JP6676816B1 - L-cysteine-containing vitamin C-rich compression molded preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compression-molded preparation having a high content of ascorbic acid and L-cysteine as medicinal components, and a method for producing the same. SOLUTION: (A) Ascorbic acid or its salt in an amount exceeding 1200 mg in terms of the amount of ascorbic acid to be taken daily, (B) In excess of 160 mg in terms of the amount of L-cysteine to be taken daily. L-cysteine or a salt thereof, (C) a polyvinyl alcohol compound, a polyvinylpyrrolidone compound, and at least one water-swelling polymer compound selected from the group consisting of cellulose compounds, and (D) a silicic acid compound. Compression molded formulation. [Selection diagram] None

Description

  The present invention relates to a compression-molded preparation having a high content of vitamin C (also referred to as “ascorbic acid” in the present invention) and L-cysteine as medicinal ingredients, and a method for producing the same.

  Pigmentation due to spots, freckles, sunburn, and the like is caused by an excessive increase in melanin due to aging, ultraviolet rays, and the like. On the other hand, vitamin C is known to have an effect of suppressing melanin production, and L-cysteine is known to have an effect of activating the metabolism of skin cells. A formulation containing calcium pantothenate, which has been known, has been conventionally manufactured and sold as a drug having an effect and an effect of alleviating pigmentation disease caused by spots, freckles, sunburn, rash, etc. 1 and 2). In addition to the above-mentioned indications, the formulation is also useful for preventing bleeding from gums and nosebleeds; and for supplementing vitamin C during physical fatigue, pregnancy, lactation, illness during illness, and senility. There are also indications and effects.

  In order for these L-cysteine-containing vitamin C-containing preparations to exhibit higher effects, it is necessary to increase the daily dose. However, since L-cysteine has poor fluidity and compression moldability, its content is low. There is a problem that it is difficult to increase the amount (see Patent Document 1 and the like). In addition, tablets containing L-cysteine and ascorbic acid can be tableted in a small amount, but when mass-produced, depending on the formulation additives to be blended, the fluidity is poor and tableting cannot be performed, or tableting such as capping is performed. There has been a problem that a desired preparation cannot be efficiently and stably produced, for example, causing an obstacle, or a variation in component content or a large deviation in weight (see Patent Document 1).

JP 2007-186470 A

Vitamin C drug product (containing L-cysteine) Package insert of “Sinal® L White Tablet” (revised September 2012) (http://www.shionogi-hc.co.jp/wellness/medicine/vitamin/ cnlw / doc / cnlw.pdf) Vitamin C drug product (containing L-cysteine) package insert of “Cinal (registered trademark) Ikushi Premium” (http://www.info.pmda.go.jp/downfiles/otc/PDF/J1801000114_01_B.pdf)

  SUMMARY OF THE INVENTION An object of the present invention is to provide a compression-molded preparation having a high content of ascorbic acid (vitamin C) and L-cysteine. Second, it is an object of the present invention to provide a method for improving the disintegration of the compression-molded preparation while having an appropriate hardness.

  Heretofore, L-cysteine-containing vitamin C-containing preparations widely approved for production have a daily L-cysteine dosage of 30 to 160 mg and an ascorbic acid (vitamin C) dosage of 300 to 1200 mg (see above). Patent Literature 1) is formulated so that two tablets are taken three times a day at a time to achieve this dose. The present inventors have been studying to develop an L-cysteine-containing vitamin C-rich compression-molded preparation containing ascorbic acid in a daily dose of more than 1200 mg and L-cysteine in an amount of more than 160 mg. When ascorbic acid is added in excess of 1200 mg, it has been found that there is a problem that the tableting properties of the tablet are remarkably reduced and tableting trouble (capping) occurs. After intensive studies to solve this, the components constituting the granulated product in a compression-molded preparation manufactured by using the granule compression-molding method (hereinafter, this may be referred to as a “compression-formed preparation”). It was confirmed that the tableting failure could be suppressed by using a specific granulating binder together with ascorbic acid as (hereinafter referred to as “granulating component”).

  In addition, the present inventors have found that, when a specific granulating binder is blended as a granulating component, tableting properties are improved and the hardness of the preparation can be increased, but on the other hand, disintegration is reduced. It was found that there was a problem that the disintegration time was delayed, and it took time for the effect to appear. Therefore, as a result of further intensive studies to solve this problem, it was found that a silicate compound is effective as a component for solving the problem during compression molding. Specifically, in the granule compression molding method, a formulation prepared by adding and compounding a silicate compound as a granulation component and / or separately from the granulated material and compression-molding the mixture is used to prepare a desired product. It was confirmed that the above-mentioned disintegration property was improved while maintaining the hardness, and the desired disintegration property was exhibited. In addition, by adding and mixing a silicate compound as a granulating component and / or separately from the granulated material and performing compression molding, the friability is reduced, and a compression molded preparation of good quality can be stably manufactured. It was confirmed.

  The present invention has been completed with further improvements based on such knowledge, and includes the following embodiments.

(I) L-cysteine-containing vitamin C-rich compression molded preparation (I-1) A compression molded preparation containing the following components (A) to (D):
(A) ascorbic acid or a salt thereof in an amount exceeding 1200 mg in terms of the amount of ascorbic acid to be taken per day,
(B) L-cysteine or a salt thereof in an amount exceeding 160 mg in terms of the amount of L-cysteine taken per day,
(C) at least one binder for granulation selected from the group consisting of a polyvinyl alcohol compound, a polyvinylpyrrolidone compound, and a cellulose compound; and (D) a silicate compound.
(I-2) A granular compression-molded preparation containing the components (A), (B), (C) and (D),
In the granulated product, at least the components (A) and (C) selected from the group consisting of the components (A), (B), (C) and (D) are included as granulated components constituting the granulated product. Being compounded,
The compression-molded preparation according to (I-1), wherein (D) is compounded as a post-addition component separately from the granulated component and / or separately from the granulated product.
(I-3) The compression-molded preparation according to (I-2), wherein (B) is compounded as a post-addition component separately from the granulated component or separately from the granulated product. .
(I-4) a compression molded product of a mixture of the granulated product 1 containing the components (A) and (C) (the granulated product 1 containing ascorbic acid) and the components (B) and (D); Or (I-1) a compression-molded product of a mixture of the granulated product 2 (ascorbic acid-containing granulated product 2) containing the components (A), (B) and (C) and the component (D). To (I-3).
(I-5) The compression-molded preparation according to (I-4), wherein the ascorbic acid-containing granules 1 and 2 further contain the component (D).
(I-6) The silicate compound of (D) is at least one selected from the group consisting of light anhydrous silicic acid and hydrous silicon dioxide, according to any one of (I-1) to (I-5). Compression molded preparation.
(I-7) The hardness is 30 N or more, and the disintegration time according to the disintegration test method (without an auxiliary panel, using purified water at 37 ° C.) specified in the Japanese Pharmacopoeia (17th revision) is 50 minutes or less. 1) The compression-molded preparation according to any one of (1-6).
(I-8) 30 to 90% by mass of the component (A), 2 to 20% by mass of the component (B), 0.1 to 10% by mass of the component (C), and ( (D) The compression-molded preparation according to any one of (I-1) to (I-7), containing the component at a ratio of 0.1 to 10% by mass.
(I-9) The proportion of the (D) component added later to the ascorbic acid-containing granulated product 1 or 2 is 10 to 100% by mass per 100% by mass of the total amount of the (D) component to be mixed into the compression-molded preparation. The compression-molded preparation according to any one of (I-2) to (I-8).
(I-10) A coated preparation, wherein the surface of the compression-molded preparation according to any one of (I-1) to (I-9) is further coated.
(I-11) The coated preparation according to (I-10), wherein the coating is a film coating or a sugar coating.
(I-12) The hardness is 30 N or more, and the disintegration time according to the disintegration test method (without an auxiliary plate, using purified water at 37 ° C.) prescribed in the Japanese Pharmacopoeia (17th revision) is within 60 minutes. 8) or the coated preparation according to (I-11).

(II) Method for producing L-cysteine-containing vitamin C-rich compression molded preparation (II-1) The method according to any one of (I-1) to (I-9), which has the following steps 1 to 3: A method for producing a compression-molded preparation or a coated preparation described in (I-10) to (I-12):
1. Contains at least the components (A) and (C) selected from the group consisting of the components (A), (B), (C) and (D), or the components (A), (C) and (D) Preparing granules,
2. 2. a step of mixing the granulated product with at least one post-addition component selected from the group consisting of the component (B), the component (D), and the lubricant; The step (II-2) of compression-molding the mixture obtained in the step 2; the compression-molded preparation according to any one of (I-4) to (I-9), comprising the following steps 1 ′ to 3 ′: Or the method for producing a coated preparation according to any one of (I-10) to (I-12):
1 '. The granulated product 1 containing the components (A) and (C), the granulated product 2 containing the components (A), (B) and (C), or the granulated product 2 containing the components (A), (B) and (C) ) And (D) a step of preparing a granulated product 3 containing the component;
2 '. The granulated product 1 is mixed with at least the components (B) and (D), or the granulated product 2 is mixed with at least the component (D), or the granulated product 3 is mixed with at least a lubricant. Mixing the
And 3 '. A step of compression-molding the mixture obtained above.
(II-3) The production method according to (II-2), wherein the granules 1 and 2 further contain the component (D).
(II-4) The coated preparation according to any one of (II-1) to (II-3), further comprising the following 4 steps in addition to the above 1 to 3 or the above 1 ′ to 3 ′ steps. Production method:
4. A step of coating the compression-molded preparation obtained in the above step 3 or 3 ′.

(III) Capping suppression method of L-cysteine-containing vitamin C-rich compression molded preparation (III-1) (A) Ascorbic acid or a salt thereof in an amount exceeding 1200 mg in terms of ascorbic acid to be taken daily,
(B) L-cysteine or a salt thereof in an amount exceeding 160 mg in terms of the amount of L-cysteine taken per day, and (D) a silicate compound,
A method for suppressing capping of a granular compression-molded preparation containing
A method for suppressing capping, comprising blending (C) at least one compound selected from the group consisting of a polyvinyl alcohol compound, a polyvinylpyrrolidone compound, and a cellulose compound as a binder for granulation.
(III-2) (A) Ascorbic acid or a salt thereof in an amount exceeding 1200 mg in terms of the amount of ascorbic acid to be taken daily,
(B) L-cysteine or a salt thereof in an amount exceeding 160 mg in terms of the amount of L-cysteine taken per day, and (D) a silicate compound,
A method for suppressing capping of a compression-molded preparation containing
In addition to the component (A) or the components (A) and (D), (C) at least one water-swellable polymer compound selected from the group consisting of a polyvinyl alcohol compound, a polyvinylpyrrolidone compound, and a cellulose compound is used. After the granulation, has a step of mixing the components (B) and (D),
In addition to the components (A) and (B) or the components (A), (B) and (D), at least one component selected from the group consisting of (C) a polyvinyl alcohol compound, a polyvinylpyrrolidone compound, and a cellulose compound After granulating with a binder for granulation, there is a step of mixing the component (D) therewith, or
In addition to the components (A), (B) and (D), (C) at least one binder for granulation selected from the group consisting of polyvinyl alcohol compounds, polyvinylpyrrolidone compounds, and cellulose compounds is used. A method for suppressing capping, comprising a step of mixing, after granulation, a post-added component containing at least a lubricant.
(III-3) The capping suppression described in (III-1) or (III-2), wherein the silicate compound of (D) is at least one selected from the group consisting of light anhydrous silicic acid and hydrous silicon dioxide. Method.

(IV) Method for improving disintegration and / or friability of L-cysteine-containing vitamin C-rich compression-molded preparation (IV-1) (A) An amount exceeding 1200 mg in terms of ascorbic acid taken daily. Ascorbic acid or a salt thereof,
(B) L-cysteine or a salt thereof in an amount exceeding 160 mg in terms of the amount of L-cysteine taken per day,
(C) at least one binder for granulation selected from the group consisting of a polyvinyl alcohol compound, a polyvinylpyrrolidone compound, and a cellulose compound, and (D) a silicate compound,
A method for improving the disintegration or / and the friability of a compression-molded preparation containing
As the granulation component, at least the components (A) and (C) selected from the group consisting of the components (A), (B), (C) and (D), or (A), (C) and (D) A) a granulated product containing the components;
A mixture of the components (A), (B), (C) and (D) is prepared by mixing at least one post-addition component selected from the group consisting of the components (B), (D) and the lubricant. And
Compression molding the mixture,
A method for improving disintegration and / or friability, characterized in that:
(IV-2) (A) Ascorbic acid or a salt thereof in an amount exceeding 1200 mg in terms of ascorbic acid taken per day,
(B) L-cysteine or a salt thereof in an amount exceeding 160 mg in terms of the amount of L-cysteine taken per day,
(C) at least one binder for granulation selected from the group consisting of a polyvinyl alcohol compound, a polyvinylpyrrolidone compound, and a cellulose compound, and (D) a silicate compound,
A method for improving the disintegration or / and the friability of a compression-molded preparation containing
The components (B) and (D) were mixed with the granulated product 1 containing the components (A) and (C), and the obtained components (A), (B), (C) and (D) were obtained. Or compression-molding the mixture of (A), (B) and (B) obtained by mixing the component (D) with the granulated material 2 containing the components (A), (B) and (C). Compression molding of a mixture of the components (C) and (D), or mixing at least a lubricant with the granulated product 3 containing the components (A), (B), (C) and (D). And compression-molding the obtained mixture containing the components (A), (B), (C) and (D), and a method for improving disintegration or / and friability.
(IV-3) The method for improving disintegration according to (IV-2), wherein the granules 1 and 2 further contain the component (D).
(IV-4) The method for improving disintegration according to any one of (IV-1) to (IV-3), which is a method for improving disintegration and / or friability while suppressing a decrease in hardness.
(IV-5) Any one of (IV-1) to (IV-4), wherein the silicate compound of (D) is at least one selected from the group consisting of light anhydrous silicic acid and hydrous silicon dioxide. And / or a method of improving the friability.

The compression-molded preparation of the present invention comprises an L-cysteine-containing vitamin containing each component such that ascorbic acid (vitamin C) exceeds a daily dose of 1200 mg and L-cysteine exceeds a daily dose of 160 mg. It is a C-rich compression-molded preparation, and the tableting trouble (capping) that can occur in the L-cysteine-containing vitamin C-rich compression-molded preparation is suppressed by including a specific granulating binder as a preparation component. It is characterized by the following. That is, the compression-molded preparation of the present invention is a L-cysteine-containing high-vitamin C-containing compression-formed preparation in which tableting trouble (capping) is suppressed.
Further, the capping suppression method of the present invention is useful as a method for suppressing tableting trouble (capping) that can occur in a L-cysteine-containing vitamin C-rich compression-molded preparation and stably and efficiently producing the preparation.

As described above, the compression-molded preparation of the present invention is an L-cysteine-containing vitamin C-rich preparation containing a specific granulating binder in addition to ascorbic acid and L-cysteine. The compression-molded preparation of the present invention includes a preparation characterized by exhibiting good disintegration properties by further containing a silicate compound while having a desired hardness by blending the granulating binder. It is. The compression-molded preparation of the present invention is an L-cysteine-containing high-vitamin C-containing compression-molded preparation having desired hardness and good disintegration properties. In addition, by adopting such a configuration, the compression-molded preparation of the present invention can suppress a decrease in friability and can stably and efficiently produce a high-quality preparation.
Further, the method for improving disintegration provided by the present invention provides a method for improving disintegration without adversely affecting the hardness which is improved by blending a predetermined granulating binder into an L-cysteine-containing vitamin C-rich compression-molded preparation. This method is useful as a method for improving the reduction of the drug effect, and avoiding and suppressing the delay (lag effect) of the drug effect onset which may be caused by the decrease in disintegration.

(I) L-cysteine-containing high-vitamin C-compressed preparation and method for producing the same The L-cysteine-containing high-vitamin C-compressed preparation of the present invention (hereinafter, also simply referred to as “the present preparation”) has the following ( It is a compression-molded product containing the components (A) to (D):
(A) ascorbic acid or a salt thereof in an amount exceeding 1200 mg in terms of the amount of ascorbic acid to be taken per day,
(B) L-cysteine or a salt thereof in an amount exceeding 160 mg in terms of the amount of L-cysteine taken per day,
(C) at least one binder for granulation selected from the group consisting of a polyvinyl alcohol compound, a polyvinylpyrrolidone compound, and a cellulose compound; and (D) a silicate compound.

Hereinafter, these components will be described.
The (A) component ascorbic acid may be any as long as it can be applied to the human body. For example, ascorbic acid listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Standards, Pharmaceutical Additives Standards, or the Official Food Additives Standard Can be used. Ascorbic acid is an optically active compound, but not limited to L-ascorbic acid (strictly, this is called vitamin C), but D-ascorbic acid can also be used. Also, a mixture of both may be used. The salt of ascorbic acid may be any as long as it can be applied to the human body, and examples thereof include an alkali metal salt and an alkaline earth metal salt of ascorbic acid. Examples of the alkali metal salt of ascorbic acid include potassium and sodium salts of ascorbic acid, and examples of the alkaline earth metal salt include calcium and magnesium salts of ascorbic acid. Component (A) is preferably ascorbic acid, more preferably L-ascorbic acid.

  The amount of ascorbic acid or a salt thereof contained in the preparation of the present invention is an amount exceeding 1200 mg in terms of the amount of ascorbic acid taken by one adult per day, and at least the amount of L-cysteine-containing vitamin C-containing preparation Any amount may be used so long as the required medicinal effect and the effect of the present invention are exhibited, and the amount can be appropriately set and adjusted within the range. Here, “the amount exceeding 1200 mg in terms of the amount of ascorbic acid taken by one adult per day” was designed so that one adult (one tablet) per day could take the preparation of the present invention. In this case, the amount of ascorbic acid or a salt thereof contained in one agent is more than 1200 mg in terms of the amount of ascorbic acid. For example, when one adult is designed to take three drugs (three tablets) per day, the amount of ascorbic acid or a salt thereof contained in one drug is converted into the amount of ascorbic acid, and Similarly, if one adult is designed to take six tablets (six tablets) per day, ascorbic acid or its The amount of the salt means that it is an amount corresponding to 1/6 of the above amount in terms of the amount of ascorbic acid. The preparation of the present invention can be taken once a day or divided into two or three times a day so that the dose of ascorbic acid per adult per day exceeds 1200 mg. The amount exceeding 1200 mg is not limited, but is preferably more than 1200 mg and 3000 mg or less, more preferably 1300 mg or more and 2000 mg or less, and still more preferably 1400 mg or more and 1800 mg or less.

  In the present invention, "adult" means a man and a woman aged 15 or older. However, the preparation of the present invention is not limited to a preparation to be taken by an adult, and may be taken by a child under 15 years of age. When taken by a child, the dose can be reduced to 1/2 or 2/3 of the daily dose taken by an adult according to each age group.

  Further, when the mass of the preparation of the present invention is 100% by mass, the proportion of ascorbic acid or a salt thereof (total mass) contained therein exhibits the medicinal effect required for the vitamin C-containing preparation containing L-cysteine and the effect of the present invention. Although it can be set appropriately within the range described above, for example, a range of 30 to 90% by mass can be exemplified. Preferably it is in the range of 40 to 80% by mass, more preferably 50 to 70% by mass.

As the component (B), L-cysteine may be any as long as it can be applied to the human body. For example, L listed in the Japanese Pharmacopoeia, Non-Japanese Pharmacopoeia Standards, Pharmaceutical Additives Standards, or Official Food Additives -Cysteine can be used. As the salt of L-cysteine, any salt which can be applied to the human body may be used, for example, inorganic acid salts such as L-cysteine hydrochloride, nitrate and acetate; alkalis such as potassium and sodium salts of L-cysteine Metal salts; and alkaline earth metal salts such as calcium and magnesium salts of L-cysteine. The salt of L-cysteine is preferably a hydrochloride of L-cysteine, that is, cysteine hydrochloride. (B) Component is preferably L-cysteine.

  The amount of L-cysteine or a salt thereof contained in the preparation of the present invention is an amount exceeding 160 mg in terms of the amount of L-cysteine taken by one adult per day, and at least contains L-cysteine-containing vitamin C. Any amount can be used as long as it exerts the medicinal effect required for the preparation and the effect of the present invention, and can be appropriately set and adjusted within the range. Here, “the amount exceeding 160 mg in terms of the amount of L-cysteine taken by one adult per day” means that one adult (for example, one tablet (1 tablet)) takes the preparation of the present invention per day. In the case of the above, it means that the amount of L-cysteine or a salt thereof contained in one agent exceeds 160 mg in terms of the amount of L-cysteine. For example, when one adult is designed to take three tablets (three tablets) per day, the amount of L-cysteine or a salt thereof contained in one drug is converted into the amount of L-cysteine. Similarly, it means that the amount is equivalent to 1/3 of the above-mentioned amount. Similarly, when one adult is designed to take 6 tablets (6 tablets) per day, the amount of L- The amount of cysteine or its salt means that it is an amount corresponding to 1/6 of the above amount in terms of the amount of L-cysteine. The preparation of the present invention can be taken once a day or divided into two or three times a day so that the daily dose of L-cysteine per adult exceeds 160 mg. The amount exceeding 160 mg is not limited, but is preferably more than 160 mg and 350 mg or less, more preferably 180 mg or more and 300 mg or less, and further preferably 200 mg or more and 240 mg or less.

  When the mass of the preparation of the present invention is 100% by mass, the proportion of L-cysteine or a salt thereof (total mass) contained in the preparation is determined by the effect required by the vitamin C-containing preparation containing L-cysteine and the effect of the present invention. Although it can be appropriately set within the range in which it is exhibited, for example, a range of 2 to 20% by mass can be exemplified. Preferably it is in the range of 4 to 17% by mass, more preferably 6 to 15% by mass.

Component (C) The binder for granulation used as the component (C) generally becomes a viscous liquid when water or ethanol is added among pharmaceutical excipients, and is a compound of a compound used as a binder for granulation. Among them, it corresponds to any of a polyvinyl alcohol compound, a polyvinylpyrrolidone compound, and a cellulose compound.

Here, the polyvinyl alcohol compound is a polymer having a structure represented by (—CH ₂ CH (OH) —) _n in the compound. Specific examples include polyvinyl alcohol or a copolymer of vinyl alcohol and another monomer compound. Here, as a copolymer of vinyl alcohol, a copolymer in which another polymer is branched from a part of the main chain, such as a graft copolymer, and a structural unit of a polymer, such as a random copolymer, are randomly arranged. Such copolymers or block copolymers can be mentioned. Specifically, any substance that can be applied to the human body may be used, and for example, polyvinyl alcohol compounds listed in the Pharmaceutical Excipient Standards or the Official Standards for Food Additives can be used. Specific examples include polyvinyl alcohol, polyvinyl alcohol acrylic acid / methacrylic acid copolymer, polyvinyl alcohol / polyethylene glycol / graft copolymer, and the like. Preferred are polyvinyl alcohol acrylic acid / methacrylic acid copolymers, and among them, polyvinyl alcohol acrylic acid / methyl methacrylate copolymer (PVA copolymer), particularly PVA copolymer having an average degree of polymerization of about 500 is preferred.

  Incidentally, polyvinyl alcohol is classified into a completely saponified product and a partially saponified product depending on the degree of saponification, and any polyvinyl alcohol can be used in the present invention. Although the molecular weight is not particularly limited, for example, those having a molecular weight of about 10,000 to 300,000, preferably about 30,000 to 200,000 can be exemplified. Although the molecular weight of the polyvinyl alcohol acrylic acid / methacrylic acid copolymer is not particularly limited, it is about 10,000 to 200,000, preferably about 30,000 to 100,000, and more preferably about 30,000 to 50,000. Can be exemplified. The molecular weight of the polyvinyl alcohol / polyethylene glycol / graft copolymer is not particularly limited, but may be about 10,000 to 100,000, preferably about 30,000 to 70,000.

  The polyvinylpyrrolidone compound is a polymer having N-vinyl-2-pyrrolidone as a monomer. Any substance can be used as long as it can be applied to the human body, and for example, a polyvinylpyrrolidone compound listed in Pharmaceutical Excipient Standards or Official Food Additives can be used. Specifically, polyvinyl pyrrolidone, cross-polyvinyl pyrrolidone and the like can be exemplified. Preferred is polyvinylpyrrolidone. The molecular weight of the polyvinylpyrrolidone compound is not particularly limited, but may be about 100,000 to 150,000.

  The cellulose compound used as the component (C) in the present invention has a property of becoming a viscous liquid when water or ethanol is added as described above. Any material can be used as long as it can be applied to the human body. For example, a cellulose compound listed as a binder in Pharmaceutical Excipient Standards or the Official Standards for Food Additives can be used. Specific examples include hydroxypropylcellulose, hypromellose (hydroxypropylmethylcellulose), and methylcellulose. Preferred are hydroxypropylcellulose and hypromellose.

  These binders for granulation can be used alone or in any combination of two or more. Preferred granulating binders are polyvinyl alcohol compounds or polyvinyl pyrrolidone compounds. When the mass of the preparation of the present invention is 100% by mass, the proportion of the binder for granulation contained therein can be appropriately set within a range where the preparation of the present invention exerts the effects of the present invention. Although not limited, for example, a range of 0.1 to 10% by mass can be exemplified. Preferably it is in the range of 0.5 to 5% by mass, more preferably 1 to 3.5% by mass.

(D) Component As the silicate compound used as the component (D), any silicate compound can be used as long as it can be applied to the human body. For example, a silicate compound listed in the Pharmaceutical Excipient Standards or the Official Standards for Food Additives is used. be able to. Specific examples include light anhydrous silicic acid, hydrous silicon dioxide, alkali metal or alkaline earth metal salts of silicic acid (for example, calcium silicate, magnesium silicate, etc.), and metasilicate aluminate. . These silicate compounds can be used alone or in any combination of two or more. Preferably, they are light silicic anhydride and hydrated silicon dioxide, more preferably light silicic anhydride.

  When the mass of the preparation of the present invention is 100% by mass, the proportion of the silicate compound contained therein can be appropriately set within a range in which the preparation of the present invention exerts the effects of the present invention. Although not limited, for example, a range of 0.1 to 10% by mass can be exemplified. Preferably it is in the range of 0.5 to 8% by mass, more preferably 1 to 6% by mass.

(E) Optional Pharmacologically Active Ingredient The preparation of the present invention further contains other pharmacologically active ingredients in addition to the aforementioned components (A) and (B), as long as the effects of the present invention are not impaired. May be. Although not limited, for example, pantothenic acids such as pantothenic acid, calcium pantothenate, sodium pantothenate and panthenol; d-α-tocopherol succinate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, acetic acid Vitamin E such as d-α-tocopherol, dl-α-tocopherol acetate, d-α-tocopherol and dl-α-tocopherol; thiamine hydrochloride, thiamine nitrate, bisthiamine nitrate, thiamine disulfide, thiamine diacetyl sulfate, fursultiamine hydrochloride Vitamin B1 such as dicetiamine hydrochloride, octiamine, sicotiamine, bisibutiamine, bisbenthamine and benfotiamine; riboflavin, riboflavin butyrate and sodium riboflavin phosphate; Vitamin B2 such as pyridoxine hydrochloride and pyridoxal phosphate; vitamin B12 such as cyanocobalamin, hydroxocobalamin hydrochloride, hydroxocobalamin acetate and mecobalamin; nicotinic acids such as nicotinic acid and nicotinamide; yoquinin, orotic acid, biotin, γ -Oryzanol, glucuronolactone, glucuronamide, ubidecarenone and the like.

  Among them, pantothenic acids are preferred, and calcium pantothenate is more preferred. When a pantothenic acid is added to the preparation of the present invention, the compounding amount may be, for example, 5 to 50 mg in terms of the amount of pantothenic acid taken by one adult per day. Further, when the mass of the preparation of the present invention is 100% by mass, the proportion of pantothenic acids (total mass) contained in the preparation is determined by the range required for the L-cysteine-containing vitamin C-rich preparation and the effect of the present invention. Can be set as appropriate, but for example, a range of 0.1 to 3% by mass can be exemplified. Preferably it is in the range of 0.3 to 2% by mass, more preferably 0.8 to 1.5% by mass.

(F) Optional Carriers and Additives In the production of the preparation of the present invention, conventionally known carriers and additives may be optionally added, as long as the effects of the present invention are not impaired, other than the above-mentioned components. it can. As these carriers and additives, for example, excipients, binders, disintegrants, disintegration aids, lubricants, stabilizers, surfactants, antioxidants, buffers, pH adjusters, dispersants, Solubilizers, superplasticizers, brighteners, flavoring agents, sweeteners, fresheners, coloring agents, flavoring agents, fragrances, adsorbents, sugar coatings, suspending agents, antistatic agents, plasticizers, and fragrances Agents and the like can be exemplified without limitation.

  The excipients are not limited as long as they do not impair the effects of the present invention, but include, for example, lactose, purified sucrose, glucose, powdered sugar, fructose, maltose, reduced maltose starch syrup, crystalline cellulose, powdered cellulose, corn starch, potato Starch, sugar alcohol (mannitol, xylitol, sorbitol, erythritol, etc.), trehalose, inorganic salt, dextran, dextrin, β-cyclodextrin, sucrose fatty acid ester, soy lecithin, tragacanth powder, gum arabic, pullulan, kaolin, etc. Can be. These can be used alone or in any combination of two or more. When the mass of the preparation of the present invention is 100% by mass, the proportion of the excipient contained therein is not limited as long as the effect of the present invention is not adversely affected, but is, for example, 0.1 to 70% by mass. A range can be exemplified. Preferably it is in the range of 0.5 to 50% by mass, more preferably 1 to 40% by mass.

  The binder is not limited as long as the effect of the present invention is not impaired, but, for example, gum arabic, gum arabic powder, gelatin, pregelatinized starch, alginic acid, sodium alginate, carboxyvinyl polymer, agar, pullulan, dextrin, Examples include shellac, sucrose, tragacanth, tragacanth powder, xanthan gum, pectin, sodium polyacrylate, guar gum and the like. When the mass of the preparation of the present invention is 100% by mass, the ratio of the binder contained therein is not limited as long as the effect of the present invention is not adversely affected, but is, for example, in the range of 0.1 to 5% by mass. Can be exemplified. Preferably it is in the range of 0.5 to 4% by mass, more preferably 1 to 3% by mass.

  Disintegrators are not limited as long as they do not impair the effects of the present invention, but include, for example, corn starch, potato starch, partially pregelatinized starch, hydroxypropyl starch, sodium starch glycolate, sodium carboxymethyl starch, and a low degree of substitution. Examples thereof include sodium carboxymethyl starch, carmellose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, crystalline cellulose, powdered cellulose, crospovidone, carmellose sodium, agar powder, and sodium hydrogen carbonate. When the mass of the preparation of the present invention is 100% by mass, the proportion of the disintegrant contained therein is not limited as long as the effect of the present invention is not adversely affected, but is, for example, in the range of 0.1 to 15% by mass. Can be exemplified. Preferably it is in the range of 0.5 to 10% by mass, more preferably 1 to 5% by mass.

  Although the lubricant is not limited as long as the effect of the present invention is not impaired, for example, magnesium stearate, calcium stearate, stearic acid, talc, sucrose fatty acid ester, sodium stearyl fumarate, carnauba wax, glycerin fatty acid ester, Hardened oils and the like can be mentioned.

  Examples of the flavoring agent include, but are not limited to, organic acids such as citric acid, tartaric acid, and malic acid, sodium glutamate, sodium 5'-inosinate, sodium 5-guanylate, sodium aspartate, and caramel.

  Examples of the sweetener include, but are not limited to, saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, lakanca, thaumatin, acesulfame potassium, sucralose, sucrose, fructose, glucose, lactose, maltose, sorbitol, maltitol, mannitol, xylitol, Highly sweeteners such as erythritol, glycerol, inositol, reduced maltose syrup, palatinose, coupling sugar and honey can be exemplified.

  The formulation of the invention has a solid form. Such formulations may include tablets, granules and pills. Preferably they are tablets. The tablet may have a single-layer structure or a multi-layer structure of two or more layers.

  The preparation of the present invention is preferably prepared by mixing at least the components (A) and (C) selected from the group consisting of the components (A), (B), (C) and (D), and granulating the mixture. Preparing an ascorbic acid-containing granulated product, and then mixing with the other components constituting the preparation of the present invention to prepare a mixture containing the components (A) to (D), and further press-molding the mixture. Can be manufactured.

  In preparing ascorbic acid-containing granules (hereinafter, also simply referred to as "granules"), at least one of the components (D) and (B) is used in addition to the components (A) and (C). You can also. Of the components (A), (B), (C) and (D), the components constituting the granulated product are preferably the components (A) and (C) or the components (A), (C) and (D). ) Component. In the preparation of the granulated product, any additives can be blended as long as the effects of the present invention are not impaired. As such additives, additives used for the production of granules in the granule compression molding method can be used, for example, excipients, binders, disintegrants, disintegration aids, adsorbents, fluidizers , A lubricant, a sweetening agent, a flavoring agent, a refreshing agent, a coloring agent, a pH adjusting agent, a surfactant, an antioxidant and the like. Preferably, but not limited to, excipients, binders, disintegrants, and glidants.

  The components (post-added components in the present invention) to be added to the granulated material include (A), (B), (C) and (D) components of the granulated material. Components not used in the preparation can be used. However, the present invention is not limited to this, and as long as the effects of the present invention are not impaired, the components used for the preparation of the granulated product can be used as a post-addition component. For example, as shown in the experimental examples described later, the component (D) acts to improve (shorten) the disintegration time by being used simultaneously with the preparation of the granulated product and also being used as a post-addition component. I do. Of the components (A), (B), (C) and (D), especially the components (B) and (D) can be suitably used as post-addition components. Further, as a post-addition component, any additive may be combined with the above-mentioned component (A), (B), (C) and / or (D), or may be used alone, as long as the effects of the present invention are not impaired. Can also be used. As such additives, additives that are used after being added to the granules in the granule compression molding method can be used. For example, excipients, binders, disintegrants, disintegration aids, adsorbents, fluids Agents, lubricants, sweeteners, flavoring agents, cooling agents, coloring agents, pH adjusters, surfactants, antioxidants and the like can be exemplified. Preferred are excipients, binders, disintegrants, glidants, and lubricants. When the above-mentioned granulated product contains all of the components (A), (B), (C) and (D), the post-addition component may be composed of only the above-mentioned additive. In this case, the additive preferably contains at least a lubricant.

The method for producing the preparation of the present invention includes the following methods.
First, after mixing the above-mentioned components (A) and (C), granulation is performed to prepare an ascorbic acid-containing granulated product (for convenience, this is also referred to as “granulated product 1”). A method in which the components (B) and (D) are mixed as components to prepare a mixture of the components (A) to (D), and the mixture is compression-molded.

As another embodiment, after mixing the above-mentioned components (A), (B) and (C), the mixture is granulated, and the granules containing ascorbic acid and cysteine (for convenience, these are also referred to as “granules 2”). A mixture of the components (A) to (D) is prepared by mixing the component (D) as a post-addition component, and then compression-molding the mixture.
As still another embodiment, after mixing the above-mentioned components (A), (B), (C) and (D), the mixture is granulated, and the granules containing ascorbic acid and cysteine (for convenience, this is referred to as “ A method of preparing a mixture containing components (A) to (D) by mixing at least a lubricant as a post-addition component, and then compression-molding the mixture.

  In preparing the granules 1 and 2, the component (D) is used in addition to the component (A) and the component (C), or the component (A), the component (B), and the component (C). You can also. When the component (D) is used as the granulation component, the component (D) may be omitted from the post-addition component, or may be used in combination. If necessary, the use of component (C) as a component to be added later to granulated product 1 or 2 is not limited, as long as the effects of the present invention are not impaired.

  From the above, the preparation of the present invention includes a granulated product containing the components (A) and (C) or a granulated product containing the components (A), (C) and (D) ( 1), a compression molded product of a composition obtained by mixing the components (B) and (D); a granulated product containing the components (A), (C) and (D) (granulated product 1); , A compression molded product of a composition obtained by mixing component (B); a granulated product (granulated product 2) containing components (A), (B) and (C) or (A), (B) , (C) and (D) Compression molded product of a composition obtained by mixing a granulated material (granulated material 3) containing component (D) with component (A), (B), (C) and A compression molded product of a composition obtained by mixing a granulated product (granulated product 3) containing the component (D) and at least an additive such as a lubricant is included.

  In the preparation of the granulated product 1, first, the binder for granulation, which is the component (C), is dissolved or suspended in an aqueous solvent such as purified water. It can be carried out by granulating ascorbic acid or a salt thereof. The concentration of the dissolution or suspension of the binder for granulation used for granulation is not limited, but may be about 1 to 20% by mass. Preferably it is about 5 to 15% by mass. The component (A) is preferably sieved in advance using, for example, a sieve having an opening of about 500 μm. When the component (D) is further added to the granulated product 1, the component (A) and the component (D) are preferably mixed in advance and sieved as described above. In addition, when mix | blending (D) component with the granulated material 1, although the compounding quantity is not restrict | limited when the whole quantity of (D) component mix | blended with this invention formulation is 100 mass%, it is 10-90 mass%. Can be selected from the range. It is preferably from 20 to 80% by mass, more preferably from 50 to 75% by mass. Further, in the preparation of the granulated product 1, the above-mentioned optional additives can be blended as long as the effects of the present invention are not impaired.

  Similarly to the preparation of the granulated material 2, similarly to the granulated material 1, first, the granulating binder as the component (C) is dissolved or suspended in an aqueous solvent such as purified water. It can be carried out by granulating a mixture of ascorbic acid or a salt thereof as the component (A) and the component (B). The concentration of the dissolution or suspension of the granulating binder used for granulation is the same as that of the granulated material 1 and is not limited, but may be about 1 to 20% by mass. It is preferable that the component (A) and the component (B) are sieved in advance using, for example, a sieve having an opening of about 500 μm.

  When the component (D) is further added to the granulated material 2, that is, for the preparation of the granulated material 3, the component (A), the component (B), and the component (D) are mixed in advance and the same as above. It is preferable to screen it. When the component (D) is blended with the granulated product 2, that is, the amount of the component (D) blended in the preparation of the granulated product 3 is blended with the preparation of the present invention similarly to the granulated product 1 (D When the total amount of the components is 100% by mass, it is not limited, but can be selected from the range of 10 to 90% by mass. Further, in the preparation of the granules 2 and 3, as in the case of the granules 1, the above-mentioned optional additives can be blended as long as the effects of the present invention are not impaired.

  For the preparation of the ascorbic acid-containing granules (granules 1, 2, and 3), a known granulator can be used without limitation. Specific examples include a fluidized bed granulator, a stirring granulator, an extrusion granulator, a rolling granulator, a Wurster granulator, and a granulator obtained by combining these. Preferably it is a fluid bed granulator. As described above, the (A) + (C) component, the (A) + (C) + (D) component, the (A) + (B) + (C) component, or the (A) + (B) + ( A solution or suspension of a binder for granulation is added to a powder mixture in which additives such as an excipient and a binder are added as necessary to the components (C) and (D), followed by mixing. Granulation using a granulator, and drying the obtained granules using, for example, a fluidized-bed dryer, to obtain granules containing ascorbic acid (granules 1, 2, and 3). Can be. In addition, the obtained granulated material may be adjusted to a desired average particle size by subjecting it to a sizing process. The average particle size is not limited, but may be in the range of 80 to 200 μm, preferably 100 to 150 μm (measurement by a sieve).

  The components to be added later (post-addition components) to the ascorbic acid-containing granules thus prepared are mixed in advance and, if necessary, sieved using, for example, a sieve having an opening of about 500 μm. May be. When the component (D) and the component (B) are used in combination as the post-addition components, both components are mixed in advance and, if necessary, sieved using, for example, a sieve having an opening of about 500 μm. The components (D) and (B) may be separately added and mixed. When the component (D) is added later to the ascorbic acid-containing granules (granules 1 to 3), the compounding amount of the component (D) is 100% by mass of the total amount of the component (D) mixed in the preparation of the present invention. %, It is not limited, but can be selected from the range of 10 to 100% by mass. It is preferably from 10 to 90% by mass, more preferably from 20 to 70% by mass, even more preferably from 25 to 50% by mass. When the component (B) is added later to the ascorbic acid-containing granules (granules 1 to 3), the compounding amount of the component (B) is 100% of the total amount of the component (B) mixed in the preparation of the present invention. In the case of mass%, it is not limited, but can be selected from the range of 10 to 100 mass%.

  As a component to be added later to the ascorbic acid-containing granules, at least one selected from the group consisting of the components (A) to (D) as described above, provided that the effects of the present invention are not impaired. In addition, optional additives can be blended. Such post-additives are preferably lubricants.

  The above-mentioned post-addition component is added to the above-mentioned ascorbic acid-containing granulated product, mixed well, and then compression-molded, whereby the compression-molded preparation of the present invention can be prepared. The compression molding can be performed according to a conventional method, and is not particularly limited. For example, compression molding using a rotary tableting machine, a single-shot tableting machine, or the like can be used. The pressure at the time of compression molding is also not particularly limited as long as a compression molded body having a desired hardness and having no cracks or chips during production or transportation can be produced. A pressure of 200 MPa can be mentioned. Preferably it is 50 to 180 MPa.

  The mass per preparation of the preparation of the present invention (naked preparation / base substance) can be appropriately set and adjusted based on the number of doses per day and the number of preparations per dose. For example, although not limited, when an adult is designed to take two tablets three times a day, the mass per preparation of the preparation of the present invention (naked / base) Can be selected from the range of 150 to 600 mg. Preferably, it is 200 to 400 mg.

  In addition, the size of the preparation of the present invention (naked / base agent) is not limited, but for example, when formed into a circular tablet (cylindrical), the diameter can be in the range of about 5 mm to about 15 mm. . Preferably it is about 7 mm to about 12 mm. The thickness is not limited, and may be in the range of about 3 mm to about 6 mm.

  The preparation of the present invention (naked agent / base agent) is characterized in that capping, which is one of the tableting problems, is suppressed. The presence or absence of capping is determined by taking 50 pieces of the compression-molded preparation in a 50 mL glass bottle with a cap, closing the cap, and shaking with a shaker (YS-8D: manufactured by Yayoi Co., Ltd.) for 5 minutes (200 strokes / minute). Evaluation can be made by counting the number of formulations that are capped (completely separated) after 5 minutes. As described in the experimental examples described below, the preparation of the present invention (naked agent / base agent) was a compression-molded preparation (Comparative Example 1 and Comparative Example 1) produced without using the component (C) when preparing ascorbic acid-containing granules. The occurrence of capping is significantly suppressed as compared with 2).

  Further, the preparation of the present invention (naked agent / base agent) preferably has a hardness of 30 N or more, and the disintegration time is preferably within 50 minutes. Here, the hardness means hardness (N) in the diameter direction (longitudinal direction) of the compression-molded preparation, as described in Examples described later. The hardness is determined by using a tablet hardness tester (SCHLEUNIGER 6D type: manufactured by Freund Corporation) to measure the hardness in the diametric direction (longitudinal direction) of 10 drugs selected at random and to obtain an average value. Can be calculated. The hardness is preferably 30 N to 300 N, more preferably 50 N to 250 N, and particularly preferably 70 N to 200 N.

  As described in Examples below, the disintegration time was determined for the six compression-molded preparations according to the disintegration test of the Japanese Pharmacopoeia General Test Method (immediate release preparation: tablet [uncoated tablet]). (Without a disc) to determine the time required for all six formulations to disintegrate. Specifically, one preparation of the sample was placed in each of the six glass tubes of the tester, and the tester was operated at 37 ± 2 ° C. using purified water as a test solution, and the state of the sample collapse was observed. Is visually observed. When no residue of the sample is observed in the glass tube, it is judged as "collapse", and the elapsed time up to that point is defined as collapse time (minutes). The disintegration time is within 50 minutes, preferably within 40 minutes, more preferably within 30 minutes, and particularly preferably within 20 minutes. Although the lower limit value is not limited, the minimum time before collapse can be, for example, about 5 minutes.

  Further, the preparation of the present invention (naked agent / base agent) preferably has a low friability of 1% or less. As described in Examples described later, the friability was measured by placing 10 preparations of the present invention in a socket having a capacity of 50 mL, and closing the lid with a shaker (YS-8D: manufactured by Yayoi Co., Ltd.) for 5 minutes ( (200 times / min) can be determined by shaking and calculating the rate of wear caused by shaking. Specifically, after measuring the mass (mass 1) of the 10 preparations of the present invention and shaking for 5 minutes with the above-mentioned shaker, the preparation in the socket was taken out through a No. 10 sieve, and the powder was sieved off. The tablet mass (mass 2) is measured again. From the mass difference (mass 1-mass 2) of the preparation before and after shaking, the friability is determined by the following formula. This experiment was performed three times (n = 3), and the average value can be used as the final friability (%). The friability is preferably 1% or less, more preferably 0.7% or less.

[Equation 1]
Abrasion degree (%) = [(mass 1−mass 2) / mass 1] × 100

  As described in the experimental examples described below, the preparation of the present invention (naked agent / base agent) not only mixes the silicate compound as the component (D) with the ascorbic acid-containing granules, but also further adds By addition, the disintegration time is shorter and the friability (%) is significantly reduced, and the occurrence of cracks and breakage is reduced as compared with the compression-molded preparations (Examples) produced by mixing only the granules. It can be suppressed significantly.

(II) Coated preparation and method for producing the coated preparation The coated preparation of the present invention (hereinafter also referred to as “the present coated preparation”) is a preparation in which the surface of the above-mentioned preparation of the present invention (naked / base material) is coated. The present coated preparation includes a sugar-coated preparation obtained by coating the surface of the preparation of the present invention with a sugar coating, and a film-coated preparation obtained by coating the surface with a film or the like. Such films include those that have properties such as fast dissolving, slow dissolving, gastric dissolving, and enteric dissolving.

  Coating with a sugar coating or a film can be performed by, for example, a pan coating method, a fluidized bed coating method, a tumbling coating method, a dry coating method, or a combination of these methods. At this time, according to a standard method, a sugar coating component or a film component is dissolved or dispersed in water or an organic solvent (such as ethanol) and spray-coated, or the film component is directly sprayed and dry-coated by applying heat or pressure. You can also.

  The sugar-coating components used for sugar-coating include, but are not limited to, monosaccharides and disaccharides such as sucrose (sucrose, purified sucrose), fructose, glucose, lactose, trehalose; erythritol, mannitol, sorbitol, xylitol, mulch Examples of the sugar include sugars such as tall, powdered reduced maltose starch syrup, and reduced lactose. Sugar coating liquid also contains excipients such as talc, precipitated calcium carbonate, calcium monohydrogen phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, calcium sulfate, calcium lactate, and kaolin, and titanium oxide and iron oxide. Coloring agents may be included.

  Examples of the film coating agent include a water-soluble polymer compound, a gastric-soluble polymer compound, and an enteric polymer compound. Examples of the water-soluble polymer compound include, but are not limited to, methylcellulose, hypromellose, hydroxypropylcellulose, polyethylene glycol, polyvinyl alcohol (partially saponified product), polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyvinyl pyrrolidone, and the like. be able to. Examples of the gastric soluble polymer compound include, but are not limited to, polyvinyl acetal polymers such as polyvinyl acetal diethylaminoacetate, methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer, methyl methacrylate-diethylaminoethyl methacrylate Gastric-soluble methacrylic acid-based polymer compounds such as copolymers can be mentioned. Examples of the enteric polymer compound include, but are not limited to, methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer, methacrylic acid copolymer S, methyl acrylate-methyl methacrylate-methacrylic acid copolymer, and the like. And methacrylic acid-based polymer compounds such as cellulose acetate phthalate, hypromellose acetate phthalate, hypromellose acetate succinate, polyvinyl acetate phthalate, and carboxymethyl ethyl cellulose.

  The coating (coating) layer (coating) formed by a sugar coating or a film may be the whole or a part of the surface of the preparation of the present invention (naked / base material). In order to obtain the effect of masking the resulting odor, it is preferable that the entire surface of the preparation of the present invention is covered. The ratio (mass ratio) of the preparation of the present invention (naked agent / base agent) to its coating layer is not limited, but for sugar coating, 100 parts by mass of the preparation of the present invention (naked agent / base agent) is applied to the coating layer. The range of 30 to 200 parts by mass, and the range of the film coating can be 3 to 10 parts by mass based on 100 parts by mass of the preparation of the present invention (naked agent / base material).

  The disintegration time of the present coated preparation is preferably within 60 minutes. Here, the disintegration time can be measured by the method described above. It is preferably within 50 minutes, more preferably within 40 minutes, even more preferably within 30 minutes.

(III) Method for suppressing capping of L-cysteine-containing vitamin C-rich compression-molded preparation The present invention suppresses capping of a compression-molded preparation containing the above-mentioned components (A), (B) and (D). Provide a way.

  In the method, at least one compound selected from the group consisting of (C) a polyvinyl alcohol-based compound, a polyvinylpyrrolidone-based compound, and a cellulose-based compound is blended as a binder for granulation in a manufacturing process of a granulated compression-molded preparation. Can be implemented. Specifically, it can be carried out by using the above-mentioned compound as a binder for granulation in the step of preparing an ascorbic acid-containing granule in the production of a granule compression-molded preparation. More specifically, after the composition containing the component (A) is granulated using the component (C), the components (B) and (D) are mixed with the resulting mixture, and the prepared mixture is compression-molded. A compression-molded preparation with suppressed capping can be prepared. In another embodiment, a composition containing the components (A) and (D) is granulated using the component (C), and then the component (B) or the components (B) and (D) are mixed. A method of compression-molding the prepared mixture; and a step of granulating a composition containing the components (A), (B) and (D) by using the component (C), and then granulating the composition with the component (D) and / or (For example, a lubricant), and the resulting mixture is compression-molded to prepare a compression-molded preparation in which capping is suppressed.

  The components (A) to (D), optional components used for preparing a compression-molded preparation, their mixing ratio, a granulation method using the component (C), a compression molding method, and the like are described above in (I). ) Can be referred to, and the description can be incorporated herein. As shown in an experimental example described later, when preparing a granulated product containing ascorbic acid, the component (C) is used as one of the granulated components to produce a compression-molded preparation, so that the component (C) is used as the granulated component. As compared with the case where the compression-molded preparation (Comparative Examples 1 and 2) is not used, the occurrence of capping can be significantly suppressed.

(IV) Method for Improving Disintegrability and / or Friability of L-Cysteine-Containing Vitamin C High-Containing Compression Molded Product The present invention relates to a disintegrable or / And a method for improving friability.

  The method comprises the steps of: preparing a granulated product containing at least the components (A) and (C) in the step of producing a granulated compression-molded preparation, by adding the component (B), the component (D), and the lubricant It can be carried out by mixing at least one selected post-addition component and compression-molding the obtained mixture of the components (A), (B), (C) and (D). The granulated product may contain a component (D) in addition to the components (A) and (C). Specifically, the (B) component and the (D) component are post-added to the granulated material containing the (A) and (C) components and mixed, and the prepared mixture is compression-molded to obtain a disintegrating property or And / or a compression-molded preparation with improved friability can be prepared. Further, the component (B) or the component (B) and the component (D) are added to and mixed with the granulated product containing the components (A), (C) and (D), and the prepared mixture is compression-molded. Thereby, a compression-molded preparation having improved disintegration and / or friability can be prepared. Further, the component (D) and / or the lubricant are added to the granulated product containing the components (A), (B), (C) and (D), and the mixture is compression-molded. Thereby, a compression-molded preparation having improved disintegration and / or friability can be prepared.

  The components (A) to (D), optional components used for preparing a granulated compression-molded preparation, their mixing ratio, a granulation method using the component (C), and a compression molding method are described above ( The description of I) can be referred to, and the description can be incorporated herein. As shown in the experimental examples described below, by blending the component (D) as a granulating component with the ascorbic acid-containing granulated product, the disintegration of the granule compression-molded preparation is increased or / and the friability is reduced. Not only can the granules containing ascorbic acid be added to the ascorbic acid-containing granules, but also the post-addition of the component (D) can enhance the disintegration of the granule compression-molded preparation and / or reduce the friability, and the disintegration is good. A stable compression-molded preparation can be manufactured and provided. Furthermore, by blending the component (D) with the ascorbic acid-containing granules and simultaneously adding the same to the granules, the disintegration time is further shortened, and the friability (%) is significantly reduced. And breakage can be significantly suppressed.

  As described above, in this specification, the terms “comprising” and “including” include the meanings of “consisting of” and “consisting essentially of”.

  Hereinafter, the present invention will be described using experimental examples in order to facilitate understanding of the configuration and effects of the present invention. However, the present invention is not limited at all by these experimental examples. The following experiments were performed at room temperature (25 ± 5 ° C.), relative humidity of 45% or less, and atmospheric pressure, unless otherwise noted. Unless otherwise specified, “%” means mass% and “parts” means parts by mass.

The compounds used in the examples are as follows.
Light anhydrous silicic acid: Adsolider 101 (Fuji Silysia)
Microcrystalline cellulose: CEOLUS KG-1000 (Asahi Kasei Corporation)
Polyvinyl alcohol acrylic acid / methyl methacrylate copolymer: POVACOAT type F (average molecular weight about 40,000) (Nissin Kasei)
Povidone (polyvinylpyrrolidone): Kollidon 90F (BASF Corporation) Hydroxypropylcellulose: HPC-L (Nippon Soda Co., Ltd.)
Hypromellose: VIVAPHARM HPMC E6 (JRS PHARMA)
Corn starch: Pharmacopoeia constarch white (Nippon Cornstarch Co., Ltd.)
Croscarmellose sodium: DISOLCEL (Meiji Chemical)
Magnesium stearate: Magnesium stearate plant (Taihei Chemical Industry)

Experimental Example 1 Production of Granular Compression Molded Preparation (Examples 1-4) and Its Evaluation (1) Production of Granular Compression Molded Preparation (Tablet) (a) Preparation of Granules Containing Ascorbic Acid Ascorbine in the amount shown in Table 1 After sieving the acid, light anhydrous silicic acid, and crystalline cellulose as an excipient with a sieve (opening 500 μm), the mixture is charged into a fluidized bed granulator (MP-01ND type: manufactured by Powrex Co., Ltd.) to obtain about 5 Mix for minutes. An aqueous solution was prepared by dissolving the granulating binder described in Table 1 in purified water in advance while flowing the mixture under an air supply condition of 80 ° C. (Examples 1 to 4 were 10% aqueous solutions. Example 1 and a 5% aqueous solution) were added at a rate of 15 g / min, and Examples 1 and 2 were granulated for about 10 minutes, and Examples 3 and 4 and Comparative Example 1 were granulated for about 20 minutes. On the other hand, in Comparative Example 2, granulated in the same manner as in Examples 1 to 4, except that purified water was used instead of the aqueous solution of the granulating binder. After the granulation, the mixture was dried until the intake temperature was about 80 ° C and the exhaust temperature was about 40 ° C, to prepare ascorbic acid-containing granules having an average particle diameter of about 100 to 150 µm.

(B) Post-addition of L-cysteine-containing composition L-cysteine, light silicic anhydride, and a fluidizing agent were added to the ascorbic acid-containing granules prepared above in the proportions shown in Table 1 as post-addition components. Crystalline cellulose, croscarmellose sodium as a disintegrant, and magnesium stearate as a lubricant were added, sieved with a sieve (opening 500 μm), and thoroughly mixed by bag mixing.

(C) Compression molding The mixed composition containing all the components was converted into a rotary tableting machine (Collect 24, manufactured by Kikusui Seisakusho Co., Ltd., mortar size: 9.0 mm) (rotating disk rotation speed: 40-60 rpm, auto feeder rotation speed: 40- 80 rpm) and tableting was performed at the three tableting pressures shown in Table 1 to produce 350 mg tablets (Examples 1 to 4 and Comparative Example 1).

(2) Physical property evaluation test of granulated compression-molded preparation (tablet) The thickness (mm), hardness (N), disintegration time (minute), friability (%), and tableting trouble (capping) of the produced tablet were measured. It was measured and evaluated according to the following method. In the test, tablets immediately after compression molding (tablet molding) were used.

(A) Thickness (mm)
The length (mm) of the tablet thickness method is measured using a thickness gauge (Model C1012BS: manufactured by Mitutoyo Corporation). Measurement was performed on 10 tablets, and the average value was determined.

(B) Hardness (N)
The hardness (N) in the diameter direction of the tablet is measured using a tablet hardness tester (SCHLEUNIGER 6D type: manufactured by Freund Corporation). Measurement was performed on 10 tablets, and the average value was determined.

(C) Disintegration time (min)
Take 6 tablets (n = 6) and carry out a disintegration test (without auxiliary panel) according to the disintegration test of the Japanese Pharmacopoeia General Test Method (immediate release preparation: tablet [uncoated tablet]) The time required for all tablets to disintegrate was measured. Specifically, one tablet of the sample was placed in each of the six glass tubes of the tester, and the tester was operated at 37 ± 2 ° C. using water as a test solution, and the state of the sample collapse was observed. Observe. When no residue of the sample was observed in the glass tube, it was judged as "disintegration", and the elapsed time up to that point was defined as disintegration time (minutes).

(D) Friability (%)
After taking 10 tablets in a socket of 50 mL capacity and closing the lid, the tablets were shaken up and down with a shaker (YS-8D: manufactured by Yayoi Co., Ltd.) for 5 minutes (200 times / minute), and the abrasion was calculated by shaking. . Specifically, after measuring the mass (mass 1) of 10 tablets, after shaking for 5 minutes with the above-mentioned shaker, the tablets in the socket were taken out through a No. 10 sieve, and the powder was sieved. The mass (mass 2) was measured again. The friability was determined by the following equation from the difference in mass (mass 1-mass 2) of the tablet before and after shaking. This experiment was performed three times (n = 3), and the average value was taken as the final friability (%).

[Equation 2]
Abrasion degree (%) = [(mass 1−mass 2) / mass 1] × 100

(E) Capping (pieces)
After taking 50 tablets into a 50 mL cap 11K glass bottle with a cap and closing the cap, shake with a shaker (YS-8D: manufactured by Yayoi Co., Ltd.) for 5 minutes (stroke number 200 times / min) and capping after 5 minutes ( The number of tablets (completely separated) was counted. This experiment was performed twice (n = 2).

表１のキャッピング試験結果に示すように、造粒工程で、造粒用結合剤を使用しないと、高い割合で打錠障害（キャッピング）が生じることが確認された（比較例２）。また造粒用結合剤としてデンプンを使用した場合でもキャッピングは十分抑制できないことが確認された（比較例１）。これに対して、造粒用結合剤として、ポリビニルアルコール系化合物、ポリビニルピロリドン系化合物、およびセルロース系化合物を用いることで、有意に打錠特性が改善されて、キャッピングが抑制できることが確認された。特にポリビニルアルコール系化合物、及びポリビニルピロリドン系化合物は、セルロース系化合物よりも少ない量でキャッピングを抑制することができる。 (3) Test result and its evaluation Table 1 shows the formulation and physical properties of each tablet.

As shown in the results of the capping test in Table 1, it was confirmed that a tableting failure (capping) occurs at a high rate without using a granulating binder in the granulating step (Comparative Example 2). It was also confirmed that capping could not be sufficiently suppressed even when starch was used as a binder for granulation (Comparative Example 1). On the other hand, it was confirmed that the use of a polyvinyl alcohol-based compound, a polyvinylpyrrolidone-based compound, and a cellulose-based compound as the binder for granulation significantly improved the tableting properties and suppressed capping. In particular, the capping of the polyvinyl alcohol-based compound and the polyvinyl pyrrolidone-based compound can be suppressed with a smaller amount than that of the cellulose-based compound.

Experimental Example 2 Production of granule compression-molded preparation (Examples 1, 2 and 5 to 12) and evaluation thereof (1) Production of granule compression-molded preparation (tablet) Table 2 (Examples 1 and 5 to 9, Comparative Example 3) According to the formulation described in Table 3 (Examples 2 and 10 to 12), as in Experimental Example 1 described above, an ascorbic acid-containing granulated product was produced, and the post-addition component was blended and mixed with the granulated product, followed by compression molding. Then, tablets of 350 mg or 333 mg per tablet were produced.

(2) Physical property evaluation test of granulated compression-molded preparation (tablet) For the manufactured tablet, similarly to Experimental Example 1, thickness (mm), hardness (N), disintegration time (min), friability (%), and compression Tablet damage (capping) was measured and evaluated. In the test, tablets immediately after compression molding (tablet molding) were used.

比較例３と実施例５に示すように、造粒成分としてケイ酸化合物を配合すると（実施例５）、配合しない場合（比較例３）と比較して、錠剤の硬度が高くなる一方で、崩壊時間は短縮し、崩壊性が改善することが確認された。さらにケイ酸化合物を、造粒成分としてだけでなく、後添加成分としても配合すると（実施例１）、より錠剤の硬度が高くなるとともに、さらに崩壊時間も短縮し、崩壊性がより一層改善することが確認された。また摩損度（％）も低下することが確認された。また実施例６〜９に示すように、ケイ酸化合物を使用することによる崩壊性改善効果は、後添加成分として配合するケイ酸化合物の量に依存することが確認された（表２参照）。
また、同様の効果は実施例２と実施例１０、及び実施例１１と１２からも確認された（表３）。
これらのことから、本発明の顆粒圧縮成形製剤において、造粒成分または造粒成分及び後添加成分としてのケイ酸化合物の使用は、顆粒圧縮成形製剤の硬度を高めるかまたは大きく影響を与えることなく、崩壊性の改善（崩壊性促進）に有用であることが確認された。また摩損度（％）の改善にも有効に作用することが確認された。 (3) Test result and its evaluation Tables 2 and 3 show the formulation and physical properties of each tablet.

As shown in Comparative Example 3 and Example 5, when the silicate compound is blended as the granulating component (Example 5), the hardness of the tablet is higher than when not blended (Comparative Example 3), It was confirmed that the disintegration time was shortened and disintegration was improved. Further, when the silicate compound is blended not only as a granulation component but also as a post-addition component (Example 1), the hardness of the tablet is further increased, the disintegration time is further shortened, and the disintegration is further improved. It was confirmed that. It was also confirmed that the friability (%) was reduced. Further, as shown in Examples 6 to 9, it was confirmed that the disintegration improving effect by using the silicate compound depends on the amount of the silicate compound to be added as a post-addition component (see Table 2).
A similar effect was also confirmed from Examples 2 and 10 and Examples 11 and 12 (Table 3).
From these facts, in the granule compression-molded preparation of the present invention, the use of the silicate compound as the granulation component or the granulated component and the post-addition component does not increase the hardness of the granule compression-molded formulation or significantly affect It was confirmed to be useful for improving disintegration (promoting disintegration). In addition, it was confirmed that it also effectively worked to improve the friability (%).

Experimental Example 3 Production of granule compression-molded preparation (Examples 6 and 13 to 18) and evaluation thereof (1) Production of granule compression-molded preparation (tablet) Described in Table 4 (Examples 6 and 13 to 18, Comparative Example 4) According to the prescription, ascorbic acid-containing granules were produced in the same manner as in Experimental Example 1 described above, and post-additives were blended and mixed with the granules, followed by compression molding to produce 333 mg tablets per tablet.

(2) Physical property evaluation test of granulated compression-molded preparation (tablet) For the manufactured tablet, similarly to Experimental Example 1, thickness (mm), hardness (N), disintegration time (min), friability (%), and compression Tablet damage (capping) was measured and evaluated. In the test, tablets immediately after compression molding (tablet molding) were used.

実施例６及び１３〜１５に示すように、造粒成分としてケイ酸化合物を配合すると、配合しない場合（比較例４）と比較して、崩壊時間は短縮し、崩壊性が改善することが確認された。またその効果は、造粒成分に配合するケイ酸化合物の量に依存して高くなることが確認された。また実施例１６及び１７に示すように、ケイ酸化合物として、軽質無水ケイ酸のみならず含水二酸化ケイ素を用いた場合も同様に、用量依存的に崩壊時間が短縮し、崩壊性が改善することが確認された。
また実施例１８に示すように、ケイ酸化合物を、造粒成分としてでなく、後添加成分として配合した場合でも、配合しない場合（比較例４）と比較して崩壊時間は短縮し、崩壊性が改善することが確認された。
以上のことから、本発明の顆粒圧縮成形製剤において、ケイ酸化合物は、所望の硬度を保ちながらも、崩壊性の改善（崩壊性促進）に有効に作用することが確認された。 (3) Test result and its evaluation Table 4 shows the formulation and physical properties of each tablet.

As shown in Examples 6 and 13 to 15, it was confirmed that when a silicate compound was blended as a granulation component, the disintegration time was shortened and disintegration was improved, as compared with the case where no silicic acid compound was blended (Comparative Example 4). Was done. It was also confirmed that the effect was enhanced depending on the amount of the silicate compound to be added to the granulation component. In addition, as shown in Examples 16 and 17, similarly to the case where not only light silicic anhydride but also hydrous silicon dioxide was used as the silicate compound, the disintegration time was reduced in a dose-dependent manner, and the disintegration was improved. Was confirmed.
Further, as shown in Example 18, even when the silicate compound was blended not as a granulation component but as a post-addition component, the disintegration time was shortened as compared with the case where it was not blended (Comparative Example 4), and the disintegration property was reduced. Was confirmed to improve.
From the above, it was confirmed that in the granular compression-molded preparation of the present invention, the silicate compound effectively acts to improve disintegration (promoting disintegration) while maintaining desired hardness.

Experimental Example 4 Production of Granular Compression Molded Preparation (Examples 19 to 20) and Its Evaluation (1) Production of Granular Compression Molded Preparation (Tablet) According to the formulation described in Table 5 (Examples 19 to 20, Comparative Example 5) In the same manner as in Experimental Example 1 described above, an ascorbic acid-containing granulated product (including cysteine) was produced, and a post-addition component was blended and mixed with the granulated product, followed by compression molding to produce a 333 mg tablet per tablet.

(2) Physical property evaluation test of granulated compression-molded preparation (tablet) For the manufactured tablet, similarly to Experimental Example 1, thickness (mm), hardness (N), disintegration time (min), friability (%), and compression Tablet damage (capping) was measured and evaluated. In the test, tablets immediately after compression molding (tablet molding) were used.

実施例１９に示すように、システインを造粒成分として配合した場合でも、造粒成分にケイ酸化合物を配合することで、配合しない場合（比較例５）と比較して、硬度が高まる一方で、崩壊時間は短縮し、崩壊性が改善することが確認された。またその傾向は、ケイ酸化合物を造粒成分として配合するとともに、後添加成分としても配合することで、より高まることが確認された。
以上のことから、本発明の顆粒圧縮成形製剤において、ケイ酸化合物は、システインが造粒成分及び後添加成分のいずれかの成分として配合されているかに関わらず、所望の硬度を保ちながらも、崩壊性の改善（崩壊性促進）に有効に作用することが確認された。 (3) Test result and its evaluation Table 5 shows the formulation of each tablet and its physical properties.

As shown in Example 19, even when cysteine was blended as a granulation component, the hardness was increased by blending the silicate compound with the granulation component as compared with the case where no cysteine was blended (Comparative Example 5). It was confirmed that the disintegration time was shortened and disintegration was improved. In addition, it was confirmed that the tendency was further increased by mixing the silicate compound as a granulation component and also as a post-addition component.
From the above, in the granule compression-molded preparation of the present invention, the silicate compound, while maintaining the desired hardness, irrespective of whether cysteine is blended as either a granulation component or a post-addition component, It was confirmed that it effectively works to improve disintegration (promoting disintegration).

Claims (9)

(A) Ascorbic acid or a salt thereof in an amount exceeding 1200 mg in terms of the amount of ascorbic acid to be taken per day,
(B) L-cysteine or a salt thereof in an amount exceeding 160 mg in terms of the amount of L-cysteine taken per day,
(C) at least one binder for granulation selected from the group consisting of polyvinyl alcohol compounds, polyvinylpyrrolidone compounds, and cellulose compounds; and (D) at least one selected from the group consisting of light anhydrous silicic acid and hydrous silicon dioxide. One silicate compound,
A compression-molded preparation containing: A granule compression-molded preparation containing the components (A), (B), (C) and (D), wherein the granulated material contains (A), (A) At least components (A) and (C) selected from the group consisting of B), (C) and (D),
(D) is compounded as a post-addition component separately from the granulated component and / or separately from the granulated material,
The compression-molded preparation according to claim 1. (B) is characterized by being blended as a post-addition component, separately from the granulated component or separately from the granulated material,
The compression-molded preparation according to claim 2.   The hardness according to any one of claims 1 to 3, wherein the hardness is 30N or more, and the disintegration time according to the disintegration test method (without an auxiliary plate, using purified water at 37 ° C) specified in the Japanese Pharmacopoeia (17th revision) is within 50 minutes. 2. The compression-molded preparation according to item 1.   A coated preparation, wherein the surface of the compression-molded preparation according to any one of claims 1 to 4 is further coated. The method for producing the compression-molded preparation according to any one of claims 1 to 4, or the coated preparation according to claim 5, comprising the following steps 1 to 3:
1. Contains at least the components (A) and (C) selected from the group consisting of the components (A), (B), (C) and (D), or the components (A), (C) and (D) Preparing granules,
2. 2. mixing the granulated product with at least one post-addition component selected from the group consisting of (B), (D) and a lubricant; A step of compression molding the mixture obtained in the step 2; The method according to claim 6, wherein the method further comprises the following 4 steps in addition to the steps 1 to 3:
4. A step of coating the compression-molded preparation obtained in the above step 3. (A) ascorbic acid or a salt thereof in an amount exceeding 1200 mg in terms of the amount of ascorbic acid to be taken per day,
(B) at least one selected from the group consisting of L-cysteine or a salt thereof in an amount exceeding 160 mg in terms of the amount of L-cysteine taken daily, and (D) light anhydrous silicic acid and hydrous silicon dioxide. Silicate compounds,
A method for suppressing capping of a granular compression-molded preparation containing
A method for suppressing capping, which further comprises blending (C) at least one compound selected from the group consisting of a polyvinyl alcohol compound, a polyvinylpyrrolidone compound, and a cellulose compound as a binder for granulation. (A) ascorbic acid or a salt thereof in an amount exceeding 1200 mg in terms of the amount of ascorbic acid to be taken per day,
(B) L-cysteine or a salt thereof in an amount exceeding 160 mg in terms of the amount of L-cysteine taken per day,
(C) at least one binder for granulation selected from the group consisting of polyvinyl alcohol compounds, polyvinylpyrrolidone compounds, and cellulose compounds; and (D) at least one selected from the group consisting of light anhydrous silicic acid and hydrous silicon dioxide. One silicate compound,
A method for improving disintegration or / and friability of a granular compression-molded preparation containing
As the granulation component, at least the components (A) and (C) selected from the group consisting of the components (A), (B), (C), and (D), or at least (A), (C), and ( D) a granulated product containing the component;
A mixture of the components (A), (B), (C) and (D) is mixed with at least one post-addition component selected from the group consisting of the components (B), (D) and the lubricant. Prepared,
The method for improving the disintegration property and / or the friability, wherein the mixture is subjected to compression molding.