JP2017210478A - Stable production method of high drug content compressed tablet - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide technical means useful for significantly improving friability of a high drug content tablet for stable industrial production of the tablet.SOLUTION: A tablet contains drugs being acetaminophen and tramadol hydrochloride of 85.0 to 95.0 wt.% based on the total uncoated tablet weight, and further contains a binder being a polyvinyl alcohol of 0.5 to 5.0 wt.% based on the total uncoated tablet weight. Preferably, the tablet further contains a disintegrator being carmellose calcium of 2.0 to 10.0 wt.% based on the total uncoated tablet weight.SELECTED DRAWING: None

Description

  The present invention presents a detailed method for producing tablets with high dissolution while improving the moldability of tablets with high drug content (especially those containing acetaminophen and tramadol hydrochloride as drugs). To do.

  Acetaminophen (generic name) is an aniline antipyretic analgesic whose chemical name is described as p-hydroxyacetanilide. In addition, tramadol hydrochloride (generic name) is an opioid analgesic whose chemical name is (1R, 2R) -2-[(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol hydrochloride It is an agent. Combination tablets of acetaminophen / tramadol hydrochloride are widely provided in the medical field as useful therapeutic agents for chronic pain / post-extraction pain (see Non-Patent Document 1, etc.).

Regarding the combination tablet of acetaminophen / tramadol hydrochloride, the formulation and production method of the preparation are introduced in the following prior patent documents 1, 2 and the like.
In Example 6 and Comparative Example 6 of Patent Document 1, a compressed tablet containing a granulated product containing acetaminophen and tramadol hydrochloride, granulated using hydroxypropylcellulose as a binder, is described and partially pregelatinized. It has been shown that the tablets of the examples containing starch, anhydrous calcium hydrogen phosphate, and the like can suppress the occurrence of tableting troubles. In US Pat. No. 6,057,056, a tablet with a bilayer composition containing acetaminophen and tramadol hydrochloride is described, which is shown to have a sustained release.
However, the technology for improving the friability of the acetaminophen / tramadol hydrochloride combination tablet is not disclosed enough information in the prior literature. Improvement of tablet friability is an important issue for stable industrial production of high-quality tablets.
Therefore, the present inventor aimed to develop a new technical means for remarkably improving the friability of a high drug content tablet.

Japanese Patent Laying-Open No. 2015-63521 Japanese Patent No. 5453280

"Tramset (registered trademark) combination tablet" pharmaceutical interview form revised in July 2015 (7th edition)

  The present invention provides a useful technical means for significantly improving the friability of a tablet in order to stably produce a drug-rich tablet industrially.

As a result of intensive studies to solve the above-mentioned problems, the present inventor has found that when polyvinyl alcohol as a binder is contained in a combination tablet of acetaminophen / tramadol hydrochloride which is a high drug content tablet, the tablet It has been found that the friability and hardness of the are significantly improved.
The inventor has conducted further intensive studies based on the findings, and has completed the present invention described below.

That is, the present invention relates to a tablet containing a high content drug and polyvinyl alcohol, and preferred forms are described in (1) to (6) below.
(1) An uncoated tablet containing 85.0 to 95.0% by weight of a drug that is acetaminophen and tramadol hydrochloride based on the total weight of the uncoated tablet, and further containing a binder that is polyvinyl alcohol.
(2) The uncoated tablet according to (1) above, which contains a binder in an amount of 0.5 to 5.0% by weight based on the total weight of the uncoated tablet.
(3) The uncoated tablet according to (1) or (2) above, containing 2.0 to 20.0% by weight of a disintegrant that is carmellose calcium based on the total weight of the uncoated tablet.
(4) The weight of the uncoated tablet is 380 to 420 mg, and the granulated product containing the drug is contained in 80.0% by weight or more based on the total weight of the uncoated tablet. The uncoated tablet described.
(5) A tablet in which the uncoated tablet according to any one of (1) to (4) is covered with a film coating layer.
(6) The raw material according to any one of (1) to (4) above, wherein a granulated product containing a drug is produced by a wet granulation method, and an uncoated tablet is produced by tableting with a compression pressure of 950 to 1300 kgf. A method of manufacturing a tablet.

  Since the drug-rich tablet of the present invention has an effect that the friability is remarkably improved, industrially stable production is possible, and a high-quality tablet can be provided to the medical field.

  Hereinafter, the formulation and manufacturing method of a tablet containing a high content drug and polyvinyl alcohol according to the present invention will be described in detail. However, the following description is an example for explaining the present invention, and is not intended to specifically limit the present invention to this description range.

<Tablet form>
The tablet of the present invention is mainly a compressed tablet, which is a plain tablet (refers to a tablet that is not covered with a film coating layer, a sugar coating layer, etc., and is formed by tableting, etc. The same shall apply hereinafter) or a plain tablet. It has a dosage form such as a tablet coated with a layer (film-coated tablet). The weight of the uncoated tablet is preferably in the range of 380 to 420 mg.
The shape of the tablet according to the present invention is not particularly limited, and any of round tablets {circular flat tablets (including corner locks, etc.), round R tablets (including corner locks, 2-stage R locks, etc.)}, deformed tablets, etc. However, it is preferably a deformed tablet.

<Physical properties of drugs>
The tablet of the present invention is a high drug content tablet characterized by a high drug content. Examples of the drug to be contained include acetaminophen and tramadol hydrochloride, and acetaminophen and tramadol hydrochloride are preferable. The drug contained in the tablet of the present invention is contained in the uncoated tablet in an amount of 85.0% by weight or more, preferably 85.0 to 95.0% by weight based on the total weight of the uncoated tablet.

<Polyvinyl alcohol>
The tablet according to the present invention contains polyvinyl alcohol, and polyvinyl alcohol can be used as a binder. Polyvinyl alcohol is contained in the uncoated tablet in an amount of 0.1% by weight or more, preferably 0.5 to 5.0% by weight, more preferably 0.8 to 4.0% by weight based on the total weight of the uncoated tablet. It is preferred that

<Pharmaceutical additives that can be used to produce tablets>
Examples of pharmaceutically acceptable pharmaceutical additives used in the manufacture of tablets according to the present invention include commonly used excipients, disintegrants, fluidizers, plasticizers, lubricants, corrigents, interfaces. Activators, colorants, coating agents and the like can be used.

<Excipient>
The excipient according to the present invention is selected from, for example, lactose hydrate, crystalline cellulose, anhydrous lactose, D-mannitol, corn starch, and the like, preferably crystalline cellulose. The excipient is preferably contained in the uncoated tablet in a range of 10.0% by weight or less based on the total weight of the uncoated tablet.

<Disintegrant>
Disintegrants according to the present invention include, for example, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, crystalline cellulose, sodium starch glycolate, light anhydrous It is selected from silicic acid and the like, and preferably carmellose calcium. The disintegrant is preferably contained in the uncoated tablet in an amount of 2.0 to 20.0% by weight, more preferably 4.0 to 15.0% by weight, based on the total weight of the uncoated tablet.

<Lubricant>
The lubricant according to the present invention is selected from, for example, magnesium stearate, calcium stearate, sodium stearyl fumarate, etc., preferably magnesium stearate. The lubricant is preferably contained in the uncoated tablet in the range of 0.1 to 3.0% by weight based on the total weight of the uncoated tablet.

<Coating agent>
The coating agent according to the present invention is selected from hypromellose, ethyl cellulose, ethyl cellulose dispersion, ethyl acrylate / methyl methacrylate copolymer dispersion, dimethylamino methacrylate / methyl methacrylate copolymer, and the like. The coating agent is preferably contained in the tablet in the range of 0.05 to 10.0% by weight based on the total weight of the tablet.

<Granulated material>
The tablet of the present invention preferably contains a drug-containing granulated product, and the granulated product is prepared by wet granulation using a solution containing polyvinyl alcohol, such as stirring granulation, fluidized bed granulation, spray drying granulation or the like. It can be produced by the grain method. The granulated product is preferably contained in the uncoated tablet in an amount of 85.0% by weight or more, more preferably 90.0 to 99.9% by weight, based on the total weight of the uncoated tablet. The granulated product can be a coated granulated product coated with a coating agent.

<Tablet production method>
The compressed tablet which is the tablet of the present invention can be produced by a general production method, for example, can be produced by the following production method.
First, a granulated product is produced by adding polyvinyl alcohol dissolved in water to a powder in which a drug substance, an excipient, a disintegrant and the like are mixed, and performing fluidized bed granulation. The obtained granulated product is sized (dry pulverization, etc.), mixed with a lubricant, etc., and compressed by a tableting machine to obtain tablets (plain tablets). Further, if desired, a film coating layer can be applied to the obtained uncoated tablet.
The punching pressure when the uncoated tablet of the present invention is tableted is 400 kgf or more, preferably 800 kgf or more, more preferably 950 to 1500 kgf, and still more preferably 950 to 1300 kgf.

  EXAMPLES The present invention will be described below with reference to examples and the like, but the present invention is not limited to these examples and the like.

Acetaminophen (manufactured by Iwaki Pharmaceutical) 390.0 g, tramadol hydrochloride (manufactured by perrigo) 45.0 g, crystalline cellulose (KG-802 / manufactured by Asahi Kasei) 19.8 g, sodium starch glycolate (manufactured by GLYCOLYS / ROQUETTE) ) 19.2 g of polyvinyl alcohol (EG-05PW / manufactured by Nippon Synthetic Chemical Co., Ltd.) in a fluid bed granulator (MP-01 model) by mixing 9.6 g of the powder in a plastic bag. A liquid dissolved in 500 g of purified water was sprayed and dried to granulate. The obtained granulated product was dry-pulverized by a granulator (Pauleck Co./Comil) and then mixed with 2.4 g of magnesium stearate (Taihei Chemical Industrial Co., Ltd.) in a plastic bag for 1 minute to obtain a tablet density. Was tableted with a pressure of 1060 kgf so as to be 1.10 mg / mm ³ to obtain a deformed tablet (major axis 16.0 mm, minor axis 7.8 mm, thickness 4.2 mm) with a mass of 405.0 mg.

[Comparative Example 1]
The polyvinyl alcohol of Example 1 was replaced with a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer (Type-F / manufactured by Nisshin Kasei Co., Ltd.), and the impact pressure was 1153 kgf so that the tablet density was 1.10 mg / mm ^3. A tablet was produced by the same formulation and production method as in Example 1 except that tableting was performed.

[Comparative Example 2]
The polyvinyl alcohol of Example 1 was replaced with hydroxypropylcellulose (SL / manufactured by Nippon Soda Co., Ltd.), and the tablet was compressed with a compression pressure of 1039 kgf so that the tablet density was 1.10 mg / mm ³ . Tablets were produced by the prescription / production method.

[Comparative Example 3]
The polyvinyl alcohol of Example 1 was replaced with pregelatinized starch (Amicol C / manufactured by Nissho Chemical Co., Ltd.), and Example 1 was used except that tableting was performed at a compression pressure of 1100 kgf so that the tablet density was 1.10 mg / mm ^3. Tablets were produced by the same formulation and production method.

[Comparative Example 4]
The polyvinyl alcohol of Example 1 was replaced with hydroxypropylmethylcellulose (TC-5M / manufactured by Shin-Etsu Chemical Co., Ltd.), and Example 1 was used except that tableting was performed at 1167 kgf so that the tablet density was 1.10 mg / mm ^3. Tablets were produced by the same formulation and production method.

The prescriptions of the tablets obtained in Example 1 and Comparative Examples 1 to 4 are listed in Table 1 below.

390.0 g of acetaminophen (manufactured by Iwaki Pharmaceutical Co., Ltd.), 45.0 g of tramadol hydrochloride (manufactured by perrigo), 23.4 g of carmellose calcium (ECG505 / manufactured by Gotoku Pharmaceutical Co., Ltd.), light anhydrous silicic acid (ADSOLIDER 101 / Freund Industries) 4.8 g of powder mixed in a plastic bag) in a fluidized bed granulator (manufactured by POWREC / MP-01), polyvinyl alcohol (EG-05PW / manufactured by Nippon Synthetic Chemical Co., Ltd.) 14. A solution obtained by dissolving 4 g in 400 g of purified water was sprayed and dried to granulate. The obtained granulated product was dry-pulverized by a granulator (Pauleck Co./Comil) and then mixed with 2.4 g of magnesium stearate (Taihei Chemical Industrial Co., Ltd.) in a plastic bag for 1 minute to obtain a tablet density. Was tableted with a compression pressure of 1060 kgf so as to be 1.10 mg / mm ³ to obtain a deformed tablet (major axis 16.0 mm, minor axis 7.8 mm, thickness 4.0 mm) with a mass of 400.0 mg.

[Comparative Example 5]
The same formulation as in Example 2 except that carmellose calcium in Example 2 was replaced with carmellose (NS300 / manufactured by Gotoku Pharmaceutical Co., Ltd.) and tableting was performed at a compression pressure of 1200 kgf so that the tablet density was 1.10 mg / mm ^3. -The tablet was manufactured with the manufacturing method.

[Comparative Example 6]
Carmellose calcium in Example 2 was replaced with croscarmellose sodium (Kickolate ND-200 / manufactured by Nichirin Chemical Co., Ltd.), and tableting was performed at a pressure of 1220 kgf so that the tablet density was 1.10 mg / mm ^3. Tablets were produced by the same prescription and production method as in Example 2.

[Comparative Example 7]
The carmellose calcium of Example 2 was replaced with low-substituted hydroxypropylcellulose (L-HPC NBD-021 / Shin-Etsu Chemical Co., Ltd.), and tableting was performed at a compression pressure of 1092 kgf so that the tablet density was 1.10 mg / mm ^3. A tablet was produced by the same prescription and production method as in Example 2 except that.

[Comparative Example 8]
Example except that carmellose calcium of Example 2 was replaced with crospovidone (manufactured by Polyplastidone XL-10 / ASHLAND), and tableting was performed at a pressure of 1330 kgf so that the tablet density was 1.10 mg / mm ^3. Tablets were produced by the same formulation and production method as in 2.

  The prescriptions of the tablets obtained in Example 2 and Comparative Examples 5 to 8 are listed in Table 2 below.

Acetaminophen (manufactured by Iwaki Pharmaceutical Co., Ltd.) 39,000 g, tramadol hydrochloride (manufactured by perrigo) 4,500 g, carmellose calcium (ECG505 / manufactured by Gotoku Pharmaceutical Co., Ltd.) 5,100 g, and light anhydrous silicic acid (ADSOLIDER 101 / Freund Industries) 480.0 g of powder is mixed and fluidized in a fluidized bed granulator (FPREC / WSG-60 model), and polyvinyl alcohol (EG-05PW / Nippon Synthetic Chemical). A solution obtained by dissolving 480.0 g in 11,000 g of purified water was sprayed and dried to obtain a granulated product. The obtained granulated product was dry-pulverized with a granulator (Pauleck Co./Comil) and then mixed with 240.0 g of magnesium stearate (Tahei Chemical Industrial Co., Ltd.) (Mitsubishi Kogyo Co., Ltd./MC800 type). ) For 5 minutes, and tableted at 1260 kgf to give a tablet density of 1.30 mg / mm ³ and 1 tablet weight 415.0 mg deformed tablet (diameter 15.0 mm, minor axis 6.3 mm, thickness 5.05 mm).
In the production of Example 3, acetaminophen used in advance was passed through a JIS150 mesh sieve, and tramadol hydrochloride used in advance was subjected to pin milling (20 Hz).

  The deformed tablet obtained in Example 3 was put into a coating machine (Powrec Co., Ltd .: PRC-200), and preliminarily hypromellose (TC-5M / Shin-Etsu Chemical Co., Ltd.) 118.0 g, Macrogol 6000 ( Sanyo Kasei Kogyo Co., Ltd.) 120.0 g, Talc (Crown Talc / Matsumura Sangyo Co., Ltd.) 576.0 g and Titanium Oxide (Titanium Oxide A-HR / Freund Sangyo Co., Ltd.) 96.0 g 4.8 g, ferric sesquioxide (manufactured by Kasei Chemical Co., Ltd.) 0.36 g added to 27,000 g of purified water, and uniformly dispersed liquid was sprayed and dried to obtain a coated tablet having a tablet mass of 431.0 mg .

  The formulations of each tablet obtained in Examples 3 and 4 are listed in Table 3 below.

(Test Example 1)
For each of the tablets obtained in Examples 1, 2, 3 and Comparative Examples 1-8, the friability was determined by the tablet friability test method of the 16th revised Japanese Pharmacopoeia / General Test Method, and the tablet hardness test method was used. Hardness was measured. The measurement results of Example 1 and Comparative Examples 1 to 4 are shown in Table 4 below, the measurement results of Example 2 and Comparative Examples 5 to 8 are shown in Table 5 below, and the measurement results of Example 3 are shown in the following table. This is shown in FIG. The friability of Comparative Examples 3 and 4 could not be measured because the tablet was broken during the friability test.

  Table 4 shows that the tablet of Example 1 containing a binder that is polyvinyl alcohol has a significantly lower friability than the tablets of Comparative Examples 1 and 2 containing a binder other than polyvinyl alcohol. It was. Therefore, it was shown that the high drug content tablet containing the polyvinyl alcohol of the present invention has an effect that the friability is significantly lower. In addition, the tablet of Example 1 was sufficiently high in hardness as compared with Comparative Examples 3 and 4, and it was shown that the high drug-containing tablet of the present invention has sufficient quality to withstand practical use.

  In Table 5, it was found that all of the tablets of Example 2 and Comparative Examples 5 to 8 having different types of disintegrants contained in the tablets had low friability and sufficiently high hardness. In addition, it has been separately confirmed by the present inventor that the tablet of Example 2 containing a disintegrant which is carmellose calcium is also good in drug dissolution and disintegration.

In Table 6, the tablet of Example 3 in which the binder contained in the amount of about 1% by weight with respect to the total weight of the tablet was polyvinyl alcohol was found to have low friability and sufficiently high hardness. Therefore, it was shown that the tablet of the present invention containing polyvinyl alcohol as a binder has an effect that the friability is remarkably low even when the amount of the binder contained in the tablet is lower.
In the tablet of Example 3, the purpose of lowering the binder amount to about 1% by weight with respect to the total weight of the tablet is to further improve the drug dissolution.

  ADVANTAGE OF THE INVENTION According to this invention, it becomes possible to industrially stably manufacture the high quality drug-rich tablet with the effect that the friability was remarkably improved, and to provide it to a medical field.

Claims (6)

An uncoated tablet containing 85.0 to 95.0% by weight of a drug that is acetaminophen and tramadol hydrochloride, and further a binder that is polyvinyl alcohol, based on the total weight of the uncoated tablet. The uncoated tablet according to claim 1, comprising a binder in an amount of 0.5 to 5.0% by weight based on the total weight of the uncoated tablet. The uncoated tablet according to claim 1 or 2, comprising 2.0 to 20.0% by weight of a disintegrant which is carmellose calcium with respect to the uncoated tablet. The uncoated tablet according to any one of claims 1 to 3, wherein the uncoated tablet has a weight of 380 to 420 mg, and contains 80.0% by weight or more of a granulated product containing the drug with respect to the total weight of the uncoated tablet. The tablet with which the uncoated tablet in any one of Claims 1-4 was covered with the film coating layer. A method for producing an uncoated tablet according to any one of claims 1 to 4, wherein a granulated product containing a drug is produced by a wet granulation method, and an uncoated tablet is produced by tableting with a compression pressure of 950 to 1300 kgf. .