KR101364561B1 - Compression molded preparation - Google Patents

Abstract

It provides a tablet which is excellent in manufacturability and contains a small amount of L-cysteine and ascorbic acid as the active ingredient.

20-40 mass% of L-cysteine or its salt in L-cysteine, 30-25 mass% of ascorbic acid or its salt in ascorbic acid, 7.5-25 mass% in total of a plurality of crystalline cellulose, and high It is related with the compression molding agent characterized by containing 1-20 mass% of swellable polymers.

Description

Compression Molding Agents {COMPRESSION MOLDED PREPARATION}

The present invention relates to a compression molding agent, and more particularly to a compression molding agent containing a high content of L-cysteine and ascorbic acid as the active ingredient.

Formulations containing L-cysteine and ascorbic acid include wrinkles, freckles, sunburn, pigmentation such as skin poisoning, systemic boredom, hangover, acne, eczema, urticaria, skin poisoning, poisoning, bleeding from gums, and nose bleeding. It has been used for the prevention of bleeding, physical fatigue, pregnancy and lactation, and physical disability after illness, and the spread of vitamin C in old age.

For example, for pigmentation such as wrinkles, freckles, sunburn, systemic boredom, hangover, acne, eczema, urticaria, and skin poisoning, the daily dose of L-cysteine is 240 mg, the ascorbic acid dose is 300 mg and pantothenic acid. Dragees with a 24 mg dose of calcium are used. In addition, wrinkles, freckles, pigmentation due to sunburn, bleeding from gums, bleeding prevention of nasal bleeding, physical fatigue, at the time of pregnancy, lactation, physical strength decline after illness, about the spread of vitamin C of old age Various preparations in which L-cysteine and ascorbic acid are used in which a dose of L-cysteine is 30 to 160 mg and an ascorbic acid is 300 to 1200 mg are used.

However, both L-cysteine and ascorbic acid have high doses per day, and in particular, L-cysteine has poor fluidity and poor compression moldability, and therefore, when formulated as a tablet, it was necessary to add a large amount of excipients. And if the amount of excipients in large amounts to increase the content of L-cysteine and ascorbic acid, there was a problem that a large tablet with a lot of mass per tablet.

On the other hand, it is also possible to reduce the mass per tablet and to take the tablet smaller, but in this case, the number of tablets to be taken at once increases, making it difficult for the patient to take. In addition, since the flowability and compression moldability of ascorbic acid are relatively good, even if the content of ascorbic acid in one tablet can be increased, the fluidity of L-cysteine is poor as described above.

As described above, formulations containing L-cysteine and ascorbic acid are often used to treat pigmentation due to wrinkles, freckles, sunburn, etc., but it takes time to turnover the skin and varies depending on the individual. To take effect, it is necessary to continue taking it for about 3 months, and taking large tablets or multiple tablets over such a long period is not only convenient for the patient, but also leads to a decrease in compliance. It was one of the reasons that could not be fully exhibited.

Actually, the tablet which contains ascorbic acid and L-cysteine simultaneously in Formulation Example 2.2, Formulation Example 2.3, and Formulation Example 2.4 of Patent Document 1 has an ascorbic acid content of about 18 mass%, and the content of L-cysteine is 9 to 15 masses. It is lowered by%. In addition, in patent document 2, patent document 3, patent document 4, patent document 5, and patent document 6, the content of ascorbic acid and L-cysteine per tablet (hereinafter referred to as "predetermined") is not coated. Although the sum total of more than 60 mass% is disclosed, although the content of ascorbic acid is 45-56% in these predetermined | prescribed amounts, the content of L-cysteine is as little as 8-19 mass%.

Moreover, although the content of L-cysteine is prescribed | regulated to 22 mass% in patent document 7, it turns out that content of ascorbic acid is reduced to 28 mass%, and 20 mass% or more of L-cysteine and predetermined | prescribed ascorbic acid in predetermined | prescribed The predetermined | prescribed thing which contains 30 mass% of acids and is excellent in manufacturability was not provided until now.

In addition, tablets containing L-cysteine and ascorbic acid can be produced in large quantities even if a small amount of tableting can be produced. Depending on the additives such as excipients to be blended, the fluidity is poor and cannot be tableted, or tableting such as sticking or capping. There are some obstacles, a large variation in the content of the components, a large variation in the weight, and some of them cannot be manufactured efficiently. Moreover, even if it can tablet as a tablet, in order to prevent a cysteine odor, when film-coating and dragging a predetermined | prescribed thing, even if there was no fall of a component content, there existed a discoloration and a crack during storage.

[Patent Document 1] Japanese Patent Publication 2004-217655

[Patent Document 2] Japanese Patent Publication 2002-179559

[Patent Document 3] Japanese Patent Publication 2003-128543

[Patent Document 4] Japanese Patent Publication 2003-155232

[Patent Document 5] Japanese Patent Publication 2004-26786

[Patent Document 6] Japanese Patent Publication 2004-149426

[Patent Document 7] Japanese Patent Publication 2004-107273

Therefore, the present invention is a compact for maximizing the therapeutic effect against pigmentation due to wrinkles, freckles, sunburn, etc., containing L-cysteine and ascorbic acid in a high content of 20% by mass and 30% by mass, respectively. It is a problem to provide high quality tablets.

MEANS TO SOLVE THE PROBLEM As a result of earnestly examining in order to solve the said subject, the present invention mix | blended L-cysteine or its salt with ascorbic acid or its salt to the carrier which combined 2 or more types of crystalline cellulose and a high swellable polymer, Despite the high content of L-cysteine and ascorbic acid, it is possible to obtain a compact tablet with a low dose variation, uneven content of ingredients, no tableting, and good dosage for mass production. And the present invention was completed.

That is, the present invention is 20 to 40% by mass in terms of L-cysteine or a salt thereof, ascorbic acid or 30 to 70% by mass in terms of ascorbic acid, and 7.5 to a plurality of crystalline cellulose in total. It is to provide a compression molding agent comprising 25% by mass and 1 to 20% by mass of a high swellable polymer.

Therefore, it becomes possible to effectively use the action which L-cysteine, ascorbic acid, etc. have as a medicine, pigmentation such as wrinkles, freckles, sunburn, systemic boredom, hangover, acne, eczema, urticaria, tingling Providing easy-to-take compression molding agents that are sure to manifest effects on the spread of vitamin C in old age at the time of bleeding from the gums, bleeding prevention of nasal bleeding, physical fatigue, during pregnancy, lactation, and physical illness after illness. Become.

BEST MODE FOR CARRYING OUT THE INVENTION [

The compression molding agent of the present invention (hereinafter referred to as "the formulation of the present invention") combines L-cysteine or its salt and ascorbic acid or its salt in a high content in a carrier containing a plurality of crystalline cellulose and a high swellable polymer, It is prepared by compression molding.

In the formulation of the present invention, as L-cysteine or a salt thereof (hereinafter referred to as "L-cysteine") used as the active ingredient, acid addition salts of L-cysteine such as L-cysteine hydrochloride and the like other than L-cysteine itself can be used. Although it is possible, it is preferable to use L-cysteine. The dosage of these L-cysteines is usually in the range of 10 to 1000 mg per day, preferably 30 to 480 mg, particularly preferably 160 to 240 mg in terms of L-cysteine for adults. The L-cysteine can be taken once or divided into 2 to 4 times per day, but more preferably divided into 2 to 3 times.

It is preferable to set it as 20-40 mass% in conversion of L-cysteine in the formulation of this invention, Furthermore, it is preferable to set it as 25-35 mass%, especially 27.5-32.5 mass%.

In the formulation of the present invention, ascorbic acid or a salt thereof (hereinafter referred to as "ascorbic acid") used as a medicinal active ingredient, in addition to ascorbic acid itself, ascorbate such as calcium ascorbate and sodium ascorbate, or directly Any of ascorbic ascorbic acid, calcium ascorbate for direct tableting and sodium ascorbate for direct tableting can be used. Among these ascorbic acids, it is preferable to use ascorbic acid for direct tableting, calcium ascorbate for direct tableting, and sodium ascorbate for direct tableting, and these can be obtained from BASF Takeda Vitamin Co., Ltd. In the present invention, the dosage of this ascorbic acid is in the range of 50 to 2000 mg, preferably 50 to 500 mg, and particularly preferably 200 to 400 mg in terms of ascorbic acid per day for adults. The ascorbic acid can be taken once or twice to four times a day like L-cysteine, but preferably divided into two to three times.

The content of ascorbic acid in the formulation of the present invention is preferably 30 to 70% by mass, more preferably 32.5 to 60% by mass, particularly 35 to 40% by mass, in terms of ascorbic acid.

You may mix | blend another pharmacologically active ingredient with the formulation of this invention in addition to said L-cysteine and ascorbic acid. Preferred examples include pantothenic acid such as pantothenic acid, calcium pantothenate, sodium pantothenate and panthenol, succinic acid d-α-tocopherol, succinic acid dl-α-tocopherol, succinic acid dl-α-tocopherol calcium, d-α-tocopherol acetate, dl-α-tocopherol acetate , vitamins such as d-α-tocopherol and dl-α-tocopherol, thiamine hydrochloride, thiamin nitrate, bistiamine nitrate, thiamine disulfide, thiaminediacetyl sulfate ester, fursulthiamine hydrochloride, dicetiamine hydrochloride, octothiamine, and coco thiamine, bis eve thiamine, bis Ben thiamine, benpo thiamine such vitamin B _1, riboflavin butyrate, riboflavin, such as vitamin B _2, pyridoxine hydrochloride, phosphate pyridoxal such as phosphoric acid riboflavin sodium vitamin B _6, cyanocobalamin, hydrochloric acid hydroxy rokso cobalamin, nicotinic acid, such as vitamin B _12, niacin, nicotinic acid amide, such as hydroxy ethyl rokso cobalamin, methyl cobalamin, yoku coix seed, Orotenic acid, biotin, gamma-oryzanol, gluronolactone, glucuronic acid amide, ubidecarenone, and the like. Among these, particularly preferred examples include pantothenic acid such as pantothenic acid, calcium pantothenate, sodium pantothenate, and panthenol, and the dosage thereof is preferably 5 to 30 mg per day for adults.

In the formulation of the present invention, a plurality of crystalline celluloses are used as a carrier. Examples of the plurality of crystalline celluloses include a combination of crystalline cellulose having a bulk density of 0.3 g / cm 3 or more and crystalline cellulose having a bulk density of less than 0.3 g / cm 3.

Among these, as the crystalline cellulose having a bulk density of 0.3 g / cm 3 or more, those having a bulk density of about 0.6 g / cm 3 or more can be preferably used, and specific examples thereof include Seolas PH-301 (volume density 0.41 g / cm 3; manufactured by Asahi Kasei Chemicals Co., Ltd.). ), Seoras PH-301D (volume density 0.41 g / cm 3; homology), Seoras PH-301Z (volume density 0.41 g / cm 3; homology), Seoras PH-302 (volume density 0.43 g / cm 3; homology), Zeoras PH-200 (volume density 0.33 g / cm 3; homology), Zeoras PH-102 (volume density 0.30 g / cm 3; homology), Vivapur-103 (volume density 0.32 g / cm 3; manufactured by Lettenmeier), Viva Poor-301 (volume density 0.38 g / cm 3; homology), Viva Poure-102 (volume density 0.31 g / cm 3; homology), Viva Pore-112 (volume density 0.35 g / cm 3; homology), Viva Pore-12 ( Volume density 0.33 g / cm <3> (homologous), Viva Poor-200 (volume density 0.34 g / cm <3>; homology), etc. are mentioned. These may be used alone or in combination of two or more. Among them, more preferred are crystalline cellulose having an average particle diameter of 90 µm or more; Zeoras PH-302, Seoras PH-200, Seoras PH-102, Vivapo-112, Vivapo-102, Vivapo-12, Vivapo-200 and the like, and more preferably, the average particle diameter 120 micrometers or more of crystalline cellulose; Vivapo-12, Vivapo-200, and Seoras PH-200.

On the other hand, as the crystalline cellulose having a bulk density of less than 0.3 g / cm 3, those having a bulk density of about 0.10 g / cm 3 can be preferably used. Specific examples thereof include Seolas KG-802 (volume density 0.21 g / cm 3; manufactured by Asahi Kasei Chemicals Co., Ltd.). ), Seoras PH-F20JP (volume density 0.23 g / cm 3; homology), Seoras PH-101 (volume density 0.29 g / cm 3; homology), Seoras PH-101D (volume density 0.29 g / cm 3; homology), Viva Poor-105 (volume density 0.23 g / cm 3; manufactured by Lettenmeier), Viva Poure-101 (volume density 0.29 g / cm 3; homology), and the like. These can be used 1 type or in mixture of 2 or more types. Among these, more preferable examples include crystalline cellulose having an average particle diameter of 50 µm or more; And the Theoras KG-802, the Theoras PH-101, the Theoras PH-101D, Vivapur-101, and the like, and more preferably, the Theoras KG-802 having the smallest bulk density.

The amount of these crystalline celluloses added to the total mass of the formulation of the present invention depends on the content of L-cysteine and ascorbic acid or the total mass of the tablet, but the crystalline cellulose having a bulk density of 0.3 g / cm 3 or more and a volume density of less than 0.3 g / cm 3 Crystal cellulose is mixed, Preferably it is 7.5-25 mass%, More preferably, it is the range of 15-20 mass%. In each case, the addition amount of the crystalline cellulose having a bulk density of 0.3 g / cm 3 or more with respect to the total mass of the preparation of the present invention is preferably in the range of 5 to 23% by mass, more preferably in the range of 10 to 15% by mass, and the bulk density of 0.3g. The addition amount of the crystalline cellulose of less than / cm 3 to the total mass of the preparation of the present invention is preferably 1 to 20% by mass, more preferably in the range of 2.5 to 10% by mass.

In the present invention, it is preferable to use a crystalline cellulose having a bulk density of 0.3 g / cm 3 or more and a crystalline cellulose having a bulk density of less than 0.3 g / cm 3 in a mass ratio of 8: 1 to 1: 4, and more preferably 4: 1 to 1: 1. It is preferable to use it in combination by mass ratio, and it is especially preferable to set it as 2.5: 1-1.5: 1. Among the crystalline celluloses, those having a bulk density of 0.3 g / cm 3 or more improve flowability during tableting of the tableting powder containing L-cysteine at a high concentration while maintaining good moldability, and have a volume density of less than 0.3 g / cm 3. The crystalline cellulose of the remarkably improves the moldability at the time of compression, and also contributes to the improvement of tablet hardness.

Moreover, the high swellable polymers used in the formulation of the present invention are insoluble in water and have high swelling properties. This high swellable polymer has fluidity before tableting in blending with L-cysteine, ascorbic acid and the like, has excellent compression moldability, does not change color after molding, and is low in reactivity. Specific examples of such high swellable polymers include croscarmellose sodium, low-substituted hydroxypropyl cellulose, crospovidone, and the like, and these may be used alone or in combination of two or more thereof. Among them, the most suitable specific examples include low-substituted hydroxypropyl cellulose (L-HPC), and especially L-HPC (LH-11 and LH-B1) having an average particle diameter of 50 µm is preferable, and in particular, fibrous powder Phosphorus L-HPC (LH-11) is more preferable.

1-20 mass% is preferable with respect to all mass, and, as for the addition amount with respect to the total mass of this formulation of this highly swellable polymer, it is the range of 2.5-10 mass% more preferably.

The formulations of the present invention include pharmacologically active ingredients such as L-cysteine and ascorbic acid, crystalline cellulose and highly swellable polymers, as necessary, known pharmaceutical additives such as excipients, binders, disintegrants, glidants, Stabilizers, surfactants, dissolution aids, reducing agents, buffers, adsorbents, glidants, antistatic agents, coatings, plasticizers, anti-sticking agents, light-shielding agents, brightening agents, antioxidants, sweeteners, tinting agents, fresheners, colorants, flavoring agents, flavoring agents It is manufactured by adding a fragrance or the like to adjust the granular material for compression molding, and compression molding according to a conventional method.

The pharmaceutical additive used in the formulation of the present invention is selected from water-soluble polymers that do not cause discoloration after compression molding in combination with L-cysteine and ascorbic acid, hard anhydrous silicic acid, sugar, sugar alcohol, starch, talc and magnesium stearate. It is preferable to mix | blend 1 type, or 2 or more types.

Among these, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyethylene glycol, etc. are mentioned as water-soluble polymer which does not cause discoloration after compression-molding with L-cysteine and ascorbic acid. Examples of starch include alpha starch, partially alpha starch, corn starch, potato starch, wheat starch, rice starch and the like, and sugar and sugar alcohols include lactose, mannitol, xylitol, dextrin, sorbitol, and the like. Since the amount of these water-soluble polymers, starches, sugars and sugar alcohols varies depending on the size of the compression molding agent and the method of producing the powder for compression molding, the amount cannot be specified. Mass%.

In addition, among the above-mentioned pharmaceutical additives, hard silicic anhydride increases the fluidity of the powder for compression molding and has an action of preventing the wetting or sticking of the compression molding agent. It is preferable that this hard silicic acid anhydride has an average particle diameter of 2-10 micrometers, and it is more preferable to use hard silicic anhydride with an average particle diameter of 2-4 micrometers. It is preferable to use 0.1-3 mass% with respect to the mass of the preparation of this invention, and, as for the addition amount, it is especially preferable to use 0.2-1 mass%.

Moreover, as for talc and magnesium stearate, it is preferable to add 0.1-3 mass% with respect to the mass before compression molding agent, or both or both, and it is especially preferable to use 0.5-1.5 mass%.

The granulated material for compression molding may be used as it is, or a part or all of the powder mixed with the above components as a granulated powder. When the powder is granulated powder, generally used granulation method, for example, wet granulation method using a spray granulation method using a solution or dispersion containing water or an organic solvent, stirring granulation method, flow granulation method, electric granulation method, electric flow granulation method, Dry granulation methods, such as consolidation and granulation methods using a granular binder, can be used.

The formulation of the present invention is produced by compression molding using a single tablet press, a rotary tablet press, or the like. At this time, it is preferable to prepare the pressure at the time of compression molding at 200 kg / cm <2> or more, More preferably, it is 400-2000 kg / cm <2>. In addition, the mass of the formulation of the present invention is not limited, but is usually about 50 to about 400 mg, more preferably about 100 to about 200 mg. It is preferable that this mass corresponds to one dosage unit per dose or one of its integers (for example, the content of a component that allows one to three tablets per dose, etc.). In addition, when the size of the formulation of the present invention is molded into, for example, a round tablet, the diameter is usually about 4 to about 12 mm, more preferably about 6 to about 10 mm.

The compression molding agent obtained as mentioned above can be made into a fast-soluble coating agent or a dragee agent by the fan coating method, the fluidized bed coating method, the electromotive coating method, the dry coating method, or a combination of these methods. At this time, the water-soluble or gas-soluble coating agent may be dissolved or dispersed in water or an organic solvent to spray coating, or the coating agent may be directly sprayed, heat or pressure may be applied, and the dry coating may be performed. Moreover, you may add a plasticizer, an antifouling agent, a light-shielding agent, an extender, a coloring agent, a flavoring agent, etc. to a coating agent.

The best embodiment of the compression molding agent of the present invention described above contains 27.5 to 32.5 mass% of L-cysteine and 35 to 40 mass% of ascorbic acid, and has a bulk density of 0.3 g / cm 3 or more and an average particle diameter of 120 µm or more. 2.5-10% by mass of crystalline cellulose having an average particle diameter of 50 µm or more at 15-20% by mass of cellulose and a mass density of less than 0.3 g / cm 3, and 0.1-5% by mass of low-substituted hydroxypropyl cellulose as a high swellable polymer. %, About 1 to 10% by weight of hard silicic anhydride, 0.1 to 3% by weight of talc and / or magnesium stearate, using a compression molding powder, about 100 to about 200 mg per formulation, about 6 to about diameter It is a compression molding agent compression-molded at the pressure of 400-2000 kg / cm <2> or more at the time of compression molding so that it may become about 10 mm.

The tableting powder used in the preparation of the present invention has very good fluidity because it contains two kinds of crystalline cellulose and high swellable polymers having different bulk densities, despite the high content of L-cysteine and ascorbic acid. It is excellent in compression moldability.

Therefore, the preparation of the present invention produced by the high-speed tableting machine using this tableting powder does not cause tableting disorder even when produced in large quantities, and results in a small tablet having a small dose difference and a variation in weight, and having excellent dosage.

Example

Hereinafter, although an Example is given and this invention is demonstrated further more concretely, this invention is not restrict | limited at all by these Examples.

Example 1

Prescribed Manufacturing (1)

960 g of L-cysteine, 1237.2 g of ascorbic acid for direct tableting, 96 g of calcium pantothenate, 458.8 g of crystalline cellulose (Vivapur-12: made by Lettenmeier), 200 g of crystalline cellulose (Seouras KG-802: made by Asahi Kasei Chemicals Co., Ltd.) , 200 g of low-substituted hydroxypropyl cellulose (LH-11: manufactured by Shin-Etsukagaku Kogyo Co., Ltd.), 16 g of hard silicic anhydride (Adsorida 101: Freundane Co., Ltd.) was mixed for 15 minutes, and 32 g of magnesium stearate was added thereto. The compression molding granules obtained by mixing for 1 minute were compression molded with a rotary tablet press to obtain a predetermined (compression molding agent) having a diameter of 8 mm, a thickness of 4.3 mm, and a mass of 200 mg.

Example 2

Prescribed Manufacturing (2)

960 g of L-cysteine, 1237.2 g of ascorbic acid for direct tableting, calcium pantothenate type S 147.6 g, 336.4 g of crystalline cellulose (Vivapur-12: Lettenmeier), 196 g of crystalline cellulose (Seouras KG-802: Asahi Kasei Chemicals) , 196 g of low-substituted hydroxypropyl cellulose (LH-11: Shin-Etsukagaku Kogyo), 15.6 g of hard silicic anhydride (Adsorida 101: Freund's acid bridge) were mixed for 15 minutes, and 31.2 g of magnesium stearate was added thereto, 1 The compression molding granules obtained by mixing for a minute were compression molded with a rotary tablet press to obtain a predetermined (compression molding agent) having a diameter of 7 mm, a thickness of 3.8 mm, and a mass of 130 mg.

Example 3

Manufacture of Film Coated Tablets

960 g of L-cysteine, 1237.2 g of ascorbic acid for direct tabletting, calcium pantothenate type S 147.6 g, crystalline cellulose (Vivapur-12: Lettenmeier) 407.2 g, crystalline cellulose (Seoras KG-802: Asahi Kasei Chemicals) 200 g, low-substituted hydroxypropyl cellulose (LH-11: Shin-Etsu Chemical Co., Ltd.) 200 g, 16 g of hard silicic anhydride (Adsorida 101: Freund's acid bridge) were mixed for 15 minutes, and 32 g of magnesium stearate was added again, 1 The compression molding granules obtained by mixing for a minute were compression molded with a rotary tablet press to obtain a predetermined (compression molding agent) having a diameter of 8 mm, a thickness of 4.3 mm, and a mass of 200 mg.

Next, this predetermined amount was placed in a coating pan and coated with an ethyl alcohol: purified water = 1: 1 coating solution containing 5% by mass of hydroxypropylmethylcellulose until the weight increase per tablet became 10 mg. Coated tablets were obtained.

Example 4

Production of dragees

960 g of L-cysteine, 1237.2 g of ascorbic acid for direct tableting, 96 g of calcium pantothenate, 388 g of crystalline cellulose (Vivapur-12: Lettenmeier), 196 g of crystalline cellulose (Seoras KG-802: Asahi Kasei Chemicals), low substitution 196 g of hydroxypropyl cellulose (LH-11: Shin-Etsukagaku Kogyo) and 15.6 g of hard silicic anhydride (Adsorida-101: Freund's bridge) were mixed for 15 minutes, and 31.2 g of magnesium stearate was added again for 1 minute. The compression molding granules obtained by mixing were compression molded with a rotary tablet press to obtain a predetermined (compression molding agent) having a diameter of 7 mm, a thickness of 3.8 mm, and a mass of 130 mg.

Next, this predetermined | prescribed was put into the coating pan, and coating was performed until the weight increase per tablet became 10 mg using the coating liquid of ethyl alcohol: purified water = 1: 1 containing 5 mass% of hydroxypropyl methylcellulose. .

Subsequently, an aqueous solution containing 2% by weight of talc, 2% by weight of titanium oxide, 3% by weight of calcium carbonate, 1% by weight of gum arabic and 60% by weight of refined sucrose would give 85 mg of weight increase per tablet. The coating was done until. Then, an aqueous solution containing 60% by mass of purified sucrose was coated until the weight increase of 1 tablet was 15 mg to obtain a dragee.

Comparative Example 1

Comparative Prescribed Manufacturing (1)

458.8 g of crystalline cellulose (Vivapure-12: Lettenmeier Co., Ltd.) and 200 g of crystalline cellulose (Ceolas KG-802: Asahi Kasei Chemicals) of Example 1 were crystallized cellulose (Seoras KG-802: Asahi Kasei Chemicals) 658.8 g. A comparative tablet (comparative compression molding agent) was produced in the same manner as in Example 1 except for replacing with g.

Comparative Example 2

Comparative Prescribed Manufacturing (2)

458.8 g of crystalline cellulose (Vivapure-12: Lettenmeyer Co., Ltd.) and 200 g of crystalline cellulose (Ceolas KG-802: Asahi Kasei Chemicals) of Example 1 were added to 658.8 g of crystalline cellulose (Vivapure-12: Lettenmeyer Co., Ltd.) A comparative tablet (comparative compression molding agent) was produced in the same manner as in Example 1 except for the replacement.

Comparative Example 3

Preparation of comparative microcrystals (3)

458.8 g of crystalline cellulose (Vivapure-12: Lettenmeier) of Example 1 and 200 g of low-substituted hydroxypropyl cellulose (LH-11: Shin-Etsu Kagaku Kogyo) were determined and crystalline cellulose (Vivapure-12: Lettenmeier) ) A comparative tablet (comparative compression molding agent) was prepared in the same manner as in Example 1 except for replacing with 658.8 g, but capping occurred.

Test Example 1

Mass deviation test:

About each 20 tablets of the predetermined | prescribed of Examples 1-4 and the comparative predetermined each of Comparative Examples 1 and 2, each mass was measured and mass deviation was investigated. The results are shown in Table 1 as CV values (%). Although all the predetermined | prescribed of the formulation of this invention had a small mass deviation, the predetermined | prescribed of Comparative Example 1 had a large mass deviation.

[Table 1]

Formulation Mass deviation
CV value (%) Example 1
Example 2
Example 3
Example 4
Comparative Example 1
Comparative Example 2 0.66
0.75
0.58
0.69
2.03
0.62

 Test Example 2

Tablet hardness:

For each of the prescribed tablets of Examples 1 to 4 and comparative tablets of Comparative Examples 1 and 2, the tablet hardness was determined by using a tablet hardness tester (TH-303MP type tablet breaking strength tester, manufactured by Toyama Sangyo Co., Ltd.). Measured. The results are shown in Table 2. The comparative predetermined of Comparative Example 2 was much smaller in hardness than the predetermined of Examples 1 and 3 of the same size.

[Table 2]

Formulation Purification hardness
(N) Example 1
Example 2
Example 3
Example 4
Comparative Example 1
Comparative Example 2 51.0
41.3
50.2
42.1
67.0
34.6

The compression molding agent of the present invention containing L-cysteine, ascorbic acid and the like as a medicinal ingredient contains a high concentration of L-cysteine and ascorbic acid by combining a plurality of crystalline celluloses and high swellable polymers, and is excellent in manufacturability. It has become possible to provide phosphorus compression molding agents.

Claims (10)

L-cysteine or a salt thereof was added to a carrier containing 7.5 to 25% by mass of crystalline cellulose having a bulk density of 0.3 g / cm 3 or more and crystalline cellulose having a bulk density of less than 0.3 g / cm 3 in total and 1 to 20% by mass of the high swellable polymer. A compression molding agent obtained by compression molding by mixing 20 to 40 mass%, ascorbic acid or its salt in terms of L-cysteine and 30 to 70 mass% in terms of ascorbic acid. delete The compression molding agent according to claim 1, wherein the ratio of crystalline cellulose having a bulk density of 0.3 g / cm 3 or more and crystalline cellulose having a bulk density of less than 0.3 g / cm 3 is in a mass ratio of 8: 1 to 1: 4. The compression molding agent according to claim 1, wherein the high swellable polymer is one or two or more selected from low-substituted hydroxypropyl cellulose, croscarmellose sodium or crospovidone. The compression molding agent according to claim 1, which further contains one or two or more kinds of components selected from water-soluble polymers, light anhydrous silicic acids, sugars, sugar alcohols, starches, talc, and magnesium stearate. The compression molding agent according to claim 1, wherein the formulation surface is again covered with a water-soluble film base. The compression molding agent according to claim 1, which again coats the surface of the preparation with a drag. L-cysteine or a salt thereof was added to a carrier containing 7.5 to 25% by mass of crystalline cellulose having a bulk density of 0.3 g / cm 3 or more and crystalline cellulose having a bulk density of less than 0.3 g / cm 3 in total and 1 to 20% by mass of the high swellable polymer. 20 to 40 mass% in terms of L-cysteine, 30 to 70 mass% in terms of ascorbic acid or a salt thereof is compounded, and compression molding is carried out. The method for producing a compression molding agent according to claim 8, wherein the ratio of the crystalline cellulose having a bulk density of 0.3 g / cm 3 or more and the crystalline cellulose having a bulk density of less than 0.3 g / cm 3 is in a mass ratio of 8: 1 to 1: 4. . The method for producing a compression molding agent according to claim 9, wherein the high swellable polymer is one or two or more selected from low-substituted hydroxypropyl cellulose, croscarmellose sodium or crospovidone.