JP6780412B2 - Coating composition and coating formulation and method for manufacturing the same - Google Patents

Description

The present invention relates to a coating composition, a coating preparation, and a method for producing the same.

Some components, such as the functional components of proteins such as lactic acid bacteria and enzymes, exhibit high functionality by preventing decomposition in the stomach, maintaining the structure and delivering to the intestine, and for these reasons they do not dissolve in the stomach and in the intestine. There is a need for a soluble, enteric formulation.

As a protective film for allowing the active ingredient to reach the intestine, a component that does not dissolve under the pH condition (acidic) in the stomach but dissolves under the pH condition (neutral) of the small intestine is required, and pharmaceuticals are methacrylic acid-based. It is common to use shelac and zein for high molecular compounds and foods, but there is a demand for a coating composition that enables excellent enteric solubility.

Japanese Unexamined Patent Publication No. 2005-027651

The present invention has been made in view of the above circumstances, and uses a coating composition that enhances solubility resistance under acidic conditions (insolubility under a gastric environment) and further enables excellent enteric solubility. It is an object of the present invention to provide the prepared preparation and the method for producing the same.

As a result of diligent studies to achieve the above object, the present inventors have found the possibility of obtaining a certain level of enteric solubility when pectin is used. However, although the film prepared with pectin does not dissolve under acidic conditions (pH 1.2), it has been found to be brittle and fragile. On the other hand, among the pectins, pectins having a low degree of methoxylation, an esterification degree of 3 to 40%, and many anionic groups were selected in combination with a film-forming component, and were resistant to dissolution under acidic conditions. It has been found that by enhancing the properties and further cross-linking pectin with a calcium salt or a magnesium salt, the solubility resistance under acidic conditions can be enhanced and high enteric solubility can be obtained. It has come to the point.

Therefore, the present invention provides the following invention.
[1]. It contains (A) one or more selected from pectin having an esterification degree of 3 to 40%, (B) calcium salt and magnesium salt, and (C) film-forming component, and is represented by calcium and magnesium / (A). A coating composition having a mass ratio of 0.002 to 0.1 and a mass ratio of the component (A) to the component (C) represented by (C) / (A) of 0.2 to 3.
[2]. The coating composition according to [1], wherein the component (C) is at least one selected from hydroxypropyl methylcellulose, polyvinyl alcohol, gum arabic, hydroxypropyl cellulose, pullulan and curdlan.
[3]. The coating composition according to [1] or [2], wherein the component (A) is a pectin crosslinked by the component (B).
[4]. A coating preparation in which a coating layer composed of the coating composition according to any one of [1] to [3] is formed on the surface of an object to be coated.
[5]. The coating preparation according to [4], which has an intermediate layer (D) containing a polymer compound having a viscosity of a 6% by mass aqueous solution at 25 ° C. of less than 300 mPa · s between the object to be coated and the coating layer.
[6]. Production of the coating preparation according to [4] or [5], which comprises a step of spray-coating the object to be coated or the object to be coated having an intermediate layer with the coating composition according to any one of [1] to [3]. Method.

According to the present invention, it is possible to provide a coating composition capable of enhancing the solubility resistance under acidic conditions and obtaining high enteric acid performance, a preparation using this coating composition, and a method for producing the same.

Hereinafter, the present invention will be described in detail.
(A) Pectin having a degree of esterification of 3 to 40% The pectin of the present invention is a pectin having a degree of esterification (methoxyl group) of 3 to 40%. From the viewpoint of gastric resistance at the initial stage and after storage and solubility in the intestinal environment, the degree of esterification is preferably 22 to 35%, more preferably 22 to 30%. When the degree of esterification exceeds 40%, cross-linking with calcium or magnesium is not sufficient, and the functions of solubility resistance under acidic conditions and insolubility under gastric environment (hereinafter collectively referred to as gastric resistance) are sufficiently fulfilled. Absent. If the degree of esterification is less than 3%, the molecular weight is small and the gastric tolerance function cannot be sufficiently exhibited. The degree of esterification can be measured by an appropriate method based on the measurement methods in FCC and FAO / WHO. In addition, pectin is roughly classified into an acid treatment type and an alkali treatment type (amide pectin) according to the difference in the deesterification method, and is not particularly limited, but is an acid treatment type in terms of solubility in the coating liquid and gelation behavior. Is preferable.

The content of the component (A) is preferably 2 to 10% by mass (solid content), more preferably 3 to 5% by mass (solid content) in the composition. Further, it is preferably 30 to 55% by mass, more preferably 35 to 50% by mass in the coating layer.

(B) One or more selected from calcium salt and magnesium salt,
Examples of the calcium salt include water-soluble calcium salts such as calcium chloride, calcium lactate and saccharin calcium, and examples of the magnesium salt include water-soluble magnesium salts such as magnesium chloride. Calcium chloride, calcium lactate, and magnesium chloride are preferable because of their high solubility in water.

The content of the component (B) is preferably 0.02 to 0.5% by mass (solid content), more preferably 0.04 to 0.2% by mass (solid content) in the composition. Further, 0.2 to 6% by mass is preferable, and 0.5 to 3% by mass is more preferable in the coating layer.

The mass ratio represented by calcium and magnesium / (A) is 0.002 to 0.1, and 0.005 to 0. From the viewpoint of gastric resistance at the initial stage and after storage and solubility in the intestinal environment. 05 is preferable, and 0.005 to 0.02 is more preferable. The amount of "calcium and magnesium" is not the amount of salt of the component (B) but the total amount of calcium and magnesium, and is the amount of calcium in the case of calcium alone and the amount of magnesium in the case of magnesium alone. If the mass ratio exceeds 0.1, the coating composition will gel, and the gastric resistance at the initial stage and after storage, and the solubility in the intestinal environment will deteriorate. If it is less than 0.002, the gastric resistance function will be sufficient. I can't show it to you.

(C) Film-forming component Examples of the film-forming component include low-viscosity film-forming components such as hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol (PVA), gum arabic, hydroxypropylcellulose (HPC), pullulan, and curdlan. These can be mentioned alone or in combination of two or more. Of these, hydroxypropyl methylcellulose, polyvinyl alcohol, and pullulan are preferable, and hydroxypropylmethyl cellulose is more preferable.

The content of the component (C) is preferably 0.5 to 5% by mass (solid content), more preferably 0.5 to 2% by mass (solid content) in the composition. Further, 5 to 45% by mass is preferable, and 10 to 30% by mass is more preferable in the coating layer.

The mass ratio of the component (A) to the component (C) represented by (C) / (A) is 0.2 to 3, and the points of gastric tolerance at the initial stage and after storage and solubility in the intestinal environment Therefore, 0.2 to 0.8 is preferable, and 0.3 to 0.5 is more preferable. If the above ratio exceeds 3, the gastric tolerance function cannot be fully exerted. On the other hand, if it is less than 0.2, the film forming property is lowered and the gastric resistance function cannot be sufficiently exhibited.

The coating composition of the present invention may contain arbitrary components as long as the effects of the present invention are not impaired. Examples of such components include plasticizers, anti-adhesion agents, lubricants, antifoaming agents, colorants and the like.

Examples of the plasticizer include surfactants such as sucrose fatty acid ester, glycerin fatty acid ester, monoglycerin fatty acid ester, and polyoxyethylene sorbitan fatty acid ester, polyhydric alcohols such as glycerin, propylene glycol, and polyethylene glycol, glucose, and fructose-dextrose liquid sugar. , Sugars such as sucrose, sugar alcohols such as sorbitol, martitol, mannitol, erythritol, xylitol, dodecanol, tridecanol, tetradecanol, pentadecanol, hexadecanol, heptadecanol, octadecanol, hexadecyl alcohol, Examples thereof include higher alcohols such as isostearyl alcohols and 2-octyldodecanols (preferably 6 to 22 carbon atoms), and fats and oils such as medium chain fatty acid esters (preferably 6 to 12 carbon atoms). These can be used alone or in combination of two or more. Among them, glycerin is preferable from the viewpoint of plasticizing effect of the coating film, surfactant is preferable from the viewpoint of enteric properties, and glycerin and / or sucrose fatty acid ester is more preferable. The content of the plasticizer is preferably 0.2 to 5% by mass (solid content), more preferably 0.5 to 2% by mass (solid content), based on the coating composition. Further, 2 to 25% by mass is preferable, and 5 to 20% by mass is more preferable in the coating layer.

Examples of the anti-adhesion agent and the lubricant include talc, calcium stearate, silicon dioxide and the like, and one type alone or two or more types can be used as appropriate. The particle size of the fine particles is 0.01 to 50 μm, preferably 0.1 to 20 μm. The particle size is measured by a laser diffraction type particle size distribution measuring device. The content of the anti-adhesion agent and the lubricant is preferably 0.1 to 2% by mass (solid content), more preferably 0.2 to 1.5% by mass (solid content) with respect to the coating composition. Further, 1 to 20% by mass is preferable, and 5 to 15% by mass is more preferable in the coating layer.

Examples of the defoaming agent include glycerin fatty acid ester, dimethylpolysiloxane, dimethylpolysiloxane / silicon dioxide mixture, hydrous silicon dioxide, silicon dioxide and the like, and one type alone or two or more types may be used as appropriate. it can.

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

[Coating composition]
(A) Pectin having an esterification degree of 3 to 40% is crosslinked by one or more selected from (B) calcium salt and magnesium salt, and the gastric tolerance function is more exhibited. The amount of water in the coating composition is not particularly limited, and is appropriately selected from 50 to 98% by mass.

[Coating formulation]
The above coating composition can be used to prepare a coating preparation in which a coating layer composed of the coating composition is formed on the surface of the object to be coated.

The coating composition of the present invention and the coating film formed from the coating composition have an enteric property, that is, "it does not dissolve in the stomach but dissolves in the intestine, and the object to be coated can reach the intestine". Is.

In the present invention, "enteric" means an dissolution test solution (pH 1.2) equivalent to gastric juice, an dissolution rate of 20% or less in 2 hours, and an dissolution test solution equivalent to intestinal juice, according to the dissolution test method of the Japanese Pharmacy. At pH 6.8), it means an elution rate of 70% or more in 2 hours.

The thickness of the coating film is not particularly limited, but is preferably 5 μm to 1 mm, more preferably 10 to 500 μm. Further, the coating film is preferably 0.5 to 30% by mass, more preferably 1 to 25% by mass, based on the coating preparation.

The water content of the coating film is preferably 10 to 30% by mass, more preferably 15 to 25% by mass, based on the coating film.

The object to be coated is not particularly limited, and examples thereof include active ingredients such as foods and pharmaceuticals. For example, lactic acid bacteria, cysteine, iron, proteins such as antibodies and lactoferrin, peptides, ATP-2Na and the like can be mentioned, and these can be used alone or in combination of two or more. Above all, it is suitable for high molecular weight components such as proteins and water-insoluble components. From the viewpoint of the appearance of the coated tablet and the dissolution property in the intestinal environment, 40 to 100 mg of crystalline cellulose (in one tablet) and 40 to 80 mg of maltitol (in one tablet) are preferable.

The shape and dosage form of the object to be coated are not particularly limited, and tablets, powders, fine granules, granules and the like are not particularly limited. The tablets may be single layer or two or more layers. Among these, tablets are preferable from the viewpoint of exhibiting more enteric properties. The size of the tablet is not particularly limited, and the diameter of the tablet is preferably 5 to 14 mmφ, more preferably 7 to 12 mmφ, from the viewpoint of ease of handling and swallowability of the tablet. The appropriate tablet mass per tablet is about 150 to 700 mg, and the shape of the tablet is not particularly limited, but is round (R tablet, two-stage R tablet, Sumikaku flat tablet, etc.), triangle, square, etc. There are hexagonal, octagonal, oval, rugby ball type and the like, and round R locks and two-stage R locks are preferable.

The coating preparation of the present invention may have an intermediate layer containing a polymer compound having a viscosity of (D) 6% by mass aqueous solution at 25 ° C. of less than 300 mPa · s between the object to be coated and the coating layer. preferable. By providing this intermediate layer, the gastric tolerance function is further improved. Examples of the polymer compound having a viscosity of a 6 mass% aqueous solution at 25 ° C. of less than 300 mPa · s include a film-forming component having a low viscosity, for example, hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), arabic gum, and hydroxypropyl. Examples thereof include cellulose (HPC), pullulan, curdlan, etc., and one type alone or two or more types can be used in combination as appropriate. Of these, hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), and hydroxypropylcellulose (HPC) are preferable, and hydroxypropylmethylcellulose (HPMC) is more preferable. The content of the component (C) is preferably 1 to 20% by mass (solid content), more preferably 2 to 10% by mass (solid content), based on the coating composition forming the intermediate layer. Further, 20 to 80% by mass is preferable, and 30 to 70% by mass is more preferable in the intermediate layer.

In addition to the component (D), the intermediate layer may contain components such as glycerin and sucrose fatty acid ester. The content of these components is preferably 0.1 to 10% by mass (solid content), more preferably 0.5 to 5% by mass (solid content), and more preferably 0.5 to 5% by mass (solid content) with respect to the coating composition forming the intermediate layer. 1 to 40% by mass is preferable, and 5 to 30% by mass is more preferable.

The amount of the intermediate layer is preferably 5 to 50% by mass, more preferably 10 to 50% by mass, based on the amount of the coating layer. When the content is 5% by mass or more, sufficient gastric tolerance over time can be obtained. Moreover, a smooth coated lock can be obtained. Further, when the content is 50% by mass or less, the dissolution property in the intestinal environment becomes good. The content of the component (D) in the coating intermediate layer is preferably 10 to 80% by mass, more preferably 20 to 70% by mass.

The water content of the intermediate layer is preferably 5 to 40% by mass, more preferably 10 to 30% by mass, based on the intermediate layer.

[Manufacturing method of coating preparation]
The coating composition can be obtained by mixing the above essential components, and the coating preparation can be obtained by spraying the coating composition as it is or a coating solution containing water on the object to be coated and drying it. It can be obtained by forming a coating film on the surface of the above. Since the coating composition of the present invention is water-based, it can be coated with water and a water-soluble film is formed.

The coating solution contains a coating composition and water, and the water content of the coating solution is preferably 50 to 98% by mass, more preferably 70 to 96% by mass. Further, an organic solvent such as ethanol may be blended as long as the effect of the present invention is not impaired.

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

The coating method is not particularly limited, and examples thereof include a method of spraying a coating solution onto an object to be coated and drying it by heating to form a film on the surface of the object to be coated. 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 1 m ³ / min of dry air volume. In addition, it is also possible to use 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 within the above-mentioned preferable range.

When providing the intermediate layer, prepare a polymer compound solution having a viscosity of (D) 6% by mass aqueous solution at 25 ° C. of less than 300 mPa · s before applying the above coating, and coat the mixture in the same manner as described above. Just do it. The water content of the intermediate layer solution is preferably 50 to 99% by mass, more preferably 80 to 99% by mass.

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

[Examples, comparative examples]
Mix the above raw materials and use a tableting machine to tablet (300 mg, φ9.0 mm, thickness 5.3 mm, 2-stage R tablet (R1 = 3.6 mm, R2 = 10.5 mm, H = 1.5 mm)) Tableting was performed so as to prepare an uncoated tablet. A coating solution and an intermediate layer solution having the compositions shown in Table 1 below were prepared, and the uncoated tablets were coated by the following method to prepare coated tablets. The obtained coated lock was evaluated as follows. The results are also shown in the table.
[Unlocked]
Mass per tablet Lactoferrin: 110 mg
Hihatsu extract powder: 50 mg
Maltitol 50 mg
Crystalline cellulose: 80.5 mg
Carboxymethyl Cellulose Calcium (CMC-Ca): 6.0 mg
Calcium Stearate 0.5mg
Fine silicon dioxide: 3.0 mg

[Intermediate layer (1st layer)]
<Preparation of intermediate layer coating liquid>
<Preparation of coating liquid>
All the raw materials were mixed and stirred to dissolve them to obtain an intermediate layer coating liquid.
<Coating>
Using a coating machine (High Coater FZ-Lab manufactured by Freund Sangyo Co., Ltd.), spray 45 g of the intermediate layer coating liquid on 200 g of the uncoated tablet and dry it so that the residual water content is about 20%. Obtained.

[Coating layer (second layer)]
<Preparation of coating liquid>
The component (A) and the component (B) were dispersed in a part of water and heated to 80 ° C. to dissolve them. Other raw materials were dispersed in the remaining water and mixed with the above solution to obtain a coating solution.
<Coating>
Using a coating machine (Freund Sangyo Co., Ltd. High Coater FZ-Lab), 300 g of the coating liquid was sprayed on 200 g of the uncoated tablet and dried so that the residual water content was 15 to 20% to obtain a coated tablet. ..

<Dissolution test>
The solubility of the coating film was evaluated by the elution of lactoferrin.
The coated lock immediately after coating and the sample after storage at 40 ° C. and 75% RH for 4 months after coating were evaluated.

<Preparation of sample solution>
An dissolution test was conducted in accordance with the Japanese Pharmacopoeia General Test Method using 1 liquid (pH 1.2) of the Japanese Pharmacopoeia.
An dissolution test was conducted in accordance with the Japanese Pharmacopoeia General Test Method using two Japanese Pharmacopoeia solutions (pH 6.8).
<Lactoferrin quantification>
The method for quantifying lactoferrin was based on the method of the 9th Edition of the Draft Food Additives.
<Quantitative>
The sampling solution 2 hours after the dissolution test was used as the sample solution. 20 μL of each of the sample solution and the standard solution having three concentrations was weighed, and liquid chromatography was performed under the following operating conditions. The lactoferrin peak area of each standard solution was measured and a calibration curve was prepared. The lactoferrin concentration in the sample solution is determined from this calibration curve and the lactoferrin area of the sample solution, and the lactoferrin elution rate for 100 mg / tablet of lactoferrin is determined by the following formula.
Lactoferrin elution rate (%) = lactoferrin concentration in sample solution (mg / mL) x 900 (mL) x purity of lactoferrin for quantification (%) x 1/100 x 1/100 (mg) x 100

Chromatography condition detector: Ultraviolet absorptiometer (measurement wavelength: 280 nm)
Column packing material: 5 μm butylated polyvinyl alcohol polymer gel for liquid chromatography (Shodex Asahipak C4P-50 4D)
Column tube: Stainless steel tube with inner diameter of 4.6 mm and length of 15 cm Guard column: Shodex Asahipak C4P-50G 4A
Column temperature: 35 ° C
Mobile phase A
Acetonitrile / sodium chloride solution containing 0.03 w / v% trifluoroacetic acid (3 → 100) mixed solution (10:90)
Mobile phase B
Acetonitrile / sodium chloride solution containing 0.03 w / v% trifluoroacetic acid (3 → 100) mixed solution (50:50)
Concentration Gradient A linear concentration gradient from A: B (50:50) to (0: 100) was performed for 25 minutes.
Flow rate: 0.8 mL / min Lactoferrin for quantification: Wako Pure Chemical Industries, Ltd. Biochemical "lactoferrin, derived from milk"
Purity (%) of lactoferrin for quantification: Wako Pure Chemical Industries, Ltd. Inspection report content (HPLC) value is used

From the dissolution rate, the results are shown according to the following criteria.
Japanese Pharmacopoeia 1 liquid (pH 1.2);
Elution 5% or less in 2 hours; ◎
Elution over 5% and 10% or less in 2 hours;
Elution over 10% and below 20% in 2 hours; ●
Elution exceeds 20% in 2 hours; ×
Japanese Pharmacopoeia 2 liquid (pH 6.8);
Elution 90% or more in 2 hours; ◎
Elution in 2 hours 70% or more and less than 90%; ○
Elution in 2 hours 30 or more and less than 70%;
Elution less than 30% in 2 hours; ×
The cases of ◎, ○, ● in the test of Japanese Pharmacopoeia 1 solution and ◎, ○ in the test of Japanese Pharmacopoeia 2 solution were considered enteric.

The raw materials used in preparing Examples and Comparative Examples are shown below. The amounts in the table are net conversion amounts.

Claims (6)

(A) One or more selected from (A) pectin having an esterification degree of 3 to 40%, (B) calcium salt and magnesium salt, (C) hydroxypropylmethyl cellulose, polyvinyl alcohol, Arabic gum, hydroxypropyl cellulose, pullulan and curdlan. It contains one or more film-forming components selected from orchids , and the mass ratio represented by calcium and magnesium / (A) is 0.002 to 0.1, represented by (C) / (A) ( An enteric coating composition having a mass ratio of component (A) to component (C) of 0.2 to 3. Component (A), (B) Pectin is a claim 1 Symbol placement coating composition crosslinked by component. A coating preparation in which a coating layer composed of the coating composition according to claim 1 or 2 is formed on the surface of the object to be coated. The coating preparation according to claim 3 , further comprising an intermediate layer containing a polymer compound having a viscosity of (D) a 6 mass% aqueous solution at 25 ° C. of less than 300 mPa · s between the object to be coated and the coating layer. The coating preparation according to claim 3 or 4, wherein the ratio of the coating layer is 0.5 to 30% by mass with respect to the coating preparation. The method for producing a coating preparation according to any one of claims 3 to 5 , which comprises a step of spray-coating the object to be coated or the object to be coated having an intermediate layer with the coating composition according to claim 1 or 2 .