JP5772169B2 - Direct compression tablet containing ipriflavone - Google Patents

Description

  The present invention relates to a tablet that can be produced by a direct hitting method by devising a combination of active ingredients and a method for producing the tablet.

  Ipriflavone is a derivative of isoflavone and is known to improve osteoporosis symptoms by suppressing the dissolution of bone calcium into the blood and promoting the secretion of calcitonin that makes bones strong. . Since only a small amount of ipriflavone can be naturally ingested from food, it is desired to ingest with tablets containing ipriflavone. In addition, it is known that when calcium compounds are taken together with isoflavone derivatives such as ipriflavone, absorption of the ingested calcium into the body is promoted. (See Patent Document 1).

  On the other hand, since the action of ipriflavone and calcium compounds is mild, the daily intake is about 600 mg / day for ipriflavone and about 500 mg / day for calcium compounds in terms of calcium. Ingestion of these amounts of ipriflavone and calcium compounds in as few tablets as possible seems to be preferable from the viewpoint of compliance, but in that case, it is necessary to increase the amount of ipriflavone and calcium compounds contained in the tablets as much as possible. is there. Further, from the viewpoint of providing the customer with a cheaper product by reducing the manufacturing cost as much as possible, it is preferable to manufacture the tablet by a direct compression method in which the manufacturing process is very simple.

JP 2002-58452 A

  When trying to manufacture tablets containing high concentrations of ipriflavone or calcium in the tablets by direct compression, there will be a manufacturing problem that powder adheres to the punch or capping occurs during tableting. . An object of the present invention is to solve the above-mentioned problems and to obtain a tablet that can be produced by a direct hitting method and has good physical properties.

  As a result of intensive studies by the present inventors, it has been found that the problem can be solved by combining a calcium compound which is one of the active ingredients in a certain combination.

That is, the present invention
(1) A direct compression tablet containing ipriflavone and a calcium compound, and containing at least calcium lactate or a hydrate thereof as the calcium compound;
(2) The calcium compound according to (1), which contains at least one selected from calcium carbonate, calcium phosphate and calcium L-aspartate or a hydrate thereof, and calcium lactate or a hydrate thereof as the calcium compound. Tablet,
(3) Ipriflavone and a calcium compound are mixed, and further magnesium stearate is mixed as a lubricant, and then the resulting mixture is directly compressed into tablets. A method for producing a direct tablet,
(4) The method for producing a direct compression tablet according to (3), wherein crystalline cellulose, light anhydrous silicic acid and carmellose calcium are further mixed with ipriflavone and a calcium compound.

  By combining a calcium compound, which is one of the active ingredients, into a certain combination, the manufacturing problem of powder adhering to the punch or capping during tableting is improved, and both hardness and disintegration time are improved. Excellent tablets were obtained.

  Ipriflavone is an oral osteoporosis therapeutic agent synthesized as an isoflavone derivative. It is a white to yellowish white crystal or crystalline powder that is slightly soluble in acetonitrile and slightly soluble in methanol or ethanol (99.5). Insoluble in water.

  The preferred amount of ipriflavone is 5 to 50% by mass, preferably 10 to 30% by mass, based on the whole uncoated tablet.

  The calcium compound means one or more selected from all natural calcium and calcium salts that can be used in pharmaceuticals and foods. For example, calcium lactate, calcium carbonate, precipitated calcium carbonate, calcium phosphate, calcium hydrogen phosphate, L- Calcium aspartate, calcium gluconate, calcium citrate, calcium chloride, calcium glycerophosphate, calcium pantothenate, calcium malate, calcium acetate, calcium fluoride, calcium stearate, carmellose calcium, calcium succinate, calcium glucuronate, borei powder One or more selected from eggshell calcium, fish bone calcium, pearl calcium, salmon calcium, fish flake calcium, beef bone calcium, scallop shell calcium, and calcined calcium Meaning. In addition, hydrates of these salts are also included in the present invention.

  In solving the problems in the present invention, it is essential that the tablet contains calcium lactate or a hydrate thereof. Here, since calcium lactate or its hydrate has a low calcium content when converted to calcium, the calcium compound in the tablet is not calcium lactate or its hydrate alone, but further other calcium compounds. It is preferable to mix.

  The preferable compounding quantity of a calcium compound is 60-90 mass% of the whole uncoated tablet, Preferably it is 70-90 mass%.

  The preferred amount of calcium lactate or hydrate thereof is 5 to 80% by mass, preferably 20 to 70% by mass, particularly preferably 50 to 70% by mass, based on the whole uncoated tablet.

  A preferred blending amount of ipriflavone and calcium compound is 85% by mass or more, preferably 90% by mass or more, based on the whole uncoated tablet.

  From the viewpoint of the compounding ratio of ipriflavone and calcium lactate hydrate in the tablet, the amount of calcium lactate hydrate in the tablet is 2.5 parts by mass or more, more preferably 3 parts by mass with respect to 1 part by mass of ipriflavone. More than a part.

  The daily intake is preferably about 600 mg / day for ipriflavone and about 500 mg / day for the calcium compound in terms of calcium, and the amount of calcium compound in the tablet depends on the calcium content in the calcium compound. The preferable amount of calcium in the tablet when converted to calcium is 0.5 to 2 parts by mass, more preferably 0.7 to 1.2 parts by mass, with respect to 1 part by mass of ipriflavone.

  The calcium equivalent means the calcium content in the calcium compound.

For example,
The amount of calcium in the calcium lactate hydrate is 13.0% by mass of the entire calcium lactate hydrate,
The amount of calcium in calcium carbonate is 40.0 mass% of the total calcium carbonate,
The amount of calcium in calcium phosphate is 29.5% by mass of the total calcium phosphate,
The amount of calcium in calcium L-aspartate is 11.2% by mass of the total calcium L-aspartate,
The amount of calcium in calcium gluconate is 8.9% by mass of the total calcium gluconate.

  If the intake amount of calcium per day is determined, the compounding amount of the calcium compound per day is determined.

  The direct compression tablet of the present invention can be blended with any food ingredient (including health foods, dietary supplements, etc.) and pharmaceutical ingredients that can be used as tablets.

  The direct compression tablet of the present invention contains ipriflavone and a calcium compound, and if necessary, other known additives such as excipients, disintegrants, binders, lubricants, antioxidants, coating agents, A colorant, a flavoring agent, a surfactant, a plasticizer, and the like can be mixed and produced by a conventional method. For example, magnesium stearate can be used as a lubricant, crystalline cellulose as an excipient, light anhydrous silicic acid as a fluidizing agent, and carmellose calcium as a disintegrant.

  The direct compression tablet means a tablet produced by a direct compression method (direct compression method) in which raw materials are mixed and the mixed powder is compressed without granulation.

  An uncoated tablet means a tablet immediately after tableting without coating. This uncoated tablet can be used as a tablet as it is, or it can be used as a tablet further coated with a sugar coating or the like.

  The components to be blended in the present invention are components that are usually used in the production of solid preparations, but the effect of being able to be produced by the direct hitting method even when blended with a high concentration of active ingredient is the effect of the calcium compound of the present invention. It was made possible specifically when combined.

  The preferred physical properties of the direct compression tablet in the present invention mean a state having a certain hardness and a fast disintegration time.

  Here, the certain hardness varies depending on the tablet diameter of the tablet, but for example, in the case of a 9 mmφ tablet, it is preferably 80 N or more, more preferably 98 N or more.

  Here, the fast disintegration time means that the disintegration time of 6 tablets is measured using a disintegration tester (NT-20H, manufactured by Toyama Sangyo Co., Ltd.) based on the 15th revised Japanese Pharmacopoeia General Test Disintegration Test Method. The average value is preferably within 60 minutes, more preferably within 30 minutes.

Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples and Test Examples.
(Production Example 1)
Example 1 and Comparative Example 1
Ipriflavone, calcium lactate hydrate, and calcium carbonate are weighed in the proportions per tablet listed in Table 1, mixed in a plastic bag, and then magnesium stearate is added as a lubricant in the proportion per tablet listed in Table 1. The mixture was sized with a 30-mesh sieve to obtain granules for tableting. The granules for tableting are compressed with a single-type tableting machine (HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.) using a compression pressure of 9.8 kN, 9 mmφ, 2-stage R-side punches, and 330 mg tablets per tablet. Obtained.
(Test Example 1)
The hardness of each 10 tablets obtained in Example 1 and Comparative Example 1 was measured using a tablet hardness meter (Schleunieger-8M, manufactured by Schleunieger), and each average value was taken as the tablet hardness. In addition, the disintegration time of each of the 6 tablets obtained in Example 1 and Comparative Example 1 was determined using a disintegration tester (NT-20H, manufactured by Toyama Sangyo Co., Ltd.) based on the Fifteenth Revised Japanese Pharmacopoeia General Test Disintegration Test Method. The average value was taken as the disintegration time. The presence or absence of capping at the time of tableting and the presence or absence of adhesion to the punch and die after tableting were confirmed by visual inspection. Table 2 shows the tablet hardness, disintegration time and presence / absence of adhesion of each tablet.

  In Comparative Example 1 in which calcium carbonate was added to ipriflavone, capping occurred. The obtained tablets had a low hardness and a disintegration time of 90 minutes or more. On the other hand, in Examples 1 and 2 in which calcium carbonate and calcium lactate hydrate were added to ipriflavone, a remarkable improvement effect was observed, and a tablet having a target hardness or higher disintegration time was obtained without causing adhesion or capping. I was able to.

(Production Example 2)
Ipriflavone, calcium lactate hydrate and calcium hydrogen phosphate were weighed in the proportions per tablet listed in Table 3, mixed in a plastic bag, and then magnesium stearate as a lubricant per tablet listed in Table 3 was mixed. The mixture was added at a ratio, and granulated with a 30 mesh sieve to obtain granules for tableting. The granules for tableting are compressed with a single-type tableting machine (HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.) using a compression pressure of 9.8 kN, 9 mmφ, 2-stage R-side punches, and 330 mg tablets per tablet. Obtained.
(Test Example 2)
The hardness of each 10 tablets obtained in Examples 3 and 4 and Comparative Examples 2 to 4 was measured using a tablet hardness meter (Schleunieger-8M, manufactured by Schleunieger), and each average value was defined as tablet hardness. Further, the disintegration time of each of the 6 tablets obtained in Examples 3 and 4 and Comparative Examples 2 to 4 was determined based on the disintegration test method (NT-20H, Toyama Sangyo Co., Ltd.) based on the 15th revised Japanese Pharmacopoeia General Test Disintegration Test Method. The average value was taken as the disintegration time. The presence or absence of adhesion was confirmed by visual observation of the punch and die after tableting. Table 4 shows the tablet hardness, disintegration time and presence / absence of adhesion of each tablet.

In Comparative Example 2 in which calcium hydrogen phosphate was added to ipriflavone, although no adhesion or capping was observed, the decay time was 90 minutes or more. In Comparative Example 3 in which the same amount of calcium lactate hydrate as ipriflavone was added and in Comparative Example 4 in which 2.5 times the amount of ipriflavone was added, the disintegration time was 60 minutes or more. On the other hand, in Example 3 and Example 4 in which calcium lactate hydrate was added in an increased amount, a remarkable improvement effect was recognized, and a tablet with a quick disintegration time could be obtained without causing adhesion.

(Production Example 3)
Ipriflavone, calcium lactate hydrate, and calcium L-aspartate were weighed in a ratio per tablet shown in Table 5, mixed in a plastic bag, and then magnesium stearate as a lubricant shown in Table 5 as a lubricant. Was added at a ratio of about 1, and granulated with a 30 mesh sieve to obtain granules for tableting. The granules for tableting are compressed with a single-type tableting machine (HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.) using a compression pressure of 9.8 kN, 9 mmφ, 2-stage R-side punches, and 330 mg tablets per tablet. Obtained.
(Test Example 3)
The hardness of each 10 tablets obtained in Example 5 and Comparative Examples 5 and 6 was measured using a tablet hardness meter (Schleunieger-8M, manufactured by Schleunieger), and each average value was defined as tablet hardness. Further, the disintegration time of each of the 6 tablets obtained in Example 5 and Comparative Examples 5 and 6 was determined based on the disintegration test method (NT-20H, manufactured by Toyama Sangyo Co., Ltd.) based on the 15th revised Japanese Pharmacopoeia General Test Disintegration Test Method. ) And each average value was taken as the disintegration time. The presence or absence of capping at the time of tableting and the presence or absence of adhesion to the punch and die after tableting were confirmed by visual inspection. Table 6 shows the tablet hardness, disintegration time and presence / absence of adhesion of each tablet.

In Comparative Example 5 in which 217.8 mg of calcium L-aspartate was added to ipriflavone, tableting could not be performed due to significant adhesion. In Comparative Example 6 in which 287.1 mg of calcium L-aspartate was added, capping occurred and tableting could not be performed. In contrast, in Example 5 where calcium L-aspartate and calcium lactate hydrate were added to ipriflavone, a marked improvement effect was observed, and tablets with excellent hardness and disintegration time were observed without causing adhesion or capping. Obtained.

(Production Example 4)
Table 7 shows ipriflavone, calcium lactate hydrate, calcium carbonate, calcium hydrogen phosphate, calcium L-aspartate, excipient (crystalline cellulose), fluidizer (light anhydrous silicic acid), and disintegrant (carmellose calcium). After weighing in the ratio per tablet and mixing in a plastic bag, magnesium stearate is added as a lubricant in the ratio per tablet described in Table 7, and the mixture is sized with a 30 mesh sieve and compressed into tablets. Granules for use were obtained. The granules for tableting are tableted using a rotary tableting machine (Burgo 19, manufactured by Kikusui Seisakusho Co., Ltd.) with a rotation speed of 30 rpm, a compression pressure of 9.8 kN, 9 mmφ, and a 2-stage R-side punch, and 330 mg per tablet. Pills were obtained.
(Test Example 4)
The hardness of each 10 tablets obtained in Examples 6 to 8 and Comparative Examples 7 to 9 was measured using a tablet hardness meter (Schleunieger-8M, manufactured by Schleunieger), and each average value was defined as tablet hardness. In addition, the disintegration time of each of the 6 tablets obtained in Examples 6-8 and Comparative Examples 7-9 was determined based on the disintegration test method of the 15th revised Japanese Pharmacopoeia General Test Method (NT-20H, Toyama Sangyo). The average value was taken as the disintegration time. The presence or absence of capping at the time of tableting and the presence or absence of adhesion to the punch and die after tableting were confirmed by visual inspection. Table 8 shows the tablet hardness, disintegration time, and presence / absence of adhesion of each tablet.

In Comparative Example 7 in which 211.9 mg of calcium carbonate was added to ipriflavone, tablets for tableting were not supplied from the hopper, and tableting could not be performed due to significant adhesion. In Comparative Example 8 in which 226.8 mg of calcium hydrogen phosphate was added to ipriflavone, tableting was possible, but adhesion to a rotating disk, pestle and mortar occurred, and the disintegration time was delayed. In Comparative Example 9 in which 271.7 mg of calcium L-aspartate was added to ipriflavone, tableting could not be performed due to significant adhesion. On the other hand, in Example 6 in which calcium carbonate and calcium lactate hydrate were added to ipriflavone, a remarkable improvement effect was observed, and tablets having excellent hardness and disintegration time were obtained without causing adhesion and capping. . Similarly, in Example 7 where calcium hydrogen phosphate and calcium lactate hydrate were added to ipriflavone and Example 8 where calcium L-aspartate was added to ipriflavone, a marked improvement effect was observed, and adhesion and capping occurred. Thus, tablets having excellent hardness and disintegration time were obtained.

  According to the present invention, it is possible to provide a tablet containing ipriflavone and a calcium compound at a high concentration, which can be produced by a direct compression method, and which has good physical properties.

Claims (5)

Contains 10 to 30% by mass of ipriflavone and calcium compound of the whole uncoated tablet, and contains at least calcium lactate or a hydrate thereof as the calcium compound, and the blending amount of the calcium lactate or the hydrate is 1 part by mass of ipriflavone. On the other hand, the direct compression tablet is 2.5 parts by mass or more . It contains 10 to 30% by mass of ipriflavone based on the whole uncoated tablet and 60 to 90% by mass of calcium compound based on the whole uncoated tablet, and at least 50 to 70% by mass of calcium lactate or its hydrate as the calcium compound. Contains direct compression tablets. The direct hit according to claim 1 or 2 , comprising at least one selected from calcium carbonate, calcium phosphate and calcium L-aspartate or a hydrate thereof, and calcium lactate or a hydrate thereof as the calcium compound. tablet. The direct compression tablet according to any one of claims 1 to 3 , wherein ipriflavone and a calcium compound are mixed and further mixed with magnesium stearate as a lubricant, and then the obtained mixture is directly compressed. Manufacturing method. The method for producing a direct compression tablet according to claim 4 , wherein crystalline cellulose, light anhydrous silicic acid and carmellose calcium are further mixed with ipriflavone and a calcium compound.