JP6722925B2 - Method for producing tablet having enteric coating - Google Patents

Description

The present invention relates to a method for producing an enteric-coated tablet, and particularly to a method for producing an enteric-coated tablet containing shellac as a component.

There are many functional ingredients that are unstable in the acidic conditions of the stomach and are absorbed by the body in the intestine. Such components are processed for delivery to the intestine while preventing degradation in the stomach. Examples of such a processed preparation include a preparation using an enteric coating that does not dissolve in the pH condition of the stomach and dissolves in the pH condition of the small intestine to release the components. Examples of enteric coatings include methacrylic acid-based polymer compounds, shellac and zein.

Methacrylic acid-based polymer compounds, shellac, and zein are drug additives listed in the Japanese Pharmacopoeia. In addition, shellac derived from natural products and zein are widely used as food additives. For example, shellac and zein are used in a method for producing an enteric-coated food containing a protein having physiological activity such as lactoferrin as a component (Patent Document 1). In addition, coating methods and coating compositions using shellac and zein have been reported (Patent Documents 2 and 3).

With the recent increasing interest in functional foods, more efficient and effective methods for forming enteric coatings have been demanded.

JP 2002-161050 A JP 2005-26551 A International publication WO2014/136857 A1

In the production of enteric-coated foods using zein and shellac, which are materials for enteric-coated preparations that can be applied not only to pharmaceuticals but also to foods, the inventors have conducted research and development for the purpose of providing a more efficient method. .. The present invention aims to provide a method for efficiently producing a tablet having a high degree of enteric property.

The present inventors have conducted research and development for the purpose of solving the above technical problems, and by adjusting the relative humidity in the coating pan, to efficiently produce tablets having a high enteric function. The inventors have found that the above can be achieved and completed the present invention. That is, the present invention provides the following inventions.

[1] An intestine containing a physiologically active ingredient, which comprises a step of spraying an aqueous solution of an enteric-coated raw material in a coater in which the relative humidity of supply air is adjusted to 6.0 to 14.0% to form an enteric-coated film. A method for producing a soluble tablet, wherein the enteric-coated raw material is selected from shellac and zein.

[2] The method according to [1], wherein the enteric coating amount in the enteric coated tablet is 5 to 20% by weight.
[3] The method according to [1] or [2], wherein the physiologically active ingredient is a protein.

[4] The method according to any one of [1] to [3], wherein the enteric-coated raw material is shellac.
[5] The method according to any one of [1] to [4], wherein the aqueous solution of the enteric-coated raw material contains a basic amino acid and/or a basic phosphate.

[6] The method according to any one of [1] to [5], wherein the aqueous solution of the enteric-coated raw material contains ethanol.
[7] The aqueous solution of the enteric raw material contains a basic amino acid, and the addition amount of the basic amino acid is 0.05 to 0.40 parts by weight with respect to 1 part by weight of shellac, [1] to [6] The method described in one of.

[8] The method according to any one of [1] to [7], wherein the physiologically active ingredient is lactoferrin.
[9] The method according to any one of [1] to [8], wherein the enteric coated tablet is used as a food.

According to the present invention, a tablet having a high enteric function can be efficiently produced.

3 is a photograph showing the appearance of tablets obtained under each condition of Test Example 1. 3 is a photograph showing the appearance of the tablet obtained in Test Example 1 after an enteric coating test in solution I.

The coater used in the present invention is not particularly limited, and may be any coater normally used for forming an enteric coating film in a preparation. For example, Aqua Coater AQC-130 (manufactured by Freund Sangyo) can be used.

The relative humidity in the coater can be set by adjusting the amount of water in the supply air of the coater and the temperature in the coater, and means the relative humidity of the supply air immediately before the coating pan. The relative humidity at the time of forming the enteric film is, for example, 5.5% or more, 6.0% or more, 6.5% or more, 7.0% or more, and 14.0% or less, 13.0% or less, 12. It may be 0% or less, 11.0% or less, 10.0% or less, 9.5% or less, 9.0% or less, 8.5% or less, 8.0% or less, and specifically, It may be set in the range of 5.5 to 15.0%, 6.0 to 14.0%, 6.5 to 11.0%, or 6.5 to 10.0%.

An aqueous solution of shellac and/or zein can be used as the aqueous solution of the enteric raw material. The aqueous solution may contain components other than the enteric raw materials, and examples thereof include basic amino acids and basic phosphates. Examples of the basic amino acid are not particularly limited, but include, for example, arginine, lysine, ornithine, and more specifically, arginine. When the basic amino acid is added to the aqueous solution, the addition amount can be 0.05 to 0.40 parts by weight with respect to 1 part by weight of shellac.

Examples of basic phosphates include, but are not limited to, trisodium phosphate, tripotassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, tetrasodium pyrophosphate, tetrapotassium pyrophosphate, and the like. To be The aqueous solution may further contain alcohol (for example, ethanol), aliphatic polyol, fatty acid ester, water-soluble sugar, triethyl citrate, polyethylene glycol, sodium lactate and the like as additional components.

The enteric raw material contained in the aqueous solution can be appropriately prepared and can be set, for example, in the range of 0.1 to 30% by weight, 1 to 20% by weight, or 5 to 15% by weight.
In the present invention, for example, AQshelax (registered trademark, manufactured by Freund Industries) can be used as the aqueous solution of the enteric raw material.

As the tablet used in the present invention, for example, a circular tablet having a diameter of 5 to 13 mm and a weight of 100 to 1000 mg, or a tablet having a size corresponding thereto can be used.
When the enteric-coated preparation is a tablet, the undercoated tablet may be coated by spraying. The undercoating can be carried out by a commonly used method, for example, shellac or zein in the solid content can be used in the range of 0.1 to 2.0% by weight.

The temperature in the coater at the time of forming the enteric coating can be appropriately adjusted, and can be set, for example, in the range of 25 to 55°C. Further, the air supply temperature at the time of forming the enteric coating can be appropriately adjusted and can be set, for example, in the range of 20 to 60°C.

The spraying flow rate in the method of the present invention can be appropriately adjusted, and can be set, for example, in a range of 60 to 240 ml/min per spraying liquid speed 1 gun for 100 kg of tablets.
The coating time can be appropriately set based on the concentration of the enteric-coated raw material aqueous solution used, the temperature in the coater, and the like, and the end point may be determined by confirming the amount of enteric-coated film formation. The coating time can be set in the range of 250 to 500 minutes, for example.

The coating amount of the enteric-coated tablet obtained by the method of the present invention is not particularly limited, but for example, the enteric-coated raw material forming the coating should be set within a range of 5 to 11% by weight based on the weight of the entire tablet. You can

The physiologically active ingredient used in the present invention is not particularly limited, and may be, for example, a low molecular weight or high molecular weight pharmaceutical compound, protein, peptide, nutritional supplement ingredient, supplement ingredient and the like. In one aspect of the invention, lactoferrin is used as the bioactive ingredient.

The term "lactoferrin" as used herein includes lactoferrin derived from living organisms extracted from milk of mammals and the like and genetically engineered lactoferrin produced by genetic engineering. Lactoferrin is known to be decomposed by pepsin, which is a proteolytic enzyme in the stomach, under acid conditions of gastric acid. That is, in order to effectively act the present composition, it is particularly technically significant to prepare an enteric coated preparation. Lactoferrin is a polymer having a molecular weight of about 80,000 and has the property of forming a chelate with two trivalent iron ions. All saturated forms are included, and all lactoferrins including human, bovine, recombinant forms, etc., regardless of origin, are included. The composition of the present invention may contain only one type of lactoferrin, or may contain two or more types.

The composition of the present invention is orally administered. The form may be a pharmaceutical composition or a food form. The composition of the present invention is preferably in a dosage form convenient for oral administration, such as powder, powder, granule, tablet or capsule.

Excipients used in formulating the composition of the present invention include lactose, sucrose, glucose, sorbitol, monosaccharides or disaccharides such as lactitol, corn starch, starches such as potato starch, crystalline cellulose, and inorganic substances. Are light silica gel, synthetic aluminum silicate, magnesium aluminometasilicate, calcium hydrogen phosphate, silicon dioxide and the like. However, when lactoferrin is used as the physiologically active ingredient, the reducing monosaccharides and disaccharides undergo an aminocarbonyl reaction with the ε-amino group of the active ingredient lactoferrin group protein (or an enzymatic degradation product of lactoferrin group protein) to denature it. May cause Especially in the presence of water or iron ions, a rapid aminocarbonyl reaction may proceed.

Excipients used when formulating the composition of the present invention include starches as disintegrants, carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC), carboxymethylcellulose sodium salt, polyvinylpyrrolidone, and the like. As the lubricant, sucrose fatty acid ester, calcium stearate, magnesium stearate and the like can be used.

The composition of the present invention may be administered alone or in combination with other drugs. In addition, the composition of the present invention can be added to foods or feeds for administration.
When lactoferrin is used as the physiologically active ingredient, lactoferrin powder is usually very light in specific gravity and cannot be tabletted as it is, so to obtain a composition of the present invention which is a stable formulation with a further maintained pharmacological effect, For example, an active ingredient, an excipient, a binder, and a disintegrant are mixed, and the mixture is subjected to high pressure molding with a slag machine to form a thin, large flat disk, which is crushed and sieved to prepare granules of a certain size. In the case of making tablets, a lubricant is added to the granules to form tablets, and the tablets are optionally covered with a coating film to obtain a product.

Whether the produced composition is enteric or not is determined by adding hydrochloric acid and water to 2.0 g of sodium chloride to dissolve it into 1000 ml, the first liquid (pH 1.2, Japanese Pharmacopoeia/General Test Method 41). And by confirming the disintegration property by using a second solution (pH 6.8) in which 250 ml of 0.2 M potassium dihydrogen phosphate reagent solution and 118 ml of 0.2 N sodium hydroxide reagent solution and water are added to make 1000 ml. You can Tablets or granules that do not disintegrate in the first liquid for 120 minutes and disintegrate in the second liquid for 60 minutes do not dissolve in the stomach and disintegrate only when they enter the duodenum, and the active ingredient is eluted. It can be determined that the substance is enteric.

The enteric coated tablet obtained in the present invention can be prepared so as to contain the physiologically active ingredient in an amount of 0.1 to 5,000 mg, 0.5 to 2,000 mg, or 10 to 1,000 mg per tablet.

When lactoferrin is used as the physiologically active ingredient, the composition of the present invention generally contains about 0.1 mg to about 5,000 mg, preferably about 0.5 mg to about 2,000 mg of lactoferrin as the active ingredient per day. Most preferably, about 10 mg to about 1,000 mg can be administered at once or in divided doses, such as before meals, after meals, between meals and/or before bedtime. The dose may be individually determined depending on the age, weight, and purpose of administration of the patient to be administered.

The enteric-coated preparation of the present invention can be used as a food such as a functional food or a supplement. Further, the enteric coated tablet of the present invention can be used as a pharmaceutical tablet.

Hereinafter, the present invention will be specifically described with reference to Examples, but the present invention is not limited thereto.
<Production Example 1>
Uncoated tablets containing 100 mg of lactoferrin in one tablet (diameter 9 mm, weight 300 mg) were coated with 0.5% by weight of solid content of shellac undercoating tablets in a coating machine (Aqua Coater AQC-130, manufactured by Freund Sangyo). The coating operation was performed using an aqueous shellac solution (AQselax (registered trademark), manufactured by Freund Industrial Co., Ltd.) under three types of relative humidity in the coater: low humidity conditions, medium humidity conditions, and high humidity conditions. The components of the aqueous shellac solution are as shown in the table below.

The above coating machine is equipped with a dehumidifying/humidifying unit that controls the weight of water in the air on the air supply side, and the absolute humidity can be set in advance according to the temperature and humidity conditions of the outside air. The temperature of the air supply just before the pan was adjusted to control the relative humidity in the coating pan.

In the low-humidity condition test, coating was performed at 5.0% relative humidity by setting the spray liquid speed at 120 ml/min and the air supply temperature at 60° C. in an environment of outside temperature of 22° C. and relative humidity of 48%. .. In the test of medium humidity condition, coating was carried out at a relative humidity of 7.5% by setting a spray liquid speed of 120 ml/min and an air supply temperature of 67° C. under an environment of an outside air temperature of 22° C. and a relative humidity of 45%. .. Also, in the high humidity test, the coating was performed at a relative humidity of 15.0% by setting the spray liquid speed at 120 ml/min and the supply temperature at 47°C under the environment of an outside temperature of 22°C and a relative humidity of 46%. went. The number of guns (3), pan rotation speed (4 rpm), and other spray conditions were all set to the same conditions. The coating amount was evaluated in 5 levels of 1, 3, 5, 8 and 11% by weight based on the weight of the plain tablet.

The spraying time required to reach the standard coating amount of 8% by weight (excluding the undercoat) varies depending on the humidity conditions. The higher the relative humidity in the coating pan, the easier the coating is to form and the higher the humidity conditions. It was 300 minutes, 420 minutes under medium humidity conditions, and 465 minutes under low humidity conditions.
<Test Example 1>
The tablets thus produced were subjected to an appearance inspection and an enteric property evaluation. The results are shown in Table 2.

In the visual inspection, the presence or absence of cracks on the tablet surface, the presence or absence of sticking, and the presence or absence of powdering were evaluated on a scale of 5 according to the following criteria (Table 3).

In the case of spraying at low humidity, powdering was observed on the tablet surface under the condition of the coating amount of 3 to 11%. This is probably because the powdered spray liquid adhered to the tablet surface. In the case of spraying at high humidity, so-called "sticking" between the tablets was observed under the condition of the coating amount of 3 to 11%. It is considered that this is because the surface of the tablets was not sufficiently dried due to high humidity, and after the tablets were adhered to each other, a trace of peeling remained. No cracks "cracks" on the tablet surface were observed under any of the conditions (see Figure 1).

The enteric evaluation was carried out based on the Japanese Pharmacopoeia 14th edition. It was confirmed that all the manufactured tablets were compatible with the test using the first liquid (pH about 1.2) and the second liquid (pH about 6.8) as enteric coated tablets. On the other hand, after the completion of the test with the first liquid, it was confirmed from the appearance that the first liquid penetrated the inside of the tablet, and it was confirmed that the acidic first liquid penetrated the tablets with a coating amount of 5% by weight or more under medium humidity conditions. No penetration was observed in the other tablets. FIG. 2 shows a photograph of the appearance of the tablet coated under the conditions of low, medium and high humidity (only the coating amount is 11% by weight) after the test with the first liquid. In the tablets under low humidity conditions, water soaked due to peeling of the coating film formed at the tablet edge portion, and in tablets under medium humidity conditions, no soaking was observed. In addition, it was observed that the tablets under high humidity conditions were soaked from the sticking and peeling traces on the tablet surface.

<Test Example 2>
A problem of the enteric film is that cracks are generated on the surface of the coating film due to insufficient coating strength. Therefore, the tablets prepared by the method of Production Example 1 under three kinds of conditions of low humidity condition, medium humidity condition and high humidity condition were put in a transparent Lamizip bag and stored at -20°C for 10 days (relative humidity: about 20%). %) and the occurrence of cracks was observed. As a result, large cracks were observed on the film surface and tablet edge portions on the 5th day in the tablets produced under low humidity conditions. On the other hand, it was confirmed that a thin crack was generated on the tablet surface on the 10th day in the tablets produced at medium and high humidity, but this was not a problem in practical use.

Claims (9)

A physiologically active ingredient is contained, which includes a step of forming an enteric coating by spraying an aqueous solution of an enteric coating material in a coater whose relative humidity of supply air is adjusted to 6.0 to 14.0% by a dehumidifying/humidifying unit. A method for producing an enteric coated tablet, wherein the enteric coated raw material is selected from shellac and zein. The method according to claim 1, wherein the enteric coating amount in the enteric coated tablet is 5 to 20% by weight. The method according to claim 1 or 2, wherein the physiologically active ingredient is a protein. The method according to any one of claims 1 to 3, wherein the enteric raw material is shellac. The method according to any one of claims 1 to 4, wherein the aqueous solution of the enteric raw material contains a basic amino acid and/or a basic phosphate. The method according to any one of claims 1 to 5, wherein the aqueous solution of the enteric raw material contains ethanol. The aqueous solution of the enteric raw material contains a basic amino acid, and the addition amount of the basic amino acid is 0.05 to 0.40 parts by weight relative to 1 part by weight of shellac. The method described in. The method according to any one of claims 1 to 7, wherein the physiologically active ingredient is lactoferrin. The method according to any one of claims 1 to 8, wherein the enteric coated tablet is used as a food product.