TWI710376B - Coating preparation and its manufacturing method - Google Patents

Abstract

The present invention provides a coating formulation that is insoluble in the stomach but dissolves in the intestine, which not only allows the coated active ingredient to reach the intestine more reliably, but also suppresses deterioration with time as much as possible, and has excellent storage stability and其制造方法。 Its manufacturing method.

A coating preparation characterized by having a coated substance, a lower layer formed thereon, and an enteric coating layer formed on the lower layer; the lower layer contains (A) a 6 mass% aqueous solution at 25°C The viscosity is less than 300mPa. s polymer compound; the enteric coating layer contains (B) alginate and (C) plasticizer.

Description

Coating preparation and its manufacturing method

The present invention relates to coating preparations used as foods, pharmaceuticals, etc., and methods for their production.

People are seeking to contain functional components such as lactic acid bacteria or enzymes, which can prevent decomposition in the stomach and maintain the structure and deliver them to the intestines to show high-functioning active ingredients, and are insoluble in the stomach but dissolve in the intestines. An enteric-coated preparation that allows the effective ingredients to reach the intestine.

As a protective film for the effective ingredients to reach the intestine, it is generally a component that does not dissolve under the pH condition of the stomach (acidic) and dissolves under the pH condition of the small intestine (neutral to alkaline), such as methacrylic acid Department of polymer compounds, shellac, zein, etc.

However, methacrylic polymer compounds are limited to pharmaceutical applications and cannot be used in foods. On the other hand, although shellac and zein can also be used in food applications, they are generally sprayed with organic solvents. In food applications, it is desirable to use a water-soluble film that is environmentally friendly and can be coated with water.

In addition, as a prior art document related to the present invention, The following can be cited.

[Prior Technical Literature] [Patent Literature]

[Patent Document 1] Japanese Patent Laid-Open No. 2002-193792

The present invention was completed in view of the above circumstances, and its purpose is to provide insoluble in the stomach but dissolve in the intestines, which not only enables the coated active ingredients to reach the intestines more reliably, but also suppresses deterioration over time as much as possible. A coating formulation with excellent storage stability and its manufacturing method.

The inventors of the present invention have previously proposed an alginate enteric coating formulation (Japanese Patent Application No. 2013-046697) that considers the environment and uses water as a solvent. This coated enteric preparation has the advantages of very good enteric solubility (inhibition of dissolution in acid, dissolution in neutral) immediately after coating. However, in the subsequent further review, it is known that although there is no change in the appearance of the coating film, over time, the dissolution inhibition under acidic conditions may decrease. Although the reason is not clear, the elution inhibitory property is reduced even though there is no change in the appearance of the coating film, so it can be presumed that a very fine structure has occurred. Caused by structural changes.

Therefore, the inventors of the present invention further conducted in-depth studies and found that after pre-coating the lower layer of the enteric coating film on this fine structural change, it unexpectedly improved the inhibition of elution caused by acid over time. Sexual decrease.

The pre-coating of the enteric coating film is generally implemented to improve the peeling of the film caused by the poor compatibility between the enteric coating film and the tablet. The inventors novelly found that the pre-coating It exerts the function of protecting the above-mentioned enteric coating film using alginate from deterioration over time, and is effective in improving the storage stability of the coating formulation, and the present invention has been completed.

Therefore, the present invention provides the following coating formulation and its manufacturing method.

[1] A coating preparation characterized by having a coated substance, a lower layer formed thereon, and an enteric coating layer formed on the lower layer; the lower layer contains (A) a 6 mass% aqueous solution in The viscosity at 25°C is less than 300mPa. s polymer compound; the enteric coating layer contains (B) alginate and (C) plasticizer.

[2] The coating preparation as described in [1], wherein the component (A) is selected from hydroxypropyl methylcellulose, pectin, curdlan, pullulan, and hydroxypropyl methylcellulose. A group consisting of propyl cellulose, polyvinyl alcohol, and gum arabic.

[3] The coating preparation as described in [2], wherein the component (A) is hydroxypropyl methylcellulose.

[4] The coating formulation as described in any one of [1] to [3], wherein: (B) Component is (B-1) The viscosity of 1% by mass aqueous solution at 20°C is 50mPa. Alginate above s.

[5] The coating formulation as described in [4], which further comprises (B-2) a 1% by mass aqueous solution whose viscosity at 20°C is less than 50 mPa. s alginate.

[6] The coating preparation as described in any one of [1] to [3], which further has on the outside of the enteric coating layer: (D) selected from gelatin, pectin, cattleya, Pullulan, gum arabic, xanthan gum, gellan gum, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and hydroxypropyl cellulose are the top layer of the polymer compound.

[7] The coating preparation according to [6], wherein the component (D) is hydroxypropyl methylcellulose.

[8] A method for manufacturing a coating formulation, characterized by comprising the following steps: by spraying the coated material containing (A) a 6 mass% aqueous solution whose viscosity at 25°C is less than 300 mPa. s solution of a polymer compound and drying to form a lower layer; and by spraying a solution containing (B) alginate and (C) plasticizer on the outer side of the lower layer, and drying to form enteric The step of coating.

[9] The method for producing a coating formulation as described in [8], which further comprises: spraying the outer side of the enteric coating layer to include (D) selected from gelatin, pectin, cattleya, Pullulan, gum arabic, xanthan gum, gellan gum, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, and hydroxypropyl cellulose The step of drying to form the outermost layer.

The coating preparation according to the present invention can provide insoluble in the stomach but dissolve in the intestines, not only can the coated active ingredients reach the intestines reliably, but can also inhibit the intestines as much as possible even under long-term storage. A coating formulation with reduced dissolution inhibition under acidic conditions and excellent storage stability.

Hereinafter, the present invention will be described in detail.

The coating preparation of the present invention has a coated substance, a lower layer formed thereon, and an enteric coating layer formed on the lower layer, between the coated substance and the lower layer, or the enteric coating One or more intermediate layers may be formed between the coating layer and the outermost layer. Among these, it is preferable to have a coated object, a lower layer formed on the surface of the coated object, and an enteric coating layer formed on the surface of the lower layer. In the present invention, as long as the enteric quality is not affected, the outermost layer may be formed on the outside of the enteric coating layer as needed. In addition, in the present invention, "enteric" refers to an agent that delivers functional components to the intestines. It refers to the test performed in accordance with the dissolution test method of the Japanese Pharmacopoeia Act. In the dissolution test solution (pH 1.2) equivalent to gastric juice, the dissolution rate is less than 50% within 2 hours (preferably 30% or less). In the dissolution test solution (pH 6.8) equivalent to intestinal juice, the dissolution rate is more than 70% within 2 hours.

(I) Covered object

In the present invention, the coated object is not particularly limited, and examples include active ingredients such as foods and pharmaceuticals. Examples include proteins such as lactic acid bacteria, cysteine, iron, antibodies or lactoferrin, peptides, ATP-2Na, and the like, and they can be used alone or in combination of two or more. Among them, high-molecular-weight components such as proteins or water-insoluble components are more suitable.

，更佳為7~12mm

。此外，作為每1錠之錠劑質量，較適切為150~700mg左右。 The shape or dosage form of the coated object is not particularly limited, and tablets, powders, fine granules, granules, etc. are not particularly limited. Tablets can be single-layer or two-layer or more. Among these, in terms of exerting more enteric solubility, it is preferable to form a tablet. The size of the tablet is not particularly limited. From the viewpoint of ease of handling and swallowability of the tablet, the diameter of the tablet is preferably 5 to 14 mm

, More preferably 7~12mm

. In addition, as the quality of each tablet, it is more appropriate to be about 150~700mg.

(II) Lower layer

The lower layer of the present invention is a layer formed before the enteric coating layer containing alginate described later, for example, a layer formed on the surface of the coated object. In the present invention, by forming a lower layer between the coated object and the enteric coating layer, it is possible to prevent the time-dependent decrease in the elution inhibitory effect under acidic conditions during storage. Thereby, the storage stability (dissolution inhibition property under acidic acid) of the coating preparation with the enteric coating layer can be significantly improved. Hereinafter, the lower layer will be described in detail.

The lower layer contains (A) 6 mass% aqueous solution and the viscosity at 25°C is less than 300mPa. s polymer compound. The above (A) becomes The components are not particularly limited. Specific examples include hydroxypropyl methylcellulose, pectin, cattleya, pullulan, hydroxypropyl cellulose, polyvinyl alcohol, gum arabic, etc., which can be used alone One type or a suitable combination of two or more types is used. In the present invention, specifically, hydroxypropyl methylcellulose can be suitably used.

The blending amount of the aforementioned (A) component is not particularly limited, but it is preferably 1 to 10% by mass, more preferably 3 to 8% by mass relative to the entire precoating composition (composition for lower layer). By setting the blending amount above the lower limit of the above range, the manufacturing time can be controlled within an appropriate time. On the other hand, by setting the blending amount to less than the upper limit of the above-mentioned range, it is possible to control the viscosity suitable for the preparation of the coating liquid or the spraying of the coating liquid.

In addition, the lower layer may contain (E) a plasticizer if necessary. (E) Component includes surfactants such as sucrose fatty acid ester, glycerin fatty acid ester, monoglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, and polyhydric alcohols such as glycerin, propylene glycol, and polyethylene glycol. , Glucose, fructose glucose liquid sugar, sucrose and other sugars, sorbitol, maltitol, mannitol, erythritol, xylitol and other sugar alcohols, dodecanol, tridecanol, myristyl alcohol, pentadecanol , Cetyl Alcohol, Heptadecyl Alcohol, Stearyl Alcohol, Cetyl Alcohol, Isostearyl Alcohol, 2-octyldodecanol, etc. (preferably C6~22) higher alcohols, medium chain fatty acid esters ( It is more suitable for oils such as carbon number 6-12). These can be used individually by 1 type or in combination of 2 or more types suitably. In the present invention, glycerin can be suitably used from the viewpoint of plasticity effect.

The blending amount of the above-mentioned (E) component is not particularly limited, but it is preferably 0.3 to 6 mass% with respect to the entire composition for the lower layer, and more preferably 0.8~5 mass%. By setting the blending amount to be more than the lower limit of the above-mentioned range, the effect of preventing the time-dependent decrease of the elution inhibition effect under acidic conditions is improved. On the other hand, by setting the blending amount below the upper limit of the above-mentioned range, the manufacturing time can be controlled within an appropriate time.

In the composition for the lower layer, (F) fine particles may be blended. By blending the fine particles, the peeling of the coating film caused by the adhesion of the tablets during the coating process can be prevented. (F) As a component, talc, calcium stearate, silicon dioxide, titanium oxide, etc. are mentioned, It can be used individually by 1 type or in combination of 2 or more types suitably. The particle size of the fine particles is 0.01-50 μm, preferably 0.1-20 μm. In addition, the measurement of the particle size is performed by a laser diffraction type particle size distribution measuring device (dry measurement).

The blending amount of the component (F) is preferably 0.05 to 7 mass% of the entire lower layer composition, more preferably 0.1 to 5 mass%, and still more preferably 0.3 to 3 mass%. By setting the blending amount to be more than the lower limit of the above range, the effect of blending the above-mentioned component (F) can be more obtained. If the blending exceeds the upper limit of the above range, there is a concern that the film-forming properties will be affected.

The composition for the lower layer may contain organic solvents such as water and ethanol. The blending amount of the solvent in the lower layer composition is appropriately selected in the range of 1 to 98% by mass relative to the entire lower layer composition, preferably 50 to 98% by mass, more preferably 70 to 96% by mass.

The thickness of the lower layer is not particularly limited, but is preferably 1 to 200 μm, more preferably 2 to 100 μm. In addition, in the case of tablets, it is preferable to set the adhesion amount of the lower layer to 0.6 to 10.5 mg/300 mg (0.2 to 3.5% by mass) relative to 300 mg of the plain tablet, more preferably to 1.5~7.5mg/300mg (0.5~2.5% by mass). In the case of granules, powders, and powders, it is preferably 0.5 to 30% by mass, and more preferably 1 to 25% by mass. By setting the thickness and adhesion amount of the lower layer to be more than the lower limit of the above-mentioned range, the effect of the present invention can be effectively obtained (that is, it is possible to prevent the decrease in the elution inhibitory effect under acidic conditions over time). On the other hand, by setting the thickness and adhesion amount of the lower layer to be equal to or less than the upper limit of the above-mentioned range, a tablet can be produced in an appropriate production time.

The method of forming the above-mentioned lower layer is not particularly limited, and a known method can be adopted. For example, a method of forming a thin film on the surface of the coated object by spraying a predetermined coating solution on the coated object and drying by heating. The coating solution can be suitably heated, and the temperature is preferably 30 to 80°C, and the drying temperature is preferably 40 to 80°C. The addition rate of the coating solution is preferably 1 to 5 g/min with respect to the drying air volume of 1 m ³ /min. In addition to this, it is also possible to adopt a dip coating method in which the coated object is immersed in a coating solution and dried. It is preferable to dry it until the moisture content in the coating formulation becomes 0.1-20 mass %, specifically, 0.5-5 mass %. In addition, the above-mentioned lower layer is not limited to one layer, and plural layers may be formed as needed.

In this case, the coating machine is not particularly limited, and a pan coating machine, a fluidized bed coating machine, a rotary coating machine, etc. can be used.

(III) Enteric coating

The enteric coating layer of the present invention is an enteric layer formed on the outer side of the lower layer, and contains (B) alginate and (C) plasticizer.

(B) Alginate

The alginate is preferably a monovalent alginate such as a sodium salt, a potassium salt, and an ammonium salt, and a water-soluble salt of alginic acid. As the alginate, the following (B-1) 1% by mass aqueous solution has a viscosity of 50 mPa at 20°C. Above s, (B-2) The viscosity of 1% by mass aqueous solution at 20°C is less than 50mPa. s may be used alone or in combination of two or more.

As (B-1) the viscosity of 1% by mass aqueous solution at 20°C is 50mPa. s or more, preferably 50mPa. s above and 600mPa. s or less, more preferably 50mPa. s above and 400mPa. s or less.

In the case of blending (B-1) alginate, the blending amount is preferably 0.1 to 5 mass% of the entire coating composition, more preferably 0.5 to 4 mass%, and still more preferably 1 to 4 mass% The scope. By setting the blending amount to be more than the lower limit of the above range, the ability to inhibit dissolution under acidic acid can be sufficiently obtained, and good enteric solubility can be obtained more. On the other hand, by setting it below the upper limit, it is possible to control the viscosity appropriate for the preparation, transfer, and spraying of the coating liquid.

As (B-2) the viscosity of 1% by mass aqueous solution at 20°C is less than 50mPa. The alginate of s is preferably 5mPa. s above and less than 50mPa. s, more preferably 10mPa. s above and less than 50mPa. s person. (B-2) Alginate is preferably sodium alginate.

In the case of blending (B-2) alginate, the blending amount is preferably 5% by mass or less of the entire coating composition, more preferably 0.1-4% by mass, and still more preferably 0.1-2.5 by mass % Range. By mixing When the total amount is set to the upper limit or less of the above range, enteric properties are improved and coating properties become better.

In addition, the blending amount of the (B) component (that is, the total amount of the (B-1) component and the (B-2) component) is preferably 0.1 to 10% by mass of the entire coating composition. In addition, the range of 1-7 mass% is more preferable, and the range of 1.5-5 mass% is more preferable. By setting the blending amount to be equal to or less than the upper limit of the above range, good enteric properties (dissolution inhibition properties under acidic conditions) can be obtained.

In the present invention, as (B) alginate, (B-1) alginate is preferably used. By using such alginate with a certain length or more, the coating property is good, and high acid resistance can be imparted to the formed coating film. In addition, by using (B-1) alginate and (B-2) alginate together, the enteric solubility can be maintained while the coating performance can be improved.

Using two kinds of alginates with different viscosities like the above (B-1) alginate and (B-2) alginate is not just to adjust the viscosity of the coating solution, but to adjust the viscosity of the coating solution, but to adjust the enteric solubility and coating properties In terms of point of view, two types of alginate are selected. The quality is relatively good (B-1): (B-2) ((B-1)/(B-2)) is 1:5~10:1 (0.2~10), and more preferably 1:3~ 5:1 (0.33~5), even more preferably 1:1.8~3:1 (0.56~3). By setting the mass ratio to more than the lower limit of the above range, the film performance under acidity is more improved, so the non-elubility becomes better, and by setting the mass ratio to less than the upper limit of the above range, the coating property becomes better , So it is better.

In addition, in the present invention, the viscosity measurement system of alginate Use a rotary viscometer (BM type) to perform. The viscosity is less than 200mPa. The viscosity of s uses the No. 1 rotor, 200mPa. s above and less than 1,000mPa. The viscosity of s was measured with a No. 2 rotor under the conditions of 20°C and 30 rpm for a 1% by mass aqueous solution, and the value after 60 seconds was used as the measured value.

The viscosity of alginate is roughly proportional to the molecular weight of alginate. For example, the weight average molecular weight (Mw) of (B-1) above is 800,000 or more, preferably 800,000 to less than 3 million, and more preferably 800,000 to less than 1.9 million. The weight average molecular weight (Mw) of (B-2) is 200,000 or more and less than 800,000, preferably 300,000 or more and less than 800,000. In addition, the method for measuring the weight average molecular weight (Mw) of the alginate of the present invention by gel chromatography is shown below.

(1) Sample preparation

The alginate was dissolved in a mobile phase (0.1M (mol/L) NaNO ₃ aqueous solution) so that the alginate concentration became 0.1% by mass, and this was used as a sample.

Standards of various molecular weights (pululan: Mw=1.66 million, Mw=380,000, Mw=100,000, Mw=12.2 million, dissolved in the mobile phase at a concentration of 0.1% by mass) were used to create a calibration curve.

(2) GPC measurement conditions

Column: Shodex OHpak SB-806M HQ (8mm I.D.×300mmL, 13μm)

Mobile phase: 0.1M (mol/L) NaNO ₃ aqueous solution

Flow rate: 0.5mL/min

Temperature: 40℃

Injection volume: 200μL (0.1% in the mobile phase)

Detector: Differential refractive index (RI) detector

(3) Analysis method

The calibration curve formula is obtained from the calibration curve sample, and the weight average molecular weight (Mw) converted to pullulan is obtained from the GPC analysis result of the sample.

(C) Plasticizer

(C) The plasticizer is a component blended for the purpose of reducing the surface tension of the coating composition or imparting flexibility to the coating layer. (C) Component includes surfactants such as sucrose fatty acid ester, glycerin fatty acid ester, monoglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, glycerin, 1,3-butanediol, and propylene glycol Polyols such as polyethylene glycol, glucose, fructose glucose liquid sugar, sugars such as sucrose, sugar alcohols such as sorbitol, maltitol, mannitol, erythritol, xylitol, dodecanol, tridecanol , Myristyl Alcohol, Pentadecyl Alcohol, Cetyl Alcohol, Heptadecanol, Stearyl Alcohol, Cetyl Alcohol, Isostearyl Alcohol, 2-Octyldodecanol, etc. Fats such as alcohols and medium-chain fatty acid esters (preferably carbon number 6-12). These can be used individually by 1 type or in combination of 2 or more types suitably. Among them, from the aspect of the plasticity effect of the coating film, glycerin is preferred.

The blending amount of the component (C) is preferably 0.3 to 5% by mass of the entire coating composition, more preferably 0.5 to 3% by mass. By setting the blending amount to be more than the lower limit of the above range, the peeling of the film during coating can be further suppressed, by Setting it to the upper limit of the above range or less can suppress stickiness during coating, make coating treatment easier, and obtain good enteric solubility.

The quality represented by (C)/(B) is preferably in the range of 0.05 to 3.0, more preferably 0.1 to 2.0, still more preferably 0.15 to 1.5, particularly preferably 0.15 to 1.1. By setting the mass ratio to more than the lower limit of the above range, the film performance under acidic conditions is further improved, and by setting the mass ratio to be less than the upper limit, the coating properties become more favorable.

In the coating composition of the present invention, a film forming component (D) other than the component (B) may be blended. (D) Film-forming components include gelatin, pectin, cattleya, pullulan, acacia, xanthan gum, gellan gum, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, Hydroxypropyl cellulose, Hantian, chitosan, tamarind gum, locust bean gum, polyvinyl alcohol, ethyl cellulose aqueous dispersion, etc. These can be used individually by 1 type or in combination of 2 or more types suitably. Among these, it is selected from gelatin, pectin, cattleya, pullulan, acacia, xanthan gum, gellan gum, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose and hydroxypropyl The cellulose component is preferable in terms of coating properties and the combination with the (B) component.

(D) The blending amount of the component is preferably 0.1 to 7 mass% of the entire coating composition, more preferably 0.2 to 5 mass%, and still more preferably 0.3 to 3 mass%. By setting the blending amount to be more than the lower limit of the above range, the effect of blending component (D) can be more obtained. If the blending exceeds the upper limit of the above range, there is a concern that enteric solubility may be affected.

In this case, use (B): (D)((B)/ (D)) The indicated content quality is preferably 1:3~1:0.05 (0.33~20), more preferably 1:1~1:0.1 (1~10), and even more preferably 1:0.8~1 : 0.2 (1.25~5). By setting it in this range, it is possible to obtain a tablet that maintains coating properties and a beautiful appearance, and, in particular, has higher dissolution inhibition ability under acidic conditions, and has excellent enteric properties.

In the coating composition, (F) fine particles may be blended. By blending the fine particles, the peeling of the coating film caused by the adhesion of the tablets during the coating process can be prevented. (F) As a component, talc, calcium stearate, silicon dioxide, titanium oxide, etc. are mentioned, It can be used individually by 1 type or in combination of 2 or more types suitably. The particle size of the fine particles is 0.01-50 μm, preferably 0.1-20 μm. In addition, as in the case of the lower layer composition, the measurement of the particle size is performed by a laser diffraction type particle size distribution measuring device (dry measurement).

The blending amount of the component (F) is preferably 0.05 to 7% by mass of the entire coating composition, more preferably 0.1 to 5% by mass, and still more preferably 0.3 to 3% by mass. By setting the blending amount to be more than the lower limit of the above range, the effect of blending the above-mentioned component (F) can be more obtained. If the blending exceeds the upper limit of the above range, there is a concern that the film-forming properties will be affected.

In addition, it is preferable that the coating composition does not contain divalent metal ions such as copper ions, barium ions, and calcium ions. This is because the alginate will be cross-linked and gelatinized by the plasma, and the coating properties will deteriorate. That is, when the monovalent alginate and divalent cations are reacted and cross-linked, although the dried film is insoluble in water, the viscosity is excessively increased due to gelation, so the spraying of the fine liquid and the The stretchability on the lozenge will become sleepy difficult. As a result, it is difficult to form a uniform film, and the appearance is deteriorated. In addition, inconsistencies in dissolution properties may occur. The allowable range of the divalent metal ion is preferably 0.5 mol or less relative to 1 mol of the alginate monomer, more preferably 0.25 mol or less, and still more preferably 0.1 mol or less.

In the above-mentioned coating composition, in addition to the above-mentioned components, one type alone or two or more components that are usually used in the coating composition may be blended in an appropriate amount. As such optional components, defoamers, colorants, and the like can be cited.

As the defoaming agent, for example, glycerin fatty acid ester, dimethylpolysiloxane, dimethylpolysiloxane/silica mixture, hydrous silicon dioxide, silicon dioxide, etc., can be used alone or It is suitable to use two or more in combination.

As the coloring agent, for example, catechin tannin, turmeric extract, yellow iron oxide, orange flavor, brown iron oxide, carbon black, caramel, carmine, carotene liquid, β-carotene, licorice Extract, gold leaf, black iron oxide, light anhydrous silicic acid, titanium oxide, iron oxide, edible blue No. 1, edible yellow No. 4, edible yellow No. 4 aluminum lake, edible yellow No. 5, edible red 2 No., Edible Red No. 3, Edible Red No. 102, Sodium Hydroxide, Sodium Copper Chlorophyllin, Copper Chlorophyll, Rye Green Leaf Extract, Medicinal Carbon, Riboflavin Butyrate, Riboflavin, Green Tea Powder, Riboflavine Phosphate Sodium and so on.

The coating composition of the present invention may contain organic solvents such as water and ethanol. The blending amount of the solvent in the coating composition is appropriately selected in the range of 1 to 98% by mass relative to the entire coating composition, preferably 50 to 98% by mass, more preferably 70 to 96% by mass.

The thickness of the enteric coating layer is not particularly limited, but is preferably 5 to 1,000 μm, more preferably 10 to 500 μm. In addition, in the case of tablets, it is preferable to set the adhesion amount of the enteric coating layer to 1.5 to 60 mg/300 mg (0.5 to 20 mass%) relative to 300 mg of the plain tablet, more preferably to 3 to 45mg/300mg (1-15% by mass). In the case of granules, powders, and powders, it is preferably set to 10-60% by mass, more preferably 15-50% by mass. By setting the thickness and adhesion amount of the enteric coating layer to be at least the lower limit of the above-mentioned range, a preparation having excellent elution inhibition ability under acidic conditions can be obtained. On the other hand, by setting the adhesion amount of the enteric coating layer to less than the upper limit of the above-mentioned range, it is possible to control the production time within an appropriate amount.

In addition, the relationship between the thickness of the lower layer and the thickness of the enteric coating layer is not particularly limited, as long as each falls within the appropriate range described above, there is no problem.

The method of forming the enteric coating layer is not particularly limited, and a known method can be used. For example, a method of forming a thin film on the surface of the covered object by spraying a predetermined coating solution on the covered object with the lower layer and drying by heating. The coating solution can be suitably heated, and the temperature is preferably 30 to 80°C, and the drying temperature is preferably 40 to 80°C. The addition rate of the coating solution is preferably 1 to 5 g/min with respect to the drying air volume of 1 m ³ /min. In addition to this, it is also possible to adopt a dip coating method in which the coated object is immersed in a coating solution and dried. It is preferable to dry it until the moisture content in the coating formulation becomes 0.1-20 mass %, specifically, 0.5-5 mass %.

In this case, the coating machine is not particularly limited, and a pan coating machine, a fluidized bed coating machine, a rotary coating machine, etc. can be used.

In addition, a suitable intermediate layer may be formed between the above-mentioned lower layer and the above-mentioned coating layer within a range that does not impair the effect of the present invention. In the present invention, for example, a shellac coating film and a hardened oil and fat coating film can be formed.

(IV) The outermost layer

In the present invention, if necessary, the outermost layer may be formed using the film-forming component (D) on the outside of the enteric coating layer. This can change the appearance, texture, and taste. (D) Component includes gelatin, pectin, cattleya, pullulan, acacia, xanthan gum, gellan gum, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl Base cellulose, Hantian, chitosan, tamarind gum, locust bean gum, polyvinyl alcohol, ethyl cellulose aqueous dispersion, etc. These can be used individually by 1 type or in combination of 2 or more types suitably. Among these, it is selected from gelatin, pectin, cattleya, pullulan, acacia, xanthan gum, gellan gum, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose and hydroxypropyl The cellulose component is preferable in terms of coating properties.

The thickness of the outermost layer is not particularly limited, but is preferably 1 to 200 μm, more preferably 2 to 100 μm. In addition, in the case of tablets, it is preferable to set the adhesion amount of the outermost layer to 0.6 to 10.5 mg/300 mg (0.2 to 3.5% by mass) relative to 300 mg of the plain tablet, and more preferably to 1.5 to 7.5 mg /300mg (0.5~2.5% by mass). In the case of granules, powders and powders, it is preferably set to 1-30% by mass, more preferably set to 2-25% by mass %. By setting the thickness and adhesion amount of the outermost layer above the lower limit of the above-mentioned range, the texture or taste can be changed. On the other hand, by setting the thickness and adhesion amount of the outermost layer below the upper limit of the above range, the manufacturing time can be appropriately controlled.

The composition for the outermost surface layer may contain organic solvents such as water and ethanol within a range that does not impair the effects of the present invention. The blending amount of the solvent in the composition for the outermost layer is appropriately selected in the range of 1 to 98% by mass relative to the composition for the outermost layer, preferably 50 to 98% by mass, more preferably 70 to 96% by mass %.

The method for forming the outermost layer is not particularly limited, and a known method can be used. For example, a method of forming a thin film on the surface of the coated object by spraying a predetermined coating solution on the coated object formed with the lower layer and enteric coating layer, and drying by heating . The coating solution can be suitably heated, and the temperature is preferably 30 to 80°C, and the drying temperature is preferably 40 to 80°C. The addition rate of the coating solution is preferably 1 to 5 g/min with respect to the drying air volume of 1 m ³ /min. In addition to this, it is also possible to adopt a dip coating method in which the coated object is immersed in a coating solution and dried. It is preferable to dry it until the moisture content in the coating formulation becomes 0.1-20 mass %, specifically, 0.5-5 mass %.

In this case, the coating machine is not particularly limited, and a pan coating machine, a fluidized bed coating machine, a rotary coating machine, etc. can be used.

(V) Manufacturing method of coating preparation

The coating preparation of the present invention can be manufactured by going through the following steps: Spraying the covered material contains (A) 6 mass% aqueous solution whose viscosity at 25°C is less than 300mPa. s is a polymer compound solution and dried to form the step of forming a lower layer; by spraying a solution containing (B) alginate and (C) plasticizer on the outer side of the lower layer, and drying to form an enteric coating The step of coating; and the step of forming the outermost layer by spraying a solution containing (D) film forming components as necessary and drying it. The details of each step are as described above, and the conditions of blending or coating of the coating solution used can be appropriately set within a range that does not impair the effects of the present invention, and there is no particular limitation.

The coating solution for forming the lower layer, the enteric coating layer, and, if necessary, the outermost layer can be obtained by mixing the necessary ingredients mentioned above. Then, by using each of the above-mentioned coating solutions, a lower layer, an enteric coating layer, and, if necessary, the outermost layer are sequentially formed on the coated object, and a package with both good enteric properties and excellent storage stability can be obtained. Coating preparations. In addition, since the coating solution of each layer uses water as a solvent, each forms a water-soluble film.

Although the enteric coating layer formed from the coating composition contains the component (B), the alginate aqueous solution is directly dried as described above to form a water-soluble film. This water-soluble film has the following characteristics: Under acidic conditions, monovalent cations will replace hydrogen ions and change into alginic acid to form an insoluble film, and will dissolve again under neutral to alkaline conditions.

The enteric coating layer formed by the above coating composition has enteric properties, that is, "insoluble in the stomach but dissolves in the intestine, allowing the coated substance to reach the intestine." Can obtain enteric coating with enteric coating Coating preparation.

Furthermore, a lower layer containing the above-mentioned (A) component is formed under the enteric coating layer. Since this lower layer functions as a base for protecting the enteric coating layer from deterioration over time, it can suppress as much as possible With the passage of time, the dissolution inhibition under acidic conditions decreases, which can significantly improve the storage stability of the coating formulation.

In addition, if necessary, by further forming the outermost layer containing the component (D) outside the enteric coating layer, changes in taste, texture, and appearance can be brought about.

[Example]

Hereinafter, examples and comparative examples are shown to specifically explain the present invention, but the present invention is not limited by the following examples. In addition, in the following examples, unless otherwise specified, the "%" of the composition means mass %, and the ratio means mass ratio.

[Examples 1-15, Comparative Examples 1, 2]

First, when preparing the coating formulation, the following plain tablets are prepared.

[Su Ding]

9.0mm，厚度5mm)。 Mix the following raw materials and use a tablet machine to make a tablet (300mg,

9.0mm, thickness 5mm).

<Composition of Vegetarian Ingots>

Lactoferrin: 1,156g

The powder of long pipe extract: 500g

Lactose: 492.5g

Crystalline cellulose: 731.5g

Sodium carboxymethyl cellulose: 60g

Sucrose fatty acid ester: 30g

Particulate silica: 30g

The details of the above components are as follows.

Lactoferrin: Morinaga Milk Co., Ltd.

Long pipe extract powder: manufactured by Maruzen Pharmaceutical Co., Ltd., "pipe pipe extract powder MF"

Lactose: Freund Sangyo Co., Ltd., "Lactose Granules"

Crystalline cellulose: manufactured by Asahi Kasei Chemicals, "Ceolus FD-101"

Sodium carboxymethylcellulose: manufactured by Nichirin Chemical Industry Co., Ltd., "ECC-FA"

Sucrose fatty acid ester: "Ryoto Sugar Ester S-370F" manufactured by Mitsubishi Chemical Foods Co., Ltd.

Particulate silicon dioxide: manufactured by DSL Japan, "Carplex FPS-500"

Next, the coating solution for forming the lower layer, enteric coating layer, and outermost layer of the composition shown in Tables 2 to 4 below was prepared in the following order.

[Preparation of coating solution for lower layer]

The (A) component and (E) component are each uniformly dissolved in water at room temperature.

[Preparation of coating solution for enteric coating]

The components (B) and (C) are separately dispersed in water, and then heated and uniformly dissolved. The dissolved liquid is mixed, other components are added, and the mixture is further mixed and stirred.

[Preparation of coating solution for the outermost layer]

The component (D) is uniformly dissolved in water at room temperature.

On the surface of the above-prepared plain tablet, the lower layer, the enteric coating layer, and the outermost layer, if necessary, are sequentially formed using the coating solutions prepared above to prepare a coating preparation (tablet). The conditions for coating each layer are as follows.

[Cover]

The conditions for coating the lower layer, enteric coating layer, and outermost layer are as follows.

[Lower level]

Using a coating machine (Powrex Coater PRC-05 manufactured by Powrex), 200 g of the plain agent was sprayed with 50 g of the coating solution at an average of 2 ml/min, and coating was performed at a product temperature of about 50°C. After spraying, let it dry at about 45°C for 2 minutes, A coated preparation (tablet) is obtained. The thickness of the coating film is in the range of 5-50μm.

[Enteric coating]

Using a coating machine (Powrex Coater PRC-05 manufactured by Powrex), 200g of the plain agent was sprayed on the coating solution at an average of 2ml/min (Example and Comparative Example 1: 150g, Comparative Example 2: 204g), and the product temperature Coating is performed at about 50°C. After spraying, it was dried at about 45°C for 2 minutes to obtain a coated preparation (tablet). The thickness of the coating film is in the range of 20~200μm.

[Top layer]

Using a coating machine (Powrex Coater PRC-05 manufactured by Powrex), 200 g of the plain agent was sprayed with 50 g of the coating solution at an average of 2 ml/min, and coating was performed at a product temperature of about 50°C. After spraying, it was dried at about 45°C for 2 minutes to obtain a coated preparation (tablet). The thickness of the coating film is in the range of 5-50μm.

The coating formulations obtained above were each evaluated for enteric solubility in the following order immediately after coating and after storage at 50°C and 75% RH for 4 months. Compare the evaluation results before and after to confirm storage stability. In addition, the appearance (coating property) of the preparation immediately after coating was evaluated.

[Acid pH dissolution test]

Use Japanese station 1 liquid (pH 1.2), according to Japanese station general test method (paddle Formula method), perform dissolution test.

◎: The dissolution rate is less than 10% within 2 hours

○: The dissolution rate is more than 10% and less than 20% within 2 hours

△: The dissolution rate is more than 20% and less than 40% within 2 hours

×: The dissolution rate is more than 40% within 2 hours

[Neutral to alkaline pH dissolution test]

Use the Japanese branch 2 liquid (pH 6.8), and perform the dissolution test in accordance with the Japanese general test method (paddle method).

○: The dissolution rate is more than 70% within 2 hours

△: The dissolution rate is more than 30% and less than 70% within 2 hours

×: The dissolution rate is less than 30% within 2 hours

In addition, in the above-mentioned [acid pH dissolution test], "△", In the case of "○" or "◎", and in the above [neutral to alkaline pH dissolution test], the case of "○" is regarded as "enteric solubility".

[Appearance evaluation]

The surface of the preparation (tablet) immediately after coating was visually observed, and the appearance was evaluated based on the following evaluation criteria.

⊚: The coating is uniformly completed, no defects or peeling are seen, and the coating surface exhibits gloss.

○: The coating is uniformly completed, and defects and peeling are hardly seen, but the coating surface is slightly rough.

△: Defects in coating are seen in some tablets.

×: Defects or peeling of coating are seen in almost all tablets.

The details of the raw materials used in the examples and comparative examples are as follows. In addition, the details of the alginate of the component (B) are separately shown in Table 1.

[Lower level]

Hydroxypropyl methylcellulose: manufactured by Shin-Etsu Chemical Co., Ltd., "Metolose SE-06"

Pectin: manufactured by Dainippon Pharmaceutical Co., Ltd., "Classic AF701"

Polyvinyl alcohol: manufactured by Nippon Synthetic Chemical Co., Ltd., "Polyvinyl Alcohol EG-22P"

Gum Arabic: "Acacia Gum" manufactured by Japan Powdered Pharmaceuticals

Hydroxypropyl cellulose: Hydroxypropyl cellulose: manufactured by Soda Co., Ltd., "HPC-SSL"

Pullulan: (stock) made by Hayashibara, "Pululan"

Sucrose: Dai Nippon Meiji Sugar Co., Ltd., "Sucrose"

[Enteric coating]

Glycerin: manufactured by Sakamoto Pharmaceutical Industry Co., Ltd., "Glycerin (Food Additive)"

Silicon oxide (particulate silicon dioxide): manufactured by Fuji Silysia Chemical Co., Ltd., "Sylopage 720"

Talc: Songcun Industry Co., Ltd., "Crown Talc PP"

[Top layer]

Hydroxypropyl methylcellulose: manufactured by Shin-Etsu Chemical Co., Ltd., "Metolose SE-06"

Claims (11)

A coating preparation comprising a coated tablet, a lower layer formed thereon, and an enteric coating layer formed on the lower layer; the lower layer contains (A) 6 mass% The viscosity of the aqueous solution at 25°C is less than 300mPa. s polymer compound and (E) plasticizer; the enteric coating layer includes (B) alginate and (C) plasticizer, characterized in that the above component (A) is selected from hydroxypropyl methylcellulose , Pectin, curdlan, pullulan, hydroxypropyl cellulose, polyvinyl alcohol, and gum arabic, one or more of the group consisting of one or more, the above (E) component system Selected from sucrose fatty acid ester, glycerin fatty acid ester, monoglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, glycerin, propylene glycol, polyethylene glycol, fructose glucose liquid sugar, dodecanol, tridecanol One or more of the group consisting of, myristyl alcohol, pentadecanol, cetyl alcohol, heptadecyl alcohol, stearyl alcohol, isostearyl alcohol, 2-octyldodecanol and medium chain fatty acid esters , The adhesion amount of the above-mentioned lower layer is 0.2~3.5% by mass relative to the mass of the plain ingot. The coating preparation of claim 1, wherein the adhesion amount of the enteric coating layer is 0.5-20% by mass relative to the mass of the plain tablet. The coating formulation of claim 1 or 2, wherein the adhesion amount of the lower layer is 0.5 to 2.5% by mass relative to the mass of the plain tablet. The coating formulation of claim 1 or 2, wherein the component (A) is hydroxypropyl methylcellulose. The coating formulation of claim 1 or 2, wherein the blending amount of component (A) is 1-10% by mass of the entire composition for the lower layer. Such as the coating formulation of claim 1 or 2, wherein the component (B) is (B-1) a 1% by mass aqueous solution and the viscosity at 20°C is 50 mPa. Alginate above s. Such as the coating formulation of claim 6, which further contains (B-2) the viscosity of a 1% by mass aqueous solution at 20°C is less than 50mPa. s alginate. The coating formulation of claim 1 or 2, wherein the enteric coating layer further contains (D) a film-forming component, and the (D) component is selected from the group consisting of gelatin, pectin, cattleya polysaccharide, pullulan, and arabic Gum, xanthan gum, gellan gum, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, cold sky, chitosan, tamarind gum, locust bean gum, polyvinyl alcohol, ethyl acetate One type or two or more types of the group formed by the aqueous dispersion of base cellulose. Such as the coating formulation of claim 1 or 2, wherein the mass ratio represented by (C)/(B) is 0.05 to 3.0. Such as the coating formulation of claim 8, wherein the mass ratio represented by (B)/(D) is 0.33-20. A manufacturing method of a coating formulation, which is a manufacturing method of a coating formulation comprising the following steps: by spraying a coated substance into a plain tablet that contains (A) a 6 mass% aqueous solution with a viscosity at 25° C. Full 300mPa. s solution of a polymer compound and drying to form a lower layer; and by spraying a solution containing (B) alginate and (C) plasticizer on the outer side of the lower layer, and drying to form enteric Of coating Step, the manufacturing method is characterized in that the above-mentioned component (A) is selected from the group consisting of hydroxypropyl methylcellulose, pectin, cattleya, pullulan, hydroxypropyl cellulose, polyvinyl alcohol, and gum arabic. For one or more types of groups, the adhesion amount of the lower layer is 0.2~3.5% by mass relative to the mass of the plain ingot.