Capsule filling composition, method of producing capsule formulation by use of the same, and capsule formulation

Abstract

To provide a capsule filling composition which can stably produce a capsule formulation by preventing contents from spilling out of a capsule body during filling, regardless of the compressibility of active ingredients such as drugs and health foods, so that favorable capsule filling can be achieved, a method of producing a capsule formulation by use of such a capsule filling composition, as well as a capsule formulation.SOLUTION: The problem is solved by a method of producing a capsule formulation, comprising the steps of subjecting a capsule filling composition containing an active ingredient and a cellulose ether powder to a funnel system powder filling or die-compression system powder filling process to prepare a compression molding, with which a capsule container is filled, resulting in the capsule formulation.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a composition for filling a capsule, a method for producing a capsule preparation using the same, and a capsule preparation. [Background technology]

[0002] In the fields of medicine and food, capsule preparations in which contents such as drugs and health foods are filled in capsule containers are produced by automatically filling hard capsules with the contents such as drugs and health foods using a capsule filling machine. Usually, capsule filling machines are configured to automatically produce capsule preparations continuously by separating an empty hard capsule, which is a hard capsule in which a cap and a body are temporarily joined, into the cap and the body, filling a certain amount of contents into the body, and joining the cap and the body again.

[0003] Non-Patent Document 1 describes seven methods for filling the contents: auger-type powder filling, die-compression-type powder filling, funnel-type powder filling, vibration-type powder filling, granule filling, tablet filling, and liquid drug filling. Among these, die-compression-type powder filling is a method in which powder is introduced into a molding plate and compressed and molded with a tapping rod, and the excess powder is scraped off and then transferred to the capsule body. Funnel-type powder filling is a method in which a filling funnel is pushed into the powder layer to solidify the powder and then transferred to the capsule body.

[0004] Both die press type powder filling and funnel type powder filling involve the step of lightly compressing and molding the powder obtained by mixing the contents, such as drugs or health foods, with additives such as excipients to make a homogenous powder, or granules made by granulating the powder using an appropriate method, and filling the powder. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Pharmaceutical Machinery Technology Handbook 2nd Edition 299-300 Summary of the Invention [Problem to be solved by the invention]

[0006] However, the contents of drugs and health foods filled in capsules are diverse, and depending on the type of the contents of drugs and health foods, sufficient compression molding may not be possible. As a result, problems such as mass variation due to the leakage of the contents of drugs and health foods from the capsule body due to mechanical vibration during filling, and inability to manufacture capsule preparations of a constant mass may occur. For example, there are many drugs and health foods that are poor in compression moldability, and it may not be possible to stably fill a capsule with a predetermined mass.

[0007] In view of the above circumstances, an object of the present invention is to provide a capsule filling composition which can suppress leakage of contents from the capsule body during filling, achieve good capsule filling, and stably produce capsule formulations, regardless of the compression moldability of active ingredients such as drugs and health foods, and to provide a method for producing a capsule formulation using the same, and a capsule formulation. [Means for solving the problem]

[0008] The present inventors have conducted extensive research to solve the above problems, and have surprisingly found that a composition containing a cellulose ether powder as an ingredient together with an active ingredient has excellent compression moldability and can suppress the leakage of the ingredient from the capsule body. By using such a composition, the variation in mass of each capsule preparation due to capsule filling can be suppressed, and a capsule preparation of a constant mass can be stably produced.

[0009] And finally, based on the above findings, the inventors have succeeded in creating, as a solution to the problems of the present invention, a method for producing a capsule formulation, which comprises at least a step of filling a capsule container with a compression molded product prepared by subjecting a capsule filling composition containing an active ingredient and cellulose ether powder to funnel-type powder filling or die-press-type powder filling, to obtain a capsule formulation; a capsule filling composition containing an active ingredient and cellulose ether powder; and a capsule formulation containing the capsule filling composition. The present invention has been completed based on findings and successful examples first discovered by the inventors.

[0010] Therefore, according to the present invention, there are provided a capsule filling composition, a method for producing a capsule formulation, and a capsule formulation according to the following aspects. [1] A method for producing a capsule formulation, comprising the step of subjecting a capsule filling composition containing an active ingredient and a cellulose ether powder to funnel-type powder filling or die-compress-type powder filling to prepare a compression molded product, and filling the compression molded product into a capsule container to obtain a capsule formulation. [2] The method for producing a capsule formulation according to [1], wherein the cellulose ether powder has an average particle size of 150 μm or less. [3] The method for producing a capsule formulation according to [1] or [2], wherein the cellulose ether powder has a loose bulk density of 0.55 g / mL or less. [4] The method for producing the capsule formulation according to any one of [1] to [3], further comprising a step of dry-mixing a raw material containing the active ingredient and a cellulose ether powder to obtain a composition for capsule filling containing the active ingredient and a cellulose ether powder. [5] The method for producing a capsule formulation according to any one of [1] to [4], wherein the cellulose ether powder is at least one type of cellulose ether powder selected from the group consisting of nonionic water-soluble cellulose ethers, ionic water-soluble cellulose ethers and salts thereof, nonionic water-insoluble cellulose ethers, and esterified cellulose ethers. [6] The method for producing a capsule formulation described in [5], wherein the nonionic water-soluble cellulose ether is at least one nonionic water-soluble cellulose ether selected from the group consisting of nonionic water-soluble alkylcellulose, nonionic water-soluble hydroxyalkylcellulose, and nonionic water-soluble hydroxyalkylalkylcellulose. [7] A capsule filling composition comprising an active ingredient and a cellulose ether powder. [8] A capsule formulation comprising the capsule filling composition described in [7]. Effect of the Invention

[0011] According to the present invention, in the manufacturing process of a capsule formulation, it is possible to prevent the contents, such as drugs and health foods, from leaking out of the capsule body during filling. According to the present invention, it is expected that the mass variation of each capsule formulation can be suppressed through good capsule filling, and capsule formulations containing a constant mass of contents can be stably manufactured. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The composition for filling a capsule, the method for producing a capsule formulation, and the capsule formulation, which are one embodiment of the present invention, will be described in detail below. However, the present invention can take various forms as long as it achieves its object.

[0013] Unless otherwise specified, each term in this specification is used in the sense commonly used by those skilled in the art and should not be interpreted as having an unduly limiting meaning. In addition, the speculations and theories made in this specification are based on the inventors' past knowledge and experience, and therefore the present invention is not limited solely to such speculations and theories.

[0014] The term "composition" is not particularly limited to the meaning normally used, and may refer to, for example, a combination of two or more components. A "raw material" refers to one component or a combination of two or more components that constitute a composition. The term "and / or" means any one or any or all combinations of two or more of the associated listed items. "Content" is synonymous with concentration and means the ratio of the amount of a component to the total amount of a composition. In this specification, unless otherwise specified, the unit of content means "mass % (wt%)". However, the total content of the components does not exceed 100 mass%. The "to" in a numerical range includes the numerical values ​​before and after it. For example, "0% by mass to 100% by mass" means a range that is equal to or greater than 0% by mass and equal to or less than 100% by mass. "Comprising" means that elements other than the elements explicitly stated as being included can be added (same meaning as "comprising at least"), but also encompasses "consisting of" and "consisting essentially of." In other words, "comprising" can mean including the elements explicitly stated and any one or more elements, consisting of the elements explicitly stated, or consisting essentially of the elements explicitly stated. Elements include limitations such as ingredients, steps, conditions, parameters, etc.

[0015] The number of digits in an integer value is the same as the number of significant digits. For example, 1 has one significant digit, and 10 has two significant digits. Also, the number of digits after the decimal point in a decimal value is the same as the number of significant digits. For example, 0.1 has one significant digit, and 0.10 has two significant digits.

[0016] <Capsule filling composition> A capsule filling composition according to one embodiment of the present invention comprises an active ingredient and a cellulose ether powder.

[0017] The active ingredient is not particularly limited as long as it is an active ingredient that can be orally administered, and examples thereof include drugs used in pharmaceuticals, and active ingredients used in health foods such as nutritional functional foods, foods for specified health uses, and foods with functional claims.

[0018] Examples of drugs used in pharmaceuticals include central nervous system drugs, circulatory system drugs, respiratory system drugs, digestive system drugs, antibiotics, antitussives and expectorants, antihistamines, antipyretic analgesics and anti-inflammatory drugs, diuretics, autonomic nervous system acting drugs, antimalarials, antidiarrheals, psychotropic drugs, vitamins and their derivatives, etc.

[0019] Examples of central nervous system drugs include diazepam, idebenone, naproxen, piroxicam, indomethacin, sulindac, lorazepam, nitrazepam, phenytoin, acetaminophen, ethenzamide, ketoprofen, and chlordiazepoxide.

[0020] Examples of cardiovascular drugs include molsidomine, vinpocetine, propranolol, methyldopa, dipyridamole, furosemide, triamterene, nifedivine, atenolol, spironolactone, metoprolol, pindolol, captopril, isosorbide dinitrate, delapril hydrochloride, meclofenoxate hydrochloride, diltiazem hydrochloride, etilefrine hydrochloride, digitoxin, and alprenolol hydrochloride.

[0021] Respiratory drugs include, for example, amlexanox, dextromethorphan, theophylline, pseudoephedrine, salbutamol, and guaifenesin.

[0022] Examples of gastrointestinal drugs include benzimidazole drugs having antiulcer effects, such as 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylsulfinyl]benzimidazole and 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]benzimidazole, cimetidine, ranitidine, pirenzepine hydrochloride, pancreatin, bisacodyl, and 5-aminosalicylic acid.

[0023] Examples of antibiotics include talampicillin hydrochloride, bacampicillin hydrochloride, cefaclor, erythromycin, etc. Examples of antitussives and expectorants include noscapine hydrochloride, carbetapentane citrate, isoaminyl citrate, dimemorfan phosphate, etc.

[0024] Examples of antihistamines include chlorpheniramine maleate, diphenhydramine hydrochloride, promethazine hydrochloride, etc. Examples of antipyretic analgesic and anti-inflammatory agents include ibuprofen, diclofenac sodium, flufenamic acid, sulpyrine, aspirin, ketoprofen, etc.

[0025] Diuretics include, for example, caffeine, etc. Autonomic nervous system agonists include, for example, dihydrocodeine phosphate, dl-methylephedrine hydrochloride, atropine sulfate, acetylcholine chloride, neostigmine, etc.

[0026] Examples of antimalarial drugs include quinine hydrochloride, etc. Examples of antidiarrheal drugs include loperamide hydrochloride, etc. Examples of psychotropic drugs include chlorpromazine, etc.

[0027] Examples of vitamins and their derivatives include vitamin A, vitamin B1, fursultiamine, vitamin B2, vitamin B6, and vitamin B 12 , vitamin C, vitamin D, vitamin E, vitamin K, calcium pantothenate, and tranexamic acid.

[0028] Examples of active ingredients used in health foods include the above-mentioned vitamins and their derivatives, minerals, carotenoids, amino acids and their derivatives, plant extracts, and health food ingredients.

[0029] Examples of minerals include calcium, magnesium, manganese, zinc, iron, copper, selenium, chromium, sulfur, and iodine.

[0030] Examples of carotenoids include β-carotene, α-carotene, lutein, cryptoxanthin, zeaxanthin, lycopene, astaxanthin, and multicarotene.

[0031] Examples of the amino acid include acidic amino acids, basic amino acids, neutral amino acids, and acidic amino acid amides. Examples of the acidic amino acids include aspartic acid and glutamic acid. Examples of the basic amino acids include lysine, arginine, and histidine.

[0032] Examples of neutral amino acids include linear aliphatic amino acids such as alanine and glycine, branched aliphatic amino acids such as valine, leucine and isoleucine, hydroxyamino acids such as serine and threonine, sulfur-containing amino acids such as cysteine ​​and methionine, aromatic amino acids such as phenylalanine and tyrosine, heterocyclic amino acids such as tryptophan, and imino acids such as proline.

[0033] Examples of acidic amino acid amides include asparagine and glutamine, etc. Examples of amino acid derivatives include acetylglutamine, acetylcysteine, carboxymethylcysteine, acetyltyrosine, acetylhydroxyproline, 5-hydroxyproline, glutathione, creatine, S-adenosylmethionine, glycylglycine, glycylglutamine, dopa, alanylglutamine, carnitine, and γ-aminobutyric acid, etc.

[0034] Examples of plant extracts include aloe, propolis, agaricus, Korean ginseng, ginkgo biloba, turmeric, curcumin, germinated brown rice, shiitake mushroom mycelium, sweet tea, sweet tea, Phellinus linteus, sesame, garlic, maca, cordyceps sinensis, chamomile, and chili pepper.

[0035] Examples of health food ingredients include royal jelly, dietary fiber, protein, bifidobacteria, lactic acid bacteria, chitosan, yeast, koji, glucosamine, lecithin, polyphenols, animal and fish cartilage, soft-shelled turtle, lactoferrin, clams, eicosapentaenoic acid, germanium, enzymes, creatine, carnitine, citric acid, raspberry ketone, coenzyme Q10, methylsulfonylmethane, and phospholipid-bound soybean peptides.

[0036] The active ingredient may be one of the above-mentioned active ingredients alone or two or more of them may be used in combination. The active ingredient may be a commercially available one or may be produced by a known method. The form of the active ingredient is not particularly limited, but considering the mixability with the cellulose ether powder, it is preferable that the active ingredient is a solid such as a powder. When the active ingredient is a liquid, it is preferable to process it into a solid using a carrier such as a powder.

[0037] The compression moldability of the active ingredient is not particularly limited, and it may be either excellent or poor in compression moldability. However, the capsule filling composition of one embodiment of the present invention contains a cellulose ether powder together with the active ingredient, and as a result, it has excellent compression moldability, so that it has the advantage that an active ingredient with poor compression moldability can be used.

[0038] The compression moldability of the active ingredient can be evaluated by the compression moldability index. From the viewpoint of stable production of the capsule preparation, the compression moldability index of the active ingredient is preferably 3% or more, more preferably 5% to 100%. The compression moldability index of the active ingredient is a value measured by the method described in the examples below.

[0039] The content of the active ingredient in the composition for filling capsules is not particularly limited, but is preferably 0.5% by mass to 99.5% by mass, more preferably 0.75% by mass to 99.0% by mass, and even more preferably 1% by mass to 95% by mass.

[0040] A capsule-filling composition according to one embodiment of the present invention contains a cellulose ether powder together with an active ingredient. In the capsule-filling composition, the cellulose ether powder functions as a binder and contributes to the compression moldability of the compression-molded product.

[0041] The properties of the cellulose ether powder are not particularly limited as long as it can improve the compression moldability of the capsule filling composition.

[0042] As described in the examples below, the smaller the average particle size of the cellulose ether powder, the better the compression moldability of the capsule filling composition. Therefore, from the viewpoint of compression moldability, the average particle size of the cellulose ether powder is preferably 150 μm or less, more preferably 1 μm to 100 μm, and even more preferably 5 μm to 80 μm. The average particle size of the cellulose ether powder is a value measured by a method described in the examples below (50% cumulative value of the cumulative particle size distribution curve based on volume by dry laser diffraction method).

[0043] From the viewpoint of compression moldability, the loose bulk density of the cellulose ether powder is preferably 0.55 g / mL or less, more preferably 0.05 g / mL to 0.45 g / mL, and even more preferably 0.05 g / mL to 0.35 g / mL. The loose bulk density of the cellulose ether powder is a value measured by the method described in the examples described later.

[0044] Examples of the cellulose ether powder include nonionic water-soluble cellulose ethers, ionic water-soluble cellulose ethers and salts thereof, nonionic water-insoluble cellulose ethers, and esterified cellulose ethers.

[0045] Examples of the nonionic water-soluble cellulose ether include nonionic water-soluble alkyl cellulose, nonionic water-soluble hydroxyalkyl cellulose, and nonionic water-soluble hydroxyalkyl alkyl cellulose.

[0046] The nonionic water-soluble alkyl cellulose is not particularly limited, but may be methyl cellulose (hereinafter also referred to as "MC"). The nonionic water-soluble hydroxyalkyl cellulose is not particularly limited, but may be hydroxypropyl cellulose (hereinafter also referred to as "HPC"). The nonionic water-soluble hydroxyalkyl alkyl cellulose is not particularly limited, but may be hydroxypropyl methyl cellulose (hereinafter also referred to as "HPMC"). The properties of the nonionic water-soluble cellulose ether, such as the functional group content and viscosity, are not particularly limited, but the preferred ranges of these properties are exemplified below from the viewpoint of the compression moldability imparted to the capsule filling composition.

[0047] The methoxy group content of MC is preferably 26.0% by mass to 33.0% by mass, and more preferably 27.5% by mass to 31.5% by mass. The methoxy group content of MC can be measured in accordance with the analytical method for methylcellulose in the 17th Edition of the Japanese Pharmacopoeia.

[0048] The hydroxypropoxy group content of HPC is preferably 53.4% ​​by mass to 77.5% by mass, and more preferably 60.0% by mass to 70.0% by mass. The hydroxypropoxy group content of HPC can be measured in accordance with the analytical method for hydroxypropyl cellulose in the 17th Edition of the Japanese Pharmacopoeia.

[0049] The methoxy group content of HPMC is preferably 16.5% by mass to 30.0% by mass, more preferably 19.0% by mass to 30.0% by mass, and even more preferably 19.0% by mass to 29.5% by mass. The hydroxypropoxy group content of HPMC is preferably 3.0% by mass to 32.0% by mass, more preferably 3.0% by mass to 12.0% by mass, and even more preferably 4.0% by mass to 12.0% by mass. The methoxy group content and hydroxypropoxy group content in HPMC can be measured by the quantitative method described in the section on "hypromellose" in the 17th Edition of the Japanese Pharmacopoeia.

[0050] The viscosity of the nonionic water-soluble cellulose ether is preferably 1.0 mPa·s to 150,000 mPa·s, more preferably 2.0 mPa·s to 120,000 mPa·s, and even more preferably 2.5 mPa·s to 6,000 mPa·s. The viscosity of the nonionic water-soluble cellulose ether is a value measured by the method described in the examples described later.

[0051] The ionic water-soluble cellulose ether and its salt are not particularly limited, and examples thereof include sodium carboxymethylcellulose (hereinafter also referred to as "CMC-Na"). The functional group content, viscosity, and other properties of the ionic water-soluble cellulose ether are not particularly limited, and from the viewpoint of compression moldability imparted to the capsule filling composition, preferred ranges of these properties are exemplified below.

[0052] The carboxymethyl group content of CMC-Na is preferably 22.0% by mass to 32.0% by mass. The carboxymethyl group content of CMC-Na is a value measured by the method described in the examples described later.

[0053] The viscosity of the ionic water-soluble cellulose ether and its salt, such as CMC-Na, is preferably 1.0 mPa·s to 2,000 mPa·s, more preferably 50 mPa·s to 500 mPa·s. The viscosity of the ionic water-soluble cellulose ether and its salt is a value measured by the method described in the examples below.

[0054] The nonionic water-insoluble cellulose ether is not particularly limited, and examples thereof include low-substituted hydroxypropyl cellulose (hereinafter also referred to as "L-HPC"). The properties of the nonionic water-insoluble cellulose ether, such as the functional group content and viscosity, are not particularly limited, but from the viewpoint of the compression moldability imparted to the capsule filling composition, the preferred ranges of these properties are exemplified below.

[0055] The hydroxypropoxy group content of L-HPC is preferably 5% by mass to 16% by mass, more preferably 6% by mass to 15% by mass, and even more preferably 7% by mass to 14% by mass. The hydroxypropoxy group content of L-HPC can be measured in accordance with the analytical method for low-substituted hydroxypropylcellulose in the 17th Edition of the Japanese Pharmacopoeia.

[0056] The viscosity of the nonionic water-insoluble cellulose ether such as L-HPC is preferably 5 mPa·s to 500 mPa·s, more preferably 10 mPa·s to 400 mPa·s, and even more preferably 30 mPa·s to 300 mPa·s. The viscosity of L-HPC is a value measured by the method described in the examples below.

[0057] The esterified cellulose ether is not particularly limited, but examples thereof include hydroxypropyl methylcellulose acetate succinate (hereinafter also referred to as "HPMCAS"), hydroxypropyl methylcellulose phthalate (hereinafter also referred to as "HPMCP"), etc. The properties of the esterified cellulose ether, such as the functional group content and viscosity, are not particularly limited, but from the viewpoint of the compression moldability imparted to the capsule filling composition, preferred ranges of these properties are exemplified below.

[0058] The methoxy group content of HPMCAS is preferably 12.0% by mass to 28.0% by mass. The hydroxypropoxy group content of HPMCAS is preferably 4.0% by mass to 23.0% by mass. The acetyl group content of HPMCAS is preferably 2.0% by mass to 16.0% by mass. The succinyl group content of HPMCAS is preferably 4.0% by mass to 28.0% by mass. The methoxy group content, hydroxypropoxy group content, acetyl group content, and succinyl group content in HPMCAS can be measured by the quantitative determination method described in the section "Hypromellose acetate succinate" of the 17th Edition of the Japanese Pharmacopoeia.

[0059] The methoxy group content of HPMCP is preferably 16.0% by mass to 26.0% by mass. The hydroxypropoxy group content of HPMCP is preferably 5.0% by mass to 10.0% by mass. The carboxybenzoyl group content of HPMCP is preferably 21.0% by mass to 35.0% by mass. The methoxy group content and hydroxypropoxy group content in HPMCP can be measured by the quantitative method described in the section "Hypromellose acetate succinate" of the Japanese Pharmacopoeia, 17th Edition, and the carboxybenzoyl group content can be measured by the quantitative method described in the section "Hypromellose phthalate" of the Japanese Pharmacopoeia, 17th Edition.

[0060] The viscosity of the esterified cellulose ether is the viscosity of a 0.43% by mass aqueous sodium hydroxide solution containing 2% by mass of the esterified cellulose ether at 20° C. The viscosity of the esterified cellulose ether is preferably 1.0 mPa·s to 100.0 mPa·s. The viscosity of the esterified cellulose ether can be measured by the method described in the pharmaceutical articles "Hypromellose acetate succinate" of the 17th Edition of the Japanese Pharmacopoeia.

[0061] The cellulose ether powder may be one of the above-mentioned cellulose ether powders alone or two or more of them may be used in combination. The cellulose ether powder may be a commercially available cellulose ether powder or a cellulose ether powder produced by a known method.

[0062] The content of the cellulose ether powder in the capsule filling composition is not particularly limited, but from the viewpoint of compression moldability, it is preferably 0.5% by mass to 99.5% by mass, more preferably 1% by mass to 50% by mass, even more preferably 3% by mass to 20% by mass, and even more preferably 3% by mass to 10% by mass.

[0063] The capsule filling composition may contain additives as necessary, including, but not limited to, excipients, disintegrants, binders, lubricants, flavoring ingredients, and fragrances.

[0064] Examples of excipients include lactose, sucrose, starch, corn starch, pregelatinized starch, sucrose, fructose, maltose, crystalline cellulose, powdered cellulose, maltose, maltitol, erythritol, mannitol, sorbitol, dextrin, maltodextrin, kaolin, calcium carbonate, calcium phosphate, and calcium sulfate.

[0065] Examples of disintegrants include corn starch, partially pregelatinized starch, sodium carboxymethyl starch, croscarmellose, croscarmellose sodium, crystalline cellulose, and crospovidone.

[0066] Examples of binders include polyvinylpyrrolidone, starch, polyvinyl alcohol, and starch syrup. Examples of lubricants include magnesium stearate, calcium stearate, talc, sodium stearyl fumarate, and sucrose fatty acid esters. Examples of flavoring ingredients include citric acid, tartaric acid, and malic acid. Examples of flavoring agents include menthol, peppermint oil, and vanillin.

[0067] The additives may be used alone or in combination of two or more of the above. In addition, the additives may be commercially available or may be produced by a known method.

[0068] The content of the additive in the capsule filling composition is not particularly limited as long as it is an amount that does not impair the compression moldability of the capsule filling composition imparted by the cellulose ether powder, and is, for example, preferably 0 to 198 parts by mass, more preferably 5 to 98.25 parts by mass, and even more preferably 8 to 90 parts by mass, relative to 1 part by mass of the cellulose ether powder.

[0069] As a specific embodiment of the composition for filling a capsule, the following composition for filling a capsule can be mentioned, but the present invention is not limited to these embodiments. (1) A composition for filling capsules, which contains 0.001 to 90 parts by mass of cellulose ether powder per part by mass of an active ingredient, and has a total flow rate of 13.0 times or more in a compression moldability evaluation. (2) A composition for filling capsules, which contains 0.01 to 20 parts by mass of cellulose ether powder per part by mass of an active ingredient and has a total flow rate of 15.0 times or more in a compression moldability evaluation. (3) A composition for filling capsules, which contains 0.001 to 90 parts by mass of cellulose ether powder per 1 part by mass of an active ingredient, and contains 10% to 95% by mass of additives in total, and which has a total outflow rate of 13.0 times or more in a compression moldability evaluation. (4) A composition for filling capsules, which contains 0.01 to 20 parts by mass of cellulose ether powder per part by mass of an active ingredient, and contains 50% to 90% by mass of additives in total, and which has a total outflow rate of 15.0 times or more in a compression moldability evaluation.

[0070] The method for producing the composition for capsule filling is not particularly limited, and may be any method that employs a means for making each component uniform. However, from the viewpoint of quantitatively filling the composition for capsule filling to ensure the quality of the capsule formulation, the method for producing the composition for capsule filling preferably includes a step of dry-mixing raw materials including the active ingredient, cellulose ether powder, and optional additives to obtain a composition for capsule filling containing the active ingredient and cellulose ether powder.

[0071] The method of dry mixing is not particularly limited, and any known method can be used in which each powder component is mixed uniformly while maintaining the powder component in a dry state.

[0072] <Method of production of capsule formulation and capsule formulation> A method for producing a capsule formulation according to one embodiment of the present invention includes a step of obtaining a capsule formulation by subjecting a capsule filling composition containing an active ingredient and a cellulose ether powder to die-compress type powder filling or funnel type powder filling to prepare a compression molded product and filling the compression molded product into a capsule container.

[0073] Die press type powder filling is a type of capsule filling method as is commonly known, in which powder is introduced into a molding plate and compressed with a tapping rod to prepare a compressed molded product, and after scraping off excess powder, the obtained compressed molded product is transferred to the capsule body.

[0074] Funnel powder filling is a commonly known capsule filling method in which a filling funnel is forced into a powder bed to compact the powder and prepare a compact, which is then transferred into a capsule body.

[0075] The die press type powder filling and funnel type powder filling can be carried out in the usual manner using a capsule filling machine capable of carrying out these filling methods. The capsule filling machine is not particularly limited, but examples thereof include the fully automatic capsule filling machine "LIQFILsuper40" (manufactured by Qualicaps Co., Ltd.) and the intermittent capsule filling machine "ZANASI 6-12-25-40" (manufactured by IMA Co., Ltd.).

[0076] The die-compress type powder filling and the funnel type powder filling are common in that a capsule filling composition containing an active ingredient and a cellulose ether powder is compression-molded to prepare a compression molded product, and the compression molded product is filled into a capsule container to obtain a capsule formulation. That is, as long as the die-compress type powder filling and the funnel type powder filling are used, the capsule filling composition is compression-molded.

[0077] The capsule container comprises a capsule cap and a capsule body. The capsule container used in the method for producing a capsule formulation according to one embodiment of the present invention is not particularly limited in type, material, size, etc.

[0078] The type of capsule container is preferably a hard capsule, since it is easy to store the capsule-filling composition that has been compressed. The material of the capsule container can be HPMC hard capsule, gelatin hard capsule, pullulan hard capsule, etc. The size of the capsule container can be 00, 0, 1, 2, 3, 4, 5, 9, etc., and any size of capsule container can be used.

[0079] The capsule container to be used may be a commercially available one, or one produced by a known method.

[0080] A capsule formulation produced by the method for producing a capsule formulation according to one aspect of the present invention contains the capsule filling composition according to one aspect of the present invention. Another aspect of the present invention is a capsule formulation containing the capsule filling composition according to one aspect of the present invention.

[0081] Furthermore, by using a cellulose ether powder having a relatively high viscosity, preferably a nonionic water-soluble cellulose ether powder such as HPMC having a viscosity of 50 mPa s to 100,000 mPa s, as the cellulose ether powder, the initial burst can be suppressed and excellent sustained release properties can be imparted to the capsule formulation. EXAMPLES

[0082] The present invention will be described in more detail below with reference to examples and comparative examples, but the present invention is not limited to these examples.

[0083] <Materials used> As active ingredients, koji powder and vitamin B2 were used. For the koji powder, "Multigrain Koji (registered trademark) 50M" (compression moldability index 25%; manufactured by Yaegaki Hakko Giken Co., Ltd.) was used. For vitamin B2, "riboflavin" (compression moldability index 5%; manufactured by Kyowa Pharma Chemical Co., Ltd.) was used.

[0084] The cellulose ether powders used were hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), hydroxypropyl cellulose (HPC), sodium carboxymethylcellulose (CMC-Na) and low-substituted hydroxypropyl cellulose (L-HPC), all of which were produced according to conventional methods. The physical properties of the cellulose ether powders are shown in Table 1.

[0085] The lactose used was "Pharmatose 100M" (DMV). The capsule container used was "HPMC Capsule Size 0" (Hillhalf Research Institute).

[0086] [Table 1]

[0087] <Physical property evaluation> [Average particle size] The average particle size represents the volume-based average particle size measured by a dry laser diffraction method, and was measured using a laser diffraction particle size distribution measuring device ("Mastersizer 3000" manufactured by Malvern) according to the Fraunhofer diffraction theory, using a dry method under conditions of a dispersion pressure of 1.5 bar and a scattering intensity of 2% to 10%, at the 50% cumulative value of a volume-based cumulative particle size distribution curve.

[0088] [Loose bulk density] The loose bulk density indicates the bulk density of the cellulose ether powder in a loosely packed state, and was measured using a powder property evaluation device "Powder Tester PT-X type" (manufactured by Hosokawa Micron Corporation) in accordance with the method 3 of "Measurement method for bulk density and tapped density" of the 17th revised edition of the Japanese Pharmacopoeia.

[0089] [viscosity] 1.HPMC, MC and HPC An amount of HPMC, MC, or HPC equivalent to 6 g of dried matter converted to water content was accurately weighed into a wide-mouthed bottle (diameter 65 mm; height 120 mm; volume 350 ml), and 98°C hot water was added to make the concentration 2% by mass. After the wide-mouthed bottle was capped, the mixture was stirred at 350 rpm to 500 rpm for 20 minutes using a stirrer until a uniform dispersion was obtained. Then, the mixture was stirred for 40 minutes in a water bath at 0°C to 5°C to dissolve the cellulose ether, thereby obtaining a 2% by mass aqueous solution of the cellulose ether as a sample solution.

[0090] The viscosity of a 2% by mass aqueous solution of cellulose ether at 20°C was measured using a single cylinder rotational viscometer in accordance with the rotational viscometer method in the "Viscosity Measurement Method" of the General Test Method in the Japanese Pharmacopoeia, 17th Edition, when the viscosity was 600 mPa s or more. On the other hand, when the viscosity was less than 600 mPa s, it was measured using an Ubbelohde viscometer in accordance with the capillary viscometer method in the "Viscosity Measurement Method" of the General Test Method in the Japanese Pharmacopoeia, 17th Edition.

[0091] 2. CMC-Na CMC-Na (approximately 2.2 g) was weighed out in a 300-mL Erlenmeyer flask with a stopper. Water was added in an amount calculated from the formula "sample (g) x (99 - water content (mass%))" and the flask was left to stand for 12 hours and then mixed for an additional 5 minutes to prepare a 1 mass% aqueous solution of CMC-Na.

[0092] The viscosity of a 1% by mass aqueous solution of CMC-Na at 25° C. was measured using a BM type viscometer (single cylinder type rotational viscometer) in accordance with JIS Z8803.

[0093] 3.L-HPC An amount of L-HPC equivalent to 15 g of dry matter calculated as moisture content was accurately weighed into a wide-mouthed bottle (diameter 65 mm; height 120 mm; volume 350 ml), and purified water at 20°C was added to make the concentration 5% by mass. After the wide-mouthed bottle was capped, the mixture was stirred at 350 rpm to 500 rpm for 20 minutes using a stirrer until a uniform dispersion was obtained, thereby obtaining a 5% by mass dispersion of water-insoluble cellulose ether as a sample solution.

[0094] The viscosity of a 5% by mass aqueous dispersion of L-HPC at 20° C. was measured using a single cylinder rotational viscometer in accordance with the “Viscosity Measurement Method” in the General Test Methods in the Japanese Pharmacopoeia, 17th Edition.

[0095] [Methoxy group content, hydroxypropoxy group content and carboxymethyl group content] The methoxy group contents of HPMC and MC were measured according to the quantitative methods described in the sections "hypromellose" and "methylcellulose" of the Japanese Pharmacopoeia, 17th Edition, respectively. The hydroxypropoxy group contents of HPMC, HPC, and L-HPC were measured according to the quantitative methods described in the sections "hypromellose," "hydroxypropyl cellulose," and "low-substituted hydroxypropyl cellulose" of the Japanese Pharmacopoeia, 17th Edition, respectively.

[0096] The carboxymethyl group content of CMC-Na was calculated from the substitution degree of CMC-Na according to the following formula: Carboxymethyl group content of CMC-Na =(81×100×CM) / (162+64×CM) CM: Degree of substitution of CMC-Na 162: Molecular weight of glucose 81: Molecular weight of CH2COONa 64: Molecular weight increase of CH2COONa

[0097] The degree of substitution of CMC-Na was measured by the following method. First, 0.5-0.7 g of a CMC-Na sample (anhydrous) was precisely weighed, wrapped in filter paper, and incinerated in a magnetic crucible. The incinerated CMC-Na was then cooled and transferred to a 500 mL beaker, to which 250 mL of water and 35 mL of 0.05 M sulfuric acid were added and boiled for 30 minutes. After cooling the boiled solution, phenolphthalein indicator was added, and the excess sulfuric acid was back-titrated with 0.1 M potassium hydroxide, and the concentration was calculated according to the following formula: Degree of substitution of CMC-Na (CM) = (162 x A) / (10000-80 x A) 162: Molecular weight of glucose 80: Molecular weight of CH2COONa-H

[0098] In the above formula, A is the amount (mL) of 0.05 M sulfuric acid consumed by the alkali in 1 g of the CMC-Na sample, and was calculated according to the following formula: A = ((a*fb*f1) / CMC-Na sample (anhydrous) (g)) - alkalinity (or + acidity) a: Amount of 0.05M sulfuric acid used (mL) f: Potency of 0.05M sulfuric acid b: Titration volume of 0.1M potassium hydroxide (mL) f1: Potency of 0.1M potassium hydroxide

[0099] Furthermore, the alkalinity (or acidity) was measured by the following method. 1 g of CMC-Na sample (anhydrous) was precisely weighed into a 300 mL flask and dissolved in 200 mL of water. 5 mL of 0.05 M sulfuric acid was added to the obtained CMC-Na solution, boiled for 10 minutes, and then cooled. Phenolphthalein indicator was added to the cooled solution, and titrated with 0.1 M potassium hydroxide (S mL). At the same time, a blank test was performed (B mL), and the concentration was calculated according to the following formula: Alkalinity = ((BS) x f2) / CMC-Na sample (anhydrous) (g) f2: Potency of 0.1M potassium hydroxide However, if the value of (BS) x f2 is negative, it is considered to be acidity.

[0100] [Compression moldability index] The active ingredient weighed out to 2000 mg was poured into a polycarbonate tube (hollow cylindrical; inner diameter 12.5 mm, height 52.0 mm; "Polycarbonate Spacer (hollow) CPC (CPC-1252); manufactured by Hirosugi Keiki Co., Ltd.) placed on a stainless steel tray. Next, a compression molding was prepared by compression molding the active ingredient in the polycarbonate tube with a cylindrical jig having a contact surface diameter of 11.28 mmΦ using a tensile compression tester ("SDT-503NB"; manufactured by Imada Seisakusho Co., Ltd.) (compression molding conditions: speed: 100 mm / min., load: 0.5 N, load maintenance time: 1 sec.). The mass of the polycarbonate tube containing the compression molding of the active ingredient was measured as the pre-test mass.

[0101] Next, the polycarbonate tube filled with the compression molded product of the active ingredient was placed on a mesh sieve (Test sieves JIS Z 8801; φ200 mm × 45 mmH, mesh size 1.4 mm; manufactured by Tokyo Screen Co., Ltd.) combined with a receiving tray, and then pinched vertically with the fingers and raised to a height of 1 cm.

[0102] The polycarbonate tube was then dropped. This was repeated three times, and the mass of the polycarbonate tube containing the remaining compression molded product of the active ingredient was measured as the post-test mass.

[0103] The amount of powder that flowed out of the polycarbonate tube was calculated by subtracting the mass after the test from the mass before the test. Furthermore, the amount of powder that flowed out of the polycarbonate tube was calculated by subtracting the mass before the test from the mass before the test. The test was performed five times, and the compression moldability index of the active ingredient was calculated by dividing the average value of the remaining amount of the compression molded active ingredient by the amount of the active ingredient (2000 mg) added.

[0104] [Compression moldability] A polycarbonate tube containing a compression molded product of the capsule filling composition was prepared as described in the above [Compression moldability index], except that the capsule filling composition described below was used instead of the active ingredient, and the mass was measured.

[0105] The polycarbonate tube containing the compression molded product of the capsule filling composition was dropped as described in the above [Compression moldability index], and the mass of the polycarbonate tube containing the compression molded product of the active ingredient remaining after three drops and after five drops was measured. The mass after the drop was subtracted from the mass before the drop to measure the amount of powder that flowed out of the polycarbonate tube. In addition, the number of drops until the entire amount of the capsule filling composition flowed out of the polycarbonate tube was measured. The number of tests was 5, and the average value was used to evaluate the compression moldability.

[0106] [Elution amount] For the capsule formulations described below, a dissolution test was performed using a dissolution tester ("NTR-6400A" manufactured by Toyama Sangyo Co., Ltd.) in accordance with the "Dissolution Test Method" described in the 17th Edition of the Japanese Pharmacopoeia (37°C, paddle method, using a sinker, 50 rpm, 900 mL of purified water as solvent), and the amount of dissolution was measured.

[0107] <Production of capsule filling composition and compression molded product> [Example 1] Using HPMC-1 as the cellulose ether powder shown in Table 1, koji powder as the active ingredient and HPMC-1 as the cellulose ether powder were weighed and dry-mixed to obtain the contents shown in Table 2 to produce a composition for filling capsules.

[0108] The capsule filling composition thus produced was compression molded in a polycarbonate tube by the method described in the above [Compression moldability] to produce a compression molded product.

[0109] [Examples 2 to 9 and Comparative Example 1] In the same manner as in Example 1, the active ingredient and the cellulose ether powder were weighed and dry-mixed to obtain the contents shown in Table 2 using the cellulose ether powder shown in Table 1, to produce a capsule filling composition and a compression molded product. In addition, in Comparative Example 1, no cellulose ether powder was used.

[0110] [Example 10 and Comparative Example 2] In the same manner as in Example 1, a capsule filling composition and a compression molded product were produced by weighing and mixing vitamin B2 as an active ingredient, cellulose ether powder, and lactose as an excipient using HPMC-3 as shown in Table 1 to obtain the contents shown in Table 3. In Comparative Example 2, no cellulose ether powder was used.

[0111] <Manufacturing of Capsule Formulations> [Example 10 and Comparative Example 2] After weighing 450 mg of each of the capsule filling compositions of Example 10 and Comparative Example 2, the compositions were placed in a 7 mm diameter mortar (IPT standard; manufactured by Kikusui Seisakusho Co., Ltd.) placed on a stainless steel tray. Using a tensile compression tester ("SDT-503NB"; manufactured by Imada Seisakusho Co., Ltd.), the capsule filling composition in the mortar was compression molded with a 7 mm diameter, 10 mmR pestle (IPT standard; manufactured by Kikusui Seisakusho Co., Ltd.) under a load of 0.19 N to prepare a compression molded product.

[0112] Next, the compressed product was extruded from the die and filled into a separated hard capsule body, and then a capsule cap was attached to prepare a capsule formulation.

[0113] <Evaluation of Compression Molded Products> The evaluation results of compression moldability of Examples 1 to 9 and Comparative Example 1 are shown in Table 2. It was found from Table 2 that the use of cellulose ether powder improves the compression moldability of the active ingredient. The use of cellulose ether powder can prevent mass variation due to outflow of the active ingredient caused by mechanical vibration during filling in the manufacturing process of the capsule formulation, and is expected to enable stable production of capsule formulations of a constant mass.

[0114] Moreover, it was found from Examples 1 and 2 that the effect of improving the compression moldability was greater as the content of the cellulose ether powder increased.

[0115] Furthermore, it was found from Examples 1 and 3 that the smaller the average particle size of the cellulose ether powder, the greater the effect of improving the compression moldability.

[0116] Moreover, it was found from Examples 1 and 3 that the lower the viscosity of the cellulose ether powder, the greater the effect of improving the compression moldability.

[0117] In addition, it was found from Examples 5 to 9 that the effect of improving the compression moldability was achieved even when various cellulose ether powders were used.

[0118] From Example 10 and Comparative Example 2, it was confirmed that even when an active ingredient different from those in Examples 1 to 9 was used and an excipient was further contained, excellent compression moldability was obtained.

[0119] <Evaluation of Capsule Formulations> The dissolution rates of vitamin B2 after 0 hours, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours and 5 hours are shown in Table 3.

[0120] From Example 10 and Comparative Example 2, it was found that the use of high viscosity cellulose ether powder can suppress the initial burst and impart excellent sustained release properties to the capsule preparation.

[0121] [Table 2]

[0122] [Table 3] [Industrial Applicability]

[0123] INDUSTRIAL APPLICABILITY The present invention can be used to stably produce capsule preparations containing a constant mass of content with reduced mass variation.

Claims

1. A method for producing a capsule formulation, comprising the steps of subjecting a capsule filling composition containing an active ingredient and a cellulose ether powder to funnel-type powder filling or die-compress-type powder filling to prepare a compression molded product, and filling the compression molded product into a capsule container to obtain a capsule formulation.

2. The method for producing a capsule formulation according to claim 1, wherein the cellulose ether powder has an average particle size of 150 μm or less.

3. The method for producing a capsule formulation according to claim 1 or 2, wherein the cellulose ether powder has a loose bulk density of 0.55 g / mL or less.

4. The method for producing the capsule formulation according to any one of claims 1 to 3 further comprises a step of dry-mixing a raw material containing the active ingredient and a cellulose ether powder to obtain a composition for capsule filling containing the active ingredient and the cellulose ether powder.

5. The method for producing a capsule formulation according to any one of claims 1 to 4, wherein the cellulose ether powder is at least one type of cellulose ether powder selected from the group consisting of nonionic water-soluble cellulose ethers, ionic water-soluble cellulose ethers and salts thereof, nonionic water-insoluble cellulose ethers, and esterified cellulose ethers.

6. The method for producing a capsule formulation according to claim 5, wherein the nonionic water-soluble cellulose ether is at least one nonionic water-soluble cellulose ether selected from the group consisting of nonionic water-soluble alkyl cellulose, nonionic water-soluble hydroxyalkyl cellulose, and nonionic water-soluble hydroxyalkyl alkyl cellulose.

7. A capsule filling composition comprising an active ingredient and a cellulose ether powder.

8. A capsule formulation comprising the capsule filling composition of claim 7.

Images