Patent Description:
In the fields of pharmaceuticals and foods, capsule formulations in which a capsule container is filled with components such as drugs and health foods, are produced in an automated process wherein a hard capsule is filled with the components using a capsule filling machine. Typically, capsule filling machines are constructed such that the continuous and automatic production of capsule formulations can be achieved by separating an empty hard capsule, in which a cap and a body supplied have been temporarily coupled together, into a cap and a body; filling the body with a constant weight of components; and then coupling the cap and the body together again.

In Non-Patent Document <NUM>, seven methods of filling capsules with components are; auger system powder filling, die-compression system powder filling, funnel system powder filling, vibration system powder filling, granule filling, tablet filling and liquid drug filling. Among them, the die-compression system powder filling process comprises the following method: compressing, with a tapping rod, powders introduced into a molding plate, scraping off excess powder, and then transferring the compressed powder into a capsule body. The funnel system powder filling process runs according to the following method: pushing a funnel for capsule filling into a powder layer to compress powders, and then transferring the compressed powders to a capsule body. Patent document <NUM> discloses a method of filling a capsule formulation that ensures dose-accuracy.

Both the die-compression system powder filling and the funnel system powder filling processes include adding and mixing additive agents such as diluting agent to components such as drugs and health foods to obtain homogenous powders or granules obtained by granulating such a homogenous powder by a suitable method, and then light compression, and a powder or granule filling step.

Non-Patent Document <NUM>: <NPL> Patent Document <NUM>: <CIT>.

The components for filling capsules cover a wide variety of drugs and health foods, so that compression may not be sufficiently achieved for some types of components. As a result, this leads to problems in which, for example, weight variations are caused by liquid drugs and health foods components spilling out of a capsule body due to mechanical vibrations during capsule filling, thereby failing to produce capsule formulations having a constant weight. Many drugs and health foods have poor compressibility, making it difficult to stably fill capsules, in other words, reliably and accurately filling capsules with such drugs and health foods with a predetermined amount.

In view of the above circumstances, it is an objective of the present invention to provide a capsule filling composition which can stably produce a capsule formulation by suppressing the flow of components out of the capsule body during capsule filling processes, regardless of the compressibility of an active ingredient such as drugs and health foods, so that a favorable capsule filling can be achieved; and a method of producing a capsule formulation with the use of such a capsule filling composition, as well as a capsule formulation.

In the course of extensive efforts to find a way to solve the above-identified problems, the present inventor has surprisingly found that a composition which contains a cellulose ether powder component, together with an active ingredient is very amenable to compression, and can prevent the flow of components out of a capsule body during capsule filling. By using such a composition, it is possible to prevent weight variations between each capsule formulation derived from capsule filling errors, and to stably produce capsule formulations having a constant weight.

Finally, on the basis of the above findings, the inventor has successfully invented a method of producing a capsule formulation at least including subjecting a capsule filling composition comprising an active ingredient and a cellulose ether powder according to the claims to a funnel system powder filling or a die-compression system powder filling to prepare a compressed product, and filling a capsule container with the compressed product to obtain the capsule formulation; Disclosed, but not claimed, is a capsule filling composition containing an active ingredient and a cellulose ether powder; and a capsule formulation containing such a capsule filling composition, as a possible solution to achieve the objective of the present invention. Such as, the present invention has been completed on the basis of the findings and successful examples that were first found or obtained by the present inventor.

According to the present invention, a method of producing a capsule formulation is provided in the following aspects:.

According to the present invention, in the step of producing a capsule formulation, the outflow of components such as drugs and health foods from the inside of a capsule body during capsule filling can be prevented. According to the present invention, it is expected that favorable capsule filling allows weight variation for capsule formulations to be suppressed so that capsule formulations containing components with a constant weight can be stably produced.

While a method of producing a capsule formulation of the present invention will now be described in detail, the present invention may take various embodiments to the extent that its objective can be achieved.

Unless otherwise specified, each term used herein is used in the meaning commonly used by those skilled in the art and should not be construed to have any meaning that is unduly limiting. Also, any speculations and theories herein are made on the basis of the knowledge and experiences of the present inventors and as such, the present invention is not bound by any such speculations and theories.

While the term "composition" is not particularly limited and means composition as commonly understood, it refers, for example, to a combination of two or more components. The term "raw material" means one component, or two or more components combined to form a composition.

The term "and/or" as used herein means either any one of, any combination of two or more of, or a combination of all listed related items.

The term "content" as used herein is equivalent to "concentration" and means the proportion of a component relative to the total amount of a composition containing the component. Unless otherwise specified, the unit of content herein indicates % by mass or "wt%. " It should be noted, however, that the total amount of the contents of components cannot exceed <NUM> wt%.

The wording "to" used to indicate a range of values, is intended to include values preceding and following the wording; for example, "<NUM> wt% to <NUM> wt%" means a range from <NUM> wt% or more and <NUM> wt% or less.

The terms "include," "comprise," and "contain" mean that an element(s) other than an element(s) as explicitly indicated can be added as inclusions, which are, for example, synonymous with "at least include," but encompasses the meaning of "consist of" and "substantially consist of". In other words, the terms may mean, for example, to include an element(s) as explicitly indicated as well as any one element, or any two or more elements, to consist of an element(s) as explicitly indicated, or substantially consist of an element(s) as explicitly indicated. Such elements include limitations such as components, steps, conditions, and parameters.

The number of digits of an integer is equal to its significant figure. For example, <NUM> has one significant figure and <NUM> has two significant figures. For a decimal number, the number of digits after a decimal point equals to its significant figure. For example, <NUM> has one significant figure and <NUM> has two significant figures.

The method of producing a capsule formulation according to one embodiment of the present invention includes an active ingredient and a cellulose ether powder.

The active ingredient is not particularly limited as long as it is an orally administrable active ingredient. The active ingredient includes, for example, drugs used in pharmaceutical products, as well as active ingredients used in health foods such as foods with nutrient function claims, vitamins or minerals, foods for specified health uses, and foods with function claims.

Examples of the drugs used in pharmaceutical products include central nervous system drugs, circulatory system drugs, respiratory system drugs, digestive system drugs, antibiotics, antitussive/expectorant agents, antihistamine agents, antipyretics, analgesics, anti-inflammatory agents, diuretic agents, autonomic nerve agents, antimalarial agents, antidiarrheal drugs, psychotropic agents, vitamins, derivatives thereof and the like.

In certain embodiments, the active ingredient according to the invention is selected from the following examples:.

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

Examples of the circulatory system drugs include molsidomine, vinpocetine, propranolol, methyldopa, dipyridamole, furosemide, triamterene, nifedipine, atenolol, spironolactone, metoprolol, pindolol, captopril, isosorbide nitrate, delapril hydrochloride, meclofenoxate hydrochloride, diltiazem hydrochloride, etilefrine hydrochloride, digitoxin, alprenolol hydrochloride and the like.

Examples of respiratory system drugs include amlexanox, dextromethorphan, theophylline, pseudoephedrine, salbutamol, guaifenesin and the like.

Examples of digestive system drugs include benzimidazole type drugs having antiulcer activity such as <NUM>-[[<NUM>-methyl-<NUM>-(<NUM>,<NUM>,<NUM>-trifluoroethoxy)-<NUM>-pyridyl]methylsulfinyl]benzimidazole and <NUM>-methoxy-<NUM>-[(<NUM> -methoxy-<NUM>,<NUM>-dimethyl-<NUM>-pyridyl)methylsulfinyl]benzimidazole, cimetidine, ranitidine, pirenzepine hydrochloride, pancreatin, bisacodyl, <NUM>-aminosalicylic acid and the like.

Examples of the antibiotics include talampicillin hydrochloride, bacampicillin hydrochloride, cefaclor, erythromycin and the like. Examples of antitussive/expectorant agents include noscapine hydrochloride, carbetapentane citrate, isoaminile citrate, dimemorfan phosphate and the like.

Examples of antihistamine agents include chlorpheniramine maleate, diphenhydramine hydrochloride, promethazine hydrochloride and the like. Examples of the antipyretic analgesic or anti-inflammatory agents include ibuprofen, diclofenac sodium, flufenamic acid, sulpyrine, aspirin, ketoprofen and the like.

Examples of diuretic agents include caffeine and the like. Examples of autonomic nerve agents include dihydrocodeine phosphate, dl-methylephedrine hydrochloride, atropine sulfate, acetylcholine chloride, neostigmine and the like.

Examples of antimalarial agents include quinine hydrochloride and the like. Examples of antidiarrheal drugs include loperamide hydrochloride and the like. Examples of the psychotropic agents include chlorpromazine and the like.

Examples of vitamins and derivatives thereof include vitamin A, vitamin B<NUM>, fursultiamine, vitamin B<NUM>, vitamin B<NUM>, vitamin B<NUM>, vitamin C, vitamin D, vitamin E, vitamin K, calcium pantothenate, tranexamic acid and the like.

Examples of active ingredients used in health foods include the vitamins and derivatives thereof, minerals, carotenoids, amino acids and derivatives thereof, plant extracts, health food materials and the like.

Examples of minerals include calcium, magnesium, manganese, zinc, iron, copper, selenium, chromium, sulfur, iodine and the like.

Examples of carotenoids include β-carotene, α-carotene, lutein, cryptoxanthin, zeaxanthin, lycopene, astaxanthin, multi-carotene and the like.

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

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; hydroxy amino 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; imino acids such as proline; and the like.

Examples of acidic amino acid amides include asparagine, glutamine and the like. Examples of amino acid derivatives include acetylglutamine, acetylcysteine, carboxymethylcysteine, acetyltyrosine, acetylhydroxyproline, <NUM>-hydroxyproline, glutathione, creatine, S-adenosylmethionine, glycylglycine, glycylglutamine, dopa, alanylglutamine, carnitine, γ-aminobutyric acid and the like.

Examples of plant extracts include aloe, propolis, agarics, ginseng, ginkgo biloba, turmeric, curcumin, germinated brown rice, shiitake mushroom mycelium, beetle tea, sweet tea, fomes yucatensis, sesame, garlic, maca, Chinese caterpillar fungus, chamomile, capsaicins and the like.

Examples of health food materials include royal jelly, dietary fiber, protein, bifidobacteria, lactic acid bacteria, chitosan, yeast, koji (rice malt), glucosamine, lecithin, polyphenol, animal fish cartilage, softshell turtle, lactoferrin, shijimi (Corbicula ), eicosapentaenoic acid, germanium, enzyme, creatine, carnitine, citric acid, raspberry ketone, coenzyme Q10, methylsulfonylmethane, phospholipid-binding soybean peptide and the like.

The active ingredient may be used either individually or in combination of two or more of the above-mentioned active ingredients. The active ingredient may be commercially available or may be produced by known methods. While the form of the active ingredient is not particularly limited, the active ingredient is preferably in a solid form such as powder, to enable favorable mixability with a cellulose ether powder. When the active ingredient is in the form of liquid, the active ingredient is preferably processed into the form of solid for use by using a carrier, for example, in the form of powder.

The active ingredient is not particularly limited in terms of compressibility. The active ingredient used may be excellent or inferior in compressibility. In this regard, the capsule filling composition according to one embodiment of the present invention contains the cellulose ether powder together with the active ingredient so that the capsule filling composition displays improved compressibility. As a result, the capsule filling composition has the advantage that any active ingredients inferior in compressibility can be used.

The compressibility of the active ingredient may be evaluated by a compressibility index. The compressibility index of the active ingredient is preferably equal to, or more than <NUM>%, more preferably <NUM>% to <NUM>%, in order to enable stable production of capsule formulations. The compressibility index of the active ingredient is a value determined according to the method as described in Examples below.

While the content of the active ingredient in the capsule filling composition is not particularly limited, the content of the active ingredient is preferably in the range between <NUM>. 5wt% and <NUM> wt%, more preferably between <NUM> wt% and <NUM> wt%, and still more preferably between <NUM> wt% and <NUM> wt% of the final capsule filling composition.

The capsule filling composition includes the cellulose ether powder together with the active ingredient. In the capsule filling composition, the cellulose ether powder serves as a binding agent, and contributes to compressibility of compressed product.

The cellulose ether powder is according to the claims, but is not particularly limited in terms of property as long as the cellulose ether powder can improve compressibility of the capsule filling composition.

As described in the Examples below, the smaller the average particle size of the cellulose ether powder is, the more compressible the capsule filling composition is. Therefore, in terms of compressibility, the average particle size of the cellulose ether powder in particular embodiments is less than <NUM>, more preferably in the range between <NUM> and <NUM>, and still more preferably between <NUM> and <NUM>. The average particle size of the cellulose ether powder is a value determined by the method as described in Examples below (<NUM>% cumulative value of volume-based cumulative particle size distribution curve according to a dry laser diffraction method).

In terms of compressibility, the loose bulk density of cellulose ether powder in particular embodiments is preferably equal to or less than <NUM>/mL, more preferably in the range between <NUM>/mL and <NUM>/mL, and still more preferably between <NUM>/mL and <NUM>/mL. The loose bulk density of cellulose ether powder is a value determined by the method as described in Examples below.

The term "cellulose ether powder" includes nonionic water-soluble cellulose ether, ionic water-soluble cellulose ether and salt thereof, nonionic water-insoluble cellulose ether, esterified cellulose ether and the like.

According to the claims, the cellulose ether powder is hydroxypropyl methylcellulose powder.

The term "nonionic water-soluble cellulose ether" includes nonionic water-soluble alkyl cellulose, nonionic water-soluble hydroxyalkyl cellulose, nonionic water-soluble hydroxyalkylalkyl cellulose and the like.

The nonionic water-soluble alkyl cellulose not claimed includes methylcellulose (hereinafter, also referred to as "MC") and the like. The nonionic water-soluble hydroxyalkyl cellulose used according to the claims is hydroxypropyl cellulose (hereinafter, also referred to as "HPC"). The nonionic water-soluble hydroxyalkylalkyl cellulose not claimed includes hydroxypropyl methylcellulose (hereinafter, also referred to as "HPMC") and the like. The nonionic water-soluble cellulose ether used is not particularly limited in terms of properties such as functional group content and viscosity. Favorable ranges of such properties are exemplified below which take into consideration compressibility of the given capsule filling composition.

In particular embodiments (not claimed), the methoxy group content of MC is preferably in the range between <NUM> wt% and <NUM> wt%, and more preferably between <NUM> wt% and <NUM> wt%. The methoxy group content of MC can be determined according to the measurement method for methylcellulose described in<NPL>on.

In particular embodiments, the hydroxypropoxy group content of HPC is preferably in the range between <NUM> wt% and <NUM> wt%, and more preferably between <NUM> wt% and <NUM> wt%. The hydroxypropoxy group content of HPC can be determined according to the measurement method for hydroxypropyl cellulose described in<NPL>on.

In particular embodiments (not claimed), the methoxy group content of HPMC is preferably in the range between <NUM> wt% and <NUM> wt%, more preferably between <NUM> wt% and <NUM>% wt%, and still more preferably between <NUM> wt% and <NUM> wt%. In particular embodiments (not claimed), the hydroxypropoxy group content of HPMC is preferably in the range between <NUM> wt% and <NUM> wt%, more preferably between <NUM> wt% and <NUM> wt%, and still more preferably between <NUM> wt% and <NUM> wt%. The methoxy group content and the hydroxypropoxy group content of HPMC can be determined according to the quantitative method described in the section "<NPL>on.

In particular embodiments, the viscosity of the nonionic water-soluble cellulose ether is preferably in the range between <NUM> mPa·s and <NUM>,<NUM> mPa·s, more preferably between <NUM> mPa·s and <NUM>,<NUM> mPa·s, and still more preferably between <NUM> mPa·s and <NUM>,<NUM> mPa·s. The viscosity of the nonionic water-soluble cellulose ether is a value determined according to the method as described in Examples below.

The ionic water-soluble cellulose ether and its salt (not claimed) include, for example, carboxymethyl cellulose sodium (hereinafter, also referred to as "CMC-Na") and the like. The ionic water-soluble cellulose ether and its salt are not particularly limited in terms of properties such as functional group content and viscosity. Favorable ranges of such properties are exemplified below which provide a favorably compressible capsule filling composition.

In particular embodiments (not claimed), the carboxymethyl group content of CMC-Na is preferably in the range between <NUM> wt% and <NUM> wt%. The carboxymethyl group content of CMC-Na is a value determined according to the method as described in the Examples below.

In particular embodiments (not claimed), the viscosity of the ionic water-soluble cellulose ether and its salt such as CMC-Na is preferably in the range between <NUM> mPa·s and <NUM>,<NUM> mPa·s, and more preferably between <NUM> mPa·s and <NUM> mPa·s. The viscosity of the ionic water-soluble cellulose ether and its salt is a value determined according to the method as described in the Examples below.

The nonionic water-insoluble cellulose ether according to the invention is not particularly limited, and includes, for example, low substituted hydroxypropyl cellulose (hereinafter also referred to as "L-HPC") and the like. The nonionic water-insoluble cellulose ether is not particularly limited in terms of properties such as functional group content and viscosity. Favorable ranges of such properties provided herein take into consideration compressibility of the resulting capsule filling composition.

In particular embodiments, the hydroxypropoxy group content of L-HPC is preferably in the range between <NUM> wt% and <NUM> wt%, more preferably between <NUM> wt% and <NUM> wt%, and still more preferably between <NUM> wt% and <NUM> wt%. The hydroxypropoxy group content of L-HPC can be determined according to the measurement method for low substituted hydroxypropyl cellulose described in<NPL>on.

In particular embodiments, the viscosity of nonionic water-insoluble cellulose ether such as L-HPC is preferably in the range between <NUM> mPa·s and <NUM> mPa·s, more preferably between <NUM> mPa·s and <NUM> mPa·s, and still more preferably between <NUM> mPa·s and <NUM> mPa·s. The viscosity of L-HPC is a value determined according to the method as described in Examples below.

The esterified cellulose ether (not claimed) includes, for example, hydroxypropyl methylcellulose acetate succinate (also referred to as "HPMCAS"), hydroxypropyl methylcellulose phthalate (also referred to as "HPMCP"), and the like. The esterified cellulose ether is not particularly limited in terms of properties such as functional group content and viscosity, favorable ranges of such properties exemplified below take into consideration compressibility of the resulting capsule filling composition.

In particular embodiments (not claimed), the methoxy group content of HPMCAS is preferably in the range between <NUM> wt% and <NUM> wt%. In particular embodiments (not claimed), the hydroxypropoxy group content of HPMCAS is preferably in the range between <NUM> wt% and <NUM> wt%. In particular embodiments (not claimed), the acetyl group content of HPMCAS is preferably in the range between <NUM> wt% and <NUM> wt%. In particular embodiments, the succinyl group content of HPMCAS is preferably in the range between <NUM> wt% and <NUM> wt%. The methoxy group content, the hydroxypropoxy group content, the acetyl group content, and the succinyl group content of HPMCAS can be determined according to the quantitative method described in the section "<NPL>on.

In particular embodiments (not claimed), the methoxy group content of HPMCP is preferably in the range between <NUM> wt% and <NUM> wt%. In particular embodiments (not claimed), the hydroxypropoxy group content of HPMCP is preferably in the range between <NUM> wt% and <NUM> wt%. In particular embodiments (not claimed), the carboxybenzoyl group content of HPMCP is preferably in the range between <NUM> wt% and <NUM> wt%. The methoxy group content and the hydroxypropoxy group content of HPMCP can be determined according to the quantitative method described in the section "<NPL>on, and the carboxybenzoyl group content of HPMCP can be determined according to the quantitative method described in the section "<NPL>on.

In certain embodiments (not claimed), the viscosity of the esterified cellulose ether is the viscosity at <NUM> of a <NUM> wt% sodium hydroxide aqueous solution containing <NUM> wt% of esterified cellulose ether. In particular embodiments (not claimed), the viscosity of the esterified cellulose ether is preferably in the range between <NUM> mPa·s and <NUM> mPa·s. The viscosity of the esterified cellulose ether can be determined according to the method described in the drug monograph "<NPL>on.

The cellulose ether powder may be used either individually or in combination of two or more of the above-mentioned cellulose ethers in the form of powder. Moreover, the cellulose ether powder may be commercially available or may be produced by known methods.

The content of the cellulose ether powder in the capsule filling composition is not particularly limited, but, taking into consideration compressibility, in particular embodiments, the content is preferably in the range between <NUM> wt% and <NUM> wt%, more preferably between <NUM> wt% and <NUM> wt%, still more preferably between <NUM> wt% and <NUM> wt%, still even more preferably between <NUM> wt% and <NUM> wt%.

Additive agents may be contained in the capsule filling composition as required. Additive agents include, but are not limited to, diluting agents, disintegrating agents, binding agents, lubricants, corrigents and flavoring agents.

Examples of diluting agents include lactose, sucrose, starch, corn starch, pregelatinized starch, saccharose, fructose, maltose, crystalline cellulose, powdered cellulose, maltose, maltitol, erythritol, mannitol, sorbitol, dextrin, maltodextrin, kaolin, calcium carbonate, calcium phosphate, calcium sulfate and the like.

Examples of the disintegrating agents include corn starch, partially pregelatinized starch, sodium carboxymethyl starch, croscarmellose, croscarmellose sodium, crystalline cellulose, crospovidone and the like.

Examples of the binding agents include polyvinylpyrrolidone, starch, polyvinyl alcohol, starch syrup and the like. Examples of the lubricants include magnesium stearate, calcium stearate, talc, sodium stearyl fumarate, sucrose fatty acid ester and the like. Examples of corrigents include citric acid, tartaric acid and malic acid and the like. Examples of flavoring agents include menthol, peppermint oil, vanillin and the like.

The additive agents may be used either individually or in combination of two or more of the above-mentioned additive agents. The additive agents may be commercially available or may be produced by known methods.

While the content of the additive agents in the capsule filling composition is not particularly limited, in particular embodiments, the content may be an amount that does not impair the compressibility of the capsule filling composition given by the cellulose ether powder. For example, the content of the additive agent is preferably in the range between <NUM> part by weight and <NUM> parts by weight more preferably between <NUM> parts by weight and <NUM> parts by weight, and still more preferably between <NUM> parts by weight and <NUM> parts by weight relative to <NUM> part by weight of the cellulose ether powder.

As one specific embodiment of the capsule filling composition, the following capsule filling composition can be included, but the present invention is not limited to these embodiments:.

The method of producing the capsule filling composition is not particularly limited, and may be any method to make all of components homogeneous. However, in terms of ensuring the quality of capsule formulations by filling capsules with an accurate quantity of the capsule filling composition, the method of producing the capsule filling composition includes dry blending a raw material containing an active ingredient, a cellulose ether powder, and optionally, an additive agent to obtain the capsule filling composition containing the active ingredient and the cellulose ether powder.

The means of dry blending is not particularly limited, and can employ known methods of blending multiple powder components maintained in a dried state homogeneously.

The method of producing a capsule formulation according to one embodiment of the present invention includes subjecting a capsule filling composition containing an active ingredient, and a cellulose ether powder, to a die-compression system powder filling process, or a funnel system powder filling process, to provide a compressed product; and filling the compressed product into a capsule container to obtain the capsule formulation.

The die-compression system powder filling (process) is one of the capsule filling methods as generally known, which includes introducing a powder into a molding plate, compressing the powder with a tapping rod to prepare a compressed product, and then scrapping off excess powder followed by transferring the compressed product into a capsule body.

The funnel system powder filling (process) is one of the capsule filling methods as generally known, which includes pushing a funnel for filling into a powder layer and compressing the powder to prepare a compressed product, and then transferring the compressed product into a capsule body.

The die-compression system powder filling and the funnel system powder filling can be performed according to conventional methods using a capsule filling machine capable of performing these filling methods. While the capsule filling machine is not particularly limited, it includes, for example, a fully automatic capsule filling machine "LIQFIL super <NUM>" (manufactured by Qualicaps Co. , Ltd), an intermittent capsule filling machine "ZANASI <NUM>-<NUM>-<NUM>-<NUM>" (manufactured by IMA S. ), and the like.

Both of the die-compression system powder filling and the funnel system powder filling have a commonality in compressing a capsule filling composition containing an active ingredient and a cellulose ether powder to prepare a compressed product, and then filling the compressed product into a capsule container to obtain a capsule formulation. In other words, the compressed product obtained with the use of the capsule filling composition is prepared as long as the die-compression system powder filling or the funnel system powder filling is employed.

A capsule container consists of a capsule cap and a capsule body. The capsule container used in the method of producing a capsule formulation according to one embodiment of the present invention is not particularly limited in type, material, size, and other properties.

The type of the capsule container is preferably a hard capsule since it allows the compressed product prepared with the use of the capsule filling composition to be easily put in the capsule container. Examples of the material of the capsule container include HPMC hard capsules, gelatin hard capsules, pullulan hard capsules and the like. Examples of the size of the capsule container include No. <NUM>, No. <NUM>, No. <NUM>, No. <NUM>, No. <NUM>, No. <NUM>, No. <NUM>, No. <NUM> and the like, but any size of capsule containers can be used.

The capsule container may be commercially available or may be manufactured by known methods.

The capsule formulation produced according to the method of producing a capsule formulation according to one embodiment of the present invention contains a capsule filling composition according to one embodiment of the present invention.

Further, in embodiments wherein the cellulose ether powder has a relatively high viscosity, particularly wherein a nonionic water-soluble cellulose ether powder such as HPMC (not claimed) having a viscosity of the range between 5C mPa·s and <NUM>,<NUM> mPa·s is used as a cellulose ether powder, the resulting capsule formulation can have an excellent sustained release property, and prevents capsule bursting events.

While the present invention will now be described in further detail with reference to Examples and Comparative Examples, the present invention is not limited to these Examples.

Koji powder and vitamin B<NUM> were used as an active ingredient. For the koji powder, "multi-grain koji (registered trademark) <NUM>" (compressibility index of <NUM>%; manufactured by YAEGAKI Bio-industry, Inc. ) was used. For the vitamin B<NUM>, "riboflavin" (compressibility index of <NUM>%; manufactured by Kyowa Pharma Chemical Co. ) was used.

Hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), hydroxypropyl cellulose (HPC), sodium carboxy methylcellulose (CMC-Na) and low substituted hydroxypropyl cellulose (L-HPC) produced according to known methods were used for a cellulose ether powder. Physical properties of cellulose ether powders are shown in Table <NUM>.

For lactose, "Pharmatose <NUM>" (manufactured by DMV) was used. For a capsule container, "size No. <NUM> HPMC capsule" (manufactured by Hiruherf Research Co. ) was used.

The average particle size represents a volume-based average particle size measured by a dry laser diffraction method. The average particle size was determined by a <NUM>% cumulative value of a volume-based cumulative particle size distribution curve under the conditions of a dispersion pressure of <NUM> bar, and a scattering intensity of the range between <NUM>% and <NUM>% by a dry method with Fraunhofer diffraction theory using a laser diffraction particle size distribution analyzer ("Mastersizer <NUM>"; manufactured by Malvern Co.

The loose bulk density represents the bulk density of cellulose ether powder in a loosely packed state. The loose bulk density was determined by using a powder property evaluation device "Powder Tester PT-X type" (manufactured by Hosokawa Micron Co. ) according to the third method of "<NPL>on.

An amount equivalent to <NUM> of the dry matter of HPMC, MC or HPC calculated on the dried basis was accurately weighed in a wide-mouth bottle (with a diameter of <NUM>; height of <NUM>; volume of <NUM>), and hot water at <NUM> was added to the wide-mouth bottle so as to be <NUM>% by weight. After a lid was put on the wide-mouth bottle, the mixture was stirred with a stirrer at between <NUM> rpm and <NUM> rpm for <NUM> minutes until a homogeneous dispersion was obtained. Subsequently, the cellulose ether was dissolved by stirring the dispersion in a water bath at between <NUM> and <NUM> for <NUM> minutes, resulting in a <NUM> wt% aqueous solution of cellulose ether as a sample solution.

The viscosity at <NUM> of the <NUM> wt% aqueous solution of cellulose ether, if its viscosity was equal to or more than <NUM> mPa·s, was determined by using a single cylindrical rotational viscometer according to the rotational viscometer method in the General Tests "<NPL>on. On the other hand, the viscosity at <NUM> of the <NUM> wt% aqueous solution of cellulose ether, if its viscosity was less than <NUM> mPa·s, was determined by using an Ubbelohde-type viscometer according to the capillary viscometer method in the General Tests "<NPL>on.

CMC-Na (about <NUM>) was placed in a <NUM>-volume Erlenmeyer flask equipped with a stopper, and weighed precisely. Water was added to the flask in an amount calculated by the following formula: sample (g) × (<NUM>-water content (wt%))", and the mixture was left to stand for <NUM> hours and further mixed for <NUM> minutes to prepare a <NUM> wt% aqueous solution of CMC-Na.

The viscosity at <NUM> of the <NUM> wt% aqueous solution of CMC-Na was determined by using a BM type viscometer (single cylindrical rotational viscometer) according to JIS Z8803.

An amount equivalent to <NUM> of the dry matter of L-HPC calculated on the dried basis was accurately weighed in a wide-mouth bottle (with a diameter of <NUM>; a height of <NUM>; a volume of <NUM>), and purified water at <NUM> was added to the wide-mouth bottle so as to be <NUM>% by weight. After a lid was put on the wide-mouthed bottle, the mixture was stirred with a stirrer at between <NUM> rpm and <NUM> rpm for <NUM> minutes until a homogeneous dispersion was obtained, resulting in a <NUM> wt% aqueous dispersion of water-insoluble cellulose ether as a sample solution.

The viscosity at <NUM> of the <NUM> wt% aqueous dispersion of L-HPC was determined by using a single cylindrical rotational viscometer according to the General Tests "<NPL>on.

The methoxy group content of HPMC and MC was determined according to the quantitative method described in the sections "<NPL>" and "<NPL>on, respectively. The hydroxypropoxy group content of HPMC, HPC and L-HPC was determined according to the quantitative method described in the sections "<NPL>," "<NPL>," and "<NPL>on, respectively.

The carboxymethyl group content of CMC-Na was calculated from the degree of substitution of CMC-Na according to the following formula: <MAT>.

The degree of substitution in CMC-Na was determined according to the following method.

First, <NUM> to <NUM> of a CMC-Na sample (anhydrous) was precisely weighed, wrapped in a filter paper, and ashed in a magnetic crucible. Next, the ashed CMC-Na was cooled, and then transferred into a <NUM>-volume beaker. Water (<NUM>) and <NUM> sulfuric acid (<NUM>) were added to the beaker, and then the solution in the beaker was boiled for <NUM> minutes. After cooling the boiled solution, a phenolphthalein indicator was added to the solution, and excess sulfuric acid was back titrated with <NUM> potassium hydroxide and the degree of substitution in CMC-Na was calculated according to the following formula: <MAT>.

"A" in the above formula stands for the amount (mL) of <NUM> sulfuric acid consumed by alkali in <NUM> of a CMC-Na sample, and was calculated according to the following formula: <MAT>.

Further, the alkalinity (or acidity) was determined by the following method.

A CMC-Na sample (anhydrous) (<NUM>) was precisely weighed in a <NUM> flask, and <NUM> of water was added to the flask and the CMC-Na sample was dissolved. Five milliliters of <NUM> sulfuric acid were added to the obtained CMC-Na solution, and the solution was boiled for <NUM> minutes and then cooled. A phenolphthalein indicator was added to the cooled solution and titrated with <NUM> potassium hydroxide (S mL). A blank test was performed concurrently (B mL). Alkalinity (or acidity) was calculated according to the following formula: <MAT>.

When the value of "(B - S) × f2" is a negative value, the term "alkalinity" represents "acidity.

The active ingredient weighing <NUM>,<NUM> was introduced into a polycarbonate tube (a hollow cylindrical form with an inner diameter of <NUM> and a height of <NUM>; "polycarbonate spacer (hollow) CPC (CPC-<NUM>); manufactured by Hirosugi Keiki Co. ) which was left to stand on a stainless-steel bat. Next, by using a tension and compression testing machine ("SDT - <NUM> NB"; manufactured by Imada Seisakusho Co. ), the active ingredient within the polycarbonate tube was compressed by a cylindrical tool having a contact surface of <NUM> mmΦ in diameter to prepare a compressed product (compression condition; speed: <NUM>/min. , load: <NUM> N, load maintaining time: <NUM> sec. The weight of the polycarbonate tube containing the compressed product of the active ingredient was noted as a weight before test.

Next, the polycarbonate tube filled with the compressed product of the active ingredient was placed on mesh sieves (test sieves JIS Z <NUM>; ϕ <NUM> × <NUM> mmH, with aperture of <NUM>; manufactured by Tokyo Screen Co. ) above a saucer, and the polycarbonate tube was pinched with fingers and lifted to a height of <NUM> in the vertical direction.

The lifted polycarbonate tube was released from the fingers, and dropped down. After repeating this procedure three times, the remaining weight of the polycarbonate tube containing the compressed product of the active ingredient was measured as a weight after test.

The amount of powder flowing out from the polycarbonate tube was determined by subtracting the weight after test from the weight before test. Furthermore, the remaining weight of the compressed product of the active ingredient was determined by subtracting the weight of powder flowing out from the polycarbonate tube from the weight before test. The number of tests was set to <NUM>, and the compressibility index of the active ingredient was calculated by dividing the average value of the remaining weight of the compressed product of the active ingredient from the <NUM> tests, by the introduced weight of the active ingredient ( <NUM> ).

A polycarbonate tube containing the compressed product of the capsule filling composition was prepared and weighed as described in [Compressibility index] above, except that the capsule filling compositions described below were used instead of the active ingredient.

The polycarbonate tube containing the compressed product of the capsule filling composition was dropped down as described in [Compressibility index] above, and the remaining weight of the polycarbonate tube containing the compressed product of the active ingredient was measured after the third dropping and the fifth dropping. The amount of powder flowing out from the polycarbonate tube was determined by subtracting the weight after dropping from the weight before dropping. Moreover, the number of drops required until the total amount of the capsule filling composition can flow out from the polycarbonate tube was counted. The number of tests was set to <NUM>, and the average value was used for evaluation of compressibility.

Dissolution amounts of capsule formulations described below were determined with the use of a dissolution tester ("NTR - <NUM> A"; manufactured by Toyama Sangyo Co. ) by carrying out the dissolution test according to "Dissolution Test"(<NUM>, paddle method, using a sinker, <NUM> rpm/minute, <NUM> of purified water for solvent) described in <NPL>on.

Using HPMC-<NUM> described in Table <NUM> as the cellulose ether powder, koji powder as the active ingredient, and HPMC-<NUM> as the cellulose ether powder, the components were combined according to weight according to Table <NUM>, and were subjected to dry blending to produce a capsule filling composition.

Using the produced capsule filling composition, a compressed product was produced by compressing the capsule filling composition within the polycarbonate tube according to the method described in [Compressibility] described above.

In the same method as in Example <NUM>, using the cellulose ether powder shown in Table <NUM>, the active ingredient and the cellulose ether powder were combined by content according to Table <NUM>, and were subjected to dry blending to produce a capsule filling composition and a compressed product. In Comparative Example <NUM>, however, cellulose ether powder was not used.

According to the same method as in Example <NUM>, HPMC-<NUM> (not claimed) shown in Table <NUM>, vitamin B<NUM> as the active ingredient, cellulose ether powder, and lactose as a diluting agent were combined by weight according to Table <NUM>, and blended to produce a capsule filling composition and a compressed product. In Comparative Example <NUM>, cellulose ether powder was not used.

<NUM> of each capsule filling composition of Example <NUM> and Comparative Example <NUM> was weighed, and then each composition was introduced in a die having a diameter of <NUM> (IPT standard; manufactured by Kikusui Seisakusho Ltd. ) that was left to stand on a stainless-steel bat. Using a tension and compression testing machine ("SDT - <NUM> NB"; manufactured by Imada Seisakusho Co. ), the capsule filling composition in the die was compressed with a load of <NUM> N using a punch having a diameter of <NUM> and <NUM> mmR.

(IPT standard; manufactured by Kikusui Seisakusho Co. ) to prepare a compressed product.

Next, the compressed product was extruded from the die and used to fill a separated hard capsule body, and then a capsule cap was bonded to the capsule body to produce a capsule formulation.

Table <NUM> shows the evaluation results of compressibility according to Examples <NUM> to <NUM> and Comparative Example <NUM>. Table <NUM> shows that the use of the cellulose ether powder improved the compressibility of the active ingredient. Accordingly, it is expected that in the production process of capsule formulations, the use of the cellulose ether powder could prevent the capsule formulations from having weight variations due to outflows of the active ingredient caused by mechanical vibrations during capsule filling, resulting in the stable production of capsule formulations with a constant weight.

From Examples <NUM> and <NUM>, it was also found that the compressibility improved when the content of the cellulose ether powder increased.

Furthermore, from Examples <NUM> and <NUM>, it was found that the smaller the average particle size of the cellulose ether powder was, the more the compressibility was improved.

Besides, from Examples <NUM> and <NUM>, it was found that the lower the viscosity of the cellulose ether powder was, the more the compressibility was improved.

In addition, from Examples <NUM> to <NUM>, it was found that the improved compressibility was observed across the various types of cellulose ether powder employed.

From Example <NUM> and Comparative Example <NUM>, it was confirmed that the favorable compressibility was observed for all the different active ingredients of Examples <NUM> to <NUM>, and also for compositions containing the diluting agent.

Table <NUM> shows the dissolution rates of vitamin B<NUM> measured at time <NUM>, <NUM> hours, <NUM> hour, <NUM> hours, <NUM> hours, <NUM> hours and <NUM> hours during the dissolution test.

From Example <NUM> and Comparative Example <NUM>, it was found that the use of the high viscosity cellulose ether powder could prevent the capsule formulations from undergoing an initial burst, and therefore achieved a favorable sustained release property of the capsule formulations.

Claim 1:
A method of producing a capsule formulation, comprising:
- dry blending a raw material comprising an active ingredient and a cellulose ether powder to obtain a capsule filling composition comprising the active ingredient and the cellulose ether powder;
- subjecting the capsule filling composition to a funnel system powder filling or a die-compression system powder filling to prepare a compressed product; and filling a capsule container with the compressed product to obtain the capsule formulation,
wherein the cellulose ether powder is hydroxypropyl methylcellulose powder having an average particle size below <NUM> determined by a <NUM>% cumulative value of a volume-based cumulative particle size distribution curve.