JP2009089982A - Method of granular material for making tablets - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method of granular materials for making tablets, where no obstacle can occur to the tablet making process but it is easy despite no addition of any lubricant, and to also provide the tablet made by this method. <P>SOLUTION: The method of granular materials for making tablets is characterized in that in the operations to granular materials for making tablets, the powder of drugs or mixed power of drugs and additives likely to obstruct the tablet making process is granulated, and then the surfaces of the granular drugs or of the drugs and additives are coated with a high molecular membrane agent. Also, the tablet made of the granular material obtained from this method using no lubricant is provided. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a granulation method for providing a granulated product that can be tableted without using a lubricant, and a tablet produced using the method.

When manufacturing a tablet of a drug, a tableting trouble (sticking or picking) may occur.
For example, the sticking phenomenon is often caused by the nature of the drug, and occurs when the drug distributed on the granulated surface contacts and adheres to the tableting mortar. Further, in recent solid preparations, the granulated particle size has shifted to fine particles, and there is a concern that the occurrence of sticking tends to be promoted.
One of the methods for preventing this tableting failure is to add a lubricant to the drug or granule before tableting to impart lubricity and prevent the drug from adhering to the mortar of the tableting machine. It has become established.
The fluidized bed granulation, which is the most widely used for tableting, will be described as the granulation mechanism. The binder mist sprayed from the nozzle to the raw material fine particles in the fluidized state randomly adheres to the particle surface. When the fine particles are adhered and aggregated repeatedly through mist and the particle growth (granulation) gradually progresses to the target particle diameter, the granulation operation is terminated and the process proceeds to the drying step.
Here, the individual granulated particles will be described. The binder that has adhered to the surface of the raw material particles and contributed to the mutual adhesion of the particles will be distributed in the interior of the granulated product. The proportion of binder distributed is reduced. Therefore, drug particles having a low adhesion / coating ratio of the binder are distributed more on the surface of the granulated product. For this reason, since it contacts directly with metal parts, such as a tableting machine mortar, the lubricant is used in order to reduce adhesiveness and adhesiveness and to prevent a tableting trouble.
Lubricants used for tableting include magnesium stearate, calcium stearate, hydrogenated oil, etc. Among them, magnesium stearate is most frequently used, and it is more lubricant than other lubricants. The effect is high and is the first choice of lubricant.
However, this lubricant, on the other hand, has a number of cases that cause problems in the quality of the preparation, such as 1) reduced tablet hardness, 2) dissolution delay, and 3) change in formulation. It is a lubricant that has a great impact on quality.

Depending on the use of the lubricant alone, the effect of preventing tableting problems may be insufficient. In such cases, the solution is mainly devised, or the combination of drugs, etc. and specific additives is devised. Patent Documents have disclosed a product obtained by coating a tablet containing a drug or a granule thereof coated with a polymer substance.
However, in any of these cases, the use of the lubricant is described in the specification or examples, and it is not intended to solve not only the tableting trouble but also the problems of the lubricant. .

JP 2007-137802 A JP 2006-143650 A Japanese Patent Laid-Open No. 9-143065 JP 2004-189653 A Japanese Patent Laid-Open No. 11-60476 Japanese Patent No. 2516408 Japanese Patent Laid-Open No. 10-77224

  An object of the present invention is to provide a granulated product that can be easily tableted without causing any tableting troubles even if tableting is performed without using a lubricant, in order to solve the above-mentioned problems of the lubricant. And a tablet obtained by tableting the granulated product.

  The present inventors diligently studied to solve the above problems. As a result, it was found that tableting can be performed without adding a lubricant by spraying the drug using a solution of a water-soluble polymer or a suspension of a water-insoluble polymer. Therefore, the present inventors have made further studies based on the findings and have completed the present invention.

That is, according to the present invention, the following (1) to (5) can be provided.
(1) In the granulation operation of a granulated product for tableting, a powder of a drug that easily develops a tableting disorder or a mixed powder of the drug and an additive is granulated, and the surface of the granulated product is polymerized. A method for granulating a granulated product for tableting, which can be tableted without adding a lubricant.
(2) The granulation method of a granulated product for tableting according to the above (1), wherein the polymer film agent is water-soluble or water-insoluble.
(3) The polymer film agent is hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, aminoalkyl methacrylate copolymer (E, RS), methacrylic acid copolymer (L, LD, S), Metrolose, and hydroxypropylmethylcellulose. The granulation method of a granulated product for tableting according to the above (1), which is one or more selected from the group consisting of phthalate, hydroxypropylmethylcellulose acetate succinate and ethylcellulose.
(4) The granulation method for tableting granules according to the above (1), (2) or (3), wherein the tableting granules have an average particle size of 30 μm to 500 μm.
(5) A granulated product obtained by granulating a powder of a drug that easily develops a tableting disorder or a mixed powder of the drug and an additive, and coating the surface of the granulated product with a polymer film agent. Tablets obtained by tableting without using.

  In the present invention, by granulating a powder of a drug that easily develops a tableting disorder or a mixed powder of the drug and an additive, and covering the surface of the granulated product with a polymer film agent, 2) granulation The surface of the product can be smoothed to improve the fluidity, 1) the particles with strong adhesion are concealed, 2) the surface of the granulated material is smoothed to improve the fluidity, and 3) the granules are bonded to each other. Improves the tablet hardness. That is, according to the present invention, it is possible to avoid tableting troubles without using a lubricant.

Examples of drugs that are likely to cause tableting disorders used in the present invention include ibuprofen, ketoprofen, loxoprofen sodium, aminopyrine, sulpyrine, ephedrine hydrochloride, thiaramide hydrochloride, doxycycline hydrochloride, pioglitazone hydrochloride, promethazine hydrochloride, lincomycin hydrochloride, atorvastatin calcium , Pranlukast hydrate, rebamipide, ascorbic acid, tranexamic acid and the like.
The preferable average particle diameter of these drugs is 0.5 μm to 500 μm, and more preferably 1 μm to 200 μm.

In the present invention, a specific method for granulating a mixed powder of a drug and an additive and coating the surface of the granulated product with a polymer film agent is not particularly difficult. Operate with a small fluidizing air volume so that the particle concentration in the (spray zone) is high (excessive air volume soars above the nozzle and does not adhere to the binder mist) and then granulates with the fluidized air volume grown. By gradually increasing the operating air flow suitable for the flow state of the material, the amount of heat required to evaporate the water added by spraying in the latter half of the process is relatively increased. Thus, an operation of coating the surface of the granulated product while suppressing particle growth due to wetting may be performed.
In addition, the water-soluble drug may be oozed out into the binder solution mist added by spraying and adhered to the surface of the raw material particles. Therefore, an intermediate drying step is appropriately incorporated to prevent the drug from bleeding out.

Preferred examples of the polymer film agent used in the present invention include water-soluble polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, methylcellulose, polyvinylpyrrolidone, and polyvinyl alcohol. Among them, hydroxypropylmethylcellulose and polyvinyl Alcohol and the like are preferable.
The use amount of these polymer film agents is preferably 1% to 30%, more preferably 3% to 20% of the total weight of the tablet.

In addition, as additives in the preparation that can be used in the present invention, other additives such as excipients, disintegrants, binders, and corrigents that are commonly used can be used.
Examples of excipients include lactose, crystalline cellulose, corn starch, potato starch, partially pregelatinized starch, D-mannitol, sucrose, sucrose, glucose, low-substituted hydroxypropylcellulose, and the like. A part or all of these excipients may be dissolved, dispersed, or suspended in the binder solution.
Examples of binders include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, aminoalkyl methacrylate copolymer (E, RS), methacrylic acid copolymer (L, LD, S), metroise and hydroxypropyl methylcellulose phthalate, hydroxy Examples thereof include propylmethylcellulose acetate succinate and ethylcellulose aqueous dispersion.
Examples of the disintegrant include carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, crospovidone, low-substituted hydroxypropyl cellulose, and partially pregelatinized starch.

Example 1
1000.0 g of ibuprofen having an average particle size of 30 μm and 16.0 g of light anhydrous silicic acid were charged into a fluidized bed granulator (manufactured by Pauleck: MP-01 type), and hydroxypropylmethylcellulose (TC-5: EW, manufactured by Shin-Etsu Chemical) A solution obtained by dissolving 200.0 g in 1800.0 g of purified water was sprayed for 310 minutes. Spraying was performed for 120 minutes from the start of spraying under the condition that the particle diameter of the granulated product increased, and after 120 minutes, spraying was performed under the condition that the surface was coated so that the particle diameter did not increase. The obtained granulated product was dried and sieved with a JIS 24 mesh sieve. The obtained sized product was compression-molded with a diameter of 8 mm using a rotary tableting machine (manufactured by Kikusui Seisakusho: VIRGO type) without adding a lubricant to obtain tablets.
[Components] [Weight per mg of 201 mg (mg)]
Ibuprofen 161.29
Light anhydrous silicic acid 6.45
Hydroxypropyl methylcellulose 32.26

Example 2
800.0 g of ibuprofen having an average particle size of 40 μm and 16.0 g of light anhydrous silicic acid were introduced into a fluidized bed granulator (manufactured by Paul W: MP-01 type), and 60.0 g of methylcellulose (SM-4, manufactured by Shin-Etsu Chemical) was added. A solution obtained by suspending 120.0 g of corn starch in a solution dissolved in 1020.0 g of purified water was sprayed for 160 minutes. The spraying was performed for 60 minutes from the start of spraying under the condition that the particle diameter of the granulated product increased, and after 60 minutes, the spraying was performed under the condition that the surface was coated so that the particle diameter did not increase. The obtained granulated product was dried and sieved with a JIS 24 mesh sieve. The obtained sized product was compression-molded with a diameter of 8 mm using a rotary tableting machine (manufactured by Kikusui Seisakusho: VIRGO type) without adding a lubricant to obtain tablets.
[Components] [Weight per 200 mg tablet (mg)]
Ibuprofen 160.64
Light anhydrous silicic acid 3.21
Methylcellulose 12.05
Corn starch 24.10

Example 3
Partially pregelatinized starch (PCS, manufactured by Asahi Kasei Chemicals) 40.0 g was mixed with 332.0 g of the granulated product obtained in Example 2, and a rotary tableting machine (manufactured by Kikusui Seisakusho: VIRGO) was added without adding a lubricant. And a tablet was obtained by compression molding with a diameter of 8 mm.
[Components] [Weight per 200 mg tablet (mg)]
Ibuprofen 143.37
Light anhydrous silicic acid 2.87
Methylcellulose 10.75
Corn starch 21.505
Partially pregelatinized starch 21.505

Example 4
800.0 g of ibuprofen having an average particle size of 40 μm and 16.0 g of light anhydrous silicic acid were charged into a fluidized bed granulator (manufactured by Paul W: MP-01 type), and polyvinyl alcohol (EG-05, manufactured by Nippon Synthetic Chemical Industry) 60 In a solution obtained by dissolving 0.0 g in 1020.0 g of purified water, a solution in which 120.0 g of corn starch was suspended was sprayed for 180 minutes. Spraying was performed for 50 minutes from the start of spraying under the condition that the particle diameter of the granulated product was increased, and after 50 minutes, spraying was performed under the condition that the surface was coated so that the particle diameter did not increase. The obtained granulated product was dried and sieved with a JIS 24 mesh sieve. The obtained sized product was compression-molded with a diameter of 8 mm using a rotary tableting machine (manufactured by Kikusui Seisakusho: VIRGO type) without adding a lubricant to obtain tablets.
[Components] [Weight per tablet (mg)]
Ibuprofen 160.64
Light anhydrous silicic acid 3.21
Polyvinyl alcohol 12.05
Corn starch 24.10

Example 5
800.0 g of ibuprofen having an average particle size of 30 μm and 16.0 g of light anhydrous silicic acid were charged into a fluidized bed granulator (manufactured by Paulek: MP-01 type), and polyvinyl alcohol (EG-05, manufactured by Nippon Synthetic Chemical Industry) 60 A solution obtained by suspending 240 g of corn starch in a solution obtained by dissolving 0.0 g in 1020.0 g of purified water was sprayed for 170 minutes. Spraying was performed for 30 minutes from the start of spraying under the condition that the particle diameter of the granulated product increased, and after 30 minutes, spraying was performed under the condition that the surface was coated so that the particle diameter did not increase. The obtained granulated product was dried and sieved with a JIS 24 mesh sieve. The obtained sized product was compression-molded with a diameter of 8 mm using a rotary tableting machine (manufactured by Kikusui Seisakusho: VIRGO type) without adding a lubricant to obtain tablets.
[Components] [Weight per 200 mg tablet (mg)]
Ibuprofen 143.37
Light anhydrous silicic acid 2.87
Polyvinyl alcohol 10.75
Corn starch 43.01

Example 6
Loxoprofen sodium (500.0 g) having an average particle size of 55 μm and light anhydrous silicic acid (16.0 g) were charged into a fluidized bed granulator (manufactured by Paulek: MP-01 type) and polyvinyl alcohol (EG-05, manufactured by Nippon Synthetic Chemical Industry). A solution obtained by suspending 500 g of corn starch in a solution obtained by dissolving 60.0 g in 1020.0 g of purified water was sprayed for 180 minutes. Spraying was performed for 30 minutes from the start of spraying under the condition that the particle diameter of the granulated product increased, and after 30 minutes, spraying was performed under the condition that the surface was coated so that the particle diameter did not increase. In addition, after 90 minutes, in order to suppress the penetration of loxoprofen sodium into the aqueous binder, the intermediate granulation step of 10 minutes was performed three times, and the obtained granulated product was dried, and a JIS24 mesh sieve was obtained. And sieved. The obtained sized product was compression-molded with a diameter of 8 mm using a rotary tableting machine (manufactured by Kikusui Seisakusho: VIRGO type) without adding a lubricant to obtain tablets.
[Components] [Weight per 200 mg tablet (mg)]
Loxoprofen sodium 92.94
Light anhydrous silicic acid 2.97
Polyvinyl alcohol 11.15
Corn starch 92.94

Example 7
269.0 g of the sized product obtained in Example 2 was mixed with 50.0 g of low-substituted hydroxypropylcellulose (L-HPC: LH-11, manufactured by Shin-Etsu Chemical Co., Ltd.), and a rotary punching was carried out without adding a lubricant. Using a tablet (manufactured by Kikusui Seisakusho: VIRGO type), compression molding was performed with a diameter of 8 mm to obtain tablets.
[Components] [Weight per 200 mg tablet (mg)]
Loxoprofen sodium 78.37
Light anhydrous silicic acid 2.51
Polyvinyl alcohol 9.40
Corn starch 78.37
Low substituted hydroxypropylcellulose 31.35

Example 8
800.0 g of rebamipide having an average particle size of 6 μm and 16.0 g of light anhydrous silicic acid were charged into a fluidized bed granulator (manufactured by POWREC: MP-01 type), and polyvinyl alcohol (EG-05, manufactured by Nippon Synthetic Chemical Industry) 60 A solution obtained by suspending 120 g of corn starch in a solution obtained by dissolving 0.0 g in 1020.0 g of purified water was sprayed for 180 minutes. Spraying was performed for 70 minutes from the start of spraying under the condition that the particle diameter of the granulated product increased, and after 70 minutes, spraying was performed under the condition that the surface was coated so that the particle diameter did not increase. The obtained granulated product was dried and sieved with a JIS 24 mesh sieve. 120 g of partially pregelatinized starch (PCS, manufactured by Asahi Kasei Chemicals Co., Ltd.) was mixed with the obtained sized product, and a rotary tableting machine (manufactured by Kikusui Seisakusho: VIRGO type) was used without adding a lubricant. The tablet was obtained by compression molding.
[Components] [Weight per 200 mg tablet (mg)]
Rebamipide 143.37
Light anhydrous silicic acid 2.87
Polyvinyl alcohol 10.75
Corn starch 21.505
Partially pregelatinized starch 21.505

Example 9
800.0 g of pranlukast hydrate having an average particle size of 10 μm and 16.0 g of light anhydrous silicic acid were introduced into a fluidized bed granulator (manufactured by POWREC: MP-01 type), and polyvinyl alcohol (EG-05, Nippon Gosei Co., Ltd.). A solution obtained by suspending 120 g of corn starch was sprayed for 160 minutes in a solution obtained by dissolving 60.0 g of Chemical Industries) in 1020.0 g of purified water. Spraying was performed for 90 minutes from the start of spraying under the condition that the particle diameter of the granulated product was increased, and after 90 minutes, spraying was performed under the condition that the surface was coated so that the particle diameter did not increase. The obtained granules were dried and sieved with a JIS 24 mesh sieve. Mix 60g of crospovidone (Polyplaston XL, manufactured by IPSP Japan) to the resulting granulated product, and add a rotary tableting machine (Kikusui Seisakusho: VIRGO type) without adding a lubricant. Used, compression-molded with a diameter of 8 mm to obtain tablets.
[Components] [Weight per 200 mg tablet (mg)]
Pranlukast Hydrate 151.52
Light anhydrous silicic acid 3.03
Polyvinyl alcohol 11.36
Corn starch 22.73
Crospovidone 11.36

Example 10
300.0 g of pioglitazone hydrochloride with an average particle size of 20 μm and 16.0 g of light anhydrous silicic acid were charged into a fluidized bed granulator (manufactured by POWREC: MP-01 type), and polyvinyl alcohol (EG-05, manufactured by Nippon Synthetic Chemical Industry) A solution obtained by suspending 600 g of corn starch in a solution obtained by dissolving 60.0 g in purified water 1020.0 g was sprayed for 200 minutes. Spraying was performed for 90 minutes from the start of spraying under the condition that the particle diameter of the granulated product was increased, and after 90 minutes, spraying was performed under the condition that the surface was coated so that the particle diameter did not increase. The obtained granulated product was dried and sieved with a JIS 24 mesh sieve. 60 g of low-substituted hydroxypropyl cellulose (L-HPC: LH-11, manufactured by Shin-Etsu Chemical Co., Ltd.) is mixed with the obtained sized product, and a rotary tableting machine (manufactured by Kikusui Seisakusho: VIRGO) is added without adding a lubricant. Type) and compression-molded with a diameter of 8 mm to obtain tablets.
[Components] [Weight per 200 mg tablet (mg)]
Pranlukast hydrate 57.92
Light anhydrous silicic acid 3.09
Polyvinyl alcohol 11.58
Corn starch 115.83
Low substituted hydroxypropylcellulose 11.58

Example 11
150.0 g of atorvastatin calcium having an average particle diameter of 2 μm and 16.0 g of light anhydrous silicic acid were charged into a fluidized bed granulator (manufactured by Paul W: MP-01 type), and polyvinyl alcohol (EG-05, manufactured by Nippon Synthetic Chemical Industry). A solution obtained by suspending 750 g of corn starch in a solution obtained by dissolving 60.0 g in purified water 1020.0 g was sprayed for 230 minutes. Spraying was performed for 90 minutes from the start of spraying under the condition that the particle diameter of the granulated product was increased, and after 90 minutes, spraying was performed under the condition that the surface was coated so that the particle diameter did not increase. The obtained granulated product was dried and sieved with a JIS 24 mesh sieve. 60 g of low-substituted hydroxypropyl cellulose (L-HPC: LH-11, manufactured by Shin-Etsu Chemical Co., Ltd.) is mixed with the obtained sized product, and a rotary tableting machine (manufactured by Kikusui Seisakusho: VIRGO) is added without adding a lubricant. Type) and compression-molded with a diameter of 8 mm to obtain tablets.
[Components] [Weight per 200 mg tablet (mg)]
Atorvastatin calcium 28.96
Light anhydrous silicic acid 3.09
Polyvinyl alcohol 11.58
Corn starch 144.79
Low substituted hydroxypropylcellulose 11.58

Comparative Example 1
800.0 g of ibuprofen having an average particle size of 40 μm, 240 g of corn starch and 16.0 g of light anhydrous silicic acid were charged into a fluidized bed granulator (manufactured by POWREC: MP-01 type), and hydroxypropylmethylcellulose (TC-5: EW, A solution prepared by dissolving 30.0 g (manufactured by Shin-Etsu Chemical) in 570.0 g of purified water was sprayed for 110 minutes. The obtained granulated product was dried and sieved with a JIS 24 mesh sieve. The obtained sized product was compression-molded with a diameter of 8 mm using a rotary tableting machine (manufactured by Kikusui Seisakusho: VIRGO type) without adding a lubricant to obtain tablets.
[Components] [Weight per 200 mg tablet (mg)]
Ibuprofen 147.33
Light anhydrous silicic acid 2.95
Hydroxypropyl methylcellulose 5.52
Corn starch 44.20

［スティッキング発生レベルスコア］
０：無、１：わずかに付着、２：薄く付着、３：少し付着、４：付着、
５：完全付着
表１に示したように、本発明に係る実施例の製造方法は、滑沢剤を添加しなくても、スティッキングを発生することなく、連続打錠が可能な顆粒が得られることが明らかであった。 [Test Example 1] (Sticking occurrence level)
Table 1 shows the level of occurrence of sticking when tableting was performed according to a conventional method for the examples and comparative examples.

[Sticking occurrence level score]
0: None, 1: Slightly adhered, 2: Thinly adhered, 3: Slightly adhered, 4: Adhered
5: Complete adhesion As shown in Table 1, the production method of the example according to the present invention can obtain granules capable of continuous tableting without causing sticking without adding a lubricant. It was clear.

  According to the present invention, it is possible to obtain a granulated product for tableting that can be tableted continuously without adding a lubricant in a tablet containing a drug with high adhesion and aggregation properties. The effect of magnesium stearate on drugs can be avoided. Therefore, it is possible to provide the medical site with excellent quality tablets that maintain the stability of the drug and have no tableting trouble.

Claims (5)

  In the granulation operation of a granulated product for tableting, a powder of a drug that easily develops a tableting disorder or a mixed powder of the drug and an additive is granulated, and the surface of the granulated product is coated with a polymer film agent. A method for granulating a granulated product for tableting which can be tableted without adding a lubricant.   The granulation method for a granulated product for tableting according to claim 1, wherein the polymer film agent is water-soluble or water-insoluble.   Polymer film agent is hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, aminoalkyl methacrylate copolymer (E, RS), methacrylic acid copolymer (L, LD, S), metroise and hydroxypropylmethylcellulose phthalate, hydroxy The granulation method for a granulated product for tableting according to claim 1, wherein the granulated product for tableting is one or more selected from the group consisting of propylmethylcellulose acetate succinate and ethylcellulose.   The granulation method for tableting granules according to claim 1, 2 or 3, wherein the granulated product for tableting has an average particle size of 30 µm to 500 µm.   Using a lubricant, granulate a powder of a drug that easily develops a tableting disorder or a mixed powder of the drug and an additive, and coat the surface of the granulated product with a polymer film agent. Tablets obtained by tableting without any problems.