulated particles, a second mixing step of preparing a powder composition containing the granulated particles, and granulated particles. It is preferable to have a tableting step of tableting the powder composition.
Hereinafter, each process will be described in more detail.

<Granulation process>
The granulation step is a step of granulating the pulverized product into granulated particles.
Various granulation methods can be used as the granulation step, and known granulation methods can be used except that the pulverized product is used.
As the granulation method, either a dry granulation method or a wet granulation method can be used.

Granulation by the dry granulation method can be performed by, for example, a dry compression method. Examples of the dry compression method include a method in which the pulverized product is compressed and granulated.
Granulation by the wet granulation method can be carried out, for example, by a method of granulating while adding an aqueous liquid containing a water-soluble polymer to the pulverized product.
In the present specification, the “water-soluble polymer” refers to a compound having a solubility in water at 20 ° C. of more than 1.3 g / 100 mL and a weight average molecular weight of 10,000 or more.
The kind of water-soluble polymer is not particularly limited, and examples thereof include polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, methyl cellulose, hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like.
Specific examples of the wet granulation method include a fluidized bed granulation method, a stirring granulation method, an extrusion granulation method, a rolling granulation method, and a kneading / crushing granulation.
Among these, the wet granulation method is preferable, and the fluidized bed granulation method or the stirring granulation method is particularly preferable.

The granulated particles produced by the fluidized bed granulation method can be produced by using, for example, the above-mentioned aqueous solution by using a stirring type fluidized granulator (for example, a multiplex manufactured by POWREC Co., Ltd. or a spira flow manufactured by FRONINT SANGYO Co., Ltd.) It can be carried out by granulating while spraying the liquid.
Production of granulated particles by the stirring granulation method, for example, using a stirring granulator (for example, a high speed mixer manufactured by Fukae Pautech Co., Ltd. or a high speed stirring granulator manufactured by Dalton Co., Ltd.) After stirring and kneading while spraying or dropping the aqueous liquid, it can be carried out by granulating using an extrusion granulator (for example, Dome Gran manufactured by Dalton Co., Ltd.).
The granulation conditions are not particularly limited, but it is preferable to carry out at a temperature lower than the melting point of the component (A). For example, when the component (A) is ibuprofen, granulation is preferably performed at a temperature lower than 65 ° C.

The content of the component (A) in the granulated particles is preferably from 30 to 97 mass%, more preferably from 40 to 95 mass%, still more preferably from 45 to 90 mass%, based on the total mass of the granulated particles. When the content of the component (A) in the granulated particles is equal to or higher than the lower limit, the tablet can be miniaturized and the dosing property tends to be good. If the content of the component (A) in the granulated particles is not more than the above upper limit value, granulation can be facilitated.
The granulated particles can further contain an optional ingredient for the tablet, if necessary, as long as the effects of the present invention are not impaired. By containing the optional components for the tablet, the granulated particles can easily improve the dissolution property and granulation property of the component (A).

<Second mixing step>
The second mixing step is a step of preparing a powder composition containing granulated particles, which is performed before tableting.
In the second mixing step, an optional component for tablets and a powder containing the component (A) pulverized in the pulverization step described above are mixed as necessary to obtain a mixture for tableting.
For mixing, a commonly used mixer can be used. Examples of the mixer include a Boule container mixer, a V-type mixer, and a ribbon mixer.
The mixing order is not particularly limited. For example, all the blended components may be charged into a mixer and mixed, or after mixing some components, other components are sequentially added thereto. And may be mixed.

<Tabletting process>
The tableting step is a step of tableting the powder composition.
In the tableting step, it is preferable to mix the pulverized product and an optional component for tablets (second mixing step), and tablet the resulting powder composition containing the granulated particles into tablets.
For tableting, a generally used tableting machine can be used. Examples of the tableting machine include a rotary tableting machine.
In the tableting step, tableting can be performed by compression molding 50 to 1500 mg, more preferably 150 to 500 mg of the powder composition. The tableting pressure in the compression molding is preferably 4-18 kN, more preferably 6-14 kN.

Tablets are obtained by tableting the powder composition, and the tablets contain the component (A).
The content of the component (A) in the tablet is preferably 30% by mass or more, more preferably 40% by mass or more, and further preferably 45% by mass or more with respect to the total mass of the tablet. When the content of the component (A) in the tablet is equal to or higher than the lower limit, the tablet can be miniaturized and the ingestibility tends to be good.
Although an upper limit is not specifically limited, It is supposed that it is 90 mass% or less.

  The tablets produced by the production method of the present invention can be used as antipyretic analgesics, cold medicines, hypnotics / sedatives, rhinitis medicines and the like. According to the production method of the present invention, since the drug dissolution property is good, the tablet size per tablet can be reduced, and the number of tablets at the time of taking once can be reduced. As a result, the burden at the time of taking can be reduced.

Hereinafter, the present invention will be described in more detail using examples, but the present invention is not limited to these examples.
The raw materials used in this example are as shown in <Used raw materials> below.

<Raw materials>
((A) component)
Ibuprofen: Trade name “Ibuprofen 25” (manufactured by Shiratori Pharmaceutical Co., Ltd.), average particle size of about 30 μm.
((B) component)
Water: Trade name “Japan Pharmacopoeia Purified Water” (manufactured by Kyoei Pharmaceutical Co., Ltd.).
(Optional ingredients for tablets)
Low-substituted hydroxypropyl cellulose (L-HPC): trade name “LH-31” (manufactured by Shin-Etsu Chemical Co., Ltd.), average particle size of about 40 μm.
Hydroxypropyl cellulose (HPC): trade name “HPC-SSL” (manufactured by Nippon Soda Co., Ltd.).
Sodium lauryl sulfate (SDS): trade name “SLS” (manufactured by Nikko Chemicals).
Crystalline cellulose: Trade name “Theolas UF-702” (manufactured by Asahi Kasei Chemicals Corporation).
Crospovidone: Trade name “Kollidon CL-SF” (manufactured by BASF).
Magnesium stearate: trade name “magnesium stearate” (manufactured by Taihei Chemical Industry Co., Ltd.).

<Manufacture of pulverized product>
[Example 1, water content 10%; -5.3 ° C ibuprofen water]
1350 g of ibuprofen and 150 g of water (20 ° C.) were mixed with a ribbon mixer (5 L, manufactured by Tokuju Kogaku Co., Ltd.) (primary mixing). The same mixing operation was further repeated 5 times to obtain an ibuprofen water mixed powder (primary mixture) having a water content of 10%. The obtained primary mixture was stored in a thermostatic chamber at −20 ° C. for 10 hours. The mixture is taken out from the temperature-controlled room, and is supplied at 14000 rpm (circumferential speed 7034 m / s) with a pin disk rotary impact pulverizer (Coroplex 160Z: manufactured by Hosokawa Micron Co., Ltd.) at a supply speed of ibuprofen of 250 g / min. For 15 minutes. The temperature of the mixture immediately before pulverization was −5.3 ° C.

(Moisture content)
In this specification, the moisture content was calculated according to the following formula.
Moisture content (%) = (mass of water in mixed powder (g)) / (mass of mixed powder including water (g))

[Example 2, moisture content 18%; -5.4 ° C ibuprofen water]
The pulverization was performed in the same manner as in Example 1 except that 1230 g of ibuprofen and 270 g of water (20 ° C.) were used. The temperature of the mixture immediately before pulverization was −5.4 ° C.

[Example 3, moisture content 25%; -5.5 ° C ibuprofen water]
Grinding was carried out in the same manner as in Example 1 except that 1125 g of ibuprofen and 375 g of water (20 ° C.) were used. The temperature of the mixture immediately before pulverization was −5.5 ° C.

[Example 4, water content 18%; -2.5 ° C ibuprofen water]
A primary mixture having a water content of 18% was obtained in the same manner as in Example 2, and stored in a thermostatic chamber at -20 ° C for 10 hours. The mixture was taken out from the temperature-controlled room and ground in the same manner as in Example 1 except that the mixture was left at room temperature until the temperature of the mixture reached −2.5 ° C. The temperature of the mixture immediately before pulverization was −2.5 ° C.

[Comparative Example 1, water content 10%; ibuprofen water at 20 ° C.]
Similar to Example 1, a primary mixture of ibuprofen water having a water content of 10% was obtained. The obtained primary mixture was pulverized for 15 minutes in the same manner as in Example 1 without storing it in a thermostatic chamber at -20 ° C. The temperature of the mixture immediately before pulverization was 20 ° C.

[Comparative Example 2, moisture content 15%; ibuprofen water at 20 ° C.]
The pulverization was performed in the same manner as in Comparative Example 1 except that 1275.5 g of ibuprofen and 224.5 g of water (20 ° C.) were used. The temperature of the mixture immediately before pulverization was 20 ° C.

[Comparative Example 3, water content 20%; ibuprofen water at 20 ° C.]
The pulverization was performed in the same manner as in Comparative Example 1 except that 1200 g of ibuprofen and 300 g of water (20 ° C.) were used. The temperature of the mixture immediately before pulverization was 20 ° C.

[Comparative Example 4, water content 30%; 20 ° C. ibuprofen water]
Grinding was conducted in the same manner as in Comparative Example 1 except that 1049.7 g of ibuprofen and 450.3 g of water (20 ° C.) were used. The temperature of the mixture immediately before pulverization was 20 ° C.

[Comparative Example 5, moisture content 0%; -5.2 ° C ibuprofen]
8000 g of ibuprofen was stored in a thermostatic chamber at −20 ° C. for 10 hours. The powder was taken out from the temperature-controlled room and ground in the same manner as in Example 1. The temperature of the mixture immediately before pulverization was −5.2 ° C.

[Comparative Example 6, water content 30%; -5.1 ° C ibuprofen water]
This was pulverized in the same manner as in Example 1 except that 1049.7 g of ibuprofen and 450.3 g of water (20 ° C.) were used. The temperature of the mixture immediately before pulverization was −5.1 ° C.

[Comparative Example 7, water content 18%; 4.1 ° C. ibuprofen water]
A primary mixture having a water content of 18% was obtained in the same manner as in Example 2, and stored in a thermostatic chamber at -20 ° C for 10 hours. The mixture was taken out from the temperature-controlled room and ground in the same manner as in Example 1 except that the mixture was left at room temperature until the temperature of the mixture reached 4.1 ° C. The temperature of the mixture immediately before pulverization was 4.1 ° C.

[Reference Example 1, water content 15%; -5.4 ° C ibuprofen L-HPC water]
91.2 g of ibuprofen, 364.5 g of low-substituted hydroxypropyl cellulose, and 224.3 g of water (20 ° C.) were mixed with a ribbon mixer (5 L, manufactured by Tokuju Kogakusho Co., Ltd.). The same mixing operation was further repeated 7 times to obtain a primary mixture of ibuprofen L-HPC water having a water content of 15%. The obtained primary mixture was stored in a thermostatic chamber at −20 ° C. for 10 hours. The mixture was taken out from the temperature-controlled room and ground in the same manner as in Example 1. The temperature of the mixture immediately before pulverization was −5.4 ° C.

<Evaluation of adhesion to equipment>
After pulverizing continuously for 15 minutes under the conditions described in each example, the powder that weakly adhered to the inside of the pulverizer was lightly dropped with a brush, and the degree of adhesion of the powder adhered to the pins and the casing was visually confirmed. . Evaluation was performed according to the following evaluation criteria. In addition, the space | interval of a pin is 5 mm. The results are shown in Tables 1-2.
(Evaluation criteria)
(Double-circle): A fixed thing is not recognized.
○: Although fixed, there is a gap between the pins, and pulverization can be continued.
X: Between the pin and the pin, the space in the casing is filled, and the powder cannot be supplied.

<Average particle size>
The volume average particle size (μm) was measured using LS13 320 (product name) manufactured by Beckman Coulter (measurement condition: dry powder module, required time 20 seconds).

<Manufacture of granulated particles, manufacture of tablets>
[Example 5]
The pulverized product obtained in Example 2 was dried with a shelf dryer at 50 ° C. for 12 hours. The dried ibuprofen (650 g) was granulated by spraying 628.6 g of a binding solution (7% HPC-SSL, 7% sodium lauryl sulfate aqueous solution) with a fluidized bed granulator (Multiplex MP-01 (manufactured by Paulek)). The obtained granulated particles 195.0 g, crystalline cellulose 158.5 g, crospovidone 12.5 g, and magnesium stearate 1.3 g are mixed in a plastic bag, and the tableting pressure is 6.5 kN so that one tablet is 139 mg. The tablet was tableted using CLUX 3L (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain a tablet having an ibuprofen content of 47% by mass. One tablet obtained was evaluated in a dissolution test.

[Reference Example 2]
Using 650 g of unpulverized ibuprofen (average particle size 30 μm), fluidized bed granulation, mixing and tableting were conducted in the same manner as in Example 5 to obtain a tablet with an uncrushed ibuprofen content of 47% by mass. Obtained. One tablet obtained was evaluated in a dissolution test.

[Reference Example 3]
1500 g of the pulverized product of ibuprofen and low-substituted hydroxypropylcellulose described in Reference Example 1 was dried at 50 ° C. for 12 hours using a shelf dryer. 800 g of the dried pulverized product was granulated by spraying 1366 g of a binding liquid (6.0% HPC-SSL, 4.8% mannitol aqueous solution) with a fluidized bed granulator (Multiplex MP-01 (manufactured by Paulek)). 500 g of the obtained granulated particles, 523.8 g of crystalline cellulose, and 0.9 g of magnesium stearate are mixed in a plastic bag, and compressed into a tablet of 225 mg. A tablet with 29% ibuprofen content in the tablet is obtained. Obtained. One tablet obtained was evaluated in a dissolution test.

<Dissolution test>
In the dissolution test, according to the dissolution test method stipulated in the 17th revised Japanese Pharmacopoeia, the dissolution test was measured using the first solution, the paddle method, 50 rpm, and the dissolution amount 10 minutes after the start of the test was measured. The elution rate was calculated. Evaluation was performed according to the following evaluation criteria. The results are shown in Table 3.
(Evaluation criteria)
A: Elution rate of 35% or more.
○: Elution rate of 20% or more and less than 35%.
X: Elution rate is less than 20%.

  As shown in Table 1, in Examples 1 to 4 to which the production method of the present invention was applied, the adhesion state after 15 minutes of pulverization was “◎” or “◯”, and the adhesion of powder to the pulverizer could be suppressed. I found out. On the other hand, as shown in Tables 1 and 2, Comparative Examples 1 to 4 having a pre-grinding temperature of 20 ° C., Comparative Example 5 not containing the component (B), and the mass% of the component (B) are outside the scope of the present invention. In Comparative Example 6 and Comparative Example 7 where the pre-grinding temperature was 4.1 ° C., the adhesion state after 15 minutes of pulverization was “x”, and pulverization could not be continued continuously for 15 minutes or more. . In Reference Example 1 containing an excipient in addition to the component (A) and the component (B), the adhesion state after 15 minutes of pulverization was “◎”, but from the powders obtained in Examples 1 to 4 Also, the particle size after pulverization was large.

  As shown in Table 3, in Example 5 to which the production method of the present invention was applied, it was found that the dissolution property was “◎” and the drug dissolution property was good. On the other hand, in Reference Example 2 prepared without pulverizing the component (A) and Reference Example 3 in which the content of the component (A) in the tablet was less than 30% by mass, the dissolution property was “◯”.

  From these results, it was found that according to the present invention, the adhesion of the powder to the pulverizer can be suppressed, and the drug dissolution property can be improved.

Claims (5)

The mixture containing the following component (A) and component (B) is pulverized, and the mixture is the component (B) / (the component (A) + the component (B)) × 100. The manufacturing method of the ground material whose mass percentage of the said (B) component represented is 5-25 mass%.
Component (A): a poorly water-soluble drug having a melting point of 250 ° C. or lower.
(B) Component: Water of 0 ° C. or less.   The method for producing a pulverized product according to claim 1, wherein the pulverization is performed using a pin disk rotary impact pulverizer.   The said mixture WHEREIN: Content of the component except the said (A) component and the said (B) component is manufacture of the ground material of Claim 1 or 2 which is 2 mass% or less with respect to the total mass of the said mixture. Method.   The method for producing a pulverized product according to any one of claims 1 to 3, wherein the component (A) is one or more selected from ibuprofen and ketoprofen.   It has the process of obtaining a ground material with the manufacturing method of the ground material as described in any one of Claims 1-4, and the process of manufacturing a tablet using the powder composition containing the obtained ground material. A method for producing a tablet.