TW201701898A - Tablet composition, and method for improving disintegration properties and elution properties of tablet composition - Google Patents

Abstract

A tablet composition having improved disintegrating properties and improved elution properties, said tablet composition comprising (A) 30% by mass or more of lactoferrin and (B) 0.12 to 1.0% by mass of a stearate salt.

Description

Method for improving disintegration/dissolution of tablet composition and tablet composition

The present invention relates to a method for improving the disintegration/dissolution property of a lactoferrin-containing tablet composition and a tablet composition.

In order to more efficiently ingest lactoferrin, which is known to have various effects, it is at least necessary to rapidly absorb it in the body. In addition, it is useful to form a tablet for ease of carrying and easy to ingest lactoferrin. However, in order to rapidly absorb the tablet in the body, it is important to at least increase the disintegration of the tablet and the solubility of lactoferrin.

In the lozenge containing lactoferrin at a high concentration, since the binding strength of the lactoferrin powder is low, it is necessary to ingot the tablet at a high pressure in order to reduce the wear of the tablet. The lozenge which is formed by high pressure also has a tendency to lower the tablet of the low pressure tablet with the binding force of the powder, and the tablet containing the powder having a low binding strength such as lactoferrin at a high concentration is inevitable There is a problem of poor collapsibility.

[Previous Technical Literature] [Patent Literature]

[Patent Document 1] Japanese Patent Laid-Open Publication No. 2007-031403

[Patent Document 2] Japanese Patent Laid-Open Publication No. 2006-083089

[Patent Document 3] Japanese Patent No. 4278773

[Patent Document 4] Japanese Patent Laid-Open Publication No. 2001-354583

[Patent Document 5] Japanese Patent No. 3183378

[Patent Document 6] International Publication No. 2014/136857

[Patent Document 7] Japanese Laid-Open Patent Publication No. 2012-121909

In the molding of a tablet, a slip agent is formulated in order to suppress the barring disorder. As the slip agent, stearate, sucrose fatty acid ester, glycerin fatty acid ester or the like is used. Generally, for a powder having a low binding property, a sucrose fatty acid ester having a low sliding effect is selected, and a powder having a high binding strength is selected as a slipping agent having a high sliding effect of stearate. In the same manner as this example, as a slip agent containing a composition of a lactoferrin-containing tablet, a sucrose fatty acid ester has hitherto been selected. However, the lozenge of lactoferrin and sucrose fatty acid ester was mixed, and although the initial disintegration property and the lactate protein were excellent in dissolvability, it was found that the problem of delayed dissolution of lactoferrin was lowered.

The present invention has been made in view of the above problems, and it is an object of the present invention to provide a tablet which has excellent moldability in the presence of high concentration of lactoferrin (in the case of tableting/adhesive on the disk surface: sometimes referred to simply as adhesion) A lactoferrin-containing tablet composition having good disintegration properties and dissolving properties, and having good disintegration and dissolvibility after long-term storage.

As a result of the positive review of the above-mentioned objects, the inventors of the present invention have found that it is excellent in formability with a tablet and is hydrophobic by using a stearate as a slip agent containing a composition of a lactoferrin-containing tablet. The stearic acid ester which interacts to retard the disintegration is reversed in characteristics, does not lower the initial disintegration property, and does not delay the breakage time even after long-term storage, and has good disintegration property and lactate dissolving property. Thus the present invention has been completed.

That is, the present invention provides a method for improving the disintegration/dissolution property of the tablet composition and the tablet composition described below.

[1] A tablet composition comprising (A) 30% by mass or more of lactoferrin and (B) 0.12 to 1.0% by mass of stearate.

[2] The tablet composition according to [1], wherein the aforementioned (B) stearate is calcium stearate or magnesium stearate.

[3] The tablet composition according to [1] or [2], wherein the mass ratio of the component (A) to the component (B) represented by (B) / (A) × 100 is 0.25 to 3.

[4] The tablet composition according to any one of [1] to [3], which further comprises 5% by mass or more of (C) a sugar or a sugar alcohol.

[5] The tablet composition according to [4], wherein the component (C) is a sugar alcohol.

[6] A tablet composition according to [5], wherein the aforementioned sugar alcohol is maltitol, isomalt or isomalt.

[7] The tablet composition according to any one of [4] to [6], wherein the mass ratio of the component (C) to the component (A) represented by (C)/(A) is 0.15 to 1.0.

[8] A method for improving the disintegration and dissolving property of a tablet composition, A method for improving the disintegration property of a tablet composition containing 30% by mass or more of lactoferrin and the solubility of the lactoferrin, characterized in that 0.12 to 1.0% by mass of stearic acid is formulated in the tablet composition. salt.

According to the present invention, there is provided an ingot which is excellent in tablet formability, good disintegrat property and dissolvability, and good in disintegration and dissolvability after long-term storage even in a composition containing a lactoferrin-containing tablet. Agent composition.

[(A) Lactoferrin]

The tablet composition of the present invention contains (A) 30% by mass or more of lactoferrin. Lactoferrin is a functional ingredient with a high fat reduction effect. The amount of the (A) lactoferrin to be added to the composition is preferably 32% by mass, more preferably 35% by mass. On the other hand, the upper limit thereof is not particularly limited, but is preferably 99.88 mass%, but is preferably 80% by mass, more preferably 70% by mass, and even more preferably 50% by mass, from the viewpoint of moldability at the time of tableting. .

As lactoferrin, it is a colostrum, a transitional milk, a regular milk, a terminal milk, or the like, or a skim milk or whey of a treatment of such milk, such as a human, a cow, a sheep, a goat, or a horse. Lactoferrin isolated by conventional methods (such as ion exchange chromatography), lactoferrin produced from plants (tomato, rice, tobacco), lactoferrin obtained by genetic recombination Wait. These may be used alone or in combination of two or more. As lactoferrin, it is preferred to be derived from a cow. Further, as the lactoferrin, a commercially available product may be used, and it may be prepared by a conventional method. Lactoferrin can be used in the usual way.

When the lactoferrin is a freeze-dried product, the shape thereof may be amorphous or amorphous, and the average particle diameter thereof is 40 to 300 μm, preferably 50 to 300 μm, more preferably 80 to 250 μm. When the average particle diameter is 40 μm or more, the disintegration property of the tablet and the solubility of lactoferrin are good, and when it is 300 μm or less, the degree of wear is low. Further, in the present invention, the average particle diameter means a 50% diameter (median diameter, volume basis) in the laser diffraction scattering type particle size distribution. In addition, in the distribution, the ratio (% by mass) of the mesh having a mesh of 63 μm (235 mesh) is preferably 60% by mass or less, more preferably 50% by mass or less, and still more preferably 30% by mass or less. It is preferably 20% by mass or less.

[(B) stearate]

In the tablet composition of the present invention, (B) stearate functions as a slip agent. The tablet composition of the present invention contains (B) stearate, which is suppressed in the decrease in the lapse of time and is also excellent in the solubility after long-term storage.

The (B) stearate is not particularly limited as long as it is a salt of stearic acid and a monovalent or divalent metal, and is preferably calcium stearate or magnesium stearate, more preferably calcium stearate.

The lower limit of the amount of the (B) stearate is 0.12% by mass, preferably 0.14% by mass, more preferably 0.15% by mass. On the other hand, the upper limit It is 1.0% by mass, preferably 0.8% by mass, more preferably 0.6% by mass. (B) When the amount of the stearate is at least the lower limit, the sliding effect and the formability are good, and if it is at most the upper limit, the breakage delay does not occur, and the disintegration property and the dissociation property are good.

The blending quality of the component (A) and the component (B) represented by (B) / (A) × 100 is preferably 0.25 to 3, more preferably 0.4 to 1.6. When it is at least the above lower limit, the breakage delay does not occur, and the disintegration property, the dissolvibility, and the tablet formability are further improved. Below the above upper limit, the initial disintegration property and the dissociation property are further improved.

[(C) sugar or sugar alcohol]

The tablet composition of the present invention may also contain a sugar or a sugar alcohol as the component (C). (C) A sugar or sugar alcohol function as an excipient. The solubility of lactoferrin can be further improved by containing (C) a sugar or a sugar alcohol.

The sugar is not particularly limited, and may be any of a monosaccharide, a disaccharide, an oligosaccharide, and a polysaccharide. In particular, lactose, starch (corn starch, potato starch, etc.), fructose, glucose, sucrose, white sugar, maltose, anhydrous lactose, dextrin, and the like are preferable, and among them, a water-soluble component is preferable, and lactose, sucrose, etc. are more preferable.

The sugar alcohol is exemplified by isomalt, maltitol, erythritol, sorbitol, xylitol or the like. Among these, isomalt, maltitol, and erythritol are preferred, and maltitol is more preferred.

(C) The lower limit of the amount of the sugar or sugar alcohol to be added is preferably 5% by mass, more preferably 10% by mass, still more preferably 15% by mass in the composition. another On the one hand, the upper limit is preferably 69.88 mass%, more preferably 50 mass%, and still more preferably 40 mass%. (C) When the amount of the sugar or the sugar alcohol is at least the lower limit, the disintegration property and the dissociation property are good, and when the amount is at most the upper limit, the moldability of the tablet is good.

The blending quality of the component (C) and the component (A) represented by (C)/(A) is preferably from 0.15 to 1.0, more preferably from 0.3 to 0.8. When the content is at least the above lower limit, the breakage delay does not occur, and the disintegration property, the dissolvibility, and the tablet moldability are good. When it is less than or equal to the above upper limit, the collapse delay does not occur, and the disintegration property is good.

[Other ingredients]

The tablet composition of the present invention may be used alone or in combination of two or more other components in an appropriate amount within the range not impairing the effects of the present invention. The other component may, for example, be a functional component other than the component (A), a slip agent other than the component (B), an excipient other than the component (C), an oil component, a disintegrating agent, a fluidizing agent, or a binder. , medicinal ingredients, plant extracts, pigments, spices, etc. Specifically, the following components can be exemplified. Further, the components having the repeated characters are repeatedly described.

The functional component other than the component (A) is, for example, a bacterial cell of Lactobacillus brevis which is one type of lactic acid bacteria. The above-mentioned cells may be bacteria or dead bacteria. The cells of the aforementioned Lactobacillus brevis can be obtained using commercially available products or by a known culture method.

The dosage of short Lactobacillus is preferably more than 100 million, more than 1 billion, and 10 billion better for adults. More than one. If the dead bacteria is better than 1 billion, more preferably 10 billion or more, and more preferably 18 billion or more. The bacteria and the dead bacteria are not particularly limited as long as they are ingested in a large amount, but they are 10 mega or less. The effect of the present invention can be further obtained in this range. Further, the identification of the lactic acid bacteria was carried out using API 50CHL BIOMERIEUX (manufactured by BIOMERIEUX, Japan). The number of bacteria was measured by anaerobic culture using MRS agar medium, and the grown colonies were measured. In the case of dead bacteria, the value measured on the MRS agar medium similar to the bacteria was used as the number of dead bacteria before the sterilization treatment.

As the functional component other than the component (A), an extract of a plant selected from the group consisting of Pepper, Ginger, and Solanaceae having a blood flow improving effect is also exemplified. The blood flow improving effect can be expected by blending the plant extract.

Specific examples of such plants include Piper nigrum L., Piper longum L., Piper retrofractum Vahl, and Zingiber officinale as Zingiber. As the Solanaceae, for example, Capsicum annuum and the like. These may be used alone or in combination of two or more.

As the aforementioned plant extract, a commercially available product or a method obtained by a conventional extraction method can be used. Examples of the solvent used in the above extraction method include water; alcohols such as methanol, ethanol, propanol, and butanol; and polyhydric alcohols such as propylene glycol and butylene glycol; and these may be used singly or as a mixed solvent of two or more kinds. The various conditions in the above extraction method are not particularly limited, but usually, the ratio of the extraction raw material to the extraction solvent is preferably in the range of the extraction raw material: extraction solvent = 1:2 to 1:50. And the extraction temperature is better The range of 5 to 80 ° C is preferably carried out by immersion and stirring in an extraction solvent for 1 hour to 1 week. Further, the extraction pH is not particularly limited unless it is extremely acidic or alkaline. When the extraction solvent is a non-toxic solvent such as water, ethanol, or water/ethanol (aqueous ethanol), the extract may be used as it is, or may be used as a diluent. Further, the extract may be used as a concentrated extract, or may be formed into a dry powder by freeze-drying or the like, or may be prepared into a paste. Further, when other solvents are used, it is preferred to distill off the solvent, and the dry portion is diluted with a non-toxic solvent and used.

The amount of the plant extract to be added is preferably from 0.01 to 30% by mass, more preferably from 0.1 to 20% by mass, based on the total amount of the composition.

Examples of the slip agent other than the component (B) are gum arabic, cocoa butter, carnauba wax, aqueous cerium oxide, dried aluminum hydroxide gel, glycerin fatty acid ester, magnesium citrate, liquid paraffin, sucrose fatty acid ester. , stearyl alcohol, stearic acid, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, fumaric acid, beeswax, and the like. When the tablet composition of the present invention contains a slip agent other than the component (B), the blending amount thereof is preferably from 0.01 to 5% by mass.

Examples of the excipient other than the component (C) include crystalline cellulose, starch, gum arabic, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, Cross-linked povidone, croscarmellose sodium, croscarmellose calcium, kaolin, cocoa butter, cerium oxide, particulate cerium oxide, citric acid or its salt, stearic acid, polyethylene Pyrrolidone, polyethylene glycol, calcium hydrogen phosphate, sodium hydrogen phosphate, and the like. When the tablet composition of the present invention contains an excipient other than the component (C), the preparation thereof The amount is preferably from 1 to 50% by mass.

Examples of the oil component include various fatty acid esters, hydrocarbons, higher fatty acids, higher alcohols, and the like. Examples of the disintegrating agent include cellulose derivatives such as agar, cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose calcium, sodium carboxymethylcellulose, starch or derivatives thereof. Wait. As the fluidizing agent, for example, fine particle cerium oxide or the like is used. Examples of the binding agent include hydroxypropylcellulose, methylcellulose, ethylcellulose, carboxymethylcellulose, gelatin, vinylpyrrolidone, partially gelatinized starch, and the like. Examples of the aforementioned medicinal ingredient are carotenoid substances (α-carotene, β-carotene, γ-carotene, lycopene, lutein, astaxanthin, zeaxanthin, etc.), coenzyme Q10, and vitamin E. , tocopherol, DHA, EPA, etc.

When the tablet composition of the present invention contains the oil component, the blending amount thereof is preferably from 0.01 to 25% by mass in the composition, and when the disintegrating agent is contained, the blending amount is preferably from 0.01 to 50% by mass in the composition. When the fluidizing agent is contained, the compounding amount is 0.01 to 5% by mass in the composition, and when the binding agent is contained, the compounding amount is preferably 0.01 to 50% by mass in the composition, and the medicinal ingredient is contained. The blending amount is preferably from 0.01 to 50% by mass in the composition.

The tablet composition of the present invention is not particularly limited to a usual oral, i.e., a swallowing type tablet, an orally disintegrating agent, etc., and is a enteric preparation of a usual swallow type. In order to become an enteric preparation, it is suitable to mix shellac, water-soluble shellac, zein, hydroxymethylcellulose phthalate, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose. , cellulose acetate phthalate, methacrylic acid copolymer, ethyl cellulose, aminoalkyl methacrylate copolymer, brewer's yeast cell wall (for example, trade name E-STRAP, etc.), tapioca starch, gelatin, fruit An enteric component such as a fat or oil such as a gel or a hardened oil. Further, in the present invention, whether or not the enteric solvent system is measured by the sixteenth revised Japanese Pharmacopoeia/disintegration test method.

The tablet composition of the present invention can be obtained by ingot by mixing lactoferrin and optional components. The molding conditions such as the tableting pressure vary depending on the tableting machine, the component type, the blending amount, the tablet diameter, and the like, but may be appropriately adjusted in consideration of disintegration, tablet strength, and intraoral collapse speed. In the case of an enteric preparation, the ingot is coated with the aforementioned enteric component. The amount of the enteric component is preferably from 0.1 to 20% by mass, more preferably from 0.5 to 10% by mass, based on the total amount of the ingot. In addition, glycerin, alginic acid or a salt thereof, talc, or particulate cerium oxide may be coated.

The size of the tablet composition of the present invention is not particularly limited, but is preferably about 5 to 12 mm in diameter, preferably 200 to 400 mg per ingot, more preferably 250 to 350 mg. When the ingot is broken in the mouth, that is, the oral type tablet, the hardness of the tablet is preferably 5 to 30 kgf, more preferably 8 to 30 kgf. When the ingot is broken in the oral cavity, it is preferably 3 to 20 kgf, more preferably 5 to 15 kgf. Further, the tablet hardness can be measured according to a usual method.

Moreover, the present invention provides a method for improving the disintegration property and the dissolving property of a tablet composition, which is a method for improving the disintegration property of a tablet composition containing 30% by mass or more of lactoferrin and the dissolvability of the lactoferrin. It is characterized in that 0.12 to 1.0% by mass of stearate is formulated in the tablet composition. The preferred ingredients, amounts and the like are the same as described above.

[Examples]

The present invention will be specifically described below by showing examples and comparative examples, but the present invention is not limited to the following examples. The raw materials used are as follows.

. Lactoferrin: Morinda Dairy Co., Ltd., Lactoferrin MLF-FG (median diameter: 80 μm)

. Extracted extract: Maruzon Pharmaceutical Co., Ltd., Iie2 extract extract powder MF

. Crystalline cellulose: Asahi Kasei Chemical Co., Ltd., CEOLUS UF-F711

. Maltitol: Mitsubishi Corporation Food Technology Co., Ltd., powder maltitol G-3

. Isomalt: FROINT industry (shares), isomaltulose

. Erythritol: Japanese MICROFOODS (share) system, erythritol granules

. Sorbitol: Mitsubishi Corporation Food Technology Co., Ltd., sorbitol

. Xylitol: Mitsubishi Corporation Food Technology Co., Ltd., Xylitol

. Lactose: FROINT industry (stock) system, lactose granulated sugar

. Carboxymethylcellulose calcium: NICHIRIN Chemical Industry Co., Ltd., E.C.G-FA

. Microparticle cerium oxide: Japan DSL. (share) system, CARPLEX FPS-500 Fuji Silysia chemical (stock) system, SILOPAGE 720

. Calcium stearate: Taiping Chemical Industry Co., Ltd., calcium stearate

. Magnesium stearate: Taiping Chemical Industry Co., Ltd., calcium stearate

. Sucrose fatty acid ester: Mitsubishi Chemical Food Co., Ltd., RYOTO Sugar S-370F

. Glycerol fatty acid ester: manufactured by Sakamoto Pharmaceutical Co., Ltd., SY GLYSTER

. Lactobacillus powder: LABRE Chuangjian (share) system, nanotype Lactobacillus (6 billion/10mg)

. Hydroxypropyl methylcellulose: Metolose, Xinyue Chemical Industry Co., Ltd., SE-06

. Glycerin: Sakamoto Pharmaceutical Industry Co., Ltd., food additive glycerin

. Sodium alginate: KIMICA (shares), KIMICA ALGIN IL-2

. Talc: KIHARA Chemicals (shares), LISBLANC

[Examples 1 to 23, Comparative Examples 1 to 6, Reference Example 1] [1] Modulation of tablets

Weigh and mix each of the raw materials described in the following Tables 1 to 4, and use a rotary tableting machine to make the tablet hardness of 8 to 15 kgf or more. Next, the obtained ingot was coated using a disk rotary coater. Further, as the coating agent, the components described in the following Tables 1 to 4 were used. Further, the shape of the tablet was a two-stage R ingot (R1 = 3.6 mm, R2 = 10.5 mm, and H = 1.5 mm).

[2] Disintegration test

For the tablet after the production (initial) and the tablet filled in a plastic bottle at 40 ° C, 75% RH for 4 months, according to the tenth The disintegration test method for the tablet contained in the revised Japanese Pharmacopoeia was carried out. The breakage time (minutes) of the tablet was measured, and the average value of the number of times of measurement was calculated six times, and the disintegration property was evaluated based on the following evaluation criteria. The results are also shown in Tables 1 to 4.

The collapse time is less than 40 minutes: ◎

The collapse time is less than 40 minutes and less than 50 minutes: ○

The collapse time is less than 50 minutes and less than 60 minutes: △

Disintegration time of more than 60 minutes: ×

[3] Dissolution test

For tablets that have been stored (initial) and filled in plastic bottles in a thermostat at 40 ° C, 75% RH for 4 months, according to the ingots contained in the 16th revised Japanese Pharmacopoeia The dissolution test of the agent was carried out by a dissolution test. The elution rate (%) of lactoferrin was measured. Specifically, the second solution (pH: 6.8) of the dissolution test was used as a test liquid, and the test was carried out at 50 rpm by an overflow method. One tablet was used, and 900 mL was used for the second solution of the dissolution test. The eluate after 2 hours from the start of the dissolution test was taken out, and the eluted lactoferrin was quantitatively determined by HPLC to calculate the elution rate. The measurement was performed three times, and the average value of the elution rate was calculated, and the dissolving property was evaluated based on the following evaluation criteria. The results are also shown in Tables 1-3.

The dissolution rate after 2 hours is 80% or more: ◎

After 2 hours, the dissolution rate is 70% or more and less than 80%: ○

After 2 hours, the dissolution rate is 60% or more and less than 70%: △

The dissolution rate after 2 hours did not reach 60%: ×

[4] Lactoferrin quantification

A standard lactoferrin 75 mg was placed in a 50 mL flask and the volume was adjusted to dissolve the test solution. Prepare 1/5, 1/20, 1/50 standard solution of the standard solution, and each standard solution is determined by high-speed liquid chromatography (HPLC) to determine the peak area of lactoferrin of each standard solution, and prepare a calibration line. .

The eluate after 2 hours from the start of the dissolution test was measured by HPLC to determine the area of the lactoferrin wave front. The concentration of lactoferrin in each sample solution was determined using a calibration line, and the lactoferrin content was determined.

<HPLC measurement conditions>

. Detector: UV spectrophotometer (measuring wavelength: 280 nm)

. Column: Shodex Asahipak C4P-50 4D (polymer column for reverse phase chromatography)

Butyl (5μm × 4.6 × 150)

Shodex Asahipak C4P-50 4D: Protective column

Column temperature 35 ° C

Import amount: 20μL

Flow rate: 0.8mL/min

. Moving layer A: acetonitrile/sodium chloride solution (3→100) mixture containing 0.03 mass% trifluoroacetic acid (10:90)

. Moving layer B: acetonitrile/sodium chloride solution (3→100) mixture containing 0.03 mass% trifluoroacetic acid (50:50)

Concentration gradient: A:B from the linear concentration gradient from (50:50) to (0:100) 30 minutes

[5] Adhesion (slurry formability) test

The ingot was continuously inflated for 2 hours, and the crucible and the disk surface were observed, and the evaluation was performed based on the following evaluation criteria. The results are shown together in Tables 1-3.

○: The adhesion of the baking powder was not confirmed on the 臼杵/pan

×: Adhesion of the ingot powder was confirmed on the plate/pan.

The evaluation criteria for the comprehensive judgment are as follows.

○: Evaluation of disintegration, dissolvability, and adhesion were all △~◎

×: Evaluation of disintegration, dissolvability, and adhesion is ×

Claims (8)

A tablet composition comprising (A) 30% by mass or more of lactoferrin and (B) 0.12 to 1.0% by mass of stearate. The tablet composition of claim 1, wherein the aforementioned (B) stearate is calcium stearate or magnesium stearate. The tablet composition of claim 1 or 2, wherein the ratio of the mass ratio of the component (A) to the component (B) represented by (B) / (A) × 100 is 0.25 to 3. The tablet composition according to any one of claims 1 to 3, which further comprises 5% by mass or more of (C) a sugar or a sugar alcohol. The tablet composition of claim 4, wherein the component (C) is a sugar alcohol. The tablet composition of claim 5, wherein the aforementioned sugar alcohol is maltitol, isomalt or erythritol. The tablet composition of claim 4, wherein the ratio of the mass ratio of the component (C) to the component (A) represented by (C)/(A) is from 0.15 to 1.0. A method for improving the disintegration and dissolving property of a tablet composition, which is a method for improving the disintegration property of a tablet composition containing 30% by mass or more of lactoferrin and the dissolvability of the lactoferrin, and is characterized in that The above tablet composition is formulated with 0.12 to 1.0% by mass of stearate.