Enteric-coated hard capsules

Abstract

To provide a hard capsule composed of a hard capsule coating, which is moldable by a cold gelling technique and has enteric-coating properties, a preparation liquid for a hard capsule, method for preparing a hard capsule preparation liquid, and a method for preparing a hard capsule.SOLUTION: A capsulated preparation liquid includes an enteric-coated methacrylic acid copolymer, a water-insoluble alkyl methacrylate copolymer, a polyvinyl alcohol, and a gelator. Such a preparation liquid enables preparation of a hard capsule which is moldable by a cold gelling technique and has enteric-coating properties.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an enteric coated hard capsule, an enteric coated hard capsule preparation, a method for preparing an enteric coated hard capsule preparation, and a method for preparing an enteric coated hard capsule. [Background technology]

[0002] "Enteric-coated" refers to a dosage form of a formulation for oral administration, and generally refers to a formulation characteristic that makes it difficult to dissolve in the stomach. Furthermore, such formulations have the characteristic of being easily soluble after being transferred to the intestine. Enteric-coated formulations do not release active pharmaceutical ingredients in the stomach, which is a strongly acidic environment, but release the active pharmaceutical ingredients after the formulation has been transferred to the intestine. Therefore, enteric-coated formulations are primarily used to protect active pharmaceutical ingredients from gastric acid or gastric enzymes, or to sustainably release active pharmaceutical ingredients by utilizing the time the formulation is transferred from the stomach to the small intestine.

[0003] In the field of pharmaceutical preparations, "enteric" is used in Japan (17th Pharmacopoeia, 6.10 Dissolution Test, 4.3 Enteric Preparations) and the United States (US Pharmacopeia Monograph <711> The definitions are almost identical in the Pharmacopeia of the United States, Europe, and the United States (European Pharmacopeia, 2.9.3, Delayed-Release Dosage Forms) and Japan (European Pharmacopeia, 2.9.3, Delayed-Release Dosage Forms). In particular, Japan, Europe, and the United States all agree on the requirement that the drug must be substantially insoluble for two hours at 37°C in an acidic environment (approximately pH 1.2, diluted hydrochloric acid). On the other hand, there are no specific time restrictions on the intestinal dissolution characteristics. The required dissolution characteristics vary depending on factors such as the target release site (small intestine, colon, or large intestine) and whether the drug release characteristics are immediate-release or sustained-release.

[0004] When the pharmaceutical dosage form is a hard capsule, enteric-coated hard capsules are prepared by a method (coating method) in which a non-enteric-coated hard capsule filled with a content is coated with an enteric polymer similar to that used for tablets, and in some cases, an enteric coating is applied to a non-enteric-coated empty capsule before it is released from a dipping pin by a dipping method (Patent Documents 1 and 2).

[0005] Furthermore, attempts have been made to make the hard capsule shell itself enteric. Examples of such prior art techniques include salifying almost all of the acid groups (especially carboxyl groups) of an enteric polymer to obtain a water-soluble derivative containing a soft water-soluble enteric polymer, or at least partially neutralizing a non-salted polymer with a basic neutralizing agent and dissolving it in water, or using a non-salted emulsion dispersion (Patent Document 3), and using alternative techniques that do not require solubilization of the polymer, such as injection molding (Patent Document 4). [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Special Publication No. 2013-500293 [Patent Document 2] Special Publication No. 2016-531984 [Patent Document 3] Special Publication No. 2015-515962 [Patent Document 4] Special Publication No. 2004-522746 Summary of the Invention [Problem to be solved by the invention]

[0007] However, in general, the preparation of enteric coated hard capsule formulations using the coating methods shown in Patent Documents 1 and 2 requires filling the capsule with the contents, fitting the cap and body together, and sealing the fitting portion before coating the surface, which makes the preparation process complicated. Furthermore, the workload resulting from the complicated preparation process falls on the manufacturer that fills the capsule with the contents, not on the hard capsule manufacturer. For these reasons, it is desirable that the hard capsule shell itself be enteric coated. Hard capsules are usually prepared by the dipping method. Specifically, the dipping method involves dissolving a capsule shell polymer material to form an aqueous solution, immersing a molding pin (typically made of stainless steel) in the aqueous polymer solution, lifting the molding pin out of the immersion liquid, inverting the molding pin, and drying the aqueous polymer solution attached to the surface of the molding pin to form a film about 100 μm thick. The dried capsule shell is then removed from the molding pin and cut to the desired length. The contents are then filled, a cap and a body are assembled, and the hard capsule is printed on the surface, followed by packaging.

[0008] The hard capsule composition described in Patent Document 3 can be coated by a thermal gel method, but the thermal gel method generally has problems such as high equipment costs, complicated preparation processes, and high drying temperatures, resulting in poor energy efficiency.

[0009] Furthermore, the hard capsule preparation liquid described in Patent Document 4 is for injection molding and cannot be used to prepare hard capsules by the dipping method. Furthermore, since the shell thickness of injection-molded hard capsules is different from that of capsules prepared by the cold gel method, there is a problem in that the contents cannot be filled into capsules using a capsule filling device that is compatible with hard capsules prepared by the dipping method.

[0010] An object of the present invention is to provide a hard capsule that can be molded by the cold gel method and that is made of a hard capsule shell having enteric properties, a hard capsule preparation solution, a method for preparing the hard capsule preparation solution, and a method for preparing the hard capsule. [Means for solving the problem]

[0011] As a result of extensive research, the present inventors have found that it is possible to prepare hard capsules having enteric properties that can be molded by the cold gel method using a capsule preparation solution containing an enteric methacrylic acid copolymer, a water-insoluble (meth)acrylic acid alkyl ester copolymer, polyvinyl alcohol, and a gelling agent.

[0012] The present invention includes the following embodiments. Item 1. An enteric hard capsule comprising a coating containing a first component, a second component, a third component, and a fourth component, wherein the first component is an enteric methacrylic acid copolymer, the second component is a water-insoluble (meth)acrylic acid alkyl ester copolymer, the third component is polyvinyl alcohol, and the fourth component is a gelling agent. Item 2. The enteric hard capsule according to Item 1, wherein the enteric methacrylic acid copolymer is at least one selected from the group consisting of a copolymer of methacrylic acid with methyl methacrylate and methyl acrylate, and a copolymer of methacrylic acid with ethyl acrylate. Item 3. The enteric hard capsule according to Item 1 or 2, wherein the enteric methacrylic acid copolymer is a copolymer consisting of 40 to 60% by mass of methacrylic acid and 60 to 40% by mass of ethyl acrylate. Item 4. The enteric hard capsule according to any one of Items 1 to 3, wherein the water-insoluble (meth)acrylic acid alkyl ester copolymer is a copolymer of methyl methacrylate and ethyl acrylate. Item 5. The enteric coated hard capsule according to any one of Items 1 to 4, further comprising 1 to 10% by mass of water, assuming the mass of the shell per capsule to be 100% by mass. Item 6. The enteric hard capsule according to any one of Items 1 to 5, further comprising, as a fifth component, a basic neutralizer that is acceptable as a pharmaceutically or food additive, wherein the content of the basic neutralizer is an amount that neutralizes 0.5 mol % to 10 mol % of the carboxyl groups of the first component, where the number of moles of carboxyl groups of the first component contained in the shell per capsule before neutralization is taken as 100 mol %. Item 7. The enteric coated hard capsule according to Item 6, wherein the basic neutralizing agent is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonia, and ammonium carbonate. Item 8. The enteric hard capsule according to any one of Items 1 to 7, further comprising a gelling aid as a sixth component. Item 9. An enteric coated hard capsule according to Item 8, wherein the gelling agent is gellan gum and the gelling aid is at least one water-soluble calcium salt selected from the group consisting of calcium lactate, calcium acetate, calcium pantothenate, calcium chloride, calcium bromide, and calcium nitrate. Item 10. The enteric hard capsule according to any one of Items 1 to 9, wherein, when the total mass of the first component, the second component, and the third component contained in the shell is taken as 100% by mass, the proportion of the first component is α% by mass, the proportion of the second component is β% by mass, and the proportion of the third component is γ% by mass, α is in the range of 50 to 80. Item 11. The enteric hard capsule according to Item 10, wherein the β is in the range of 10 to 40. Item 12. The enteric hard capsule according to Item 10 or 11, wherein γ is in the range of 5 to 40. Item 13. The enteric coated hard capsule according to any one of Items 1 to 12, wherein the ratio of the content of the fourth component to the total mass of the first component, second component, and third component contained in the shell is 5 or less, where the total mass of the first component, second component, and third component is 100. Item 14. The enteric coated hard capsule according to Items 8 to 13, wherein the ratio of the content of the fifth component to the total mass of the first component, second component, and third component contained in the shell is 5 or less, where the total mass of the first component, second component, and third component is 100. Item 15. The enteric coated hard capsule according to any one of Items 6 to 14, wherein at least a portion of the first component forms a salt with the basic neutralizing agent. Item 16. The enteric hard capsule according to any one of Items 1 to 14, further comprising a plasticizer and / or a light-blocking agent. Item 17. The enteric hard capsule according to any one of Items 1 to 16, wherein the shell has a thickness of 50 to 250 μm. Item 18. The enteric coated hard capsule according to any one of Items 1 to 17, wherein the elastic modulus of the shell at 25°C and a relative humidity of 22% is 1 GPa to 5 GPa. Item 19. The enteric coated hard capsule according to any one of Items 1 to 18, wherein the shell has a breaking elongation of 2% to 30% at 25°C and a relative humidity of 22%. Item 20. The enteric hard capsule according to any one of Items 1 to 19, wherein the enteric hard capsule has a dissolution rate of 25% or less after 2 hours in a dissolution test using a solution having a pH of 1.2. Item 21. The enteric coated hard capsule according to Item 20, wherein the dissolution rate of the enteric coated hard capsule in the dissolution test is 10% or less. Item 22. An enteric coated hard capsule preparation solution comprising component i, component ii, component iii, component iv, and a solvent, wherein component i is an enteric methacrylic acid copolymer, component ii is a water-insoluble (meth)acrylic acid alkyl ester copolymer, component iii is polyvinyl alcohol, and component iv is a gelling agent; and the enteric coated hard capsule preparation solution. Item 23. An enteric coated hard capsule preparation according to Item 22, wherein component v further comprises a basic neutralizing agent that is acceptable as a pharmaceutically or food additive, and a portion of component i is partially neutralized by component v. Item 24. The enteric coated hard capsule preparation solution according to Item 23, wherein the content of the basic neutralizing agent is an amount that neutralizes 0.5 mol % or more and 10 mol % or less of the carboxyl groups of the first component, when the number of moles of carboxyl groups of the first component contained in the shell per capsule before neutralization is taken as 100 mol %. Item 25. The enteric coated hard capsule preparation according to any one of Items 22 to 24, wherein the component i is dispersed as colloidal particles. Item 26. The enteric coated hard capsule preparation solution according to any one of Items 21 to 24, wherein the enteric methacrylic acid copolymer is at least one selected from the group consisting of a copolymer of methacrylic acid with methyl methacrylate and methyl acrylate, and a copolymer of methacrylic acid with ethyl acrylate. Item 27. The enteric coated hard capsule preparation according to any one of Items 22 to 26, wherein the water-insoluble (meth)acrylic acid alkyl ester copolymer is a copolymer of methyl methacrylate and ethyl acrylate. Item 28. The enteric coated hard capsule preparation according to any one of Items 22 to 27, wherein the component ii is dispersed as colloidal particles. Item 29. The enteric coated hard capsule preparation solution according to any one of Items 22 to 28, wherein the basic neutralizing agent is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonia, and ammonium carbonate. Item 30. The enteric coated hard capsule preparation according to any one of Items 22 to 29, further comprising a gelling aid as component vi. Item 31. An enteric coated hard capsule preparation according to Item 30, wherein the gelling agent is gellan gum and the gelling aid is at least one water-soluble calcium salt selected from the group consisting of calcium lactate, calcium acetate, calcium pantothenate, calcium chloride, calcium bromide, and calcium nitrate. Item 32. The enteric coated hard capsule according to any one of Items 21 to 30, wherein α' is in the range of 50 to 80, where the total mass of components i, ii, and iii contained in the shell is taken as 100% by mass, the proportion of the first component is α'% by mass, the proportion of the second component is β'% by mass, and the proportion of the third component is γ'% by mass. Item 33. The enteric coated hard capsule preparation according to Item 32, wherein the β' is in the range of 10 to 40. Item 34. The enteric coated hard capsule preparation according to Item 32 or 33, wherein the γ' is in the range of 5 to 40. Item 35. The enteric coated hard capsule preparation according to any one of Items 22 to 34, wherein, when the total mass of components i, ii, and iii contained in the shell is taken as 100, the ratio of the content of component iv to the total mass is 5 or less. Section 36. Item 36. The enteric coated hard capsule preparation according to any one of Items 22 to 35, wherein the ratio of the content of component v to the total mass of components i, ii, and iii contained in the shell is 5 or less, where the total mass of components i, ii, and iii is taken as 100. Item 37. The enteric coated hard capsule preparation according to any one of Items 22 to 36, wherein the total amount of the components i, ii, and iii is 10 to 30% by mass when the enteric coated hard capsule preparation is taken as 100% by mass. Item 38. The enteric coated hard capsule preparation according to any one of Items 22 to 37, having a viscosity of 100 to 10,000 mPa·s. Item 39. A method for preparing an enteric coated hard capsule preparation, comprising mixing component i, component ii, component iii, and component iv, each of which has been partially neutralized with component v, wherein component i is an enteric methacrylic acid copolymer, component ii is a water-insoluble (meth)acrylic acid alkyl ester copolymer, component iii is polyvinyl alcohol, component iv is a gelling agent, and component v is a basic neutralizing agent that is acceptable as a pharmaceutically or food additive. Item 40. The method for preparing an enteric coated hard capsule preparation solution according to Item 37, wherein the enteric methacrylic acid copolymer is at least one selected from the group consisting of a copolymer of methacrylic acid with methyl methacrylate and methyl acrylate, and a copolymer of methacrylic acid with ethyl acrylate. Item 41. The method for preparing an enteric coated hard capsule preparation liquid according to Item 37 or 38, wherein the water-insoluble (meth)acrylic acid alkyl ester copolymer is a copolymer of methyl methacrylate and ethyl acrylate. Item 42. The method for preparing an enteric coated hard capsule preparation solution according to any one of Items 39 to 41, wherein the basic neutralizing agent is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonia, and ammonium carbonate. Item 43. A method for preparing an enteric coated hard capsule preparation solution according to any one of Items 39 to 42, wherein component i, component ii, component iii, and component iv that have been partially neutralized with component v are mixed by the following steps A to D: step A: dissolving component iii in an aqueous solvent at 80°C to 90°C; step B: adding component i to the solution of component iii; step C: adding component v to the solution obtained in step B; and step D: adding component ii and component iv to the solution obtained in step C. Item 44. A method for preparing an enteric coated hard capsule preparation liquid according to any one of Items 39 to 41, wherein component i, component ii, component iii, and component iv that have been partially neutralized with component v are mixed by the following steps: Step A': preparing a partially neutralized liquid by partially neutralizing component i with component v; Step B': mixing the partially neutralized liquid prepared in Step A' with component iii, component ii, and component iv. Item 45. The method for preparing an enteric coated hard capsule preparation solution according to Item 43 or 44, wherein the content of the basic neutralizing agent is an amount that neutralizes 0.5 mol % or more and 10 mol % or less of the carboxyl groups of component i, when the number of moles of carboxyl groups of component i contained in the shell per capsule before neutralization is taken as 100 mol %. Item 46. The method for preparing an enteric coated hard capsule preparation according to any one of Items 39 to 45, wherein the viscosity of the enteric coated hard capsule preparation is 100 to 10,000 mPa·s. Item 47. A method for preparing enteric-coated hard capsules, comprising the steps of: a first step of immersing a mold pin having a surface temperature lower than that of the enteric-coated hard capsule preparation liquid according to any one of Items 22 to 38 into the enteric-coated hard capsule preparation liquid; and a second step of removing the mold pin from the enteric-coated hard capsule preparation liquid and drying the enteric-coated hard capsule preparation liquid adhering to the mold pin. Item 48. The method for preparing enteric coated hard capsules according to Item 47, wherein the temperature of the enteric coated hard capsule preparation liquid is 50 to 60°C. Item 49. The method for preparing an enteric coated hard capsule according to Item 47 or 48, wherein the surface temperature of the mold pin before immersion in the preparation liquid is 5 to 40°C. Item 50. The method for preparing enteric coated hard capsules according to any one of Items 47 to 49, wherein the enteric coated hard capsule preparation liquid attached to the mold pin is dried at a temperature of less than 40°C. [Effects of the Invention]

[0013] The present invention provides a hard capsule that can be molded by the cold gel process and has a hard capsule shell with enteric properties. Furthermore, the hard capsule can be filled with a content using a conventional capsule filling machine. DETAILED DESCRIPTION OF THE INVENTION

[0014] 1. Explanation of terms and materials First, the terms and materials used in the present specification and claims will be explained. Unless otherwise specified, the terms and materials related to this disclosure follow the explanations in this section.

[0015] In the present disclosure, a "hard capsule" refers to an empty capsule for filling the manufactured capsule shell with contents. Typically, a hard capsule consists of a cap portion and a body portion, and is also called a hard capsule or a two-piece capsule. The "hard capsule" in the present disclosure can be given a shape identical to or similar to that of conventional hard capsules that are commercially available and intended for oral administration to human or animal subjects.

[0016] It should be noted that the "hard capsules" according to the present disclosure do not include soft capsules, which are manufactured by filling the contents between two films and gluing the films together, seamless capsules, which are manufactured by dropping the contents together with a coating solution into a coagulating liquid, and microcapsules, which are prepared by incorporating an active ingredient inside by precipitating or emulsifying a base material.

[0017] In addition, in this disclosure, empty hard capsules are simply referred to as hard capsules or capsules, and those filled with contents are referred to as "hard capsule formulations."

[0018] In the present disclosure, the term "enteric hard capsule" refers to a hard capsule in which the capsule body shell itself has "enteric" properties that meet the following conditions: That is, "enteric" refers to a property that satisfies at least the following condition (i):

[0019] (i) In the dissolution test described in the 17th Edition of the Japanese Pharmacopoeia (hereinafter sometimes simply referred to as the "17th Pharmacopoeia"), when a test subject is immersed in Fluid 1 at 37°C ± 0.5°C for 2 hours, the dissolution rate of the contents is 25% or less, preferably 10% or less. Preferably, the pH of Fluid 1 is approximately 1.2. Fluid 1 can be prepared, for example, by adding 7.0 ml of hydrochloric acid and water to 2.0 g of sodium chloride to make a total volume of 1000 ml.

[0020] "Enteric" preferably satisfies the above condition (i) as well as the following condition (ii): (ii) In the dissolution test, the contents are dissolved when the test subject is immersed in the second fluid at 37°C ± 0.5°C. The pH of the second fluid is preferably about 6.8. The second fluid can be prepared, for example, by dissolving 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate in water, and adding 1 volume of water to 1000 mL of phosphate buffer solution.

[0021] Here, there is no limit to the time for measuring the dissolution rate of the contents in the second liquid. For example, when relatively rapid dissolution is required after reaching the intestine, the dissolution rate 30 minutes after immersion of the test subject in the second liquid is 50%, preferably 70% or more, and more preferably 80% or more. Also, for example, the dissolution rate 45 minutes after immersion of the test subject in the second liquid is 75% or more, preferably 80%, and more preferably 90% or more. Furthermore, for example, the dissolution rate 1 hour after immersion of the test subject in the second liquid is 75% or more, preferably 80%, and more preferably 90% or more.

[0022] Dissolution tests can be conducted in accordance with the dissolution test method prescribed in the 17th Pharmacopoeia (17th Pharmacopoeia, 6.10-1.2 Paddle Method (paddle rotation speed 50 rpm) and use of a sinker corresponding to Figure 6.10-2a in the same document).

[0023] The content to be used in the dissolution test is not limited as long as it dissolves rapidly in the test solution and can be quantified by a known method, such as acetaminophen.

[0024] "Methacrylic acid copolymer" is also called "methacrylate copolymer." A methacrylic acid copolymer is a polymer that contains methacrylic acid monomer units in the backbone.

[0025] More preferably, the methacrylic acid copolymer is composed of a methacrylic acid monomer unit, which is an anionic group, and a neutral alkyl ester monomer unit of acrylic acid or methacrylic acid. The alkyl ester bonded to acrylic acid or methacrylic acid may be an alkyl having 1 to 4 carbon atoms, preferably an alkyl having 1 to 3 carbon atoms. More specifically, the alkyl ester of acrylic acid or methacrylic acid may be at least one selected from the group consisting of methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate, and butyl acrylate.

[0026] The methacrylic acid copolymer is preferably enteric. More preferably, the enteric methacrylic acid copolymer is a copolymer of methacrylic acid (formula (I)) with methyl methacrylate (formula (II)) and methyl acrylate (formula (III)), or a copolymer of methacrylic acid (formula (I)) with ethyl acrylate (formula (IV)).

[0027] [ka]

[0028] The copolymer preferably contains at least 5%, preferably 5 to 70%, particularly 8 to 60%, and more preferably 30 to 60% of methacrylic acid monomer units, where the total number of monomers forming the copolymer (total number of units or total number of groups) is taken as 100. The proportion of each monomer unit can be easily converted to mass % using the molecular weight of each monomer unit.

[0029] A preferred methacrylic acid copolymer is a polymer composed of 40-60% by weight of methacrylic acid (molecular weight 86.04) and 60-40% by weight of methyl methacrylate (molecular weight 100.05) or 60-40% by weight of ethyl acrylate (molecular weight 100.05) (e.g., EUDRAGIT® L100 or EUDRAGIT® L100-55). EUDRAGIT® L100-55 is particularly suitable, being a copolymer composed of 50% by weight of methacrylic acid and 50% by weight of ethyl acrylate. EUDRAGIT® L30D-55 is an aqueous dispersion containing approximately 30% by weight of EUDRAGIT® L100-55. These methacrylic acid copolymers are designed to dissolve at a pH of approximately 5.5 or higher.

[0030] Another preferred example is a polymer composed of 5-15% by weight of methacrylic acid, 10-35% by weight of methyl methacrylate, and 50-70% by weight of methyl acrylate (molecular weight 86.04). More specifically, EUDRAGIT® FS is a copolymer composed of 10% by weight of methacrylic acid, 25% by weight of methyl methacrylate, and 65% by weight of methyl acrylate. EUDRAGIT® FS 30D is a dispersion containing approximately 30% by weight of EUDRAGIT® FS. This methacrylic acid copolymer is designed to dissolve at a pH of approximately 7 or higher, and may be used when intended for delivery to the large intestine, which has a higher pH.

[0031] The above-mentioned enteric methacrylic acid copolymer is generally prepared by an emulsion polymerization process, in which a monomer is copolymerized in an aqueous solution to produce an aqueous emulsion containing very small colloidal particles. Therefore, an aqueous dispersion of very fine colloidal particles with an average particle size of less than 1 μm can be obtained without going through a dissolution process by neutralizing the solid polymer component with a basic neutralizing agent.

[0032] Examples of aqueous dispersions equivalent to EUDRGIT series (Evonik) L30D-55 and equivalent commercial methacrylic acid copolymers include, but are not limited to, Kollicoat series (BASF) MAE30D / DP and Polyquid series (Sanyo Chemical Industries) PA-30. Note that these aqueous dispersions (aqueous emulsions) typically contain less than 0.3% residual monomers, and trace amounts of polysorbate 80 and sodium lauryl sulfate for manufacturing and stabilization purposes, but these are acceptable as unavoidable impurities in the hard capsule shell and hard capsule preparation solution according to the present disclosure.

[0033] The methacrylic acid copolymer may be fully or partially neutralized with a basic neutralizing agent that is pharmaceutically or food additive-acceptable. The carboxyl groups contained in the methacrylic acid copolymer can form salts by neutralization. The basic neutralizing agent is preferably at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonia, and ammonium carbonate.

[0034] The term "(meth)acrylic acid alkyl ester copolymer" refers to a substantially neutral (meth)acrylic acid copolymer, primarily composed of methacrylic acid or acrylic acid alkyl ester neutral monomer units. The alkyl ester bonded to acrylic acid or methacrylic acid may be an alkyl having 1 to 4 carbon atoms, preferably an alkyl having 1 to 3 carbon atoms. The alkyl ester of acrylic acid or methacrylic acid may more specifically be at least one selected from the group consisting of methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate, and butyl acrylate. To be substantially neutral, the proportion of neutral monomers is, for example, greater than 95% by mass, greater than 98% by mass, greater than 99% by mass, or 100% by mass. However, this does not completely exclude the presence of ionic groups in the polymer, and methacrylic acid copolymers having a content of ionic groups, particularly anionic groups, of less than 5% by mass, preferably less than 2% by mass, and preferably less than 1% by mass may be included. The (meth)acrylic acid alkyl ester copolymer is preferably water-insoluble.

[0035] More preferably, a copolymer consisting of 20-40% by weight of methyl methacrylate (molecular weight 100.05) and 60-80% by weight of ethyl acrylate (molecular weight 100.05) (EUDRAGIT® NE or EUDRAGIT® NM type) is suitable. Among these, EUDRAGIT® NE is suitable, which is a copolymer consisting of 70% by weight of ethyl acrylate and 30% by weight of methyl methacrylate. In either case, the copolymer may contain less than 5% by weight, preferably less than 2% by weight, and more preferably less than 1% by weight of methacrylic acid (molecular weight 86.04).

[0036] These water-insoluble (meth)acrylic acid alkyl ester copolymers have a glass transition temperature of less than 100°C or a film-forming temperature (Minimum Film-forming Temperature, MFT) of less than 50°C, and are particularly effective in promoting interparticle fusion when a dispersion containing colloidal particles of enteric methacrylic acid copolymer is dried to form a film, resulting in a transparent, crack-resistant dried film. Furthermore, water-insoluble (meth)acrylic acid alkyl ester copolymers have the advantage that, when added in appropriate amounts, they do not impair acid resistance.

[0037] The water-insoluble (meth)acrylic acid alkyl ester copolymer can also be produced by an emulsion polymerization process, starting from the monomer level through a copolymerization process in an aqueous solution, to produce an aqueous emulsion containing very small colloidal particles. Therefore, an aqueous dispersion of very fine colloidal particles with an average particle size of less than 1 μm can be obtained without going through a dissolution process involving neutralization of the solid polymer component with a basic neutralizing agent.

[0038] "Polyvinyl alcohol" (PVA) is a polymer obtained by saponifying polyvinyl acetate, and is usually classified as a fully saponified product having a degree of saponification of 97% or more and represented by the following formula (1), or a partially saponified product having a degree of saponification of 78 to 96% and represented by the following formula (2). In the present disclosure, either the fully saponified product or the partially saponified product can be used. Although not particularly limited, a partially saponified product having a degree of saponification, n / (n+m), of 78 to 90%, particularly 87 to 90%, is preferably used.

[0039] [ka] (wherein n and m represent any integers)

[0040] The average degree of polymerization (n) of the PVA is not particularly limited as long as it is within a range that allows film-forming ability to be exhibited, but is usually preferably about 400 to 3300, and particularly about 1000 to 3000. The weight-average molecular weight of the PVA calculated from the average degree of polymerization and degree of saponification is about 18,000 to about 200,000, but is not particularly limited to this range. Addition of PVA can provide the capsule shell with appropriate mechanical strength (elastic modulus and resistance to cracking) while maintaining enteric properties.

[0041] In the present disclosure, PVA and a PVA copolymer may be used in combination. Examples of the PVA copolymer include the PVA copolymer obtained by copolymerizing the above-mentioned PVA with a polymerizable vinyl monomer.

[0042] A preferred PVA copolymer is a polymer copolymer obtained by copolymerizing acrylic acid and methyl methacrylate with the partially saponified PVA as the backbone. Examples of commercially available PVA copolymers include the POVACOAT (registered trademark) series (Nissin Chemical Industry Co., Ltd.).

[0043] In this specification, the methacrylic acid copolymer, the (meth)acrylic acid alkyl ester copolymer, and the polyvinyl alcohol may be collectively referred to as the "polymer solid component."

[0044] An example of a "basic neutralizing agent that is acceptable as a pharmaceutically or food additive" is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonia, and ammonium carbonate. In this specification, a basic neutralizing agent that is acceptable as a pharmaceutically or food additive may be simply referred to as a "basic neutralizing agent."

[0045] The "gelling agent" is not limited as long as it can gel the polymer solid component. An example of the gelling agent is gum. A preferred example of gum is gellan gum.

[0046] The "gelling aid" is not limited as long as it can assist the gelling of the gelling agent, and examples thereof include at least one water-soluble calcium salt selected from the group consisting of calcium lactate, calcium acetate, calcium pantothenate, calcium chloride, calcium bromide, and calcium nitrate.

[0047] 2. Enteric-coated hard capsules Certain embodiments disclosed herein relate to enteric coated hard capsules. Specifically, the present invention relates to an enteric hard capsule comprising a coating containing a first component, a second component, a third component, and a fourth component. The first component is a methacrylic acid copolymer, preferably an enteric methacrylic acid copolymer. The second component is a (meth)acrylic acid alkyl ester copolymer, preferably a water-insoluble (meth)acrylic acid alkyl ester copolymer. The third component is polyvinyl alcohol. The fourth component is a gelling agent, preferably gellan gum.

[0048] The coating may contain, as a fifth component, a basic neutralizing agent that is acceptable as a pharmaceutically or food additive. The coating may also contain a gelling aid as a sixth component.

[0049] Furthermore, the coating may contain pharmaceutically and food-acceptable plasticizers, surfactants (emulsifiers), binders (excluding PVA), coating agents, etc. It may also contain sustained-release agents, solubilizers, solubilizers, etc. to control solubility, particularly dissolution characteristics in the neutral pH range. Examples of additives that are acceptable as pharmaceutical additives include, but are not limited to, those listed by application in the Dictionary of Pharmaceutical Additives, 2016 Edition (edited by the Japan Pharmaceutical Additives Association, published by Yakuji Nipposha). Note that these additives may be classified as having multiple applications.

[0050] The plasticizer is not necessarily limited to the specific substances shown in the above-mentioned Dictionary of Pharmaceutical Additives, and is not particularly limited as long as it can be used in pharmaceutical or food compositions and can be added to the capsule shell to impart flexibility. However, suitable substances generally have a molecular weight (Mw) of 100 to 20,000 and have one or more hydrophilic groups, such as hydroxyl groups, ester groups, or amino groups, in one molecule. Examples include dioctyl adipate, adipic acid polyester, epoxidized soybean oil, epoxy hexahydrophthalic acid diester, kaolin, triethyl citrate, glycerin, glycerin fatty acid ester, sesame oil, dimethylpolysiloxane-silicon dioxide mixture, D-sorbitol, medium-chain triglyceride, corn starch-derived sugar alcohol liquid, triacetin, concentrated glycerin, castor oil, phytosterol, diethyl phthalate, dioctyl phthalate, dibutyl phthalate, butylphthalyl butyl glycolate, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, macrogol isopropyl myristate, cottonseed oil-soybean oil mixture, glycerin monostearate, isopropyl linoleate, and polyethylene glycols of various molecular weights (macrogol 400, 600, 1500, 4000, 6000).

[0051] Surfactants (also known as emulsifiers) are used as solubilizers, suspending agents, emulsifiers, dispersants, solubilizers, stabilizers, etc. Specific examples include benzalkonium chloride, benzethonium chloride polyoxyethylene (40) monostearate (polyoxyl 40 stearate*), sorbitan sesquioleate (sorbitan sesquioleate*), polyoxyethylene (20) sorbitan monooleate (polysorbate 80*), glyceryl monostearate (glyceryl monostearate*), sodium lauryl sulfate, and polyoxyethylene lauryl ether (lauromacrogol*). (*: Notation in the Japanese Pharmacopoeia). Other examples include sodium alkylbenzenesulfonate, sucrose fatty acid ester, polyethylene glycol monooleate, polyethylene glycol dioleate, propylene glycol fatty acid ester (proolein glycol monostearate), polyoxyethylene hydrogenated castor oil, polyoxyethylene glycerin monostearate, polyoxyethylene (160) polyoxypropylene (30) glycol, and polyoxyethylene noniphenyl ether.

[0052] The enteric hard capsule shell according to the present disclosure may further contain a lubricant, a sequestering agent, a coloring agent, a light-blocking agent, a binder, etc. Examples of the sequestering agent include ethylenediaminetetraacetic acid, acetic acid, boric acid, citric acid, gluconic acid, lactic acid, phosphoric acid, tartaric acid, or salts thereof, metaphosphate, dihydroxyethylglycine, lecithin, β-cyclodextrin, or combinations thereof.

[0053] The lubricant is not particularly limited as long as it can be used in pharmaceutical or food compositions, and examples thereof include calcium stearate, magnesium stearate, sodium stearyl fumarate, carnauba wax, starch, sucrose fatty acid esters, light anhydrous silicic acid, macrogol, talc, and hydrogenated vegetable oil.

[0054] Sequestering agents can include ethylenediaminetetraacetic acid, acetic acid, boric acid, citric acid, gluconic acid, lactic acid, phosphoric acid, tartaric acid, or salts thereof, metaphosphate, dihydroxyethylglycine, lecithin, β-cyclodextrin, or combinations thereof.

[0055] The coloring agent and the light-blocking agent are not particularly limited as long as they can be used in pharmaceutical or food compositions. Examples of the coloring agent include acacia tannin powder, turmeric extract, methylrosaniline chloride, yellow iron oxide, yellow ferric oxide, Opaspray K-1-24904, orange essence, brown iron oxide, carbon black, caramel, carmine, carotene solution, β-carotene, photosensitizer No. 201, licorice extract, gold leaf, kumazasa extract, black iron oxide, light anhydrous silicic acid, ketsuke, zinc oxide, titanium oxide, red ferric oxide, disazo yellow, food blue No. 1 and its aluminum lake, food blue No. 2 and its aluminum lake, food yellow No. 4 and its aluminum lake, Aluminum Lake, Food Yellow No. 5 and Aluminum Lake, Food Green No. 3 and Aluminum Lake, Food Red No. 2 and Aluminum Lake, Food Red No. 3 and Aluminum Lake, Food Red No. 102 and Aluminum Lake, Food Red No. 104 and Aluminum Lake, Food Red No. 105 and Aluminum Lake, Food Red No. 106 and Aluminum Lake, Sodium Hydroxide, Talc, Copper Chlorophine Sodium, Copper Chlorophyll, Naked Barley Green Tea Extract Powder, Naked Barley Green Tea Extract, Fe Nol Red, fluorescein sodium, d-borneol, malachite green, octyldodecyl myristate, methylene blue, medicinal charcoal, riboflavin butyrate, riboflavin, green tea powder, manganese ammonium phosphate, riboflavin sodium phosphate, rose oil, turmeric pigment, chlorophyll, carminic acid pigment, Food Red No. 40 and its aluminum lake, water-soluble annatto, iron chlorophyllin sodium, Dunaliella carotene, chili pepper pigment, carrot carotene, potassium norbixin, sodium norbixin, palm oil Carotene, beet red, grape skin pigment, blackcurrant pigment, monascus pigment, safflower red pigment, safflower yellow pigment, marigold pigment, riboflavin phosphate ester sodium, madder pigment, alkanet pigment, aluminum, potato carotene, shrimp pigment, krill pigment, orange pigment, cocoa pigment, cocoa charcoal powder pigment, oyster pigment, crab pigment, carob pigment, fish scale leaf, silver, hollyhock pigment, gardenia blue pigment, gardenia red pigment, gardenia yellow pigment, kuro pigment, chlorophin, sorghum pigment, bone charcoal pigment, bamboo pigment, shea nut pigment,Lithospermum root pigment, rosewood pigment, plant charcoal powder pigment, Suo pigment, spirulina pigment, onion pigment, tamarind pigment, corn pigment, tomato pigment, peanut pigment, Phaffia pigment, pecan nut pigment, Monascus yellow pigment, Annatto powder pigment, Haematococcus algae pigment, purple sweet potato pigment, purple corn pigment, purple yam pigment, lamprey smoke pigment, lac pigment, rutin, Sophora japonica extract, whole buckwheat extract, logwood pigment, red cabbage pigment, Akagome pigment, red radish pigment, adzuki bean pigment, sweet potato extract, squid ink pigment, Japanese bush warbler pigment, elderberry pigment, olive tea, cowberry pigment, gooseberry pigment, cranberry pigment, Examples of pigments include salmonberry pigment, strawberry pigment, dark sweet cherry pigment, cherry pigment, tumbleberry pigment, dewberry pigment, pineapple juice, huckleberry pigment, grape juice pigment, blackcurrant pigment, blackberry pigment, plum pigment, blueberry pigment, berry juice, boysenberry pigment, watermelon pigment, mulberry pigment, morello cherry pigment, raspberry pigment, redcurrant pigment, lemon juice, loganberry pigment, chlorella powder, cocoa, saffron pigment, perilla pigment, chicory pigment, seaweed pigment, hibiscus pigment, malt extract, paprika powder, red beet juice, and carrot juice.

[0056] Examples of light-blocking agents include titanium oxide, calcium compounds, ferric oxide, yellow ferric oxide, black ferric oxide, Food Blue No. 1 Aluminum Lake, Food Blue No. 2 Aluminum Lake, Food Yellow No. 4 Aluminum Lake, Food Yellow No. 5 Aluminum Lake, Food Green No. 3 Aluminum Lake, Food Red No. 2 Aluminum Lake, Food Red No. 3 Aluminum Lake, Food Red No. 102 Aluminum Lake, Food Red No. 104 Aluminum Lake, Food Red No. 105 Aluminum Lake, Food Red No. 106 Aluminum Lake, and Food Red No. 40 Aluminum Lake.

[0057] In pharmaceutical hard capsules, titanium oxide and / or calcium compounds may be added as a light-blocking agent to prevent deterioration of the contents due to ultraviolet rays, etc. Examples of calcium-containing compounds include inorganic calcium salts such as calcium carbonate and calcium bicarbonate, calcium hydroxide, calcium oxide, calcium complexes such as dolomite and hydroxyapatite, and other compounds containing calcium element.

[0058] In the enteric hard capsule of this embodiment, where the total mass of the first component, second component, and third component contained in the shell is 100% by mass, the proportion of the first component is α% by mass, the proportion of the second component is β% by mass, and the proportion of the third component is γ% by mass, α can be in the range of 50 to 80, β can be in the range of 10 to 40, and γ can be in the range of 5 to 40. Preferably, α can be in the range of 55 to 70, β can be in the range of 20 to 37, and γ can be in the range of 8 to 25. More preferably, α can be in the range of 60 to 65, β can be in the range of 20 to 30, and γ can be in the range of 10 to 15.

[0059] The fourth component can be added so that the ratio of the content of the fourth component to the total mass of the first, second, and third components contained in the coating is 5 or less, assuming that the total mass of the first, second, and third components is 100. The ratio of the content of the fourth component can be preferably in the range of 0.05 to 5, and more preferably in the range of 0.2 to 1.

[0060] When the coating contains a sixth component, the sixth component can be added so that the ratio of the content of the sixth component to the total mass of the first, second, and third components contained in the coating is 5 or less, where the total mass of the first, second, and third components contained in the coating is 100. The ratio of the content of the sixth component can be preferably in the range of 0.05 to 5, and more preferably in the range of 0.2 to 1.

[0061] The coating may further contain a plasticizer, a surfactant, a binder, a lubricant, a sequestering agent, a colorant, a light-blocking agent, and residual moisture. When the total mass of the first, second, and third components contained in the coating is taken as 100, the ratio of the content of the plasticizer, surfactant, binder, lubricant, sequestering agent, colorant, and light-blocking agent to the total mass is 0.00001 to 20. Preferably, the total content ratio is in the range of 0.05 to 20, more preferably 1 to 18, and even more preferably 3 to 15. When the coating contains a light-blocking agent, when the total mass of at least the first, second, and third components is taken as 100, the content ratio of the light-blocking agent alone can be in the range of 2 to 10, preferably 3 to 6. When the coating contains a plasticizer, the content ratio of the plasticizer alone can be in the range of 0.00001 to 20, preferably in the range of 2 to 17, and more preferably in the range of 5 to 12. When the coating contains a surfactant, a binder, a lubricant, a sequestering agent, or a colorant, the content ratio of these components alone can be in the range of 0.00001 to 5. The upper and lower limits of the above preferred ranges can be combined as appropriate.

[0062] The capsule shell according to the present disclosure may contain salts resulting from at least partial neutralization of the first component, as well as neutralized products of other shell components. Examples of such salts include at least one salt selected from the group consisting of alkali metal salts, alkaline earth metal salts, and ammonium salts. Preferably, the salt includes at least one salt selected from the group consisting of sodium (Na) salts and potassium (K) salts. Na salts are particularly preferred. These salts can be added to the capsule shell as basic neutralizers. The content of the basic neutralizer in the capsule shell can be determined depending on the mole number of carboxyl groups in the first component to be neutralized.

[0063] Specifically, the carboxyl groups in the first component are neutralized with metal ions such as Na and can stably exist in the solid coating as groups such as -COONa. The proportion of these neutralized carboxyl groups is preferably 10% or less, more preferably 8% or less, and even more preferably 5% or less, when the number of moles (groups) of carboxyl residues before neutralization contained in the methacrylic acid copolymer (the first component) is taken as 100%. The proportion of neutralized carboxyl groups is preferably 0.5% or more, more preferably 1% or more, even more preferably 2% or more, and even more preferably 3% or more. This is referred to as the degree of neutralization (a detailed definition of the degree of neutralization will be described later). The presence of excessive salt is undesirable because it can cause the coating to crack easily, deteriorate due to salting out, or collapse due to excessive water penetration. On the other hand, the presence of an appropriate amount of salt promotes water penetration and swelling of the capsule coating containing the first component. The swelling of the capsule shell seals the gap between the cap and the body, effectively preventing dissolution. If the degree of neutralization is too low, the strength of the shell decreases, while if it is too high, poor gelation occurs. Therefore, the degree of neutralization is preferably 1 to 8%, more preferably 2 to 6%.

[0064] In other words, when the total number of moles of salted and unsalted carboxyl groups in the first component contained in the coating is taken as 100 mol%, the content of salted carboxyl groups is 0.5 mol% or more, preferably 1 mol% or more, more preferably 2 mol% or more, and even more preferably 3 mol% or more. Also, the content of salted carboxyl groups is 10 mol% or less, preferably 8 mol% or less, and more preferably 5 mol% or less.

[0065] In other words, when the salt contained in the capsule shell is a Na salt, its hydroxide (NaOH mass) content is preferably 0.1 mass% or more, more preferably 0.2 mass%, based on the shell weight, and is preferably 5 mass% or less, more preferably 2 mass% or less, and even more preferably 1 mass% or less.

[0066] To maintain resistance to cracking, the shell preferably contains 2 to 10% by mass of residual moisture. An appropriate amount of moisture acts as a plasticizer without significantly affecting the solubility of the capsule. The amount of moisture also depends on the environmental humidity during capsule storage, but in a relative humidity range of approximately 20 to 60%, it changes reversibly in proportion to the environmental humidity. In the present disclosure, the moisture content of the capsule shell is the saturated value after storage (humidification) at a constant relative humidity of 43% at room temperature for several days.

[0067] The moisture content after conditioning can be measured by the loss on drying method as follows. <Method for measuring the amount of water contained in the capsule shell using loss on drying method> The sample (hard capsule or film) was placed in a desiccator containing saturated potassium carbonate salt and placed in a constant humidity atmosphere, then sealed and conditioned at 25°C for one week. The following saturated salts (aqueous solutions) were used for the humidity conditioning. Specifically, the presence of saturated potassium acetate, saturated potassium carbonate, and saturated ammonium nitrate salts produced atmospheres with relative humidities of approximately 22%, 43%, and 60%, respectively. After measuring the mass (wet mass) of the sample after conditioning, the sample was then heated and dried at 105°C for two hours, and the mass (dry mass) of the sample was measured again. The moisture content (moisture content) was calculated from the difference between the mass before drying (wet mass) and the mass after drying (dry mass) according to the following formula:

[0068]

number

[0069] As the amount of moisture contained at room temperature and 43% relative humidity, the moisture content is preferably at least 2%, more preferably 3% or more, and even more preferably 4% or more. If it is less than 2%, it will be prone to cracking. On the other hand, if the moisture content is too high, it may react with the drug filled inside when stored for a long period of time, so it is preferably 10% or less, more preferably 8% or less, and even more preferably 6% or less.

[0070] The enteric hard capsule according to the present disclosure desirably has the same or similar shape and mechanical strength (hardness and resistance to breakage) as conventional commercially available hard capsules intended for oral administration to humans or animals. Commercially available hard capsules that should be used as reference are gelatin or HPMC (hypromellose) capsules. Therefore, the thickness of the capsule shell is 50 μm or more, preferably 60 μm or more, and more preferably 70 μm or more. On the other hand, the upper limit is 250 μm or less, preferably 200 μm or less, and more preferably 150 μm or less. In particular, a thickness in the range of 70 to 150 μm is suitable for use directly in commercially available filling machines. At this thickness, it is necessary for the capsule shell to have the same mechanical strength as a commercially available hard capsule shell. The mechanical strength can be evaluated by the "tensile strength test" typically applied to polymeric films using a film prepared in strip form (Aqueous Polymeric Coating For Pharmaceutical Dosage Forms, 4th edition, CRC Press, 2017, Chapter 4).

[0071] When evaluating the mechanical strength of hard capsule shells, it is important to compare test shells with the same thickness. Therefore, the mechanical strength of the shell, which depends on the component composition of the hard capsule, can be evaluated by producing a film by a casting method using a preparation liquid having the same component composition as the hard capsule preparation liquid, and using the cast film.

[0072] To make a cast film, a metal applicator is placed on a glass surface or PET film kept at room temperature, and the prepared solution at 50-60°C is poured into it and moved at a constant speed to produce a uniform film of 100 μm thickness.The film is then dried at room temperature to 30°C for approximately 10 hours. To obtain a film with a uniform thickness of 100 μm, an applicator with a gap of 0.4 mm to 1.5 mm may be used appropriately.

[0073] The prepared film can be cut into, for example, a 5 mm x 75 mm dumbbell shape (specified in JIS K-7161-2-1BA) and then subjected to tensile testing using, for example, a small benchtop testing machine (Shimadzu EZ-LX). Specifically, both ends of the film are set in holders (gap length 60 mm) and pulled at a tensile speed of 10 mm / min. The film elongation and the stress (tensile stress)-elongation (strain) curve generated within the film are shown. Figure 5 shows a typical elongation-tensile stress test result. The elastic modulus, an index of hardness, can be calculated from the slope of the elastic deformation region at low stress in the graph, and the elongation at break (%) can be calculated (Aqueous Polymeric Coating For Pharmaceutical Dosage Forms, 4th edition, CRC Press, 2017, Chapter 4).

[0074] It is desirable that the mechanical strength be maintained under normal usage conditions (temperature of about 5 to 30°C, relative humidity of about 20 to 60%). For example, the prepared film can be conditioned for at least one week at 25°C and a relative humidity of 22% (using saturated potassium acetate), and then subjected to a tensile test to evaluate the mechanical strength. The tensile test is preferably performed in a temperature and humidity environment of 25°C and a relative humidity of 22%. Alternatively, the prepared film can be conditioned for at least one week at 25°C and a relative humidity of 60% (using saturated ammonium nitrate), and then subjected to a tensile test to evaluate the mechanical strength. The tensile test is preferably performed in a temperature and humidity environment that is the same as the conditioned humidity conditions.

[0075] The elastic modulus (Young's modulus), which is an index of hardness, is preferably 1 to 5 GPa, and more preferably 2 to 4 GPa. The breaking elongation, which is an index of resistance to cracking evaluated by a tensile test, is preferably about 2 to 30%, and more preferably about 3 to 30%. Usually, the hardness and resistance to cracking of the enteric hard capsule shell according to the present disclosure are often in a trade-off relationship within this range. Coating shells and soft capsule shells are often softer and have a higher breaking elongation. For example, a shell with a breaking elongation of more than 30% is usually too soft and is often not suitable as a self-standing hard capsule shell. On the other hand, if the breaking elongation is less than 2%, it becomes significantly more susceptible to cracking even during normal handling.

[0076] As mentioned above, the presence of several percent of moisture in the capsule shell typically acts as a plasticizer, affecting mechanical strength, particularly crack resistance. Under low relative humidity conditions for use and storage, the moisture content decreases. For example, at around 2-3%, the capsule becomes more susceptible to cracking, i.e., the elongation at break tends to decrease. On the other hand, at higher humidity levels, the moisture content increases and the modulus of elasticity tends to decrease. Ultimately, the elongation at break is a problem at low humidity levels, while the modulus of elasticity is a problem at high humidity levels. In the present disclosure, humidity conditioning and tensile testing are performed in a relatively low humidity environment (22% relative humidity and 25°C), yielding a shell with a breaking elongation of 2-30%. Furthermore, humidity conditioning and tensile testing are performed in a relatively high humidity environment (60% relative humidity and 25°C), yielding a shell with a modulus of elasticity of 1-5 GPa. As a result, the enteric-coated hard capsules according to the present disclosure achieve a modulus of elasticity in the range of 1-5 GPa and a breaking elongation of 3-30% over most relative humidity and temperature ranges under room conditions. More preferably, the elastic modulus is in the range of 2 to 5 GPa, and the elongation at break is in the range of 3 to 10%.

[0077] 3. Enteric-coated hard capsule preparation and its preparation method 3-1. Composition of the preparation solution Another embodiment disclosed herein relates to a preparation solution for preparing the enteric-coated hard capsule described in 2. above. The hard enteric-coated capsule according to the present disclosure comprises a coating obtained by drying the preparation solution of this embodiment to remove the solvent. Therefore, the explanations of the terms in 2. above are individually incorporated by reference.

[0078] Specifically, the present invention relates to a preparation solution for enteric hard capsules, comprising components i, ii, iii, iv, and a solvent. Component i is a methacrylic acid copolymer, preferably an enteric methacrylic acid copolymer. Component ii is a (meth)acrylic acid alkyl ester copolymer, preferably a water-insoluble (meth)acrylic acid alkyl ester copolymer. Component iii is polyvinyl alcohol. Component iv is a gelling agent, preferably gellan gum. The preparation solution may contain, as component v, a basic neutralizer that is acceptable as a pharmaceutically or food additive. The preparation liquid may also contain a gelling aid as component vi.

[0079] Here, the solvent used in the preparation solution is an aqueous solvent containing water as the main component, and the aqueous solvent can be a mixed solvent of water and at least one selected from ethanol and absolute ethanol, or water. During the preparation of the preparation solution or the immersion step in the present disclosure, most of the ethanol evaporates, so the preparation solution during immersion actually has a water content of 80% by mass, more preferably 90% by mass or more. Excluding unavoidable impurities, substantially 100% purified water can be used.

[0080] Hereinafter, the solution will be referred to as a "neutralized solution" or "partially neutralized solution," even if at least a portion of the solution is neutralized and dissolved. This "neutralized solution" may be a suspension containing dispersed undissolved fine particles. The basic neutralizing agent is not limited as long as it is a compound acceptable as a pharmaceutically or food additive. Examples of the basic neutralizing agent include at least one selected from the group consisting of alkali metal salts, alkaline earth metal salts, and ammonium salts. Preferably, the basic neutralizing agent is at least one selected from the group consisting of sodium salts and ammonium salts. More preferably, the basic neutralizing agent is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonia, and ammonium carbonate. Even more preferably, the basic neutralizing agent is sodium hydroxide, and in some cases, at least one selected from the group consisting of ammonia and ammonium carbonate. When the basic neutralizing agent is ammonia, it is desirable to volatilize the ammonia after the film is formed to remove as much salt as possible from the film. The amount of basic neutralizing agent required to neutralize component i can be defined as follows:

[0081] Complete neutralization of the methacrylic acid copolymer can be achieved by adding an equivalent or greater amount of cations derived from the basic neutralizing agent (component v) to one mole of carboxyl groups contained in the methacrylic acid copolymer. If the cations derived from the basic neutralizing agent are divalent or greater, the valence is expressed as 1 / valence. Complete neutralization occurs when the cations derived from the basic neutralizing agent are dissolved in a solvent in an amount nearly equivalent to the amount of carboxyl groups contained in the enteric polymer. The equivalent number of moles of cations, i.e., "equimolar amount," is, for example, the number of moles of cations that can sequester 100% of the moles (number of groups) of carboxyl residues contained in the methacrylic acid copolymer before neutralization.

[0082] Specifically, the mass of KOH (molecular weight 56.10) required to neutralize 1 g of the target methacrylic acid copolymer can be defined as (KOH) mg / g (KOH equivalent). The degree of neutralization is defined as the ratio of the mass of the basic neutralizer actually added to the equivalent mass of the basic neutralizer required for complete neutralization. When the basic neutralizers are sodium hydroxide (NaOH) (molecular weight 40.00), calcium hydroxide (Ca(OH)2) (molecular weight 74.09), ammonia (NH3) (molecular weight 17.03), and ammonium carbonate (NH4)2CO3 (molecular weight 96.09), the equivalents are calculated using the following formula:

[0083]

number

[0084] Typically, the equivalent amount of basic neutralizing agent required for complete neutralization (neutralization equivalent) is indicated by the manufacturer with a tolerance of ±10 to 20% as the degree of carboxyl group substitution. A more accurate neutralization equivalent can be determined by a standard titration method.

[0085] For example, if the i-th component is Eudragit L30D55, L100-55, or L100 manufactured by Evonik, the KOH equivalent is 301.2 mg / g, and if the basic neutralizing agent is sodium hydroxide, the KOH equivalent is 214.8 mg / g. If the basic neutralizing agent is ammonia, the KOH equivalent is 91.4 mg / g. If the i-th component is Eudragit FS30D manufactured by Evonik, the KOH equivalent is 56.7 mg / g, and if the basic neutralizing agent is sodium hydroxide, the KOH equivalent is 40.4 mg / g, and if the basic neutralizing agent is ammonia, the KOH equivalent is 17.2 mg / g.

[0086] The degree of neutralization is defined as the mass ratio of the amount of basic neutralizing agent actually added to the amount of basic neutralizing agent corresponding to the neutralization equivalent. At the same time, the degree of neutralization is equal to the number of moles of carboxyl groups neutralized and blocked out of the total number of moles of carboxyl groups:

[0087]

number

[0088] For example, when E (g) of NaOH is used for Γ (g) of methacrylic acid copolymer L30D55, the degree of neutralization is E / (0.2418 × Γ) × 100 (%). Alternatively, when E (g) of NaOH is used for L30D55, the degree of neutralization is E / (0.065 × Γ) × 100 (%).

[0089] In the case of the first component, methacrylic acid polymer, an emulsion polymerization process is used to directly obtain an acidic dispersion (aqueous emulsion) containing extremely small colloidal particles with diameters of greater than 0.01 μm and less than 1 μm, produced through a copolymerization process in an aqueous solution from the monomer level. In this case, a dispersion of extremely fine colloidal particles with an average diameter of less than 1 μm is provided without going through a dissolution process involving neutralization with a basic neutralizer. A specific example is the aforementioned Evonik L30D55. The pH of the L30D-55 colloidal dispersion is approximately 2.5.

[0090] Enteric methacrylic acid copolymer powders synthesized by emulsion polymerization in a solution, then dried and converted into solid particles (specifically, L100-55 by Evonik, etc.) can be redispersed in water and partially neutralized with a basic neutralizer to obtain a finely divided aqueous dispersion. In this case, a sufficiently finely divided aqueous dispersion can be obtained even with a neutralization degree of about 2 to 20%.

[0091] In the preparation liquid for the enteric coated hard capsule in this embodiment, when the total mass of component i, component ii, and component iii contained in the preparation liquid is 100% by mass, the proportion of component i is α'% by mass, the proportion of component ii is β'% by mass, and the proportion of component iii is γ'% by mass, α' can be in the range of 50 to 80, β' can be in the range of 10 to 40, and γ' can be in the range of 5 to 40. Preferably, α' can be in the range of 55 to 70, β' can be in the range of 20 to 37, and γ' can be in the range of 8 to 25. More preferably, α' can be in the range of 60 to 65, β can be in the range of 20 to 30, and γ' can be in the range of 10 to 15.

[0092] Component iv can be added so that the ratio of the content of component iv to the total mass of components i, ii, and iii contained in the preparation solution is 5 or less, where the total mass of component i, ii, and iii is 100. The ratio of the content of component iv can be preferably in the range of 0.05 to 5, and more preferably in the range of 0.2 to 1.

[0093] When the preparation liquid contains component vi, the component vi can be added so that the ratio of the content of component vi to the total mass of components i, ii, and ii contained in the preparation liquid is 5 or less, where the total mass of component i, ii, and ii contained in the preparation liquid is 100. The ratio of the content of component vi can be preferably in the range of 0.05 to 5, and more preferably in the range of 0.2 to 1. The explanation of the number of moles and mass % of the basic neutralizing agent when the component i is partially neutralized with the component v is given in the explanation of 2. above.

[0094] The preparation liquid may further contain a plasticizer, a surfactant, a binder, a lubricant, a sequestering agent, a colorant, a light-blocking agent, and the like. When the total mass of the i-th component, the second component, and the third component contained in the preparation liquid is taken as 100, the plasticizer, surfactant, binder, lubricant, sequestering agent, colorant, and light-blocking agent may be added to the preparation liquid so that the total content ratio of the plasticizer, surfactant, binder, lubricant, sequestering agent, colorant, and light-blocking agent to the total is 0.00001 to 20. Preferably, the total content ratio is in the range of 0.05 to 20, more preferably 1 to 18, and even more preferably 3 to 15. When the preparation liquid contains a light-blocking agent, when the total mass of at least the i-th component, the second component, and the third component is taken as 100, the content ratio of the light-blocking agent alone may be in the range of 2 to 10, preferably 3 to 6. When the preparation liquid contains a plasticizer, the content ratio of the plasticizer alone can be in the range of 0.00001 to 20, preferably in the range of 2 to 17, and more preferably in the range of 5 to 12. When the preparation liquid contains a surfactant, a binder, a lubricant, a sequestering agent, or a colorant, the content ratio of these components alone can be in the range of 0.00001 to 5. The upper and lower limits of the above-mentioned preferred ranges can be combined as appropriate.

[0095] Furthermore, the total polymer solids content of the components i, ii, and iii contained in the preparation solution is not limited as long as it allows the preparation of a hard capsule preparation solution. For example, when the preparation solution is taken as 100% by mass, the total polymer solids content is preferably about 10 to 30% by mass, more preferably 13 to 25% by mass. When plasticizers, surfactants, binders, lubricants, sequestering agents, colorants, light-blocking agents, etc. are contained, they can be added to the preparation solution so that the total concentration of the plasticizers, surfactants, binders, lubricants, sequestering agents, colorants, light-blocking agents, etc. is 0.00001 to 20% by mass, when the preparation solution is taken as 100% by mass. Preferably, the total content ratio is in the range of 0.05 to 20% by mass, more preferably 1 to 18% by mass, and even more preferably 3 to 15% by mass. When the preparation solution contains a light-blocking agent, the content ratio of the light-blocking agent alone can be in the range of 2 to 10% by mass, preferably 3 to 6% by mass, where the total mass of at least the first, second, and third components is 100% by mass. When the preparation solution contains a plasticizer, the content ratio of the plasticizer alone can be in the range of 0.00001 to 20% by mass, preferably 2 to 17% by mass, and more preferably 5 to 12% by mass. When the preparation solution contains a surfactant, binder, lubricant, sequestering agent, or colorant, the content ratio of each of these components alone can be in the range of 0.00001 to 5% by mass. The upper and lower limits of the above preferred ranges can be combined as appropriate.

[0096] Generally, the solids dissolved or dispersed in the capsule shell other than the components i to vi remain in the capsule shell at almost the same ratio as the components i to vi. In addition, as described above, some of the water in the solvent may remain in the shell.

[0097] 3-2. Preparation method of capsule preparation solution An embodiment disclosed herein relates to a method for preparing an enteric-coated hard capsule preparation as described in 3-1 above. The explanations of the terms used in 3-1 above are incorporated herein by reference. The method for preparing the preparation solution includes mixing component i, component ii, component iii, and component iv, which have been partially neutralized with component v.

[0098] There are no limitations on the mixing of component i, component ii, component iii, and component iv that have been partially neutralized with component v, as long as they are mixed together. For example, this embodiment includes several preparation examples.

[0099] (1) Preparation Example 1 Preparation Example 1 involves first dissolving PVA, which is component iii, and then adding component i and then component v to partially neutralize component i. That is, Preparation Example 1 includes the following steps A to D: Step A: dissolving component iii in an aqueous solvent at 80°C to 90°C; Step B: adding component i to a solution of component iii; Step C: adding component v to the solution obtained in step B; Step D: A step of adding components ii and iv to the solution obtained in step C. More specifically, step A is a step of dissolving PVA, which is component iii, in an aqueous solvent. Since PVA is poorly soluble in cold water, it is preferable to dissolve it by heating to 80 to 90°C after dispersing it in cold water. The dissolution time is not limited as long as the PVA dissolves. For example, it is about 30 to 120 minutes. When adding plasticizers, surfactants, binders, lubricants, sequestering agents, colorants, light-blocking agents, etc., they can be added in this step.

[0100] In step B, a methacrylic acid copolymer, which is component i, is added to the PVA solution dissolved in step A. At this time, it is preferable that the liquid temperature is maintained at the same temperature as in step A. Component i can be added as a commercially available methacrylic acid copolymer dispersion. After adding component i, it is preferable to mix for about 5 to 60 minutes.

[0101] In step C, a basic neutralizing agent, which is component v, is added. At this time, the liquid temperature is preferably maintained at the same temperature as in step A. After component v is added, mixing is preferably carried out for about 5 to 60 minutes.

[0102] In step D, components ii and iv are added to the solution obtained in step C. Preferably, the liquid temperature is maintained at the same temperature as in step A. Component ii can be added as a commercially available (meth)acrylic acid alkyl ester copolymer dispersion. Adding component iv to at least a partially unneutralized component i may result in aggregation of component iv. Therefore, it is preferable to add at least component iv after neutralizing component i with component v. There are no limitations on the timing of adding component ii. Therefore, component ii may be added in any of steps A to D. In this case, too, it is preferable to maintain the liquid temperature at 80°C to 90°C. After adding components ii and iv, mixing is preferably performed for approximately 30 to 120 minutes. Furthermore, when component vi, a gelling aid, is added, it is preferable to add it in step D or after step D.

[0103] (2) Preparation Example 2 Preparation Example 2 involves first partially neutralizing component i with component v to prepare a partially neutralized solution, and then adding components iii, ii, and iv to the solution. That is, Preparation Example 2 includes the following steps A' and B': Step A': a step of preparing a partially neutralized solution by partially neutralizing the i-th component with the v-th component; Step B': A step of mixing the partially neutralized solution prepared in step A' with component iii, component ii and component iv.

[0104] More specifically, step A' is a step of partially neutralizing the methacrylic acid copolymer, which is component i, to prepare a partially neutralized liquid. The partially neutralized liquid may be purchased or prepared. When preparing the partially neutralized liquid, for example, it can be prepared by adding a commercially available methacrylic acid copolymer dispersion to an aqueous solvent, adding component v, and mixing.

[0105] In step B', component iii is dispersed in the partially neutralized solution prepared in step A' and heated to 80°C to 90°C to dissolve component iii. The dissolution time is not limited as long as the PVA dissolves. For example, it is about 30 to 120 minutes. When adding plasticizers, surfactants, binders, lubricants, sequestering agents, colorants, light-blocking agents, etc., they can be added in this step.

[0106] Next, components ii and iv are added to the solution of component iii. At this time, the liquid temperature is preferably maintained at 80°C to 90°C. Component ii can be added as a commercially available (meth)acrylic acid alkyl ester copolymer dispersion. After adding components ii and iv, mixing is preferably performed for approximately 30 to 120 minutes. If component iv is added to component i that has not been at least partially neutralized, component iv may aggregate. Therefore, it is preferable to add at least component iv after neutralizing component i with component v. There are no restrictions on the timing of adding component ii. Therefore, component i may be added to component v when dissolving component iii in the partially neutralized solution. In this case, the liquid temperature is also preferably maintained at 80°C to 90°C.

[0107] It is desirable to carry out stirring continuously in all steps of Preparation Examples 1 and 2. For example, when the preparation steps are carried out in a cylindrical vessel, it is preferable to carry out stirring by rotating a propeller-shaped stirring blade at 1 to several hundred rpm. Furthermore, after completion of Preparation Example 1 or Preparation Example 2, a step of lowering the temperature of the capsule preparation liquid to 50°C to 60°C, preferably 52°C to 57°C may be carried out.

[0108] The viscosity of the preparation solution at 50 to 60°C is not limited as long as it allows the preparation of hard capsules by the immersion method, but can be, for example, approximately 100 to 10,000 mPa·s. The viscosity of the preparation solution can be measured using a single-cylinder rotational viscometer (Brookfield viscometer, B-type viscometer). For example, the capsule preparation solution (600 ml) is prepared in a 1-L beaker, and then an M3 rotor (measurement range: 0 to 10,000 mPa·s) is placed in the preparation solution maintained at 55°C, and the viscosity can be measured at a rotor speed of 12 rpm for a measurement time of 50 seconds.

[0109] 4. Preparation method of enteric-coated hard capsules One embodiment disclosed herein relates to a method for preparing enteric-coated hard capsules. According to the present disclosure, enteric-coated hard capsules can be prepared using a capsule preparation machine used to prepare other hard capsules. The enteric-coated hard capsules according to the present disclosure are formed by a dipping method, particularly the "cold pin dipping method." The "cold pin dipping method" is characterized in that the surface temperature of the forming pin during dipping is lower than the temperature of the capsule preparation liquid.

[0110] The preparation (molding) method for enteric-coated hard capsules is not particularly limited as long as it includes a step of preparing capsules using the enteric-coated hard capsule preparation solution according to the present disclosure. Enteric-coated hard capsules are generally produced by immersing a mold pin (a capsule-molding pin) that serves as a capsule mold in the enteric-coated hard capsule preparation solution, and then curing and drying the film that adheres when the pin is pulled out, thereby obtaining the desired capsule shape and thickness (dipping method). Specifically, the preparation method for enteric-coated hard capsules includes a step of preparing an enteric-coated hard capsule preparation solution by the above-mentioned method or by purchasing the enteric-coated hard capsule preparation solution, and a preparation step of immersing a mold pin in the enteric-coated hard capsule preparation solution, pulling it out, inverting the mold pin, and drying the solution that adheres to the mold pin. More specifically, the enteric hard capsule used in the present disclosure can be produced through the following molding process. (1) a step of immersing a mold pin in an enteric-coated hard capsule preparation solution (immersion step);

[0111] (2) A step of removing the mold pin from the enteric-coated hard capsule preparation liquid (immersion liquid) and drying the enteric-coated hard capsule preparation liquid adhering to the outer surface of the mold pin (drying step); (3) A process of detaching the dried capsule film (skin) from the capsule molding pin (detachment process). Here, the enteric hard capsule preparation liquid preferably has a liquid temperature of 50°C to 60°C when the mold pins are immersed in the liquid.

[0112] On the other hand, the surface temperature of the mold pins during immersion is preferably lower than the temperature of the enteric coated hard capsule preparation liquid, for example, in the range of 20 to 30°C, more preferably 20 to 28°C. The drying step (2) can be carried out at room temperature (20 to 30° C.), although there are no particular limitations thereon. Usually, it is carried out by blowing air at room temperature.

[0113] The capsule shell thus prepared can be cut to a predetermined length and then provided as an enteric hard capsule with or without the body and cap portions fitted together.

[0114] The shell thickness of enteric-coated hard capsules is typically in the range of 50 to 250 μm. In particular, the thickness of the side wall of currently commercially available capsules is typically 75 to 150 μm, more preferably 80 to 120 μm. Enteric-coated hard capsules come in a variety of sizes, including No. 00, No. 0, No. 1, No. 2, No. 3, No. 4, and No. 5, and the present disclosure can prepare enteric-coated hard capsules of any size.

[0115] 5. Enteric-coated hard capsule formulation The enteric hard capsule according to the present disclosure may be filled with a filler such as a general food, a health food (a food with functional claims, a nutrient-functional food, a food for specified health uses), a quasi-drug, a pharmaceutical, etc. Examples of the filler include components derived from plants (including unicellular green algae) (raw plants, partially dried microorganisms, or completely dried plants, processed plant products, plant extracts, etc.), microorganisms (bacteria, yeast, euglena, etc.) or components derived from the microorganisms (raw microorganisms, partially dried microorganisms, or completely dried microorganisms, processed microbial products, microbial extracts, etc.), tonic health supplements, antipyretic analgesic anti-inflammatory agents, psychotropic agents, antianxiety agents, antidepressants, hypnotics, sedatives, antispasmodics, central nervous system agents, cerebral metabolism improvers, cerebral circulation improvers, antiepileptics, sympathomimetics, Examples of active ingredients include gastrointestinal agents, antacids, antiulcer agents, antitussives and expectorants, antiemetics, respiratory stimulants, bronchodilators, antiallergic agents, dental and oral preparations, antihistamines, cardiac stimulants, antiarrhythmic agents, diuretics, antihypertensives, vasoconstrictors, coronary vasodilators, peripheral vasodilators, antihyperlipidemic agents, choleretics, antibiotics, chemotherapeutic agents, antidiabetic agents, osteoporosis agents, antirheumatic agents, skeletal muscle relaxants, antispasmodics, hormones, alkaloid narcotics, sulfonamides, gout treatments, anticoagulants, and anti-cancer agents, or compositions containing the active ingredients. These fillers are not particularly limited and include a wide range of known fillers. These ingredients can be used alone or in combination with other ingredients. The fillers may be in any form, such as solid, powder, granules, pulverized material, liquid, or gel. These ingredients are filled in known amounts as appropriate, depending on the condition, age, etc. of the recipient.

[0116] Examples of tonic health supplements include vitamins such as vitamin A, vitamin D, vitamin E (d-α-tocopherol acetate, etc.), vitamin B1 (dibenzoylthiamine, fursultiamine hydrochloride, etc.), vitamin B2 (riboflavin butyrate, etc.), vitamin B6 (pyridoxine hydrochloride, etc.), vitamin C (ascorbic acid, sodium L-ascorbate, etc.), and vitamin B12 (hydroxocobalamin acetate, cyanocobalamin, etc.), minerals such as calcium, magnesium, and iron, proteins, amino acids, oligosaccharides, and herbal medicines.

[0117] Examples of antipyretic, analgesic, and anti-inflammatory agents include, but are not limited to, aspirin, acetaminophen, ethenzamide, ibuprofen, diphenhydramine hydrochloride, dl-chlorpheniramine maleate, dihydrocodeine phosphate, noscapine, methylephedrine hydrochloride, phenylpropanolamine hydrochloride, caffeine, anhydrous caffeine, serrapeptase, lysozyme chloride, tolfenamic acid, mefenamic acid, diclofenac sodium, flufenamic acid, salicylamide, aminopyrine, ketoprofen, indomethacin, bucolome, and pentazocine.

[0118] The use of enteric-coated hard capsules is particularly useful when there is a risk of adverse reactions to the stomach if dissolved in the stomach, or when a drug is acid-unstable and needs to be absorbed in the intestine without dissolving in the stomach. That is, the enteric-coated hard capsule formulation of the present disclosure is particularly useful for formulations in which the efficacy of the active ingredient may be reduced by gastric acid, because it can protect the active ingredient from gastric acid and allow it to pass through the stomach effectively and be delivered to the intestine.

[0119] For example, aspirin is known to have a side effect of causing stomach ulcer-like symptoms when administered in large amounts as naked granules, and is one of the typical drugs for which application of enteric-coated hard capsules is desirable.

[0120] On the other hand, examples of acid-labile active ingredients include proton pump inhibitors (PPIs), such as omeprazole, lansoprazole, rabeprazole sodium, and esomeprazole magnesium hydrate. PPIs reach parietal cells via the bloodstream and are activated by contact with high concentrations of hydrogen ions in the secretory tubules of parietal cells. However, PPIs are extremely unstable in acidic environments, and if they are exposed to acid before reaching the parietal cells, they lose their full effectiveness. For this reason, PPIs are usually formulated as enteric-coated formulations to exert their strong acid secretion inhibitory effect.

[0121] Duloxetine, an antidepressant called a serotonin-norepinephrine reuptake inhibitor, is also an example of an active ingredient that is preferably formulated as an enteric-coated formulation because it is sensitive to acid.

[0122] The enteric hard capsules according to the present disclosure can be filled with general foods or health functional foods (foods with functional claims, foods with nutrient functions, foods for specified health uses), such as fucoidan, heme iron, polyphenols, peptides or amino acids (e.g., royal jelly, ornithine, citrulline, aminolevulinic acid, black vinegar, or hydrophobic amino acids such as methionine, valine, leucine, and isoleucine), proteins (milk proteins such as lactoferrin, collagen, placenta, and the like), glycoproteins, enzyme-fermented foods (e.g., nattokinase), coenzymes (e.g., coenzyme Q10), vitamins (e.g., β-carotene), minerals, live microorganisms (e.g., euglena, chlorella, yeast, lactic acid bacteria, bifidobacteria), plant extracts (herbal medicines, herbs, e.g., turmeric extract, ginseng extract, plum extract, ginkgo leaf extract, blueberry extract, sweet tea extract, and the like), natural organic substances such as propolis, or any combination thereof. However, it is not limited to these.

[0123] Filling of such contents into enteric-coated hard capsules can be carried out using a capsule filling machine known per se, such as a fully automatic capsule filling machine (model: LIQFILsuper80 / 150, manufactured by Qualicaps Co., Ltd.) or a capsule filling and sealing machine (model: LIQFILsuperFS, manufactured by Qualicaps Co., Ltd.). The body and cap portions of the hard capsule thus obtained are joined by filling the contents into the body portion, then covering the body portion with the cap portion and fitting the two together. If necessary, the filled capsule can then be made tamper-proof by using an appropriate technique for permanently sealing the seam. Typically, sealing or banding (hereinafter referred to as sealing) techniques can be used, and these techniques are well known to those skilled in the capsule art. As a specific example, a polymer solution sealant (hereinafter also referred to as a seal preparation solution) can be applied once or multiple times, preferably once or twice, to the surfaces of the body and cap parts in a circumferential direction of the body and cap parts over a certain width centered on the edge of the cap part to seal the fitting part and produce an enteric-coated hard capsule formulation. The polymer solution can be a diluted aqueous solution of the enteric polymer used in the capsule shell, or a solution dissolved in water / ethanol or water / isopropanol. When a diluted aqueous solution or a solution dissolved in water / ethanol or water / isopropanol is used, it can also be partially neutralized and dissolved with a basic neutralizer as described above.

[0124] The polymer contained in the seal preparation solution preferably consists of the same enteric polymer as that contained in the enteric hard capsule shell to which the seal is applied.

[0125] The polymer contained in the seal preparation solution preferably contains the same enteric polymer or nonionic water-soluble cellulose compound (e.g., hydroxypropylmethylcellulose, hydroxypropylcellulose, etc.) as the enteric hard capsule shell to which the seal is applied. This not only provides excellent adhesion to the capsule shell, but also prevents unnecessary additive components from being included in the capsule formulation. In this case, the viscosity of the nonionic water-soluble cellulose compound may be 100 mPa·s.

[0126] During capsule sealing, the seal preparation liquid can generally be used at room temperature or heated. From the viewpoint of preventing liquid leakage from hard capsules, it is desirable to use a seal preparation liquid having a temperature within the range of preferably about 23 to 45°C, more preferably about 23 to 35°C, and most preferably about 25 to 35°C. The temperature of the seal preparation liquid can be adjusted by a known method such as a panel heater or a hot water heater. However, it is preferable to adjust the temperature using, for example, a circulating hot water heater or a seal pan unit of the integrated capsule filling and sealing machine modified to a circulating hot water heater, because this allows for fine adjustment of the temperature range.

[0127] The enteric-coated hard capsule formulation according to the present disclosure obtained in this manner is designed to be acid-resistant in the stomach when administered and ingested into the body of a human or animal, and to migrate mainly to the intestine, where the capsule shell dissolves and the contents are released. For this reason, it is suitable as a formulation filled with medicines or foods that should not be released in the stomach.

[0128] In the present disclosure, the capsule shell may be externally coated with one or more additional polymer layers to enhance enteric function, further control drug delivery, or control gas or water permeability.

[0129] Unless otherwise specified, a functional polymer layer refers to a layer containing a functional polymer that imparts specific mechanical or chemical properties to the coated capsule shell, such as enteric polymers and / or colonic-releasing polymers (i.e., polymers used to disintegrate the coated dosage form in the colonic region of a subject) that are conventionally used to coat pharmaceutical solid dosage forms.

[0130] 6. Hard capsule formulation A novel application example of the enteric-coated hard capsule according to the present disclosure is a hard capsule formulation characterized by encapsulating the enteric-coated hard capsule according to the present disclosure inside a hard capsule that dissolves under acidic conditions. Examples of hard capsules that dissolve under acidic conditions include, but are not limited to, gelatin capsules, hypromellose capsules, and pullulan capsules. In particular, hypromellose hard capsules have a nominal viscosity (viscosity grade) of 3 to 15 mPa·s for water-soluble cellulose (see JP-A-08-208458, JP-A-2001-506692, JP-A-2010-270039, and JP-A-2011-500871). In these capsules, nearly 100% of the shell (which may contain gelling agents, gelling aids, light-blocking agents, colorants, etc., and about 0 to 5% by mass and about 0 to 10% by mass of residual moisture) is water-soluble cellulose, particularly HPMC. The enteric-coated hard capsule according to the present disclosure is pre-filled with active ingredient B, and then a hard capsule that dissolves under acidic conditions is filled with active ingredient A and the filled enteric-coated hard capsule. This double capsule formulation enables selective delivery of different active ingredients to multiple sites, such as releasing active ingredient A in the stomach and releasing active ingredient B after it reaches the intestine. Examples of active ingredients A and B include the active ingredients described in 5 above. [Example]

[0131] The present invention will be described in more detail below with reference to examples, but the present invention should not be construed as being limited to these examples.

[0132] I. Materials used The materials used in the examples are as follows: (1) Methacrylic acid copolymer L30D55 and FS30D from the EUDRAGIT® series manufactured by Evonik Industries AG were used. Both were aqueous dispersions with a solid content of 30% by mass. Furthermore, L10055, a dried, finely powdered version of L30D55, was dispersed in purified water and stirred, after which NaOH (10% aqueous solution) was added to achieve a predetermined degree of neutralization. This resulted in an aqueous dispersion of finely divided particles, although slightly coarser than the colloidal particles of L30D-55.

[0133] (2) (Meth)acrylic acid alkyl ester copolymer NE30D from the Eudragit® series manufactured by Evonik Industries AG was used, and was provided as an aqueous dispersion with a solids content of 30% by weight.

[0134] (3) Polyvinyl alcohol and gelling agent The Gohsenol® series EG48P from Nippon Synthetic Chemical Industry Co., Ltd. and partially saponified polyvinyl alcohol 3500 from Fujifilm Wako Pure Chemical Industries, Ltd. were used. The degree of saponification of EG48P was 86.5-89.0%, with an estimated degree of polymerization of 2500. The degree of saponification of partially saponified polyvinyl alcohol 3500 was 86.0-90.0%, with an estimated degree of polymerization of 3100-3900. The gelling agent was gellan gum (Kelcogel) purchased from San-Ei Gen F.F.I.

[0135] (4) Other Sodium hydroxide (granular, special grade reagent) was purchased from Wako Pure Chemical Industries, Ltd. Titanium oxide (Tipake A-100) was purchased from Ishihara Sangyo Kaisha, Ltd.

[0136] II. Measurement and Test Methods 1. Capsule dissolution test In this disclosure, the dissolution test method prescribed in the 17th edition of the Japanese Pharmacopoeia was generally applied. However, since the Japanese Pharmacopoeia does not specify the solubility of empty hard capsules themselves, in this disclosure, the solubility (dissolution characteristics) of the capsules themselves was evaluated by evaluating the dissolution of fast-dissolving acetaminophen. Each capsule was filled with 40 mg of acetaminophen, 140 mg of lactose, and 20 mg of sodium starch glycolate (hereinafter referred to as "acetaminophen mixed powder"). The resulting enteric-coated hard capsule formulation was tested according to the dissolution test method prescribed in the Japanese Pharmacopoeia (17th edition, 6.10-1.2 paddle method (paddle rotation speed: 50 rpm) and using a sinker corresponding to Figure 6.10-2a), and the time course of the dissolution rate of acetaminophen was measured. A Distek Model 2100 Bath-type dissolution tester was used for the dissolution test. The same volume of acetaminophen was separately dissolved in the solution in the dissolution tester bath. The absorbance at 244 nm when the entire amount was dissolved was set at 100%, and the dissolution rate was calculated from the absorbance at 244 nm of the solution in the dissolution tester bath, which increased as acetaminophen was dissolved from the capsules. The following aqueous solutions were used as the first solution, second solution, and buffer solution. The temperature of the solution in each bath was 37°C.

[0137] First solution: 2.0 g of sodium chloride was dissolved in 7.0 mL of hydrochloric acid and water, and the total volume was adjusted to 1000 mL (pH was approximately 1.2, hereinafter sometimes referred to as the acidic solution).

[0138] Solution 2: 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate were dissolved in water, and 1 volume of water was added to 1000 mL of phosphate buffer solution (pH approximately 6.8, hereinafter sometimes referred to as neutral solution).

[0139] Buffer solution: 3.378 g of citric acid hydrate and 2.535 g of anhydrous disodium hydrogen phosphate were dissolved in water to prepare 1000 mL (pH: about 4, hereinafter sometimes simply referred to as buffer solution).

[0140] 2. Moisture content (moisture content) <Method for measuring moisture content in capsule shell using loss on drying method> The sample (hard capsule or film) was placed in a desiccator containing a saturated aqueous solution of potassium carbonate, and the sample was sealed and conditioned at 25°C for one week. The following saturated salts (aqueous solutions) were used for the humidity conditioning: saturated potassium acetate, saturated potassium carbonate, and saturated ammonium nitrate were used to create atmospheres with relative humidities of approximately 22%, 43%, and 60%, respectively. The mass (wet mass) of the sample after humidity conditioning was measured, and then the sample was dried by heating at 105°C for two hours. The mass (dry mass) of the sample was then measured again. The moisture content (% by mass) was calculated from the difference between the mass (wet mass) before drying and the mass (dry mass) after drying, using the following formula:

number

[0141] 3. Mechanical strength of capsule shell (measurement of elastic modulus and elongation at break) When evaluating the mechanical strength of hard capsule shells, it is important to compare test shells with the same thickness. Therefore, the mechanical strength of the shell, which depends on the component composition of the hard capsule, was evaluated using a film produced by a casting method using a preparation liquid with the same component composition as the hard capsule preparation liquid, instead of hard capsules molded by the dipping method. This film has excellent thickness uniformity and reproducibility of evaluation, and well reflects the mechanical strength of the capsule shell.

[0142] The cast film was prepared by placing a metal applicator on a glass surface or PET film maintained at room temperature, pouring the prepared solution at 50 to 60°C, and moving it at a constant speed to produce a uniform film of 100 μm.The film was then dried at room temperature to 30°C for approximately 10 hours. To obtain a film with a uniform thickness of 100 μm, applicators with gaps ranging from 0.4 mm to 1.5 mm were used appropriately.

[0143] The resulting film was cut into a 5mm x 75mm dumbbell shape (specified in JIS K-7161-2-1BA) and subjected to a tensile test using a small benchtop testing machine (Shimadzu EZ-LX). Both ends of the film were set in holders (gap length 60 mm) and stretched at a rate of 10 mm / min. The film elongation and the stress (tensile stress)-elongation (strain) curve generated within the film were obtained. The elastic modulus, an index of hardness, was calculated from the slope of the elastic deformation region at low stress, and the elongation at the break point was defined as the break elongation (%).

[0144] Using the same saturated salt as used in the moisture content measurement above, the specimens were conditioned at 25°C and 22% relative humidity for at least one week, after which tensile tests were conducted to evaluate the mechanical strength. The tensile tests were conducted at the same temperature and humidity as the conditioned conditions for each specimen.

[0145] III. Preparation of the solution A capsule preparation solution was prepared according to the following procedure. All operations were performed while stirring the solution. Hereinafter, the solid contents of component i (enteric methacrylic acid copolymer), component ii (water-insoluble (meth)acrylic acid alkyl ester copolymer), and component iii (polyvinyl alcohol) will be referred to as polymer solids. The total solution mass is the total mass of purified water (solvent), polymer solids, component iv (gelling agent), basic neutralizer, and other solids (light-blocking agent). The polymer solids concentration refers to the ratio (% by mass) of the total polymer solids mass to the total solution mass.

[0146] a. Taking into consideration the water content of the aqueous dispersion of methacrylic acid copolymer (solid content concentration 30% by mass), the (meth)acrylic acid alkyl ester copolymer dispersion (solid content concentration 30% by mass), and the dispersion of titanium oxide (concentration 22% by mass) as a light-blocking agent, purified water was prepared at room temperature in an amount such that the polymer solid content concentration (total of component i, component ii, and component iii) after completion of the capsule preparation process would reach the specified concentration (approximately 19.2%). b. PVA3500 and titanium oxide were added to the water prepared in a. above at room temperature, and the temperature was raised to approximately 85°C while stirring with a three-one motor. While maintaining the temperature, a predetermined amount of methacrylic acid copolymer dispersion was added, followed by sodium hydroxide (NaOH) as a basic neutralizer to prepare a partially neutralized solution. NaOH was used in an amount equivalent to partially neutralizing approximately 4% of the carboxyl groups in the methacrylic acid copolymer. The neutralization equivalent of NaOH per 1 g of methacrylic acid copolymer solids is 214.8 mg. In this example, 8.3 mg of NaOH, which corresponds to approximately 4% of the neutralization equivalent, was added per 1 g of methacrylic acid copolymer solids. The degree of neutralization in this case was approximately 3.9%. The pH of the partially neutralized solution (partially neutralized solution) was generally in the range of 4 to 6. c) While maintaining the temperature of the partially neutralized solution prepared in b) above at approximately 85°C, the (meth)acrylic acid alkyl ester copolymer was added to this partially neutralized solution, and the mixture was thoroughly stirred with a three-one motor. Then, while maintaining the temperature at approximately 85°C, gellan gum was added to a concentration of 0.52% by mass relative to 100% by mass of polymer solids, and the mixture was dispersed uniformly to avoid lumps, to prepare a suspension, which was then degassed. d. The temperature of the solution prepared in c above was lowered to 52°C to 57°C. The viscosity of the solution was measured using a Brookfield viscometer and was in the range of approximately 500 to 5,000 mPa·s. The final total solids concentration was fine-tuned by adding and evaporating warm pure water to keep the viscosity within this range. In all of the above steps, the mixture was stirred at 100 to 1,000 rpm using a Three-One motor.

[0147] IV. Capsule Forming Using the capsule preparation solution prepared in III above, size 2 hard capsules were prepared by the cold pin dipping method. The holding temperature T5 was approximately 55°C. A mold pin (size 2) that had been left at room temperature (approximately 25°C) was immersed in the capsule preparation solution, which was maintained at a nearly constant temperature, for several seconds, and then removed from the atmosphere. The mold pin with the capsule preparation solution attached was turned upside down and dried at room temperature for 2 to 10 hours or more. The immersion time and removal speed of the mold pin were appropriately adjusted so that the film thickness of the cylindrical capsule side was approximately 100 μm. The capsule portion was then pulled out from the mold pin, and the cylindrical portion was cut to the specified length. The above procedure was performed for both the cap and the body. The composition of the prepared capsules and the composition of the ingredients used to prepare the capsule preparation solution are shown in Table 1.

[0148] V. Performance Evaluation The performance of the prepared hard capsules and films was evaluated, and the results are shown in Table 1. The obtained hard capsules were subjected to dissolution tests in the first and second liquids according to II.1 above. The dissolution rate after 2 hours of immersion of the capsules in the first liquid was 7.3%, indicating poor solubility in acidic solutions. On the other hand, the dissolution rate after 30 minutes of immersion of the capsules in the second liquid was 100%, indicating that the capsules were readily soluble in neutral solutions.

[0149] Furthermore, the dissolution rate after 2 hours at pH 4.0 was 13.8%, confirming that the drug exhibited resistance to dissolution even when mixed with gastric juice and duodenal juice.

[0150] The moisture content was measured according to II.2 above, and the moisture content was found to be 4.76% at a relative humidity of 60% and 2.74% at a relative humidity of 22%.

[0151] Furthermore, the elastic modulus and elongation at break of the film prepared by the method described in III were measured in accordance with II.3 above. The elastic modulus was 1.9 GPa and the elongation was 5.5%.

[0152]

Table 1

Claims

1. An enteric hard capsule comprising a coating containing a first component, a second component, a third component, and a fourth component, The first component is an enteric methacrylic acid copolymer; the second component is a water-insoluble (meth)acrylic acid alkyl ester copolymer; The third component is polyvinyl alcohol, and The fourth component is gellan gum, and when the total mass of the first component, the second component, and the third component contained in the coating is 100, the ratio of the content of gellan gum to the total mass is in the range of 0.2 to 1. Enteric-coated hard capsule.

2. 2. The enteric hard capsule according to claim 1, wherein the enteric methacrylic acid copolymer is at least one selected from the group consisting of a copolymer of methacrylic acid with methyl methacrylate and methyl acrylate, and a copolymer of methacrylic acid with ethyl acrylate.

3. 3. The enteric hard capsule according to claim 1, wherein the enteric methacrylic acid copolymer is a copolymer consisting of 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of ethyl acrylate.

4. 4. The enteric coated hard capsule according to claim 1, wherein the water-insoluble (meth)acrylic acid alkyl ester copolymer is a copolymer of methyl methacrylate and ethyl acrylate.

5. The enteric hard capsule according to any one of claims 1 to 4, further containing 1 to 10% by mass of water when the mass of the shell per capsule is 100% by mass.

6. 6. The enteric hard capsule according to claim 1, further comprising, as a fifth component, a basic neutralizer that is acceptable as a pharmaceutically or food additive, and the content of the basic neutralizer is an amount that neutralizes 0.5 mol % or more and 10 mol % or less of the carboxyl groups of the first component, when the number of moles of carboxyl groups of the first component contained in the shell per capsule before neutralization is taken as 100 mol %.

7. 7. The enteric coated hard capsule according to claim 6, wherein the basic neutralizing agent is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonia, and ammonium carbonate.

8. The enteric hard capsule according to any one of claims 1 to 7, further comprising a gelling aid as a sixth component.

9. 9. The enteric coated hard capsule according to claim 8, wherein the gelling aid is at least one water-soluble calcium salt selected from the group consisting of calcium lactate, calcium acetate, calcium pantothenate, calcium chloride, calcium bromide, and calcium nitrate.

10. The enteric hard capsule according to any one of claims 1 to 9, wherein α is in the range of 50 to 80, where the total mass of the first component, the second component, and the third component contained in the shell is 100% by mass, the proportion of the first component is α%, the proportion of the second component is β%, and the proportion of the third component is γ% by mass.

11. 11. The enteric coated hard capsule according to claim 10, wherein the β is in the range of 10 to 40.

12. 12. The enteric hard capsule according to claim 10, wherein γ is in the range of 5 to 40.

13. The enteric hard capsule according to any one of claims 8 to 12, wherein the ratio of the content of the fifth component to the total mass of the first component, the second component, and the third component contained in the shell is 5 or less, when the total mass of the first component, the second component, and the third component is 100.

14. 14. The enteric coated hard capsule according to claim 6, wherein at least a portion of the first component forms a salt with the basic neutralizing agent.

15. The enteric coated hard capsule according to any one of claims 1 to 13, further comprising a plasticizer and / or a light-blocking agent.

16. The enteric hard capsule according to any one of claims 1 to 15, wherein the thickness of the coating is 50 to 250 µm.

17. 17. The enteric coated hard capsule according to claim 1, wherein the elastic modulus of the coating at 25°C and a relative humidity of 22% is 1 GPa to 5 GPa.

18. 18. The enteric coated hard capsule according to claim 1, wherein the shell has a breaking elongation of 2% to 30% at 25°C and a relative humidity of 22%.

19. The enteric hard capsule according to any one of claims 1 to 18, wherein the dissolution rate of the enteric hard capsule after 2 hours is 25% or less in a dissolution test using a solution having a pH of 1.

2.

20. 20. The enteric hard capsule according to claim 19, wherein the dissolution rate of the enteric hard capsule in the dissolution test is 10% or less.

21. An enteric coated hard capsule preparation comprising component i, component ii, component iii, component iv, and a solvent, The i-th component is an enteric methacrylic acid copolymer, Component ii is a water-insoluble (meth)acrylic acid alkyl ester copolymer; component iii is polyvinyl alcohol, and the component iv is gellan gum, and when the total mass of the components i, ii, and iii contained in the enteric coated hard capsule preparation solution is taken as 100, the ratio of the content of the component iv to the total mass is in the range of 0.2 to 1; Enteric coated hard capsule preparation.

22. 22. The enteric coated hard capsule preparation according to claim 21, further comprising a basic neutralizing agent that is pharmaceutically or food additive-acceptable as a component v, wherein a portion of component i is partially neutralized by component v.

23. 23. The enteric coated hard capsule preparation solution according to claim 22, wherein the content of the basic neutralizing agent is an amount that neutralizes 0.5 mol % or more and 10 mol % or less of the carboxyl groups of the i-th component, when the number of moles of carboxyl groups of the i-th component contained in the shell per capsule before neutralization is taken as 100 mol %.

24. The enteric coated hard capsule preparation liquid according to any one of claims 21 to 23, wherein the component i is dispersed as colloidal particles.

25. The enteric coated hard capsule preparation according to any one of claims 21 to 24, wherein the enteric methacrylic acid copolymer is at least one selected from the group consisting of a copolymer of methacrylic acid with methyl methacrylate and methyl acrylate, and a copolymer of methacrylic acid with ethyl acrylate.

26. 26. The enteric coated hard capsule preparation according to any one of claims 21 to 25, wherein the water-insoluble (meth)acrylic acid alkyl ester copolymer is a copolymer of methyl methacrylate and ethyl acrylate.

27. 27. The enteric coated hard capsule preparation according to any one of claims 21 to 26, wherein the component ii) is dispersed as colloidal particles.

28. The enteric coated hard capsule preparation solution according to any one of claims 22, 23, and 24 to 27 which cite claim 22, wherein the basic neutralizing agent is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonia, and ammonium carbonate.

29. The enteric coated hard capsule preparation solution according to any one of claims 21 to 28, further comprising a gelling aid as component vi.

30. 30. The enteric coated hard capsule preparation of claim 29, wherein the gelling aid is at least one water-soluble calcium salt selected from the group consisting of calcium lactate, calcium acetate, calcium pantothenate, calcium chloride, calcium bromide, and calcium nitrate.

31. The enteric coated hard capsule preparation liquid according to any one of claims 21 to 30, wherein α' is in the range of 50 to 80, where the total mass of the i-th component, the ii-th component, and the iii-th component contained in the enteric coated hard capsule preparation liquid is taken as 100% by mass, the proportion of the first component is α'% by mass, the proportion of the second component is β'% by mass, and the proportion of the third component is γ'% by mass.

32. 32. The enteric coated hard capsule preparation of claim 31, wherein β' is in the range of 10 to 40.

33. 33. The enteric coated hard capsule preparation according to claim 31 or 32, wherein the γ' is in the range of 5 to 40.

34. The enteric coated hard capsule preparation liquid according to any one of claims 22 to 33, wherein, when the total mass of the components i, ii, and iii contained in the enteric coated hard capsule preparation liquid is taken as 100, the ratio of the content of the component v to the total mass is 5 or less.

35. The enteric coated hard capsule preparation liquid according to any one of claims 21 to 34, wherein the total amount of the component i, component ii, and component iii is 10 to 30% by mass when the enteric coated hard capsule preparation liquid is taken as 100% by mass.

36. The enteric coated hard capsule preparation liquid according to any one of claims 21 to 35, having a viscosity of 100 to 10,000 mPa·s.

37. A method for preparing an enteric coated hard capsule preparation solution, comprising mixing component i, component ii, component iii, and component iv, each of which has been partially neutralized with component v, The i-th component is an enteric methacrylic acid copolymer, Component ii is a water-insoluble (meth)acrylic acid alkyl ester copolymer; component iii is polyvinyl alcohol; The component iv is gellan gum, and when the total mass of the components i, ii, and iii contained in the enteric coated hard capsule preparation solution is taken as 100, the ratio of the content of the component iv to the total mass is in the range of 0.2 to 1; and The component v is a basic neutralizer that is acceptable as a pharmaceutically or food additive. The preparation method.

38. 38. The method for preparing an enteric coated hard capsule preparation liquid according to claim 37, wherein the enteric methacrylic acid copolymer is at least one selected from the group consisting of a copolymer of methacrylic acid with methyl methacrylate and methyl acrylate, and a copolymer of methacrylic acid with ethyl acrylate.

39. 39. The method for preparing an enteric coated hard capsule preparation according to claim 37 or 38, wherein the water-insoluble (meth)acrylic acid alkyl ester copolymer is a copolymer of methyl methacrylate and ethyl acrylate.

40. The method for preparing an enteric coated hard capsule preparation liquid according to any one of claims 37 to 39, wherein the basic neutralizing agent is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonia, and ammonium carbonate.

41. The method for preparing an enteric coated hard capsule preparation liquid according to any one of claims 37 to 40, wherein the mixing of the component i, the component ii, the component iii, and the component iv partially neutralized with the component v is carried out by the following steps A to D: Step A: dissolving component iii in an aqueous solvent at 80°C to 90°C; Step B: adding the i-th component to a solution of the iii-th component; Step C: adding component v to the solution obtained in step B; Step D: A step of adding components ii and iv to the solution obtained in step C.

42. The method for preparing an enteric coated hard capsule preparation liquid according to any one of claims 37 to 40, wherein the component i, component ii, component iii, and component iv partially neutralized with the component v are mixed by the following steps: Step A': a step of preparing a partially neutralized solution by partially neutralizing the i-th component with the v-th component; Step B': A step of mixing the partially neutralized solution prepared in step A', component iii, component ii and component iv.

43. 43. The method for preparing an enteric coated hard capsule preparation solution according to claim 41 or 42, wherein the content of the basic neutralizing agent is an amount that neutralizes 0.5 mol % or more and 10 mol % or less of the carboxyl groups of the i-th component, when the number of moles of carboxyl groups of the i-th component contained in the shell per capsule before neutralization is taken as 100 mol %.

44. The method for preparing an enteric coated hard capsule preparation liquid according to any one of claims 37 to 43, wherein the viscosity of the enteric coated hard capsule preparation liquid is 100 to 10,000 mPa·s.

45. A method for preparing an enteric coated hard capsule, comprising the steps of: A first step of immersing a mold pin having a surface temperature lower than that of the enteric coated hard capsule preparation liquid according to any one of claims 21 to 36 into the enteric coated hard capsule preparation liquid; and The second step is to remove the mold pins from the enteric-coated hard capsule preparation liquid and dry the enteric-coated hard capsule preparation liquid adhering to the mold pins.

46. 46. The method for preparing an enteric coated hard capsule according to claim 45, wherein the temperature of the enteric coated hard capsule preparation liquid is 50 to 60°C.

47. 47. The method for preparing an enteric coated hard capsule according to claim 45 or 46, wherein the surface temperature of the mold pin before immersion in the preparation liquid is 5 to 40°C.

48. The method for preparing an enteric coated hard capsule according to any one of claims 45 to 47, wherein the temperature for drying the enteric coated hard capsule preparation liquid attached to the mold pin is less than 40°C.

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