Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
  • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
  • A61J3/07—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use
  • A61J3/071—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use into the form of telescopically engaged two-piece capsules
  • A61J3/077—Manufacturing capsule shells
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38—Cellulose; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4816—Wall or shell material

Definitions

• This specification discloses a hard capsule, a hard capsule preparation liquid, and a hard capsule preparation method.
• acid-resistant hard capsules used in pharmaceutical preparations.
• “Acid resistance” generally refers to the property of a formulation that dissolves poorly in the stomach.
• acid-resistant hard capsules have the property of being easily dissolved after being transferred to the intestine.
• acid-resistant hard capsules are mainly used for the purpose of protecting active drug ingredients from gastric acid or gastric enzymes, and for the purpose of continuously releasing active drug ingredients by taking advantage of the time it takes for the preparation to move from the stomach to the small intestine. used.
• Patent Documents 1 to 4 describe acid-resistant hard capsules in which hydroxypropylmethylcellulose is used as a film base.
• the hard capsules described in Patent Documents 1 to 4 are all compositions used for pharmaceutical preparations. At least in Japanese regulations, there is a clear distinction between capsule components that can be used in pharmaceutical formulations and capsule components that can be used in health foods. is not limited. In addition, although acid-resistant hard capsules that can be used in health foods have been provided, their acid resistance is not sufficient. An object of the present invention is to provide a hard capsule that has higher acid resistance and can be used in health foods.
• Section 1 An acid-resistant hard capsule comprising a film containing hydroxypropylmethylcellulose having a viscosity value of 15 mPa ⁇ s or more and gellan gum.
• Section 2. Item 2. The acid-resistant hard capsule according to Item 1, wherein the hydroxypropylmethylcellulose comprises a first hydroxypropylmethylcellulose and a second hydroxypropylmethylcellulose having different viscosity values.
• Item 3. Item 3. The acid-resistant hard capsule according to Item 1 or 2, further comprising pectin. Section 4. Item 4.
• Item 5. The acid resistance according to any one of Items 1 to 4, wherein the content of the gellan gum is in the range of 1% by mass or more and 7% by mass or less when the total mass of the solid content of the film components is 100% by mass. hard capsule.
• Item 7. Item 5.
• Item 8 The acid resistance according to any one of Items 3 to 7, wherein the content of the pectin is in the range of 20% by mass or more and 40% by mass or less when the total mass of the solid content of the film components is 100% by mass. hard capsule.
• Item 11. The acid-resistant hard material according to any one of Items 1 to 10, which contains a gelling aid in a range of 0% or more and 0.003% by mass or less when the total mass of the solid content of the film components is 100% by mass. capsule.
• Item 12. A preparation liquid for preparing an acid-resistant hard capsule, containing hydroxypropylmethylcellulose having a viscosity value of 15 mPa ⁇ s or more and gellan gum.
• Item 13 Item 13.
• Item 15. The liquid preparation according to any one of Items 12 to 14, wherein the content of the gellan gum is in the range of 1% by mass or more and 7% by mass or less when the total mass of the solid content of the film components is 100% by mass. .
• Item 21. The preparation liquid according to Items 12 to 20, containing the gelling aid in a range of 0% or more and 0.003% by mass or less when the total mass of the solid content of the film components is 100% by mass.
• a method for preparing an acid-resistant hard capsule comprising the step of immersing a mold pin at a temperature lower than the temperature of the preparation liquid in the preparation liquid according to any one of Items 12 to 21.
• the hard capsule can be manufactured by a conventionally used hard capsule manufacturing apparatus.
• the "hard capsule” is an empty capsule for filling the manufactured capsule shell with contents.
• a hard capsule usually consists of a cap portion and a body portion, and is also called a hard capsule or a two-piece capsule.
• a “hard capsule” in the present invention has the same or similar shape as a commercially available conventional hard capsule intended for oral administration to human or animal subjects.
• the "hard capsule” of the present invention includes a soft capsule manufactured by filling the contents between two films and bonding the films together, and a seamless capsule manufactured by dropping the contents together with the coating solution into the coagulating liquid. It does not include capsules and microcapsules prepared by entrapping an active ingredient inside by precipitation or emulsification of a base material.
• an empty hard capsule is simply referred to as a hard capsule or capsule, and a filled product is referred to as a "hard capsule formulation.”
• the term “acid-resistant hard capsule” refers to a hard capsule in which the shell itself of the capsule body has “acid-resistant" properties that meet the following conditions.
• acid resistance refers to a characteristic that satisfies at least the following condition (i).
• the elution rate of the content is 40% or less, preferably 30% or less.
• 0.1N hydrochloric acid can be used as the acid solution.
• the dissolution rate is determined according to the dissolution test described in the Japanese Pharmacopoeia 17th Edition (hereinafter sometimes simply referred to as "17th Pharmacopoeia"), except that the first liquid is changed to an acidic liquid.
• the dissolution test is performed according to the dissolution test method specified in the 17th pharmacopoeia (17th pharmacopoeia, 6.10-1.2 paddle method (paddle rotation speed 50 rpm), and the same figure 6.10-2a corresponding sinker use).
• "Acid resistance” preferably satisfies the following condition (ii) in addition to the above condition (i).
• the disintegration time is within 2 hours when the test subject is tested according to the disintegration test described in the 17th pharmacopoeia using the dissolution test liquid 2 at 37 ° C. ⁇ 0.5 ° C., preferably is within 1 hour.
• the content used in the dissolution test is not limited as long as it is a content that dissolves quickly in the test solution and can be quantified by a known method.
• acetaminophen can be mentioned.
• hydroxypropylmethylcellulose is preferably 16.5 to 30.0% by mass, more preferably 19.0 to 30.0% by mass, particularly preferably 28 .0 to 30.0% by mass, and the degree of substitution of the hydroxypropoxy group is preferably 4.0 to 32.0% by mass, more preferably 4.0 to 12.0% by mass, particularly preferably 7.0 to 7.0% by mass. It is 12.0% by mass.
• hydroxypropylmethylcellulose represented by the following formula is the most suitable cellulose compound in that it has excellent film moldability and mechanical strength under low moisture conditions.
• the hydroxypropyl methylcellulose used in the present invention includes hypromellose with substitution grades (types) 2910, 2906, and 2208 as defined in the 17th Pharmacopoeia. Among them, substitution degree types 2910 and 2906 are more preferable.
• the hydroxypropyl methylcellulose of the present invention also contains hypromellose having the following molecular weight, which is approved for use as a food additive in Japan.
• hypromellose having the following molecular weight, which is approved for use as a food additive in Japan.
• Unsubstituted structural unit 162.14
• Substituted structural units about 180 (degree of substitution 1.19), about 210 (degree of substitution 2.37)
• hydroxypropyl methylcelluloses include Shin-Etsu Chemical Co., Ltd.
• hydroxypropylmethylcellulose with a "viscosity value" of 15 mPa ⁇ s or more as a 2% by mass aqueous solution at 20°C.
• this viscosity value may be simply indicated as “viscosity value”.
• the “viscosity value” is measured according to the section on hypromellose formulated based on the Draft International Harmonization from the 15th Pharmacopoeia onwards. That is, the "viscosity value” refers to the viscosity value (mPa ⁇ s) of a 2% by mass aqueous solution of hydroxypropylmethylcellulose at 20°C ⁇ 0.1°C.
• the general test method 2.53 Viscosity measurement method 1 (Ubbelohde method) is used.
• the second method of General Test Methods 2.53 Viscosity Measurement Method 2.1.2 Single Cylindrical Rotational Viscometer (Brookfield Viscometer) is used.
• the "viscosity value” can also adopt the displayed viscosity (sometimes referred to as the viscosity grade value) by the compound manufacturer.
• the display viscosity and the range of the display viscosity for example, in the METOLOSE (trademark) series of Shin-Etsu Chemical, when the display viscosity is less than 600 mPa s, the display viscosity is 80 to 120%, and when the display viscosity is 600 mPa s or more, , 75 to 140% of the indicated viscosity.
• the displayed viscosity can be used as it is as the "viscosity value" as long as it does not impair the gist of the present invention.
• the preferred lower limit of the "viscosity value” is 15 mPa ⁇ s.
• a preferred "viscosity value” as the upper limit is 10,000 mPa ⁇ s.
• the hydroxypropylmethylcellulose in the present invention may be a mixture of the first hydroxypropylmethylcellulose and the second hydroxypropylmethylcellulose having different viscosity values.
• the viscosity value may be such that the 2% viscosity value of the catalog value of at least one type of hydroxypropylmethylcellulose is 15 mPa ⁇ s or more.
• Solid-state hydroxypropylmethylcellulose is usually provided as solid fine particles having a particle size on the order of 1 to several hundred ⁇ m.
• the average particle size (average particle size) is preferably in the range of 1 to 100 ⁇ m.
• the average particle size means the volume average particle size (MV) of the primary particles.
• Particle size distribution diameter MT3300IIEX" Preferably, the volume fraction of particles with a particle size of 100 ⁇ m or less is 50% or more, more preferably 60% or more.
• gellan gum is obtained by separating from the culture broth of a specific Gram-negative bacterium (seed monas) using saccharides as a nutrient source, and the main component is polysaccharides.
• Gellan gum can be classified into acylated gellan gum (native gellan gum) and deacylated gellan gum depending on the presence or absence of acylation, but both can be used without distinction in the present invention.
• Gellan gum (trade name of San-Eigen FFI Co., Ltd.) and Kelcogel (trade name of DSP Gokyo Food & Chemical Co., Ltd.) may be mentioned, but are not limited to these.
• pectin is not particularly limited. Commercially available pectins include low-methoxy pectin and high-methoxy pectin. Low methoxy pectin is preferred. Low methoxy pectin having a degree of esterification of 15 to 50, preferably 20 to 45, more preferably 23 to 40, is preferably used as low methoxy pectin. The degree of esterification of pectin is according to the manufacturer's stated value. Use LM-102AS-J (degree of esterification 30), Explorer 60CS (degree of esterification 38), LM-106AS-YA-J (degree of esterification 23), LM-13CG-J, etc. as low methoxy pectin. can be done.
• manufacturers of pectin include, but are not limited to, San-Eigen FFI Co., Ltd., CPKelco, DSP Gokyo Food & Chemical Co., Ltd., Kyoritsu Foods Co., Ltd., Sansho Co., Ltd. isn't it.
• Low methoxy pectin includes acid-treated and alkali-treated amide pectins. Pectin tends to have a higher viscosity value and weaker acid resistance as the degree of esterification increases. On the other hand, when the degree of esterification is too low, there is a tendency not to form a film.
• Hard Capsules A first embodiment of the present disclosure relates to hard capsules.
• the hard capsule has acid resistance.
• the hard capsule consists of a film containing hydroxypropylmethylcellulose having a viscosity value of 15 mPa ⁇ s or more and gellan gum.
• the hard capsule may also contain hydroxypropylmethylcellulose with a viscosity of 15 mPa ⁇ s or more, gellan gum, and pectin.
• the hard capsule may contain a first hydroxypropylmethylcellulose, a second hydroxypropylmethylcellulose, and gellan gum with different viscosity values.
• the gellan gum content is 1% by mass or more and 7% by mass or less, preferably 2% by mass or more and 6% by mass or less, when the total mass of the solid content of the film components is 100% by mass. More preferably, the range is higher than 3% by mass and 5% by mass or less.
• the content of pectin is 10% by mass or more and 50% by mass or less, preferably 15% by mass or more and 45% by mass or less, more preferably 20% by mass, when the total mass of the solid content of the film components is 100% by mass.
• the range is 40 mass % or less.
• the content of hydroxypropylmethyl cellulose with a viscosity value of 15 mPa s or more in the hard capsule is the total mass ratio (%) of the other solid content from the total mass of the solid content of the film components (100 mass%). Subtracted mass ratio (%). For example, 35% by mass to 99% by mass.
• the hard capsule may contain a gelling aid in the range of 0% or more and 0.003% by mass or less when the total mass of the solid content of the film components is 100% by mass.
• a gelling aid is not essential in the hard capsule of the present embodiment.
• gelling aids include compounds capable of providing one or more of sodium ions, potassium ions, calcium ions and magnesium ions in water, such as sodium chloride, potassium chloride, calcium chloride, magnesium chloride and magnesium sulfate. can be mentioned.
• citric acid or sodium citrate can also be used as an organic acid or its water-soluble salt.
• the hard capsule shell may further contain plasticizers, surfactants (emulsifiers), binders, etc. that are acceptable as pharmaceutical and food additives.
• plasticizers surfactants (emulsifiers), binders, etc.
• it may contain a sustained-release agent, a solubilizer, a solubilizer, etc. for controlling the solubility, particularly the dissolution characteristics in the neutral pH range.
• solubilizer for example, those listed in the Dictionary of Pharmaceutical Excipients, 2021 edition (edited by the Japan Pharmaceutical Excipients Association, Yakuji Nippo Co., Ltd.) can be used for each of the above uses. are not limited to these.
• these additives may be classified into multiple uses.
• the plasticizer is not necessarily limited to the specific substances shown in the dictionary of pharmaceutical excipients, and is not particularly limited as long as it can be used in pharmaceuticals or food compositions and can be added to the capsule shell to impart flexibility.
• Suitable substances generally have a molecular weight (Mw) of 100 to 20,000 and have one or more hydrophilic groups per molecule, such as hydroxyl, ester or amino groups.
• dioctyl adipate dioctyl adipate, polyester adipate, epoxidized soybean oil, epoxyhexahydrophthalic acid diester, kaolin, triethyl citrate, glycerin, glycerin fatty acid ester, sesame oil, dimethylpolysiloxane/silicon dioxide mixture, D-sorbitol, medium chain Fatty acid triglyceride, sugar alcohol liquid derived from corn starch, triacetin, concentrated glycerin, castor oil, phytosterol, diethyl phthalate, dioctyl phthalate, dibutyl phthalate, butylphthalyl butyl glycolate, propylene glycol, polyoxyethylene (105) polyoxy Propylene (5) glycol, polysorbate 80, macrogol 1500, macrogol 400, macrogol 4000, macrogol 600, macrogol 6000, isopropyl myristate, cottonseed oil/soybean oil mixture,
• Propylene glycol and polyethylene glycol are particularly preferred from the viewpoint of excellent compatibility and imparting high glossiness.
• the weight average molecular weight of polyethylene glycol is not particularly limited, but is preferably 200 to 35,000 from the viewpoint of imparting high gloss.
• Hydroxypropyl cellulose (HPC) which is softer than MC and HPMC, can be used as a plasticizer.
• Surfactants include benzalkonium chloride, benzethonium chloride polyoxyethylene (40) monostearate (polyoxyl stearate 40*), sorbitan sesquioleate (sorbitan sesquioleate*), polyoxyethylene (20) sorbitan monooleate ate (polysorbate 80*), glyceryl monostearate (glyceryl monostearate*), sodium lauryl sulfate, polyoxyethylene lauryl ether (lauromacrogol*), and the like. (*: Notation in the Japanese Pharmacopoeia).
• Surfactants (or emulsifiers) may contain components that inevitably remain after emulsion polymerization of methacrylic acid copolymers or (meth)acrylic acid alkyl ester copolymers, as described above.
• the coating of the hard capsule may further contain a lubricant, a sequestering agent, a coloring agent, a light shielding agent, a binder, etc. at most about 5% by mass.
• Sequestering agents include ethylenediaminetetraacetic acid, acetic acid, boric acid, citric acid, gluconic acid, lactic acid, phosphoric acid, tartaric acid, or salts thereof, metaphosphate, dihydroxyethylglycine, lecithin, ⁇ -cyclodextrin, or their Combinations can be mentioned.
• the lubricant is not particularly limited as long as it can be used for pharmaceuticals or food compositions.
• examples thereof include calcium stearate, magnesium stearate, sodium stearyl fumarate, carnauba wax, starch, sucrose fatty acid ester, light anhydrous silicic acid, talc, and hydrogenated vegetable oil.
• Sequestering agents include ethylenediaminetetraacetic acid, acetic acid, boric acid, citric acid, gluconic acid, lactic acid, phosphoric acid, tartaric acid, or salts thereof, metaphosphate, dihydroxyethylglycine, lecithin, ⁇ -cyclodextrin, or their Combinations can be mentioned.
• the colorant and light shielding agent are not particularly limited as long as they can be used in pharmaceuticals or food compositions.
• coloring agents include acenyakutannin powder, turmeric extract, methylrosaniline chloride, yellow iron oxide, yellow ferric oxide, opas spray K-1-24904, orange essence, brown iron oxide, carbon black, caramel, carmine, carotene liquid. , ⁇ -carotene, photosensitive element 201, licorice extract, gold leaf, kumazasa extract, black iron oxide, light anhydrous silicic acid, kets, zinc oxide, titanium oxide, iron sesquioxide, disazo yellow, food blue No. 1 and its aluminum lake , Food Blue No. 2 and its aluminum lake, Food Yellow No.
• Examples of light shielding agents include titanium oxide, iron sesquioxide, yellow iron sesquioxide, black iron oxide, food blue No. 1 aluminum lake, food blue No. 2 aluminum lake, food yellow No. 4 aluminum lake, food yellow No. 5 aluminum lake, Food Green No. 3 Aluminum Lake, Food Red No. 2 Aluminum Lake, Food Red No. 3 Aluminum Lake, Food Red No. 102 Aluminum Lake, Food Red No. 104 Aluminum Lake, Food Red No. 105 Aluminum Lake, Food Red No. 106 Aluminum Lake, Edible Red No. 40 aluminum lake may be mentioned. Titanium oxide can be added as a light shielding agent to the coating of the hard capsule in order to prevent deterioration of the contents due to ultraviolet rays or the like.
• the content of the plasticizer, surfactant (emulsifier), binder, lubricant, sequestering agent, colorant, light-shielding agent, and binder is based on the total solid content of the film components being 100% by mass. It is preferred not to exceed 10% by weight.
• the hard capsule shell preferably contains 2 to 10% by mass of residual moisture (water content) in order to maintain appropriate plasticity and resistance to cracking.
• residual moisture water content
• the hard capsule shell preferably contains 2 to 10% by mass of residual moisture (water content) in order to maintain appropriate plasticity and resistance to cracking.
• the molded capsules are dried at a temperature in the range of 30°C to 100°C, they settle to a predetermined saturated residual moisture content.
• the drying treatment at a high temperature takes a shorter time to reach the saturated moisture value.
• Residual moisture depends on environmental humidity during capsule storage, but changes almost reversibly. That is, the residual moisture content after sufficient drying treatment at 30 to 100° C. converges to a constant saturated moisture content when stored for several days under constant temperature and relative humidity.
• the saturated moisture value after several days of storage at room temperature and 43% relative humidity is used.
• the solid content of the film includes hydroxypropyl methylcellulose, gellan gum, and, if necessary, pectin, gelling aid, plasticizer, surfactant (emulsifier), binder, lubricant, sequestering agent, colorant. , sunscreens, and binders other than residual moisture.
• Hard capsule preparation liquid and method for preparing the same It relates to a preparation liquid (also simply referred to as "preparation liquid") for preparing the hard capsule described in .
• the hard capsule consists of a film obtained by drying the liquid preparation of the present embodiment to remove the solvent.
• Hard capsule preparations are also called jelly.
• the hard capsule preparation liquid contains hydroxypropyl methylcellulose with a "viscosity value" of 15 mPa ⁇ s or more, gellan gum, and an aqueous solvent.
• the hard capsule coating contains pectin
• the hard capsule preparation liquid contains pectin.
• the hard capsule shell contains a gelling aid, a plasticizer, a surfactant (emulsifier), a binder, a lubricant, a sequestering agent, a coloring agent, a light-shielding agent, or a binder
• the hard capsule preparation liquid Contains ingredients of
• the hydroxypropylmethylcellulose may include a first hydroxypropylmethylcellulose and a second hydroxypropylmethylcellulose having different viscosity values.
• Water or a mixture of water and ethanol can be used as the aqueous solvent.
• Ethanol may be absolute ethanol.
• the content of ethanol is, for example, 10 to 20 volumes when the volume of the aqueous solvent is 100.
• the hard capsule preparation liquid When manufacturing the hard capsule preparation liquid, first add gellan gum to purified water and stir for 1 to 10 minutes until dispersed. Next, the liquid temperature of the dispersion liquid was raised to about 80 to 85° C., and the liquid was stirred for about 10 to 120 minutes until it was dissolved. After the gellan gum has dissolved, add hydroxypropyl methylcellulose while maintaining the liquid temperature at 80-85° C., disperse, and slowly stir for 60-180 minutes until bubbles disappear. Thereafter, the liquid temperature is lowered to 50 to 75° C. while stirring to prepare a hard capsule preparation liquid.
• pectin When pectin is added to the shell of the hard capsule, it is added after the gellan gum has dissolved before adding hydroxypropylmethylcellulose, stirred for 10 to 120 minutes until dissolved, and after dissolution, the hydroxypropylmethylcellulose is added. It is dispersed and defoamed while stirring, and the temperature is lowered.
• the hard capsule shell contains a plasticizer, a surfactant (emulsifier), a binder, a lubricant, a sequestering agent, a colorant, a light-shielding agent, or a binder, these components can be added at any time. good.
• Stirring is preferably carried out by rotating a propeller-shaped stirring blade at 1 to several hundred rpm.
• hydroxypropylmethylcellulose may be added, and after the temperature lowering step is completed, the temperature rising step to 55 to 75° C. may be performed again. All hard capsule preparation liquids may be appropriately maintained at 50 to 75° C. in order to obtain optimum viscosity after preparation.
• the solid content of the film other than the aqueous solvent is preferably 10 to 30 wt%, and 12 to 25 wt%, when the hard capsule preparation liquid is taken as 100 wt%. is more preferable.
• the third embodiment of the present disclosure relates to a method for preparing hard capsules.
• a capsule preparation machine that prepares other hard capsules can be used to prepare acid-resistant hard capsules.
• Hard capsules are formed by dipping methods, among them the "cold pin dipping method".
• the "cold pin immersion method” is characterized in that the surface temperature of the molding pin during immersion is lower than the temperature of the capsule preparation liquid.
• the hard capsule preparation (molding) method is the same as in 3. above. is not particularly limited as long as it includes the step of preparing capsules using the hard capsule preparation liquid described in .
• Hard capsules are generally produced by immersing a mold pin (capsule molding pin), which serves as a mold for capsules, in a hard capsule preparation solution, and curing and drying the film that adheres when the pin is lifted out to form the desired capsule. Obtain shape and thickness (dipping method).
• the method for preparing hard capsules includes the steps of preparing a hard capsule preparation liquid by the above method or preparing by purchasing a hard capsule preparation liquid, and immersing a mold pin in the hard capsule preparation liquid. After that, it is pulled up, the mold pins are turned upside down, and the solution adhering to the mold pins is dried.
• the acid-resistant hard capsule used in the present invention can be produced through the following molding steps. (1) a step of immersing the mold pin in the hard capsule preparation solution (immersion step); (2) a step of pulling up the mold pin from the hard capsule preparation liquid preparation (immersion liquid) and drying the hard capsule preparation liquid adhering to the outer surface of the mold pin (drying step); (3) A step of removing the dried capsule film (coating) from the capsule-forming pin (separating step).
• the capsule shell prepared by the above method After the capsule shell prepared by the above method is cut into a predetermined length, it can be provided as an acid-resistant hard capsule in a state in which the body portion and the cap portion are fitted together or not. .
• the thickness of the hard capsule is usually in the range of 50-250 ⁇ m.
• the thickness of the side wall portion of the capsule is usually 70 to 150 ⁇ m, more preferably 80 to 120 ⁇ m, for capsules currently on the market.
• the acid-resistant hard capsules have sizes of 00, 0, 1, 2, 3, 4, 5, etc. In the present invention, hard capsules of any size can be prepared.
• the hard capsules of the present disclosure can be used to prepare hard capsule formulations in which the hard capsule is filled with an active drug.
• Hard capsules are suitable for filling health foods.
• Health foods including food for specified health use, food with nutrient function claims, and food with function claims, fucoidan, heme iron, polyphenols, etc.
• peptides and amino acids include peptides and amino acids (e.g., royal jelly, ornithine, citrulline, aminolevulinic acid, black vinegar).
• Filling of such contents into hard capsules can be carried out by a per se known capsule filling machine, for example, a fully automatic capsule filling machine (model name: LIQFILsuper80/150, manufactured by Qualicaps Co., Ltd.), a capsule filling/sealing machine (model name : LIQFILsuper FS, manufactured by Qualicaps Co., Ltd.) and the like.
• the body and cap of the hard capsule thus obtained are joined together by filling the body with the contents, covering the body with the cap and fitting them together.
• the filled capsule can then be made tamper-proof by using suitable techniques to seal the seams. Typically sealing or banding techniques may be used. Here, these techniques are well known to those skilled in the art of capsules.
• a sealant of a polymer solution is applied once on the surface of the body and the surface of the cap with a constant width around the edge of the cap in the circumferential direction of the body and the cap.
• the fitting portion can be sealed to form an acid-resistant hard capsule preparation.
• the polymer solution is not limited as long as it forms a film, but it is preferable to use a prepared solution containing an enteric-coated, acid-resistant or sustained-release polymer.
• a mixture or a solution dissolved in a solvent including a mixture of water and isopropanol can be used.
• the enteric polymer has a property of dissolving under the neutral conditions of the small intestine (for example, in the second liquid for the dissolution test described above).
• Acid-resistant polymers have the property of being difficult to dissolve in the acidic conditions of the stomach.
• Sustained-release polymers have the property of slow dissolution rates in various solutions.
• the polymer concentration in the band seal liquid is not limited as long as the band seal function can be exhibited. For example, it can be in the range of 10% by mass to 50% by mass.
• hydroxypropylmethylcellulose acetate succinate can also be used as the enteric polymer.
• the seal liquid is a mixture of 10 to 40% by mass of HPMCAS-MF (manufactured by Shin-Etsu Chemical Co., Ltd.) and the balance of ethanol and water.
• HPMCAS-MF is 12.5 to 35% by mass, and the remainder is a mixture of ethanol and water. More preferably, HPMCAS-MF is 15 to 30% by mass, and the balance is an 80:20 mixture of ethanol and water.
• preparation liquids having acid-resistant polymers include food materials such as pectin, alginate, and shellac, and enteric bases for pharmaceuticals.
• preparation liquids having sustained-release polymers include zein, high-molecular-weight water-soluble polymers, and sustained-release bases for pharmaceuticals.
• the band seal preparation solution can generally be used at room temperature or under heating. From the viewpoint of preventing liquid leakage from hard capsules, it is desirable to use a seal preparation liquid having a temperature range of preferably about 23-45°C, more preferably about 23-35°C, and most preferably about 25-35°C.
• the temperature of the seal preparation liquid can be adjusted by a method known per se using a panel heater, a hot water heater, or the like. It is preferable to adjust the temperature with a hot water heater type, because the temperature range can be finely adjusted.
• Pectin LM-102AS-J and LM-106AS-YA-J manufactured by CPKelco, which are low methoxy pectins, or LM-13CG-J manufactured by Sansho Co., Ltd. were used.
• Step A is a step of dispersing gellan gum and dissolving gellan gum and pectin.
• Gellan gum was stirred for 1 to 10 minutes until dispersed, and then stirred for 10 to 120 minutes after heating until dissolved. After that, pectin was added and stirred for 10 to 120 minutes until dissolved. In addition, only gellan gum was dissolved in the formulation without the addition of pectin.
• Step B is a step of dispersing and defoaming the HPMC, and the dispersion was slowly stirred for about 1 to 3 hours until bubbles disappeared.
• Step C was a temperature-lowering step, and the temperature was lowered to an optimum temperature in 1 to 3 hours, and the mixture was stirred with a three-one motor.
• Example 1 the temperature of step C was set to 52° C. for the purpose of adjusting the viscosity of the capsule preparation liquid.
• the temperature of step C was 60° C. or 55° C. as shown in Tables 3 and 4.
• the capsule preparations of Examples 1, 6, and 9 proceeded to Step D after Step C.
• Step E was skipped without Step D.
• Step D was a temperature raising step, and the temperature was raised to an optimum temperature in 1 to 3 hours, and the mixture was stirred with a three-one motor.
• Step E is a holding and dipping step, in which the capsule preparation liquid poured into a dipping pan is held at the optimum temperature for dipping, and then a mold pin (size 2) left at room temperature (about 25°C) is immersed for several seconds in the atmosphere. Pulled inside to dry. The molding pin to which the capsule preparation liquid was adhered was turned upside down and dried at room temperature for 10 hours or more.
• the optimum temperature in step E is intended to be a temperature suitable for preparing capsules conforming to specifications when the mold pins are immersed in the capsule preparation liquids of Comparative Examples and Examples.
• step A was carried out according to the following procedure.
• Gellan gum was stirred in pure water at 65°C for 1 to 10 minutes until dispersed.
• pectin was added and stirred for about 10 to 120 minutes until dispersed.
• the dispersion was then heated to 85° C. and stirred until the gellan gum and pectin were dissolved.
• Steps B to E were carried out in the same manner as above under the conditions shown in (Table 14).
• the capsule shell prepared as described above was cut into a predetermined length to prepare a hard capsule preparation for performance testing.
• Hard capsule preparations were prepared with and without a band seal at the fitting portion of the cap and body.
• Band seals were prepared and applied by the following method. Hydroxypropyl methylcellulose acetate succinate (HPMCAS), purified water, and ethanol were mixed so as to have final concentrations of 20% by mass, 16% by mass, and 64% by mass, respectively, and HPMCAS was dissolved to obtain a band sealing solution.
• the band seal liquid was applied in a band shape having a width of about 5 mm in the circumferential direction of the fitting portion so as to cover the fitting portion between the cap of the band seal liquid capsule and the body, dried at room temperature, and band-sealed.
• Example 5 A preparation example of Example 5 is shown.
• Gellan gum (6.75 g) was added to purified water, and the mixture was stirred with a three-one motor for about 5 minutes until it was dispersed.
• Pectin LM-102AS-J (45 g) was added while the liquid temperature was kept at 85° C., and stirred with a three-one motor until dissolved in approximately 60 minutes (step A).
• 60SH-10000 (128.25 g) and 60SH-50 (45 g) were added and dispersed, and slowly stirred for about 3 hours until bubbles disappeared (step B).
• step C the temperature was lowered, the temperature was raised to 65° C. again, and the mixture was stirred for about 1 hour (Step D).
• Hard capsules were prepared by pouring the capsule preparation liquid prepared above into a dip pan and applying the cold pin dipping method.
• a mold pin (size 2) left at room temperature (approximately 25°C) was immersed for several seconds in the capsule preparation solution maintained at 58-63°C in a dipping pan, and then pulled up into the atmosphere.
• the molding pin to which the capsule preparation liquid was adhered was turned upside down and dried at room temperature for 10 hours or more (step E).
• the capsule shell prepared as described above was cut into a predetermined length to prepare a hard capsule preparation for performance testing.
• Hard capsule preparations were prepared with and without a band seal at the fitting portion of the cap and body.
• a band seal was prepared and applied in the same manner as in the other preparation examples.
• Dissolution test By evaluating the dissolution of fast-dissolving acetaminophen, the above 2. The solubility (dissolution characteristics) of the capsules themselves prepared in was evaluated. 40 mg of acetaminophen, 140 mg of lactose, and 20 mg of sodium starch glycolate were filled per capsule, and the resulting hard capsule formulation was subjected to the dissolution test method specified in the Japanese Pharmacopoeia (17th Pharmacopoeia, 6.10-1. The test was performed according to the 2-paddle method (paddle rotation speed of 50 rpm) and using a sinker corresponding to Fig. 6.10-2a), and the time change of the acetaminophen dissolution rate was measured.
• a bath-type dissolution tester Model 2100 manufactured by Distek was used for the dissolution test.
• the absorbance at 244 nm when the same volume of acetaminophen is separately dissolved in the solution in the dissolution tester bath is set to 100%, and the absorbance in the dissolution tester bath increases with the elution of acetaminophen from the capsule.
• the elution rate was determined from the absorbance at 244 nm of the solution of .
• Disintegration Test was performed according to the Japanese Pharmacopoeia 17th Edition, section "6.09 Disintegration test method". The disintegration test this time was conducted using a device that meets the conditions described in section "6.09 Disintegration test method" and an auxiliary board. The outline of the equipment and auxiliary panel is shown below.
• Test equipment (i) The equipment used for the disintegration test is a 1000 mL low-profile beaker with a height of 138 to 160 mm and an inner diameter of the immersion part of 97 to 115 mm, a constant temperature bath that can be temperature-controlled at 37 ⁇ 2°C, and 1 minute29 It consists of a tester and a motor that moves up and down with ⁇ 32 reciprocations and an amplitude of 53 ⁇ 57mm.
• the amount of test liquid to be put into the beaker is such that the net surface of the tester is at least 15 mm below the liquid surface when the tester is at its highest point, and when the tester is at its lowest point, the net surface is above the bottom of the beaker. 25 mm or more, so that the tester was not completely submerged.
• the up and down travel times of the motors were equal, and the up and down direction changes were made smooth rather than abrupt.
• the tester was intended to operate along the vertical axis, with no horizontal movement or movement of the axis.
• 6 transparent glass tubes of length 77.5 ⁇ 2.5 mm, inner diameter 20.7 to 23 mm, thickness 1.0 to 2.8 mm, both ends of which are open, are placed vertically in the tester.
• a flat stainless steel mesh with a mesh opening of 1.8 to 2.2 mm and a wire diameter of 0.57 to 0.66 mm is attached to the lower surface of the lower plastic plate.
• the tester is assembled and fixed using three posts that penetrate two plastic plates.
• the tester conforms to the structure shown in Figure 6.09-1 of the Japanese Pharmacopoeia 17th Edition.
• the tester was suspended from a motor so that it could move up and down along its central axis.
• Auxiliary discs were used by inserting one into each glass tube.
• the auxiliary plate is cylindrical with a height of 9.5 ⁇ 0.15 mm and a diameter of 20.7 ⁇ 0.15 mm, and is made of transparent plastic with a specific gravity of 1.18-1.20.
• the auxiliary plate has five parallel holes with a diameter of 2 ⁇ 0.1 mm that penetrate vertically through the top and bottom of the plate, one at the center of the auxiliary plate and the other four at a distance of 6 ⁇ 0.2 mm from the center. are equally spaced.
• the trapezoid On the side surface of the auxiliary board, there are four identical trapezoidal cuts at equal intervals, substantially perpendicular to the board surface.
• the trapezoid is symmetrical, with the upper and lower parallel lines parallel to the line connecting two adjacent holes 6 mm from the central axis.
• the underline of the trapezoid is 1.6 ⁇ 0.1mm long and 1.5-1.8mm deep from the circumference, and the upper line is 9.4 ⁇ 0.2mm long and 2.6 ⁇ 0.1mm deep. .
• the auxiliary plate conforms to the standards shown in Figure 6.09-1, and all surfaces are smooth.
• test capsules put one sample in each of the six glass tubes of the tester, use the dissolution test liquid 2 as the test liquid, and operate the tester at 37 ⁇ 2 ° C. . As appropriate, lift the tester out of the test solution and observe the disintegration of the sample. A sample was considered to have disintegrated when no residue of the capsule filling was observed in the glass tube, and the disintegration time of 6 samples was measured.
• each capsule to be tested was filled with 40 mg of acetaminophen, 140 mg of lactose and 20 mg of sodium starch glycolate, and the obtained hard capsule preparation was used for the test. All test capsules used in the disintegration test were not band-sealed.
• Tables 7 to 12 and Table 15 show the formulations and dissolution rates of the capsules prepared in Comparative Examples 1 to 4 and Examples 1 to 19.
• the content of each component is shown in terms of % by mass when the solid content of the coating component is taken as 100% by mass.
• the elution rate was 40% or less, indicating that the acid resistance was improved.
• Table 13 shows the disintegration test results. All the capsules subjected to the disintegration test with the dissolution test liquid 2 disintegrated within 1 hour.

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