WO2023145869A1 - Production method for composition for formulation and production method for formulation - Google Patents

Production method for composition for formulation and production method for formulation Download PDF

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Publication number
WO2023145869A1
WO2023145869A1 PCT/JP2023/002611 JP2023002611W WO2023145869A1 WO 2023145869 A1 WO2023145869 A1 WO 2023145869A1 JP 2023002611 W JP2023002611 W JP 2023002611W WO 2023145869 A1 WO2023145869 A1 WO 2023145869A1
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Prior art keywords
binder
formulation
pharmaceutical composition
producing
active ingredient
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PCT/JP2023/002611
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French (fr)
Japanese (ja)
Inventor
元晴 藤崎
彰 木村
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住友精化株式会社
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Publication of WO2023145869A1 publication Critical patent/WO2023145869A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K9/20—Pills, tablets, discs, rods

Definitions

  • the present invention relates to a method for producing a pharmaceutical composition and a method for producing a formulation.
  • formulations typified by controlled release formulations that release drugs can be obtained by various methods. For example, a method is known in which raw materials containing an active ingredient and a binder are mixed and prepared, the resulting mixture is used to form granules, and the granules are tableted to obtain a formulation.
  • Wet granulation and dry granulation are known methods for obtaining the above granules.
  • Wet granulation methods include water-based or solvent-based methods, but these methods have problems such as increased energy load during production, and dry granulation is advantageous in this respect. It is known.
  • As this dry granulation method a method of kneading and granulating raw materials with a twin-screw extruder has been proposed (see, for example, Patent Document 1, etc.). Such a method requires a small energy load during production, and can be applied to raw materials containing drugs that are sensitive to moisture.
  • the present invention has been made in view of the above, and manufactures a pharmaceutical composition that suppresses the decomposition of a drug during manufacture, has excellent granulation properties, and can easily obtain a highly rigid drug product. It is an object to provide methods and methods of manufacturing formulations.
  • the present inventors have found that the above object can be achieved by adjusting the temperature conditions of twin-screw extrusion, the type of binder and the ratio of use, and have completed the present invention. came to.
  • the present invention includes, for example, the subject matter described in the following sections.
  • Item 1 A step 1 of kneading and granulating a mixture containing an active ingredient and a binder in a barrel by a twin-screw extrusion method, The temperature in the barrel is 130° C. or less, The weight average molecular weight of the binder is 1000000 g/mol or less, A method for producing a pharmaceutical composition, wherein the mixture contains 80% by mass or more of the active ingredient relative to the total mass of the active ingredient and the binder.
  • Item 2 Item 2. The method for producing a pharmaceutical composition according to Item 1, wherein the binder is a water-soluble polymer.
  • the binder is selected from the group consisting of polyethylene oxide, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polymethacrylate, copolymers of N-vinylpyrrolidone and vinyl acetate, and copolymers of N-vinylcaprolactam, vinyl acetate and ethylene glycol. 3.
  • Item 4 Item 4.
  • Item 5 A method for producing a formulation, comprising the method for producing a pharmaceutical composition according to 1 to 4, A method for producing a formulation, comprising Step 2 of obtaining a formulation from the pharmaceutical composition obtained in Step 1 above.
  • the drug is suppressed from being decomposed during production, and has excellent granulation properties.
  • the composition obtained by the method for producing a composition for pharmaceutical preparation of the present invention a pharmaceutical preparation with high hardness can be easily obtained.
  • FIG. 1 is a schematic diagram showing an example of a screw used in manufacturing the pharmaceutical composition of the present invention.
  • FIG. It is the schematic which shows an example of the screw used in the Example.
  • the upper limit or lower limit of the numerical range at one stage can be arbitrarily combined with the upper limit or lower limit of the numerical range at another stage.
  • the upper and lower limits of the numerical ranges may be replaced with values shown in Examples or values that can be uniquely derived from Examples.
  • a numerical value connected with "-" means a numerical range including numerical values before and after "-" as lower and upper limits.
  • the method for producing a pharmaceutical composition of the present invention comprises a step 1 of kneading and granulating a mixture containing an active ingredient and a binder in a barrel by a twin-screw extrusion method,
  • the temperature in the barrel is 130° C. or less
  • the weight average molecular weight of the binder is 1,000,000 g/mol or less
  • the mixture contains 80 weights of the active ingredient based on the total weight of the active ingredient and the binder. % or more.
  • the raw materials are mixed at a temperature in the barrel of 130° C. or lower, so that the pharmaceutical composition is excellent in granulation while suppressing decomposition of the active ingredient drug. can be obtained.
  • the tablet prepared using the pharmaceutical composition obtained by the method for producing the pharmaceutical composition of the present invention has high hardness
  • the composition obtained by the method for producing the pharmaceutical composition of the present invention is suitable as a raw material for producing formulations with high hardness.
  • a mixture containing an active ingredient and a binder can be used as raw materials.
  • the type of active ingredient is not particularly limited, and a wide range of known active ingredients can be applied.
  • active ingredients include drugs such as acetaminophen, which are used as antipyretics and analgesics.
  • the active ingredient can be produced by a known method, or can be obtained from commercial products.
  • binder is not particularly limited.
  • binders used in formulations can be widely used in the present invention.
  • various polymer materials having a weight average molecular weight of 1000000 g/mol or less are used as binders. do.
  • the type of binder is not particularly limited as long as it is a polymer with a mass average molecular weight of 1,000,000 g/mol or less.
  • the binder is a polymer with a mass average molecular weight of 1,000,000 g/mol or less, so that a formulation with high hardness can be prepared even though the barrel temperature in step 1 is low (130° C. or less).
  • a pharmaceutical composition can be obtained.
  • Binders may be homopolymers or copolymers.
  • the binder is preferably a water-soluble polymer because it has excellent solubility in water.
  • water-soluble polymers include polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl acetate, copolymers of N-vinylcaprolactam, vinyl acetate and ethylene glycol, and copolymers of N-vinylpyrrolidone and vinyl propionate. , cellulose esters, cellulose ethers, hydroxyalkylcelluloses (e.g. hydroxypropylcellulose, hydroxypropylmethylcellulose), cellulose phthalates, cellulose succinates, polyalkylene oxides (e.g.
  • the binder is from the group consisting of polyethylene oxide, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone, polymethacrylates, copolymers of N-vinylpyrrolidone and vinyl acetate, and copolymers of N-vinylcaprolactam, vinyl acetate and ethylene glycol. At least one selected is more preferable. In this case, even if the temperature in the barrel is low, it is easy to granulate the composition for formulation (that is, it has excellent granulation properties), and it is easy to prepare a formulation with high hardness.
  • the binder is at least one selected from the group consisting of polyethylene oxide and hydroxypropyl cellulose, because it is particularly excellent in granulation even when kneaded at a low temperature and it is easy to prepare a formulation with higher hardness.
  • polyethylene oxide is particularly preferred.
  • the binder is polyethylene oxide, the granulation properties are excellent even when kneaded at a lower temperature, and a preparation having particularly high hardness can be easily prepared.
  • the weight average molecular weight of the binder is preferably 50000 g/mol or more and 1000000 g/mol or less. In this case, even if the temperature in the barrel is low, it is easy to granulate the composition for pharmaceutical preparation, and it is easy to prepare a pharmaceutical composition with high hardness.
  • the weight average molecular weight of the binder is more preferably 80000 g/mol or more, further preferably 100000 g/mol or more, and more preferably 850000 g/mol or less, and 750000 g/mol or less. is more preferable, and 300000 g/mol or less is particularly preferable.
  • a preferable binder is polyethylene oxide having a mass average molecular weight of 50000 g/mol or more and 1000000 g/mol or less, and particularly preferably polyethylene oxide having a mass average molecular weight of 100000 g/mol or more and 300000 g/mol or less.
  • the binder can be produced by a known method, or can be obtained from commercial products.
  • the binder is a polyalkylene oxide
  • the polyalkylene oxide can be produced by polymerization of the alkylene oxide in the presence of a catalyst.
  • the active ingredients contained in the raw materials used in the present invention can be one type, or can be two or more types.
  • the raw materials used in the present invention may contain one binder, or two or more binders.
  • the raw material used in the method for producing the pharmaceutical composition of the present invention may contain other ingredients as long as it contains the mixture of the active ingredient and the binder. That is, it is possible to consist only of the active ingredient and the binder).
  • examples of such other components include various additives contained in known formulations. Examples of such additives include fillers, excipients, diluents, lubricants, dyes, pigments, etc. Specific examples include silica such as Aerosil.
  • the content of the other components is preferably 10% by mass or less, more preferably 10% by mass or less, based on the total mass of the active ingredient and the binder. is 5% by mass or less, more preferably 1% by mass or less, and particularly preferably 0.5% by mass or less.
  • the mixture contained in the raw material contains 80% by weight or more of the active ingredient relative to the total weight of the active ingredient and the binder (i.e., the mixture contains 20% by mass or less of the binder). This makes it easy to granulate the composition for formulation even when the temperature in the barrel is low, and to prepare a formulation with high hardness.
  • the content of the binder exceeds 20% by mass with respect to the total mass of the active ingredient and the binder, formulation from the pharmaceutical composition becomes difficult, for example, tablets are partially formed.
  • the content of the binder in the mixture is preferably 5% by mass or more with respect to the total mass of the active ingredient and the binder, and is 7.5% by mass. % or more is more preferable.
  • the mixture more preferably contains 85% by mass or more of the active ingredient with respect to the total mass of the active ingredient and the binder.
  • the mixture preferably contains 99% by mass or less, more preferably 97% by mass or less, and preferably 95% by mass or less of the active ingredient with respect to the total mass of the active ingredient and the binder. More preferably, it is particularly preferably 92.5% by mass or less.
  • the method of preparing the raw material containing the mixture is not particularly limited.
  • a raw material containing the mixture can be prepared by mixing the active ingredient and the binder in a predetermined ratio.
  • ingredients other than the active ingredient and the binder can be mixed with the raw materials.
  • the raw material containing the mixture can be prepared, for example, by mixing means using a known mixer or the like.
  • Step 1 is a step of kneading and granulating raw materials containing the mixture in a barrel by a twin-screw extrusion method. Granules containing an active ingredient and a binder can be obtained by such Step 1.
  • raw materials are kneaded and granulated using a twin-screw extruder.
  • twin-screw extruder for example, widely known twin-screw extruders can be used.
  • the type of screw provided in the twin-screw extruder used in step 1 is also not particularly limited, and a wide range of known screws can be used.
  • a screw is composed of a Pre-Conditioning section (also referred to as a transfer section), an Agglomeration section (also referred to as a kneading section), and a Breakage section (also referred to as a crushing section).
  • the screw used in the present invention preferably includes at least an Agglomeration section (kneading section), and more preferably includes all of a Pre-Conditioning section (transfer section), an Agglomeration section (kneading section) and a Breakage section (crushing section). . If the screw does not have a Breakage section (pulverization section), it is preferable to provide a pulverization step after twin-screw extrusion.
  • the kneading section is composed of a kneading type screw and the rest of the kneading section is composed of a so-called full flight screw.
  • the kneading section is composed of a kneading type screw and the rest of the kneading section is composed of a so-called full flight screw.
  • FIG. 1 is a schematic diagram of a screw that can be suitably used in the method for producing a pharmaceutical composition of the present invention.
  • the kneading section preferably occupies 15 to 30% of the length of the entire screw. In this case, even if the temperature in the barrel is low, it is easy to granulate the composition for pharmaceutical preparation, and it is easy to prepare a pharmaceutical composition with high hardness.
  • the kneading portion is positioned at 0 to 90% when the tip side (granule outlet side) of both ends of the screw is 0% and the rear end side (raw material input side or raw material inlet side) is 100%. It is preferable that it is arranged at any site within the range of
  • the tip side of the screw means the downstream side in the flow direction of the raw material
  • the rear end side of the screw means the upstream side in the flow direction of the raw material.
  • the screw shown in FIG. it is preferable to use the screw shown in FIG. In this case, even if the temperature in the barrel is low, it is easy to granulate the composition for pharmaceutical preparation, and it is easy to prepare a pharmaceutical composition with high hardness.
  • FIG. 1 is a schematic diagram of a screw that can be suitably used in the method for producing a pharmaceutical composition of the present invention.
  • the screw shown in FIG. 1 for example, there is a notation "36/24", where “36” means the length (mm) of each unit of the screw, and “24” means that the screw has made one rotation. Sometimes it means the length (mm) that the wing advances, the so-called lead.
  • the conditions for kneading the raw materials in the barrel of the extruder are not particularly limited as long as the temperature in the barrel is 130°C or less.
  • the composition for pharmaceutical preparation can be granulated, and a highly rigid preparation can be prepared.
  • decomposition of the active ingredient, that is, the drug can be suppressed. Since a plurality of barrels are usually used, the temperature inside all the barrels is set to 130° C. or lower in the present invention.
  • the temperature in the barrel is preferably 120°C or lower, more preferably 110°C or lower, even more preferably 100°C or lower, and particularly preferably 90°C or lower.
  • a polyalkylene oxide, particularly polyethylene oxide is used as a binder, it is possible to prepare a preparation with excellent granulation properties even at 90° C. or lower and with higher hardness.
  • the temperature inside the barrel is not particularly limited, and is, for example, 20°C or higher, preferably 30°C or higher, more preferably 40°C or higher.
  • the number of revolutions of the screw is not particularly limited, and, for example, the same conditions as in the method of producing a pharmaceutical composition by a known twin-screw extrusion method can be used.
  • the screw speed can be 50-500 rpm (same for commercial screws).
  • granules containing the active ingredient and the binder By twin-screw extruding the raw material containing the mixture, granules containing the active ingredient and the binder can be obtained.
  • the obtained granules can be pulverized if necessary.
  • the pulverization method is not particularly limited, and for example, the granules can be pulverized using a known pulverization means.
  • the granules or the pulverized granules may be classified, if necessary.
  • the granules obtained in step 1 are in the form of particles, and the shape thereof is not particularly limited. Agglomerated particles may also be used.
  • the size of the granules is also not particularly limited, and can be adjusted as appropriate according to the intended formulation, for example.
  • the granules preferably have a median particle size of 100 to 500 ⁇ m.
  • the pharmaceutical composition obtained by the method for producing a pharmaceutical composition of the present invention contains granules containing an active ingredient and a binder, and depending on the production conditions, the pharmaceutical composition consists only of granules. .
  • the granules may consist only of the active ingredient and the binder, or may contain ingredients other than the active ingredient and the binder, such as the additives described above.
  • the granules preferably contain 80% by mass or more of the active ingredient with respect to the total mass of the active ingredient and the binder (that is, the granules contain the total mass of the active ingredient and the binder). (It is preferable that the binder is contained in an amount of 20% by mass or less). This makes it easy to prepare a formulation with a high degree of hardness. In the granules, if the content of the binder exceeds 20% by mass with respect to the total mass of the active ingredient and the binder, formulation from the pharmaceutical composition becomes difficult. The problem of partial defect tends to occur, and even if it can be formulated, it is difficult to have high hardness. Further, from the viewpoint of excellent granulation properties during production, the content of the binder in the granules is preferably 5% by mass or more with respect to the total mass of the active ingredient and the binder. , 7.5% by mass or more.
  • the granules more preferably contain 85% by mass or more of the active ingredient with respect to the total mass of the active ingredient and the binder.
  • the granule preferably contains 99% by mass or less, more preferably 97% by mass or less, and 95% by mass or less of the active ingredient with respect to the total mass of the active ingredient and the binder. is particularly preferred.
  • the decomposition of the drug is suppressed by being produced as described above. It can be used preferably.
  • the method for producing a formulation of the present invention includes the above-described method for producing the composition for formulation of the present invention, and includes Step 2 of obtaining a formulation from the composition for formulation obtained in Step 1 above.
  • Step 1 a granule containing an active ingredient and a binder is obtained, and in step 2, a formulation is obtained using the granule obtained in step 1. can be done.
  • the method of obtaining a formulation using the granules obtained in step 1 is not particularly limited.
  • tablet formulations can be obtained by compressing granules.
  • the tableting method is not particularly limited, and for example, it can be performed using a known tableting machine.
  • the dosage form of the formulation obtained in step 2 is not particularly limited, preferably tablets.
  • the drug product obtained by the method for producing a drug product of the present invention is formed from the pharmaceutical composition obtained in step 1, so that the drug is inhibited from decomposing and has a high hardness.
  • a formulation obtained by the method for producing a formulation of the present invention can have a compressive strength of 2 MPa or more.
  • the concentration of the active ingredient contained in the formulation is high, it is particularly effective as a formulation, and for example, even with a small dose, the efficacy of the active ingredient is likely to be exhibited.
  • each configuration (property, structure, function, etc.) described in each embodiment of the present disclosure may be combined in any way. That is, the present disclosure encompasses all subject matter consisting of any combination of each of the combinable features described herein.
  • Example 1 Acetaminophen (manufactured by Chemexpress) as an active ingredient and polyethylene oxide (manufactured by Sumitomo Seika Chemicals, mass average molecular weight 160,335 g / mol) as a binder at a ratio of 92.5: 7.5 (active ingredient: binder)
  • a mixture was prepared by mixing at a mass ratio. By adding 0.1% Aerosil (manufactured by Evonik) to this mixture and mixing for 150 minutes or more with a blender (manufactured by Misgi, Mazemazeman SKH-40CA: 0.7 rpm) , to obtain a raw material for twin-screw extrusion.
  • the obtained raw material is fed to a twin-screw extruder (TEM-18SS-10/2V: Toshiba Machine) equipped with a screw shown in FIG.
  • a granulated product is obtained by charging at a supply rate of 8 kg/h, granulating under conditions of a temperature of 25° C. in heating zone 1, a temperature of 30° C. in heating zones 2 to 5, and a screw rotation speed of 200 rpm. rice field.
  • the twin-screw extruder used consisted of 10 barrels, each of which had a length of 75 mm. As shown in Fig.
  • the area from the feed port is zone 0
  • the area from 75 to 225 mm is heating zone 1
  • the area from 225 to 375 mm is heating zone 2
  • the area from 375 to 525 mm is heating zone 0. 3.
  • An area of 525 to 675 mm was designated as heating zone 4, and an area of 675 to 750 mm was designated as heating zone 5, and the heating temperature was controlled independently for each heating zone.
  • the kneading section is located in the heating zone 3 and the heating zone 4 (shaded area in FIG. 2).
  • the obtained granules were pulverized with a food processor (ZOJIRUSHI, model BM-RT08) (10 seconds/time ⁇ 3 times), and coarse powder was removed with a 32-mesh (500 ⁇ m mesh) sieve to obtain granules.
  • a pharmaceutical composition consisting of was obtained.
  • Example 2 A pharmaceutical composition was obtained in the same manner as in Example 1, except that the temperature of heating zones 2 to 5 was changed to 40°C.
  • Example 3 A pharmaceutical composition was obtained in the same manner as in Example 1, except that the temperature of heating zones 2 to 5 was changed to 50°C.
  • Example 4 A pharmaceutical composition was obtained in the same manner as in Example 1, except that the temperature of heating zones 2 to 5 was changed to 130°C.
  • Example 5 A pharmaceutical composition was prepared in the same manner as in Example 1 except that the binder was changed to hydroxypropylcellulose (manufactured by Sigma-Aldrich, mass average molecular weight 61,334) and the temperature of heating zones 2 to 5 was changed to 100 ° C. got stuff
  • Example 6 A pharmaceutical composition was obtained in the same manner as in Example 5, except that the temperature of heating zones 2 to 5 was changed to 120°C.
  • Example 7 A pharmaceutical composition was obtained in the same manner as in Example 1, except that the binder was changed to polyethylene oxide (manufactured by Sumitomo Seika, mass average molecular weight: 105,216).
  • Example 8 A pharmaceutical composition was obtained in the same manner as in Example 1, except that the binder was changed to polyethylene oxide (manufactured by Sumitomo Seika, mass average molecular weight: 820,913).
  • composition was obtained in the same manner as in Example 1, except that the binder was changed to polyethylene oxide (manufactured by Sumitomo Seika, mass average molecular weight: 1,057,017).
  • composition was obtained in the same manner as in Example 1, except that the mass ratio of the active ingredient and the binder was changed to 70:30 (active ingredient:binder).
  • Example 3 A pharmaceutical composition was obtained in the same manner as in Example 1, except that the temperature of heating zones 2 to 5 was changed to 140°C.
  • Example 4 A pharmaceutical composition was obtained in the same manner as in Example 1, except that the temperature of heating zones 2 to 5 was changed to 160°C.
  • the hardness of the formulation was evaluated by measuring the compressive strength of the tablets. Specifically, 500 mg of the pharmaceutical composition (granules) obtained in each of Examples and Comparative Examples was taken, and a tableting machine (Shimadzu Autograph AGS-J) was used to compress the tablet at a tableting pressure of 10 kN. A flat tablet (10.7 mm ⁇ , flat tablet) was produced under the conditions. The thickness of the tablet was measured with a thickness gauge (Tekclock).
  • the hardness was measured using a hardness tester (TBH325 tablet hardness tester manufactured by ERWEKA) under the conditions of a sensitivity of 10 N, a measurement speed of 2.3 mm/s, a measurement pressure of 20 N/s, and a measurement mode of Speed.
  • the hardness measured in this measurement was converted to compressive strength using the following formula.
  • the weight average molecular weight of polyethylene oxide was determined by gel permeation chromatography. Specifically, 0.02 g of polyethylene oxide was added to 40 mL of 0.19 M sodium nitrate aqueous solution and dissolved over 3 hours. The solution was filtered using a 0.8 ⁇ m membrane filter, and the obtained filtrate was subjected to gel permeation chromatography It was measured by lithography (“HLC-8220GPC” manufactured by Tosoh Corporation, guard column: TSKgel guardcolumn PWXL).
  • size exclusion columns were TSKgel G6000PWXL, TSKgel GMPWXL and TSKgel G3000PWXL
  • the mobile phase was 0.20 M sodium nitrate aqueous solution
  • the flow rate was 0.5 mL/min
  • the column temperature was 40°C
  • the differential refractometer temperature was 40°C.
  • the injection amount was 500 ⁇ L
  • the measurement time was 90 minutes.
  • a standard sample of polyethylene oxide having a known mass average molecular weight was measured in the same manner to prepare a calibration curve, and the mass average molecular weight of polyethylene oxide was calculated based on this calibration curve.
  • the granulation property was judged by visual observation. Specifically, the pharmaceutical composition obtained in each example was visually observed, and excessive granulation was observed (that is, a lumpy substance that was difficult to pulverize), and powder as it was It was judged that granulation was not possible for those with , and it was judged that granulation was possible for the others. When it was determined that granulation was possible, it was rated as "O”, and when it was determined that granulation was impossible, it was rated as "x".
  • Table 1 shows the manufacturing conditions (mixing ratio of active ingredient and binder and temperature of each heating zone) of the pharmaceutical composition manufactured in each example and comparative example, and also shows the granulation properties of the pharmaceutical composition and the 1 shows the evaluation results of compression strength of tablets obtained from pharmaceutical compositions.
  • the temperature in the barrel is 130° C. or less
  • the weight average molecular weight of the binder is 1000000 g/mol or less
  • the active ingredient is 80 masses based on the total mass of the active ingredient and the binder. % or more was used as a raw material, the composition for formulation was excellent in granulation properties and a formulation with high hardness could be obtained.

Abstract

Provided are a method for producing a composition for a formulation and a method for producing a formulation that prevent degradation of a drug during production and can readily provide a formulation with excellent granulation properties and high hardness.　This method for producing a composition for a formulation comprises step 1 for kneading and granulating a mixture containing an active component and a binder in a barrel by twin-screw extrusion, wherein the temperature in the barrel is 130°C or lower, the binder has a mass average molecular weight of 1,000,000 g/mol or less and the mixture contains 80% by mass or more active component relative to the total mass of the active component and the binder.

Description

製剤用組成物の製造方法及び製剤の製造方法Method for producing composition for formulation and method for producing formulation
　本発明は、製剤用組成物の製造方法及び製剤の製造方法に関する。 The present invention relates to a method for producing a pharmaceutical composition and a method for producing a formulation.
　薬物を放出する薬物放出制御製剤等に代表される製剤は、種々の方法によって得られることが知られている。例えば、活性成分と結合剤とを含む原料を混合して調製し、得られた混合物を用いて造粒物を形成し、この造粒物を用いて錠剤化して製剤を得る方法が知られている。 It is known that formulations typified by controlled release formulations that release drugs can be obtained by various methods. For example, a method is known in which raw materials containing an active ingredient and a binder are mixed and prepared, the resulting mixture is used to form granules, and the granules are tableted to obtain a formulation. there is
　上記の造粒物を得る方法としては、湿式造粒法及び乾式造粒法が知られている。湿式造粒では、水系又は溶剤系で行う方法が挙げられるが、これらの方法では、製造時のエネルギー負荷が大きくなること等の問題があることから、この点では乾式造粒法が有利であることが知られている。この乾式造粒法としては、二軸押出機で原料を混練して造粒させる方法が提案されている（例えば、特許文献１等を参照）。斯かる方法では、製造時のエネルギー負荷が小さく、水分に弱い薬剤を含む原料に対しても適用することが可能となる。 Wet granulation and dry granulation are known methods for obtaining the above granules. Wet granulation methods include water-based or solvent-based methods, but these methods have problems such as increased energy load during production, and dry granulation is advantageous in this respect. It is known. As this dry granulation method, a method of kneading and granulating raw materials with a twin-screw extruder has been proposed (see, for example, Patent Document 1, etc.). Such a method requires a small energy load during production, and can be applied to raw materials containing drugs that are sensitive to moisture.
特開２００８－５４０５４０号公報Japanese Patent Application Laid-Open No. 2008-540540
　しかしながら、従来の二軸押出機を用いた乾式造粒法で得られた造粒物から錠剤（製剤）を製造した場合、硬度が十分ではなかったので、製剤として不適になりやすいという問題があった。硬度を向上させるために二軸押出の条件を変更することが考えられるが、この場合は、造粒性が低下することがあり、却って目的の製剤を得ることが難しくなるという問題があった。 However, when tablets (formulations) are produced from granules obtained by a conventional dry granulation method using a twin-screw extruder, there is a problem that they tend to be unsuitable as formulations because the tablets (formulations) are not sufficiently hard. rice field. Although it is conceivable to change the conditions of twin-screw extrusion in order to improve the hardness, there is a problem that in this case, granulation properties may deteriorate, making it difficult to obtain the desired formulation.
　本発明は、上記に鑑みてなされたものであり、製造時の薬物の分解を抑制しつつ、造粒性に優れ、また、硬度が高い製剤を容易に得ることができる製剤用組成物の製造方法及び製剤の製造方法を提供することを目的とする。 The present invention has been made in view of the above, and manufactures a pharmaceutical composition that suppresses the decomposition of a drug during manufacture, has excellent granulation properties, and can easily obtain a highly rigid drug product. It is an object to provide methods and methods of manufacturing formulations.
　本発明者らは、上記目的を達成すべく鋭意研究を重ねた結果、二軸押出の温度条件、結合剤の種類及び使用割合を調節することにより上記目的を達成できることを見出し、本発明を完成するに至った。 As a result of intensive studies aimed at achieving the above object, the present inventors have found that the above object can be achieved by adjusting the temperature conditions of twin-screw extrusion, the type of binder and the ratio of use, and have completed the present invention. came to.
　すなわち、本発明は、例えば、以下の項に記載の主題を包含する。
項１
二軸押出法により、活性成分と結合剤とを含む混合物をバレル内で混練して造粒する工程１を具備し、
前記バレル内の温度が１３０℃以下であり、
前記結合剤の質量平均分子量が１００００００ｇ／ｍｏｌ以下であり、
前記混合物は、前記活性成分及び前記結合剤の全質量に対して前記活性成分を８０質量％以上含む、製剤用組成物の製造方法。
項２
前記結合剤は水溶性高分子である、項１に記載の製剤用組成物の製造方法。
項３
前記結合剤はポリエチレンオキシド、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、ポリメタクリレート、Ｎ－ビニルピロリドンと酢酸ビニルのコポリマー、及び、Ｎ－ビニルカプロラクタムと酢酸ビニルとエチレングリコールとのコポリマーからなる群より選ばれる少なくとも１種である、項１又は２に記載の製剤用組成物の製造方法。
項４
前記結合剤は、質量平均分子量が５００００ｇ／ｍｏｌ以上、１００００００ｇ／ｍｏｌ以下であるポリエチレンオキシドである、項１～３のいずれか１項に記載の製剤用組成物の製造方法。
項５
１～４に記載の製剤用組成物の製造方法を含む、製剤の製造方法であって、
前記工程１で得られた製剤用組成物から製剤を得る工程２を含む、製剤の製造方法。 That is, the present invention includes, for example, the subject matter described in the following sections.
Item 1
A step 1 of kneading and granulating a mixture containing an active ingredient and a binder in a barrel by a twin-screw extrusion method,
The temperature in the barrel is 130° C. or less,
The weight average molecular weight of the binder is 1000000 g/mol or less,
A method for producing a pharmaceutical composition, wherein the mixture contains 80% by mass or more of the active ingredient relative to the total mass of the active ingredient and the binder.
Item 2
Item 2. The method for producing a pharmaceutical composition according to Item 1, wherein the binder is a water-soluble polymer.
Item 3
The binder is selected from the group consisting of polyethylene oxide, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polymethacrylate, copolymers of N-vinylpyrrolidone and vinyl acetate, and copolymers of N-vinylcaprolactam, vinyl acetate and ethylene glycol. 3. A method for producing a pharmaceutical composition according to Item 1 or 2, wherein at least one selected.
Item 4
Item 4. The method for producing a pharmaceutical composition according to any one of Items 1 to 3, wherein the binder is polyethylene oxide having a mass average molecular weight of 50000 g/mol or more and 1000000 g/mol or less.
Item 5
A method for producing a formulation, comprising the method for producing a pharmaceutical composition according to 1 to 4,
A method for producing a formulation, comprising Step 2 of obtaining a formulation from the pharmaceutical composition obtained in Step 1 above.
　本発明の製剤用組成物の製造方法によれば、製造時の薬物の分解が抑制されつつ、造粒性に優れるものである。また、本発明の製剤用組成物の製造方法で得られた組成物を用いることで、硬度が高い製剤を容易に得ることができる。 According to the method for producing the pharmaceutical composition of the present invention, the drug is suppressed from being decomposed during production, and has excellent granulation properties. In addition, by using the composition obtained by the method for producing a composition for pharmaceutical preparation of the present invention, a pharmaceutical preparation with high hardness can be easily obtained.
本発明の製剤用組成物の製造で使用するスクリューの一例を示す概略図である。1 is a schematic diagram showing an example of a screw used in manufacturing the pharmaceutical composition of the present invention. FIG. 実施例で使用したスクリューの一例を示す概略図である。It is the schematic which shows an example of the screw used in the Example.
　以下、本発明の実施形態について詳細に説明する。なお、本明細書中において、「含有」及び「含む」なる表現については、「含有」、「含む」、「実質的にからなる」及び「のみからなる」という概念を含む。 Hereinafter, embodiments of the present invention will be described in detail. In this specification, the expressions "contain" and "include" include the concepts of "contain", "include", "substantially consist of" and "consist only of".
　本明細書に段階的に記載されている数値範囲において、ある段階の数値範囲の上限値又は下限値は、他の段階の数値範囲の上限値又は下限値と任意に組み合わせることができる。本明細書に記載されている数値範囲において、その数値範囲の上限値又は下限値は、実施例に示されている値又は実施例から一義的に導き出せる値に置き換えてもよい。また、本明細書において、「～」で結ばれた数値は、「～」の前後の数値を下限値及び上限値として含む数値範囲を意味する。 In the numerical ranges described stepwise in this specification, the upper limit or lower limit of the numerical range at one stage can be arbitrarily combined with the upper limit or lower limit of the numerical range at another stage. In the numerical ranges described herein, the upper and lower limits of the numerical ranges may be replaced with values shown in Examples or values that can be uniquely derived from Examples. Further, in this specification, a numerical value connected with "-" means a numerical range including numerical values before and after "-" as lower and upper limits.
　１．製剤用組成物の製造方法
　本発明の製剤用組成物の製造方法は、二軸押出法により、活性成分と結合剤とを含む混合物をバレル内で混練して造粒する工程１を具備し、前記バレル内の温度が１３０℃以下であり、前記結合剤の質量平均分子量が１００００００ｇ／ｍｏｌ以下であり、前記混合物は、前記活性成分及び前記結合剤の全質量に対して前記活性成分を８０質量％以上含む。 1. Method for producing a pharmaceutical composition The method for producing a pharmaceutical composition of the present invention comprises a step 1 of kneading and granulating a mixture containing an active ingredient and a binder in a barrel by a twin-screw extrusion method, The temperature in the barrel is 130° C. or less, the weight average molecular weight of the binder is 1,000,000 g/mol or less, and the mixture contains 80 weights of the active ingredient based on the total weight of the active ingredient and the binder. % or more.
　本発明の製剤用組成物の製造方法によれば、バレル内の温度が１３０℃以下で原料が混合されるので、活性成分たる薬物の分解が抑制されつつ、造粒性に優れる製剤用組成物を得ることができる。また、本発明の製剤用組成物の製造方法によって得られる製剤用組成物を使用して調製される錠剤は、硬度が高いので、本発明の製剤用組成物の製造方法で得られた組成物は、硬度が高い製剤を製造するための原料として適したものである。 According to the method for producing a pharmaceutical composition of the present invention, the raw materials are mixed at a temperature in the barrel of 130° C. or lower, so that the pharmaceutical composition is excellent in granulation while suppressing decomposition of the active ingredient drug. can be obtained. In addition, since the tablet prepared using the pharmaceutical composition obtained by the method for producing the pharmaceutical composition of the present invention has high hardness, the composition obtained by the method for producing the pharmaceutical composition of the present invention is suitable as a raw material for producing formulations with high hardness.
　（原料）
　本発明の製剤用組成物の製造方法では、活性成分と結合剤とを含む混合物を原料として用いることができる。 (material)
In the method for producing the pharmaceutical composition of the present invention, a mixture containing an active ingredient and a binder can be used as raw materials.
　活性成分の種類は特に限定されず、公知の活性成分を広く適用することができる。活性成分としては、例えば、解熱剤や鎮痛剤として用いられるアセトアミノフェン等の薬物が挙げられる。 The type of active ingredient is not particularly limited, and a wide range of known active ingredients can be applied. Examples of active ingredients include drugs such as acetaminophen, which are used as antipyretics and analgesics.
　活性成分は、公知の方法で製造することができ、あるいは、市販品等から入手することもできる。 The active ingredient can be produced by a known method, or can be obtained from commercial products.
　結合剤の種類は特に限定されず、例えば、製剤に用いられる結合剤を本発明でも広く用いることができ、特には、質量平均分子量が１００００００ｇ／ｍｏｌ以下である各種のポリマー材料を結合剤として使用する。 The type of binder is not particularly limited. For example, binders used in formulations can be widely used in the present invention. In particular, various polymer materials having a weight average molecular weight of 1000000 g/mol or less are used as binders. do.
　結合剤は、質量平均分子量が１００００００ｇ／ｍｏｌ以下のポリマーである限り、その種類は特に限定的ではない。結合剤は、質量平均分子量が１００００００ｇ／ｍｏｌ以下のポリマーであることで、工程１におけるバレル内温度が低温（１３０℃以下）であるにもかかわらず、硬度の高い製剤を調製することが可能な製剤用組成物を得ることができる。結合剤はホモポリマーであってもよいし、コポリマーであってもよい。 The type of binder is not particularly limited as long as it is a polymer with a mass average molecular weight of 1,000,000 g/mol or less. The binder is a polymer with a mass average molecular weight of 1,000,000 g/mol or less, so that a formulation with high hardness can be prepared even though the barrel temperature in step 1 is low (130° C. or less). A pharmaceutical composition can be obtained. Binders may be homopolymers or copolymers.
　結合剤は、水への溶解性に優れる点で、水溶性高分子であることが好ましい。斯かる水溶性高分子としては、例えば、ポリビニルピロリドン、Ｎ－ビニルピロリドンと酢酸ビニルとのコポリマー、Ｎ－ビニルカプロラクタムと酢酸ビニルとエチレングリコールとのコポリマー、Ｎ－ビニルピロリドンとプロピオン酸ビニルとのコポリマー、セルロースエステル、セルロースエーテル、ヒドロキシアルキルセルロース（例えば、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース）、セルロースフタレート、セルロースサクシネート、ポリアルキレンオキシド（例えば、ポリエチレンオキシド、ポリプロピレンオキシド）、エチレンオキシドとプロピレンオシドとのコポリマー、ポリアクリレート、ポリメタクリレート、ポリアクリルアミド、酢酸ビニルポリマー、ポリビニルアルコール、オリゴ糖、多糖類等が例示される。 The binder is preferably a water-soluble polymer because it has excellent solubility in water. Examples of such water-soluble polymers include polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl acetate, copolymers of N-vinylcaprolactam, vinyl acetate and ethylene glycol, and copolymers of N-vinylpyrrolidone and vinyl propionate. , cellulose esters, cellulose ethers, hydroxyalkylcelluloses (e.g. hydroxypropylcellulose, hydroxypropylmethylcellulose), cellulose phthalates, cellulose succinates, polyalkylene oxides (e.g. polyethylene oxide, polypropylene oxide), copolymers of ethylene oxide and propylene oxide , polyacrylates, polymethacrylates, polyacrylamides, vinyl acetate polymers, polyvinyl alcohols, oligosaccharides, polysaccharides, and the like.
　結合剤は、ポリエチレンオキシド、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース及びポリビニルピロリドン、ポリメタクリレート、Ｎ－ビニルピロリドンと酢酸ビニルのコポリマー、及び、Ｎ－ビニルカプロラクタムと酢酸ビニルとエチレングリコールとのコポリマーからなる群より選ばれる少なくとも１種であることがより好ましい。この場合、バレル内温度が低温であっても製剤用組成物を造粒しやすく（すなわち、造粒性に優れ）、また、硬度の高い製剤を調製しやすい。 The binder is from the group consisting of polyethylene oxide, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone, polymethacrylates, copolymers of N-vinylpyrrolidone and vinyl acetate, and copolymers of N-vinylcaprolactam, vinyl acetate and ethylene glycol. At least one selected is more preferable. In this case, even if the temperature in the barrel is low, it is easy to granulate the composition for formulation (that is, it has excellent granulation properties), and it is easy to prepare a formulation with high hardness.
　低温で混練しても造粒性に特に優れ、硬度のより高い製剤を調製しやすい点で、結合剤は、ポリエチレンオキシド及びヒドロキシプロピルセルロースからなる群より選ばれる少なくとも１種であることがさらに好ましく、ポリエチレンオキシドであることが特に好ましい。特に結合剤がポリエチレンオキシドである場合は、より低温で混練しても造粒性に優れるものとなり、しかも、硬度が特に高い製剤を調製しやすい。 It is more preferable that the binder is at least one selected from the group consisting of polyethylene oxide and hydroxypropyl cellulose, because it is particularly excellent in granulation even when kneaded at a low temperature and it is easy to prepare a formulation with higher hardness. , polyethylene oxide is particularly preferred. Especially when the binder is polyethylene oxide, the granulation properties are excellent even when kneaded at a lower temperature, and a preparation having particularly high hardness can be easily prepared.
　結合剤の質量平均分子量は、５００００ｇ／ｍｏｌ以上、１００００００ｇ／ｍｏｌ以下であることが好ましい。この場合、バレル内温度が低温であっても製剤用組成物を造粒しやすく、また、硬度の高い製剤を調製しやすい。結合剤の質量平均分子量は、８００００ｇ／ｍｏｌ以上であることがより好ましく、１０００００ｇ／ｍｏｌ以上であることがさらに好ましく、また、８５００００ｇ／ｍｏｌ以下であることがより好ましく、７５００００ｇ／ｍｏｌ以下であることがさらに好ましく、３０００００ｇ／ｍｏｌ以下であることが特に好ましい。 The weight average molecular weight of the binder is preferably 50000 g/mol or more and 1000000 g/mol or less. In this case, even if the temperature in the barrel is low, it is easy to granulate the composition for pharmaceutical preparation, and it is easy to prepare a pharmaceutical composition with high hardness. The weight average molecular weight of the binder is more preferably 80000 g/mol or more, further preferably 100000 g/mol or more, and more preferably 850000 g/mol or less, and 750000 g/mol or less. is more preferable, and 300000 g/mol or less is particularly preferable.
　好ましい結合剤は、質量平均分子量が５００００ｇ／ｍｏｌ以上、１００００００ｇ／ｍｏｌ以下であるポリエチレンオキシドであり、特に好ましくは、１０００００ｇ／ｍｏｌ以上、３０００００ｇ／ｍｏｌ以下であるポリエチレンオキシドである。 A preferable binder is polyethylene oxide having a mass average molecular weight of 50000 g/mol or more and 1000000 g/mol or less, and particularly preferably polyethylene oxide having a mass average molecular weight of 100000 g/mol or more and 300000 g/mol or less.
　結合剤は、公知の方法で製造することができ、あるいは、市販品等から入手することもできる。例えば、結合剤がポリアルキレンオキシドである場合は、例えば、触媒の存在下、アルキレンオキシドの重合反応により、ポリアルキレンオキシドを製造できる。 The binder can be produced by a known method, or can be obtained from commercial products. For example, when the binder is a polyalkylene oxide, the polyalkylene oxide can be produced by polymerization of the alkylene oxide in the presence of a catalyst.
　本発明で使用する原料に含まれる活性成分は１種とすることができ、あるいは２種以上とすることもできる。同様に、本発明で使用する原料に含まれる結合剤は１種とすることができ、あるいは２種以上とすることもできる。 The active ingredients contained in the raw materials used in the present invention can be one type, or can be two or more types. Similarly, the raw materials used in the present invention may contain one binder, or two or more binders.
　本発明の製剤用組成物の製造方法で使用する原料は、前記活性成分及び前記結合剤からなる混合物を含む限りは、他の成分を含むことも可能であり、また、原料は、前記混合物（すなわち、前記活性成分及び前記結合剤）のみからなることも可能である。当該他の成分としては、例えば、公知の製剤に含まれる各種添加剤を挙げることができる。斯かる添加剤としては、フィラー、賦形剤、希釈剤、滑沢剤、染料、色素等が挙げられ、具体的にはアエロジル等のシリカを挙げることができる。 The raw material used in the method for producing the pharmaceutical composition of the present invention may contain other ingredients as long as it contains the mixture of the active ingredient and the binder. That is, it is possible to consist only of the active ingredient and the binder). Examples of such other components include various additives contained in known formulations. Examples of such additives include fillers, excipients, diluents, lubricants, dyes, pigments, etc. Specific examples include silica such as Aerosil.
　原料が前記混合物以外に他の成分（例えば、前記添加剤）を含む場合、他の成分の含有割合は、前記活性成分及び前記結合剤の全質量に対し、好ましくは１０質量％以下、より好ましくは５質量％以下、さらに好ましくは１質量％以下、特に好ましくは０．５質量％以下とすることができる。 When the raw material contains other components (for example, the additives) in addition to the mixture, the content of the other components is preferably 10% by mass or less, more preferably 10% by mass or less, based on the total mass of the active ingredient and the binder. is 5% by mass or less, more preferably 1% by mass or less, and particularly preferably 0.5% by mass or less.
　原料に含まれる前記混合物は、前記活性成分及び前記結合剤の全質量に対して前記活性成分を８０質量％以上含む（すなわち、前記混合物は、前記活性成分及び前記結合剤の全質量に対して前記結合剤を２０質量％以下含む）。これにより、バレル内温度が低温であっても製剤用組成物を造粒しやすく、また、硬度の高い製剤を調製しやすい。前記混合物において、前記結合剤の含有割合が、前記活性成分及び前記結合剤の全質量に対して２０質量％を超過すると、製剤用組成物からの製剤化が困難となり、例えば、錠剤が部分的に欠損するという問題が生じやすく、また、製剤化できたとしても、高い硬度を有しにくい。また、造粒性に優れるという観点から、前記混合物において、前記結合剤の含有割合は、前記活性成分及び前記結合剤の全質量に対して５質量％以上であることが好ましく、７．５質量％以上であることがより好ましい。 The mixture contained in the raw material contains 80% by weight or more of the active ingredient relative to the total weight of the active ingredient and the binder (i.e., the mixture contains 20% by mass or less of the binder). This makes it easy to granulate the composition for formulation even when the temperature in the barrel is low, and to prepare a formulation with high hardness. In the mixture, if the content of the binder exceeds 20% by mass with respect to the total mass of the active ingredient and the binder, formulation from the pharmaceutical composition becomes difficult, for example, tablets are partially formed. In addition, even if it can be formulated, it is difficult to have high hardness. Further, from the viewpoint of excellent granulation properties, the content of the binder in the mixture is preferably 5% by mass or more with respect to the total mass of the active ingredient and the binder, and is 7.5% by mass. % or more is more preferable.
　前記混合物は、前記活性成分及び前記結合剤の全質量に対して前記活性成分を８５質量％以上含むことがより好ましい。また、前記混合物は、前記活性成分及び前記結合剤の全質量に対して前記活性成分を９９質量％以下含むことが好ましく、９７質量％以下含むことがさらに好ましく、９５質量％以下であることがさらに好ましく、９２．５質量％以下であることが特に好ましい。 The mixture more preferably contains 85% by mass or more of the active ingredient with respect to the total mass of the active ingredient and the binder. The mixture preferably contains 99% by mass or less, more preferably 97% by mass or less, and preferably 95% by mass or less of the active ingredient with respect to the total mass of the active ingredient and the binder. More preferably, it is particularly preferably 92.5% by mass or less.
　前記混合物を含む原料を調製する方法は特に限定されない。例えば、活性成分と結合剤とを所定の割合で混合することで、前記混合物を含む原料を調製することができる。原料を調製するにあたって、必要に応じて、活性成分と結合剤以外の成分を原料に混合することもできる。前記混合物を含む原料は、例えば、公知の混合機等を用いた混合手段によって調製することができる。 The method of preparing the raw material containing the mixture is not particularly limited. For example, a raw material containing the mixture can be prepared by mixing the active ingredient and the binder in a predetermined ratio. In preparing the raw materials, if necessary, ingredients other than the active ingredient and the binder can be mixed with the raw materials. The raw material containing the mixture can be prepared, for example, by mixing means using a known mixer or the like.
　（工程１）
　工程１は、二軸押出法により、前記混合物を含む原料をバレル内で混練して造粒する工程である。斯かる工程１により、活性成分と結合剤とを含む造粒物を得ることができる。 (Step 1)
Step 1 is a step of kneading and granulating raw materials containing the mixture in a barrel by a twin-screw extrusion method. Granules containing an active ingredient and a binder can be obtained by such Step 1.
　工程１では、二軸押出機を使用して原料の混練及び造粒を行う。二軸押出機は、例えば、公知の二軸押出機を広く使用することができる。 In process 1, raw materials are kneaded and granulated using a twin-screw extruder. As the twin-screw extruder, for example, widely known twin-screw extruders can be used.
　工程１で使用する二軸押出機が備えるスクリューの種類も特に限定されず、公知のスクリューを広く使用できる。 The type of screw provided in the twin-screw extruder used in step 1 is also not particularly limited, and a wide range of known screws can be used.
　一般にスクリューは、Ｐｒｅ－Ｃｏｎｄｉｔｉｏｎｉｎｇ部（移送部ともいう）、Ａｇｇｌｏｍｅｒａｔｉｏｎ部（混練部ともいう）及びＢｒｅａｋａｇｅ部（粉砕部ともいう）で構成される。本発明で使用するスクリューは、少なくともＡｇｇｌｏｍｅｒａｔｉｏｎ部（混練部）を備えることが好ましく、Ｐｒｅ－Ｃｏｎｄｉｔｉｏｎｉｎｇ部（移送部）、Ａｇｇｌｏｍｅｒａｔｉｏｎ部（混練部）及びＢｒｅａｋａｇｅ部（粉砕部）すべてを備えることがより好ましい。スクリューがＢｒｅａｋａｇｅ部（粉砕部）を備えない場合は、二軸押出後に粉砕工程を設けることがよい。 Generally, a screw is composed of a Pre-Conditioning section (also referred to as a transfer section), an Agglomeration section (also referred to as a kneading section), and a Breakage section (also referred to as a crushing section). The screw used in the present invention preferably includes at least an Agglomeration section (kneading section), and more preferably includes all of a Pre-Conditioning section (transfer section), an Agglomeration section (kneading section) and a Breakage section (crushing section). . If the screw does not have a Breakage section (pulverization section), it is preferable to provide a pulverization step after twin-screw extrusion.
　特に本発明では、混練部を混練タイプのスクリューで構成し、それ以外をフルフライトと称されるスクリューで構成することが好ましい。この場合、バレル内温度が低温であっても製剤用組成物を造粒しやすく、また、硬度の高い製剤を調製しやすい。 In particular, in the present invention, it is preferable that the kneading section is composed of a kneading type screw and the rest of the kneading section is composed of a so-called full flight screw. In this case, even if the temperature in the barrel is low, it is easy to granulate the composition for pharmaceutical preparation, and it is easy to prepare a pharmaceutical composition with high hardness.
　図１は、本発明の製剤用組成物の製造方法で好適に使用することができるスクリューの概略図である。 FIG. 1 is a schematic diagram of a screw that can be suitably used in the method for producing a pharmaceutical composition of the present invention.
　前記混練部は、スクリュー全体の長さに対して１５～３０％の割合を占めることが好ましい。この場合、バレル内温度が低温であっても製剤用組成物を造粒しやすく、また、硬度の高い製剤を調製しやすい。 The kneading section preferably occupies 15 to 30% of the length of the entire screw. In this case, even if the temperature in the barrel is low, it is easy to granulate the composition for pharmaceutical preparation, and it is easy to prepare a pharmaceutical composition with high hardness.
　また、前記混練部は、スクリュー両端のうちの先端側（造粒物出口側）を０％、後端側（原料投入側又は原料入口側）を１００％とした場合、０～９０％の位置する範囲内のいずれかの部位に配置されていることが好ましい。ここで、スクリューの先端側とは原料の流れ方向の下流側を意味し、スクリューの後端側とは原料の流れ方向の上流側を意味する。 In addition, the kneading portion is positioned at 0 to 90% when the tip side (granule outlet side) of both ends of the screw is 0% and the rear end side (raw material input side or raw material inlet side) is 100%. It is preferable that it is arranged at any site within the range of Here, the tip side of the screw means the downstream side in the flow direction of the raw material, and the rear end side of the screw means the upstream side in the flow direction of the raw material.
　特に本発明では、図１に示すスクリューを使用することが好適である。この場合、バレル内温度が低温であっても製剤用組成物を造粒しやすく、また、硬度の高い製剤を調製しやすい。 Especially in the present invention, it is preferable to use the screw shown in FIG. In this case, even if the temperature in the barrel is low, it is easy to granulate the composition for pharmaceutical preparation, and it is easy to prepare a pharmaceutical composition with high hardness.
　図１は、本発明の製剤用組成物の製造方法で好適に使用することができるスクリューの概略図である。この図１に示すスクリューでは、例えば、「３６／２４」なる表記があり、この表記において「３６」はスクリューの各単位の長さ（ｍｍ）を意味し、「２４」はスクリューが一回転した時に羽が進む長さ（ｍｍ）、いわゆるリードを意味する。また、「２８／５Ｒ４５°」なる表記があり、この表記において「２８」はスクリューの各単位の長さ（ｍｍ）を意味し、「５」はニーディングディスクの枚数を意味し、「４５°」はニーディングディスクの角度を意味し、また、「Ｒ」は右巻きにニーディングディスクが付いていることを意味する。「７／１４切欠」なる表記において「７」はスクリューの各単位の長さ（ｍｍ）を意味し、「１４」はスクリューが一回転した時に羽が進む長さ（ｍｍ）、いわゆるリードを意味し、「切欠」は切り欠けが入れられたスクリューを意味する。なお、図１において、Ｒの表記がないものでも、右巻きのスクリューであることを意味する。 FIG. 1 is a schematic diagram of a screw that can be suitably used in the method for producing a pharmaceutical composition of the present invention. In the screw shown in FIG. 1, for example, there is a notation "36/24", where "36" means the length (mm) of each unit of the screw, and "24" means that the screw has made one rotation. Sometimes it means the length (mm) that the wing advances, the so-called lead. In addition, there is a notation "28/5R45 °", in this notation, "28" means the length (mm) of each unit of the screw, "5" means the number of kneading discs, "45 ° ' means the angle of the kneading disc, and 'R' means that the kneading disc is attached to the right hand. In the notation "7/14 notch", "7" means the length (mm) of each unit of the screw, and "14" means the length (mm) that the blade advances when the screw rotates once, the so-called lead. and "notched" means a notched screw. In addition, even if there is no notation of R in FIG. 1, it means that it is a right-handed screw.
　工程１において、押出機内で原料をバレル内で混練する条件は、バレル内の温度が１３０℃以下である限り、特に限定されない。バレル内の温度が１３０℃以下で原料を混練することで、製剤用組成物を造粒することができ、また、硬度の高い製剤を調製することができる。また、バレル内の温度が１３０℃以下で原料を混練することで、活性成分、すなわち薬物の分解を抑制することもできる。なお、通常、バレルは複数で構成されるものであるので、本発明ではすべてのバレル内の温度を１３０℃以下とする。 In step 1, the conditions for kneading the raw materials in the barrel of the extruder are not particularly limited as long as the temperature in the barrel is 130°C or less. By kneading the raw materials at a temperature in the barrel of 130° C. or lower, the composition for pharmaceutical preparation can be granulated, and a highly rigid preparation can be prepared. Moreover, by kneading the raw materials at a temperature in the barrel of 130° C. or less, decomposition of the active ingredient, that is, the drug can be suppressed. Since a plurality of barrels are usually used, the temperature inside all the barrels is set to 130° C. or lower in the present invention.
　工程１において、バレル内の温度は、１２０℃以下であることが好ましく、１１０℃以下であることがより好ましく、１００℃以下であることがさらに好ましく、９０℃以下であることが特に好ましい。また、結合剤としてポリアルキレンオキシド、特にポリエチレンオキシドを使用した場合は、９０℃以下であっても造粒性に優れ、硬度のより高い製剤を調製することも可能となる。 In step 1, the temperature in the barrel is preferably 120°C or lower, more preferably 110°C or lower, even more preferably 100°C or lower, and particularly preferably 90°C or lower. Moreover, when a polyalkylene oxide, particularly polyethylene oxide, is used as a binder, it is possible to prepare a preparation with excellent granulation properties even at 90° C. or lower and with higher hardness.
　工程１において、バレル内の温度は特に限定されず、例えば、２０℃以上、好ましくは３０℃以上、より好ましくは４０℃以上である。 In step 1, the temperature inside the barrel is not particularly limited, and is, for example, 20°C or higher, preferably 30°C or higher, more preferably 40°C or higher.
　二軸押出法において、スクリューの回転数は特に限定されず、例えば、公知の二軸押出法で製剤用組成物を製造する方法と同様の条件とすることができる。例えば、スクリューの回転数は、５０～５００ｒｐｍ（商業用のスクリューでも同様）とすることができる。 In the twin-screw extrusion method, the number of revolutions of the screw is not particularly limited, and, for example, the same conditions as in the method of producing a pharmaceutical composition by a known twin-screw extrusion method can be used. For example, the screw speed can be 50-500 rpm (same for commercial screws).
　前記混合物を含む原料を二軸押出することで、活性成分と結合剤とを含む造粒物を得ることができる。得られた造粒物は、必要に応じて粉砕処理をすることができる。粉砕処理の方法は特に限定されず、例えば、公知の粉砕手段を用いて造粒物の粉砕処理をすることができる。造粒物又は前記粉砕処理された造粒物は、必要に応じて、分級処理をしてもよい。 By twin-screw extruding the raw material containing the mixture, granules containing the active ingredient and the binder can be obtained. The obtained granules can be pulverized if necessary. The pulverization method is not particularly limited, and for example, the granules can be pulverized using a known pulverization means. The granules or the pulverized granules may be classified, if necessary.
　工程１で得られる造粒物は粒子状であり、その形状は特に限定されず、例えば、真球状、楕円球状、不定形状等であってもよいし、また、複数の粒子が凝集してなる凝集粒子であってもよい。前記造粒物の大きさも特に限定されず、例えば、目的とする製剤に応じて適宜調節することができる。例えば、前記造粒物は、中位粒子径が１００～５００μｍであることが好ましい。 The granules obtained in step 1 are in the form of particles, and the shape thereof is not particularly limited. Agglomerated particles may also be used. The size of the granules is also not particularly limited, and can be adjusted as appropriate according to the intended formulation, for example. For example, the granules preferably have a median particle size of 100 to 500 μm.
　本発明の製剤用組成物の製造方法で得られる製剤用組成物は、活性成分と結合剤とを含む造粒物を含有し、製造条件によっては、製剤用組成物は造粒物のみからなる。造粒物は、活性成分及び結合剤のみからなるものであってもよいし、活性成分及び結合剤以外の成分、例えば、前記添加剤が含まれていてもよい。 The pharmaceutical composition obtained by the method for producing a pharmaceutical composition of the present invention contains granules containing an active ingredient and a binder, and depending on the production conditions, the pharmaceutical composition consists only of granules. . The granules may consist only of the active ingredient and the binder, or may contain ingredients other than the active ingredient and the binder, such as the additives described above.
　前記造粒物は、前記活性成分及び前記結合剤の全質量に対して前記活性成分を８０質量％以上含むことが好ましい（すなわち、前記造粒物は、前記活性成分及び前記結合剤の全質量に対して前記結合剤を２０質量％以下含むことが好ましい）。これにより、製剤用組成物は、硬度の高い製剤を調製しやすい。前記造粒物において、前記結合剤の含有割合が、前記活性成分及び前記結合剤の全質量に対して２０質量％を超過すると、製剤用組成物からの製剤化が困難となり、例えば、錠剤が部分的に欠損するという問題が生じやすく、また、製剤化できたとしても、高い硬度を有しにくい。また、製造時の造粒性に優れるという観点から、前記造粒物において、前記結合剤の含有割合は、前記活性成分及び前記結合剤の全質量に対して５質量％以上であることが好ましく、７．５質量％以上であることがより好ましい。 The granules preferably contain 80% by mass or more of the active ingredient with respect to the total mass of the active ingredient and the binder (that is, the granules contain the total mass of the active ingredient and the binder). (It is preferable that the binder is contained in an amount of 20% by mass or less). This makes it easy to prepare a formulation with a high degree of hardness. In the granules, if the content of the binder exceeds 20% by mass with respect to the total mass of the active ingredient and the binder, formulation from the pharmaceutical composition becomes difficult. The problem of partial defect tends to occur, and even if it can be formulated, it is difficult to have high hardness. Further, from the viewpoint of excellent granulation properties during production, the content of the binder in the granules is preferably 5% by mass or more with respect to the total mass of the active ingredient and the binder. , 7.5% by mass or more.
　前記造粒物は、前記活性成分及び前記結合剤の全質量に対して前記活性成分を８５質量％以上含むことがより好ましい。また、前記造粒物は、前記活性成分及び前記結合剤の全質量に対して前記活性成分を９９質量％以下含むことが好ましく、９７質量％以下含むことがさらに好ましく、９５質量％以下含むことが特に好ましい。 The granules more preferably contain 85% by mass or more of the active ingredient with respect to the total mass of the active ingredient and the binder. In addition, the granule preferably contains 99% by mass or less, more preferably 97% by mass or less, and 95% by mass or less of the active ingredient with respect to the total mass of the active ingredient and the binder. is particularly preferred.
　本発明の製剤用組成物の製造方法で得られる製剤用組成物は、上記のように製造されることで、薬物の分解が抑制されており、硬度の高い製剤を得るために製剤用原料として好適に使用することができる。 In the pharmaceutical composition obtained by the method for producing a pharmaceutical composition of the present invention, the decomposition of the drug is suppressed by being produced as described above. It can be used preferably.
　２．製剤の製造方法
　本発明の製剤の製造方法は、前述の本発明の製剤用組成物の製造方法を含むものであって、前記工程１で得られた製剤用組成物から製剤を得る工程２を含む。すなわち、本発明の製剤の製造方法は、工程１により、活性成分と結合剤とを含む造粒物を得た後、工程２により、工程１で得た造粒物を用いて製剤を得ることができる。 2. Method for producing a formulation The method for producing a formulation of the present invention includes the above-described method for producing the composition for formulation of the present invention, and includes Step 2 of obtaining a formulation from the composition for formulation obtained in Step 1 above. include. That is, in the method for producing the formulation of the present invention, in step 1, a granule containing an active ingredient and a binder is obtained, and in step 2, a formulation is obtained using the granule obtained in step 1. can be done.
　工程１で得た造粒物を用いて製剤を得る方法特に限定されない。例えば、造粒物を打錠することで錠剤状の製剤を得ることができる。打錠する方法は特に限定されず、例えば、公知の打錠機を用いて行うことができる。 The method of obtaining a formulation using the granules obtained in step 1 is not particularly limited. For example, tablet formulations can be obtained by compressing granules. The tableting method is not particularly limited, and for example, it can be performed using a known tableting machine.
　工程２で得られる製剤の剤形は特に限定されず、好ましくは錠剤である。 The dosage form of the formulation obtained in step 2 is not particularly limited, preferably tablets.
　本発明の製剤の製造方法で得られる製剤は、前記工程１で得られた製剤用組成物から形成されるものであることで、薬物の分解が抑制されており、かつ、硬度の高いものである。例えば、本発明の製剤の製造方法で得られる製剤は、例えば、圧縮強度が２ＭＰａ以上になり得るものである。 The drug product obtained by the method for producing a drug product of the present invention is formed from the pharmaceutical composition obtained in step 1, so that the drug is inhibited from decomposing and has a high hardness. be. For example, a formulation obtained by the method for producing a formulation of the present invention can have a compressive strength of 2 MPa or more.
　また、製剤に含まれる活性成分の濃度も高いので、製剤として特に有効であり、例えば、少量の服用であっても活性成分の効能が発揮されやすい。 In addition, since the concentration of the active ingredient contained in the formulation is high, it is particularly effective as a formulation, and for example, even with a small dose, the efficacy of the active ingredient is likely to be exhibited.
　本開示に包含される発明を特定するにあたり、本開示の各実施形態で説明した各構成（性質、構造、機能等）は、どのように組み合わせられてもよい。すなわち、本開示には、本明細書に記載される組み合わせ可能な各構成のあらゆる組み合わせからなる主題が全て包含される。 In specifying the inventions included in the present disclosure, each configuration (property, structure, function, etc.) described in each embodiment of the present disclosure may be combined in any way. That is, the present disclosure encompasses all subject matter consisting of any combination of each of the combinable features described herein.
　以下、実施例により本発明をより具体的に説明するが、本発明はこれら実施例の態様に限定されるものではない。 The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the embodiments of these examples.
　（実施例１）
　活性成分としてアセトアミノフェン（Ｃｈｅｍｅｘｐｒｅｓｓ社製）と、結合剤としてポリエチレンオキシド（住友精化製，質量平均分子量１６０，３３５ｇ／ｍｏｌ）とを９２．５：７．５（活性成分：結合剤）の質量比で混合して混合物を調製した。この混合物に対して０．１％のアエロジル（エボニック社製）を添加し、ブレンダー（ミスギ社製、まぜまぜマンＳＫＨ－４０ＣＡ：０．７回転／秒）で１５０分以上混合処理をすることで、二軸押出用の原料を得た。 (Example 1)
Acetaminophen (manufactured by Chemexpress) as an active ingredient and polyethylene oxide (manufactured by Sumitomo Seika Chemicals, mass average molecular weight 160,335 g / mol) as a binder at a ratio of 92.5: 7.5 (active ingredient: binder) A mixture was prepared by mixing at a mass ratio. By adding 0.1% Aerosil (manufactured by Evonik) to this mixture and mixing for 150 minutes or more with a blender (manufactured by Misgi, Mazemazeman SKH-40CA: 0.7 rpm) , to obtain a raw material for twin-screw extrusion.
　得られた原料を、図２に示すスクリューを備えた二軸押出機（ＴＥＭ－１８ＳＳ－１０／２Ｖ：東芝機械）に重量式フィーダー（クボタ計装、型式ＣＥ－Ｗ－ＯＥ－ＭＰ）で１．８ｋｇ／ｈの供給量で投入し、加熱ゾーン１の温度を２５℃、加熱ゾーン２～５の温度を３０℃、スクリュー回転数２００ｒｐｍの条件下で造粒を行うことで造粒物を得た。使用した二軸押出機は１０個のバレルから構成され、一つのバレルの長さは７５ｍｍとした。図２に示すように、フィード口からの距離が０～７５ｍｍのエリアをゾーン０、７５～２２５ｍｍのエリアを加熱ゾーン１、２２５～３７５ｍｍのエリアを加熱ゾーン２、３７５～５２５ｍのエリアを加熱ゾーン３、５２５～６７５ｍｍのエリアを加熱ゾーン４、６７５～７５０ｍｍのエリアを加熱ゾーン５とし、加熱ゾーン毎に独立して加熱温度を制御した。なお、混練部は加熱ゾーン３及び加熱ゾーン４に位置する（図２の網掛け部分）。 The obtained raw material is fed to a twin-screw extruder (TEM-18SS-10/2V: Toshiba Machine) equipped with a screw shown in FIG. A granulated product is obtained by charging at a supply rate of 8 kg/h, granulating under conditions of a temperature of 25° C. in heating zone 1, a temperature of 30° C. in heating zones 2 to 5, and a screw rotation speed of 200 rpm. rice field. The twin-screw extruder used consisted of 10 barrels, each of which had a length of 75 mm. As shown in Fig. 2, the area from the feed port is zone 0, the area from 75 to 225 mm is heating zone 1, the area from 225 to 375 mm is heating zone 2, and the area from 375 to 525 mm is heating zone 0. 3. An area of 525 to 675 mm was designated as heating zone 4, and an area of 675 to 750 mm was designated as heating zone 5, and the heating temperature was controlled independently for each heating zone. The kneading section is located in the heating zone 3 and the heating zone 4 (shaded area in FIG. 2).
　得られた造粒物をフードプロセッサー（ＺＯＪＩＲＵＳＨＩ、型式ＢＭ－ＲＴ０８）で粉砕し（１０秒／回×３回）、３２メッシュ（目開き５００μｍ）の篩で粗紛を除去することで造粒物からなる製剤用組成物を得た。 The obtained granules were pulverized with a food processor (ZOJIRUSHI, model BM-RT08) (10 seconds/time × 3 times), and coarse powder was removed with a 32-mesh (500 µm mesh) sieve to obtain granules. A pharmaceutical composition consisting of was obtained.
　（実施例２）
　加熱ゾーン２～５の温度を４０℃に変更したこと以外は実施例１と同様の方法で製剤用組成物を得た。 (Example 2)
A pharmaceutical composition was obtained in the same manner as in Example 1, except that the temperature of heating zones 2 to 5 was changed to 40°C.
　（実施例３）
　加熱ゾーン２～５の温度を５０℃に変更したこと以外は実施例１と同様の方法で製剤用組成物を得た。 (Example 3)
A pharmaceutical composition was obtained in the same manner as in Example 1, except that the temperature of heating zones 2 to 5 was changed to 50°C.
　（実施例４）
　加熱ゾーン２～５の温度を１３０℃に変更したこと以外は実施例１と同様の方法で製剤用組成物を得た。 (Example 4)
A pharmaceutical composition was obtained in the same manner as in Example 1, except that the temperature of heating zones 2 to 5 was changed to 130°C.
　（実施例５）
　結合剤をヒドロキシプロピルセルロース（Ｓｉｇｍａ－Ａｌｄｒｉｃｈ製、質量平均分子量６１，３３４）に変更し、加熱ゾーン２～５の温度を１００℃に変更したこと以外は実施例１と同様の方法で製剤用組成物を得た。 (Example 5)
A pharmaceutical composition was prepared in the same manner as in Example 1 except that the binder was changed to hydroxypropylcellulose (manufactured by Sigma-Aldrich, mass average molecular weight 61,334) and the temperature of heating zones 2 to 5 was changed to 100 ° C. got stuff
　（実施例６）
　加熱ゾーン２～５の温度を１２０℃に変更したこと以外は実施例５と同様の方法で製剤用組成物を得た。 (Example 6)
A pharmaceutical composition was obtained in the same manner as in Example 5, except that the temperature of heating zones 2 to 5 was changed to 120°C.
　（実施例７）
　結合剤をポリエチレンオキシド（住友精化製，質量平均分子量１０５，２１６）に変更したこと以外は実施例１と同様の方法で製剤用組成物を得た。 (Example 7)
A pharmaceutical composition was obtained in the same manner as in Example 1, except that the binder was changed to polyethylene oxide (manufactured by Sumitomo Seika, mass average molecular weight: 105,216).
　（実施例８）
　結合剤をポリエチレンオキシド（住友精化製，質量平均分子量８２０，９１３）に変更したこと以外は実施例１と同様の方法で製剤用組成物を得た。 (Example 8)
A pharmaceutical composition was obtained in the same manner as in Example 1, except that the binder was changed to polyethylene oxide (manufactured by Sumitomo Seika, mass average molecular weight: 820,913).
　（比較例１）
　結合剤をポリエチレンオキシド（住友精化製，質量平均分子量１，０５７，０１７）に変更したこと以外は実施例１と同様の方法で製剤用組成物を得た。 (Comparative example 1)
A pharmaceutical composition was obtained in the same manner as in Example 1, except that the binder was changed to polyethylene oxide (manufactured by Sumitomo Seika, mass average molecular weight: 1,057,017).
　（比較例２）
　活性成分と結合剤との質量比を７０：３０（活性成分：結合剤）に変更したこと以外は実施例１と同様の方法で製剤用組成物を得た。 (Comparative example 2)
A pharmaceutical composition was obtained in the same manner as in Example 1, except that the mass ratio of the active ingredient and the binder was changed to 70:30 (active ingredient:binder).
　（比較例３）
　加熱ゾーン２～５の温度を１４０℃に変更したこと以外は実施例１と同様の方法で製剤用組成物を得た。 (Comparative Example 3)
A pharmaceutical composition was obtained in the same manner as in Example 1, except that the temperature of heating zones 2 to 5 was changed to 140°C.
　（比較例４）
　加熱ゾーン２～５の温度を１６０℃に変更したこと以外は実施例１と同様の方法で製剤用組成物を得た。 (Comparative Example 4)
A pharmaceutical composition was obtained in the same manner as in Example 1, except that the temperature of heating zones 2 to 5 was changed to 160°C.
　（評価方法）
　＜製剤の硬度測定＞
　製剤の硬度は、錠剤の圧縮強度を測定することで評価した。具体的には、各実施例及び比較例で得られた製剤用組成物（造粒物）を５００ｍｇ分取し、打錠機（島津製オートグラフＡＧＳ－Ｊ）により、打錠圧１０ｋＮでの条件で平型（１０．７ｍｍφ、平錠）のタブレットを作製した。タブレットの厚みはシックネスゲージ（テクロック）で測定した。このタブレットを錠剤として、硬度計（ＥＲＷＥＫＡ製錠剤硬度計ＴＢＨ３２５）を用いて感度１０Ｎ、測定速度２．３ｍｍ／ｓ、測定圧力２０Ｎ／ｓ、測定モードＳｐｅｅｄの条件で測定した。この測定で計測された硬度を以下の式より圧縮強度に換算した。 (Evaluation method)
<Measurement of hardness of formulation>
The hardness of the formulation was evaluated by measuring the compressive strength of the tablets. Specifically, 500 mg of the pharmaceutical composition (granules) obtained in each of Examples and Comparative Examples was taken, and a tableting machine (Shimadzu Autograph AGS-J) was used to compress the tablet at a tableting pressure of 10 kN. A flat tablet (10.7 mmφ, flat tablet) was produced under the conditions. The thickness of the tablet was measured with a thickness gauge (Tekclock). Using this tablet as a tablet, the hardness was measured using a hardness tester (TBH325 tablet hardness tester manufactured by ERWEKA) under the conditions of a sensitivity of 10 N, a measurement speed of 2.3 mm/s, a measurement pressure of 20 N/s, and a measurement mode of Speed. The hardness measured in this measurement was converted to compressive strength using the following formula.
Figure JPOXMLDOC01-appb-M000001
Figure JPOXMLDOC01-appb-M000001
　＜ポリエチレンオキシドの質量平均分子量測定＞
　ポリエチレンオキシドの質量平均分子量をゲル浸透クロマトグラフィーによって測定した。具体的に、ポリエチレンオキシド０．０２ｇを０．１９Ｍ硝酸ナトリウム水溶液４０ｍＬに加えて３時間かけて溶解させた溶液を、０．８μｍのメンブレンフィルターを用いてろ過し、得られたろ液をゲル浸透クロマトグラフィー（東ソー株式会社製「ＨＬＣ－８２２０ＧＰＣ」、ガードカラム：ＴＳＫｇｅｌ　ｇｕａｒｄｃｏｌｕｍｎ　ＰＷＸＬ）により測定した。この測定では、サイズ排除カラムをＴＳＫｇｅｌ　Ｇ６０００ＰＷＸＬ、ＴＳＫｇｅｌ　ＧＭＰＷＸＬ及びＴＳＫｇｅｌ　Ｇ３０００ＰＷＸＬとし、移動相を０．２０Ｍ硝酸ナトリウム水溶液、流速を０．５ｍＬ／ｍｉｎ、カラム温度を４０℃、示差屈折率計温度を４０℃、インジェクション量を５００μＬ、測定時間を９０分間とした。これとは別に、質量平均分子量が既知のポリエチレンオキシド標準試料を用いて同様に測定して検量線を作成し、この検量線に基づいてポリエチレンオキシドの質量平均分子量を算出した。 <Measurement of mass average molecular weight of polyethylene oxide>
The weight average molecular weight of polyethylene oxide was determined by gel permeation chromatography. Specifically, 0.02 g of polyethylene oxide was added to 40 mL of 0.19 M sodium nitrate aqueous solution and dissolved over 3 hours. The solution was filtered using a 0.8 μm membrane filter, and the obtained filtrate was subjected to gel permeation chromatography It was measured by lithography (“HLC-8220GPC” manufactured by Tosoh Corporation, guard column: TSKgel guardcolumn PWXL). In this measurement, size exclusion columns were TSKgel G6000PWXL, TSKgel GMPWXL and TSKgel G3000PWXL, the mobile phase was 0.20 M sodium nitrate aqueous solution, the flow rate was 0.5 mL/min, the column temperature was 40°C, and the differential refractometer temperature was 40°C. , the injection amount was 500 μL, and the measurement time was 90 minutes. Separately, a standard sample of polyethylene oxide having a known mass average molecular weight was measured in the same manner to prepare a calibration curve, and the mass average molecular weight of polyethylene oxide was calculated based on this calibration curve.
　＜造粒性＞
　造粒性は目視により判断した。具体的に、各実施例で得られた製剤用組成物を目視し、過剰造粒が見られたもの（すなわち、塊状物質であって粉砕も困難であったもの）、及び、粉体のままであったものは造粒不可であると判断し、それ以外を造粒可能と判断した。造粒可能と判断した場合を「〇」、造粒不可であると判断した場合を「×」とした。 <Granulation>
The granulation property was judged by visual observation. Specifically, the pharmaceutical composition obtained in each example was visually observed, and excessive granulation was observed (that is, a lumpy substance that was difficult to pulverize), and powder as it was It was judged that granulation was not possible for those with , and it was judged that granulation was possible for the others. When it was determined that granulation was possible, it was rated as "O", and when it was determined that granulation was impossible, it was rated as "x".
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　表１には、各実施例及び比較例で製造した製剤用組成物の製造条件（活性成分及び結合剤の配合割合並びに各加熱ゾーンの温度）を示すと共に、製剤用組成物の造粒性及び製剤用組成物から得られた錠剤の圧縮強度の評価結果を示している。 Table 1 shows the manufacturing conditions (mixing ratio of active ingredient and binder and temperature of each heating zone) of the pharmaceutical composition manufactured in each example and comparative example, and also shows the granulation properties of the pharmaceutical composition and the 1 shows the evaluation results of compression strength of tablets obtained from pharmaceutical compositions.
　表１の結果から、バレル内の温度が１３０℃以下であり、結合剤の質量平均分子量が１００００００ｇ／ｍｏｌ以下であり、前記活性成分及び前記結合剤の全質量に対して前記活性成分を８０質量％以上含む混合物を原料として使用した場合は、製剤用組成物は造粒性に優れるものであり、かつ、硬度が高い製剤を得ることができた。 From the results in Table 1, the temperature in the barrel is 130° C. or less, the weight average molecular weight of the binder is 1000000 g/mol or less, and the active ingredient is 80 masses based on the total mass of the active ingredient and the binder. % or more was used as a raw material, the composition for formulation was excellent in granulation properties and a formulation with high hardness could be obtained.

Claims (5)

  1. 二軸押出法により、活性成分と結合剤とを含む混合物をバレル内で混練して造粒する工程１を具備し、
    前記バレル内の温度が１３０℃以下であり、
    前記結合剤の質量平均分子量が１００００００ｇ／ｍｏｌ以下であり、
    前記混合物は、前記活性成分及び前記結合剤の全質量に対して前記活性成分を８０質量％以上含む、製剤用組成物の製造方法。     A step 1 of kneading and granulating a mixture containing an active ingredient and a binder in a barrel by a twin-screw extrusion method,
    The temperature in the barrel is 130° C. or less,
    The weight average molecular weight of the binder is 1000000 g/mol or less,
    A method for producing a pharmaceutical composition, wherein the mixture contains 80% by mass or more of the active ingredient relative to the total mass of the active ingredient and the binder.
  2. 前記結合剤は水溶性高分子である、請求項１に記載の製剤用組成物の製造方法。 2. The method for producing a pharmaceutical composition according to claim 1, wherein the binder is a water-soluble polymer.
  3. 前記結合剤はポリエチレンオキシド、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、ポリメタクリレート、Ｎ－ビニルピロリドンと酢酸ビニルのコポリマー、及び、Ｎ－ビニルカプロラクタムと酢酸ビニルとエチレングリコールとのコポリマーからなる群より選ばれる少なくとも１種である、請求項１に記載の製剤用組成物の製造方法。 The binder is selected from the group consisting of polyethylene oxide, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polymethacrylate, copolymers of N-vinylpyrrolidone and vinyl acetate, and copolymers of N-vinylcaprolactam, vinyl acetate and ethylene glycol. The method for producing a pharmaceutical composition according to claim 1, wherein at least one is selected.
  4. 前記結合剤は、質量平均分子量が５００００ｇ／ｍｏｌ以上、１００００００ｇ／ｍｏｌ以下であるポリエチレンオキシドである、請求項１に記載の製剤用組成物の製造方法。 2. The method for producing a pharmaceutical composition according to claim 1, wherein the binder is polyethylene oxide having a mass average molecular weight of 50000 g/mol or more and 1000000 g/mol or less.
  5. 請求項１～４に記載の製剤用組成物の製造方法を含む、製剤の製造方法であって、
    前記工程１で得られた製剤用組成物から製剤を得る工程２を含む、製剤の製造方法。     A method for producing a formulation, comprising the method for producing the pharmaceutical composition according to claims 1 to 4,
    A method for producing a formulation, comprising Step 2 of obtaining a formulation from the pharmaceutical composition obtained in Step 1 above.
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Publication number Priority date Publication date Assignee Title
JP2004524300A (en) * 2001-01-30 2004-08-12 スミスクライン　ビーチャム　パブリック　リミテッド　カンパニー Pharmaceutical prescription
WO2007072908A1 (en) * 2005-12-22 2007-06-28 Otsuka Pharmaceutical Co., Ltd. Method of producing drug-containing wax matrix particles, extruder to be used in the method and sustained-release preparation containing cilostazol
JP2008540540A (en) * 2005-05-10 2008-11-20 ノバルティス アクチエンゲゼルシャフト Method for producing a composition having a therapeutic compound with poor compressibility
JP2015500273A (en) * 2011-12-09 2015-01-05 パーデュー、ファーマ、リミテッド、パートナーシップ Pharmaceutical dosage forms comprising poly (epsilon-caprolactone) and polyethylene oxide
JP2016511223A (en) * 2012-12-21 2016-04-14 サノフイ Fexofenadine-rich solid unit and process for producing the same
JP2018507180A (en) * 2015-01-06 2018-03-15 プロキャプス エスエイエス Dosage form containing solid solution of amorphous drug (DOSAGE FORM INCORPORATION AN AMORPHOUSE DRUG SOLID SOLUTION)

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004524300A (en) * 2001-01-30 2004-08-12 スミスクライン　ビーチャム　パブリック　リミテッド　カンパニー Pharmaceutical prescription
JP2008540540A (en) * 2005-05-10 2008-11-20 ノバルティス アクチエンゲゼルシャフト Method for producing a composition having a therapeutic compound with poor compressibility
WO2007072908A1 (en) * 2005-12-22 2007-06-28 Otsuka Pharmaceutical Co., Ltd. Method of producing drug-containing wax matrix particles, extruder to be used in the method and sustained-release preparation containing cilostazol
JP2015500273A (en) * 2011-12-09 2015-01-05 パーデュー、ファーマ、リミテッド、パートナーシップ Pharmaceutical dosage forms comprising poly (epsilon-caprolactone) and polyethylene oxide
JP2016511223A (en) * 2012-12-21 2016-04-14 サノフイ Fexofenadine-rich solid unit and process for producing the same
JP2018507180A (en) * 2015-01-06 2018-03-15 プロキャプス エスエイエス Dosage form containing solid solution of amorphous drug (DOSAGE FORM INCORPORATION AN AMORPHOUSE DRUG SOLID SOLUTION)

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