JPH09169651A - Vitamin-containing tablet and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject tablet stable for a long period of time even if an active ingredient is added in high concentration, capable of reducing a daily dose, by blending a vitamin B6 -containing granular granule with the active ingredient such as vitamin B4 , etc. SOLUTION: This tablet is obtained by blending (A) a granular granule containing 75-97wt.% of a vitamin B6 (preferably pyridoxin hydrochloride or pyridoxal phosphate) with (B) a vitamin B1 (preferably bisbentiamine) and (C) a vitamin B12 and another active ingredient (preferably a vitamin E, a nicotinic acid, a pantothenic acid or gamma-oryzanol) so as to make 65-80wt.% total content of the whole active ingredients in a raw tablet. The component B and the component C are added as the granular granule and the weight of one granule of the raw granule is preferably 160-220mg.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to vitamin B ₁ , vitamin B ₆ , and vitamin B ₁₂ active ingredient vitamin-containing tablets which are easy to take and are stable over time, and a method for producing the same.

[0002]

2. Description of the Related Art Vitamin is an essential nutrient, especially vitamin B ₁ , vitamin B ₆ and vitamin B ₁₂ cause neuralgia,
It is effective in alleviating various symptoms such as muscle pain, joint pain, numbness of limbs, and eye fatigue. It is also desirable to supplement these vitamins during physical fatigue and during pregnancy and lactation.

[0003] medicaments containing vitamins in high unit vitamin agent formulation prepared in general for pharmaceutical manufacturing (import) approval criteria (1995) (import) and the reference is defined as the acceptance criteria, vitamin B _1, vitamin Regarding B ₆ and vitamin B ₁₂ , the formulation rules and amounts have been determined as the vitamin B ₁ B ₆ B ₁₂ main drug formulation. Therefore, in accordance with this standard, pharmaceuticals containing various dosage forms and various shapes of vitamin B ₁ , vitamin B ₆ and vitamin B ₁₂ are commercially available.

On the other hand, the stability of vitamins depends on pH, light, heat,
Although it is affected by the storage environment such as water content, the content decreases due to various additives and coexisting components such as different vitamins. In addition, the stability varies depending on the dosage form selected and further on the vitamin component used in the same medicinal vitamin. Therefore, when designing a formulation containing vitamins, the manufacturing method, shape, and vitamin component species are selected within the range of the approval criteria, taking into consideration stability, productivity, ingestion feeling, absorption, etc., while considering stability. . As a means for stabilization,
Attempts have been made to add stabilizers such as antioxidants, but such means are not preferable because they will ingest what is unnecessary for the patient. Therefore, it is more desirable to achieve stabilization by formulating a pharmaceutical formulation such as avoiding contact between incompatible ingredients without adding a new additive.

Also in the vitamin B ₁ B ₆ B ₁₂ active drug formulation, coexistence of vitamin B ₁ and vitamin B ₆ causes a decrease in content. Therefore, in order to avoid contact between the two components, it may be possible to use a layered tablet or a dry-coated tablet to stabilize it by means of pharmaceutical formulation. In this case, however, the manufacturing process becomes complicated. However, it is unavoidable that the shape of the tablet becomes large.

[0006] In the vitamin B ₁ B ₆ B ₁₂ main drug formulation, each vitamin is incorporated in a high unit, and since many components which are allowed to be incorporated in the approval standard are added, 1
The compounding amount of the medicinal component per tablet increases. However, it is necessary to add a large amount of excipients in order to suppress contact between incompatible ingredients and, in addition, due to the moldability of some ingredients, the active ingredient concentration in uncoated tablets is high even in commercial products. The amount is 60% by weight, and many are designed with lower active ingredient concentrations. As a result, the dose for one dose increases, and the shape of the tablet also increases, which imposes a great burden on the patient when taking the drug.

Vitamin B ₁ component which is allowed to be mixed is 10 in the approval standard for manufacturing (import) vitamin-based drug preparation.
Although more than one species are listed, among them, bisbenchamine is recommended as a vitamin B ₁ component because of its relatively high stability and excellent absorption. However, since bisbentamine has a difficulty in moldability, it is necessary to add a large amount of excipients for tableting, and the tablet containing bisbentamine also has a large shape, which is further described above. since bad miscibility such as causing a content decrease with respect to vitamin B _6, containing bisbentiamine at high unit shape is small, vitamin B ₁ B with a reduced burden on the patient to a reduced number of dose ₆ B ₁₂ active drug tablets were not available on the market.

[0008]

Therefore, the object of the present invention is to provide a highly stable vitamin B ₁ B ₆ because the shape is small and the vitamin B ₁ and the vitamin B ₆ do not come into contact with each other.
It is intended to provide a vitamin-containing tablet having a B ₁₂ active ingredient and a method for producing the same.

[0009]

[Means for Solving the Problems] In view of the above circumstances, the present invention
As a result of intensive research conducted by the brighter, vitamin B₆A suitable
Granulate by the method and add vitamin B₁,vitamin
B₁₂, Vitamin B₁B₆B ₁₂Allowed to be mixed according to the standard of efficacy of the main drug
Add the necessary ingredients and necessary additives to the tablet to prepare a tablet.
By tableting, the content of all active ingredients in one tablet is 65
Vitamin-containing tablets with good stability even if the amount is over
They have found that they can be obtained and have completed the present invention.

That is, the present invention provides vitamin B ₆ of 75
A tablet obtained by compounding a granular granulated product containing 97 to 97% by weight of vitamin B ₁ , vitamin B ₁₂ and vitamin B ₁ B ₆ B _{12 with} ingredients that are allowed to be mixed on the basis of the efficacy of the main drug. , The total content of all active ingredients is 65-80% by weight
A vitamin-containing tablet and a method for producing the same are provided.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION Examples of vitamin B ₆ used in the present invention include pyridoxine hydrochloride, pyridoxal phosphate and the like. In the present invention, pyridoxine hydrochloride is preferable from the viewpoint of stability and the like. The content of vitamin B _{6 in} one vitamin-containing tablet of the present invention is 1 of the maximum daily amount based on the compounding standard of the vitamin-based drug preparation that is approved for over-the-counter drug manufacturing (import).
/ 2, that is, according to the 1995 standard, it is preferable to use 50 mg when pyridoxine hydrochloride is used.

The content of vitamin B ₆ is 7 in the granulated product.
It is 5 to 97% by weight, and preferably 85 to 91% by weight. If the content is less than 75% by weight, the shape of the tablet becomes large if a predetermined amount of vitamin B ₆ is contained in one tablet, and the size of the tablet is suppressed within a predetermined range. Then, it is necessary to reduce the amount of additives such as an excipient added when tableting together with vitamins B ₁ and B ₁₂ , so that the degree of contact between vitamin B ₆ and vitamin B ₁ becomes high, which is not preferable. . Also, vitamin B ₆
If the content of is more than 97% by weight, it will not be a granular granulated product.

Examples of vitamin B ₁ used in the present invention include bisbentiamine, fursultiamine, benfotiamine, octothiamine and the like. In the present invention, bisbenchamine is preferred from the viewpoint of stability and absorbability. Cyanocobalamin is preferred as the vitamin B ₁₂ . The content of Vitamin B ₁ and Vitamin B _{12 in} one tablet containing vitamin of the present invention is 1 / maximum of the maximum daily amount of the vitamin C drug formulation standard of the over-the-counter drug manufacturing (import) approval standard.
2, that is, according to the 1995 standard, it is preferable to use 50 mg when bisbentamine is used and 750 μg when cyanocobalamin is used.

Further, other active ingredients that can be added together with vitamin B ₁ and vitamin B ₁₂ include nicotinic acids, vitamin Es, pantothenic acids, gamma-oryzanol, etc. There is no limitation as long as the ingredients are allowed to be mixed according to the approval criteria.

Vitamin B in the vitamin-containing tablet of the present invention
The total content of ₁ , B ₆ , B ₁₂ and other active ingredients is 6
It is 5 to 80% by weight, preferably 65 to 70% by weight. If the content is less than 65% by weight, the tablet shape becomes large when it is attempted to contain a predetermined amount of vitamin in one tablet, and the feeling of ingestion is impaired, and the size of one tablet falls within a predetermined range. In the case of the above, the number of tablets to be taken increases when trying to take the required amount of vitamins, which puts a burden on the user.

In order to produce the vitamin-containing tablet of the present invention, first, a suitable granulating machine such as a stirring granulator is used to add an excipient to vitamin B ₆ and granulate it by a wet method. Granulate to produce vitamin B ₆ granules. Here, examples of the excipient include crystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, D-mannitol, and the like, but are not particularly limited as long as they are allowed to be added to a drug. Also, vitamin B
_{6 The} granulated product may be coated with a water-soluble or water-insoluble polymer film.

Next, the vitamin B ₆ granules are added with vitamin B ₁ , vitamin B ₁₂ and other active ingredients to form tablets. In this case, from the viewpoint of imparting fluidity, it is preferable that these components are granulated in advance in the same manner as in the production of the vitamin B ₆ granulated product.

[0018] Excipients in granulate and vitamin B ₆ granulate containing the vitamin B ₁ · B _12, disintegrants, additives necessary for the compression molding of such lubricants, vitamin B _1, vitamin The total content of all active ingredients such as B ₆ and vitamin B ₁₂ is 65
-80% by weight, and then compression-molded and tableted using a tableting machine. It is preferable that the size of the tablet be 160 to 220 mg per plain tablet from the viewpoint of reducing the burden of administration and obtaining a good feeling during use. Also,
The diameter of the uncoated tablet at that time is particularly preferably 7.5 to 8.5 mm.

The obtained tablets can be used as they are, but they are used as film-coated tablets in order to prevent permeation of moisture from the outside to enhance stability and to mask unpleasant bitterness to facilitate administration. Preferably
Dragees are more preferred.

[0020]

INDUSTRIAL APPLICABILITY According to the present invention, the active ingredient is added to the plain tablet portion 6
A formulation that is stable for a long period of time can be produced even when blended at a high concentration of 5% by weight or more. In addition, since the active ingredient can be blended in a high unit in one tablet, it is possible to produce a preparation that has a small daily dose and a moderate size that is easy to take, thus reducing the burden on the user. it can.

[0021]

The present invention will be described below with reference to specific examples, but the present invention is not limited thereto.

Example 1 100 parts by weight of bisbenchamine, cyanocobalamin 1.
5 parts by weight, 60 parts by weight of nicotinic acid amide, 30 parts by weight of low-substituted hydroxypropyl cellulose, 14.5 parts by weight of D-mannitol, and 4 parts by weight of hydroxypropyl cellulose were mixed with a VG granulator (manufactured by Paulec, vertical granulator). After mixing, adding ethanol and kneading,
It was dried to produce B ₁ · B ₁₂ granules.

Next, 100 parts by weight of pyridoxine hydrochloride was added to V
It was taken in a G granulator, and 6 parts by weight of crystalline cellulose and 4 parts by weight of hydroxypropyl cellulose were added to ethanol as a granulating liquid and granulated to obtain a B ₆ granulated product.

210 parts by weight of B ₁ · B ₁₂ granules and 110 parts by weight of B ₆ granules, 59 parts by weight of crystalline cellulose, 1 disintegrant
5 parts by weight and 6 parts by weight of lubricant were added and mixed to give a diameter of 8.5.
mm, and tablets were made so that each tablet would be 200 mg.

Example 2 10 parts by weight of hydroxypropylmethylcellulose and 10 parts by weight of magnesium stearate were applied to 110 parts by weight of the B ₆ granules obtained in Example 1 by using a fluidized bed coating apparatus (Flatt Industrial Co., Ltd., Grat). Part was coated. To 130 parts by weight of the coated granules, 210 parts by weight of the B ₁ · B ₁₂ granules obtained in Example 1 were added, and further 34 parts by weight of crystalline cellulose, 20 parts by weight of a disintegrating agent, and 6 parts by weight of a lubricant were added. Were mixed and tableted so that the diameter was 8.5 mm and one tablet was 200 mg.

Example 3 210 parts by weight of B ₁ .B ₁₂ granulated product obtained in Example 1 and B ₆
27 parts by weight of crystalline cellulose, 7 parts by weight of disintegrant and 6 parts by weight of lubricant were added to 110 parts by weight of the granulated product and mixed to give a diameter of 8 m.
Tablets were prepared so that each tablet would be 180 mg.

Comparative Example 1 100 parts by weight of bisbentamine, cyanocobalamin 1.
5 parts by weight, 100 parts by weight of pyridoxine hydrochloride, 60 parts by weight of nicotinic acid amide, 30 parts by weight of low-substituted hydroxypropyl cellulose, 24.5 parts by weight of D-mannitol, 4 parts by weight of hydroxypropyl cellulose were mixed with a VG granulator. Ethanol was added, the mixture was kneaded, and then dried. Next, 59 parts by weight of crystalline cellulose, 15 parts by weight of a disintegrant, and 6 parts by weight of a lubricant are added and mixed, and a diameter of 8.5 mm and 1 tablet 200
Tableted to give mg.

Comparative Example 2 100 parts by weight of pyridoxine hydrochloride was placed in a VG granulator, and 50 parts by weight of crystalline cellulose and 4 parts by weight of hydroxypropyl cellulose were added as a granulating liquid to ethanol and granulated.
₆ granules were used.

To 154 parts by weight of B ₆ granules, 210 parts by weight of B ₁ · B ₁₂ granules obtained in Example 1, 15 parts by weight of crystalline cellulose, 15 parts by weight of disintegrant, and 6 parts by weight of lubricant were added. Were mixed and tableted so that the diameter was 8.5 mm and one tablet was 200 mg.

Comparative Example 3 100 parts by weight of bisbentamine, cyanocobalamin 1.
5 parts by weight, 60 parts by weight of nicotinic acid amide, 40 parts by weight of low-substituted hydroxypropyl cellulose, 34.5 parts by weight of D-mannitol, and 4 parts by weight of hydroxypropyl cellulose were mixed in a VG granulator, and ethanol was added and kneaded. After combining, it was dried. To 240 parts by weight thereof, 110 parts by weight of the B ₆ granulated product obtained in Example 1, 129 parts by weight of crystalline cellulose, 15 parts by weight of a disintegrating agent, and 6 parts by weight of a lubricant were added and mixed, and the diameter was 9 mm and the tablet was 250 mg. It was locked so that

Comparative Example 4 100 parts by weight of bisbenchamine, cyanocobalamin 1.
5 parts by weight, 60 parts by weight of nicotinic acid amide, 40 parts by weight of low-substituted hydroxypropyl cellulose, 34.5 parts by weight of D-mannitol, and 4 parts by weight of hydroxypropyl cellulose were mixed in a VG granulator, and ethanol was added and kneaded. After combining, it was dried. To 240 parts by weight thereof, 110 parts by weight of the B ₆ granule obtained in Example 1, 162 parts by weight of crystalline cellulose, 20 parts by weight of a disintegrating agent, and 8 parts by weight of a lubricant were added and mixed, and a diameter of 8 mm and a tablet of 180 mg were added. It was locked so that

Test Example 1 The plain tablets obtained in Examples 1 to 3 and Comparative Examples 1 to 4 were sugar-coated by a conventional method and stored at 40 ° C. for 3 months to obtain bisbentamine (vitamin B ₁ ) and cyanocobalamin ( The stability of vitamin B ₁₂ ) and pyridoxine hydrochloride (vitamin B ₆ ) were compared. Table 1 shows the results.

[0033]

[Table 1]

From Table 1, Examples 1 to 3 according to the present invention had high stability, and the content decrease from the beginning of storage was hardly seen or was slight. On the other hand, in Comparative Example 1 in which the active ingredient coexists, the content decrease remarkably,
In addition, as in Examples 1 to 3, a decrease in the content is also seen in Comparative Example 2, which has a design in which the incompatible ingredients are isolated. This is because the additive amount of the B ₆ granulated product was increased, so that the amount of the excipient added at the time of mixing the granulated product was reduced, and as a result, the B ₁ · B ₁₂ granulated product and the B ₆ granulated product were added. It is thought that this is due to the increase in contact opportunities. This is the content of vitamin B ₆ in B ₆ granulated product in the present invention 75
It indicates that the amount is required to be at least wt%. In Comparative Example 3, the chances of contact between the incompatible ingredients are reduced, and thus the stability is increased, but as shown in Table 2, the feeling of ingestion was not satisfied.

Test Example 2 With respect to the tablets obtained in Examples 1 and 3 and Comparative Examples 3 and 4, which were coated with sugar, 10 subjects took the tablets and the feeling of ingestion was examined. Table 2 shows the results. Table 2 shows the shapes and daily doses of these sugar-coated tablets.

[0036]

[Table 2]

From Table 2, the shape (diameter) of the sugar-coated tablet is 9.6.
Those with a diameter of mm have less resistance to dosing, but when the diameter exceeds 10 mm, more subjects feel resistance to dosing, and in Comparative Example 4, more subjects feel that the number of doses is 3 tablets. In Comparative Example 3, the stability was high in Test Example 1, but dissatisfaction remained with the feeling of ingestion. On the other hand, Example 1 and Example 3 in which the content of the active ingredient in the plain tablet was increased to 65% by weight or more
Since the number of doses is small and the dose is appropriate, the burden on the recipient is reduced.

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Claims (11)

[Claims] 1. A tablet produced by mixing a granular granulated product containing 75 to 97% by weight of vitamin B ₆ with vitamin B ₁ , vitamin B ₁₂ and other active ingredients to produce a tablet, which is the sum of all active ingredients. A vitamin-containing tablet having a content of 65 to 80% by weight in the plain tablet. 2. The tablet according to claim _{1, wherein the} vitamin B ₁ is bisbentiamine. 3. The tablet according to claim 1, wherein the other active ingredient is vitamin Es, nicotinic acids, pantothenic acids or gamma-oryzanol. 4. The tablet according to claim ₁ , wherein vitamin B ₁ , vitamin B ₁₂ and other active ingredients are added as a granulated product. 5. Vitamin B ₆ is pyridoxine hydrochloride or pyridoxal phosphate, according to any one of claims 1 to 4.
The tablet according to the item. 6. The weight per plain tablet is 160 to 22.
It is 0 mg, The tablet of any one of Claims 1-5. 7. A granular granulated product containing 75 to 97% by weight of vitamin B _{6, so} that the total content of vitamin B ₁ , vitamin B ₁₂ and other active ingredients is 65 to 80% by weight in an uncoated tablet. A method for producing a vitamin-containing tablet, which comprises compounding into a tablet. 8. The method for producing a tablet according to claim 7, wherein the vitamin B ₁ is bisbentiamine. 9. The method for producing a tablet according to claim 7, wherein vitamin B ₁ , vitamin B ₁₂ and other active ingredients are added as a granulated product. 10. The method for producing a tablet according to claim 7, wherein the vitamin B ₆ is pyridoxine hydrochloride or pyridoxal phosphate. 11. The weight per plain tablet is 160 to 2
20 mg, The manufacturing method of the tablet of any one of Claims 7-10.