JP2006240998A - Oral solid preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a tablet preparation blended with active ingredients such as vitamin B<SB>12</SB>, etc., and mucopolysaccharide, and produced not by a wet granule compression method by using solvent and wetting the granules, but by a direct powder compression method having less number of processes and economically advantageous, i.e. direct tablet-forming method, and also showing a good content uniformity, disintegrating property and stability. <P>SOLUTION: This solid preparation is obtained by crushing a matrix such as microspheres, etc., containing the active ingredients such as the vitamin B<SB>12</SB>, etc., as necessary, and blending the same with the mucopolysaccharide. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

The present invention relates to an oral solid preparation containing a matrix containing an active ingredient and mucopolysaccharide, and relates to an oral solid preparation having good content uniformity, stability and disintegration.

There are many cases where the amount of the active ingredient blended into a solid preparation such as a pharmaceutical or food is extremely small. For example, vitamin B ₁₂ is used for the purpose of alleviating symptoms of neuralgia and joint pain. In the case of a vitamin main drug preparation (general drug), 1-1500 μg, and a vitamin-containing health agent (new designated quasi drug), There is a rule of blending 1 to 60 μg (Non-Patent Document 1 and Non-Patent Document 2).
When such an active ingredient with a small blending amount is blended into a solid preparation, a problem of content uniformity occurs. To solve this problem, by dispersing the vitamin B ₁₂ compounds in a mixture of starch and dextrin to a powder, a technique for the pre-mix formulation material is disclosed (Patent Document 1). However, this disclosed technique does not mention solid preparations such as tablets and granules that can be taken by patients, and overcomes various problems that occur when ingredients with high hygroscopicity such as mucopolysaccharides are blended. In order to do so, further ingenuity was necessary.
Matrix is a coating in which active ingredients are uniformly dispersed in a coating agent such as gelatin. Among them, liquid phase method (in-liquid granulation method) or gas phase method (in-air granulation method) The spherical particles produced by) are called microspheres or beads. Microspheres are generally used for the purpose of stabilizing quality, avoiding contraindications, and retaining volatile substances, and it is effective to apply microsphere technology to vitamin B ₁₂ and the like. It is known that there is (Non-patent Document 3).

  On the other hand, mucopolysaccharides, such as chondroitin sulfate and / or salts thereof, which are one of the constituent elements of the present invention, are a kind of high molecular polysaccharides, exist between cells in the living body, and enter cells of moisture and nutrition. It works to replenish cells and keep cells hydrated. By this function, the cellular tissue connecting the bones becomes lubricated and the flexibility is maintained. Due to the decrease in mucopolysaccharides, bones collide with each other, causing joint pain. Therefore, mucopolysaccharide is taken for the relief of joint pain diseases and the like. However, when formulated, mucopolysaccharides have high hygroscopicity, so there are restrictions on blending with other agents that impair stability due to the influence of moisture, and gel formation easily occurs due to moisture, making it difficult to disintegrate. There were many cases that affected bioavailability. In order to overcome these problems, a technique for reducing the moisture content of the tablet by using a thin-layer sugar-coated tablet has been disclosed (Patent Document 2), but there has been a drawback that the properties of the tablet are significantly deteriorated due to the influence of outside air humidity. Moreover, although the stabilization technique of the formulation by a film coat tablet is disclosed (patent document 3), various additives necessary for the film coat are necessary and it is difficult to say that it is preferable from the viewpoint of safety. Furthermore, the manufacturing method shown in the technique naturally requires a film process, which requires a lot of manufacturing steps and increases costs.

Moreover, in order to suppress the formation of a mucopolysaccharide-derived gel mass at the time of disintegration, a technique has been disclosed in which disintegration is improved by the incorporation of aminosaccharides (Patent Document 4), but aminosaccharides with poor compression moldability are disclosed. Formulation was essential and there were restrictions on the manufacturing method. In other words, a costly manufacturing method has been selected.
That is, in order to solve the problems such as content uniformity, stability, and disintegration simultaneously by mixing an active ingredient such as the above-mentioned vitamin B ₁₂ and the like and an mucopolysaccharide at the same time, it is originally necessary for treatment. The use of non-additives and manufacturing methods tended to be costly.

On the other hand, it is high demand of the patient's joint pain such as preparations formulated with vitamin B ₁₂ compound and sodium chondroitin sulfate are already commercially available (for example, Non-Patent Document 4). Since these preparations improve the content uniformity, a granulation process is essential, and it is considered that these preparations were not always satisfied from the viewpoint of production cost.
As an application of the above-mentioned microsphere technology, technologies relating to sustained release of drugs have been disclosed (Patent Documents 5 and 6), but technologies related to content uniformity and disintegration in tablets, and further to microspheres The technology of simultaneously blending mucopolysaccharide has not been known yet.

What should be desired as a general-purpose pharmaceutical is not to mention that it is stable in the distribution process, and that tablets must satisfy formulation characteristics such as content uniformity and disintegration (non-patented). Reference 5). In addition, a pharmaceutical design that can be manufactured at a low cost is desired for a manufacturer that manufactures a pharmaceutical product. Development launch tablet mucopolysaccharide was compounded at the same time, such as the active ingredient and chondroitin sulfate and / or salts thereof is small amount of vitamin B _12, etc. that combines these conditions has been desired.
JP-A-3-173823 JP 2002-179559 A JP2003-3000883A JP 2002-145780 A JP 2004-83575 A JP 2002-12670 A Vitamin active ingredient manufacturing (import) approval criteria Notification of Yakuhin No. 90 Pharmacy Director (1988) Criteria for the manufacture (import) of vitamin-containing health care products Riken Vitamin Microcapsule “Beads” Catalog Technical Data RIKEN VITAMIN CO., LTD. “Attachment AN lock package insert” Takeda Pharmaceutical Company Limited 14th revised Japanese Pharmacopoeia General Rules for Preparations

The object of the present invention is not a wet granule compression method, which is produced by wetting using a solvent, but a direct powder compression method, ie, a direct compression method, which has few steps and is economically advantageous. Another object of the present invention is to provide a tablet containing an active ingredient such as vitamin B _{12 having} good disintegration and stability and mucopolysaccharide.

As a result of intensive studies to overcome the above-mentioned problems, the inventors of the present invention pulverized a matrix such as a microsphere containing an active ingredient such as vitamin B ₁₂ as necessary, and this matrix is mucopolysaccharide preparation. By blending with, the above-mentioned problems were successfully overcome and the present invention was completed.

According to the present invention, for example, an active ingredient such as vitamin B ₁₂ is included in a matrix such as microsphere, and if necessary, the particle size of this matrix is pulverized and adjusted to be blended with mucopolysaccharide, and content uniformity It was possible to produce tablets with improved stability and disintegration at the same time by a low-cost direct powder compression method.

Examples of the active ingredient used in the present invention include vitamin B12 (cyanocobalamin, hydroxocobalamin, hydroxocobalamin hydrochloride, hydroxocobalamin acetate, methylcobalamin), ubidecalenone and the like. Of these, regarding vitamin B12, cyanocobalamin and hydroxocobalamin are preferable in consideration of stability and supply of raw materials used.
The matrix used in the present invention may be any matrix as long as the active ingredient is uniformly dispersed in the matrix, and is prepared by a known method regardless of the shape. Gelatin, agar, etc. are generally used as the constituent components of the matrix. Among these, the form of microspheres commercially available from Riken Vitamin Co., Ltd. is most preferable because the effects of the present invention are remarkable and the supply of used raw materials is good. When these matrices are blended in a tablet, it is preferable that the matrix is pulverized as necessary so that particles having a size of less than 150 μm are in a state of 80% (w / w) or more. Furthermore, the particle size distribution of the matrix is preferably particles having a size of 1 μm or more and less than 600 μm under the above-mentioned conditions. However, the particle size distribution is not limited to this as long as the particle size distribution achieves the present invention.

  Examples of the matrix containing the above-mentioned active ingredient include, for example, Riken Dry B12-B1CN (RIKEN Vitamin Co., Ltd.), which is a microsphere containing 0.1% ciaconovalamine, and Hydroxocobalamin microsphere containing 0.1% hydroxocobalamin ( Riken Vitamin Co., Ltd.), ubidecalenone microspheres containing 40% ubidecalenone (RIKEN VITAMIN CO., LTD.) Or cyanocobalamin 0.1% powder (BASF Takeda Vitamin Co., Ltd.) can be used. It is not a thing.

  Furthermore, as the mucopolysaccharide used in the present invention, for example, one or more kinds of sodium chondroitin sulfate listed in the Japanese Pharmacopoeia Standards for Drug Components or oral food grade sodium hyaluronate sold by Kibun Food Chemifa Co., Ltd. It can be used but is not limited to this. Among these, it is preferable to use sodium chondroitin sulfate from the viewpoint of medicinal effect.

  Carriers used in the preparation of the preparation of the present invention include excipients such as crystalline cellulose, lactose, starch and mannitol, glidants such as light anhydrous silicic acid, lubricants such as magnesium stearate, calcium stearate and talc. In addition, a disintegrating agent, a buffering agent, a preservative, a fragrance, a pigment, a corrigent and the like can be used as necessary.

  Examples of the tablet production method in the present invention include a preparation machine technology handbook (formulation machine technology study group 10th anniversary publication editorial committee, Jinshokan), powder compression molding technology (powder engineering / formulation The direct powder compression method described in publications such as “Particle Design Division, Nikkan Kogyo Shimbun” can be used.

  EXAMPLES Hereinafter, although an Example etc. demonstrate this invention further in detail, this invention is not limited to these.

Example 1
150 g of RIKEN dry B12-B1CN manufactured by Riken Vitamin Co., Ltd. was put into a pulverizer (K3-1, Dalton) and pulverized to obtain a pulverized product with 81.1% (w / w) particles less than 150 μm. . 120 g of this pulverized product, 1800 g of sodium chondroitin sulfate, 60 g of thiamine nitrate, 40 g of pyridoxine hydrochloride, 100 g of tocopherol calcium succinate, 765 g of lactose, 300 g of crystalline cellulose, 100 g of carmellose calcium, and 15 g of magnesium stearate were mixed in a plastic bag to obtain The tableted powder was rotograted with a rotary tableting machine (HT-AP15-SS2, Hata Iron Works) using a mortar with a diameter of 9.0 mm and an R-face punch with a radius of curvature of 12 mm. Tablets were obtained to obtain a tablet of 6 mm.

(Example 2)
150 g of hydroxocobalamin microspheres manufactured by Riken Vitamin Co., Ltd. were put into a pulverizer (K3-1, Dalton) and pulverized to obtain a pulverized product in which particles less than 150 μm were 86.2% (w / w). 120 g of this pulverized product, 1800 g of sodium chondroitin sulfate, 60 g of thiamine nitrate, 40 g of pyridoxine hydrochloride, 100 g of tocopherol calcium succinate, 765 g of lactose, 300 g of crystalline cellulose, 100 g of carmellose calcium, and 15 g of magnesium stearate were mixed in a plastic bag to obtain The tableted powder was rotograted with a rotary tableting machine (HT-AP15-SS2, Hata Iron Works) using a mortar with a diameter of 9.0 mm and an R-face punch with a radius of curvature of 12 mm. Tablets were obtained so as to be 5 mm.

(Example 3)
120 g of cyanocobalamin 0.1% powder sold by BASF Takeda Vitamin Co., Ltd., 1800 g of chondroitin sulfate sodium, 60 g of thiamine nitrate, 40 g of pyridoxine hydrochloride, 100 g of tocopherol calcium succinate, 765 g of lactose, 300 g of crystalline cellulose, 100 g of carmellose calcium, magnesium stearate 15 g was mixed in a plastic bag, and the resulting tableting powder was rotated with a rotary tableting machine (HT-AP15-SS2, Hata Iron Works) with a mortar having a diameter of 9.0 mm and an R facet having a radius of curvature of 12 mm. Tablets were obtained by tableting so that the weight per tablet was 275 mg and the thickness was 4.5 mm.

Example 4
150 g of RIKEN DRY B12-B1CN manufactured by Riken Vitamin Co., Ltd. was put into a pulverizer (K3-1, Dalton) and pulverized to obtain a pulverized product having 88.1% (w / w) particles less than 150 μm. . 120 g of this ground product, 1800 g of sodium chondroitin sulfate, 24 g of riboflavin, 40 g of pyridoxine hydrochloride, 100 g of tocopherol calcium succinate, 801 g of lactose, 300 g of crystalline cellulose, 100 g of carmellose calcium, and 15 g of magnesium stearate are mixed in a plastic bag. Using a rotary tableting machine (HT-AP15-SS2, Hata Iron Works), a tablet with a diameter of 9.0 mm and an R facet with a radius of curvature of 12 mm, the weight per tablet is 275 mg, and the thickness is 4. Tablets were obtained so as to be 5 mm.

(Example 5)
150 g of RIKEN dry B12-B1CN manufactured by Riken Vitamin Co., Ltd. was put into a pulverizer (K3-1, Dalton) and pulverized to obtain a pulverized product with 84.9% (w / w) particles less than 150 μm. . 120 g of this pulverized product, 1800 g of sodium chondroitin sulfate, 60 g of thiamine nitrate, 40 g of nicotinic acid amide, 100 g of tocopherol calcium succinate, 765 g of lactose, 300 g of crystalline cellulose, 100 g of carmellose calcium, and 15 g of magnesium stearate are mixed in a plastic bag. Using a rotary tableting machine (HT-AP15-SS2, Hata Iron Works), the resulting tableting powder was milled with a mortar with a diameter of 9.0 mm and an R facet with a radius of curvature of 12 mm, and the weight per tablet was 275 mg. Tablets were obtained so as to be 4.5 mm.

(Example 6)
150 g of RIKEN DRY B12-B1CN manufactured by Riken Vitamin Co., Ltd. was put into a pulverizer (K3-1, Dalton) and pulverized to obtain a pulverized product having 89.2% (w / w) of particles less than 150 μm. . 120 g of this pulverized product was mixed with 60 g of sodium hyaluronate, 60 g of thiamine nitrate, 40 g of pyridoxine hydrochloride, 100 g of tocopherol calcium succinate, 1011 g of lactose, 300 g of crystalline cellulose, 100 g of carmellose calcium, and 9 g of magnesium stearate in a plastic bag. Using a rotary tableting machine (HT-AP15-SS2, Hata Iron Works), the resulting tableting powder was 150 mg in weight per tablet with a mortar with a diameter of 8.0 mm and an R-face with a curvature radius of 10.0 mm. Tablets were obtained by tableting to a thickness of 3.7 mm.

(Example 7)
150 g of RIKEN DRY B12-B1CN manufactured by Riken Vitamin Co., Ltd. was put into a pulverizer (K3-1, Dalton) and pulverized to obtain a pulverized product with 85.3% (w / w) particles less than 150 μm. . 120 g of this ground product, 1800 g of chondroitin sulfate sodium, 60 g of thiamine nitrate, 40 g of pyridoxine hydrochloride, 100 g of tocopherol calcium succinate, 765 g of powdered reduced maltose starch syrup, 300 g of crystalline cellulose, 100 g of carmellose calcium, and 15 g of magnesium stearate are mixed in a plastic bag. The tableting powder thus obtained was 275 mg in weight per tablet using a rotary tableting machine (HT-AP15-SS2, Hata Iron Works) with a 9.0 mm diameter mortar and a 12 mm radius of curvature. And tablets were obtained so as to have a thickness of 4.5 mm.

(Example 8)
120 g of cyanocobalamin 0.1% powder sold by BASF Takeda Vitamin Co., Ltd., 1800 g of chondroitin sulfate, 24 g of riboflavin, 40 g of pyridoxine hydrochloride, 100 g of tocopherol calcium succinate, 801 g of lactose, 300 g of crystalline cellulose, 100 g of carmellose calcium, 15 g of magnesium stearate Were mixed in a plastic bag, and the resulting tableting powder was mixed with a rotary tableting machine (HT-AP15-SS2, Hata Iron Works) using a mortar with a diameter of 9.0 mm and an R facet with a radius of curvature of 12 mm. Tablets were obtained by tableting so that the weight per tablet was 275 mg and the thickness was 4.5 mm.

Example 9
150 g of hydroxocobalamin microspheres manufactured by Riken Vitamin Co., Ltd. were put into a pulverizer (K3-1, Dalton) and pulverized to obtain a pulverized product having particles less than 150 μm of 88.3% (w / w). 120 g of this ground product, 1800 g of sodium chondroitin sulfate, 24 g of riboflavin, 40 g of pyridoxine hydrochloride, 100 g of tocopherol calcium succinate, 801 g of lactose, 300 g of crystalline cellulose, 100 g of carmellose calcium, and 15 g of magnesium stearate are mixed in a plastic bag. Using a rotary tableting machine (HT-AP15-SS2, Hata Iron Works), a tablet with a diameter of 9.0 mm and an R facet with a radius of curvature of 12 mm, the weight per tablet is 275 mg, and the thickness is 4. Tablets were obtained so as to be 5 mm.

(Example 10)
150 g of RIKEN DRY B12-B1CN manufactured by Riken Vitamin Co., Ltd. was put into a pulverizer (K3-1, Dalton) and pulverized to obtain a pulverized product in which particles less than 150 μm were 90.3% (w / w). . In addition, 150 g of ubidecarenone microspheres manufactured by Riken Vitamin Co., Ltd. was put into a pulverizer (K3-1, Dalton) and pulverized to obtain a pulverized product in which particles less than 150 μm were 87.7% (w / w). . 120 g of each pulverized product, 1800 g of sodium chondroitin sulfate, 60 g of thiamine nitrate, 40 g of pyridoxine hydrochloride, 100 g of tocopherol calcium succinate, 645 g of lactose, 300 g of crystalline cellulose, 100 g of carmellose calcium, and 15 g of magnesium stearate are mixed in a plastic bag. The obtained tableting powder was 275 mg in weight per tablet with a rotary tableting machine (HT-AP15-SS2, Hata Iron Works) using a mortar with a diameter of 9.0 mm and an R-face punch with a radius of curvature of 12 mm. Tablets were obtained by tableting to a thickness of 4.5 mm.

(Example 11)
Riken Vitamin Co., Ltd. manufactured by Riken Dry B12-B1CN 120g, chondroitin sodium sulfate 1800g, thiamine nitrate 60g, pyridoxine hydrochloride 40g, tocopherol calcium succinate 100g, lactose 765g, crystalline cellulose 300g, carmellose calcium 100g, magnesium stearate 15g Each tablet is mixed with a bag, and the resulting tableting powder is per tablet using a rotary tableting machine (HT-AP15-SS2, Hata Iron Works) with a 9.0 mm diameter mortar and a 12 mm radius of curvature. Was tableted to give a tablet having a weight of 275 mg and a thickness of 4.5 mm.

(Comparative Example 1)
150 g of RIKEN DRY B12-B1CN manufactured by Riken Vitamin Co., Ltd. was put into a pulverizer (K3-1, Dalton) and pulverized to obtain a pulverized product with 85.2% (w / w) of particles less than 150 μm. . 120 g of this pulverized product, 1800 g of sodium chondroitin sulfate, 60 g of thiamine nitrate, 40 g of pyridoxine hydrochloride, 100 g of tocopherol calcium succinate, 765 g of lactose, 300 g of crystalline cellulose, and 100 g of carmellose calcium are mixed with a high-speed stirring mixer (FM-VG-25, Paulek) To add 1500 mL of 80% ethanol aqueous solution and granulate. The obtained granulated product is dried with a fluid bed dryer (FLO5, Freund Sangyo), and then mixed with 15 g of magnesium stearate in a plastic bag to obtain a tableting powder. Using a rotary tableting machine (HT-AP15SS2, Hata Iron Works), the obtained tableting powder was crushed with a mortar having a diameter of 9.0 mm and an R facet having a curvature radius of 12 mm, and the weight per tablet was 275 mg, and the thickness was 4. Tablets were obtained so as to be 6 mm.

(Comparative Example 2)
12 mg of cyanocobalamin is mixed with 100 g of carmellose calcium in a plastic bag to prepare a powdered powder. A powdered powder, 1800 g of sodium chondroitin sulfate, 60 g of thiamine nitrate, 40 g of pyridoxine hydrochloride, 100 g of tocopherol calcium succinate, 885 g of lactose, 300 g of crystalline cellulose, 100 g of carmellose calcium and 15 g of magnesium stearate were obtained in a plastic bag. Using a rotary tableting machine (HT-AP45LS, Hata Iron Works), the tableting powder was crushed with a diameter of 9.0 mm and radiused with a curvature radius of 12 mm. The weight per tablet was 275 mg and the thickness was 4.6 mm. Tablets were obtained.

[Test example]
The formulation evaluation tests of Examples 1, 2, and 11 and Comparative Examples 1 and 2 were performed. The test items were 1) content uniformity test of vitamin B ₁₂ class, 2) disintegration test, and 3) stability test, and comprehensive judgment was made from these test results.

1) Content uniformity test of vitamin B ₁₂ class of Examples and Comparative Examples Arbitrary 10 tablets obtained in Examples 1, 2, and 11 and Comparative Examples 1 and 2 were taken and subjected to reverse phase partition high performance liquid chromatography. , quantified vitamin B ₁₂ compounds in tablets (cyanocobalamin or hydroxocobalamin), obtains the relative standard deviation (CV) indicative of content variations, the following evaluation criteria were evaluated content uniformity.
Evaluation criteria ○: There is almost no variation in content. (CV value is less than 2%)
Δ: Slight variation in content is observed. (CV value is 2% or more and less than 3%)
X: Content variation is remarkable. (CV value is 3% or more)
The results are shown in Table 1.

In unmilled tablets containing a combination of microspheres (Example 11) and triturated with Comparative Example 2, prepared, CV value indicating the content variation of vitamin B ₁₂ is 2.99% and 2.20%, respectively, A slight variation in content was observed. On the other hand, in the tablets (Example 1 and Example 2) in which the microspheres are pulverized and blended, the CV value indicating the content variation of the active ingredient is 1.52% to 1.78%, and there is almost no content variation. It was shown that. From this result, it was found that the content uniformity is more advantageous as the particle size of the microsphere is smaller when it is produced by the direct powder compression method.

表２に示したように、直接粉末圧縮法で製造した錠剤（実施例１、２及び１１）は、湿式顆粒圧縮法で製造した錠剤（比較例１）に対し、優れた崩壊性を示した。 2) Disintegration test of Examples and Comparative Examples Six tablets obtained in Examples 1, 2, and 11 and Comparative Examples 1 and 2 were arbitrarily taken, and disintegration tests (Japanese Pharmacopoeia 14 revised general test method disintegration test) were conducted. The disintegration property was evaluated according to the following evaluation criteria.
Evaluation criteria ○: Average disintegration time within 20 minutes and maximum disintegration time within 20 minutes Δ: Average disintegration time within 20 minutes, and maximum disintegration time exceeding 20 minutes and within 30 minutes ×: Average disintegration time The measurement results are shown in Table 2 for 20 minutes or more.

As shown in Table 2, the tablets produced by the direct powder compression method (Examples 1, 2 and 11) showed excellent disintegration properties compared to the tablets produced by the wet granule compression method (Comparative Example 1). .

ビタミンＢ_１２類を倍散して製造した比較例２に対し、マイクロスフェア粉砕物中のビタミンＢ_１２（シアノコバラミン及びヒドロキソコバラミン）は、４０℃苛酷経時条件下において有意に安定であった。 3) Stability test of vitamin B ₁₂ of Examples and Comparative Examples The tablets obtained in Examples 1, 2, and 11 and Comparative Examples 1 and 2 were filled into glass bottles, sealed with caps, and subjected to 2 conditions under 40 ° C. The stability of vitamin B ₁₂ after storage for 4 and 6 months was evaluated. Note that determination of vitamin B ₁₂ compound is by reverse phase high performance liquid chromatography, after measuring the content was calculated residual ratio by the following equation.
Residual rate (%) = Ws / Wo × 100
Ws: component content after 40 ° C.-2, 4 and 6 months Wo: component content immediately after production In addition, stability was determined according to the following evaluation criteria.
Evaluation criteria ○: Residual rate at 40 ° C-6 months is 95% or more Δ: Residual rate at 40 ° C-6 months is 90% or more and less than 95% x: Residual rate at 40 ° C-6 months is less than 90% It is shown in Table 3.

To Comparative Example 2, prepared was triturated vitamin B _12, vitamin B ₁₂ in the microsphere pulverized _{(cyanocobalamin} and hydroxocobalamin), was significantly more stable at 40 ° C. severe aging conditions.

表４より明らかなように、実施例１、２及び１１は、含量均一性試験におけるＣＶ値が３％未満、崩壊試験における平均崩壊時間が２０分間以内、且つ、安定性試験における４０℃−６箇月の残存率が９０％以上であり製剤評価試験に適合した。一方、比較例は、含量均一性試験におけるＣＶ値が３％以上、又は崩壊試験における平均崩壊時間が２０分間、又は安定性試験における４０℃−６箇月の残存率が９０％未満であり、製剤評価試験の判定は不適であった。
また、表４の製造工数に着目すると比較例１は、製造工程数が多く、製造コストが割高となる。
4) Determination Based on the above test results, a comprehensive determination was performed according to the following evaluation criteria.
Criteria conformity: CV value in content uniformity test is less than 3%, average disintegration time in disintegration test is within 20 minutes, maximum disintegration time is within 30 minutes, and residual rate of 40 ° C.-6 months in stability test Is not suitable for 90% or more: CV value in content uniformity test is 3% or more, or average disintegration time in disintegration test is 20 minutes or more, or residual rate of 40 ° C-6 months in stability test is less than 90% The characteristics of the test specimen, characteristics of the manufacturing method, and the determination results based on the preparation evaluation test results are shown.

As is apparent from Table 4, in Examples 1, 2 and 11, the CV value in the content uniformity test was less than 3%, the average disintegration time in the disintegration test was within 20 minutes, and 40 ° C.-6 in the stability test. The remaining rate of 90 months was 90% or more, which was suitable for the preparation evaluation test. On the other hand, in the comparative example, the CV value in the content uniformity test is 3% or more, or the average disintegration time in the disintegration test is 20 minutes, or the residual rate at 40 ° C.-6 months in the stability test is less than 90%. The evaluation test was inappropriate.
Further, when paying attention to the manufacturing man-hours in Table 4, Comparative Example 1 has a large number of manufacturing steps, and the manufacturing cost becomes high.

Claims (8)

Tablets containing one or more types of matrix containing active ingredients and mucopolysaccharide. The tablet according to claim 1, wherein the matrix is a microsphere. The tablet according to claim 1 or 2, wherein the matrix is 80% (w / w) or more of particles having a particle size of less than 150 µm. The tablet according to claims 1 to 3, wherein the mucopolysaccharide is chondroitin sulfate and / or a salt thereof. The tablet according to claim 1, wherein the active ingredient is one or more selected from vitamin B ₁₂ and ubidecarenone. The tablet according to claim 5, wherein the vitamin B ₁₂ is one or more selected from cyanocobalamin or hydroxocobalamin. The tablet according to claim 1, which is produced by a direct powder compression method. The method of manufacturing the tablet of Claims 1-6 by the direct powder compression method.