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WO2023145871A1 - Procédé de fabrication de composition pour préparation pharmaceutique, et procédé de fabrication de préparation pharmaceutique - Google Patents

Procédé de fabrication de composition pour préparation pharmaceutique, et procédé de fabrication de préparation pharmaceutique Download PDF

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Publication number
WO2023145871A1
WO2023145871A1 PCT/JP2023/002614 JP2023002614W WO2023145871A1 WO 2023145871 A1 WO2023145871 A1 WO 2023145871A1 JP 2023002614 W JP2023002614 W JP 2023002614W WO 2023145871 A1 WO2023145871 A1 WO 2023145871A1
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WIPO (PCT)
Prior art keywords
binder
filler
mass
pharmaceutical composition
formulation
Prior art date
Application number
PCT/JP2023/002614
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English (en)
Japanese (ja)
Inventor
元晴 藤崎
彰 木村
Original Assignee
住友精化株式会社
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Filing date
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Publication of WO2023145871A1 publication Critical patent/WO2023145871A1/fr

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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 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 found that the above object can be achieved by adjusting the temperature conditions of twin-screw extrusion and the type and use ratio of the binder, and 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 a filler, an active ingredient and a binder in a barrel by a twin-screw extrusion method, The temperature in the barrel is 140° C.
  • the weight average molecular weight of the binder is 1000000 g/mol or less
  • the mixture contains the filler and the active ingredient in a ratio of 80% by mass or more and 95% by mass or less with respect to the total mass of the filler, the active ingredient and the binder,
  • a method for producing a pharmaceutical composition wherein the content of the filler is 1 to 94% by mass with respect to the total mass of the filler, 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 the pharmaceutical composition according to any one of Items 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 decomposition of the drug during production is suppressed, the granulation property is excellent, and the drug concentration can be widely adjusted.
  • 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 the method for producing a 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.
  • Method for producing a pharmaceutical composition comprises a step 1 of kneading and granulating a mixture containing a filler, an active ingredient and a binder in a barrel by a twin-screw extrusion method. do.
  • the temperature in the barrel is 140° C.
  • the weight average molecular weight of the binder is 1000000 g/mol or less
  • the mixture comprises the filler, the active ingredient And with respect to the total mass of the binder, the filler and the active ingredient are contained in a ratio of 80% by mass or more and 95% by mass or less, and the content ratio of the filler is the ratio of the filler, the active ingredient, and the binder It is 1 to 94% by mass with respect to the total mass.
  • raw materials having a specific component ratio are mixed at a temperature in the barrel of 140° C. or less, so that decomposition of the drug as an active ingredient is suppressed and granulation is facilitated. It is possible to obtain a pharmaceutical composition excellent in the granulation property, and the granulation property is not impaired even when the drug concentration is varied widely.
  • tablets prepared using the pharmaceutical composition obtained by the method for producing the pharmaceutical composition of the present invention have high hardness even when the drug concentration is varied widely. Therefore, the composition obtained by the method for producing a pharmaceutical composition of the present invention is suitable as a raw material for producing a pharmaceutical composition with high hardness.
  • a mixture containing a filler, an active ingredient, and a binder can be used as raw materials.
  • the type of filler is not particularly limited, and for example, a wide range of pharmaceutically acceptable fillers used in formulations can be cited.
  • fillers include granulated sugar, dextrate, dextrin, dextrose, lactose, lactose monohydrate, mannitol, microcrystalline cellulose, sorbitol, sucrose, talc, and inorganic salts.
  • inorganic salts include alkali metal salts such as sodium chloride.
  • the filler preferably has a melting point equal to or higher than the temperature of the binder, and particularly preferably sodium chloride lactose monohydrate.
  • 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 mass 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 (140° 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, granules (particles) with excellent moldability are easily obtained even when kneading at a lower temperature. Easy to prepare formulations.
  • 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 filler contained in the raw material used in the present invention can be of one type, or can be of two or more types.
  • the ingredients used in the present invention may contain one active ingredient, or two or more active ingredients.
  • the binder contained in the raw material used in the present invention can be of one type, or can be of two or more types.
  • the raw materials used in the method for producing the pharmaceutical composition of the present invention may contain other ingredients as long as they contain a mixture of the filler, the active ingredient and the binder. It is also possible to consist only of said mixture (ie said filler, said active ingredient and said binder).
  • examples of such other components include various additives contained in known formulations. Examples of such additives include 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 mass or more and 95% by mass or less of the filler and the active ingredient with respect to the total mass of the filler, the active ingredient, and the binder (that is, the mixture contains the 5% by weight or more and 20% by weight or less of said binder based on the total weight of filler, said active ingredient and said binder).
  • the content of the binder in the mixture exceeds 20% by mass with respect to the total mass of the filler, the active ingredient and the binder, it becomes difficult to form a formulation from the pharmaceutical composition. However, even if it can be formulated, it is difficult to have a high hardness.
  • the content of the binder in the mixture is preferably 7.5% by mass or more with respect to the total mass of the filler, the active ingredient and the binder. more preferred.
  • the total mass of the filler and the active ingredient is more preferably 85% by mass or more with respect to the total mass of the filler, the active ingredient and the binder. Further, in the mixture, the total mass of the filler and the active ingredient is more preferably 92.5% by mass or less with respect to the total mass of the filler, the active ingredient and the binder.
  • the content ratio of the filler is 1 to 94% by mass with respect to the total mass of the filler, active ingredient, and binder. This facilitates the production of a pharmaceutical composition, facilitates the preparation of a highly rigid formulation, and does not impair the granulation properties and the hardness of the formulation even when the drug concentration is varied over a wide range.
  • the content of the filler is preferably 22.5% by mass or more and preferably 91.5% by mass or less with respect to the total mass of the filler, active ingredient and binder.
  • 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 a filler, an active ingredient, and a binder in predetermined proportions.
  • ingredients other than fillers, active ingredients and binders can be mixed with the raw materials, if desired.
  • 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 140°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.
  • 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.
  • polyalkylene oxide or hydroxyalkyl cellulose especially polyethylene oxide or hydroxypropyl cellulose
  • granulation is excellent even at 100°C or less, and it is possible to prepare a formulation with higher hardness. becomes. Since a plurality of barrels are usually used, the temperature inside all the barrels is set to 140° C. or lower in the present invention.
  • 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).
  • a granule containing a filler, an active ingredient and a binder can be obtained by twin-screw extruding the raw material containing the mixture.
  • 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 a filler, an active ingredient, and a binder. Consists only of things.
  • the granules may consist only of a filler, an active ingredient and a binder, or may contain ingredients other than the active ingredient and the binder, such as the additives described above.
  • the granules contain 80% by mass or more and 95% by mass or less of the filler and the active ingredient with respect to the total mass of the filler, the active ingredient and the binder (that is, the granules contain the 5 mass % or more and 20 mass % or less of said binder based on the total mass of filler, said active ingredient and said binder). This facilitates the production of the pharmaceutical composition, and facilitates the preparation of a highly rigid formulation. In the granules, if the content of the binder exceeds 20% by mass with respect to the total mass of the filler, the active ingredient and the binder, it becomes difficult to form a formulation from the pharmaceutical composition.
  • the problem of partial chipping of the tablet tends to occur, and even if it can be formulated, it is difficult to have high hardness.
  • the content of the binder in the granules is 7.5% by mass with respect to the total mass of the filler, the active ingredient and the binder. It is more preferable to be above.
  • the granules more preferably contain 85% by mass or more of the filler and the active ingredient with respect to the total mass of the filler, the active ingredient and the binder. Further, it is more preferable that the granules contain the filler and the active ingredient at a ratio of 92.5% by mass or less with respect to the total mass of the filler, the active ingredient and the binder.
  • the content ratio of the filler is 1 to 94% by mass with respect to the total mass of the filler, active ingredient, and binder. This facilitates the production of the pharmaceutical composition, facilitates the preparation of a highly rigid formulation, and prevents the granulation and hardness of the formulation from being impaired even when the drug concentration is varied widely.
  • the content of the filler is preferably 22.5% by mass or more and preferably 91.5% by mass or less with respect to the total mass of the filler, active ingredient and binder.
  • 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.
  • concentration of the active ingredient contained in the formulation can be adjusted over a wide range, it is particularly effective as a formulation.
  • 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 In a 20 L drum can, acetaminophen (manufactured by Chemexpress) as an active ingredient, sodium chloride (manufactured by Nacalai Tesque) as a filler, and polyethylene oxide (manufactured by Sumitomo Seika Chemicals, mass average molecular weight 160,335 g / mol) as a binder. were mixed in a weight ratio of 10:82.5:7.5 (active:filler:binder) to prepare a mixture.
  • acetaminophen manufactured by Chemexpress
  • sodium chloride manufactured by Nacalai Tesque
  • polyethylene oxide manufactured by Sumitomo Seika Chemicals, mass average molecular weight 160,335 g / mol
  • 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 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 6 A pharmaceutical composition was prepared in the same manner as in Example 2 except that the mass ratio of the active ingredient, filler, and binder was changed to 1:91.5:7.5 (active ingredient: filler: binder). got
  • Example 7 A pharmaceutical composition was prepared in the same manner as in Example 1, except that the mass ratio of the active ingredient, filler, and binder was changed to 70:22.5:7.5 (active ingredient: filler: binder). got
  • Example 8 A pharmaceutical composition was obtained 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).
  • Example 9 A pharmaceutical composition was obtained in the same manner as in Example 8, except that the temperature of heating zones 2 to 5 was changed to 80°C.
  • Example 10 A pharmaceutical composition was obtained in the same manner as in Example 8, except that the temperature of heating zones 2 to 5 was changed to 100°C.
  • Example 11 A pharmaceutical composition was obtained in the same manner as in Example 8, except that the temperature of heating zones 2 to 5 was changed to 120°C.
  • Example 12 A pharmaceutical composition was obtained in the same manner as in Example 8, except that the temperature of heating zones 2 to 5 was changed to 130°C.
  • Example 13 A pharmaceutical composition was prepared 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) and the temperature of heating zones 2 to 5 was changed to 60 ° C. Obtained.
  • Example 14 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).
  • Example 15 A pharmaceutical composition was obtained in the same manner as in Example 1, except that the filler component was changed to lactose monohydrate (manufactured by Fujifilm Wako Pure Chemical Industries).
  • Comparative example 1 A pharmaceutical composition was obtained in the same manner as in Comparative Example 1, except that the mass ratio of the active ingredient, filler, and binder was changed to 10:60:30 (active ingredient:filler:binder).
  • 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).
  • 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 150°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 140° C. or less
  • the weight average molecular weight of the binder is 1000000 g/mol or less
  • the filler and The active ingredient contains the filler and the active ingredient at a ratio of 80% by mass or more and 95% by mass or less, and the content ratio of the filler is 1 to 1 with respect to the total mass of the filler, the active ingredient, and the binder.
  • the composition for pharmaceutical formulation was excellent in granulation properties and a formulation with high hardness could be obtained.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention fournit un procédé de fabrication de composition pour préparation pharmaceutique et un procédé de fabrication de préparation pharmaceutique selon lesquels la dégradation de médicament lors de la fabrication est inhibée, et une préparation pharmaceutique dotée d'excellentes propriétés de granulation et d'une dureté élevée, peut être facilement obtenue.　Le procédé de fabrication de composition pour préparation pharmaceutique de l'invention comporte une étape (1) au cours de laquelle un mélange contenant une charge, un principe actif et un agent de liaison, est malaxé à l'intérieur d'un cylindre selon un procédé d'extrusion à double vis, et soumis à une granulation, la température à l'intérieur dudit cylindre étant inférieure ou égale à 140°C, et la masse moléculaire moyenne en poids dudit agent de liaison étant inférieure ou égale à １００００００ｇ／ｍｏｌe. Ledit mélange contient, selon une proportion de 80% en masse ou plus à 95% en masse ou moins ladite charge et ledit principe actif pour la masse totale de ladite charge, dudit principe actif et dudit agent de liaison. La proportion de teneur en charge est comprise entre 1 et 94% en masse pour la masse totale de ladite charge, dudit principe actif et dudit agent de liaison.
PCT/JP2023/002614 2022-01-31 2023-01-27 Procédé de fabrication de composition pour préparation pharmaceutique, et procédé de fabrication de préparation pharmaceutique WO2023145871A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004524300A (ja) * 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 医薬処方
WO2007072908A1 (fr) * 2005-12-22 2007-06-28 Otsuka Pharmaceutical Co., Ltd. Méthode pour produire des particules à matrice de cire contenant un médicament, extrudeuse à utiliser dans ladite méthode et préparation à libération prolongée contenant du cilostazol
JP2008540540A (ja) * 2005-05-10 2008-11-20 ノバルティス アクチエンゲゼルシャフト 圧縮性に乏しい治療用化合物を有する組成物の製造法
JP2015500273A (ja) * 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 ポリ（イプシロン−カプロラクトン）およびポリエチレンオキシドを含む医薬剤形
JP2016511223A (ja) * 2012-12-21 2016-04-14 サノフイ フェキソフェナジン高含有固形単位およびその製造法
JP2018507180A (ja) * 2015-01-06 2018-03-15 プロキャプス エスエイエス 非晶質薬物の固溶体を含む剤型（ｄｏｓａｇｅ ｆｏｒｍ ｉｎｃｏｒｐｏｒａｔｉｎｇ ａｎ ａｍｏｒｐｈｏｕｓ ｄｒｕｇ ｓｏｌｉｄ ｓｏｌｕｔｉｏｎ）

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004524300A (ja) * 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 医薬処方
JP2008540540A (ja) * 2005-05-10 2008-11-20 ノバルティス アクチエンゲゼルシャフト 圧縮性に乏しい治療用化合物を有する組成物の製造法
WO2007072908A1 (fr) * 2005-12-22 2007-06-28 Otsuka Pharmaceutical Co., Ltd. Méthode pour produire des particules à matrice de cire contenant un médicament, extrudeuse à utiliser dans ladite méthode et préparation à libération prolongée contenant du cilostazol
JP2015500273A (ja) * 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 ポリ（イプシロン−カプロラクトン）およびポリエチレンオキシドを含む医薬剤形
JP2016511223A (ja) * 2012-12-21 2016-04-14 サノフイ フェキソフェナジン高含有固形単位およびその製造法
JP2018507180A (ja) * 2015-01-06 2018-03-15 プロキャプス エスエイエス 非晶質薬物の固溶体を含む剤型（ｄｏｓａｇｅ ｆｏｒｍ ｉｎｃｏｒｐｏｒａｔｉｎｇ ａｎ ａｍｏｒｐｈｏｕｓ ｄｒｕｇ ｓｏｌｉｄ ｓｏｌｕｔｉｏｎ）

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