KR102392313B1 - Coated preparation and method for producing same - Google Patents

Abstract

A coating formulation that does not dissolve in the stomach but dissolves in the intestine, can reach the coated active ingredient more reliably into the intestine, suppress deterioration over time, and is excellent in storage stability, and its manufacture provide a way A lower layer comprising a material to be coated and a high molecular compound having a viscosity of less than 300 mPa·s at 25° C. of (A) a 6 mass% aqueous solution formed thereon, and (B) alginate and (C) a plasticizer formed on the lower layer A coating formulation having an enteric coating layer comprising a.

Description

Coating formulation and its manufacturing method

BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to a coating formulation used as a food product, a pharmaceutical product, or the like, and a method for manufacturing the same.

Like functional components of proteins such as lactic acid bacteria and enzymes, there are active ingredients that prevent decomposition in the stomach, maintain structure, and deliver high functionality to the intestines. There is a need for an enteric formulation that can reach the intestine.

As a protective film for allowing the active ingredient to reach the intestine, a component that does not dissolve under the pH conditions (acidic) in the stomach, but dissolves under the pH conditions (neutral to alkaline) of the small intestine, for example, a methacrylic acid-based high molecular compound; Shellac, zein, etc. are common.

However, the methacrylic acid-based high molecular compound is limited to pharmaceutical use and cannot be used for food. On the other hand, shellac and zein are also used for food purposes, but the method of spraying using an organic solvent is common. The use of a water-soluble film agent that can be coated with water in consideration of the environment even for food use is desired.

In addition, as prior art documents concerning this invention, the following are mentioned.

Japanese Patent Laid-Open No. 2002-193792

The present invention has been made in view of the above circumstances, it is not dissolved in the stomach but dissolves in the intestine, and the coated active ingredient can be more reliably reached into the intestine, deterioration with time can be suppressed as much as possible, and it is excellent in storage stability An object of the present invention is to provide a coating formulation and a method for producing the same.

The present inventors first proposed an alginate enteric coating formulation using water as a solvent in consideration of the environment (Japanese Patent Application No. 2013-046697). The enteric preparation subjected to this coating has advantages such as very good enteric properties immediately after coating (dissolution inhibition under acidic conditions, dissolution properties under moderate conditions). However, in further examination after that, it turned out that although there is no change in the external appearance of a coating film, the dissolution inhibiting property in acidic condition may fall with the passage of time. Although the cause is not clear, although there is no change in the external appearance of a coating film, since the elution suppression property is falling, it is estimated that it is because the very minute structural change has occurred.

Therefore, as a result of further intensive studies, the present inventors have performed pre-coating to become the lower layer of the enteric coating film for this minute structural change, and unexpectedly found that the decrease in dissolution inhibition under acidic conditions due to time-lapse can be improved. did

Pre-coating for the enteric coating film is generally performed in order to improve peeling of the film caused by poor compatibility between the enteric coating film and the tablet, but the present inventors found that the pre-coating is the alginic acid The present invention has been achieved by newly discovering that an enteric coating film using a salt exhibits a function of protecting it from deterioration over time and is effective for improvement of storage stability of a coating formulation.

Accordingly, the present invention provides the following coating formulation and a method for preparing the same.

[One]

A lower layer containing a high molecular compound having a viscosity of less than 300 mPa·s at 25° C. of the (A) 6 mass % aqueous solution formed thereon, and (B) alginate formed on the lower layer; ( C) A coating formulation comprising an enteric coating layer comprising a plasticizer.

[2]

(A) The coating formulation according to [1], wherein the component is selected from the group consisting of hydroxypropylmethylcellulose, pectin, cardlane, fullulan, hydroxypropylcellulose, polyvinyl alcohol, and gum arabic.

[3]

(A) The coating formulation as described in [2] whose component is hydroxypropylmethylcellulose.

[4]

(B) The coating formulation as described in any one of [1]-[3] whose component (B-1) is an alginate whose viscosity in 20 degreeC of 1 mass % aqueous solution is 50 mPa*s or more.

[5]

Furthermore, (B-2) The coating formulation as described in [4] containing the alginate whose viscosity in 20 degreeC of 1 mass % aqueous solution is less than 50 mPa*s.

[6]

In addition, on the outside of the enteric coating layer (D) from the group consisting of gelatin, pectin, cardlane, fullulan, gum arabic, xanthan gum, gellan gum, hydroxypropylmethylcellulose, carboxymethylcellulose sodium, and hydroxypropylcellulose The coating formulation according to any one of [1] to [5], which has an outermost layer containing a selected polymer compound.

[7]

(D) The coating formulation as described in [6] whose component is hydroxypropylmethylcellulose.

[8]

A step of forming a lower layer by spraying (A) a solution containing a high molecular compound having a viscosity of less than 300 mPa·s at 25° C. of a 6 mass % aqueous solution to the object to be coated, and drying the solution; B) A method for producing a coating formulation comprising the steps of forming an enteric coating layer by spraying and drying a solution containing an alginate and (C) a plasticizer.

[9]

In addition, on the outside of the enteric coating layer (D) gelatin, pectin, cardlane, fullulan, gum arabic, xanthan gum, gellan gum, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and a group consisting of hydroxypropylcellulose The manufacturing method of the coating formulation as described in [8] including the process of forming the outermost layer by spraying the solution containing the high molecular compound selected from and drying.

According to the coating formulation of the present invention, it is not dissolved in the stomach but dissolves in the intestine, and the coated active ingredient can be reliably delivered to the intestine, and even when stored for a long period of time, it is possible to suppress the decrease in the dissolution inhibiting property under acidic condition as much as possible. , it is possible to provide a coating formulation excellent in storage stability.

Hereinafter, the present invention will be described in detail.

The coating formulation 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, and between the object to be coated and the lower layer or between the enteric coating layer and the outermost layer, 1 It is also possible to form an intermediate layer of more than one layer. Among them, it is preferable to have an object to be coated, a lower layer formed on the surface of the object to be coated, and an enteric coating layer formed on the surface of the lower layer. In the present invention, the outermost layer may be formed on the outside of the enteric coating layer, if necessary, within a range that does not affect the enteric quality. In addition, in the present invention, "enteric properties" refers to an agent that delivers functional ingredients to the intestine. The test is carried out according to the method of the dissolution test method of the Japanese Pharmacopoeia Act, and in a dissolution test solution (pH 1.2) equivalent to gastric juice, the dissolution rate is less than 50% (suitably 30% or less) in 2 hours, and intestinal juice equivalent In the dissolution test solution (pH 6.8), it means a dissolution rate of 70% or more in 2 hours.

(I) object to be coated

In this invention, the thing to be coated is not specifically limited, Active ingredients, such as food and a pharmaceutical, etc. are mentioned. For example, lactic acid bacteria, cysteine, iron, proteins such as antibodies and lactoferrin, peptides, ATP-2Na, etc. are mentioned, and these can be used individually by 1 type or in combination of 2 or more types. Especially, it is suitable for high molecular weight components, such as a protein, and a water-insoluble component.

The form 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. A tablet may be single-layered or two or more layers may be sufficient as it. Among these, it is preferable to set it as a tablet from the point which exhibits more enteric property. The size of the tablet is not particularly limited, and from the viewpoint of ease of handling and swallowability (swallowability) of the tablet, the diameter of the tablet is preferably 5 to 14 mm phi, more preferably 7 to 12 mm phi Do. Moreover, as a tablet mass per tablet, about 150-700 mg is suitable.

(Ⅱ) lower floor

The lower layer of the present invention is a layer formed prior to the enteric coating layer containing an alginate described later, for example, a layer formed on the surface of the object to be coated. In the present invention, by forming the lower layer between the object to be coated and the enteric coating layer, it is possible to prevent the chronological decrease in the dissolution inhibitory effect under acidic conditions during storage. Thereby, the storage stability (dissolution inhibiting property under acidic condition) of the coating formulation in which the enteric coating layer was formed can be improved remarkably. Hereinafter, the lower layer will be described in detail.

A lower layer contains the high molecular compound whose viscosity in 25 degreeC of (A) 6 mass % aqueous solution is less than 300 mPa*s. The component (A) is not particularly limited, but as specific examples, hydroxypropylmethylcellulose, pectin, cardlane, fullulan, hydroxypropylcellulose, polyvinyl alcohol, and gum arabic can be exemplified, It can be used individually by 1 type or in combination of 2 or more types. In the present invention, in particular, hydroxypropylmethylcellulose can be suitably used.

Although the compounding quantity in particular of the said (A) component is not restrict|limited, With respect to the whole precoat composition (composition for lower layer), Preferably it is 1-10 mass %, More preferably, it is 3-8 mass %. By carrying out a compounding quantity more than the lower limit of the said range, manufacturing time can be settled within an appropriate time. On the other hand, when the blending amount is below the upper limit of the above range, it is possible to achieve a viscosity suitable for preparation of a coating solution or spraying of a coating solution.

Moreover, in the said lower layer, you may contain (E) a plasticizer as needed. (E) As a component, surfactant, such as sucrose fatty acid ester, glycerol fatty acid ester, monoglycerol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyhydric alcohols, such as glycerol, propylene glycol, polyethyleneglycol, glucose, fructose glucose solution sugar, sucrose Sugars such as sorbitol, maltitol, mannitol erythritol, sugar alcohols such as xylitol, dodecanol, tridecanol, tetradecanol, pentadecanol, hexadecanol, heptadecanol, octadecanol, hexadecanol Fats and oils such as decyl alcohol, isostearyl alcohol, 2-octyldodecanol (suitably having 6 to 22 carbon atoms) and medium chain fatty acid esters (preferably having 6 to 12 carbon atoms) are mentioned. These can be used individually by 1 type or in combination of 2 or more types. In this invention, glycerol can be used suitably from a viewpoint of a plasticizing effect.

Although the compounding quantity in particular of the said (E) component is not restrict|limited, With respect to the whole composition for lower layers, Preferably it is 0.3-6 mass %, More preferably, it is 0.8-5 mass %. By carrying out a compounding quantity more than the lower limit of the said range, the effect which prevents the time-dependent fall of the dissolution inhibitory effect in acidity becomes high. On the other hand, by making a compounding quantity below the upper limit of the said range, manufacturing time can be settled within an appropriate time.

You may mix|blend (F) microparticles|fine-particles with the composition for lower layers. By mix|blending microparticles|fine-particles, peeling of the coating film by the adhesion of tablets at the time of a coating process can be prevented. (F) As a component, a talc, a calcium stearate, a silicon dioxide, a titanium oxide, etc. are mentioned, It can be used individually by 1 type or in combination of 2 or more type suitably. The particle diameter of microparticles|fine-particles is 0.01-50 micrometers, and 0.1-20 micrometers is preferable. Incidentally, the particle size is measured with a laser diffraction type particle size distribution measuring device (dry measurement).

(F) 0.05-7 mass % of the whole composition for lower layers is preferable, as for the compounding quantity of (F) component, 0.1-5 mass % is more preferable, and its 0.3-3 mass % is still more preferable. By making a compounding quantity more than the lower limit of the said range, the effect of mix|blending the said (F)component can be acquired more, and when mix|blending exceeding the upper limit of the said range, there exists a possibility of affecting film-formability.

The composition for the lower layer may contain an organic solvent such as water and ethanol. The solvent compounding quantity in the composition for lower layers is suitably selected in 1-98 mass % with respect to the whole composition for lower layers, 50-98 mass % is preferable, and its 70-96 mass % is more preferable.

Although the thickness of a lower layer is not specifically limited, 1-200 micrometers is preferable and 2-100 micrometers is more preferable. Moreover, in the case of a tablet, it is preferable to make the adhesion amount of the lower layer into 0.6-10.5 mg/300 mg (0.2-3.5 mass %) with respect to predetermined 300 mg, 1.5-7.5 mg/300 mg (0.5- 2.5 mass %) is more preferable. In the case of granules, powders, and powders, it is preferable to set it as 0.5-30 mass %, and it is more preferable to set it as 1-25 mass %. By making the thickness and adhesion amount of the lower layer more than the lower limit of the said range, the effect of this invention (that is, preventing the dissolution inhibitory effect in acidic condition from falling with time) can be acquired effectively. On the other hand, by making the thickness and adhesion amount of the lower layer below the upper limit of the said range, a tablet can be produced in an appropriate manufacturing time.

The method for forming the said lower layer is not restrict|limited in particular, A well-known method is employable. For example, a method of forming a film on the surface of the object to be coated by spraying a predetermined coating solution onto the object to be coated and drying by heating is exemplified. The coating solution can be appropriately warmed, and the temperature is preferably 30 to 80°C, and the drying temperature is preferably 40 to 80°C. As for the addition rate of a coating solution, 1-5 g/min is preferable with respect to 1 m<3>/min of dry air volume. In addition, it is also possible to adopt the method of dip coating in which the object to be coated is immersed in the coating solution and dried. Drying is preferably carried out until the moisture content in the coating formulation is 0.1 to 20% by mass, particularly 0.5 to 5% by mass. In addition, the said lower layer is not limited to one layer, You may form multiple layers as needed.

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

(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) alginate and (C) a plasticizer.

(B) alginate

As alginate, monovalent alginates, such as sodium salt, potassium salt, and ammonium salt, and alginic acid water-soluble salt are preferable. As alginate, the viscosity at 20 degreeC of the following limit (B-1) 1 mass % aqueous solution is 50 mPa*s or more, (B-2) The viscosity at 20 degreeC of 1 mass % aqueous solution is less than 50 mPa*s These are mentioned, and can be used individually by 1 type or in combination of 2 or more types.

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

(B-1) When mix|blending an alginate, 0.1-5 mass % of the whole coating composition is preferable, as for a compounding quantity, 0.5-4 mass % is more preferable, The range of 1-4 mass % is still more preferable. By carrying out a compounding quantity more than the lower limit of the said range, the dissolution inhibiting ability in acidic condition can fully be acquired, and favorable enteric property can be acquired more. On the other hand, by setting it below the upper limit, it is possible to set the viscosity to a suitable viscosity for preparation, transfer, and spraying of the coating liquid.

(B-2) As an alginate whose viscosity at 20 degreeC of 1 mass % aqueous solution is less than 50 mPa*s, it is preferable that they are 5 mPa*s or more and less than 50 mPa*s, 10 mPa*s or more and 50 mPa*s Less than that is more preferable. (B-2) As alginate, sodium alginate is preferable.

(B-2) When mix|blending an alginate, as a compounding quantity, 5 mass % or less of the whole coating composition is preferable, 0.1-4 mass % is more preferable, The range of 0.1-2.5 mass % is still more preferable. By making the compounding quantity below the upper limit of the said range, enteric property improves and coatability becomes favorable.

Moreover, it is preferable that the compounding quantity of (B) component (that is, the total amount of (B-1) component and (B-2) component) is 0.1-10 mass % of the whole coating composition. Moreover, the range of 1-7 mass % is more preferable, and the range of 1.5-5 mass % is still more preferable. Good enteric properties (dissolution inhibiting properties under acidic conditions) can be obtained by making the blending amount equal to or less than the upper limit of the above range.

In this invention, it is preferable to use (B-1) alginate as (B) alginate. By using such an alginate of a certain length or more, the coating property is good. High acid resistance can be imparted to the formed coating film. In addition, by using (B-1) alginate and (B-2) alginate together, the coating performance can be further improved while maintaining enteric properties.

The use of two types of alginates having different viscosities, such as (B-1) alginate and (B-2) alginate, is not only for adjusting the viscosity of the coating solution, but from the viewpoint of enteric properties and coating properties, Two types of alginate were selected. The mass ratio (B-1):(B-2)((B-1)/(B-2)) is preferably 1:5-10:1 (0.2-10), 1:3-5: 1 (0.33-5) is more preferable, and 1:1.8-3:1 (0.56-3) is still more preferable. By making the mass ratio more than the lower limit of the above range, the coating performance under acidic conditions becomes higher, so that the specific dissolution property becomes good, and by setting it below the upper limit of the above range, the coatability becomes more favorable, so it is more preferable.

In addition, in this invention, the viscosity measurement of alginate is performed using a rotational viscometer (BM type). If the viscosity is less than 200 mPa·s, the rotor No. 1 is used, and the viscosity of 200 mPa·s or more and less than 1,000 mPa·s is the rotor No. 2, a 1 mass % aqueous solution is measured on the conditions of 20 degreeC and 30 rpm, and let the value after 60 second be a measured value.

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

(1) Preparation of samples

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

A calibration curve is prepared using standard products of various molecular weights (flurane: Mw = 16.6 million, Mw = 380,000, Mw = 100,000, Mw = 1.22 million, dissolved at a concentration of 0.1% by mass in the mobile phase).

(2) GPC measurement conditions

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

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

Flow rate: 0.5ml/min

Temperature: 40℃

Injection volume: 200 μl (0.1% in mobile phase)

Detector: Differential refractive index (RI) detector

(3) Analysis method

Calibration curve A calibration curve equation is obtained from the sample, and the weight average molecular weight (Mw) converted to fullulane is obtained from the GPC analysis result of the sample.

(C) plasticizer

(C) A plasticizer is a component mix|blended for the purpose of reducing the surface tension of a coating composition, or providing softness|flexibility to a coating layer. (C) As a component, surfactant, such as sucrose fatty acid ester, glycerol fatty acid ester, monoglycerol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, Polyhydric alcohol, such as glycerol, 1, 3- butylene glycol, propylene glycol, polyethyleneglycol , glucose, fructose glucose solution, sugars such as sucrose, sugar alcohols such as sorbitol, maltitol, mannitol, erythritol and xylitol, dodecanol, tridecanol, tetradecanol, pentadecanol, hexadecanol, heptadecanol , higher alcohols such as octadecanol, hexadecyl alcohol, isostearyl alcohol, 2-octyldodecanol (suitably having 6 to 22 carbon atoms), medium chain fatty acid esters (suitably having 6 to 12 carbon atoms), etc. there is. These can be used individually by 1 type or in combination of 2 or more types. Especially, the point of the plasticizing effect of a coating film to glycerol is preferable.

(C) 0.3-5 mass % of the whole coating composition is preferable, and, as for the compounding quantity of component, 0.5-3 mass % is more preferable. By making the compounding quantity more than the lower limit of the above range, peeling of the film during coating is more suppressed, and by setting it below the upper limit of the above range, stickiness at the time of coating is suppressed, the coating process becomes easier, and good enteric properties are obtained can

The range of 0.05-3.0 is preferable, as for mass ratio represented by (C)/(B), 0.1-2.0 are more preferable, 0.15-1.5 are still more preferable, 0.15-1.1 are especially preferable. By carrying out mass ratio more than the lower limit of the said range, the film performance in acidity becomes higher, and coating property becomes more favorable by setting it as below an upper limit.

You may mix|blend film formation components (D) other than (B) component with the coating composition of this invention. (D) As the film-forming component, gelatin, pectin, cardlane, fullulan, gum arabic, xanthan gum, gellan gum, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, agar, chitosan, tamarind Seed rubber, locust bean rubber, polyvinyl alcohol, ethyl cellulose aqueous dispersion, etc. are mentioned. These can be used individually by 1 type or in combination of 2 or more types. Among these, a component selected from gelatin, pectin, cardlane, fullulan, gum arabic, xanthan gum, gellan gum, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and hydroxypropylcellulose has a coating property and (B) It is preferable at the point of combination with a component.

(D) 0.1-7 mass % of the whole coating composition is preferable, as for the compounding quantity of component, 0.2-5 mass % is more preferable, and its 0.3-3 mass % is still more preferable. By making a compounding quantity more than the lower limit of the said range, the effect of (D)component mixing|blending can be acquired more, and when mix|blending exceeding the upper limit of the said range, there exists a possibility of affecting enteric property.

In this case, the content mass ratio represented by (B):(D)((B)/(D)) is preferably 1:3 to 1:0.05 (0.33 to 20), and 1:1 to 1:0.1 ( 1-10) are more preferable, and 1:0.8-1:0.2 (1.25-5) are still more preferable. By setting it as this range, it is possible to obtain a tablet excellent in enteric performance, which maintains the coatability and the beauty of appearance, and has a higher dissolution inhibiting ability especially under acidic conditions.

You may mix|blend (F) microparticles|fine-particles with a coating composition. By mix|blending microparticles|fine-particles, peeling of the coating film by the adhesion of tablets at the time of a coating process can be prevented. (F) As a component, a talc, a calcium stearate, a silicon dioxide, a titanium oxide, etc. are mentioned, It can be used individually by 1 type or in combination of 2 or more type suitably. The particle diameter of microparticles|fine-particles is 0.01-50 micrometers, and 0.1-20 micrometers is preferable. Incidentally, as in the case of the composition for the lower layer, the particle size is measured with a laser diffraction type particle size distribution measuring device (dry measurement).

(F) 0.05-7 mass % of the whole coating composition is preferable, as for the compounding quantity of component, 0.1-5 mass % is more preferable, 0.3-3 mass % is still more preferable. By making a compounding quantity more than the lower limit of the said range, the effect of mix|blending the said (F)component can be acquired more, and when mix|blending exceeding the upper limit of the said range, there exists a possibility of affecting film-formability.

Moreover, it is preferable not to contain divalent metal ions, such as a copper ion, a barium ion, and a calcium ion, in the said coating composition. This is because the alginate is crosslinked to form a gel, and the coating property is deteriorated. That is, when a monovalent alginate is reacted with a divalent cation to crosslink, the dried film is insoluble in water, but the viscosity becomes too high due to gelation, making it difficult to spray delicate liquids and expandability on tablets. As a result, it becomes difficult to form a uniform film, and in addition to worsening an external appearance, a dispersion|variation may arise in dissolution property. 0.5 mol or less is preferable with respect to 1 mol of monomers of alginate, as for the permissible range of a divalent metal ion, 0.25 mol or less is more preferable, 0.1 mol or less is still more preferable.

In the above-mentioned coating composition, in addition to the above-mentioned components, components normally used in the coating composition may be blended singly or in an appropriate amount by one type or two or more. As such an optional component, an antifoaming agent, a coloring agent, etc. are mentioned.

Examples of the antifoaming agent include glycerin fatty acid ester, dimethylpolysiloxane, dimethylpolysiloxane/silicon dioxide mixture, hydrous silicon dioxide, silicon dioxide, and the like, and can be used alone or in combination of two or more.

As a coloring agent, For example, subarachnoid tannin powder, turmeric extract, yellow iron trioxide, orange essence, brown iron oxide, carbon black, caramel, carmine, carotene liquid, β-carotene, licorice extract, Gold leaf, black iron oxide, light silicic anhydride, titanium oxide, iron 32 oxide, food blue No. 1, food yellow No. 4, food yellow No. 4 aluminum lake, food yellow No. 5, food red No. 2, food red No. 3, Food Red No. 102, Sodium Hydroxide, Sodium Copper Chlorophin, Copper Chlorophyll, Namaek Green Leaf Extract, Medicinal ??(炭), Butyric Acid Riboflavin, Riboflavin, Matcha Green Tea, Sodium Riboflavin Phosphate, etc. can be heard

The coating composition of this invention may contain organic solvents, such as water and ethanol. The solvent compounding quantity in a coating composition is suitably selected in 1-98 mass % with respect to the whole coating composition, 50-98 mass % is preferable, and its 70-96 mass % is more preferable.

Although the thickness of the said enteric coating layer is not specifically limited, 5-1,000 micrometers is preferable, and 10-500 micrometers is more preferable. Moreover, in the case of a tablet, it is preferable that the adhesion amount of an enteric coating layer be 1.5-60 mg/300 mg (0.5-20 mass %) with respect to predetermined 300 mg, and 3-45 mg/300 mg (1-15 mass %) ) is more preferable. In the case of granules, powders and powders, it is preferable to set it as 10-60 mass %, and it is more preferable to set it as 15-50 mass %. By setting the thickness and adhesion amount of the enteric coating layer to be equal to or greater than the lower limit of the above range, a formulation excellent in the ability to inhibit dissolution under acidic conditions can be obtained. On the other hand, by making the adhesion amount of the enteric coating layer below the upper limit of the above range, it can be settled within an appropriate manufacturing time.

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

A method of forming the enteric coating layer is not particularly limited, and a known method may be employed. For example, a method of forming a film on the surface of the object to be coated is exemplified by spraying a predetermined coating solution on the object to be coated with the lower layer and drying by heating. The coating solution can be appropriately warmed, and the temperature is preferably 30 to 80°C, and the drying temperature is preferably 40 to 80°C. As for the addition rate of a coating solution, 1-5 g/min is preferable with respect to 1 m<3>/min of dry air volume. In addition, it is also possible to adopt the method of dip coating in which the object to be coated is immersed in the coating solution and dried. Drying is preferably carried out until the moisture content in the coating formulation is 0.1 to 20% by mass, particularly 0.5 to 5% by mass.

In this case, the coater is not particularly limited, and a pan coater, a fluidized bed coater, an electric coater, or the like can be used.

Further, an appropriate intermediate layer may be formed between the lower layer and the coating layer within a range that does not impair the effects of the present invention. In the present invention, it is possible to form, for example, a shellac coating film and a cured oil and fat coating film.

(IV) outermost layer

In the present invention, if necessary, the outermost layer may be formed on the outside of the enteric coating layer by using the film-forming component (D). Thereby, the appearance, mouthfeel, and taste can be changed. (D) As a component, gelatin, pectin, cardlane, fullulane, gum arabic, xanthan gum, gellan gum, hydroxypropyl methyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl cellulose, agar, chitosan, tamarind gum , locust bean rubber, polyvinyl alcohol, ethyl cellulose aqueous dispersion, and the like. These can be used individually by 1 type or in combination of 2 or more types. Among these, a component selected from gelatin, pectin, cardlane, fullulan, gum arabic, xanthan gum, gellan gum, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and hydroxypropylcellulose is preferable from the viewpoint of coating properties. .

Although the thickness of the said outermost layer is not specifically limited, 1-200 micrometers is preferable and 2-100 micrometers is more preferable. Moreover, in the case of a tablet, it is preferable to set the adhesion amount of the outermost layer to 0.6-10.5 mg/300 mg (0.2-3.5 mass %) with respect to predetermined 300 mg, and 1.5-7.5 mg/300 mg (0.5-2.5 mass %). ) is more preferable. In the case of granules, powders, and powders, it is preferable to set it as 1-30 mass %, and it is more preferable to set it as 2-25 mass %. By making the thickness and adhesion amount of an outermost layer more than the lower limit of the said range, a mouthfeel and taste can be changed. On the other hand, by making the thickness and adhesion amount of an outermost layer into below the upper limit of the said range, manufacturing time can be set suitably.

Organic solvents, such as water and ethanol, can be contained in said composition for outermost layer in the range which does not impair the effect of this invention. The solvent compounding quantity in the composition for outermost layers is suitably selected in 1-98 mass % with respect to the whole composition for outermost layers, 50-98 mass % is preferable, and its 70-96 mass % is more preferable.

The method in particular for forming the said outermost layer is not restrict|limited, A well-known method is employable. 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 with the lower layer and the enteric coating layer formed thereon and drying by heating is exemplified. The coating solution can be appropriately warmed, and the temperature is preferably 30 to 80°C, and the drying temperature is preferably 40 to 80°C. As for the addition rate of a coating solution, 1-5 g/min is preferable with respect to 1 m<3>/min of dry air volume. In addition, it is also possible to adopt the method of dip coating in which the object to be coated is immersed in the coating solution and dried. Drying is preferably carried out until the moisture content in the coating formulation is 0.1 to 20% by mass, particularly 0.5 to 5% by mass.

In this case, the coater is not particularly limited, and a pan coater, a fluidized bed coater, an electric coater, or the like can be used.

(V) method for preparing the coating formulation

The coating formulation of the present invention comprises a step of forming a lower layer by spraying (A) a solution containing a high molecular compound having a viscosity of less than 300 mPa·s at 25° C. of a 6 mass % aqueous solution onto the object to be coated, and drying; A solution containing (B) alginate and (C) a plasticizer is sprayed on the outside of the lower layer to form an enteric coating layer by drying, and if necessary, (D) a solution containing a film-forming component is sprayed And it can manufacture by passing through the process of forming an outermost layer by drying. The details of each step are as described above, but the formulation of the coating solution to be used, the conditions of the coating, etc. can be appropriately set within a range that does not impair the effects of the present invention, and is not particularly limited.

A coating solution for forming each layer of the lower layer, the enteric coating layer and, if necessary, the outermost layer can be obtained by mixing the above-mentioned essential components. Then, by sequentially forming the lower layer, the enteric coating layer, and, if necessary, the outermost layer on the object to be coated using each of the above-described coating solutions, a coating formulation having both good enteric properties and excellent storage stability can be obtained. In addition, since the coating solution of each layer uses water as a solvent, a water-soluble film|membrane is formed respectively.

The enteric coating layer formed from the coating composition contains the component (B), and as described above, an aqueous alginate solution is directly dried to form a water-soluble film. This water-soluble film has the characteristics of being soluble in neutral to alkaline properties by replacing monovalent cations with hydrogen ions under acidic conditions to change to alginic acid to form an insoluble film.

The enteric coating layer formed from the coating composition is enteric, that is, has the property of "dissolving in the intestines without dissolving in the stomach, and allowing the object to be coated to reach the intestines." An enteric coating formulation having an enteric coating film can be obtained.

Further, under the enteric coating layer, a lower layer containing the component (A) is formed, and since the lower layer functions as a base for protecting the enteric coating layer from deterioration over time, dissolution inhibiting property under acidic conditions with the passage of time This fall can be suppressed as much as possible, and the storage stability of a coating formulation can be improved remarkably.

In addition, if necessary, by forming the outermost layer containing the component (D) again on the outside of the enteric coating layer, it is possible to bring about a change in taste, mouth feel, and appearance.

Example

Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not limited to the following Example. In addition, in the following example, when there is no particular specification, "%" of a composition shows mass %, and a ratio shows mass ratio.

[Examples 1 to 15, Comparative Examples 1 and 2]

First, in producing a coating formulation, the following predetermined|prescribed were prepared.

[Sojeong (素錠)]

The following raw materials were mixed, and tableting was performed using a tableting machine to obtain tablets (300 mg, φ9.0 mm, thickness 5 mm).

<Predetermined composition>

Lactoferrin: 1,156g

Bibal(卑撥) Extract Mal(末) : 500g

Lactose: 492.5g

Crystalline Cellulose: 731.5g

Carboxymethylcellulose sodium: 60g

Sucrose fatty acid ester: 30g

Fine silicon dioxide: 30g

The detail of each component mentioned above is as follows.

Lactoferrin: Morinaga Milk Co., Ltd.

Bival Extract: Maruzen Pharmaceutical Co., Ltd., 「Hihatsu Extract MF」

Lactose: Furointo Industrial Co., Ltd., 「Lactose Grunyu」

Crystalline cellulose: Asahi Kasei Chemicals Co., Ltd., 「Theoras FD-101」

Sodium carboxymethyl cellulose: Nichirin Chemical Industry Co., Ltd., 「ECC-FA」

Sucrose Fatty Acid Ester: Mitsubishi Chemical Foods Co., Ltd., 「Ryoto Sugar Ester S-370F」

Fine silicon dioxide: DSL Japan Co., Ltd., 「Capurex FPS-500」

Next, coating solutions for forming the lower layer, the enteric coating layer, and the outermost layer having the compositions shown in Tables 2 to 4 below were prepared in the following order.

[Preparation of coating solution for lower layer]

(A) component and (E) component were each uniformly melt|dissolved in water at room temperature.

[Preparation of coating solution for enteric coating layer]

(B) component and (C)component were disperse|distributed to water, respectively, after it was heated, it melt|dissolved uniformly, the melt|dissolved liquid was mixed, other components were added, and mixing and stirring were carried out again.

[Preparation of coating solution for outermost layer]

(D) The component was uniformly melt|dissolved in water at room temperature.

On the predetermined surface prepared above, using each of the coating solutions prepared above, the lower layer, the enteric coating layer, and, if necessary, the outermost layer were sequentially formed to prepare a coating formulation (tablet). The conditions at the time of coating each layer are as follows.

[coating]

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

[substratum]

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

[Enteric coating layer]

Using a coating machine (Paurec Coater PRC-05 made by Paurek), the coating solution (Example and Comparative Example 1: 150 g, Comparative Example 2: 204 g) was sprayed at an average of 2 ml/min for 200 g of the cleaning agent, and the temperature was about 50 Coating was carried out at °C. After spraying, it was dried at about 45° C. for 2 min to obtain a coating formulation (tablet). The thickness of the coating film was in the range of 20 to 200 μm.

[Outermost layer]

Using a coating machine (Paurec Coater PRC-05 made by Pau Lec), 50 g of the coating solution was sprayed with an average of 2 ml/min for 200 g of the cleaning agent, and coating was performed at a temperature of about 50°C. After spraying, it was dried at about 45° C. for 2 min to obtain a coating formulation (tablet). The thickness of the coating film was in the range of 5-50 μm.

The coating formulation obtained above was evaluated for enteric properties in the following order immediately after coating and after storage for 4 months at 50 ° C. and 75% RH. By comparing the evaluation results before and after storage of enteric properties Storage stability was confirmed. In addition, the appearance (coatability) of the formulation immediately after coating was evaluated.

[Acid pH dissolution test]

A dissolution test was performed in accordance with the one country general test method (paddle method) using one country (日局) solution (pH 1.2).

◎: Less than 10% dissolution in 2 hours

○: 10% or more and less than 20% dissolution in 2 hours

△: 20% or more and less than 40% dissolution in 2 hours

×: more than 40% dissolution in 2 hours

[Neutral to alkaline pH dissolution test]

A dissolution test was carried out using a national two-solution (pH 6.8) according to the one-country general test method (paddle method).

○: 70% or more dissolution in 2 hours

△: 30% or more and less than 70% dissolution in 2 hours

×: less than 30% dissolution in 2 hours

In addition, in the above [acid pH dissolution test], "Δ", "○" or "double-circle", and the case of "○" in the above [neutral to alkaline pH dissolution test] was referred to as "enteric solubility".

[Evaluation of appearance]

The surface of the formulation (tablet) immediately after coating was visually observed, and the appearance was evaluated according to the following evaluation criteria.

(double-circle) : Coating is made uniformly, flaking and peeling are not seen, and the coating surface is glossy.

(circle): The coating is made uniformly, and although peeling and peeling are hardly seen, there is a little roughness on the coating surface.

(triangle|delta): The peeling of a coating is seen in some tablets.

x: The peeling and peeling of a coating are seen in most tablets.

The detail of the raw material used by an Example and a comparative example is as follows. In addition, about the detail of the alginate which is (B) component, it displayed in Table 1 separately.

[substratum]

Hydroxypropylmethylcellulose: manufactured by Shin-Etsu Chemical Co., Ltd., 「Metoroju SE-06」

Pectin: manufactured by Daishin Pharmaceutical Co., Ltd., 「Classic AF701」

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

Gum arabic: manufactured by Japan Powdered Pharmaceutical Co., Ltd., 「Gum arabic」

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

Flulan: Hayashibara Co., Ltd., 「Flurane」

Sucrose: Dainippon Meiji Jedang Co., Ltd., 「Sucrose」

[Enteric coating layer]

Glycerin: manufactured by Sakamoto Pharmaceutical Co., Ltd., 「Glycerin (food additive)」

Silica (fine silicon dioxide): Fuji Silysia Chemical Co., Ltd., 「Silopage 720」

Talc: Made by Matsumura Industrial Co., Ltd., 「Crown Talc PP」

[Outermost layer]

Hydroxypropylmethylcellulose: manufactured by Shin-Etsu Chemical Co., Ltd., 「Metorose SE-06」

[Table 1]

[Table 2]

[Table 3]

[Table 4]

Claims (11)

(A) a lower layer containing a high molecular compound having a viscosity of less than 300 mPa·s at 25° C. of (A) a 6% by mass aqueous solution formed thereon, and (B) alginate and (C) a plasticizer formed on the lower layer As a coating formulation having an enteric coating layer comprising:
The component (A) is one or more selected from the group consisting of hydroxypropylmethylcellulose, pectin, cardlane, fullulan, hydroxypropylcellulose, polyvinyl alcohol, and gum arabic;
The coating formulation characterized in that the adhesion amount of the said lower layer is 0.2-3.5 mass % with respect to predetermined mass. According to claim 1,
A coating formulation characterized in that it contains at least one selected from lactic acid bacteria, cysteine, protein, and peptide, which is an object to be coated. 3. The method of claim 1 or 2,
A coating formulation characterized in that the amount of the enteric coating layer applied is 0.5 to 20 mass % with respect to a predetermined mass. 3. The method of claim 1 or 2,
(A) A component is hydroxypropylmethylcellulose, The coating formulation characterized by the above-mentioned. 3. The method of claim 1 or 2,
(B) The coating formulation characterized in that component is an alginate whose viscosity in 20 degreeC of (B-1) 1 mass % aqueous solution is 50 mPa*s or more. 6. The method of claim 5,
Furthermore, (B-2) The viscosity in 20 degreeC of 1 mass % aqueous solution contains the alginate of less than 50 mPa*s, The coating formulation characterized by the above-mentioned. 3. The method of claim 1 or 2,
In addition, the enteric coating layer contains (D) a film-forming component, and the (D) component is gelatin, pectin, cardlane, fullulan, gum arabic, xanthan gum, gellan gum, hydroxypropylmethylcellulose, carboxymethyl A coating formulation, characterized in that one or two or more selected from the group consisting of sodium cellulose, hydroxypropyl cellulose, agar, chitosan, tamarind seed rubber, locust bean rubber, polyvinyl alcohol, and ethyl cellulose aqueous dispersion. 3. The method of claim 1 or 2,
In addition, the lower layer contains (E) a plasticizer, and the (E) component is sucrose fatty acid ester, glycerin fatty acid ester, monoglycerol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, glycerin, propylene glycol, polyethylene glycol, glucose, Fructose glucose solution sugar, sucrose, sorbitol, maltitol, mannitol, erythritol, xylitol, dodecanol, tridecanol, tetradecanol, pentadecanol, hexadecanol, heptadecanol, octadecanol, hexadecyl alcohol, iso A coating formulation, characterized in that at least one selected from the group consisting of stearyl alcohol, 2-octyldodecanol, and medium chain fatty acid esters. 3. The method of claim 1 or 2,
(C) The mass ratio represented by /(B) is 0.05-3.0, The coating formulation characterized by the above-mentioned. 8. The method of claim 7,
(B) The mass ratio represented by /(D) is 0.33-20, The coating formulation characterized by the above-mentioned. According to claim 1,
The coating formulation, characterized in that it contains lactoferrin, which is the object to be coated.