WO2016035756A1 - Coated preparation and method for producing same - Google Patents

Coated preparation and method for producing same Download PDF

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Publication number
WO2016035756A1
WO2016035756A1 PCT/JP2015/074731 JP2015074731W WO2016035756A1 WO 2016035756 A1 WO2016035756 A1 WO 2016035756A1 JP 2015074731 W JP2015074731 W JP 2015074731W WO 2016035756 A1 WO2016035756 A1 WO 2016035756A1
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WO
WIPO (PCT)
Prior art keywords
coating
mass
layer
enteric
component
Prior art date
Application number
PCT/JP2015/074731
Other languages
French (fr)
Japanese (ja)
Inventor
千晶 高橋
あゆみ 松野
木津　典生
Original Assignee
ライオン株式会社
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Application filed by ライオン株式会社 filed Critical ライオン株式会社
Priority to KR1020177002830A priority Critical patent/KR102392313B1/en
Priority to JP2016546638A priority patent/JP6642438B2/en
Priority to CN201580046747.3A priority patent/CN106794253B/en
Publication of WO2016035756A1 publication Critical patent/WO2016035756A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to a coating preparation used as a food, a medicine and the like and a method for producing the same.
  • ingredients that do not dissolve under the pH conditions (acidic) in the stomach but dissolve under the pH conditions (neutral to alkaline) of the small intestine such as methacrylic acid polymers Compounds, shellac, zein and the like are common.
  • methacrylic acid polymer compounds are limited to pharmaceutical use and cannot be used for food.
  • shellac and zein are also used for food applications, but spraying using an organic solvent is common.
  • the use of a water-soluble film agent capable of coating with water in consideration of the environment for food applications has been desired.
  • the present invention has been made in view of the above circumstances, and it is possible not only to dissolve in the stomach but to dissolve in the intestine, and to ensure that the coated active ingredient reaches the intestine more reliably, and to prevent deterioration over time as much as possible. It aims at providing the coating formulation which can be suppressed, and is excellent also in storage stability, and its manufacturing method.
  • the present inventors previously proposed an alginate enteric coating preparation using water as a solvent in consideration of the environment (Japanese Patent Application No. 2013-046697).
  • the enteric preparation provided with this coating has advantages such as very good entericity immediately after coating (elution suppression under acidic conditions, dissolution under neutral conditions).
  • elution inhibition property under acidic conditions may decrease over time even though the appearance of the coating film does not change.
  • the cause is not clear, but it is presumed to be that a very fine structural change has occurred since the elution suppression property has decreased despite the fact that there is no change in the appearance of the coating film.
  • the inventors applied a pre-coating as the lower layer of the enteric coating film for this fine structural change, and surprisingly, suppression of elution under acidic conditions over time. It was found that the deterioration of the property can be improved.
  • the pre-coating with respect to the enteric coating film is generally carried out in order to improve the peeling of the film due to poor compatibility between the enteric coating film and the tablet.
  • the present inventors have newly found that pre-coating has a function of protecting the enteric coating film using the above-mentioned alginate from deterioration over time and is effective for improving the storage stability of the coating preparation. It has come.
  • the present invention provides the following coating preparation and method for producing the same.
  • An object to be coated a lower layer containing a polymer compound having a viscosity of less than 300 mPa ⁇ s at 25 ° C. of a 6% by mass aqueous solution (A) formed thereon, and formed on the lower layer
  • a coating preparation comprising an enteric coating layer containing an alginate and (C) a plasticizer.
  • the component (A) is selected from the group consisting of hydroxypropylmethylcellulose, pectin, curdlan, pullulan, hydroxypropylcellulose, polyvinyl alcohol, and gum arabic.
  • the outer side of the enteric coating layer (D) is selected from the group consisting of gelatin, pectin, curdlan, pullulan, gum arabic, xanthan gum, gellan gum, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and hydroxypropylcellulose. 6.
  • (A) A step of forming a lower layer by spraying a solution containing a polymer compound having a viscosity of less than 300 mPa ⁇ s at 25 ° C.
  • the coating preparation of the present invention not only does it dissolve in the stomach but dissolves in the intestine, so that the coated active ingredient can surely reach the intestine, and even when stored for a long period of time, it suppresses dissolution under acidic conditions.
  • the coating formulation which can suppress the fall of property as much as possible and is excellent also in storage stability can be provided.
  • the coating preparation of the present invention has an object to be coated, a lower layer formed thereon, and an enteric coating layer formed on the lower layer.
  • One or more intermediate layers may be formed between the soluble coating layer and the outermost layer.
  • those having a coating object, a lower layer formed on the surface of the coating object, and an enteric coating layer formed on the surface of the lower layer are preferable.
  • the outermost layer can be formed on the outer side of the enteric coating layer as necessary, as long as the enteric quality is not affected.
  • enteric refers to an agent that delivers a functional component to the intestine.
  • dissolution test method of Japanese Pharmacy Method
  • dissolution rate was less than 50% (preferably 30% or less) in 2 hours in dissolution test solution (pH 1.2) corresponding to gastric juice.
  • Dissolution rate of 70% or more in 2 hours with dissolution test solution (pH 6.8).
  • the object to be coated is not particularly limited, and examples thereof include active ingredients such as foods and pharmaceuticals.
  • active ingredients such as foods and pharmaceuticals.
  • examples include lactic acid bacteria, cysteine, iron, proteins such as antibodies and lactoferrin, peptides, ATP-2Na, and the like, and these can be used alone or in 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 object to be coated are not particularly limited, and there are no particular limitations on tablets, powders, fine granules, granules and the like.
  • the tablet may be a single layer or two or more layers. Among these, it is preferable to set it as a tablet from the point which exhibits enteric property more.
  • the size of the tablet is not particularly limited, and the tablet diameter is preferably 5 to 14 mm ⁇ and more preferably 7 to 12 mm ⁇ from the viewpoint of easy handling and swallowability.
  • the tablet mass per tablet is suitably about 150 to 700 mg.
  • 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.
  • an enteric coating layer containing an alginate described later for example, a layer formed on the surface of an object to be coated.
  • the present invention by forming a lower layer between the object to be coated and the enteric coating layer, it is possible to prevent a temporal decrease in the elution suppression effect under acidity during storage. Thereby, the storage stability (elution suppression property under acidic conditions) of the coating preparation in which the enteric coating layer is formed can be remarkably improved.
  • the lower layer will be described in detail.
  • the lower layer contains (A) a polymer compound whose viscosity at 25 ° C. in a 6% by mass aqueous solution is less than 300 mPa ⁇ s.
  • the component (A) is not particularly limited, and specific examples include hydroxypropylmethylcellulose, pectin, curdlan, pullulan, hydroxypropylcellulose, polyvinyl alcohol, and gum arabic. One species can be used alone, or two or more species can be used in appropriate combination. 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 entire precoating composition (lower layer composition).
  • 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 entire precoating composition (lower layer composition).
  • the lower layer may contain (E) a plasticizer as necessary.
  • (E) Component includes surfactants such as sucrose fatty acid ester, glycerin fatty acid ester, monoglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyhydric alcohols such as glycerin, propylene glycol, polyethylene glycol, glucose, fructose glucose Sugars such as liquid sugar, sucrose, sugar alcohols such as sorbitol, maltitol, mannitol, erythritol, and xylitol, dodecanol, tridecanol, tetradecanol, pentadecanol, hexadecanol, heptadecanol, octadecanol, hexadecyl Examples include higher alcohols such as alcohol, isostearyl alcohol, 2-octyldodecanol (preferably having 6 to 22 carbon atoms),
  • the amount of the component (E) is not particularly limited, but is preferably 0.3 to 6% by mass, more preferably 0.8 to 5% by mass, based on the entire lower layer composition.
  • the lower layer composition may contain (F) fine particles.
  • the fine particles By blending the fine particles, it is possible to prevent peeling of the coating film due to adhesion between tablets during the coating process.
  • the component (F) include talc, calcium stearate, silicon dioxide, titanium oxide, and the like, which can be used alone or in combination of two or more.
  • the particle diameter of the fine particles is 0.01 to 50 ⁇ m, preferably 0.1 to 20 ⁇ m. The particle size is measured with a laser diffraction particle size distribution measuring device (dry measurement).
  • the blending amount of the component (F) is preferably 0.05 to 7% by mass, more preferably 0.1 to 5% by mass, and still more preferably 0.3 to 3% by mass with respect to the entire lower layer composition.
  • the above 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 in the range of 1 to 98% by mass, preferably 50 to 98% by mass, and more preferably 70 to 96% by mass with respect to the entire lower layer composition.
  • the thickness of the lower layer is not particularly limited, but is preferably 1 to 200 ⁇ m, more preferably 2 to 100 ⁇ m.
  • the lower layer adhesion amount is preferably 0.6 to 10.5 mg / 300 mg (0.2 to 3.5% by mass) with respect to 300 mg of uncoated tablet, and 1.5 to 7. More preferably, it is 5 mg / 300 mg (0.5 to 2.5 mass%).
  • the content is preferably 0.5 to 30% by mass, and more preferably 1 to 25% by mass.
  • the effect of the present invention (that is, preventing the elution suppression effect under acidic conditions from decreasing with time) is effectively obtained. be able to.
  • a tablet can be produced in an appropriate production time by setting the thickness and adhesion amount of the lower layer to be equal to or lower than the upper limit of the above range.
  • the method for forming the lower layer is not particularly limited, and a known method can be adopted.
  • a method of forming a film on the surface of the object to be coated by spraying a predetermined coating solution on the object to be coated and drying by heating is exemplified.
  • the coating solution can be appropriately 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 a dry air volume of 1 m 3 / min.
  • the lower layer is not limited to a single layer, and a plurality of layers may be formed as necessary.
  • the coating machine is not particularly limited, and a pan coating machine, a fluidized bed coating machine, a rolling coating machine or the like can be used.
  • the enteric coating layer of the present invention is an enteric layer formed on the outside of the lower layer and contains (B) an alginate and (C) a plasticizer.
  • (B) Alginic acid salt As the alginic acid salt, monovalent alginate such as sodium salt, potassium salt and ammonium salt, and alginic acid water-soluble salt are preferable.
  • the alginate the following (B-1) 1% by mass aqueous solution having a viscosity at 20 ° C. of 50 mPa ⁇ s or more, (B-2) 1% by mass aqueous solution having a viscosity at 20 ° C. of less than 50 mPa ⁇ s: Can be used, and one kind can be used alone, or two or more kinds can be used in appropriate combination.
  • a 1% by weight aqueous solution having a viscosity at 20 ° C. of 50 mPa ⁇ s or more is preferably 50 mPa ⁇ s or more and 600 mPa ⁇ s or less, more preferably 50 mPa ⁇ s or more and 400 mPa ⁇ s or less. preferable.
  • the blending amount is preferably 0.1 to 5% by weight, more preferably 0.5 to 4% by weight, and more preferably 1 to 4% by weight of the entire coating composition. Further preferred.
  • the blending amount is preferably 0.1 to 5% by weight, more preferably 0.5 to 4% by weight, and more preferably 1 to 4% by weight of the entire coating composition. Further preferred.
  • Alginates having a viscosity of 1% by weight aqueous solution at 20 ° C. of less than 50 mPa ⁇ s are preferably from 5 mPa ⁇ s to less than 50 mPa ⁇ s, and preferably from 10 mPa ⁇ s to less than 50 mPa ⁇ s. More preferred.
  • B-2 As the alginate, sodium alginate is preferable.
  • the blending amount is preferably 5% by mass or less, more preferably 0.1 to 4% by mass, and more preferably 0.1 to 2.5% by mass of the entire coating composition.
  • a range is more preferred. By making a compounding quantity below the upper limit of the said range, enteric property improves and coating property becomes favorable.
  • the blending amount of the component (B) (that is, the total amount of the component (B-1) and the component (B-2)) is preferably 0.1 to 10% by mass of the entire coating composition. Further, the range of 1 to 7% by mass is more preferable, and the range of 1.5 to 5% by mass is more preferable. When the blending amount is not more than the upper limit of the above range, good enteric properties (elution suppression under acidic conditions) can be obtained.
  • (B-1) alginate As (B) alginate, it is preferable to use (B-1) alginate as (B) alginate.
  • the coating property is good and high acid resistance can be imparted to the formed coating film.
  • the coating performance can be further improved while maintaining enteric properties.
  • the use of two types of alginate having different viscosities such as (B-1) alginate and (B-2) alginate is not simply the adjustment of the viscosity of the coating solution, but enteric and coating properties. From the viewpoint of the above, two types of alginate 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 (0.33-5) is more preferred, and 1: 1.8-3: 1 (0.56-3) is even more preferred.
  • the viscosity of the alginate is measured using a rotary viscometer (BM type). Viscosity with a viscosity of less than 200 mPa ⁇ s 1 and a viscosity of 200 mPa ⁇ s or more and less than 1,000 mPa ⁇ s is rotor No. 2 is used to measure a 1% by mass aqueous solution under the conditions of 20 ° C. and 30 rpm, and the value after 60 seconds is taken as the measurement value.
  • BM type rotary viscometer
  • the viscosity of alginate is almost proportional to the molecular weight of alginate.
  • the weight average molecular weight (Mw) of (B-1) is 800,000 or more, preferably from 80 to less than 3 million, more preferably from 80 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 measuring method of the gel chromatography of the weight average molecular weight (Mw) of the alginate of this invention is shown below.
  • Preparation alginate concentration of the sample is to this sample was dissolved in mobile phase so that 0.1 wt% (0.1M (mol / L) NaNO 3 solution).
  • Plasticizer is a component blended for the purpose of lowering the surface tension of the coating composition and imparting flexibility to the coating layer.
  • surfactants such as sucrose fatty acid ester, glycerin fatty acid ester, monoglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, etc., glycerin, 1,3-butylene glycol, propylene glycol, polyethylene glycol and the like
  • Sugars such as monohydric alcohol, glucose, fructose glucose liquid sugar, sucrose, sugar alcohols such as sorbitol, maltitol, mannitol, erythritol, xylitol, dodecanol, tridecanol, tetradecanol, pentadecanol, hexadecanol, heptadecanol, heptadecanol Higher alcohols such as octadecanol, hex
  • the blending amount of the component (C) is preferably 0.3 to 5% by mass, more preferably 0.5 to 3% by mass, based on the entire coating composition.
  • 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 15 to 1.1 is particularly preferred.
  • the coating composition of the present invention may contain a film forming component (D) other than the component (B).
  • D Gelatin, pectin, curdlan, pullulan, gum arabic, xanthan gum, gellan gum, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, agar, chitosan, tamarind seed gum, locust bean gum, polyvinyl Alcohol, ethylcellulose aqueous dispersion, etc. are mentioned. These can be used individually by 1 type or in combination of 2 or more types.
  • components selected from gelatin, pectin, curdlan, pullulan, gum arabic, xanthan gum, gellan gum, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and hydroxypropylcellulose are from the viewpoint of coating properties and combination with component (B). preferable.
  • the blending amount of the component (D) is preferably 0.1 to 7% by mass, more preferably 0.2 to 5% by mass, and still more preferably 0.3 to 3% by mass based on the entire coating composition.
  • 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: 0.1 (1-10) is more preferred, and 1: 0.8-1: 0.2 (1.25-5) is even more preferred.
  • Fine particles may be blended in the coating composition. By blending the fine particles, it is possible to prevent peeling of the coating film due to adhesion between tablets during the coating process.
  • the component (F) include talc, calcium stearate, silicon dioxide, titanium oxide, and the like, which can be used alone or in combination of two or more.
  • the particle diameter of the fine particles is 0.01 to 50 ⁇ m, preferably 0.1 to 20 ⁇ m. As in the case of the lower layer composition, the particle size is measured with a laser diffraction particle size distribution analyzer (dry measurement).
  • the blending amount of the component (F) is preferably 0.05 to 7% by mass, more preferably 0.1 to 5% by mass, and still more preferably 0.3 to 3% by mass based on the entire coating composition.
  • the said coating composition does not contain bivalent metal ions, such as a copper ion, barium ion, and calcium ion. This is because the alginate is cross-linked and gelled, and the coating property is deteriorated. In other words, when monovalent alginate is reacted with a divalent cation to crosslink, the dried membrane is insoluble in water, but the viscosity becomes too high due to gelation, so a fine liquid spray and on the tablet It becomes difficult to spread. As a result, it is difficult to form a uniform film, the appearance is deteriorated, and the elution property 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 still more preferably 0.1 mol or less with respect to 1 mol of the alginate monomer.
  • the above-mentioned coating composition can be blended with a component usually used in a coating composition singly or in appropriate amounts.
  • a component usually used in a coating composition singly or in appropriate amounts.
  • optional components include antifoaming agents and coloring agents.
  • antifoaming agent examples include glycerin fatty acid ester, dimethylpolysiloxane, dimethylpolysiloxane / silicon dioxide mixture, hydrous silicon dioxide, silicon dioxide and the like, and these may be used alone or in combination of two or more. it can.
  • colorant examples include asenyakutannin powder, turmeric extract, yellow ferric oxide, orange essence, brown iron oxide, carbon black, caramel, carmine, carotene solution, ⁇ -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 include sodium hydroxide, copper chlorofin sodium, copper chlorophyll, green leaf extract, 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 in the range of 1 to 98% by mass, preferably 50 to 98% by mass, and more preferably 70 to 96% by mass with respect to the entire coating composition.
  • the thickness of the enteric coating layer is not particularly limited, but is preferably 5 to 1,000 ⁇ m, more preferably 10 to 500 ⁇ m.
  • the amount of the enteric coating layer attached is preferably 1.5 to 60 mg / 300 mg (0.5 to 20% by mass) with respect to 300 mg of the uncoated tablet, and preferably 3 to 45 mg / 300 mg (1 It is more preferable that the content be ⁇ 15% by mass.
  • the content is preferably 10 to 60% by mass, more preferably 15 to 50% by mass.
  • the thickness of the enteric coating layer and the adhesion amount By setting the thickness of the enteric coating layer and the adhesion amount to be equal to or more than the lower limit of the above range, a preparation excellent in elution suppression ability under acidic conditions can be obtained. On the other hand, when the amount of the enteric coating layer deposited is not more than the upper limit of the above range, it can be kept 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 is within the appropriate range described above.
  • the method for forming the enteric coating layer is not particularly limited, and a known method can be adopted.
  • a method of forming a film on the surface of the object to be coated by spraying a predetermined coating solution on the object to be coated on which the lower layer is formed and drying by heating is exemplified.
  • the coating solution can be appropriately 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 a dry air volume of 1 m 3 / min.
  • 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 is 0.1 to 20% by mass, particularly 0.5 to 5% by mass.
  • the coating machine is not particularly limited, and a pan coating machine, a fluidized bed coating machine, a rolling coating machine or 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.
  • a shellac coating film and a hardened oil / fat coating film can be formed.
  • the outermost layer can be formed using the (D) film-forming component on the outside of the enteric coating layer as necessary. Thereby, an external appearance, mouthfeel, and a taste can be changed.
  • component (D) gelatin, pectin, curdlan, pullulan, gum arabic, xanthan gum, gellan gum, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, agar, chitosan, tamarind seed gum, locust bean gum, polyvinyl alcohol, Examples thereof include an aqueous ethyl cellulose dispersion. These can be used individually by 1 type or in combination of 2 or more types.
  • components selected from gelatin, pectin, curdlan, pullulan, gum arabic, xanthan gum, gellan gum, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and hydroxypropylcellulose are preferable from the viewpoint of coating properties.
  • the thickness of the outermost layer is not particularly limited, but is preferably 1 to 200 ⁇ m, more preferably 2 to 100 ⁇ m.
  • the amount of the outermost layer is preferably 0.6 to 10.5 mg / 300 mg (0.2 to 3.5% by mass) with respect to 300 mg of the uncoated tablet, 1.5 to 7 More preferably, it is 5 mg / 300 mg (0.5 to 2.5% by mass).
  • the content is preferably 1 to 30% by mass, more preferably 2 to 25% by mass.
  • the above outermost layer composition may contain an organic solvent such as water and ethanol as long as the effects of the present invention are not impaired.
  • the amount of the solvent in the outermost layer composition 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 with respect to the entire outermost layer composition. .
  • the method for forming the outermost layer is not particularly limited, and a known method can be adopted.
  • a method of forming a film on the surface of the object to be coated by spraying a predetermined coating solution on the object to be coated on which the lower layer and the enteric coating layer are formed and drying by heating is exemplified.
  • the coating solution can be appropriately 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 a dry air volume of 1 m 3 / min.
  • 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 is 0.1 to 20% by mass, particularly 0.5 to 5% by mass.
  • the coating machine is not particularly limited, and a pan coating machine, a fluidized bed coating machine, a rolling coating machine or the like can be used.
  • the coating formulation of this invention sprays the solution containing the high molecular compound whose viscosity in 25 degreeC of (A) 6 mass% aqueous solution is less than 300 mPa * s on to-be-coated object, A step of forming a lower layer by drying, a step of spraying a solution containing (B) an alginate and (C) a plasticizer on the outside of the lower layer, and forming an enteric coating layer by drying, and as required Accordingly, it can be produced by spraying a solution containing the film-forming component (D) and drying it to form the outermost layer.
  • the details of each step are as described above, but the composition of the coating solution to be used, the coating conditions, and the like can be appropriately set within a range not impairing the effects of the present invention, and are not particularly limited.
  • the coating solution for forming each of the lower layer, the enteric coating layer and, if necessary, the outermost layer can be obtained by mixing the above-described essential components. Then, by using each of the above coating solutions, a coating preparation having both good enteric properties and excellent storage stability by sequentially forming a lower layer, an enteric coating layer and, if necessary, an outermost layer on the object to be coated Can get. Moreover, since the coating solution of each layer uses water as a solvent, a water-soluble film is formed respectively.
  • the enteric coating layer formed from the above coating composition contains the component (B), but as described above, the aqueous alginate 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 with hydrogen ions to form alginic acid to form an insoluble film, and further, it dissolves in neutral to alkaline conditions.
  • the enteric coating layer formed from the above coating composition is enteric, that is, has the property of being “dissolvable in the intestine without being dissolved in the stomach and allowing the article to be coated to reach the intestine”.
  • An enteric coating preparation in which the coating film is enteric is obtained.
  • a lower layer containing the 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 over time. It can suppress as much as possible that the elution suppression property under acidic condition falls, and the storage stability of a coating formulation can be improved significantly.
  • Lactoferrin Morinaga Milk Industry Hihatsu Extract Powder: Maruzen Pharmaceutical Co., Ltd.
  • Lactose "Lactose granule” manufactured by Freund Sangyo Co., Ltd.
  • Crystalline cellulose “Theolas FD-101” manufactured by Asahi Kasei Chemicals Corporation Sodium carboxymethyl cellulose: Nichirin Chemical Industries, “ECC-FA” 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
  • a coating solution for forming a lower layer, an enteric coating layer, and an outermost layer having the compositions shown in Tables 2 to 4 below was prepared by the following procedure.
  • 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).
  • Conditions for coating each layer are as follows.
  • the coating preparation obtained above was evaluated for entericity by the following procedure immediately after coating and after being stored for 4 months under the conditions of 50 ° C. and 75% RH. The storage stability was confirmed by comparison. Moreover, the external appearance (coating property) of the preparation immediately after coating was evaluated.
  • Pectin Dainippon Pharmaceutical Co., Ltd., “Classic AF701” Polyvinyl alcohol: manufactured by Nippon Synthetic Chemical Co., Ltd., “Polyvinyl alcohol EG-22P” Gum arabic: Made by Nippon Powder Chemical Co., Ltd., “Gum arabic” Hydroxypropyl cellulose: Hydroxypropyl cellulose: Nippon Soda Co., Ltd., “HPC-SSL” Pullulan: “Pullulan” manufactured by Hayashibara Co., Ltd. Sucrose: Dainippon Meiji Sugar Co., “Sucrose” [Enteric coating layer] Glycerin: “Glycerin (food additive)” manufactured by Sakamoto Pharmaceutical Co., Ltd.
  • Silica fine silicon dioxide
  • Talc “Crown Talc PP” manufactured by Matsumura Sangyo Co., Ltd.
  • Hydroxypropyl methylcellulose “Metroze SE-06” manufactured by Shin-Etsu Chemical Co., Ltd.

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Abstract

Provided are: a coated preparation which cannot be dissolved in the stomach but can be dissolved in the intestine to ensure a coated active ingredient to reach the intestine, and can be prevented expeditiously from being deteriorated over time, and has excellent storage stability; and a method for producing the coated preparation. A coated preparation comprising: a substance to be coated; an under layer which is formed on the substance and contains a polymeric compound (A) having such a property that an aqueous 6 mass% solution has a viscosity of less than 300 mPa·s at 25°C; and an enteric coating layer which is formed on the under layer and contains an alginate salt (B) and a plasticizer (C).

Description

コーティング製剤及びその製造方法Coating preparation and method for producing the same
　本発明は、食品、医薬品等として使用されるコーティング製剤及びその製造方法に関するものである。 The present invention relates to a coating preparation used as a food, a medicine and the like and a method for producing the same.
　乳酸菌や酵素等のタンパク質の機能成分のように、胃での分解を防ぎ、構造を維持して腸まで届けることにより高い機能性を出す有効成分があり、胃で溶けず腸で溶解し、有効成分を腸に到達させる腸溶性の製剤が求められている。 Like active ingredients of proteins such as lactic acid bacteria and enzymes, there are active ingredients that prevent degradation in the stomach and maintain high structure by delivering to the intestine, and dissolve in the intestine without being dissolved in the stomach. There is a need for enteric preparations that allow the ingredients to reach the intestines.
　有効成分を腸まで到達させるための保護膜としては、胃の中のｐＨ条件(酸性)で溶解せず、小腸のｐＨ条件(中性～アルカリ性)で溶解する成分、例えば、メタクリル酸系高分子化合物、シェラック、ツェイン等が一般的である。 As a protective film for reaching the intestines to the active ingredient, ingredients that do not dissolve under the pH conditions (acidic) in the stomach but dissolve under the pH conditions (neutral to alkaline) of the small intestine, such as methacrylic acid polymers Compounds, shellac, zein and the like are common.
　しかしながら、メタクリル酸系高分子化合物は医薬品用途に限られ、食品には用いることができない。一方、シェラック、ツェインは食品用途にも用いられるが、有機溶剤を用いて噴霧する方法が一般的である。食品用途でも環境を配慮した、水を用いたコーティングができる水溶性膜剤の利用が望まれていた。 However, methacrylic acid polymer compounds are limited to pharmaceutical use and cannot be used for food. On the other hand, shellac and zein are also used for food applications, but spraying using an organic solvent is common. The use of a water-soluble film agent capable of coating with water in consideration of the environment for food applications has been desired.
　なお、本発明に関連する先行技術文献としては下記のものが挙げられる。 In addition, the following are mentioned as prior art documents relevant to the present invention.
特開２００２－１９３７９２号公報JP 2002-193792 A
　本発明は、上記事情に鑑みなされたものであり、胃で溶けず腸で溶解し、コーティングされた有効成分をより確実に腸へと到達させることができるだけでなく、経時劣化を可及的に抑制し得、保存安定性にも優れるコーティング製剤及びその製造方法を提供することを目的とする。 The present invention has been made in view of the above circumstances, and it is possible not only to dissolve in the stomach but to dissolve in the intestine, and to ensure that the coated active ingredient reaches the intestine more reliably, and to prevent deterioration over time as much as possible. It aims at providing the coating formulation which can be suppressed, and is excellent also in storage stability, and its manufacturing method.
　本発明者らは、先に環境を配慮した、水を溶剤として用いるアルギン酸塩腸溶性コーティング製剤を提案した（特願２０１３－０４６６９７号）。このコーティングを施した腸溶性製剤は、コーティング直後の腸溶性（酸性下での溶出抑制、中性下での溶出性）が非常に良好である等の利点を有するものである。しかし、その後の更なる検討において、コーティング膜の外観には変化がないにもかかわらず、時間の経過に伴い酸性下における溶出抑制性が低下する場合があることがわかった。その原因は明らかではないが、コーティング膜の外観に変化がないにもかかわらず、溶出抑制性が低下していることから、非常に微細な構造変化が起こっていることによるものと推測される。 The present inventors previously proposed an alginate enteric coating preparation using water as a solvent in consideration of the environment (Japanese Patent Application No. 2013-046697). The enteric preparation provided with this coating has advantages such as very good entericity immediately after coating (elution suppression under acidic conditions, dissolution under neutral conditions). However, in further studies thereafter, it has been found that the elution inhibition property under acidic conditions may decrease over time even though the appearance of the coating film does not change. The cause is not clear, but it is presumed to be that a very fine structural change has occurred since the elution suppression property has decreased despite the fact that there is no change in the appearance of the coating film.
　そこで、本発明者らは、更に鋭意検討を行った結果、この微細な構造変化に対し、腸溶性コーティング膜の下層となるプレコーティングを施したところ、意外にも経時による酸性下での溶出抑制性低下を改善できることを見出した。 Therefore, as a result of further intensive studies, the inventors applied a pre-coating as the lower layer of the enteric coating film for this fine structural change, and surprisingly, suppression of elution under acidic conditions over time. It was found that the deterioration of the property can be improved.
　腸溶性コーティング膜に対するプレコーティングは、腸溶性コーティング膜と錠剤との相溶性の悪さに起因する膜の剥がれを改善するために一般的に実施されるものであるが、本発明者らは、当該プレコーティングが上記アルギン酸塩を用いた腸溶性コーティング膜を経時の劣化から保護する機能を発揮し、コーティング製剤の保存安定性の改善に対して有効であることを新たに見出し、本発明をなすに至ったものである。 The pre-coating with respect to the enteric coating film is generally carried out in order to improve the peeling of the film due to poor compatibility between the enteric coating film and the tablet. The present inventors have newly found that pre-coating has a function of protecting the enteric coating film using the above-mentioned alginate from deterioration over time and is effective for improving the storage stability of the coating preparation. It has come.
　従って、本発明は下記のコーティング製剤及びその製造方法を提供する。
［１］被コーティング物と、その上に形成された（Ａ）６質量％水溶液の２５℃での粘度が３００ｍＰａ・ｓ未満である高分子化合物を含む下層と、該下層上に形成された（Ｂ）アルギン酸塩と（Ｃ）可塑剤とを含む腸溶性コーティング層とを有することを特徴とするコーティング製剤。
［２］（Ａ）成分が、ヒドロキシプロピルメチルセルロース、ペクチン、カードラン、プルラン、ヒドロキシプロピルセルロース、ポリビニルアルコール、及びアラビアガムからなる群より選ばれる［１］記載のコーティング製剤。
［３］（Ａ）成分が、ヒドロキシプロピルメチルセルロースである［２］記載のコーティング製剤。
［４］（Ｂ）成分が、（Ｂ－１）１質量％水溶液の２０℃での粘度が５０ｍＰａ・ｓ以上のアルギン酸塩である［１］～［３］のいずれか１項記載のコーティング製剤。
［５］更に、（Ｂ－２）１質量％水溶液の２０℃での粘度が５０ｍＰａ・ｓ未満のアルギン酸塩を含む［４］記載のコーティング製剤。
［６］更に、腸溶性コーティング層の外側に（Ｄ）ゼラチン、ペクチン、カードラン、プルラン、アラビアガム、キサンタンガム、ジェランガム、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロースナトリウム、及びヒドロキシプロピルセルロースからなる群より選ばれる高分子化合物を含む最表層を有する［１］～［５］のいずれか１項記載のコーティング製剤。
［７］（Ｄ）成分が、ヒドロキシプロピルメチルセルロースである［６］記載のコーティング製剤。
［８］被コーティング物に、（Ａ）６質量％水溶液の２５℃での粘度が３００ｍＰａ・ｓ未満である高分子化合物を含む溶液を噴霧し、乾燥することにより下層を形成する工程と、該下層の外側に（Ｂ）アルギン酸塩と（Ｃ）可塑剤とを含む溶液を噴霧し、乾燥することにより腸溶性コーティング層を形成する工程とを含むことを特徴とするコーティング製剤の製造方法。
［９］更に、上記腸溶性コーティング層の外側に（Ｄ）ゼラチン、ペクチン、カードラン、プルラン、アラビアガム、キサンタンガム、ジェランガム、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロースナトリウム、及びヒドロキシプロピルセルロースからなる群より選ばれる高分子化合物を含む溶液を噴霧し、乾燥することにより最表層を形成する工程を含む［８］記載のコーティング製剤の製造方法。 Accordingly, the present invention provides the following coating preparation and method for producing the same.
[1] An object to be coated, a lower layer containing a polymer compound having a viscosity of less than 300 mPa · s at 25 ° C. of a 6% by mass aqueous solution (A) formed thereon, and formed on the lower layer ( B) A coating preparation comprising an enteric coating layer containing an alginate and (C) a plasticizer.
[2] The coating preparation according to [1], wherein the component (A) is selected from the group consisting of hydroxypropylmethylcellulose, pectin, curdlan, pullulan, hydroxypropylcellulose, polyvinyl alcohol, and gum arabic.
[3] The coating preparation according to [2], wherein the component (A) is hydroxypropylmethylcellulose.
[4] The coating preparation according to any one of [1] to [3], wherein the component (B) is an alginate having a viscosity at 20 ° C. of a 1% by mass aqueous solution of (B-1) of 50 mPa · s or more. .
[5] The coating preparation according to [4], further comprising (B-2) an alginate having a viscosity at 20 ° C. of a 1 mass% aqueous solution of less than 50 mPa · s.
[6] Further, the outer side of the enteric coating layer (D) is selected from the group consisting of gelatin, pectin, curdlan, pullulan, gum arabic, xanthan gum, gellan gum, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and hydroxypropylcellulose. 6. The coating preparation according to any one of [1] to [5], which has an outermost layer containing a molecular compound.
[7] The coating preparation according to [6], wherein the component (D) is hydroxypropylmethylcellulose.
[8] (A) A step of forming a lower layer by spraying 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 on the object to be coated; And (B) 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.
[9] Further, selected from the group consisting of (D) gelatin, pectin, curdlan, pullulan, gum arabic, xanthan gum, gellan gum, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and hydroxypropylcellulose outside the enteric coating layer. The method for producing a coating preparation according to [8], comprising a step of spraying a solution containing the polymer compound and drying to form an outermost layer.
　本発明のコーティング製剤によれば、胃で溶けず腸で溶解し、コーティングされた有効成分を確実に腸へと到達させることができるだけでなく、長期間保存した場合においても、酸性下における溶出抑制性の低下を可及的に抑制し得、保存安定性にも優れるコーティング製剤を提供することができる。 According to the coating preparation of the present invention, not only does it dissolve in the stomach but dissolves in the intestine, so that the coated active ingredient can surely reach the intestine, and even when stored for a long period of time, it suppresses dissolution under acidic conditions. The coating formulation which can suppress the fall of property as much as possible and is excellent also in storage stability can be provided.
　以下、本発明について詳細に説明する。
　本発明のコーティング製剤は、被コーティング物と、その上に形成された下層と、該下層上に形成された腸溶性コーティング層とを有するものであり、被コーティング物と下層との間や、腸溶性コーティング層と最表層との間に、１層以上の中間層を形成することもできる。中でも、被コーティング物と、該被コーティング物の表面に形成された下層と、該下層の表面に形成された腸溶性コーティング層とを有するものが好ましい。本発明では、腸溶性品質に影響を及ぼさない範囲で、必要に応じて腸溶性コーティング層の外側に最表層を形成することができる。なお、本発明において「腸溶性」とは、機能性成分を腸まで届ける剤のことをいう。日本薬局法の溶出試験法の方法に準じて試験を行い、胃液相当の溶出試験液（ｐＨ１．２）にて、２時間で溶出率５０％未満（好適には３０％以下）、腸液相当の溶出試験液（ｐＨ６．８）で、２時間で溶出率７０％以上をいう。 Hereinafter, the present invention will be described in detail.
The coating preparation of the present invention has an object to be coated, a lower layer formed thereon, and an enteric coating layer formed on the lower layer. One or more intermediate layers may be formed between the soluble coating layer and the outermost layer. Among them, those having a coating object, a lower layer formed on the surface of the coating object, 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 on the outer side of the enteric coating layer as necessary, as long as the enteric quality is not affected. In the present invention, “enteric” refers to an agent that delivers a functional component to the intestine. The test was conducted according to the method of dissolution test method of Japanese Pharmacy Method, and dissolution rate was less than 50% (preferably 30% or less) in 2 hours in dissolution test solution (pH 1.2) corresponding to gastric juice. Dissolution rate of 70% or more in 2 hours with dissolution test solution (pH 6.8).
（Ｉ）被コーティング物
　本発明において、被コーティング物は、特に限定されるものではなく、食品、医薬品等の有効成分等が挙げられる。例えば、乳酸菌、システイン、鉄、抗体やラクトフェリン等のタンパク質、ペプチド、ＡＴＰ－２Ｎａ等が挙げられ、これらは１種単独で又は２種以上を適宜組み合わせて用いることができる。中でも、タンパク質等の高分子量成分や水不溶性の成分に好適である。 (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. Examples include lactic acid bacteria, cysteine, iron, proteins such as antibodies and lactoferrin, peptides, ATP-2Na, and the like, and these can be used alone or in combination of two or more. Among them, it is suitable for high molecular weight components such as proteins and water insoluble components.
　被コーティング物の形や、剤型は特に限定されず、錠剤、散剤、細粒剤、顆粒剤等特に限定されない。錠剤は単層でも二層以上でもよい。この中でも、腸溶性をより発揮する点から、錠剤とすることが好ましい。錠剤の寸法は特に限定されず、錠剤の取り扱いやすさと嚥下性の観点から、錠剤の径として５～１４ｍｍφが好ましく、７～１２ｍｍφがより好ましい。また、１錠あたりの錠剤質量としては１５０～７００ｍｇ程度が適切である。 The shape and dosage form of the object to be coated are not particularly limited, and there are no particular limitations on tablets, powders, fine granules, granules and the like. The tablet may be a single layer or two or more layers. Among these, it is preferable to set it as a tablet from the point which exhibits enteric property more. The size of the tablet is not particularly limited, and the tablet diameter is preferably 5 to 14 mmφ and more preferably 7 to 12 mmφ from the viewpoint of easy handling and swallowability. The tablet mass per tablet is suitably about 150 to 700 mg.
（ＩＩ）下層
　本発明の下層は、後述するアルギン酸塩を含む腸溶性コーティング層に先立って形成される層であり、例えば、被コーティング物の表面に形成される層である。本発明では、被コーティング物と腸溶性コーティング層との間に下層を形成することにより、保存中における酸性下での溶出抑制効果の経時的低下を防ぐことができる。これにより腸溶性コーティング層を形成したコーティング製剤の保存安定性（酸性下での溶出抑制性）を著しく改善することができる。以下、下層について詳細に説明する。 (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 object to be coated and the enteric coating layer, it is possible to prevent a temporal decrease in the elution suppression effect under acidity during storage. Thereby, the storage stability (elution suppression property under acidic conditions) of the coating preparation in which the enteric coating layer is formed can be remarkably improved. Hereinafter, the lower layer will be described in detail.
　下層は、（Ａ）６質量％水溶液の２５℃での粘度が３００ｍＰａ・ｓ未満である高分子化合物を含有するものである。上記（Ａ）成分は、特に制限されるものではないが、具体例として、ヒドロキシプロピルメチルセルロース、ペクチン、カードラン、プルラン、ヒドロキシプロピルセルロース、ポリビニルアルコール、及びアラビアガム等を例示することができ、１種単独で又は２種以上を適宜組み合わせて用いることができる。本発明では、特にヒドロキシプロピルメチルセルロースを好適に使用することができる。 The lower layer contains (A) a polymer compound whose viscosity at 25 ° C. in a 6% by mass aqueous solution is less than 300 mPa · s. The component (A) is not particularly limited, and specific examples include hydroxypropylmethylcellulose, pectin, curdlan, pullulan, hydroxypropylcellulose, polyvinyl alcohol, and gum arabic. One species can be used alone, or two or more species can be used in appropriate combination. In the present invention, hydroxypropylmethylcellulose can be particularly preferably used.
　上記（Ａ）成分の配合量は、特に制限されないが、プレコーティング組成物（下層用組成物）全体に対して、好ましくは１～１０質量％、より好ましくは３～８質量％である。配合量を上記範囲の下限以上とすることで製造時間を適切な時間内におさめることができる。一方、配合量を上記範囲の上限以下とすることで、コーティング液の調製やコーティング液噴霧に適した粘度におさめることができる。 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 entire precoating composition (lower layer composition). By setting the blending amount to be equal to or higher than the lower limit of the above range, the production time can be kept within an appropriate time. On the other hand, by setting the blending amount to be equal to or less than the upper limit of the above range, the viscosity suitable for preparation of coating liquid and spraying of coating liquid can be achieved.
　また、上記下層には、必要に応じて（Ｅ）可塑剤を含有してもよい。（Ｅ）成分としては、ショ糖脂肪酸エステル、グリセリン脂肪酸エステル、モノグリセリン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル等の界面活性剤、グリセリン、プロピレングリコール、ポリエチレングリコール等の多価アルコール、ブドウ糖、果糖ブドウ糖液糖、ショ糖等の糖、ソルビトール、マルチトール、マンニトール、エリスリトール、キシリトール等の糖アルコール、ドデカノール、トリデカノール、テトラデカノール、ペンタデカノール、ヘキサデカノール、ヘプタデカノール、オクタデカノール、ヘキサデシルアルコール、イソステアリルアルコール、２－オクチルドデカノール等（好適には炭素数６～２２）の高級アルコール、中鎖脂肪酸エステル（好適には炭素数６～１２）等の油脂が挙げられる。これらは１種単独で又は２種以上を適宜組み合わせて用いることができる。本発明では、可塑効果の観点から、グリセリンを好適に使用することができる。 In addition, the lower layer may contain (E) a plasticizer as necessary. (E) Component includes surfactants such as sucrose fatty acid ester, glycerin fatty acid ester, monoglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyhydric alcohols such as glycerin, propylene glycol, polyethylene glycol, glucose, fructose glucose Sugars such as liquid sugar, sucrose, sugar alcohols such as sorbitol, maltitol, mannitol, erythritol, and xylitol, dodecanol, tridecanol, tetradecanol, pentadecanol, hexadecanol, heptadecanol, octadecanol, hexadecyl Examples include higher alcohols such as alcohol, isostearyl alcohol, 2-octyldodecanol (preferably having 6 to 22 carbon atoms), and oils and fats such as medium chain fatty acid esters (preferably having 6 to 12 carbon atoms).These can be used individually by 1 type or in combination of 2 or more types. In the present invention, glycerin can be preferably used from the viewpoint of the plastic effect.
　上記（Ｅ）成分の配合量は、特に制限されないが、下層用組成物全体に対して、好ましくは０．３～６質量％、より好ましくは０．８～５質量％である。配合量を上記範囲の下限以上とすることで酸性下での溶出抑制効果の経時的低下を防ぐ効果が高くなる。一方、配合量を上記範囲の上限以下とすることで製造時間を適切な時間内におさめることができる。 The amount of the component (E) is not particularly limited, but is preferably 0.3 to 6% by mass, more preferably 0.8 to 5% by mass, based on the entire lower layer composition. By setting the blending amount to be equal to or more than the lower limit of the above range, the effect of preventing a temporal decrease in the elution suppression effect under acidity is enhanced. On the other hand, the production time can be kept within an appropriate time by making the blending amount not more than the upper limit of the above range.
　下層用組成物には、（Ｆ）微粒子を配合してもよい。微粒子を配合することで、コーティング処理時の錠剤同士の付着によるコーティング膜のはがれを防止することができる。（Ｆ）成分としては、タルク、ステアリン酸カルシウム、二酸化ケイ素、酸化チタン等が挙げられ、１種単独で又は２種以上を適宜組み合わせて用いることができる。微粒子の粒径は０．０１～５０μｍであり、０．１～２０μｍが好ましい。なお、粒径の測定はレーザー回折式粒度分布測定装置（乾式測定）にて行う。 The lower layer composition may contain (F) fine particles. By blending the fine particles, it is possible to prevent peeling of the coating film due to adhesion between tablets during the coating process. Examples of the component (F) include talc, calcium stearate, silicon dioxide, titanium oxide, and the like, which can be used alone or in combination of two or more. The particle diameter of the fine particles is 0.01 to 50 μm, preferably 0.1 to 20 μm. The particle size is measured with a laser diffraction particle size distribution measuring device (dry measurement).
　（Ｆ）成分の配合量は、下層用組成物全体の０．０５～７質量％が好ましく、０．１～５質量％がより好ましく、０．３～３質量％が更に好ましい。配合量を上記範囲の下限以上とすることで、上記（Ｆ）成分を配合する効果をより得ることができ、上記範囲の上限を超えて配合すると、成膜性に影響を与えるおそれがある。 The blending amount of the component (F) is preferably 0.05 to 7% by mass, more preferably 0.1 to 5% by mass, and still more preferably 0.3 to 3% by mass with respect to the entire lower layer composition. By setting the blending amount to be equal to or more than the lower limit of the above range, the effect of blending the component (F) can be further obtained, and when blending exceeding the upper limit of the above range, the film forming property may be affected.
　上記の下層用組成物には、水、エタノール等の有機溶剤を含むことができる。下層用組成物中の溶媒配合量は、下層用組成物全体に対して、１～９８質量％の範囲で適宜選定され、５０～９８質量％が好ましく、７０～９６質量％がより好ましい。 The above 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 in the range of 1 to 98% by mass, preferably 50 to 98% by mass, and more preferably 70 to 96% by mass with respect to the entire lower layer composition.
　下層の厚さは特に限定されないが、１～２００μｍが好ましく、２～１００μｍがより好ましい。また、錠剤の場合は、下層の付着量を素錠３００ｍｇに対して０．６～１０．５ｍｇ／３００ｍｇ（０．２～３．５質量％）とすることが好ましく、１．５～７．５ｍｇ／３００ｍｇ（０．５～２．５質量％）とすることがより好ましい。顆粒剤、散剤、粉末の場合は０．５～３０質量％とすることが好ましく、１～２５質量％とすることがより好ましい。下層の厚さ及び付着量を上記範囲の下限以上とすることで、本発明の効果（即ち、時間の経過に伴い酸性下での溶出抑制効果が低下することを防ぐこと）を効果的に得ることができる。一方、下層の厚さ及び付着量を上記範囲の上限以下とすることで、適正な製造時間で錠剤を作製することができる。 The thickness of the lower layer is not particularly limited, but is preferably 1 to 200 μm, more preferably 2 to 100 μm. In the case of tablets, the lower layer adhesion amount is preferably 0.6 to 10.5 mg / 300 mg (0.2 to 3.5% by mass) with respect to 300 mg of uncoated tablet, and 1.5 to 7. More preferably, it is 5 mg / 300 mg (0.5 to 2.5 mass%). In the case of granules, powders, and powders, the content is preferably 0.5 to 30% by mass, and more preferably 1 to 25% by mass. By making the thickness and the amount of adhesion of the lower layer more than the lower limit of the above range, the effect of the present invention (that is, preventing the elution suppression effect under acidic conditions from decreasing with time) is effectively obtained. be able to. On the other hand, a tablet can be produced in an appropriate production time by setting the thickness and adhesion amount of the lower layer to be equal to or lower than the upper limit of the above range.
　上記下層を形成する方法は、特に制限されるものではなく、公知の方法を採用し得る。例えば、被コーティング物に、所定のコーティング溶液を噴霧し、加温により乾燥させることにより、被コーティング物の表面にフィルム化させる方法が挙げられる。コーティング溶液は適宜加温することができ、温度は３０～８０℃が好ましく、乾燥温度は４０～８０℃が好ましい。コーティング溶液の添加速度は、乾燥風量１ｍ3／ｍｉｎに対し、１～５ｇ／ｍｉｎが好ましい。その他、コーティング溶液に、被コーティング物を浸漬して乾燥させるディップコートの方法をとることも可能である。乾燥はコーティング製剤中の水分量が０．１～２０質量％、特に０．５～５質量％になるまで乾燥させることが好ましい。なお、上記下層は、１層に限られず、必要に応じて複数層形成してもよい。 The method for forming the lower layer is not particularly limited, and a known method can be adopted. For example, a method of forming a film on the surface of the object to be coated by spraying a predetermined coating solution on the object to be coated and drying by heating is exemplified. The coating solution can be appropriately 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 a dry air volume 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 immersed in a coating solution and dried. Drying is preferably performed until the water content in the coating preparation is 0.1 to 20% by mass, particularly 0.5 to 5% by mass. The lower layer is not limited to a single layer, and a plurality of layers may be formed as necessary.
　この場合、コーティング機は特に限定されず、パンコーティング機、流動層コーティング機、転動コーティング機等を用いることができる。 In this case, the coating machine is not particularly limited, and a pan coating machine, a fluidized bed coating machine, a rolling coating machine or the like can be used.
（ＩＩＩ）腸溶性コーティング層
　本発明の腸溶性コーティング層は、上記下層の外側に形成される腸溶性を有する層であり、（Ｂ）アルギン酸塩及び（Ｃ）可塑剤を含有する。 (III) Enteric Coating Layer The enteric coating layer of the present invention is an enteric layer formed on the outside of the lower layer and contains (B) an alginate and (C) a plasticizer.
（Ｂ）アルギン酸塩
　アルギン酸塩としては、ナトリウム塩、カリウム塩、アンモニウム塩等の一価のアルギン酸塩、アルギン酸水溶性塩が好ましい。アルギン酸塩としては、下記の（Ｂ－１）１質量％水溶液の２０℃での粘度が５０ｍＰａ・ｓ以上のもの、（Ｂ－２）１質量％水溶液の２０℃での粘度が５０ｍＰａ・ｓ未満のものが挙げられ、１種単独で又は２種以上を適宜組み合わせて用いることができる。 (B) Alginic acid salt As the alginic acid salt, monovalent alginate such as sodium salt, potassium salt and ammonium salt, and alginic acid water-soluble salt are preferable. As the alginate, the following (B-1) 1% by mass aqueous solution having a viscosity at 20 ° C. of 50 mPa · s or more, (B-2) 1% by mass aqueous solution having a viscosity at 20 ° C. of less than 50 mPa · s: Can be used, and one kind can be used alone, or two or more kinds can be used in appropriate combination.
　（Ｂ－１）１質量％水溶液の２０℃での粘度が５０ｍＰａ・ｓ以上のものとしては、５０ｍＰａ・ｓ以上６００ｍＰａ・ｓ以下のものが好ましく、５０ｍＰａ・ｓ以上４００ｍＰａ・ｓ以下のものがより好ましい。 (B-1) A 1% by weight aqueous solution having a viscosity at 20 ° C. of 50 mPa · s or more is preferably 50 mPa · s or more and 600 mPa · s or less, more preferably 50 mPa · s or more and 400 mPa · s or less. preferable.
　（Ｂ－１）アルギン酸塩を配合する場合は、配合量はコーティング組成物全体の０．１～５質量％が好ましく、０．５～４質量％がより好ましく、１～４質量％の範囲が更に好ましい。配合量を上記範囲の下限以上とすることで、酸性下での溶出抑制能を十分に得ることができ、良好な腸溶性をより得ることができる。一方、上限以下にすることでコーティング液の調製や移送、噴霧に適切な粘度におさめることができる。 (B-1) When an alginate is blended, the blending amount is preferably 0.1 to 5% by weight, more preferably 0.5 to 4% by weight, and more preferably 1 to 4% by weight of the entire coating composition. Further preferred. By setting the blending amount to be equal to or more than the lower limit of the above range, it is possible to sufficiently obtain the ability to suppress elution under acidic conditions and to obtain better enteric properties. On the other hand, by making it below the upper limit, it is possible to keep the viscosity appropriate for the preparation, transfer and spraying of the coating liquid.
　（Ｂ－２）１質量％水溶液の２０℃での粘度が５０ｍＰａ・ｓ未満のアルギン酸塩としては、５ｍＰａ・ｓ以上５０ｍＰａ・ｓ未満のものが好ましく、１０ｍＰａ・ｓ以上５０ｍＰａ・ｓ未満のものがより好ましい。（Ｂ－２）アルギン酸塩としては、アルギン酸ナトリウム塩が好ましい。 (B-2) Alginates having a viscosity of 1% by weight aqueous solution at 20 ° C. of less than 50 mPa · s are preferably from 5 mPa · s to less than 50 mPa · s, and preferably from 10 mPa · s to less than 50 mPa · s. More preferred. (B-2) As the alginate, sodium alginate is preferable.
　（Ｂ－２）アルギン酸塩を配合する場合は、配合量としてはコーティング組成物全体の５質量％以下が好ましく、０．１～４質量％がより好ましく、０．１～２．５質量％の範囲が更に好ましい。配合量を上記範囲の上限以下とすることで、腸溶性が向上し、かつコーティング性が良好となる。 (B-2) When the alginate is blended, the blending amount is preferably 5% by mass or less, more preferably 0.1 to 4% by mass, and more preferably 0.1 to 2.5% by mass of the entire coating composition. A range is more preferred. By making a compounding quantity below the upper limit of the said range, enteric property improves and coating property becomes favorable.
　また、（Ｂ）成分の配合量（即ち、（Ｂ－１）成分及び（Ｂ－２）成分の合計量）は、コーティング組成物全体の０．１～１０質量％であることが好ましい。また、１～７質量％の範囲がより好ましく、１．５～５質量％の範囲が更に好ましい。配合量を上記範囲の上限以下とすることで良好な腸溶性（酸性下での溶出抑制性）を得ることができる。 Further, the blending amount of the component (B) (that is, the total amount of the component (B-1) and the component (B-2)) is preferably 0.1 to 10% by mass of the entire coating composition. Further, the range of 1 to 7% by mass is more preferable, and the range of 1.5 to 5% by mass is more preferable. When the blending amount is not more than the upper limit of the above range, good enteric properties (elution suppression under acidic conditions) can be obtained.
　本発明においては、（Ｂ）アルギン酸塩として、（Ｂ－１）アルギン酸塩を用いることが好ましい。このような一定以上の長さのアルギン酸塩を用いることで、コーティング性がよく、形成されたコーティング膜に高い耐酸性を付与することができる。また、（Ｂ－１）アルギン酸塩と（Ｂ－２）アルギン酸塩とを併用することにより、腸溶性を維持しつつ、コーティング性能をより向上することができる。 In the present invention, it is preferable to use (B-1) alginate as (B) alginate. By using an alginate having 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 in combination, the coating performance can be further improved while maintaining enteric properties.
　上記（Ｂ－１）アルギン酸塩と、（Ｂ－２）アルギン酸塩とのように、粘度の異なる２種のアルギン酸塩を用いるのは、単にコーティング溶液の粘度の調整ではなく、腸溶性及びコーティング性の観点から、２種類のアルギン酸塩を選択したものである。その質量比は（Ｂ－１）：（Ｂ－２）（（Ｂ－１）／（Ｂ－２））は１：５～１０：１（０．２～１０）が好ましく、１：３～５：１（０．３３～５）がより好ましく、１：１．８～３：１（０．５６～３）が更に好ましい。質量比を上記範囲の下限以上とすることで酸性下での皮膜性能がより高くなるため非溶出性が良好となり、上記範囲の上限以下とすることでコーティング性がより良好となるため更に好ましい。 The use of two types of alginate having different viscosities such as (B-1) alginate and (B-2) alginate is not simply the adjustment of the viscosity of the coating solution, but enteric and coating properties. From the viewpoint of the above, two types of alginate 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 (0.33-5) is more preferred, and 1: 1.8-3: 1 (0.56-3) is even more 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, so that the non-eluting property is improved. By setting the mass ratio to be equal to or lower than the upper limit of the above range, the coating property is further improved.
　なお、本発明において、アルギン酸塩の粘度測定は回転式粘度計（ＢＭ型）を用いて行う。粘度が２００ｍＰａ・ｓ未満の粘度はローターＮｏ．１を用い、２００ｍＰａ・ｓ以上１，０００ｍＰａ・ｓ未満の粘度はローターＮｏ．２を用いて、１質量％水溶液を２０℃、３０ｒｐｍの条件にて測定し、６０秒後の値を測定値とする。 In the present invention, the viscosity of the alginate is measured using a rotary viscometer (BM type). Viscosity with a viscosity of less than 200 mPa · s 1 and a viscosity of 200 mPa · s or more and less than 1,000 mPa · s is rotor No. 2 is used to measure a 1% by mass aqueous solution under the conditions of 20 ° C. and 30 rpm, and the value after 60 seconds is taken as the measurement value.
　アルギン酸塩の粘度は、アルギン酸塩の分子量にほぼ比例するものである。例えば上記、（Ｂ－１）の重量平均分子量（Ｍｗ）は８０万以上であり、８０～３００万未満が好ましく、８０～１９０万未満がより好ましい。（Ｂ－２）の重量平均分子量（Ｍｗ）は２０万以上８０万未満であり、３０万以上８０万未満が好ましい。なお、本発明のアルギン酸塩の重量平均分子量（Ｍｗ）のゲルクロマトグラフィーの測定方法を以下に示す。 The viscosity of alginate is almost proportional to the molecular weight of alginate. For example, the weight average molecular weight (Mw) of (B-1) is 800,000 or more, preferably from 80 to less than 3 million, more preferably from 80 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. In addition, the measuring method of the gel chromatography of the weight average molecular weight (Mw) of the alginate of this invention is shown below.
（１）サンプルの調製
　アルギン酸塩濃度が０．１質量％となるように移動相（０．１Ｍ（ｍｏｌ／Ｌ）ＮａＮＯ3水溶液）に溶かしこれをサンプルとする。
　各種分子量の標準品（プルラン：Ｍｗ＝１６６万、Ｍｗ＝３８万、Ｍｗ＝１０万、Ｍｗ＝１．２２万、移動相に０．１質量％濃度で溶解）を用いて検量線を作成する。
（２）ＧＰＣ測定条件
カラム：Ｓｈｏｄｅｘ　ＯＨｐａｋ　ＳＢ－８０６Ｍ　ＨＱ（８ｍｍＩ．Ｄ．×３００ｍｍＬ．，１３μｍ）
移動相：０．１Ｍ（ｍｏｌ／Ｌ）ＮａＮＯ3水溶液
流　量：０．５ｍＬ／ｍｉｎ
温　度：４０℃
注入量：２００μＬ（０．１％　ｉｎ移動相）
検出器：示差屈折率（ＲＩ）検出器
（３）解析方法
　検量線サンプルより検量線式を求め、試料のＧＰＣ分析結果からプルランに換算した重量平均分子量（Ｍｗ）を求める。 (1) Preparation alginate concentration of the sample is to this sample was dissolved in mobile phase so that 0.1 wt% (0.1M (mol / L) NaNO 3 solution).
A calibration curve is prepared using standard products of various molecular weights (pullulan: Mw = 16.6 million, Mw = 380,000, Mw = 100,000, Mw = 12,000, 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）可塑剤
　（Ｃ）可塑剤は、コーティング組成物の表面張力低下や、コーティング層への柔軟性付与を目的として配合する成分である。（Ｃ）成分としては、ショ糖脂肪酸エステル、グリセリン脂肪酸エステル、モノグリセリン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル等の界面活性剤、グリセリン、１，３－ブチレングリコール、プロピレングリコール、ポリエチレングリコール等の多価アルコール、ブドウ糖、果糖ブドウ糖液糖、ショ糖等の糖、ソルビトール、マルチトール、マンニトール、エリスリトール、キシリトール等の糖アルコール、ドデカノール、トリデカノール、テトラデカノール、ペンタデカノール、ヘキサデカノール、ヘプタデカノール、オクタデカノール、ヘキサデシルアルコール、イソステアリルアルコール、２－オクチルドデカノール等（好適には炭素数６～２２）の高級アルコール、中鎖脂肪酸エステル（好適には炭素数６～１２）等の油脂が挙げられる。これらは１種単独で又は２種以上を適宜組み合わせて用いることができる。中でも、コーティング膜の可塑効果の点から、グリセリンが好ましい。 (C) Plasticizer (C) A plasticizer is a component 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, etc., glycerin, 1,3-butylene glycol, propylene glycol, polyethylene glycol and the like Sugars such as monohydric alcohol, glucose, fructose glucose liquid sugar, sucrose, sugar alcohols such as sorbitol, maltitol, mannitol, erythritol, xylitol, dodecanol, tridecanol, tetradecanol, pentadecanol, hexadecanol, heptadecanol, heptadecanol Higher alcohols such as octadecanol, hexadecyl alcohol, isostearyl alcohol, 2-octyldodecanol (preferably having 6 to 22 carbon atoms), medium chain fatty acid esters (preferably having 6 carbon atoms) 12) include oils and fats, and the like. These can be used individually by 1 type or in combination of 2 or more types. Among these, glycerin is preferable from the viewpoint of the plastic effect of the coating film.
　（Ｃ）成分の配合量は、コーティング組成物全体の０．３～５質量％が好ましく、０．５～３質量％がより好ましい。配合量を上記範囲の下限以上とすることで、コーティング時の膜のはがれがより抑制され、上記範囲の上限以下とすることで、コーティング時のベタツキが抑制され、コーティング処理がより容易となるとともに、良好な腸溶性が得られる。 The blending amount of the component (C) is preferably 0.3 to 5% by mass, more preferably 0.5 to 3% by mass, based on the entire coating composition. By making the blending amount 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 making the amount not more than the upper limit of the above range, stickiness at the time of coating is suppressed and the coating treatment becomes easier. Good enteric properties are obtained.
　（Ｃ）／（Ｂ）で表わされる質量比は、０．０５～３．０の範囲が好ましく、０．１～２．０がより好ましく、０．１５～１．５が更に好ましく、０．１５～１．１が特に好ましい。質量比を上記範囲の下限以上とすることで、酸性下での皮膜性能がより高くなり、上限以下とすることでコーティング性がより良好となる。 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 15 to 1.1 is 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 acidity becomes higher, and when it is lower than the upper limit, the coating property becomes better.
　本発明のコーティング組成物には、（Ｂ）成分以外の皮膜形成成分（Ｄ）を配合してもよい。（Ｄ）皮膜形成成分としては、ゼラチン、ペクチン、カードラン、プルラン、アラビアガム、キサンタンガム、ジェランガム、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロースナトリウム、ヒドロキシプロピルセルロース、寒天、キトサン、タマリンドシードガム、ローカストビーンガム、ポリビニルアルコール、エチルセルロース水分散液等が挙げられる。これらは１種単独で又は２種以上を適宜組み合わせて用いることができる。これらの中でも、ゼラチン、ペクチン、カードラン、プルラン、アラビアガム、キサンタンガム、ジェランガム、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロースナトリウム及びヒドロキシプロピルセルロースから選ばれる成分が、コーティング性及び（Ｂ）成分との組み合わせの点から好ましい。 The coating composition of the present invention may contain a film forming component (D) other than the component (B). (D) Gelatin, pectin, curdlan, pullulan, gum arabic, xanthan gum, gellan gum, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, agar, chitosan, tamarind seed gum, locust bean gum, polyvinyl Alcohol, ethylcellulose aqueous dispersion, etc. are mentioned. These can be used individually by 1 type or in combination of 2 or more types. Among these, components selected from gelatin, pectin, curdlan, pullulan, gum arabic, xanthan gum, gellan gum, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and hydroxypropylcellulose are from the viewpoint of coating properties and combination with component (B). preferable.
　（Ｄ）成分の配合量は、コーティング組成物全体の０．１～７質量％が好ましく、０．２～５質量％がより好ましく、０．３～３質量％が更に好ましい。配合量を上記範囲の下限以上とすることで、（Ｄ）成分配合の効果をより得ることができ、上記範囲の上限を超えて配合すると、腸溶性に影響を与えるおそれがある。 The blending amount of the component (D) is preferably 0.1 to 7% by mass, more preferably 0.2 to 5% by mass, and still more preferably 0.3 to 3% by mass based on the entire coating composition. By setting the blending amount to be equal to or more than the lower limit of the above range, the effect of component (D) blending can be further obtained, and when the blending exceeds the upper limit of the above range, entericity may be affected.
　この場合、（Ｂ）：（Ｄ）（（Ｂ）／（Ｄ））で表される含有質量比は、１：３～１：０．０５（０．３３～２０）が好ましく、１：１～１：０．１（１～１０）がより好ましく、１：０．８～１：０．２（１．２５～５）が更に好ましい。この範囲とすることで、コーティング性と外観の美しさを維持した上で、特に酸性下での溶出抑制能がより高い腸溶性能に優れる錠剤を得ることができる。 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: 0.1 (1-10) is more preferred, and 1: 0.8-1: 0.2 (1.25-5) is even more preferred. By setting it as this range, while maintaining the coating property and the beauty of an external appearance, the tablet which is excellent in the enteric performance in which the elution inhibitory ability especially in an acidic condition is higher can be obtained.
　コーティング組成物には、（Ｆ）微粒子を配合してもよい。微粒子を配合することで、コーティング処理時の錠剤同士の付着によるコーティング膜のはがれを防止することができる。（Ｆ）成分としては、タルク、ステアリン酸カルシウム、二酸化ケイ素、酸化チタン等が挙げられ、１種単独で又は２種以上を適宜組み合わせて用いることができる。微粒子の粒径は０．０１～５０μｍであり、０．１～２０μｍが好ましい。なお、下層用組成物の場合と同様、粒径の測定はレーザー回折式粒度分布測定装置（乾式測定）にて行う。 (F) Fine particles may be blended in the coating composition. By blending the fine particles, it is possible to prevent peeling of the coating film due to adhesion between tablets during the coating process. Examples of the component (F) include talc, calcium stearate, silicon dioxide, titanium oxide, and the like, which can be used alone or in combination of two or more. The particle diameter of the fine particles is 0.01 to 50 μm, preferably 0.1 to 20 μm. As in the case of the lower layer composition, the particle size is measured with a laser diffraction particle size distribution analyzer (dry measurement).
　（Ｆ）成分の配合量は、コーティング組成物全体の０．０５～７質量％が好ましく、０．１～５質量％がより好ましく、０．３～３質量％が更に好ましい。配合量を上記範囲の下限以上とすることで、上記（Ｆ）成分を配合する効果をより得ることができ、上記範囲の上限を超えて配合すると、成膜性に影響を与えるおそれがある。 The blending amount of the component (F) is preferably 0.05 to 7% by mass, more preferably 0.1 to 5% by mass, and still more preferably 0.3 to 3% by mass based on the entire coating composition. By setting the blending amount to be equal to or more than the lower limit of the above range, the effect of blending the component (F) can be further obtained, and when blending exceeding the upper limit of the above range, the film forming property may be affected.
　なお、上記コーティング組成物には、銅イオン、バリウムイオン、カルシウムイオン等の二価金属イオンを含まないことが好ましい。これらにより、アルギン酸塩が架橋されてゲル化し、コーティング性が悪くなるからである。つまり、一価アルギン酸塩を二価の陽イオンと反応させ架橋させた場合、乾燥させた膜は水不溶性であるが、ゲル化により粘度が高くなりすぎるため、細かな液の噴霧及び錠剤上での展延性が困難となる。その結果、均一な皮膜形成が困難になり、外観が悪くなる他、溶出性でばらつきが生じる場合がある。二価の金属イオンの許容範囲は、アルギン酸塩のモノマー１モルに対して０．５モル以下が好ましく、０．２５モル以下がより好ましく、０．１モル以下が更に好ましい。 In addition, it is preferable that the said coating composition does not contain bivalent metal ions, such as a copper ion, barium ion, and calcium ion. This is because the alginate is cross-linked and gelled, and the coating property is deteriorated. In other words, when monovalent alginate is reacted with a divalent cation to crosslink, the dried membrane is insoluble in water, but the viscosity becomes too high due to gelation, so a fine liquid spray and on the tablet It becomes difficult to spread. As a result, it is difficult to form a uniform film, the appearance is deteriorated, and the elution property 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 still more preferably 0.1 mol or less with respect to 1 mol of the alginate monomer.
　上記のコーティング組成物には、上記成分の他に、コーティング組成物に通常用いられる成分を１種単独で又は２種以上、適量配合することができる。このような任意成分としては、消泡剤、着色剤等が挙げられる。 In addition to the above-mentioned components, the above-mentioned coating composition can be blended with a component usually used in a coating composition singly or in appropriate amounts. Examples of such optional components include antifoaming agents and coloring agents.
　消泡剤としては、例えば、グリセリン脂肪酸エステル、ジメチルポリシロキサン、ジメチルポリシロキサン・二酸化ケイ素混合物、含水二酸化ケイ素、二酸化ケイ素等が挙げられ、１種単独で又は２種以上を適宜組み合わせて用いることができる。 Examples of the antifoaming agent include glycerin fatty acid ester, dimethylpolysiloxane, dimethylpolysiloxane / silicon dioxide mixture, hydrous silicon dioxide, silicon dioxide and the like, and these may be used alone or in combination of two or more. it can.
　着色剤としては、例えば、アセンヤクタンニン末、ウコン抽出液、黄色三二酸化鉄、オレンジエッセンス、褐色酸化鉄、カーボンブラック、カラメル、カルミン、カロチン液、β－カロテン、カンゾウエキス、金箔、黒酸化鉄、軽質無水ケイ酸、酸化チタン、三二酸化鉄、食用青色１号、食用黄色４号、食用黄色４号アルミニウムレーキ、食用黄色５号、食用赤色２号、食用赤色３号、食用赤色１０２号、水酸化ナトリウム、銅クロロフィンナトリウム、銅クロロフィル、ハダカムギ緑葉抽出エキス、薬用炭、酪酸リボフラビン、リボフラビン、緑茶末、リン酸リボフラビンナトリウム等が挙げられる。 Examples of the colorant include asenyakutannin powder, turmeric extract, yellow ferric oxide, 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 include sodium hydroxide, copper chlorofin sodium, copper chlorophyll, green leaf extract, medicinal charcoal, riboflavin butyrate, riboflavin, green tea powder, and sodium riboflavin phosphate.
　本発明のコーティング組成物には、水、エタノール等の有機溶剤を含むことができる。コーティング組成物中の溶媒配合量は、コーティング組成物全体に対して、１～９８質量％の範囲で適宜選定され、５０～９８質量％が好ましく、７０～９６質量％がより好ましい。 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 in the range of 1 to 98% by mass, preferably 50 to 98% by mass, and more preferably 70 to 96% by mass with respect to the entire coating composition.
　上記腸溶性コーティング層の厚さは特に限定されないが、５～１，０００μｍが好ましく、１０～５００μｍがより好ましい。また、錠剤の場合は、腸溶性コーティング層の付着量を素錠３００ｍｇに対して１．５～６０ｍｇ／３００ｍｇ（０．５～２０質量％）とすることが好ましく、３～４５ｍｇ／３００ｍｇ（１～１５質量％）とすることがより好ましい。顆粒剤、散剤、粉末の場合は１０～６０質量％とすることが好ましく、１５～５０質量％とすることがより好ましい。腸溶性コーティング層の厚さ及び付着量を上記範囲の下限以上とすることで、酸性下での溶出抑制能に優れる製剤を得ることができる。一方、腸溶性コーティング層の付着量を上記範囲の上限以下とすることで、適切な製造時間内におさめることができる。 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 attached is preferably 1.5 to 60 mg / 300 mg (0.5 to 20% by mass) with respect to 300 mg of the uncoated tablet, and preferably 3 to 45 mg / 300 mg (1 It is more preferable that the content be ˜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. By setting the thickness of the enteric coating layer and the adhesion amount to be equal to or more than the lower limit of the above range, a preparation excellent in elution suppression ability under acidic conditions can be obtained. On the other hand, when the amount of the enteric coating layer deposited is not more than the upper limit of the above range, it can be kept within an appropriate production time.
　また、上記下層の厚さと腸溶性コーティング層の厚さの関係は、特に限定せず、それぞれが上述した適切な範囲内に入っていれば問題ない。 Also, 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 is within the appropriate range described above.
　上記腸溶性コーティング層を形成する方法は、特に制限されるものではなく、公知の方法を採用し得る。例えば、下層が形成された被コーティング物に、所定のコーティング溶液を噴霧し、加温により乾燥させることにより、該被コーティング物の表面にフィルム化させる方法が挙げられる。コーティング溶液は適宜加温することができ、温度は３０～８０℃が好ましく、乾燥温度は４０～８０℃が好ましい。コーティング溶液の添加速度は、乾燥風量１ｍ3／ｍｉｎに対し、１～５ｇ／ｍｉｎが好ましい。その他、コーティング溶液に、該被コーティング物を浸漬して乾燥させるディップコートの方法をとることも可能である。乾燥はコーティング製剤中の水分量が０．１～２０質量％、特に０．５～５質量％になるまで乾燥させることが好ましい。 The method for forming the enteric coating layer is not particularly limited, and a known method can be adopted. For example, a method of forming a film on the surface of the object to be coated by spraying a predetermined coating solution on the object to be coated on which the lower layer is formed and drying by heating is exemplified. The coating solution can be appropriately 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 a dry air volume 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 is 0.1 to 20% by mass, particularly 0.5 to 5% by mass.
　この場合、コーティング機は特に限定されず、パンコーティング機、流動層コーティング機、転動コーティング機等を用いることができる。 In this case, the coating machine is not particularly limited, and a pan coating machine, a fluidized bed coating machine, a rolling coating machine or the like can be used.
　なお、上記下層と上記コーティング層との間には、本発明の効果を損なわない範囲で適宜な中間層を形成してもよい。本発明では、例えば、シェラックコーティング膜、硬化油脂コーティング膜を形成することができる。 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 hardened oil / fat coating film can be formed.
（ＩＶ）最表層
　本発明においては、必要に応じて上記腸溶性コーティング層の外側に上記（Ｄ）皮膜形成成分を用いて最表層を形成することもできる。これにより外観、口当たり、味を変化させることができる。（Ｄ）成分としては、ゼラチン、ペクチン、カードラン、プルラン、アラビアガム、キサンタンガム、ジェランガム、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロースナトリウム、ヒドロキシプロピルセルロース、寒天、キトサン、タマリンドシードガム、ローカストビーンガム、ポリビニルアルコール、エチルセルロース水分散液等が挙げられる。これらは１種単独で又は２種以上を適宜組み合わせて用いることができる。これらの中でも、ゼラチン、ペクチン、カードラン、プルラン、アラビアガム、キサンタンガム、ジェランガム、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロースナトリウム及びヒドロキシプロピルセルロースから選ばれる成分が、コーティング性の点から好ましい。 (IV) Outermost layer In the present invention, the outermost layer can be formed using the (D) film-forming component on the outside of the enteric coating layer as necessary. Thereby, an external appearance, mouthfeel, and a taste can be changed. As component (D), gelatin, pectin, curdlan, pullulan, gum arabic, xanthan gum, gellan gum, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, agar, chitosan, tamarind seed gum, locust bean gum, polyvinyl alcohol, Examples thereof include an aqueous ethyl cellulose dispersion. These can be used individually by 1 type or in combination of 2 or more types. Among these, components selected from gelatin, pectin, curdlan, pullulan, gum arabic, xanthan gum, gellan gum, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and hydroxypropylcellulose are preferable from the viewpoint of coating properties.
　上記最表層の厚さは特に限定されないが、１～２００μｍが好ましく、２～１００μｍがより好ましい。また、錠剤の場合は、最表層の付着量を素錠３００ｍｇに対して０．６～１０．５ｍｇ／３００ｍｇ（０．２～３．５質量％）とすることが好ましく、１．５～７．５ｍｇ／３００ｍｇ（０．５～２．５質量％）とすることがより好ましい。顆粒剤、散剤、粉末の場合は１～３０質量％とすることが好ましく、２～２５質量％とすることがより好ましい。最表層の厚さ及び付着量を上記範囲の下限以上とすることで、口当たりや味を変化させることができる。一方、最表層の厚さ及び付着量を上記範囲の上限以下とすることで、製造時間を適切におさめることができる。 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 the outermost layer is preferably 0.6 to 10.5 mg / 300 mg (0.2 to 3.5% by mass) with respect to 300 mg of the uncoated tablet, 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 1 to 30% by mass, more preferably 2 to 25% by mass. By setting the thickness of the outermost layer and the amount of adhesion to the lower limit of the above range, the mouth feel and taste can be changed. On the other hand, the manufacturing time can be appropriately reduced by setting the thickness of the outermost layer and the amount of adhesion to the upper limit of the above range.
　上記の最表層用組成物には、本発明の効果を損なわない範囲で、水、エタノール等の有機溶剤を含むことができる。最表層用組成物中の溶媒配合量は、最表層用組成物全体に対して、１～９８質量％の範囲で適宜選定され、５０～９８質量％が好ましく、７０～９６質量％がより好ましい。 The above outermost layer composition may contain an organic solvent such as water and ethanol as long as the effects of the present invention are not impaired. The amount of the solvent in the outermost layer composition 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 with respect to the entire outermost layer composition. .
　上記最表層を形成する方法は、特に制限されるものではなく、公知の方法を採用し得る。例えば、下層及び腸溶性コーティング層が形成された被コーティング物に、所定のコーティング溶液を噴霧し、加温により乾燥させることにより、該被コーティング物の表面にフィルム化させる方法が挙げられる。コーティング溶液は適宜加温することができ、温度は３０～８０℃が好ましく、乾燥温度は４０～８０℃が好ましい。コーティング溶液の添加速度は、乾燥風量１ｍ3／ｍｉｎに対し、１～５ｇ／ｍｉｎが好ましい。その他、コーティング溶液に、該被コーティング物を浸漬して乾燥させるディップコートの方法をとることも可能である。乾燥はコーティング製剤中の水分量が０．１～２０質量％、特に０．５～５質量％になるまで乾燥させることが好ましい。 The method for forming the outermost layer is not particularly limited, and a known method can be adopted. For example, a method of forming a film on the surface of the object to be coated by spraying a predetermined coating solution on the object to be coated on which the lower layer and the enteric coating layer are formed and drying by heating is exemplified. The coating solution can be appropriately 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 a dry air volume 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 is 0.1 to 20% by mass, particularly 0.5 to 5% by mass.
　この場合、コーティング機は特に限定されず、パンコーティング機、流動層コーティング機、転動コーティング機等を用いることができる。 In this case, the coating machine is not particularly limited, and a pan coating machine, a fluidized bed coating machine, a rolling coating machine or the like can be used.
（Ｖ）コーティング製剤の製造方法
　本発明のコーティング製剤は、被コーティング物に、（Ａ）６質量％水溶液の２５℃での粘度が３００ｍＰａ・ｓ未満である高分子化合物を含む溶液を噴霧し、乾燥することにより下層を形成する工程、該下層の外側に（Ｂ）アルギン酸塩と（Ｃ）可塑剤とを含む溶液を噴霧し、乾燥することにより腸溶性コーティング層を形成する工程、及び必要に応じて、（Ｄ）皮膜形成成分を含む溶液を噴霧し、乾燥することにより最表層を形成する工程を経ることにより製造することができる。各工程の詳細は上記の通りであるが、使用するコーティング溶液の配合やコーティングの条件等は本発明の効果を損なわない範囲で適宜設定することができ、特に制限されるものではない。 (V) Manufacturing method of coating formulation The coating formulation of this invention sprays the solution containing the high molecular compound whose viscosity in 25 degreeC of (A) 6 mass% aqueous solution is less than 300 mPa * s on to-be-coated object, A step of forming a lower layer by drying, a step of spraying a solution containing (B) an alginate and (C) a plasticizer on the outside of the lower layer, and forming an enteric coating layer by drying, and as required Accordingly, it can be produced by spraying a solution containing the film-forming component (D) and drying it to form the outermost layer. The details of each step are as described above, but the composition of the coating solution to be used, the coating conditions, and the like can be appropriately set within a range not impairing the effects of the present invention, and are not particularly limited.
　上記の下層、腸溶性コーティング層、必要に応じて最表層の各層を形成するためのコーティング溶液は上述した必須成分を混合することにより得ることができる。そして、上記の各コーティング溶液を用いて、被コーティング物に下層、腸溶性コーティング層、必要に応じて最表層を順次形成することにより、良好な腸溶性と優れた保存安定性を兼ね備えたコーティング製剤を得ることできる。また、各層のコーティング溶液は溶媒として水を用いているため、それぞれ水溶性膜が形成される。 The coating solution for forming each of the lower layer, the enteric coating layer and, if necessary, the outermost layer can be obtained by mixing the above-described essential components. Then, by using each of the above coating solutions, a coating preparation having both good enteric properties and excellent storage stability by sequentially forming a lower layer, an enteric coating layer and, if necessary, an outermost layer on the object to be coated Can get. Moreover, since the coating solution of each layer uses water as a solvent, a water-soluble film is formed respectively.
　上記のコーティング組成物から形成された腸溶性コーティング層は、上記（Ｂ）成分を含有するが、上述したようにアルギン酸塩水溶液を直接乾燥させて水溶性の膜を形成させている。この水溶性の膜は、酸性下において、一価の陽イオンが水素イオンと置き換わり、アルギン酸へ変化して不溶性の膜を形成し、更に中性～アルカリ性で溶解するという特性を有する。 The enteric coating layer formed from the above coating composition contains the component (B), but as described above, the aqueous alginate 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 with hydrogen ions to form alginic acid to form an insoluble film, and further, it dissolves in neutral to alkaline conditions.
　上記コーティング組成物から形成される腸溶性コーティング層は、腸溶性、つまり「胃で溶けず腸で溶解し、被コーティング物を腸に到達させることができる。」という性質を有するものである。コーティング膜が腸溶性である腸溶性コーティング製剤が得られる。 The enteric coating layer formed from the above coating composition is enteric, that is, has the property of being “dissolvable in the intestine without being dissolved in the stomach and allowing the article to be coated to reach the intestine”. An enteric coating preparation in which the coating film is enteric is obtained.
　更に、腸溶性コーティング層の下には上記（Ａ）成分を含む下層が形成されており、該下層が腸溶性コーティング層を経時の劣化から保護する土台として機能するため、時間の経過に伴って酸性下での溶出抑制性が低下することを可及的に抑制することができ、コーティング製剤の保存安定性を著しく改善することができる。 Further, a lower layer containing the 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 over time. It can suppress as much as possible that the elution suppression property under acidic condition falls, and the storage stability of a coating formulation can be improved significantly.
　また、必要に応じ、上記腸溶性コーティング層の外側に更に（Ｄ）成分を含む最表層を形成することにより、味、口当たり、外観に変化をもたらすことができる。 Further, if necessary, by forming the outermost layer containing the component (D) on the outside of the enteric coating layer, changes in taste, mouthfeel and appearance can be brought about.
　以下、実施例及び比較例を示し、本発明を具体的に説明するが、本発明は下記の実施例に制限されるものではない。なお、下記の例において特に明記のない場合は、組成の「％」は質量％、比率は質量比を示す。 Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example. In the following examples, unless otherwise specified, “%” in the composition represents mass%, and the ratio represents mass ratio.
　　［実施例１～１５、比較例１、２］
　まず、コーティング製剤を作製するにあたって、以下の素錠を調製した。
[素錠]
　下記原料を混合し、打錠機を用いて錠剤（３００ｍｇ、φ９．０ｍｍ、厚み５ｍｍ）になるよう打錠を行った。
＜素錠組成＞
ラクトフェリン：１，１５６ｇ
ヒハツエキス末：５００ｇ
乳糖：４９２．５ｇ
結晶セルロース：７３１．５ｇ
カルボキシメチルセルロースナトリウム：６０ｇ
ショ糖脂肪酸エステル：３０ｇ
微粒二酸化ケイ素：３０ｇ [Examples 1 to 15, Comparative Examples 1 and 2]
First, in preparing a coating preparation, the following uncoated tablets were prepared.
[Uncoated tablet]
The following raw materials were mixed and compressed into tablets (300 mg, φ9.0 mm, thickness 5 mm) using a tableting machine.
<Uncoated tablet composition>
Lactoferrin: 1,156g
Hihatsu extract powder: 500g
Lactose: 492.5g
Crystalline cellulose: 731.5 g
Sodium carboxymethylcellulose: 60g
Sucrose fatty acid ester: 30 g
Fine silicon dioxide: 30g
　上記の各成分の詳細は以下の通りである。
ラクトフェリン：森永乳業（株）製
ヒハツエキス末：丸善製薬（株）製、「ヒハツエキス末ＭＦ」
乳糖：フロイント産業（株）製、「乳糖グラニュー」
結晶セルロース：旭化成ケミカルズ（株）製、「セオラスＦＤ－１０１」
カルボキシメチルセルロースナトリウム：ニチリン化学工業（株）製、「ＥＣＣ－ＦＡ」
ショ糖脂肪酸エステル：三菱化学フーズ（株）製、「リョートーシュガーエステルＳ－３７０Ｆ」
微粒二酸化ケイ素：ＤＳＬジャパン（株）製、「カープレックスＦＰＳ－５００」 Details of each of the above components are as follows.
Lactoferrin: Morinaga Milk Industry Hihatsu Extract Powder: Maruzen Pharmaceutical Co., Ltd., Hihatsu Extract Powder MF
Lactose: "Lactose granule" manufactured by Freund Sangyo Co., Ltd.
Crystalline cellulose: “Theolas FD-101” manufactured by Asahi Kasei Chemicals Corporation
Sodium carboxymethyl cellulose: Nichirin Chemical Industries, “ECC-FA”
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
　次に、下記表２～４に示す組成の下層、腸溶性コーティング層、及び最表層を形成するためのコーティング溶液を下記の手順で調製した。 Next, a coating solution for forming a lower layer, an enteric coating layer, and an outermost layer having the compositions shown in Tables 2 to 4 below was prepared by the following procedure.
［下層用のコーティング溶液の調製］
　（Ａ）成分及び（Ｅ）成分をそれぞれ、室温にて水に均一溶解させた。 [Preparation of coating solution for lower layer]
Each of the component (A) and the component (E) was uniformly dissolved in water at room temperature.
［腸溶性コーティング層用のコーティング溶液の調製］
　（Ｂ）成分及び（Ｃ）成分をそれぞれ、水に分散させた後加温し均一溶解させ、溶解した液を混合し、他成分を加え、更に混合攪拌した。 [Preparation of coating solution for enteric coating layer]
Each of the component (B) and the component (C) was dispersed in water, heated and uniformly dissolved, the dissolved liquid was mixed, the other components were added, and the mixture was further stirred.
［最表層用のコーティング溶液の調製］
　（Ｄ）成分を室温にて水に均一溶解させた。 [Preparation of coating solution for outermost layer]
(D) The component was uniformly dissolved in water at room temperature.
　上記で作製した素錠の表面に、上記で調製した各コーティング溶液を用いて下層、腸溶性コーティング層、及び必要に応じて最表層を順次形成し、コーティング製剤（錠剤）を調製した。各層をコーティングした際の条件は以下の通りである。 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). Conditions for coating each layer are as follows.
［コーティング］
　下層、腸溶性コーティング層及び最表層をコーティングする際の条件はそれぞれ以下の通りである。 [coating]
Conditions for coating the lower layer, the enteric coating layer and the outermost layer are as follows.
〔下層〕
　コーティング機（パウレック製　パウレックコーターＰＲＣ－０５）を用い、素剤２００ｇに対し、コーティング溶液５０ｇを平均２ｍｌ／ｍｉｎで噴霧し、品温約５０℃でコーティングを施した。噴霧後約４５℃で２ｍｉｎ間乾燥させ、コーティング製剤（錠剤）を得た。コーティング膜の厚さは５～５０μｍの範囲内であった。 〔Underlayer〕
Using a coating machine (Paurec Coater PRC-05 manufactured by Paulek), 50 g of the coating solution was sprayed at an average of 2 ml / min to 200 g of the base material, 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 coating preparation (tablet). The thickness of the coating film was in the range of 5 to 50 μm.
〔腸溶性コーティング層〕
　コーティング機（パウレック製　パウレックコーターＰＲＣ－０５）を用い、素剤２００ｇに対し、コーティング溶液（実施例及び比較例１：１５０ｇ、比較例２：２０４ｇ）を平均２ｍｌ／ｍｉｎで噴霧し、品温約５０℃でコーティングを施した。噴霧後約４５℃で２ｍｉｎ間乾燥させ、コーティング製剤（錠剤）を得た。コーティング膜の厚さは２０～２００μｍの範囲内であった。 [Enteric coating layer]
Using a coating machine (Powrec Coater PRC-05, manufactured by Paulek), 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. The coating was applied at about 50 ° C. After spraying, it 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 to 200 μm.
〔最表層〕
　コーティング機（パウレック製　パウレックコーターＰＲＣ－０５）を用い、素剤２００ｇに対し、コーティング溶液５０ｇを平均２ｍｌ／ｍｉｎで噴霧し、品温約５０℃でコーティングを施した。噴霧後約４５℃で２ｍｉｎ間乾燥させ、コーティング製剤（錠剤）を得た。コーティング膜の厚さは５～５０μｍの範囲内であった。 [Outermost layer]
Using a coating machine (Paurec Coater PRC-05 manufactured by Paulek), 50 g of the coating solution was sprayed at an average of 2 ml / min to 200 g of the base material, 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 coating preparation (tablet). The thickness of the coating film was in the range of 5 to 50 μm.
　上記で得たコーティング製剤は、コーティング直後、及び５０℃、７５％ＲＨの条件で４ヶ月保管した後のそれぞれにおいて下記の手順で腸溶性を評価し、両者の腸溶性の保存前後における評価結果を比較することにより保存安定性を確認した。また、コーティング直後の製剤の外観（コーティング性）を評価した。 The coating preparation obtained above was evaluated for entericity by the following procedure immediately after coating and after being stored for 4 months under the conditions of 50 ° C. and 75% RH. The storage stability was confirmed by comparison. Moreover, the external appearance (coating property) of the preparation immediately after coating was evaluated.
［酸性ｐＨ溶出性試験］
　日局１液（ｐＨ１．２）を用い、日局一般試験法（パドル法）に則り、溶出試験を行った。
◎：２時間で溶出性１０％未満
○：２時間で溶出性１０％以上２０％未満
△：２時間で溶出性２０％以上４０％未満
×：２時間で溶出性４０％以上 [Acid pH dissolution test]
The dissolution test was conducted using JP 1 liquid (pH 1.2) according to the JP General Test Method (Paddle Method).
◎: Less than 10% dissolution in 2 hours ○: 10% to less than 20% dissolution in 2 hours △: More than 20% but less than 40% dissolution in 2 hours ×: More than 40% dissolution in 2 hours
［中性～アルカリｐＨ溶出性試験］
　日局２液（ｐＨ６．８）を用い、日局一般試験法（パドル法）に則り、溶出試験を行った。
○：２時間で溶出性７０％以上
△：２時間で溶出性３０％以上７０％未満
×：２時間で溶出性３０％未満
　なお、上記［酸性ｐＨ溶出性試験］で、「△」、「○」又は「◎」、かつ上記［中性～アルカリｐＨ溶出性試験］で「○」の場合を「腸溶性」とした。 [Neutral to alkaline pH dissolution test]
Dissolution test was conducted using JP 2 liquid (pH 6.8) according to JP General Test Method (Paddle Method).
○: Dissolution of 70% or more in 2 hours Δ: Dissolution of 30% or more and less than 70% in 2 hours ×: Dissolution of less than 30% in 2 hours In the above [Acid pH dissolution test], “△” “O” or “◎” and “O” in the above [Neutral to Alkaline pH dissolution test] were defined as “enteric”.
［外観の評価］
　コーティング直後の製剤（錠剤）の表面を目視で観察し、下記評価基準に従って外観を評価した。
◎：均一にコーティングがなされ、欠け、はがれが見られず、コーティング表面にツヤがある。
○：均一にコーティングがなされ、欠け、はがれがほとんど見られないが、ややコーティング表面に荒れがある。
△：一部の錠剤にコーティングの欠けが見られる。
×：錠剤のほとんどにコーティングの欠けやはがれが見られる。 [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.
A: The coating is made uniformly, no chipping or peeling is observed, and the coating surface is glossy.
○: The coating was made uniformly, and almost no chipping or peeling was observed, but the coating surface was somewhat rough.
(Triangle | delta): The chip of a coating is seen in a part of tablet.
×: Most of the tablets have chipped or peeled coating.
　実施例及び比較例において使用した原料の詳細は、以下の通りである。なお、（Ｂ）成分のアルギン酸塩の詳細については別途表１に示した。
〔下層〕
ヒドロキシプロピルメチルセルロース：信越化学工業（株）製、「メトローズＳＥ－０６」
ペクチン：大日本製薬（株）製、「クラシックＡＦ７０１」
ポリビニルアルコール：日本合成化学（株）製、「ポリビニルアルコール　ＥＧ－２２Ｐ」
アラビアガム：日本粉末薬品（株）製、「アラビアガム」
ヒドロキシプロピルセルロース：ヒドロキシプロピルセルロース：日本曹達（株）製、「ＨＰＣ－ＳＳＬ」
プルラン：（株）林原製、「プルラン」
ショ糖：大日本明治製糖（株）製、「ショ糖」
〔腸溶性コーティング層〕
グリセリン：阪本薬品工業（株）製、「グリセリン（食品添加物）」
シリカ（微粒二酸化ケイ素）：富士シリシア化学（株）製、「サイロページ７２０」
タルク：松村産業（株）製、「クラウンタルクＰＰ」
〔最表層〕
ヒドロキシプロピルメチルセルロース：信越化学工業（株）製、「メトローズＳＥ－０６」 Details of the raw materials used in the examples and comparative examples are as follows. Details of the component (B) alginate are shown in Table 1.
〔Underlayer〕
Hydroxypropyl methylcellulose: “Metroze SE-06” manufactured by Shin-Etsu Chemical Co., Ltd.
Pectin: Dainippon Pharmaceutical Co., Ltd., “Classic AF701”
Polyvinyl alcohol: manufactured by Nippon Synthetic Chemical Co., Ltd., “Polyvinyl alcohol EG-22P”
Gum arabic: Made by Nippon Powder Chemical Co., Ltd., “Gum arabic”
Hydroxypropyl cellulose: Hydroxypropyl cellulose: Nippon Soda Co., Ltd., “HPC-SSL”
Pullulan: “Pullulan” manufactured by Hayashibara Co., Ltd.
Sucrose: Dainippon Meiji Sugar Co., “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: “Crown Talc PP” manufactured by Matsumura Sangyo Co., Ltd.
[Outermost layer]
Hydroxypropyl methylcellulose: “Metroze SE-06” manufactured by Shin-Etsu Chemical Co., Ltd.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004

Claims (9)

  1. 　被コーティング物と、その上に形成された（Ａ）６質量％水溶液の２５℃での粘度が３００ｍＰａ・ｓ未満である高分子化合物を含む下層と、該下層上に形成された（Ｂ）アルギン酸塩と（Ｃ）可塑剤とを含む腸溶性コーティング層とを有することを特徴とするコーティング製剤。 A lower layer containing a polymer compound having a viscosity of less than 300 mPa · s at 25 ° C. of a 6% by mass aqueous solution (A) formed thereon, and (B) alginic acid formed on the lower layer A coating preparation comprising an enteric coating layer containing a salt and (C) a plasticizer.
  2. 　（Ａ）成分が、ヒドロキシプロピルメチルセルロース、ペクチン、カードラン、プルラン、ヒドロキシプロピルセルロース、ポリビニルアルコール、及びアラビアガムからなる群より選ばれる請求項１記載のコーティング製剤。 The coating preparation according to claim 1, wherein the component (A) is selected from the group consisting of hydroxypropylmethylcellulose, pectin, curdlan, pullulan, hydroxypropylcellulose, polyvinyl alcohol, and gum arabic.
  3. 　（Ａ）成分が、ヒドロキシプロピルメチルセルロースである請求項２記載のコーティング製剤。 The coating preparation according to claim 2, wherein the component (A) is hydroxypropylmethylcellulose.
  4. 　（Ｂ）成分が、（Ｂ－１）１質量％水溶液の２０℃での粘度が５０ｍＰａ・ｓ以上のアルギン酸塩である請求項１～３のいずれか１項記載のコーティング製剤。 The coating preparation according to any one of claims 1 to 3, wherein the component (B) is an alginate having a viscosity at 20 ° C of a 1% by mass aqueous solution of (B-1) of 50 mPa · s or more.
  5. 　更に、（Ｂ－２）１質量％水溶液の２０℃での粘度が５０ｍＰａ・ｓ未満のアルギン酸塩を含む請求項４記載のコーティング製剤。 5. The coating preparation according to claim 4, further comprising (B-2) an alginate having a viscosity at 20 ° C. of a 1 mass% aqueous solution of less than 50 mPa · s.
  6. 　更に、腸溶性コーティング層の外側に（Ｄ）ゼラチン、ペクチン、カードラン、プルラン、アラビアガム、キサンタンガム、ジェランガム、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロースナトリウム、及びヒドロキシプロピルセルロースからなる群より選ばれる高分子化合物を含む最表層を有する請求項１～５のいずれか１項記載のコーティング製剤。 And (D) a polymer compound selected from the group consisting of gelatin, pectin, curdlan, pullulan, gum arabic, xanthan gum, gellan gum, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and hydroxypropylcellulose on the outside of the enteric coating layer. The coating preparation according to any one of claims 1 to 5, which has an outermost layer containing the coating preparation.
  7. 　（Ｄ）成分が、ヒドロキシプロピルメチルセルロースである請求項６記載のコーティング製剤。 The coating preparation according to claim 6, wherein the component (D) is hydroxypropylmethylcellulose.
  8. 　被コーティング物に、（Ａ）６質量％水溶液の２５℃での粘度が３００ｍＰａ・ｓ未満である高分子化合物を含む溶液を噴霧し、乾燥することにより下層を形成する工程と、該下層の外側に（Ｂ）アルギン酸塩と（Ｃ）可塑剤とを含む溶液を噴霧し、乾燥することにより腸溶性コーティング層を形成する工程とを含むことを特徴とするコーティング製剤の製造方法。 (A) A step of forming a lower layer by spraying 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, and forming an outer layer of the lower layer; And (B) spraying a solution containing an alginate and (C) a plasticizer and drying the solution to form an enteric coating layer.
  9. 　更に、上記腸溶性コーティング層の外側に（Ｄ）ゼラチン、ペクチン、カードラン、プルラン、アラビアガム、キサンタンガム、ジェランガム、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロースナトリウム、及びヒドロキシプロピルセルロースからなる群より選ばれる高分子化合物を含む溶液を噴霧し、乾燥することにより最表層を形成する工程を含む請求項８記載のコーティング製剤の製造方法。 And (D) a polymer compound selected from the group consisting of gelatin, pectin, curdlan, pullulan, gum arabic, xanthan gum, gellan gum, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and hydroxypropylcellulose outside the enteric coating layer. The manufacturing method of the coating formulation of Claim 8 including the process of forming the outermost layer by spraying and drying the solution containing this.
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