JP2004262860A - Chitosan-containing tablet and method for producing the same - Google Patents

Abstract

Kind Code: A1 The present invention solves problems such as a decrease in flowability caused when a high content of chitosan powder is contained, and has improved moldability in processing into tablets and improved disintegration in gastric juice. And tablets thereof by a direct compression method.
Kind Code: A1 A chitosan-containing tablet obtained by blending a calcium powder material and crystalline cellulose with chitosan powder and tableting.
[Selection diagram] None

Description

【００３０】
表１の通り、実施例１、２、３では、いずれも打錠末の流動性および硬度が十分得られた。
一方、比較例１、２ではいずれの場合も崩壊性が悪く、比較例３に至っては、３６０分経過しても崩壊しなかった。また、比較例１、２、３ではいずれの場合も打錠末の流動性は不十分であり、時折、打錠機のホッパー内で、打錠末が詰まっているのが認められた。本発明では、ムラのないきれいなコーティングができているが、比較例２，３では、コーティングムラが生じ、更に、比較例２，３では、錠剤の欠けが認められた。
さらに硬度に関しても、実施例１、２、３よりも劣っており、打錠に不向きである結果であった。
【００３１】
【発明の効果】
本発明に依れば、キトサン粉末を高含有させた場合に起こる流動性が悪い等の問題を解決され、かつ、錠剤に加工する際の成形性、胃液中での崩壊性が改善された錠剤を得ることができる。この崩壊性は、錠剤によく適用されるコーティングを施しても維持され、実用上重要な要素である。
食事直後にこの錠剤を服用すると、脂肪、胆汁酸、糖質、塩素イオン等が小腸から吸収されずに排泄されることとなる。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to tablets comprising chitosan powder.
[0002]
[Prior art]
Chitosan powder exhibits various physiological activities such as a fat absorption inhibitory effect, a cholesterol lowering effect, a blood pressure lowering effect, a blood uric acid level lowering effect, and a heavy metal adsorption ability. .
These physiological activities are exhibited by dissolving chitosan powder in gastric juice and inhibiting digestion and absorption by adsorbing fats, bile acids, carbohydrates, chloride ions and the like. Therefore, how quickly a chitosan-containing tablet disintegrates in gastric juice is important for exerting the effect of chitosan.
However, tablets containing, for example, 30% by weight or more of chitosan powder do not disintegrate sufficiently in gastric juice, migrate into the intestine while the tablet surface is gelled, and are excreted in the stool as it is. Such a phenomenon has been observed, and particularly, as the content of the chitosan powder increases, such a tendency increases. It is difficult for such a chitosan-containing tablet having poor disintegration in gastric juice to sufficiently exert the effect of chitosan.
[0003]
As a conventional technique, there is a technique relating to a tablet containing chitosan powder (see Patent Documents 1 and 2). Patent Document 1 discloses a method of preparing a powder, granule, solution, capsule or tablet containing chitosan as an active ingredient, which has the same phosphorus-adsorbing ability as aluminum hydroxide gel in Pharmacopoeia and has side effects. No oral adsorbent is proposed. Patent Document 2 discloses kneading using chitosan and a thickening agent such as carrageenan, gum, pectin, agar, and methylcellulose in order to provide a lubricant capable of producing a tablet having a high content of chitosan. After granulation and sizing, eggshell powder is added as a lubricant and tableting is performed to produce tablets with a high dietary fiber content. Both are simply tablets of chitosan powder, and the disintegration in gastric juice is not improved.
[0004]
In addition, chitosan powder has a low bulk specific gravity and poor powder fluidity. Therefore, when a large amount of chitosan powder is blended, the filling amount is limited in the form of granules, tablets, hard capsules and the like. As a method of increasing bulk specific gravity and improving powder fluidity, a granulation method using a binder such as a thickening polysaccharide, starch, a cellulose derivative and a solvent such as water or an aqueous ethanol solution as conventionally performed is used. Then, the more the chitosan powder is blended, the more brittle the granules. In particular, when processing into tablets, the bulk specific gravity is low and the moldability is poor, so that there is a problem that the weight adjustment is limited and the tablet becomes highly friable.
It solves problems such as low bulk specific gravity, poor fluidity, brittle granules after granulation, and poor disintegration in gastric juice when processed into tablets when chitosan is contained in high content. As means, there is one proposed by the present applicant (see Patent Documents 3 and 4).
The content is, for example, after uniformly mixing the chitosan powder and the calcium powder material, stirring and kneading while dropping or spraying an organic acid aqueous solution or an organic acid ethanol aqueous solution or a fruit juice as a granulation liquid to perform granulation. Is the way.
Since it is mixed with a liquid material, a wet granulation method is suitable as a granulation method. Specifically, a stirring granulation method, an extrusion granulation method, a crushing granulation method, and the like are effective. When is adopted, the bulk specific gravity tends to be low. For this reason, there is a case where a formulation unsuitable for the simplest fluidized bed granulation method among wet granulations in which mixing, granulation, and drying can be performed simultaneously in the same apparatus is produced. In addition, as described above, the bulk specific gravity is low and the moldability is poor, so that there is a limit in weight adjustment, and there is a problem that the tablet becomes highly friable.
Therefore, with respect to chitosan powder, it has been desired to develop a direct tableting method in which intermediate steps such as granulation and drying are omitted. As a conventional technique relating to the direct compression method of chitosan powder, an invention relating to the development of an oral sustained-release preparation is known (see Patent Document 5).
However, Patent Document 5 is a technique from the viewpoint of how long a tablet stays in the gastrointestinal tract without disintegration to maintain its medicinal effect, and does not improve disintegration with gastric acid.
[0005]
[Patent Document 1] JP-A-5-213762 [Patent Document 2] JP-A-10-225285 [Patent Document 3] JP-A-11-302201 [Patent Document 4] JP-A-11-302183 [Patent Document 4] Reference 5: Japanese Patent Application Laid-Open No. 62-81328
[Problems to be solved by the invention]
The present invention solves problems such as a decrease in flowability caused when a high content of chitosan powder is contained, and a tablet having improved moldability when processed into a tablet and disintegrability in gastric juice, and a tablet thereof. Is provided by the direct compression method.
[0007]
[Means for Solving the Problems]
The present inventors have conducted intensive studies to solve these problems, and as a result, have found that it is effective to add a calcium powder material and crystalline cellulose to chitosan powder, and have reached the present invention.
[0008]
That is, the present invention
1. Chitosan-containing tablets, which are characterized in that calcium powder material and microcrystalline cellulose are blended into chitosan powder and tableted,
2. The chitosan-containing tablet according to 1, wherein the tablet is directly compressed.
3. It is characterized by mixing 0.03 to 0.27 parts by mass of a calcium powder material and 0.02 to 0.27 parts by mass of crystalline cellulose with 1.00 part by mass of chitosan powder and tableting. Or the chitosan-containing tablet according to 2,
4. Natural calcium powder such as scallop calcium, oyster shell calcium, coral calcium, sea urchin shell calcium, petrified seaweed calcium, pearl calcium, cow bone calcium, fish bone powder calcium, fish scale calcium, milk calcium, dolomite, etc. Any one or more of materials selected from one or more selected from purified calcium powder materials such as calcium carbonate, calcium phosphate, calcium lactate, calcium gluconate, calcium citrate, calcium chloride, etc. Chitosan-containing tablets according to,
5. The chitosan-containing tablet according to any one of 1 to 4, wherein the bulk specific gravity of the crystalline cellulose to be blended is 0.12 to 0.40 g / ml,
6. Chitosan-containing tablet according to any one of 1 to 5, characterized in that gastric disintegration was within 30 minutes,
7. The chitosan-containing tablet according to any one of 1 to 6, wherein an inert ingredient and / or a coating base is added,
8.1 A method for producing a chitosan-containing tablet, characterized in that the chitosan-containing tablet according to any one of 1 to 7 is made into a tablet using a direct compression method.
About.
[0009]
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, the present invention will be described in detail.
The chitosan powder referred to in the present invention is a polymer powder in which glucosamine obtained from a shell such as a shrimp or a crab, a squid shell or the like as a raw material is β-1,4 bonded. Specifically, the shells of shrimp, crab and the like are washed with water, dried, and optionally ground. The shell powder is subjected to a dilute hydrochloric acid or EDTA (ethylenediaminetetraacetic acid) treatment to perform a demineralization treatment. Next, the crust from which the ash has been removed is boiled with an aqueous sodium hydroxide solution to carry out a protein removal operation. Chitosan powder is obtained by deacetylating the chitin powder, which is a polymer of N-acetylglucosamine obtained through these steps, with, for example, a 30 to 50% aqueous solution of concentrated sodium hydroxide.
[0010]
In the present invention, a naturally produced calcium powder material and a purified calcium powder material can be used as the calcium powder material. Naturally occurring calcium powder materials used in the present invention include, for example, shell calcium (scallop calcium, oyster shell calcium, etc.), coral calcium, sea urchin shell calcium, petrified seaweed calcium, pearl calcium, bovine bone calcium, fish bone powder calcium, Natural calcium that can be used in foods such as fish scale calcium, milk calcium and dolomite. Further, the purified calcium powder material is any calcium powder material that can be used in foods such as calcium carbonate, calcium phosphate, calcium lactate, calcium gluconate, calcium citrate, calcium chloride and the like. In the present invention, these calcium-rich materials or purified calcium powder materials produced from nature can be used alone or in combination of two or more.
[0011]
A general method for producing a calcium powder material produced from nature is a series of flows in which raw materials are sorted, crushed, sieved, heat sterilized, and the like, and then ground to a predetermined particle size. For example, in a general method for producing scallop calcium, it is produced by sorting, crushing, and sieving, followed by dry heat sterilization at, for example, 200 ° C., and pulverization to a predetermined particle size. In general, coral calcium is generally obtained by first collecting coral sand or coral fossils, removing foreign matters after washing with water, and then sterilizing and drying by heating at, for example, 100 ° C. or more, to a predetermined particle size. It is manufactured by a method of pulverizing so as to be.
[0012]
Next, among the purified calcium powder materials, for example, calcium carbonate is a method of reacting calcium oxide obtained by calcining limestone with water to form calcium hydroxide, and obtaining colloidal or light calcium carbonate through carbon dioxide gas. Alternatively, there is a method in which a sodium carbonate solution is reacted with a calcium chloride solution to produce precipitated calcium carbonate, or a method in which natural limestone is pulverized and then converted into heavy calcium carbonate. Further, there is a purified calcium material obtained by reacting calcium carbonate or calcium oxide with various acidic solutions. For example, calcium citrate is generally produced by dissolving citric acid in water, purifying by neutralizing with calcium oxide, collecting a precipitate, and drying. Calcium lactate is generally produced by adding calcium carbonate as a neutralizing agent during lactic acid fermentation to obtain crude calcium lactate and collecting and purifying it, or by adding calcium carbonate to synthetic lactic acid.
[0013]
The crystalline cellulose in the present invention is an insoluble dietary fiber obtained by using a plant pulp fiber as a raw material and extracting and purifying a cellulose crystal region, that is, a portion where cellulose molecular chains are densely and regularly present.
The bulk specific gravity of the crystalline cellulose in the present invention is 0.12 to 0.40 g / ml, preferably 0.14 to 0.30 g / ml, and particularly preferably 0.16 to 0.25 g / ml. . If the bulk specific gravity of the crystalline cellulose deviates from these ranges, the moldability at the time of processing into tablets is lost, and during transportation of the product or when coating is performed, cracking or chipping of the tablets occurs, so the above range. It is desirable to be within.
The average particle size of such crystalline cellulose is generally 15 to 80 μm, preferably 16 to 70 μm, and particularly preferably 17 to 60 μm, but commercially available products can be used.
[0014]
The tablets obtained by the present invention have good disintegration of chitosan in gastric juice. Chitosan disintegrates and dissolves in gastric juice to make sufficient contact with fats, cholesterol, heavy metals, etc., and when it migrates to the small intestine, it gels and adsorbs or wraps fats, cholesterol, heavy metals, etc. There is. Therefore, enhancing the disintegration of chitosan in gastric juice effectively inhibits various physiological activities of chitosan, such as fat absorption inhibitory effect, cholesterol lowering effect and blood pressure lowering effect, blood uric acid level lowering effect, and heavy metal adsorption ability. This is useful for expressing in
Although the mechanism of the effect of enhancing the disintegration of the tablet obtained in the present invention in gastric juice is not always clear, it is probably that the calcium contained in the chitosan tablet obtained according to the present invention is ionized or carbon dioxide gas comes into contact with the gastric juice. It is presumed that the occurrence of may cause the bond of the chitosan particles to be easily cut and broken.
[0015]
In the present invention, the test method for confirming disintegration in gastric juice conforms to the disintegration test method described in the Japanese Pharmacopoeia, 14th Edition. That is, the test solution used was the first solution (aqueous solution of pH 1.2, which was prepared by adding 7.0 ml of hydrochloric acid and water to 2.0 g of sodium chloride and dissolving to 1000 ml), and is described in the Japanese Pharmacopoeia 14th Edition. In accordance with the evaluation method of “(1) Tablet”, the disintegration is adjusted so as to disintegrate within 30 minutes.
The amounts of the calcium powder material and the crystalline cellulose are 0.03 to 0.27 mass% and 0.02 to 0.27 mass%, preferably 0.09 to 0.27 mass%, respectively, relative to 1.00 mass% of chitosan powder. It is desirably 0.21% by mass and 0.06 to 0.21% by mass, particularly preferably 0.11 to 0.16% by mass and 0.10 to 0.15% by mass. When the compounding amount of the calcium powder material and the crystalline cellulose deviates from the above range, the disintegration of the tablet is lowered, the fluidity of the mixed powder is lost, the weight variation of the tablet is increased, or when the tablet is processed. Since the moldability of the tablet is lost and the tablet may be cracked or chipped at the time of transportation or coating of the product, it is preferable that the ratio is within the above range.
[0016]
If necessary, the following inactive components can be contained for the purpose of enhancing the productivity. Inactive components in the present invention include dextrin, wheat starch, rice starch, corn starch, potato starch, pregelatinized starch, partially pregelatinized starch, tapioca starch, lactose, maltose, reduced lactose, reduced maltose, sorbitol, mannitol, erythritol , Xylitol, trehalose, sucrose, glucose, guar gum, xanthan gum, sodium alginate, gum arabic, tragacanth, pullulan, carrageenan, agar, gelatin, soy dietary fiber, methylcellulose, ethylcellulose, low-substituted hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylstarch , Polyvinylpyrrolidone, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethyl starch sodium Food and pharmaceutical industry, such as vegetable oil, vegetable hardened oil, vegetable oil and fat, carnauba wax, cacao butter, sucrose fatty acid ester, stearic acid, magnesium stearate, aluminum stearate, calcium stearate, silicon dioxide, talc and aluminum silicate And all commercially available products can be used.
[0017]
The tablet of the present invention is not affected by its shape and weight, and is manufactured according to a general manufacturing method.
For example, it can be manufactured by compression-molding a mixture of chitosan powder, the above-mentioned calcium powder material and crystalline cellulose, and mixing them according to a conventional method. If necessary, the inactive component may be blended. In this case, two or more of the inactive components may be used in combination. In some cases, pulverization, sieving, or the like may be performed so as to obtain an appropriate particle size before formulation, in order to improve formulation suitability.
[0018]
Further, for the purpose of improving the texture, a coating may be applied by an ordinary method. In that case, as a coating base, gelatin, dextrin, sodium alginate, carboxymethylethylcellulose, cellulose acetate phthalate, ethylcellulose, corn protein, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate Copolymer, methacrylic acid copolymer, hydroxypropylmethylcellulose phthalate, shellac, hydroxypropylmethylcellulose acetate succinate and the like.
The disintegration in gastric juice when the coating is applied also conforms to the disintegration test method described in the Japanese Pharmacopoeia 14th Edition. As described above, as the test solution, the first solution (pH 1.2 aqueous solution obtained by adding 7.0 ml of hydrochloric acid and water to 2.0 g of sodium chloride and dissolving) was used, and described in the Japanese Pharmacopoeia 14th Edition. In accordance with the evaluation method of “(2) Tablet coated with an appropriate coating agent”, the disintegration is adjusted so as to disintegrate within 60 minutes.
[0019]
The disintegration time of the chitosan-containing tablet is not short in order to sufficiently exert the bioactivity of the chitosan powder. The shorter the time it takes for the chitosan powder dissolved in gastric juice to adsorb fats, bile acids, carbohydrates, chloride ions, etc., the more efficiently the digestion and absorption of these are inhibited, the fat absorption inhibitory effect, This is because various physiological activities such as an action, a blood pressure lowering effect, a blood uric acid level lowering effect, and a heavy metal adsorption ability are surely exhibited.
Therefore, the disintegration time in the present invention is desirably 30 minutes or less, preferably 20 minutes or less, and particularly preferably 10 minutes or less according to the disintegration test method described in the 14th revised Japanese Pharmacopoeia.
In the case where the coating is applied, the coating is performed within 60 minutes, preferably 30 minutes, according to the evaluation method of “(2) Tablet coated with an appropriate coating agent” described in the Japanese Pharmacopoeia, Fourteenth Edition. It is desirable that the time be within minutes, particularly preferably within 20 minutes, more preferably within 10 minutes.
[0020]
【Example】
Hereinafter, examples of the present invention will be described, but the present invention is not limited thereto.
Embodiment 1
65.0 kg of chitosan powder, 10.0 kg of crystalline cellulose, 10.0 kg of dextrin, and 12.5 kg of dolomite sieved using a 100-mesh sieve were mixed in a V-type mixer (MIX WELL BLENDER V-200, manufactured by Tokuju Kosakusho). Charged and mixed for 10 minutes. Further, 2.5 kg of vegetable hardened oil was added and mixed for 5 minutes. Next, 200 mg tablets were produced at a pressure of 1000 kg / cm 2 using a rotary tableting machine (AP-22, manufactured by Hatatetsu Kogyo KK).
[0021]
Embodiment 2
74.0 kg of chitosan powder, 9.0 kg of crystalline cellulose, 5.5 kg of dextrin, 9.0 kg of scallop calcium sieved using a 100-mesh sieve were mixed with a V-type mixer (MIX WELL BLENDER V-200, manufactured by Tokuju Kousakusho). And mixed for 10 minutes. Further, 2.5 kg of vegetable hardened oil was added and mixed for 5 minutes. Next, 200 mg tablets were produced at a pressure of 1000 kg / cm 2 using a rotary tableting machine (AP-22, manufactured by Hatatetsu Kogyo KK). The obtained tablets were put into a coating machine (HI-COATER MODEL HCF-150 type Freund Corporation), and each tablet was coated so that shellac would take 2 mg as a solid content.
[0022]
Embodiment 3
86.0 kg of chitosan powder, 7.0 kg of crystalline cellulose, 2.0 kg of dextrin, and 2.5 kg of calcium carbonate sieved using a 100-mesh sieve were mixed with a V-type mixer (MIX WELL BLENDER V-200, manufactured by Tokuju Corporation). And mixed for 10 minutes. Further, 2.5 kg of vegetable hardened oil was added and mixed for 5 minutes. Next, 200 mg tablets were produced at a pressure of 1000 kg / cm 2 using a rotary tableting machine (AP-22, manufactured by Hatatetsu Kogyo KK). The obtained tablets were put into a coating machine (HI-COATER MODEL HCF-150 type Freund Corporation), and each tablet was coated so that shellac would take 2 mg as a solid content.
[0023]
[Comparative Example 1]
A tablet was produced in the same manner as in Example 1 except that reduced maltose was used instead of dolomite.
[0024]
[Comparative Example 2]
A coated tablet was produced in the same manner as in Example 2 except that partially pregelatinized starch was used instead of scallop calcium.
[0025]
[Comparative Example 3]
A coated tablet was produced in the same manner as in Example 3 except that lactose was used instead of crystalline cellulose.
[0026]
Test method 1.
The test solution used was the first solution (an aqueous solution having a pH of 1.2, which was prepared by adding 7.0 ml of hydrochloric acid and water to 2.0 g of sodium chloride and dissolving the solution to 1000 ml). A disintegration test was performed according to the test method.
[0027]
Test method 2.
It was measured by the angle of repose injection method. As the operation method, using a powder tester PT-R type (Hosokawa Micron), each of the mixed powders before tableting was put into a sieve having an opening of 710 μm, vibrated, and supplied to a sample on a circular table through a funnel. Was measured with a semiconductor laser. The angle of repose is the angle formed between the generatrix of the cone of the sample supplied as described above and the horizontal plane. Generally, a powder having good fluidity has a small value of the angle of repose.
[0028]
Test method 3.
Tablets containing chitosan powder are considered to have poor moldability, that is, it is difficult to obtain tablet hardness. Therefore, tablet hardness was measured and compared. As an operation method, the hardness of 10 tablets was measured using a Kiya type digital hardness meter KHT-20N (Fujiwara Seisakusho), and the average value was displayed.
[0029]
[Table 1] Test results

[0030]
As shown in Table 1, in Examples 1, 2, and 3, the fluidity and hardness of the tablet powder were sufficiently obtained.
On the other hand, in each of Comparative Examples 1 and 2, the disintegration property was poor, and in Comparative Example 3, it did not disintegrate even after 360 minutes. In each of Comparative Examples 1, 2, and 3, the fluidity of the tableting powder was insufficient, and it was recognized that the tableting powder was occasionally clogged in the hopper of the tableting machine. In the present invention, a clear coating without unevenness was formed. However, in Comparative Examples 2 and 3, coating unevenness occurred, and in Comparative Examples 2 and 3, chipping of the tablet was observed.
Further, the hardness was inferior to those of Examples 1, 2, and 3, and the result was not suitable for tableting.
[0031]
【The invention's effect】
ADVANTAGE OF THE INVENTION According to this invention, the problem, such as poor fluidity which arises at the time of making chitosan powder contain high, was solved, and the moldability at the time of processing into a tablet, the disintegration in gastric juice improved the tablet. Can be obtained. This disintegration is maintained even when a coating commonly applied to tablets is applied, and is a practically important factor.
If this tablet is taken immediately after a meal, fats, bile acids, carbohydrates, chloride ions and the like will be excreted without being absorbed from the small intestine.

Claims (8)

A chitosan-containing tablet obtained by blending a calcium powder material and crystalline cellulose with chitosan powder and tableting. The tablet containing chitosan according to claim 1, wherein the tablet is directly compressed. A tablet is prepared by compounding 0.03 to 0.27 parts by mass of a calcium powder material and 0.02 to 0.27 parts by mass of crystalline cellulose with 1.00 part by mass of chitosan powder. Item 6. The chitosan-containing tablet according to item 1 or 2. The calcium powder material to be blended is naturally occurring calcium powder such as scallop calcium, oyster shell calcium, coral calcium, sea urchin shell calcium, petrified seaweed calcium, pearl calcium, bovine bone calcium, fish bone powder calcium, fish scale calcium, milk calcium, dolomite, etc. 4. A material according to claim 1, wherein the material is at least one material selected from the group consisting of calcium carbonate, calcium phosphate, calcium lactate, calcium gluconate, calcium citrate, and calcium chloride. The chitosan-containing tablet according to any one of the above. The chitosan-containing tablet according to any one of claims 1 to 4, wherein the bulk specific gravity of the crystalline cellulose to be blended is 0.12 to 0.40 g / ml. The chitosan-containing tablet according to any one of claims 1 to 5, wherein disintegration in the stomach is within 30 minutes. The chitosan-containing tablet according to any one of claims 1 to 6, further comprising an inert component and / or a coating base. A method for producing a chitosan-containing tablet, wherein the chitosan-containing tablet according to any one of claims 1 to 7 is tableted using a direct compression method.