JP5446716B2 - Method for producing tablets containing arginine and carnitine - Google Patents

Description

  The present invention relates to a method for producing a tablet containing arginine and carnitine, and is used in the fields of foods, pharmaceuticals and quasi drugs.

  Arginine is commercially available as a supplement and the like because it has the effect of increasing basal metabolism such as promoting growth hormone secretion and improving blood flow. The commercially available arginine preparations are mainly capsules and granules, but there are problems as described below in order to ingest an amount that can be expected to be effective with capsules and granules. That is, since the capsules have not undergone the compression process, a large amount of large capsules must be ingested, the granules are worried about the taste and smell of arginine, and the packaging is costly. . Accordingly, it is desired to provide tablets containing arginine.

  There have been reported examples of tablets containing arginine so far, but most of them have been coated (see Patent Documents 1 to 4). One possible reason is the water absorption of arginine. Since arginine absorbs water and swells, it is considered that many tablets having a coating layer have been reported to avoid water absorption. However, the coating has advantages such as prevention of bad taste and bad odor, ensuring stability from external conditions such as water, light, oxygen, etc., but also has the problem of increased production cost due to long production time. If there is little necessity, it is preferable not to coat the tablet.

  On the other hand, carnitine is a living body resident component related to energy metabolism such as lipolysis, energy production, and anti-fatigue action, and is marketed as a supplement in the same manner as arginine. With increasing awareness of obesity, the provision of a tablet containing both arginine, which promotes secretion of growth hormone and improves blood flow, and carnitine, which has lipolytic action, is one of the causes of obesity. It is desired.

JP 2007-1873 A JP 2007-197378 A WO 2004/078171 JP 2005-298373 A

  The present inventors have discovered that if a tablet contains a certain amount or more of arginine, cracking or disintegration of the tablet occurs under humidified conditions, and a powder for tableting containing water-containing arginine. It has been found that cracking and disintegration of the tablet can be suppressed by obtaining an arginine-containing tablet by using this, and a patent application has been filed for this invention (Japanese Patent Application No. 2009-102614).

  The inventors of the present invention thought that the tablet containing arginine and carnitine could suppress the cracking and disintegration of the tablet by adding moisture to the arginine. Of tableting powder and capping of tablets).

  Therefore, the subject of this invention is providing the tablet which suppressed the crack and disintegration of an arginine and a carnitine containing tablet, and also suppressed the tableting trouble.

  As a result of various investigations, the present inventors have found that arginine and carnitine-containing tablets are cracked without coating by adding moisture to arginine and containing a certain amount of sucrose fatty acid ester in the tableting powder. Further, the present inventors have found that no collapse occurs and that further tableting troubles can be suppressed.

That is, the present invention
(1) A tableting powder containing 4.5 to 9.5% by mass of a sucrose fatty acid ester with respect to water containing arginine, carnitine, and tablets. A method for producing a tablet in which cracking and disintegration of the tablet due to swelling are suppressed.
(2) The method for producing a tablet according to (1), wherein the arginine containing water contained in the powder for tableting is obtained by spraying water on arginine using a wet granulator.
(3) The method for producing a tablet according to (1) or (2) above, wherein the water content of water-containing arginine is 8.1% by mass or more.
(4) The method for producing a tablet according to (1) above, wherein the tableting powder has a water content of 4.0% by mass or more.
(5) The method for producing a tablet according to any one of (1) to (4) above, wherein no coating is applied.
(6) Content of arginine is 16.9 mass% or more with respect to a tablet, The manufacturing method of the tablet of any one of said (1)-(5) characterized by the above-mentioned.
It is.

  According to the present invention, an arginine- and carnitine-containing tablet in which cracking and disintegration does not occur in the tablet and the tableting trouble is suppressed can be produced without coating.

It is the photograph after preserve | saving for 3 hours on 25 degreeC60% RH conditions of the tablet manufactured in Reference Example 1. It is the photograph after preserve | saving for 2 hours on 25 degreeC60% RH conditions of the tablet manufactured in Reference Example 2. It is the photograph after preserve | saving for 2 hours on 25 degreeC60% RH conditions of the tablet manufactured in Reference Example 3.

  In the present invention, arginine is preferably L-form arginine and may take the form of a salt. The arginine salt is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include hydrochloride, glutamate, and citrate. In the present invention, when an arginine salt is used, the content of arginine in the tablet is an amount converted to free arginine.

  In the present invention, carnitine is preferably L-form carnitine and may take the form of a salt. The carnitine salt is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include hydrochloride and tartrate. When a carnitine salt is used in the present invention, the content of carnitine in the tablet is an amount converted to free carnitine, and can generally be blended in an amount of about 1 to 30% by mass with respect to the tablet. .

  In the present invention, examples of the fatty acid composition of the sucrose fatty acid ester include lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, erucic acid, and behenic acid. When the blending amount is 4.5 to 9.5% by mass with respect to the tablet, the tableting powder does not adhere to the punch and die, and capping of the tablet can be suppressed. As the sucrose fatty acid ester, those used in pharmaceuticals and foods can be used. For example, sugar ester S-370F, S-1170F (manufactured by Mitsubishi Chemical Foods), DK ester F-50, F-20W (No. 1) Ichi Kogyo Seiyaku Co., Ltd.).

  The crack and disintegration of the tablet means a state in which the tablet surface or edge portion is torn and collapses so as to peel off from the tablet surface. A photograph of an example of a tablet in which cracks and collapse have occurred is shown in the drawing. The state in which the crack has occurred in the tablet is the state shown in FIG. 2, and the state in which the tablet has collapsed is the state shown in FIG. It is considered that cracking and disintegration of the tablet occurs when arginine absorbs water and swells.

  “Tabletting powder containing arginine containing moisture, carnitine, and 4.5 to 9.5% by mass of sucrose fatty acid ester with respect to tablets (hereinafter referred to as tableting powder)” In addition to containing arginine, carnitine, and sucrose fatty acid ester, they may be composed of conventional excipients, additives, and the like, and may contain other active ingredients such as crude drugs and vitamins. In addition, powders obtained by granulating each of the above components and adding other conventional components to the granulated product as necessary are also included in the category of the above tableting powders. Further, the tableting powder includes arginine, carnitine, and a sucrose fatty acid ester, and if necessary, a powder mixed with conventional excipients, additives, active ingredients, etc. A granulated product obtained by wet granulation using a mixed solution of alcohol (or a solution in which a binder is dissolved) is also included, and a powder obtained by further adding other conventional components to the granulated product is also included. That is, it is important that the arginine in the “tablet powder” in the present invention contains water and swells in some way before tableting.

  In the present invention, although it varies depending on the content of arginine in the tablet, it is preferable that the arginine contains water of 8.1% by mass or more. The tableting powder preferably contains 4.0% by mass or more of water. By carrying out like this, the crack and disintegration of a tablet can be suppressed. Note that the upper limit of the moisture content can be appropriately determined by those skilled in the art in consideration of ease of tableting and the like.

  The tablet obtained by the production method of the present invention contains moisture. Tablets dried by reducing the amount of water contained in the tablets do not show cracking or disintegration of the tablets even under humidified conditions. That is, it is important that arginine contains moisture at the time of tableting, and the tablet after tableting can be dried. From the viewpoint of the stability of the obtained tablet, it is preferable that the water content in the tablet is small. Therefore, it is preferable to further perform a drying step on the obtained tablets in the production method of the present invention.

  Coating is to form and coat various substances on the surface of tablets and granules, preventing bad taste and odor, ensuring stability from external conditions such as water, light, oxygen, intestines, etc. It is applied for the purpose of imparting functions such as solubility and sustained release. In addition, although the tablet of this invention and the granulated product in the middle of the manufacture are not cracked and disintegrated even if it is not coated, the coating is not prevented. For example, it is effective to coat the tablet of the present invention when a component having bad taste or bad odor is blended or when a component unstable to water, light, oxygen or the like is blended.

  In the present invention, the value determined by the loss on drying method (70 ° C. for 30 minutes) is used as the water content. That is, it is a value calculated from the weight decreased by placing tablets, tableting powder, and water-containing arginine under conditions of 70 ° C. for 30 minutes.

  An excipient can be blended in the tablet of the present invention. Examples of the excipient include lactose, starch, corn starch, crystalline cellulose, reduced maltose starch syrup, trehalose, sugar, glucose, calcium hydrogen phosphate, light anhydrous silicic acid and the like. These excipients can be used alone or in combination.

  Furthermore, the tablet of the present invention may contain a conventional additive. Examples of the additive include a binder, a disintegrant, a lubricant, and a flavoring agent. These additives can be used alone or as a mixture.

  Examples of the binder include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, and pullulan. Examples of the disintegrant include carboxymethyl cellulose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, crospovidone, carmellose calcium, carboxymethyl starch sodium, and partially pregelatinized starch.

  Furthermore, in the present invention, various commonly used active ingredients such as various amino acids and salts thereof, various vitamins, other crude drugs and herbal extracts can be blended.

Hereinafter, the present invention will be described in detail with reference examples, examples, comparative examples, and test examples.
Reference Examples 1-4
The following operations were performed to produce Reference Examples 1 to 4 so that the composition ratio shown in Table 1 was obtained.

  L arginine, reduced maltose starch syrup, hydroxypropyl cellulose, light anhydrous silicic acid and calcium stearate were weighed, mixed and pulverized, and then tableted with a tableting machine to produce a tablet with a mass of 370 mg. All units in the table are mass%.

Test example 1
The tablets produced in Reference Examples 1 to 4 were used as test samples. The test sample was stored for an arbitrary period of time at 25 ° C. and 60% RH, and then the appearance change of the test sample was evaluated. The test results are shown in Table 2. Moreover, the typical photograph about each tablet was shown in FIGS.

The evaluation results in Table 2 are as follows.
0: No change 1: Crack in tablet 2: Disintegration of tablet From the reference example, the change in appearance of the test sample under the condition of 25 ° C. and 60% RH depends on the content of L arginine, and the content of L arginine is 16 At 9 mass% or more, cracks and disintegration were confirmed in the tablet. Therefore, the present invention is particularly effective when arginine is contained in an amount of 16.9% by mass or more based on the tablet. It should be noted that the present invention can also be applied to tablets having an arginine content of less than 16.9% by mass in order to suppress water absorption and swelling of arginine.

  The compounding ratio (mass%) of the compounding components of the following Examples and Comparative Examples is the compounding ratio when the total of components other than water is 100 mass%.

Example 1
With respect to 31.7% by mass of L-arginine, water was sprayed using a fluidized bed granulator, and the water content was determined by the loss on drying method (70 ° C., 30 minutes) using 5 g of L-arginine. L arginine which becomes mass% was obtained. L-arginine soaked in water was mixed with 1.9% by mass of L-carnitine L-tartrate, 4.5% by mass of sucrose fatty acid ester, and 1.9% by mass of light anhydrous silicic acid. , Pulverized powder of 39.7% by mass of L-lysine hydrochloride, mixed with 18.2% by mass of crystalline cellulose, 1.9% by mass of carmellose calcium, and 0.2% by mass of black pepper extract To obtain a mixture. The water content of the mixture was determined by the loss on drying method (70 ° C., 30 minutes) using 5 g of the mixture, and was 6.4% by mass. The mixture was tableted with a tableting machine to produce tablets each having a mass of 350 mg. The obtained tablet was dried using a dryer (60 ° C. for 1 hour).

Example 2
The sucrose fatty acid ester of Example 1 was changed to 7.0% by mass and crystalline cellulose was changed to 15.7% by mass, and tablets were obtained through the same production process. The moisture content was determined by the loss on drying method (70 ° C., 30 minutes) using 5 g of L-arginine and the mixture before tableting. The moisture content of L-arginine was 15.2% by mass, and the moisture content of the mixture before tableting The amount was 6.3% by mass.

Example 3
The sucrose fatty acid ester of Example 1 was changed to 9.5% by mass and crystalline cellulose was changed to 13.2% by mass, and tablets were obtained through the same production process. The water content was determined by the loss on drying method (70 ° C., 30 minutes) using 5 g of L-arginine and the mixture before tableting. The water content of L-arginine was 14.0% by mass, and the water content of the mixture before tableting The amount was 6.1% by mass.

Comparative Example 1
The sucrose fatty acid ester of Example 1 was changed to 2.0 mass% and the crystalline cellulose was changed to 20.7 mass%, and tablets were obtained through the same production process. The moisture content was determined by the loss on drying method (70 ° C., 30 minutes) using 5 g of L-arginine and the mixture before tableting. The moisture content of L-arginine was 15.2% by mass, and the moisture content of the mixture before tableting The amount was 6.3% by mass.

Comparative Example 2
The sucrose fatty acid ester of Example 1 was changed to 12.0% by mass and crystalline cellulose was changed to 10.7% by mass, and tablets were obtained through the same production process. The water content was determined by the loss on drying method (70 ° C., 30 minutes) using 5 g of L-arginine and the mixture before tableting. The water content of L-arginine was 14.0% by mass, and the water content of the mixture before tableting The amount was 6.0% by mass.

Comparative Example 3
With respect to 31.7 mass% of L arginine, water was sprayed using a fluidized bed granulator, and the water content was determined by a loss on drying method (70 ° C., 30 minutes) using 5 g of L arginine. L arginine which becomes mass% was obtained. L arginine soaked in water was mixed with 1.9% by mass of L carnitine L tartrate, 1.9% by mass of calcium stearate, and 0.9% by mass of light anhydrous silicic acid. A powder obtained by roughly crushing 39.7% by mass of lysine hydrochloride was mixed, and further 21.8% by mass of crystalline cellulose, 1.9% by mass of carmellose calcium, and 0.2% by mass of black pepper extract were mixed, A mixture was obtained. The water content of the mixture was determined by the loss on drying method (70 ° C., 30 minutes) using 5 g of the mixture and was 3.2% by mass. The mixture was tableted with a tableting machine to produce tablets each having a mass of 350 mg.

Comparative Example 4
Tablets were obtained through the same production steps as in Comparative Example 3, and dried using a dryer (60 ° C. for 1 hour). The water content was determined by the loss on drying method (70 ° C., 30 minutes) using 5 g of L-arginine and the mixture before tableting. The water content of L-arginine was 8.1% by mass, and the water content of the mixture before tableting The amount was 4.0% by mass.

Comparative Example 5
With respect to 31.7 mass% of L arginine, water was sprayed using a fluidized bed granulator, and the water content was determined by a loss on drying method (70 ° C., 30 minutes) using 5 g of L arginine, 14.0 L arginine which becomes mass% was obtained. L arginine soaked in water was mixed with 1.9% by mass of L carnitine L tartrate, 4.5% by mass of calcium stearate, and 1.9% by mass of light anhydrous silicic acid. A powder obtained by roughly crushing 39.7% by mass of lysine hydrochloride was mixed, and further, 18.2% by mass of crystalline cellulose, 1.9% by mass of carmellose calcium, and 0.2% by mass of black pepper extract were mixed, A mixture was obtained. The water content of the mixture was determined by the loss on drying method (70 ° C., 30 minutes) using 5 g of the mixture, and was 6.0% by mass. The mixture was tableted with a tableting machine to produce tablets each having a mass of 350 mg.

Comparative Example 6
The calcium stearate of Comparative Example 5 was changed to 7.0% by mass and the crystalline cellulose was changed to 15.7% by mass, and tablets were obtained through the same production process. The water content was determined by the loss on drying method (70 ° C., 30 minutes) using 5 g of L-arginine and the mixture before tableting. The water content of L-arginine was 14.0% by mass, and the water content of the mixture before tableting The amount was 5.9% by mass.

Comparative Example 7
With respect to 31.7 mass% of L arginine, water was sprayed using a fluidized bed granulator, and the water content was determined by a loss on drying method (70 ° C., 30 minutes) using 5 g of L arginine. L arginine which becomes mass% was obtained. L-arginine soaked with water was mixed with 1.9% by mass of L-carnitine L-tartrate, 1.0% by mass of magnesium stearate, and 1.9% by mass of light anhydrous silicic acid. A powder obtained by roughly crushing 39.7% by mass of L-lysine hydrochloride was mixed, and further 21.7% by mass of crystalline cellulose, 1.9% by mass of carmellose calcium, and 0.2% by mass of black pepper extract were mixed. A mixture was obtained. The water content of the mixture was determined by the loss on drying method (70 ° C., 30 minutes) using 5 g of the mixture, and was 6.4% by mass. The mixture was tableted with a tableting machine to produce tablets each having a mass of 350 mg.

Comparative Example 8
The magnesium stearate of Comparative Example 7 was changed to 1.9% by mass and the crystalline cellulose was changed to 20.8% by mass, and tablets were obtained through the same production process. The water content is determined by the loss on drying method (70 ° C., 30 minutes) using 5 g of L-arginine and the mixture before tableting. The water content of L-arginine is 13.0% by mass, and the water content of the mixture before tableting The amount was 6.6% by mass.

Comparative Example 9
The magnesium stearate of Comparative Example 7 was changed to 4.5 mass% and the crystalline cellulose was changed to 18.2 mass%, and tablets were obtained through the same production process. The water content is determined by the loss on drying method (70 ° C., 30 minutes) using 5 g of L-arginine and the mixture before tableting. The water content of L-arginine is 13.0% by mass, and the water content of the mixture before tableting The amount was 5.3% by mass.

Comparative Example 10
With respect to 31.7 mass% of L arginine, water was sprayed using a fluidized bed granulator, and the water content was determined by a loss on drying method (70 ° C., 30 minutes) using 5 g of L arginine. L arginine which becomes mass% was obtained. L arginine soaked with water was mixed with 1.9% by mass of L carnitine L tartrate, 2.0% by mass of talc, and 1.9% by mass of light anhydrous silicic acid. A powder obtained by roughly crushing 39.7% by mass of hydrochloride is mixed, and further 20.7% by mass of crystalline cellulose, 1.9% by mass of carmellose calcium, and 0.2% by mass of black pepper extract are mixed, Got. The water content of the mixture was determined by the loss on drying method (70 ° C. for 30 minutes) using 5 g of the mixture and was 5.3% by mass. The mixture was tableted with a tableting machine to produce tablets each having a mass of 350 mg.

Comparative Example 11
The talc of Comparative Example 10 was changed to 7.0 mass% and the crystalline cellulose was changed to 15.7 mass%, and tablets were obtained through the same production process. The water content is determined by the loss on drying method (70 ° C., 30 minutes) using 5 g of L-arginine and the mixture before tableting. The water content of L-arginine is 13.0% by mass, and the water content of the mixture before tableting The amount was 5.2% by mass.

Comparative Example 12
The talc of Comparative Example 10 was changed to 12.0 mass% and the crystalline cellulose was changed to 10.7 mass%, and tablets were obtained through the same production process. The water content is determined by the loss on drying method (70 ° C., 30 minutes) using 5 g of L-arginine and the mixture before tableting. The water content of L-arginine is 13.0% by mass, and the water content of the mixture before tableting The amount was 4.8% by mass.

Comparative Example 13
With respect to 31.7 mass% of L arginine, water was sprayed using a fluidized bed granulator, and the water content was determined by a loss on drying method (70 ° C., 30 minutes) using 5 g of L arginine. L arginine which becomes mass% was obtained. L arginine soaked with water was mixed with 1.9% by mass of L carnitine L tartrate, 2.0% by mass of hardened oil, and 1.9% by mass of light anhydrous silicic acid. A powder obtained by roughly crushing 39.7% by mass of lysine hydrochloride was mixed, and further 20.7% by mass of crystalline cellulose, 1.9% by mass of carmellose calcium, and 0.2% by mass of black pepper extract were mixed, A mixture was obtained. The water content of the mixture was determined by the loss on drying method (70 ° C., 30 minutes) using 5 g of the mixture and was 5.2% by mass. The mixture was tableted with a tableting machine to produce tablets each having a mass of 350 mg.

Comparative Example 14
The hardened oil of Comparative Example 13 was changed to 7.0% by mass and crystalline cellulose was changed to 15.7% by mass, and tablets were obtained through the same production process. The water content is determined by the loss on drying method (70 ° C., 30 minutes) using 5 g of L-arginine and the mixture before tableting. The water content of L-arginine is 13.0% by mass, and the water content of the mixture before tableting The amount was 5.4% by mass.

Comparative Example 15
The hardened oil of Comparative Example 13 was changed to 12.0% by mass and crystalline cellulose was changed to 10.7% by mass, and tablets were obtained through the same production process. The water content is determined by the loss on drying method (70 ° C., 30 minutes) using 5 g of L-arginine and the mixture before tableting. The water content of L-arginine is 13.0% by mass, and the water content of the mixture before tableting The amount was 5.0% by mass.

Test example 2
The tablets produced in Examples 1 to 3 and Comparative Examples 3 and 4 were used as test samples. The test sample was stored for an arbitrary period of time at 25 ° C. and 60% RH, and then the appearance change of the test sample was evaluated. The test results are shown in Table 3.

The evaluation results in Table 3 are as follows.
0: No change 1: Crack in tablet 2: Disintegration of tablet

  When the appearance change of the test samples obtained in Examples 1 to 3 and Comparative Example 4 under conditions of 25 ° C. and 60% RH was evaluated, no cracks or disintegration of the tablets were confirmed. However, when the appearance change of the test sample obtained in Comparative Example 3 under the conditions of 25 ° C. and 60% RH was evaluated, cracking and disintegration of the tablet over time were confirmed. Therefore, if the water content of L arginine is 8.1% by mass or more, or the water content of the powder for tableting is 4.0% by mass or more, the tablet is stable under conditions of 25 ° C. and 60% RH. Could be provided.

Test example 3
The tablets produced in Examples 1 to 3 and Comparative Examples 1, 2, 4 to 15 were used as test samples. The adhesion state of the punch and mortar of the powder for tableting during the production of the test sample and the capping of the test sample were evaluated. The test results are shown in Table 4.

The evaluation results in Table 4 are as follows.
0: The tableting powder does not adhere to the pestle and die, and no capping is observed in the obtained tablets.
1: Adhesion of powder for tableting to the pestle and die is observed.
2: Capping is seen in the obtained tablet.
3: Adhesion of the powder for tableting to the pestle and die and capping of the obtained tablet are both seen.

  When the test sample obtained in Examples 1 to 3 and the adhesion state of the punch and powder of the tableting powder at the time of manufacturing the test sample were evaluated, adhesion to the punch and die and capping of the tablet were not confirmed. It was. However, in Comparative Examples 1, 2, 4 to 15, one or both of adhesion to the pestle and die and capping of the tablets occurred.

  From the results of Test Example 3, only when the sucrose fatty acid ester was blended in an amount of 4.5% to 9.5% by weight with respect to the tablet, the tableting failure (attachment of the tableting powder to the mortar and pestle and It was found that tablet capping) can be suppressed.

  The method for producing a tablet containing arginine and carnitine of the present invention can be used in the fields of foods, pharmaceuticals, quasi drugs and the like.

Claims (5)

Tableting powder for tableting containing arginine, carnitine having a water content of 8.1% by mass or more , and sucrose fatty acid ester of 4.5 to 9.5% by mass with respect to the tablet. A method for producing a tablet in which cracking and disintegration of the tablet due to swelling of arginine is suppressed. The arginine whose water content contained in the powder for tableting is 8.1 mass% or more is obtained by spraying water with respect to arginine using a wet granulator. Production method. The method for producing a tablet according to claim 1, wherein the tableting powder has a water content of 4.0% by mass or more. The method for producing a tablet according to any one of claims 1 to 3 , wherein no coating is applied. Content of arginine is 16.9 mass% or more with respect to a tablet, The manufacturing method of the tablet of any one of Claims 1-4 characterized by the above-mentioned.

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