WO2015020186A1

WO2015020186A1 - Tablet composition

Info

Publication number: WO2015020186A1
Application number: PCT/JP2014/070979
Authority: WO
Inventors: 渚速水; 大輔金島; 鈴木　則行; 三四郎成松; 岩崎　英明
Original assignee: ライオン株式会社
Priority date: 2013-08-09
Filing date: 2014-08-08
Publication date: 2015-02-12
Also published as: JP6512099B2; JPWO2015020186A1

Abstract

By means of a tablet composition containing lactoferrin having an average particle size of 40-300 μm, provided is a tablet composition that contains lactoferrin, has a low friability, and has superior lactoferrin leachability and tablet disintegration properties.

Description

Tablet composition

The present invention relates to a tablet composition containing lactoferrin particles.

Metabolic syndrome, the so-called metabolic syndrome, has been reported that one in every two men over the age of 40 and one in five women are reserves (Ministry of Health, Labor and Welfare: May 2006) 8th). Metabolic syndrome causes hypertension, hyperlipidemia, and diabetes, and further develops into cerebral infarction and myocardial infarction due to arteriosclerosis. The symptom upstream of this metabolic syndrome is obesity, which is caused by adipocytokines that arise from visceral fat. Obesity is not only a problem from the viewpoint of beauty, but it is a big problem regardless of gender as an important factor causing metabolic syndrome.

Under such circumstances, lactoferrin has been shown to have a high fat reducing effect on fat, particularly visceral fat, and has been confirmed to be a promising substance. Moreover, since lactoferrin is easily decomposed | disassembled in the stomach, it has been confirmed that the effect is demonstrated by using an intestinal solvent. In addition, lactoferrin is also attracting attention as a substance that plays an important role in defense of the body. In addition, it maintains the health such as growth of bifidobacteria, regulation of iron absorption related to iron binding ability, anti-inflammatory action, and lipid metabolism improvement action.・ It is also known to improve.

Thus, in order to ingest lactoferrin having various actions more effectively, it needs to be absorbed into the body as soon as possible. In addition, it is useful to make tablets in order to make lactoferrin easy to carry and ingest, but in order to absorb it quickly into the body, it is necessary to improve the disintegration of the tablets and the dissolution of lactoferrin as much as possible. Is important.

JP 2008-69121 A

In general, improving tablet disintegration often results in lower tablet hardness and higher friability (tablet is fragile). An object of the present invention is to provide a tablet composition that is excellent in tablet disintegration and lactoferrin dissolution and has low friability and contains lactoferrin particles.

As a result of intensive investigations to achieve the above-mentioned object, the present inventors have blended lactoferrin particles having a specific average particle size, so that the disintegration property of tablets and the dissolution properties of lactoferrin can be maintained while maintaining low friability. It has been found that it has been improved and has led to the present invention.

Accordingly, the present invention provides the following tablet composition.
[1] A tablet composition containing lactoferrin particles having an average particle size of 40 to 300 μm.
[2] The tablet composition according to [1], which is an enteric solvent.
[3] The tablet composition according to [1] or [2], further containing lactose or maltitol.

According to the present invention, it is possible to provide a tablet composition containing lactoferrin particles which is excellent in tablet disintegration and lactoferrin elution and has low friability.

It is a graph which shows the solubility of uncoated tablet samples 1 and 2 and enteric-coated tablet samples 1 and 2. FIG.

Hereinafter, the present invention will be described in detail.
The tablet composition of the present invention contains lactoferrin having an average particle size of 40 to 300 μm.

Lactoferrin includes commercially available lactoferrin, mammals (eg, humans, cows, sheep, goats, horses, etc.) colostrum, transitional milk, regular milk, end milk, etc. Examples include lactoferrin separated by a conventional method (for example, ion exchange chromatography), lactoferrin produced from plants (tomato, rice, tobacco), and lactoferrin obtained by genetic recombination. Lactoferrin may be a commercially available product or can be prepared and used by a known method. These can be used individually by 1 type or in combination of 2 or more types. In addition, as a lactoferrin, the thing derived from a cow is preferable. Although the thing manufactured by the normal manufacturing method can be used for lactoferrin, a freeze-dried product is preferable.

The lactoferrin particles may be regular or irregular, and the average particle size is 40 to 300 μm, preferably 50 to 300 μm, more preferably 80 to 250 μm. When the average particle size is less than 40 μm, the disintegration property of the tablet and the dissolution property of lactoferrin are insufficient, while when it exceeds 300 μm, the friability increases. The average particle diameter refers to a 50% diameter (median diameter, volume basis) in the laser diffraction / scattering particle size distribution. In the above distribution, the mass% passing through a 63 μm mesh (235 mesh) is preferably 60% by mass or less, more preferably 50% by mass or less, still more preferably 30% by mass or less, and most preferably 20% by mass or less. preferable.

In general, it is effective to increase the particle size of the raw material to be mixed in order to increase the disintegration property of the tablet. However, the moldability of the tablet tends to decrease as the particle size is increased. In such a case, it is necessary to increase the tableting pressure in order to reliably mold the tablet. Therefore, even if the particle size of the raw material is increased in order to increase the disintegration property of the tablet, it is necessary to compress the tablet with a high tableting pressure. As a result, the hardness of the resulting tablet increases and the disintegration property deteriorates. It was. Therefore, the target disintegration property could not be obtained simply by increasing the particle size of the raw material. On the other hand, as described above, in the case of a small particle size of about 30 μm or less that has been conventionally used, the intended tablet disintegration may not be obtained. In the present invention, by using lactoferrin having a particle size in the specific range specified above, even when tableting is performed by increasing the tableting pressure, the hardness of the resulting tablet may be excessively increased. And tablets having good disintegration and excellent friability can be produced.

The content of lactoferrin is, for example, preferably 1 to 250 mg / 300 mg (0.3 to 83% by mass) per 300 mg of tablet composition, more preferably 10 to 200 mg (3.3 to 67% by mass), 20 to 150 mg (6.7 to 50% by mass) is more preferable. By setting it as this range, various effects peculiar to lactoferrin are exhibited, and excellent tablet disintegration and low friability can be obtained.

In the tablet composition, an arbitrary amount of arbitrary components can be used alone or in an appropriate combination of two or more, as long as the effects of the present invention are not impaired. Examples of optional components include oily components, lubricants, excipients, disintegrants, binders, functional components other than the above components, plant extracts, pigments, and fragrances. Specifically, the following components can be mentioned. In addition, the component which has the role which the component overlapped is described redundantly.

Examples of the oil component include various fatty acid esters, hydrocarbons, higher fatty acids, higher alcohols and the like. Lubricants include gum arabic, cacao butter, carnauba wax, hydrous silicon dioxide, dry aluminum hydroxide gel, glycerin, magnesium silicate, liquid paraffin, crystalline cellulose, sucrose fatty acid ester, stearyl alcohol, stearic acid, gelatin, lactose Sucrose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, carboxymethylcalcium, carboxymethylammonium, fumaric acid, beeswax and the like. Excipients include gum arabic, ethylcellulose, kaolin, cacao butter, fructose, silicon dioxide, xylitol, citric acid or salts thereof, crystalline cellulose, stearic acid or salts thereof, dextran, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose Sodium carboxymethyl cellulose, carboxymethyl calcium, carboxymethyl ammonium, polyvinylpyrrolidone, macrogol, calcium hydrogen phosphate, sodium hydrogen phosphate, sucrose, glucose, maltitol, erythritol, isomalt, mannitol, sorbitol, lactitol, corn starch, potato A starch etc. are mentioned. Examples of the disintegrant include cellulose or a derivative thereof, starch or a derivative thereof. Examples of the binder include hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose sodium, carboxymethyl calcium, carboxymethyl ammonium, gelatin, vinyl pyrrolidone, and partially pregelatinized starch. Examples of the functional component include carotenoid substances (α-carotene, β-carotene, γ-carotene, lycopene, lutein, astaxanthin, zeaxanthin, etc.), coenzyme Q10, vitamin E, tocotrienol, DHA, EPA, lactic acid bacteria and the like. Examples of plant extracts include pepper plant extracts such as baboons, araceae plant extracts, and vinegar powder.

The blending amount of each optional component in the tablet composition is 0 to 25% by mass of an oily component, 0.01 to 5% by mass of a lubricant, 1 to 95% by mass of an excipient, 0 to 80% by mass of a disintegrant, 0.5 to 60% by mass, binder 0.01 to 60% by mass, functional components other than the above components, plant extract 0 to 60% by mass, particularly 0.5 to 50% by mass are preferred.

Above all, the disintegration of tablets is improved by adding lactose. The content of lactose is, for example, preferably 10 to 299 mg / 300 mg (3 to 99.7% by mass) per 300 mg of tablet composition, more preferably 0 to 280 mg / 300 mg (0 to 93% by mass), and 0 to More preferred is 200 mg / 300 mg (0 to 66.7% by mass). Further, in the present invention, sugar alcohols such as maltitol, erythritol and sorbitol can be blended for the same purpose in addition to the above-mentioned lactose, but tablet disintegration and tableting trouble (such as adhesion of powder to a rotating disk) Lactose and maltitol can be preferably used from the viewpoint of the difficulty of occurrence of). In addition, content of these sugar alcohols may be the same as that of the said lactose.

In addition, when blending crystalline cellulose, 0 to 299 mg / 300 mg (0 to 99.7% by mass) per 300 mg of tablet composition is preferable, and 0 to 280 mg / 300 mg (0 to 93.3% by mass) is more preferable. preferable. When carboxymethylcellulose is blended, 0 to 10 mg / 300 mg (0 to 3.3% by mass) per 300 mg of tablet composition is preferable. When silicon dioxide is blended, 0 to 10 mg / 300 mg (0 to 3.3% by mass) per 300 mg of tablet composition is preferable. When sucrose fatty acid ester is blended, 0 to 50 mg / 300 mg (0 to 16.7% by mass) per 300 mg of tablet composition is preferable.

The tablet composition is not particularly limited, such as a normal oral, that is, a swallowable tablet, or an orally disintegrating tablet, but in the case of a normal swallowable tablet, it is preferably an enteric preparation. For enteric preparations, shellac, water-soluble shellac, zein, hydroxymethylcellulose phthalate, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, cellulose acetate phthalate, methacrylic acid copolymer, ethylcellulose, aminoalkyl methacrylate copolymer, beer Enteric components such as yeast cell wall (for example, brand name yeast wrap), tapioca starch, gelatin, pectin, fats and oils such as hydrogenated oil, and the like may be blended. In the present invention, whether it is an enteric preparation depends on the 14th revised Japanese Pharmacopeia / Disintegration Test Method.

The tablet composition of the present invention can be obtained by mixing lactoferrin and optional ingredients and tableting. Molding conditions such as tableting pressure vary depending on the tableting machine, the type and amount of ingredients, the tablet diameter, etc., but are adjusted as appropriate in consideration of disintegration properties, tablet strength, oral disintegration rate, and the like. When making an enteric preparation, the uncoated tablet is coated with the enteric component. The amount of the enteric component is preferably 0.1 to 10% by mass, more preferably 0.5 to 10% by mass with respect to the uncoated tablet.

The size of the orally disintegrating tablet of the present invention is not particularly limited, but is preferably about 5 to 12 mm in diameter, preferably 200 to 400 mg, more preferably 250 to 350 mg per tablet. When the tablet is not an orally disintegrating tablet, that is, an oral type tablet, the tablet hardness is preferably 5 to 30 kgf, more preferably 8 to 30 kgf. In the case of an orally disintegrating tablet, 3 to 20 kgf is preferable, and 5 to 15 kgf is more preferable. The tablet hardness represents the force required for the tablet to break up by standing the tablet vertically on the anvil and applying a static pressure to the tablet with a moving plunger. For example, the hardness is Pharma test WHT-2ME. (Measured by Japan Machinery Co., Ltd.)

Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example.

[Test example]
Using an actual machine LIBRA2 (manufactured by Kikusui Seisakusho Co., Ltd.), an uncoated tablet (diameter 9 mm, 1 tablet 300 mg) having the composition shown in Table 2 below is prepared, and further coated with shellac, and the enteric solution having the composition shown in Table 2 below is prepared. A tablet (diameter 9.3 mm, 1 tablet 330 mg) was prepared.
The obtained uncoated tablets and enteric tablets were subjected to the following tests and evaluations. The results are also shown in Table 2.
The average particle diameter and tablet hardness of lactoferrin were measured by the following methods.
Average particle diameter: measured with a laser diffraction particle size distribution analyzer (LS13 320 manufactured by BECKMAN COULTER) (50% diameter (median diameter, volume basis)).
Tablet hardness: Measured with Pharma test WHT-2ME (manufactured by Japan Machinery Co., Ltd.).

[Tablet friability]
The test was conducted in accordance with the tablet friability test method of 16 Japanese Pharmacopoeia.
A result is shown on the following evaluation criteria from a friability.
<Evaluation criteria for friability>
A: Less than 0.1% by mass O: 0.1% by mass or more and less than 0.2% by mass Δ: 0.2% by mass or more and less than 0.5% by mass x: 0.5% by mass or more

[Collapse]
The obtained tablets (six samples) were tested at 50 revolutions per minute by the paddle method (16 Japanese Pharmacopoeia) using 900 mL of the test solution, and the following evaluation was performed.
As the test solution, second solution for dissolution test (pH about 6.8: 16 Japanese Pharmacopoeia) and distilled water were used. The results are divided into uncoated tablets and intestinal solvents from the disintegration time, and are shown by the following evaluation criteria suitable for each dosage form.

The following dissolution test was performed on the uncoated tablet samples 1 and 2 and the enteric tablet samples 1 and 2. The results are shown in FIG.
[Dissolution test]
For the obtained tablets (six samples), 900 mL of dissolution test second liquid (pH about 6.8: 16 Japanese Pharmacopoeia) is used as a test liquid, and 50 rotations per minute by the paddle method (16 Japanese Pharmacopoeia). The lactoferrin in the test solution after 0, 60, 90 and 120 minutes was quantified by high performance liquid chromatography. The results of elution rate (%) are shown in FIG.

From the results of Table 2, the disintegration property of the tablet of sample 2 was improved in the second liquid: pH about 6.8, distilled water. In general, when disintegration is improved, tablet hardness decreases and friability often increases. As is clear from the above results, disintegration improvement could be achieved while maintaining the same friability.
In addition, from the results of Table 2 and FIG. 1, it was confirmed that lactoferrin was improved by improving disintegration.

[Examples 1 to 13, Comparative Examples 1 to 3]
An uncoated tablet was prepared using an actual machine LIBRA2 (manufactured by Kikusui Seisakusho Co., Ltd.) and coated with shellac to prepare enteric tablets having the compositions shown in Tables 3 and 4 below (diameter 9 mm, 1 tablet 300 mg).
About the obtained enteric-coated tablet, the test and evaluation similar to Test Example 1 were performed. In addition, in the said test example, since the same result was obtained with 2nd liquid: pH about 6.8 and distilled water about uncoated tablet and intestinal solvent, hereafter, about Example, it is 2nd as uncoated tablet and test liquid. The solution was evaluated.

The use of lactoferrin with an average particle size of 40 μm or more resulted in a significant improvement in disintegration time. On the other hand, when the average particle size was larger than 300 μm, it was confirmed that the hardness decreased and the friability deteriorated.

[Study on sugar alcohol]
An uncoated tablet sample and an enteric tablet sample in which lactose used in the above examples was changed to maltitol were prepared and evaluated in the same manner as in the above examples. The results are shown in Table 5.

[Prescription example]
Using an actual machine LIBRA2 (manufactured by Kikusui Seisakusho Co., Ltd.), uncoated tablets (diameter 9 mm, 1 tablet 300 mg) having the composition shown in the following table were prepared.

Claims

Tablet composition containing lactoferrin particles having an average particle size of 40 to 300 μm.
The tablet composition according to claim 1, which is an enteric solvent.
The tablet composition according to claim 1 or 2, further comprising lactose or maltitol.