JP6642438B2 - Coating preparation and method for producing the same - Google Patents

Description

  TECHNICAL FIELD The present invention relates to a coating preparation used as foods, pharmaceuticals, and the like, and a method for producing the same.

  Like active components of proteins such as lactic acid bacteria and enzymes, there are active components that prevent degradation in the stomach, maintain their structure, and deliver high functionality by delivering them to the intestine. There is a need for enteric formulations that allow the components to reach the intestine.

  As a protective film for allowing the active ingredient to reach the intestine, a component that does not dissolve under the pH condition (acid) in the stomach but dissolves under the pH condition of the small intestine (neutral to alkaline), for example, a methacrylic acid-based polymer Compounds, shellac, zein and the like are common.

  However, methacrylic acid-based polymer compounds are limited to pharmaceutical applications and cannot be used in foods. On the other hand, shellac and zein are also used for food, but a method of spraying using an organic solvent is generally used. It has been desired to use a water-soluble film agent that can be coated with water in consideration of the environment even in food applications.

  Prior art documents related to the present invention include the following.

JP-A-2002-193792

  The present invention has been made in view of the above circumstances, and not only does not dissolve in the stomach but dissolves in the intestine, allowing the coated active ingredient to more reliably reach the intestine, and also minimizes deterioration with time. An object of the present invention is to provide a coating preparation which can be suppressed and has excellent storage stability and a method for producing the same.

  The present inventors have previously proposed an alginate enteric-coated preparation using water as a solvent in consideration of the environment (Japanese Patent Application No. 2013-046667). The enteric preparation coated with this coating has advantages such as very good enteric properties immediately after coating (dissolution inhibition under acidic conditions and dissolution characteristics under neutral conditions). However, in further studies, it has been found that the elution-suppressing property under acidic conditions may decrease with time in spite of no change in the appearance of the coating film. Although the cause is not clear, it is supposed that a very fine structural change has occurred because the elution inhibiting property is lowered despite no change in the appearance of the coating film.

  Therefore, the present inventors conducted further intensive studies and, as a result of applying a pre-coating as a lower layer of the enteric coating film to this fine structural change, surprisingly, elution suppression under acidity with time. It has been found that the deterioration of the properties can be improved.

  The pre-coating on the enteric coating film is generally performed to improve the peeling of the film due to poor compatibility between the enteric coating film and the tablet. The present inventors have found that the pre-coating has a function of protecting the enteric coating film using the alginate from deterioration with time, and is effective for improving the storage stability of the coating preparation. It has been reached.

Accordingly, the present invention provides the following coating preparations and a method for producing the same.
[1] An uncoated tablet containing lactoferrin to be coated, a lower layer containing a polymer compound having a viscosity of less than 300 mPa · s at 25 ° C. of (A) a 6% by mass aqueous solution formed thereon, A coating formulation having an enteric coating layer comprising (B) alginate and (C) a plasticizer formed on a lower layer,
The component (A) is one or more selected from the group consisting of hydroxypropylmethylcellulose, pectin, curdlan, pullulan, hydroxypropylcellulose, polyvinyl alcohol, and gum arabic;
A coating preparation, wherein the amount of adhesion of the lower layer is 0.2 to 3.5% by mass based on the mass of the uncoated tablet.
[2] The coated preparation according to [1], wherein the amount of the enteric coating layer attached is 0.5 to 20% by mass based on the mass of the uncoated tablet.
[3] The coating preparation according to [1] or [2], wherein the component (A) is hydroxypropyl methylcellulose.
[4] The coating preparation according to any one of [1] to [3], wherein the amount of the component (A) is 1 to 10% by mass of the whole composition for the lower layer.
[5] The coating preparation according to any one of [1] to [4], wherein the component (B) is an alginate having a viscosity of 50 mPa · s or more at 20 ° C of a (B-1) 1% by mass aqueous solution. .
[6] The coating preparation according to [5], further comprising (B-2) an alginate having a viscosity of less than 50 mPa · s at 20 ° C. of a 1% by mass aqueous solution.
[7] The enteric coating layer further comprises (D) a film-forming component, wherein the (D) component is gelatin, pectin, curdlan, pullulan, gum arabic, xanthan gum, gellan gum, hydroxypropylmethylcellulose, sodium carboxymethylcellulose. [1] to [6], one or more selected from the group consisting of hydroxypropylcellulose, agar, chitosan, tamarind seed gum, locust bean gum, polyvinyl alcohol, and aqueous dispersion of ethylcellulose. The coated preparation according to the above.
[8] Further, the lower layer contains (E) a plasticizer, and the (E) component contains sucrose fatty acid ester, glycerin fatty acid ester, monoglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, glycerin, propylene glycol, and polyethylene. Glycol, glucose, fructose-glucose liquid sugar, sucrose, sorbitol, maltitol, mannitol, erythritol, xylitol, dodecanol, tridecanol, tetradecanol, pentadecanol, hexadecanol, heptadecanol, octadecanol, hexadecyl alcohol The coating preparation according to any one of [1] to [7], which is one or more selected from the group consisting of isostearyl alcohol, 2-octyldodecanol, and medium-chain fatty acid esters.
[9] The coated preparation according to any one of [1] to [8], wherein the mass ratio represented by (C) / (B) is 0.05 to 3.0.
[10] The coated preparation according to any one of [1] to [9], wherein the mass ratio represented by (B) / (D) is 0.33 to 20.
[11] An uncoated tablet containing lactoferrin, which is the object to be coated, is sprayed with a solution containing a polymer compound having a viscosity of less than 300 mPa · s at 25 ° C. in a 6% by mass aqueous solution of (A), and dried by drying. Forming a enteric coating layer by spraying a solution containing (B) alginate and (C) a plasticizer on the outside of the lower layer, and drying the solution to form an enteric coating layer. And
The component (A) is one or more selected from the group consisting of hydroxypropylmethylcellulose, pectin, curdlan, pullulan, hydroxypropylcellulose, polyvinyl alcohol, and gum arabic;
A method for producing a coated preparation, wherein the amount of adhesion of the lower layer is 0.2 to 3.5% by mass based on the mass of the uncoated tablet.

  According to the coating preparation of the present invention, not only dissolving in the stomach but dissolving in the intestine, not only can ensure that the coated active ingredient reaches the intestine, but also when stored for a long time, dissolution inhibition under acidic conditions It is possible to provide a coating preparation which can suppress deterioration of the properties as much as possible and which has excellent storage stability.

Hereinafter, the present invention will be described in detail.
The coating preparation of the present invention has an article to be coated, a lower layer formed thereon, and an enteric coating layer formed on the lower layer, and is provided between the article to be coated and the lower layer, One or more intermediate layers may be formed between the soluble coating layer and the outermost layer. Among them, those having an object to be coated, a lower layer formed on the surface of the object to be coated, and an enteric coating layer formed on the surface of the lower layer are preferable. In the present invention, the outermost layer can be formed outside the enteric coating layer, if necessary, within a range that does not affect the enteric quality. In the present invention, "enteric" refers to an agent that delivers a functional ingredient to the intestine. It was tested according to the method of dissolution test of the Japanese Pharmacopoeia, gastric juice equivalent dissolution test medium at (pH 1.2), (less than preferably 20%) for 2 h at elution rate of less than 40%, intestinal fluid equivalent Dissolution rate of 70% or more in 2 hours with a dissolution test solution (pH 6.8).

(I) Object to be Coated In the present invention, the object to be coated is not particularly limited, and examples thereof include active ingredients such as foods and pharmaceuticals. For example, lactic acid bacteria, cysteine, iron, proteins such as antibodies and lactoferrin, peptides, ATP-2Na and the like can be mentioned, and these can be used alone or in an appropriate combination of two or more. Among them, it is suitable for high molecular weight components such as proteins and water-insoluble components.

  The shape and dosage form of the material to be coated are not particularly limited, and are not particularly limited, such as tablets, powders, fine granules, and granules. The tablet may be a single layer or two or more layers. Among these, a tablet is preferred from the viewpoint of exhibiting more enteric properties. The size of the tablet is not particularly limited, and from the viewpoint of ease of handling and swallowing of the tablet, the tablet diameter is preferably 5 to 14 mmφ, more preferably 7 to 12 mmφ. In addition, the tablet mass per tablet is suitably about 150 to 700 mg.

(II) Lower Layer The lower layer of the present invention is a layer formed prior to an enteric coating layer containing an alginate described later, for example, a layer formed on the surface of an object to be coated. In the present invention, by forming a lower layer between the material to be coated and the enteric coating layer, it is possible to prevent a time-dependent decrease in the elution suppressing effect under acidic conditions during storage. Thereby, the storage stability (dissolution inhibition under acidic conditions) of the coating preparation having the enteric coating layer formed thereon can be remarkably improved. Hereinafter, the lower layer will be described in detail.

  The lower layer contains a (A) polymer compound having a viscosity of less than 300 mPa · s at 25 ° C. in a 6% by mass aqueous solution. The component (A) is not particularly limited, but specific examples include hydroxypropylmethylcellulose, pectin, curdlan, pullulan, hydroxypropylcellulose, polyvinyl alcohol, and gum arabic. These can be used alone or in combination of two or more. In the present invention, hydroxypropylmethylcellulose can be particularly preferably used.

  The amount of the component (A) is not particularly limited, but is preferably 1 to 10% by mass, more preferably 3 to 8% by mass, based on the whole precoating composition (composition for lower layer). The production time can be reduced to an appropriate time by setting the blending amount to be equal to or more than the lower limit of the above range. On the other hand, when the amount is not more than the upper limit of the above range, the viscosity can be reduced to a value suitable for preparation of the coating liquid and spraying of the coating liquid.

  Further, the lower layer may contain (E) a plasticizer as needed. As the component (E), surfactants such as sucrose fatty acid ester, glycerin fatty acid ester, monoglycerin fatty acid ester and polyoxyethylene sorbitan fatty acid ester, polyhydric alcohols such as glycerin, propylene glycol and polyethylene glycol, glucose and fructose glucose Liquid sugars, sugars such as sucrose, sorbitol, maltitol, mannitol, erythritol, sugar alcohols such as xylitol, dodecanol, tridecanol, tetradecanol, pentadecanol, hexadecanol, heptadecanol, octadecanol, hexadecyl Examples thereof include higher alcohols (preferably having 6 to 22 carbon atoms) such as alcohols, isostearyl alcohol, and 2-octyldodecanol, and fats and oils such as medium-chain fatty acid esters (preferably having 6 to 12 carbon atoms).These can be used alone or in combination of two or more. In the present invention, glycerin can be suitably used from the viewpoint of the plasticizing effect.

  The amount of the component (E) is not particularly limited, but is preferably 0.3 to 6% by mass, and more preferably 0.8 to 5% by mass, based on the entire lower layer composition. By setting the amount to be equal to or more than the lower limit of the above range, the effect of preventing a time-dependent decrease in the elution suppression effect under acidic conditions is enhanced. On the other hand, the production time can be kept within an appropriate time by setting the blending amount at or below the upper limit of the above range.

  Fine particles (F) may be added to the composition for the lower layer. By blending the fine particles, it is possible to prevent the coating film from peeling off due to the adhesion of tablets during the coating process. As the component (F), talc, calcium stearate, silicon dioxide, titanium oxide, and the like can be given, and one type can be used alone or two or more types can be used in appropriate combination. The particle size of the fine particles is 0.01 to 50 μm, preferably 0.1 to 20 μm. The particle size is measured by a laser diffraction type particle size distribution analyzer (dry measurement).

  The compounding amount of the component (F) is preferably from 0.05 to 7% by mass, more preferably from 0.1 to 5% by mass, even more preferably from 0.3 to 3% by mass of the entire lower layer composition. By setting the amount to be equal to or more than the lower limit of the above range, the effect of mixing the component (F) can be further obtained. If the amount is more than the upper limit of the above range, the film formability may be affected.

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

  Although the thickness of the lower layer is not particularly limited, it is preferably 1 to 200 μm, more preferably 2 to 100 μm. In the case of a tablet, the amount of adhesion of the lower layer is preferably 0.6 to 10.5 mg / 300 mg (0.2 to 3.5% by mass) based on 300 mg of the uncoated tablet, and 1.5 to 7. More preferably, it is 5 mg / 300 mg (0.5 to 2.5% by mass). In the case of granules, powders, and powders, the content is preferably 0.5 to 30% by mass, more preferably 1 to 25% by mass. By making the thickness and the amount of adhesion of the lower layer not less than the lower limit of the above range, the effect of the present invention (that is, preventing the effect of suppressing elution under acidic conditions from being reduced with time) can be effectively obtained. be able to. On the other hand, when the thickness and the amount of adhesion of the lower layer are not more than the upper limit of the above range, a tablet can be produced in an appropriate production time.

The method for forming the lower layer is not particularly limited, and a known method can be employed. For example, there is a method in which a predetermined coating solution is sprayed on the object to be coated and dried by heating to form a film on the surface of the object to be coated. The coating solution can be appropriately heated, the temperature is preferably from 30 to 80C, and the drying temperature is preferably from 40 to 80C. The addition rate of the coating solution is preferably 1 to ⁵ g / min with respect to the dry air flow of 1 m ³ / min. In addition, it is also possible to adopt a dip coating method in which an object to be coated is dipped in a coating solution and dried. Drying is preferably performed until the water content in the coating preparation becomes 0.1 to 20% by mass, particularly 0.5 to 5% by mass. The lower layer is not limited to one layer, and a plurality of lower layers may be formed as necessary.

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

(III) Enteric coating layer The enteric coating layer of the present invention is an enteric layer formed outside the lower layer and contains (B) an alginate and (C) a plasticizer.

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

  (B-1) As the 1% by mass aqueous solution having a viscosity at 20 ° C. of 50 mPa · s or more, those having a viscosity of 50 mPa · s or more and 600 mPa · s or less are preferable, and those having a viscosity of 50 mPa · s or more and 400 mPa · s or less are more preferable. preferable.

  (B-1) When alginate is blended, the blending amount is preferably 0.1 to 5% by mass, more preferably 0.5 to 4% by mass, and preferably 1 to 4% by mass of the whole coating composition. More preferred. By adjusting the amount to be equal to or more than the lower limit of the above range, the ability to suppress dissolution under acidic conditions can be sufficiently obtained, and good enteric properties can be further obtained. On the other hand, by adjusting the viscosity to the upper limit or less, the viscosity can be adjusted to an appropriate level for preparation, transfer, and spraying of the coating liquid.

  (B-2) The alginate having a viscosity of less than 50 mPa · s at 20 ° C. of a 1% by mass aqueous solution is preferably 5 mPa · s or more and less than 50 mPa · s, more preferably 10 mPa · s or more and less than 50 mPa · s. More preferred. (B-2) Alginate is preferably sodium alginate.

  (B-2) When alginate is blended, the blending amount is preferably 5% by mass or less of the entire coating composition, more preferably 0.1 to 4% by mass, and more preferably 0.1 to 2.5% by mass. The range is more preferred. By controlling the amount to be equal to or less than the upper limit of the above range, enteric solubility is improved and coating properties are improved.

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

  In the present invention, it is preferable to use (B-1) alginate as (B) alginate. By using such an alginate having a length equal to or more than a certain length, coating properties are good and high acid resistance can be imparted to the formed coating film. Further, by using (B-1) alginate and (B-2) alginate in combination, it is possible to further improve the coating performance while maintaining enteric solubility.

  The use of two types of alginate having different viscosities, such as the above (B-1) alginate and (B-2) alginate, is not simply adjustment of the viscosity of the coating solution, but rather enteric and coating properties. In view of the above, two types of alginates are selected. The mass ratio of (B-1) :( B-2) ((B-1) / (B-2)) is preferably 1: 5 to 10: 1 (0.2 to 10), and 1: 3 to 5: 1 (0.33 to 5) is more preferable, and 1: 1.8 to 3: 1 (0.56 to 3) is still more preferable. When the mass ratio is equal to or more than the lower limit of the above range, the film performance under acidic condition becomes higher, so that the non-eluting property becomes good.

  In the present invention, the viscosity of alginate is measured using a rotary viscometer (BM type). If the viscosity is less than 200 mPa · s, the rotor No. The viscosity of 200 mPa · s or more and less than 1,000 mPa · s is used for rotor No. 1. 2 was used to measure a 1% by mass aqueous solution at 20 ° C. and 30 rpm, and the value after 60 seconds was taken as the measured value.

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

(1) Preparation of Sample A sample was prepared by dissolving in a mobile phase (aqueous 0.1 M (mol / L) NaNO ₃ ) so that the alginate concentration was 0.1% by mass.
A calibration curve is prepared using standard products of various molecular weights (Pullulan: Mw = 1.66 million, Mw = 380,000, Mw = 100,000, Mw = 120,000, dissolved in the mobile phase at a concentration of 0.1% by mass). .
(2) GPC measurement condition column: Shodex OHpak SB-806M HQ (8 mm ID × 300 mm L., 13 μm)
Mobile phase: 0.1 M (mol / L) NaNO ₃ aqueous solution Flow rate: 0.5 mL / min
Temperature: 40 ° C
Injection volume: 200 μL (0.1% in mobile phase)
Detector: Differential refractive index (RI) detector (3) Analysis method A calibration curve equation is obtained from a calibration curve sample, and a 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 that is blended for the purpose of lowering the surface tension of the coating composition and imparting flexibility to the coating layer. As the component (C), surfactants such as sucrose fatty acid ester, glycerin fatty acid ester, monoglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester and the like, and glycerin, 1,3-butylene glycol, propylene glycol, polyethylene glycol, etc. Polyhydric alcohols, glucose, fructose-glucose liquid sugar, sugars such as sucrose, sorbitol, maltitol, mannitol, erythritol, sugar alcohols such as xylitol, dodecanol, tridecanol, tetradecanol, pentadecanol, hexadecanol, heptadecanol Higher alcohols such as octadecanol, hexadecyl alcohol, isostearyl alcohol, and 2-octyldodecanol (preferably having 6 to 22 carbon atoms), and medium-chain fatty acid esters (preferably having 6 carbon atoms). 12) include oils and fats, and the like. These can be used alone or in combination of two or more. Among them, glycerin is preferable from the viewpoint of the plasticizing effect of the coating film.

  (C) As for the compounding quantity of a component, 0.3-5 mass% of the whole coating composition is preferable, and 0.5-3 mass% is more preferable. By setting the blending amount to be equal to or more than the lower limit of the above range, peeling of the film at the time of coating is further suppressed, and by being equal to or less than the upper limit of the above range, stickiness at the time of coating is suppressed, and the coating process becomes easier. , Good enteric solubility is obtained.

  The mass ratio 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, and more preferably 0.1 to 1.5. 15 to 1.1 are particularly preferred. By setting the mass ratio to be equal to or higher than the lower limit of the above range, the film performance under acidic conditions becomes higher, and by setting the mass ratio to be lower than or equal to the upper limit, the coatability becomes better.

  The coating composition of the present invention may contain a film-forming component (D) other than the component (B). (D) As film-forming components, gelatin, pectin, curdlan, pullulan, gum arabic, xanthan gum, gellan gum, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, agar, chitosan, tamarind seed gum, locust bean gum, polyvinyl Examples thereof include alcohol and an aqueous dispersion of ethyl cellulose. These can be used alone or in combination of two or more. Among these, components selected from gelatin, pectin, curdlan, pullulan, gum arabic, xanthan gum, gellan gum, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and hydroxypropylcellulose are preferred in terms of coating properties and combination with component (B). preferable.

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

  In this case, the content ratio represented by (B) :( D) ((B) / (D)) is preferably 1: 3 to 1: 0.05 (0.33 to 20), and preferably 1: 1. １ ： 1: 0.1 (1１０10) is more preferred, and 1: 0.8〜1: 0.2 (1.25５〜5) is even more preferred. Within this range, it is possible to obtain a tablet having excellent enteric performance, which has higher dissolution inhibiting ability, particularly under acidic conditions, while maintaining the coating properties and the beautiful appearance.

  The coating composition may contain (F) fine particles. By blending the fine particles, it is possible to prevent the coating film from peeling off due to the adhesion of tablets during the coating process. As the component (F), talc, calcium stearate, silicon dioxide, titanium oxide, and the like can be given, and one type can be used alone or two or more types can be used in appropriate combination. The particle size of the fine particles is 0.01 to 50 μm, preferably 0.1 to 20 μm. As in the case of the composition for the lower layer, the particle size is measured by a laser diffraction type particle size distribution measuring device (dry measurement).

  The compounding amount of the component (F) is preferably 0.05 to 7% by mass, more preferably 0.1 to 5% by mass, and even more preferably 0.3 to 3% by mass of the whole coating composition. By setting the amount to be equal to or more than the lower limit of the above range, the effect of mixing the component (F) can be further obtained. If the amount is more than the upper limit of the above range, the film formability may be affected.

  In addition, it is preferable that the said coating composition does not contain bivalent metal ions, such as a copper ion, a barium ion, and a calcium ion. This is because the alginate is crosslinked and gelled by these, and the coating property deteriorates. In other words, when monovalent alginate is reacted with a divalent cation and crosslinked, the dried film is insoluble in water, but the viscosity becomes too high due to gelation, so that fine liquids are sprayed and applied on tablets. Becomes difficult to spread. As a result, it is difficult to form a uniform film, the appearance is deteriorated, and the dissolution may vary. The allowable range of the divalent metal ion is preferably 0.5 mol or less, more preferably 0.25 mol or less, and even more preferably 0.1 mol or less, per 1 mol of the alginate monomer.

  In the above-mentioned coating composition, in addition to the above-mentioned components, components usually used in the coating composition can be used alone or in an appropriate amount of two or more. Examples of such optional components include an antifoaming agent and a coloring agent.

  Examples of the antifoaming agent include glycerin fatty acid ester, dimethylpolysiloxane, a mixture of dimethylpolysiloxane and silicon dioxide, hydrated silicon dioxide, silicon dioxide, and the like. One type may be used alone, or two or more types may be used in appropriate combination. it can.

  Examples of the coloring agent include, for example, acacia tannin powder, turmeric extract, yellow iron sesquioxide, orange essence, brown iron oxide, carbon black, caramel, carmine, carotene solution, β-carotene, licorice extract, gold leaf, black iron oxide Light anhydrous silicic acid, titanium oxide, iron sesquioxide, edible blue No. 1, edible yellow No. 4, edible yellow No. 4, aluminum lake, edible yellow No. 5, edible red No. 2, edible red No. 3, edible red No. 102, Examples thereof include sodium hydroxide, sodium copper chlorofin, copper chlorophyll, extract of green leaf of leaf mustard, medicinal charcoal, riboflavin butyrate, riboflavin, green tea powder, and sodium riboflavin phosphate.

  The coating composition of the present invention can contain an organic solvent such as water and ethanol. The amount of the solvent in the coating composition is appropriately selected within the range of 1 to 98% by mass, preferably 50 to 98% by mass, and more preferably 70 to 96% by mass, based on the entire coating composition.

  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 the case of tablets, the amount of the enteric coating layer to be applied is preferably 1.5 to 60 mg / 300 mg (0.5 to 20% by mass) based on 300 mg of uncoated tablets, and preferably 3 to 45 mg / 300 mg (1%). To 15% by mass). In the case of granules, powders and powders, the content is preferably 10 to 60% by mass, more preferably 15 to 50% by mass. When the thickness and the amount of the enteric coating layer are not less than the lower limit of the above range, it is possible to obtain a preparation excellent in dissolution inhibiting ability under acidic conditions. On the other hand, when the amount of the enteric coating layer to be adhered is equal to or less than the upper limit of the above range, it can be controlled within an appropriate production time.

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

The method for forming the enteric coating layer is not particularly limited, and a known method can be employed. For example, there is a method in which a predetermined coating solution is sprayed on an object to be coated on which a lower layer is formed and dried by heating to form a film on the surface of the object to be coated. The coating solution can be appropriately heated, the temperature is preferably from 30 to 80C, and the drying temperature is preferably from 40 to 80C. The addition rate of the coating solution is preferably 1 to ⁵ g / min with respect to the dry air flow of 1 m ³ / min. In addition, it is also possible to adopt a dip coating method in which the object to be coated is dipped in a coating solution and dried. Drying is preferably performed until the water content in the coating preparation becomes 0.1 to 20% by mass, particularly 0.5 to 5% by mass.

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

  An appropriate intermediate layer may be formed between the lower layer and the coating layer as long as the effects of the present invention are not impaired. In the present invention, for example, a shellac coating film and a cured oil / fat coating film can be formed.

(IV) Outermost layer In the present invention, the outermost layer can be formed on the outside of the enteric coating layer by using the above (D) film-forming component, if necessary. Thereby, the appearance, mouthfeel, and taste can be changed. (D) As components, gelatin, pectin, curdlan, pullulan, gum arabic, xanthan gum, gellan gum, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, agar, chitosan, tamarind seed gum, locust bean gum, polyvinyl alcohol, Ethyl cellulose aqueous dispersion and the like can be mentioned. These can be used alone or in combination of two or more. Among these, components selected from gelatin, pectin, curdlan, pullulan, gum arabic, xanthan gum, gellan gum, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and hydroxypropylcellulose are preferred from the viewpoint 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 the case of a tablet, the amount of adhesion of the outermost layer is preferably 0.6 to 10.5 mg / 300 mg (0.2 to 3.5% by mass) based on 300 mg of the uncoated tablet, and 1.5 to 7%. It is more preferable to be 0.5 mg / 300 mg (0.5 to 2.5% by mass). In the case of granules, powders and powders, the content is preferably 1 to 30% by mass, more preferably 2 to 25% by mass. By setting the thickness and the amount of adhesion of the outermost layer to the lower limits of the above ranges, the mouthfeel and taste can be changed. On the other hand, when the thickness and the amount of adhesion of the outermost layer are not more than the upper limits of the above ranges, the production time can be appropriately reduced.

  The above composition for the outermost layer may contain an organic solvent such as water or ethanol as long as the effects of the present invention are not impaired. The compounding amount of the solvent in the composition for the outermost layer is appropriately selected in the range of 1 to 98% by mass, preferably 50 to 98% by mass, more preferably 70 to 96% by mass, based on the entire composition for the outermost layer. .

The method for forming the outermost layer is not particularly limited, and a known method can be employed. For example, there is a method in which a predetermined coating solution is sprayed on the object to be coated on which the lower layer and the enteric coating layer are formed and dried by heating to form a film on the surface of the object to be coated. The coating solution can be appropriately heated, the temperature is preferably from 30 to 80C, and the drying temperature is preferably from 40 to 80C. The addition rate of the coating solution is preferably 1 to ⁵ g / min with respect to the dry air flow of 1 m ³ / min. In addition, it is also possible to adopt a dip coating method in which the object to be coated is dipped in a coating solution and dried. Drying is preferably performed until the water content in the coating preparation becomes 0.1 to 20% by mass, particularly 0.5 to 5% by mass.

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

(V) Production method of coating preparation The coating preparation of the present invention is obtained by spraying (A) a solution containing a polymer compound having a viscosity of less than 300 mPa · s at 25 ° C of a 6% by mass aqueous solution on an object to be coated, A step of forming a lower layer by drying, a step of spraying a solution containing (B) an alginate and a (C) plasticizer on the outside of the lower layer, and a step of forming an enteric coating layer by drying; Accordingly, it can be produced by spraying a solution containing the (D) film-forming component and drying the solution to form the outermost layer. The details of each step are as described above, but the composition of the coating solution to be used and the conditions of the coating can be appropriately set without impairing the effects of the present invention, and are not particularly limited.

  The coating solution for forming the lower layer, the enteric coating layer, and, if necessary, the outermost layer can be obtained by mixing the above essential components. Then, by using each of the above-mentioned coating solutions, a lower layer, an enteric coating layer, and an outermost layer as needed are sequentially formed on the object to be coated, so that a coating preparation having both good enteric properties and excellent storage stability. Can be obtained. Further, since water is used as a solvent for the coating solution of each layer, a water-soluble film is formed for each layer.

  The enteric coating layer formed from the above coating composition contains the above-mentioned component (B), but as described above, the alginate aqueous solution is directly dried to form a water-soluble film. This water-soluble film has the property that, under acidic conditions, monovalent cations are replaced by hydrogen ions, converted to alginic acid to form an insoluble film, and furthermore, neutral to alkaline and dissolved.

  The enteric coating layer formed from the coating composition has an enteric property, that is, a property that "the substance does not dissolve in the stomach but dissolves in the intestine and can be coated to reach the intestine." An enteric coating preparation in which the coating film is enteric is obtained.

  Further, a lower layer containing the above-mentioned component (A) is formed under the enteric coating layer, and the lower layer functions as a base for protecting the enteric coating layer from deterioration with time, so that the lower layer can be used with time. It is possible to suppress as much as possible the decrease in the dissolution inhibiting property under acidic conditions, and it is possible to significantly improve the storage stability of the coated preparation.

  Further, if necessary, by forming an outermost layer containing the component (D) outside the enteric coating layer, the taste, mouthfeel, and appearance can be changed.

  Hereinafter, the present invention will be described specifically with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples. In the following examples, unless otherwise specified, “%” in the composition indicates% by mass, and the ratio indicates the mass ratio.

[Examples 1 to 15, Comparative Examples 1 and 2]
First, the following plain tablets were prepared for preparing a coating preparation.
[Uncoated]
The following raw materials were mixed, and tableting was performed using a tableting machine so as to obtain tablets (300 mg, φ9.0 mm, thickness 5 mm).
<Uncoated tablet composition>
Lactoferrin: 1,156 g
Hihats extract powder: 500g
Lactose: 492.5g
Microcrystalline cellulose: 731.5 g
Sodium carboxymethylcellulose: 60 g
Sucrose fatty acid ester: 30 g
Fine silicon dioxide: 30g

Details of each of the above components are as follows.
Lactoferrin: Morinaga Milk Industry Co., Ltd. Hihatsu Extract Powder: Maruzen Pharmaceutical Co., Ltd., "Hihats Extract Powder MF"
Lactose: "Lactose Granule", manufactured by Freund Corporation
Crystalline cellulose: "CEOLUS FD-101" manufactured by Asahi Kasei Chemicals Corporation
Sodium carboxymethylcellulose: "ECC-FA" manufactured by Nichirin Chemical Industry Co., Ltd.
Sucrose fatty acid ester: "Ryoto Sugar Ester S-370F" manufactured by Mitsubishi Chemical Foods Corporation
Fine silicon dioxide: Carplex FPS-500, manufactured by DSL Japan Co., Ltd.

  Next, a coating solution for forming the lower layer, the enteric coating layer, and the outermost layer having the compositions shown in Tables 2 to 4 below was prepared by the following procedure.

[Preparation of coating solution for lower layer]
The components (A) and (E) were each uniformly dissolved in water at room temperature.

[Preparation of coating solution for enteric coating layer]
The component (B) and the component (C) were each dispersed in water, then heated and uniformly dissolved, the dissolved liquid was mixed, other components were added, and the mixture was further mixed and stirred.

[Preparation of coating solution for outermost layer]
The component (D) was uniformly dissolved in water at room temperature.

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

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

〔Underlayer〕
Using a coating machine (Powrex Coater PRC-05 manufactured by Powrex), 50 g of a coating solution was sprayed at an average rate of 2 ml / min on 200 g of the base material, and coating was performed at a product temperature of about 50 ° C. After spraying, the mixture was dried at about 45 ° C. for 2 minutes to obtain a coating preparation (tablet). The thickness of the coating film was in the range of 5 to 50 μm.

(Enteric coating layer)
The coating solution (Example and Comparative Example 1: 150 g, Comparative Example 2: 204 g) was sprayed at an average of 2 ml / min to 200 g of the base material using a coating machine (Powrex Coater PRC-05 manufactured by Powrex), and the product temperature was measured. The coating was applied at about 50 ° C. After spraying, the mixture was dried at about 45 ° C. for 2 minutes to obtain a coating preparation (tablet). The thickness of the coating film was in the range of 20-200 μm.

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

  The coated preparation obtained above was evaluated for enteric solubility immediately after coating and after storage for 4 months at 50 ° C. and 75% RH according to the following procedure. The storage stability was confirmed by comparison. In addition, the appearance (coatability) of the preparation immediately after coating was evaluated.

[Acid pH dissolution test]
A dissolution test was performed using one JP solution (pH 1.2) according to the JP General Test Method (paddle method).
◎: Dissolution of less than 10% in 2 hours ○: Dissolution of 10% to less than 20% in 2 hours △: Dissolution of 20% to less than 40% in 2 hours ×: Dissolution of 40% or more in 2 hours

[Neutral to alkaline pH dissolution test]
A dissolution test was performed using two Japanese Pharmacopoeia solutions (pH 6.8) in accordance with the Japanese Pharmacopoeia General Test Method (paddle method).
○: 70% or more of dissolution in 2 hours Δ: 30% or more and less than 70% in 2 hours X: Dissolution of less than 30% in 2 hours In addition, “酸性”, “ "O" or "A" and "O" in the above [Neutral to alkaline pH dissolution test] were regarded as "enteric".

[Evaluation of appearance]
The surface of the preparation (tablet) immediately after coating was visually observed, and the appearance was evaluated according to the following evaluation criteria.
◎: Uniform coating, no chipping or peeling, and gloss on the coating surface.
：: Uniform coating, little chipping or peeling, but little roughness on the coating surface.
Δ: Chipping of coating is observed in some tablets.
X: Chipping or peeling of the coating is observed in almost all of the tablets.

The details of the raw materials used in Examples and Comparative Examples are as follows. The details of the alginate component (B) are shown in Table 1 separately.
〔Underlayer〕
Hydroxypropyl methylcellulose: “Metroze SE-06” manufactured by Shin-Etsu Chemical Co., Ltd.
Pectin: Dainippon Pharmaceutical Co., Ltd., "Classic AF701"
Polyvinyl alcohol: Nippon Gohsei Chemical Co., Ltd., "Polyvinyl alcohol EG-22P"
Gum arabic: Nippon Powder Chemical Co., Ltd., "Gum arabic"
Hydroxypropylcellulose: Hydroxypropylcellulose: "HPC-SSL", manufactured by Nippon Soda Co., Ltd.
Pullulan: "Pulllan", made by Hayashibara
Sucrose: Dainippon Meiji Seika Co., Ltd., "Sucrose"
(Enteric coating layer)
Glycerin: “Glycerin (food additive)” manufactured by Sakamoto Pharmaceutical Co., Ltd.
Silica (fine silicon dioxide): Silopage 720, manufactured by Fuji Silysia Chemical Ltd.
Talc: Matsumura Sangyo Co., Ltd. “Crown Talc PP”
(Outermost layer)
Hydroxypropyl methylcellulose: “Metroze SE-06” manufactured by Shin-Etsu Chemical Co., Ltd.

Claims (11)

An uncoated tablet containing lactoferrin to be coated, a lower layer containing a polymer compound having a viscosity of less than 300 mPa · s at 25 ° C. of a (A) 6 mass% aqueous solution formed thereon, A coating formulation having (B) an alginate formed and an enteric coating layer comprising (C) a plasticizer,
The component (A) is one or more selected from the group consisting of hydroxypropylmethylcellulose, pectin, curdlan, pullulan, hydroxypropylcellulose, polyvinyl alcohol, and gum arabic;
A coating preparation, wherein the amount of adhesion of the lower layer is 0.2 to 3.5% by mass based on the mass of the uncoated tablet.   The coated preparation according to claim 1, wherein the amount of the enteric coating layer attached is 0.5 to 20% by mass relative to the mass of the uncoated tablet.   3. The coating preparation according to claim 1, wherein the component (A) is hydroxypropylmethylcellulose.   The coating formulation according to any one of claims 1 to 3, wherein the amount of the component (A) is 1 to 10% by mass of the whole composition for the lower layer.   The coating formulation according to any one of claims 1 to 4, wherein the component (B) is an alginate having a viscosity at 20 ° C of (B-1) a 1 mass% aqueous solution of 50 mPa · s or more.   The coating preparation according to claim 5, further comprising (B-2) an alginate having a viscosity at 20 ° C of a 1% by mass aqueous solution of less than 50 mPa · s.   Furthermore, the enteric coating layer contains (D) a film-forming component, and the (D) component is gelatin, pectin, curdlan, pullulan, gum arabic, xanthan gum, gellan gum, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, hydroxypropyl The coating preparation according to any one of claims 1 to 6, which is at least one selected from the group consisting of cellulose, agar, chitosan, tamarind seed gum, locust bean gum, polyvinyl alcohol, and aqueous dispersion of ethyl cellulose.   Further, the lower layer contains (E) a plasticizer, and the (E) component contains sucrose fatty acid ester, glycerin fatty acid ester, monoglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, glycerin, propylene glycol, polyethylene glycol, and glucose. , Fructose glucose liquid sugar, sucrose, sorbitol, maltitol, mannitol, erythritol, xylitol, dodecanol, tridecanol, tetradecanol, pentadecanol, hexadecanol, heptadecanol, octadecanol, hexadecyl alcohol, isostearyl The coating preparation according to any one of claims 1 to 7, wherein the coating preparation is one or more selected from the group consisting of alcohol, 2-octyldodecanol, and a medium-chain fatty acid ester.   The coating formulation according to any one of claims 1 to 8, wherein a mass ratio represented by (C) / (B) is 0.05 to 3.0.   The coating formulation according to any one of claims 1 to 9, wherein the mass ratio represented by (B) / (D) is 0.33 to 20. A lower layer is formed by spraying a solution containing a polymer compound having a viscosity at 25 ° C. of a 6% by mass aqueous solution (A) of less than 300 mPa · s onto a plain tablet containing lactoferrin, which is an object to be coated, and drying. A method for producing a coating preparation, comprising: a step of spraying a solution containing (B) an alginate and (C) a plasticizer on the outside of the lower layer, and drying to form an enteric coating layer. ,
The component (A) is one or more selected from the group consisting of hydroxypropylmethylcellulose, pectin, curdlan, pullulan, hydroxypropylcellulose, polyvinyl alcohol, and gum arabic;
A method for producing a coated preparation, wherein the amount of adhesion of the lower layer is 0.2 to 3.5% by mass based on the mass of the uncoated tablet.