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WO2024225348A1 - Matériau granulé et son procédé de production, composition granulée et composition pour préparations - Google Patents

Matériau granulé et son procédé de production, composition granulée et composition pour préparations Download PDF

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Publication number
WO2024225348A1
WO2024225348A1 PCT/JP2024/016156 JP2024016156W WO2024225348A1 WO 2024225348 A1 WO2024225348 A1 WO 2024225348A1 JP 2024016156 W JP2024016156 W JP 2024016156W WO 2024225348 A1 WO2024225348 A1 WO 2024225348A1
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excipient
binder
granulated
polyethylene oxide
composition
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PCT/JP2024/016156
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English (en)
Japanese (ja)
Inventor
智貴 井上
元晴 藤崎
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住友精化株式会社
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Publication of WO2024225348A1 publication Critical patent/WO2024225348A1/fr

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  • the present invention relates to a granulated product and a method for producing the same, a granulated composition, and a pharmaceutical composition.
  • preparations such as controlled release preparations that release drugs can be obtained by various methods.
  • a method is known in which raw materials containing excipients, binders, and various other components added as necessary are mixed and prepared, the mixture obtained is granulated to form particles (granulated material), and the granulated material is then used to tablet the desired shape to obtain the preparation.
  • Methods for obtaining the above-mentioned granulated material include wet granulation and dry granulation.
  • Dry granulation is advantageous in that it can granulate without using organic solvents as in wet granulation and therefore has a small environmental impact.
  • dry granulation methods using a dry compression granulator (roller compactor) and a twin-screw extruder are known. In the former case, a large amount of fine powder is likely to be generated, so in this respect, a granulation method using a twin-screw extruder is advantageous.
  • Patent Document 1 proposes a method of kneading and granulating raw materials containing an active ingredient and a binder in a twin-screw extruder.
  • the present invention has been made in view of the above, and aims to provide a granulated material that is suitable for producing a formulation with excellent dimensional stability and also has excellent granulation properties, a method for producing the same, a granulated composition, and a composition for use in a formulation.
  • the present invention encompasses, for example, the subject matter described in the following paragraphs.
  • Item 1 A granulation comprising an excipient and a binder, The passing rate through a 5 mesh (opening 4000 ⁇ m) sieve is 100%, The excipient contains polyethylene oxide having a 2% aqueous solution viscosity of 200 mPa s or more, The melting start temperature T2 (°C) of the binder; A granulated product, wherein the difference T2-T1 from the melting onset temperature T1 (°C) of the excipient is 0.5 or less.
  • the granule further contains an active ingredient, Item 2.
  • Item 3 Item 2. The granule according to item 1, wherein the granule does not contain an active ingredient.
  • Item 4 Item 4.
  • a granulated composition comprising the granulated material according to any one of Items 1 to 3.
  • Item 5 Item 5.
  • a pharmaceutical composition comprising the granulation composition according to item 4.
  • the osmotic pump preparation comprises a core portion formed by laminating the drug layer and the pump layer.
  • the method includes a step of kneading and granulating a mixture containing an excipient and a binder in a barrel by a twin-screw extrusion method,
  • the excipient contains polyethylene oxide having a 2% aqueous solution viscosity of 200 mPa s or more,
  • the melting start temperature T1 (°C) of the excipient The temperature T3 (°C) inside the barrel;
  • Item 7-1 A method for producing a granulated product according to any one of items 1 to 3, The method includes a step of kneading and granulating a mixture containing an excipient and a binder in a barrel by a twin-screw extrusion method,
  • the excipient contains polyethylene oxide having a 2% aqueous solution viscosity of 200 mPa s or more,
  • the melting start temperature T1 (°C) of the excipient The temperature T3 (°C) inside the barrel;
  • the granulated material of the present invention is suitable for producing a preparation with excellent dimensional stability, and also has excellent granulation properties.
  • FIG. 1 is a cross-sectional view showing an outline of one embodiment of an osmotic pump formulation.
  • FIG. 2 is a schematic diagram showing an example of a screw used in the production of the pharmaceutical composition of the present invention.
  • FIG. 2 is a schematic diagram showing an example of a screw used in the examples.
  • the upper or lower limit of a certain numerical range can be arbitrarily combined with the upper or lower limit of a numerical range of another stage.
  • the upper or lower limit of the numerical range may be replaced with a value shown in an example or a value that can be unambiguously derived from an example.
  • a numerical value connected with " ⁇ " means a numerical range that includes the numerical values before and after " ⁇ " as the upper and lower limits.
  • Granules The granules of the present invention contain an excipient and a binder, The passing rate through a 5 mesh (opening 4000 ⁇ m) sieve is 100%, The excipient contains polyethylene oxide having a 2% aqueous solution viscosity of 200 mPa s or more, The melting start temperature T2 (°C) of the binder; The difference between the melting start temperature T1 (° C.) of the excipient, T2-T1, is 0.5 or less.
  • the granulated material of the present invention is suitable for producing preparations with excellent dimensional stability, and also has excellent granulation properties. For this reason, the granulated material of the present invention is suitable as a raw material for preparing various preparations, such as tablets and osmotic pump-type preparations described below.
  • a granulated material having excellent granulation properties means that the passing rate of the granulated material through a 5 mesh (mesh opening 4000 ⁇ m) sieve is 100% and that dusting is unlikely to occur. Whether dusting is unlikely to occur or not can be determined by the evaluation method described in the "Dust Evaluation" disclosed in the Examples.
  • 5 mesh (mesh opening 4000 ⁇ m) means that the sieve is 5 mesh and the opening of the sieve is 4000 ⁇ m.
  • the JIS standard sieve "STANDARD SIEVE" (mesh opening 4000 ⁇ m) manufactured by Seishin Enterprise Co., Ltd. can be used.
  • the granules of the present invention contain an active ingredient described below, the granules have excellent sustained release properties for the active ingredient.
  • the excipient contains polyethylene oxide having a 2% aqueous solution viscosity of 200 mPa ⁇ s or more. As in conventional preparations, the excipient is used for the purposes of imparting moldability to solid preparations, diluting them, etc.
  • the viscosity of a 2% aqueous solution of polyethylene oxide is less than 200 mPa ⁇ s, it may be difficult to obtain a granulated product. For example, even if granulation is achieved, it may be difficult to set the average particle size of the granulated product within the desired range, or lumps may be easily formed, resulting in a pass rate of less than 100% through a 5 mesh (4000 ⁇ m opening) sieve, making it difficult to produce the desired granulated product.
  • the viscosity of a 2% aqueous solution of polyethylene oxide is less than 200 mPa ⁇ s, even if granulation is achieved, it may be difficult to form a preparation with excellent dimensional stability, and it may also be difficult to control the dissolution rate of the active ingredient within the desired range.
  • the viscosity of a 2% aqueous solution of polyethylene oxide is preferably 1000 mPa ⁇ s or more, more preferably 2000 mPa ⁇ s or more, even more preferably 10000 mPa ⁇ s or more, even more preferably 20000 mPa ⁇ s or more, and particularly preferably 30000 mPa ⁇ s or more.
  • the viscosity of a 2% aqueous solution of polyethylene oxide is, for example, preferably 500,000 mPa ⁇ s or less, more preferably 400,000 mPa ⁇ s or less, even more preferably 300,000 mPa ⁇ s or less, and particularly preferably 200,000 mPa ⁇ s or less.
  • the viscosity of a 2% by weight aqueous solution of polyethylene oxide can be measured using a rotational viscometer ("RV DVII+" manufactured by BROOK FIELD).
  • the 2% by weight aqueous solution of polyethylene oxide used for measuring the viscosity can be prepared by the following procedure. First, 12 g of polyethylene oxide, 588 g of ion-exchanged water, and 125 ml of isopropyl alcohol are placed in a beaker and stirred for 3 hours at 60 rpm in a jar tester to prepare an aqueous solution (containing isopropyl alcohol).
  • the aqueous solution thus obtained is allowed to stand in a thermostatic water bath (25°C ⁇ 0.1) for 0.5 hours or more to obtain a 2% by weight aqueous solution of polyethylene oxide.
  • the viscosity of such an aqueous solution is measured by the rotational viscometer under conditions of 25°C.
  • the concentration "2%" in the "2% aqueous solution of polyethylene oxide” means the mass concentration (2% by weight) of polyethylene oxide relative to the total mass of water and polyethylene oxide, and for convenience in calculating this concentration, the content of isopropyl alcohol contained in the aqueous solution is not taken into account.
  • Polyethylene oxide is a polymer having at least structural units derived from ethylene oxide. Polyethylene oxide can also have structural units other than those derived from ethylene oxide. That is, polyethylene oxide can be either a homopolymer or a copolymer.
  • the method for producing polyethylene oxide is not particularly limited, and for example, known methods for producing polyethylene oxide can be widely adopted in the present invention.
  • polyethylene oxide can be obtained by a polymerization reaction of ethylene oxide in the presence of an alkali or metal catalyst.
  • the metal catalyst can be, for example, a wide variety of metal catalysts that have been conventionally used in the production of polyethylene oxide, and among these, an organic zinc catalyst is preferable.
  • the organic zinc catalyst can be obtained by a known production method, and among these, it is preferable to obtain it by a process in which an organic zinc compound is reacted with an aliphatic polyhydric alcohol and a monohydric alcohol to produce a particulate reaction product.
  • the amount of the metal catalyst used is also not particularly limited, and can be, for example, a catalytic amount.
  • the polymerization reaction of ethylene oxide can be carried out in a solvent.
  • a solvent can be a wide variety of solvents used in known methods for producing polyethylene oxide, including at least one hydrocarbon solvent selected from the group consisting of n-pentane, n-hexane, n-heptane, and cyclohexane.
  • n-Hexane or n-pentane is preferably used because it is industrially easily available, has a boiling point lower than the melting point of the resulting polyethylene oxide, and is easy to remove after the polymerization reaction.
  • a chain transfer agent can also be used in the polymerization reaction. There are no particular limitations on the temperature and other conditions for the polymerization reaction of alkylene oxide, and they can be the same as known conditions.
  • the shape of the polyethylene oxide is not particularly limited, and may be, for example, particulate, or may be in a shape other than particulate.
  • Polyethylene oxide may also be in various forms such as powder, granules, pellets, etc.
  • the particle size, bulk density, mass average molecular weight, etc. of the polyethylene oxide are not particularly limited, and can be set, for example, to the same range as the particle size, bulk density, etc. of polyethylene oxide particles used in conventional formulations.
  • the excipient contains the polyethylene oxide (i.e., polyethylene oxide having a 2% aqueous solution viscosity of 200 mPa ⁇ s or more), it may contain other components, and for example, known excipients may be used in combination with the polyethylene oxide.
  • the excipient may consist essentially of the polyethylene oxide, or may consist only of the polyethylene oxide.
  • the excipient may contain one or more of the polyethylene oxides.
  • the excipient melting start temperature T1 (°C) is not particularly limited as long as the aforementioned value of "T2 - T1" is 0.5 or less.
  • the excipient melting start temperature T1 is preferably 50°C or higher, more preferably 52°C or higher, even more preferably 53°C or higher, and particularly preferably 54°C or higher.
  • the excipient melting start temperature T1 is preferably 70°C or lower, more preferably 60°C or lower, even more preferably 59°C or lower, and particularly preferably 58°C or lower.
  • the melting onset temperature T1 can be measured by a differential scanning calorimeter (DSC). Specifically, an aluminum pan containing a sealed sample is placed in a thermal analysis device, and measurements are taken at a heating rate of 1°C/min starting at 30°C. The amount of heat absorbed is plotted against the measurement time, and the temperature is read when the slope of the tangent to the curve (hereinafter sometimes referred to as the DDSC value) exceeds 20 ⁇ W/min, and this temperature is taken as the melting onset temperature.
  • DSC differential scanning calorimeter
  • binder The type of binder is not particularly limited, and for example, binders used for preparing conventional preparations can be widely used. Such binders are preferably polymer components, and among them, water-soluble polymer compounds are more preferable.
  • water-soluble polymer compounds include polyethylene glycol, copolymers of ethylene glycol and propylene glycol, polyalkylene oxides (e.g., polyethylene oxide, polypropylene oxide), polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl acetate, copolymers of N-vinylcaprolactam, vinyl acetate and ethylene glycol, copolymers of N-vinylpyrrolidone and vinyl propionate, cellulose esters, cellulose ethers, hydroxyalkylcelluloses (e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose), cellulose phthalate, cellulose succinate, copolymers of ethylene oxide and propylene oxide, polyacryl
  • the water-soluble polymer compounds may be homopolymers or copolymers. In the case of a copolymer, examples include a random copolymer and a block copolymer (diblock copolymer, triblock copolymer, etc.).
  • the binder may be the same as or different from the excipient. If the binder is polyethylene oxide, it may have a different 2% aqueous solution viscosity from the polyethylene oxide of the excipient, and may have a 2% aqueous solution viscosity of less than 200 mPa ⁇ s.
  • the binder is preferably at least one selected from the group consisting of polyethylene glycol, copolymers of ethylene glycol and propylene glycol, polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polymethacrylate, copolymers of N-vinylpyrrolidone and vinyl acetate, and copolymers of N-vinylcaprolactam, vinyl acetate, and ethylene glycol.
  • the granules are more likely to be formed and have excellent granulation properties.
  • the weight average molecular weight of the binder is not particularly limited and can be, for example, 1,000 to 1,500,000 g/mol.
  • the polymer component contained in the binder can be one type or two or more types. Accordingly, the water-soluble polymer compound contained in the binder can also be one type or two or more types.
  • the binder may contain, for example, a known binder in addition to the polymer component.
  • the binder may consist essentially of the polymer component, or the binder may consist of the polymer component.
  • the binder can be produced by known methods or can be obtained commercially.
  • the binder's melting start temperature T2 (°C) is not particularly limited as long as the aforementioned value of "T2 - T1" is 0.5 or less.
  • the binder's melting start temperature T2 can be 60°C or less, preferably 55.5°C or less, more preferably 53°C or less, even more preferably 50°C or less, and particularly preferably 48°C or less.
  • the binder's melting start temperature T2 is preferably 20°C or more, more preferably 30°C or more, even more preferably 35°C or more, and particularly preferably 40°C or more.
  • the melting start temperature T2 of the binder can also be measured using a differential scanning calorimeter (DSC) in the same manner as described above.
  • DSC differential scanning calorimeter
  • the granulated product of the present invention contains at least a granulated product containing an excipient and a binder.
  • the difference "T2-T1" between the melting start temperature T2 (°C) of the binder and the melting start temperature T1 (°C) of the excipient is 0.5 or less. That is, the melting start temperature T2 of the binder is [the melting start temperature T1 of the excipient + 0.5] (°C) or less. It is more preferable that the melting start temperature T2 of the binder is equal to or less than said T1.
  • T2-T1 is preferably 0.3 or less, more preferably 0 or less, even more preferably -3 or less, and particularly preferably -5 or less.
  • the value of T2-T1 may be -80 or more, -70 or more, -60 or more, -50 or more, -40 or more, -30 or more, or -20 or more, and is preferably -17 or more.
  • the content ratio of the excipient and binder is not particularly limited.
  • the content ratio of the binder relative to the total mass of the excipient and binder is preferably 1 to 70 mass%, more preferably 3 to 60 mass%, and even more preferably 5 to 50 mass%.
  • the granulated material may contain ingredients other than the excipient and binder.
  • the content of the binder is preferably 5 to 15% by mass relative to the total mass of the granulated material.
  • the granulated material may further contain an active ingredient.
  • 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 the active ingredients of drugs such as medicines, quasi-drugs, and agricultural chemicals, i.e., medicinal ingredients, such as acetaminophen, which is used as an antipyretic or analgesic.
  • the active ingredient can be produced by a known method, or can be obtained from a commercially available product, etc.
  • the content of the binder is preferably 5 to 15% by mass based on the total mass of the excipient, the binder, and the active ingredient.
  • the desired granule is easily obtained, dusting is easily suppressed, and a formulation with excellent dimensional stability is easily formed.
  • one embodiment of the granule of the present invention further contains an active ingredient, and the content of the binder is 5 to 15% by mass based on the total mass of the excipient, the binder, and the active ingredient.
  • the content of the active ingredient is not particularly limited, and can be, for example, 5 to 90% by mass, preferably 8 to 85% by mass, based on the total mass of the excipient, binder, and active ingredient.
  • the active ingredient may be one type or two or more types.
  • the granulated product may be one that does not contain an active ingredient.
  • the granulated product of the present invention when preparing an osmotic pump-type formulation described below using the granulated product of the present invention, particularly when forming the pump layer, it is preferable that the granulated product of the present invention does not contain the active ingredient.
  • the granulated product may contain other ingredients in addition to the excipient, binder and active ingredient.
  • other ingredients include fillers, diluents, lubricants, dyes and pigments.
  • the content of other ingredients may be preferably 10% by mass or less, more preferably 5% by mass or less, even more preferably 1% by mass or less, and particularly preferably 0.5% by mass or less, based on the total mass of the granulated product.
  • the granulated material may consist only of the excipient and the binder, or the granulated material may consist only of the excipient, the binder, and the active ingredient.
  • the granulated material of the present invention has a passing rate of 100% through a 5 mesh sieve (mesh opening 4000 ⁇ m). If the granulated material does not have a passing rate of 100% through a 5 mesh sieve (mesh opening 4000 ⁇ m), it is difficult to prepare the desired formulation, and even if the formulation can be prepared, the dimensional stability is reduced and it is difficult to control the dissolution rate, which may result in poor sustained release properties.
  • Whether the passage rate of the granulated material through a 5 mesh (4000 ⁇ m mesh) sieve is 100% can be determined using a 5 mesh (4000 ⁇ m mesh) sieve. That is, if 50 g of the granulated material of the present invention is passed through a 5 mesh (4000 ⁇ m mesh) sieve and no granulated material remains on the sieve, it can be determined that the passage rate of the granulated material of the present invention through a 5 mesh (4000 ⁇ m mesh) sieve is 100%.
  • the granulated material of the present invention When passed through a 100 mesh (150 ⁇ m) sieve, it is preferable that 30% by mass or less of the granulated material passes through the 100 mesh (150 ⁇ m) sieve. In this case, the granulated material of the present invention has excellent granulation properties, is suppressed from dusting, and is likely to form a formulation with excellent dimensional stability.
  • the amount of granulated material that passes through the 100 mesh (150 ⁇ m) sieve may be 0% by mass.
  • the shape of the granulated material is not particularly limited, and may be, for example, a perfect sphere, an oval sphere, an irregular shape, or an aggregated particle formed by aggregating multiple particles.
  • a granulated composition can be prepared using the granulated product of the present invention.
  • the granulated composition can contain 50% by mass or more of the granulated product, preferably 80% by mass or more, more preferably 90% by mass or more, even more preferably 95% by mass or more, and particularly preferably 99% by mass or more.
  • the granulated composition can also consist of only the granulated product.
  • the granulation composition is suitable as a raw material for preparing various preparations, and therefore can be suitably used as a pharmaceutical composition.
  • the pharmaceutical composition contains the granulation composition, and therefore it is possible to produce a preparation having excellent dimensional stability and easy control of dissolution rate.
  • the formulation composition may contain only the granulation composition, or may contain additives as necessary.
  • additives include a wide range of known ingredients contained in formulations.
  • the method for preparing a formulation using the formulation composition is not particularly limited.
  • a formulation can be obtained by compressing the formulation composition.
  • the formulation is, for example, a tablet.
  • the dosage form of the preparation is not particularly limited, and examples include tablets and osmotic pump-type preparations described below.
  • an osmotic pump formulation When an osmotic pump formulation is produced using a formulation composition, it is preferable that the pump layer of the resulting osmotic pump formulation is formed using a formulation composition containing the granules that do not contain the active ingredient.
  • the configuration other than the formulation composition that forms the pump layer can be, for example, the same as that of a known osmotic pump formulation.
  • One embodiment of an osmotic pump formulation includes an osmotic pump formulation that includes a pump layer using a granule that does not contain the active ingredient and a drug layer, and in which the drug layer and the pump layer are laminated to form a core portion.
  • FIG. 1 is a cross-sectional view showing an outline of one embodiment of an osmotic pump formulation.
  • osmotic pump formulation A shown in FIG. 1 a core is formed by laminating a drug layer 1 and a pump layer 2 in this order, and the core is covered by a coating layer 3.
  • An opening 4 is provided in the coating layer 3.
  • the osmotic pump formulation has an osmotic pump structure that includes a core and a coating layer, it can have a structure other than that shown in FIG. 1; for example, the configurations of known osmotic pump formulations can be widely adopted.
  • Osmotic pump formulations have an osmotic pump structure with a core and a coating layer, so that when administered to a patient's body, water and bodily fluids penetrate into the core through the semipermeable membrane, causing the pump layer to swell due to osmotic pressure, and allowing the drug to elute from an opening in the coating layer.
  • the drug layer can have a configuration similar to that of known osmotic pump formulations, and an example of the drug layer is one that contains a drug and a polymer component.
  • the drug is, for example, the active ingredient described above.
  • the drug content in the drug layer can be 5% by mass or more and 60% by mass or less, based on the total mass of the drug layer.
  • the drug content in the drug layer is preferably 10% by mass or more, more preferably 15% by mass or more, and preferably 50% by mass or less, and more preferably 40% by mass or less.
  • the type of polymer component contained in the drug layer is not particularly limited, and can be, for example, the same as the polymer component constituting the binder described above.
  • the drug layer may also contain other additives such as diluents, excipients, lubricants, dyes, and pigments. These additives may be any of those used in conventional osmotic pump formulations.
  • the method for forming the drug layer is not particularly limited, and for example, the drug layer forming methods used in known osmotic pump-type preparations can be widely used in the present invention.
  • the material of the pump layer may contain, for example, an osmotic pressure inducer, in addition to granules that do not contain an active ingredient.
  • Osmotic pressure inducers can be a wide variety of substances that have no adverse effects on the formulation, and for example, osmotic pressure inducers that are used in known osmotic pump formulations can be widely used in the present invention.
  • examples include water-soluble substances that can be used as additives for pharmaceuticals, such as inorganic salts, water-soluble salts of organic acids, and water-soluble nonionic organic substances.
  • Inorganic salts include chlorides, sulfates, carbonates, bicarbonates, phosphates, hydrogen or dihydrogen phosphates, etc. of alkali metals or alkaline earth metals such as lithium, sodium, potassium, magnesium, calcium, etc.
  • Water-soluble salts of organic acids include acetates, succinates, benzoates, citric acid, ascorbates, etc.
  • Water-soluble non-ionic organic substances include carbohydrates such as sugars and amino acids. Of these, sodium chloride is preferably used from the viewpoints of ease of handling and low cost.
  • the osmotic pressure inducer contained in the pump layer can be one type or two or more types.
  • the content of the osmotic pressure inducer can be 10% by mass or more and 55% by mass or less, based on the total mass of the pump layer.
  • the content of the osmotic pressure inducer in the pump layer is preferably 15% by mass or more, more preferably 20% by mass or more, and is preferably 45% by mass or less, more preferably 40% by mass or less.
  • the pump layer may contain additives such as diluents, excipients, lubricants, dyes, and pigments, as necessary. These additives may be any of those used in conventional osmotic pump formulations.
  • the method for forming the pump layer is not particularly limited, and for example, the methods for forming the pump layer employed in known osmotic pump preparations can be widely used in the present invention.
  • the core is formed by laminating the drug layer and the pump layer in this order.
  • the mass ratio of the drug layer to the pump layer is, for example, preferably 1 to 5, and more preferably 2 to 3.
  • the core can be formed by laminating the drug layer and the pump layer by a known method such as compression molding. For example, it can be molded into the shape of a two-layered tablet as shown in Figure 1.
  • the size of the core varies depending on the application of the formulation and cannot be determined in general terms, but it can be, for example, 5 to 12 mm in diameter and 3 to 7 mm in thickness, which is suitable for tablets that are administered orally.
  • the core part is covered with a covering layer.
  • the covering layer can be formed of a medicamentously acceptable material.
  • the covering layer is, for example, at least a part or the whole of a semipermeable membrane.
  • the proportion of semipermeable membrane in the covering layer is not particularly limited as long as the core part is covered with the semipermeable membrane to an extent that the penetration of water or body fluids is not impaired. From the viewpoint of facilitating covering of the core part, it is preferable that the entire covering layer is made of a semipermeable membrane, that is, it is preferable that the core part is covered with a semipermeable membrane.
  • a semipermeable membrane is a membrane that is permeable to water but not to drugs or osmotic pressure inducers.
  • Materials for forming semipermeable membranes are preferably known polymeric substances that are not metabolized in the gastrointestinal tract. From this perspective, materials for forming semipermeable membranes include cellulose acetate and other cellulose acetate derivatives such as cellulose acetate, triacetyl cellulose, cellulose acetate ethyl carbamate, cellulose acetate methyl sulfonate, and cellulose acetate diethylaminoacetate; poly(vinyl methyl ether) copolymers; selectively permeable aromatic nitrogen compounds containing polymer membranes that are permeable to water but almost not permeable to solutes; polymeric epoxides; substances made from copolymers of alkene oxides and alkyl glycidyl ethers; semipermeable corrosive polyglycolic acid, and the like.
  • the semipermeable membrane may contain, as necessary, a plasticizer such as polyethylene glycol; a substance for increasing the porosity of the semipermeable membrane such as sucrose, lactose, sodium chloride, or potassium chloride; a light-blocking substance such as titanium dioxide or iron oxide; etc.
  • a plasticizer such as polyethylene glycol
  • a substance for increasing the porosity of the semipermeable membrane such as sucrose, lactose, sodium chloride, or potassium chloride
  • a light-blocking substance such as titanium dioxide or iron oxide
  • the method for forming the coating layer is not particularly limited, and for example, a wide variety of known methods can be used.
  • the coating layer can be formed by spray coating the core portion with a solution of a substance for forming the coating layer, preferably a material for forming a semipermeable membrane.
  • the thickness of the coating layer is not particularly limited, as it varies depending on factors such as the size of the preparation, and can be appropriately designed taking into account the rate at which water or body fluids penetrate into the core portion.
  • the coating layer may have an opening (see opening 4 in FIG. 1).
  • the opening facilitates the release of the drug to the outside through the opening.
  • At least one opening is provided in the coating layer.
  • the opening may be provided in the coating layer after the core portion having the drug layer containing the drug and the pump layer containing the osmotic pressure inducer is covered with the coating layer.
  • the opening may be provided in the coating layer by a method of forming a hole with a laser, a method of forming a hole mechanically, a method of forming a hole by punching, or the like, and methods known in the art may be widely adopted.
  • the size of the opening may be set within an appropriate range depending on the size of the formulation, and may be, for example, preferably 0.2 to 2 mm in diameter, more preferably 0.5 to 1.5 mm.
  • the osmotic pump formulation is configured as described above, so that when the osmotic pump formulation is administered into the patient's body, the patient's bodily fluids permeate the coating layer and cause the pump layer to swell.
  • the pump layer swells, the drug layer is pushed toward the opening, and the drug contained in the drug layer is released, for example, from the opening.
  • the method for producing the osmotic pump formulation of the present invention is not particularly limited, and for example, any known method for producing an osmotic pump formulation can be widely adopted.
  • the production of each layer can include a granulation step, and various solvents can be used for granulation.
  • additives such as diluents, excipients, lubricants, dyes, and pigments can be blended into the materials for forming each layer as necessary. These additives can be widely used from those used in conventional osmotic pump formulations.
  • the manufacturing method of the granulated material of the present invention is not particularly limited, and known manufacturing methods can be widely adopted.
  • the manufacturing method of the granulated material of the present invention preferably includes a step of kneading and granulating a mixture containing an excipient and a binder in a barrel by a twin-screw extrusion method.
  • Step A such a step is referred to as "Step A”.
  • Step A the difference T1-T3 between the melting start temperature T1 (°C) of the excipient and the temperature T3 (°C) in the barrel is 0.5 or more.
  • excipients and binders used in step A are the same as the excipients and binders contained in the granules of the present invention described above. Therefore, the excipients used in step A contain polyethylene oxide having a 2% aqueous solution viscosity of 200 mPa ⁇ s or more, as described above.
  • the content of the binder is preferably 5 to 15% by mass based on the total mass of the mixture.
  • the mixture may further contain an active ingredient.
  • the mixture preferably does not contain an active ingredient and preferably contains an osmotic pressure inducer.
  • the method for preparing the mixture is not particularly limited.
  • a raw material containing the mixture can be prepared by mixing an excipient, a binder, and other components added as necessary in a predetermined ratio.
  • the mixture can be prepared by a mixing means using, for example, a known mixer.
  • the twin-screw extruder used in step A can be, for example, any known twin-screw extruder. There is no particular limitation on the type of screw that the twin-screw extruder used in step A has, and any known screw can be used.
  • a screw is composed of a pre-conditioning section (also called a transport section), an agglomeration section (also called a kneading section), and a breakage section (also called a crushing section).
  • the screw used in the present invention preferably has at least an agglomeration section (kneading section), and more preferably has all of a pre-conditioning section (transport section), an agglomeration section (kneading section), and a breakage section (crushing section). If the screw does not have a breakage section (crushing section), it is recommended that a crushing process be provided after twin-screw extrusion.
  • the kneading section is composed of a kneading type screw, and the rest are composed of screws called full flight. It is preferable that the kneading section occupies 10 to 25% of the total screw length. In this case, granulation properties are likely to be improved.
  • the kneading section is located somewhere within the range of 0 to 90%, assuming that the tip end (the granulated material outlet side) of both ends of the screw is 0% and the rear end (the raw material input side or raw material inlet side) is 100%.
  • the tip of the screw means the downstream side in the direction of the flow of the raw material
  • the rear of the screw means the upstream side in the direction of the flow of the raw material.
  • FIG 2 is a schematic diagram of a screw that can be suitably used in the method for producing granulated materials of the present invention.
  • a notation such as "36/24", where "36” means the length (mm) of each unit of the screw, and “24” means the length (mm) of the blade when the screw rotates once, that is, the so-called lead.
  • step 1 when the raw materials are mixed in the barrel of the extruder, the temperature T3 (°C) inside the barrel is set so that the difference between the melting start temperatures T1 (°C) and T3 (°C) of the excipient, "T1-T3,” is 0.5 or more, as described above.
  • step A if the value of "T1-T3" is less than 0.5, it will be difficult to obtain a granulated product; for example, even if granulation is achieved, it will be difficult to set the average particle size of the granulated product within the desired range, or lumps will tend to form, making it difficult to produce the desired granulated product. Also, if the viscosity of a 2% aqueous solution of polyethylene oxide is less than 200 mPa ⁇ s, even if granulation is achieved, it will be difficult to form a preparation with excellent dimensional stability, and it will also be difficult to control the dissolution rate of the active ingredient within the desired range.
  • the value of T1-T3 is preferably 1 or more, more preferably 1.2 or more, even more preferably 1.5 or more, and particularly preferably 1.8 or more, and is preferably 20 or less, more preferably 15 or less, even more preferably 10 or less, and particularly preferably 8 or less.
  • the temperature T3 inside the barrel is preferably set to 45°C or higher, more preferably 48°C or higher, even more preferably 50°C or higher, and particularly preferably 53°C or higher.
  • T3 is also preferably set to 65°C or lower, more preferably 60°C or lower, even more preferably 58°C or lower, and particularly preferably 57°C or lower.
  • the screw rotation speed is not particularly limited, and can be the same as that in the known twin-screw extrusion method for producing a pharmaceutical composition.
  • the screw rotation speed can be 50 to 500 rpm (the same applies to commercial screws).
  • the raw material containing the mixture is extruded from the outlet of the twin-screw extruder to obtain the granulated product of the present invention.
  • PEO-A Polyethylene oxide "PEO-27NF” manufactured by Sumitomo Seika Chemicals (2% aqueous solution viscosity is 61,700 mPa ⁇ s, melting initiation temperature T1 is 57.01°C)
  • PEO-B Polyethylene oxide "PEO-8NF” manufactured by Sumitomo Seika Chemicals (2% aqueous solution viscosity is 2240 mPa ⁇ s, melting initiation temperature T1 is 57.66°C)
  • PEO-C Polyethylene oxide "PEO-5NF” manufactured by Sumitomo Seika Chemicals (2% aqueous solution viscosity is 210 mPa ⁇ s, melting initiation temperature T1 is 55.15°C)
  • PEO-D Polyethylene oxide "PEO-2NF” manufactured by Sumitomo Seika Chemicals (2% aqueous solution viscosity is 56 mPa ⁇ s, melting onset temperature T1 is 51.47°C)
  • PEG4000 polyethylene glycol manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. (mass average molecular weight 4000, melting onset temperature T2 is 45.15° C.)
  • PEG20000 polyethylene glycol manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.
  • PEO-E Polyethylene oxide "PEO-1NF” manufactured by Sumitomo Seika Chemicals (2% aqueous solution viscosity is 11 mPa ⁇ s, melting onset temperature T2 is 51.43°C)
  • PEO-C Polyethylene oxide "PEO-5NF” manufactured by Sumitomo Seika Chemicals (2% aqueous solution viscosity is 210 mPa ⁇ s, melting starting temperature T2 is 55.15°C)
  • Kolliphor P188 Sigma-Aldrich "Poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)" (initial melting temperature T2 is 41.86°C)
  • Poloxamer 407 Sigma-Aldrich "Poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)” (initial melting temperature T2 is 44.20°
  • Acetaminophen manufactured by Chemexpress, indicated as AAP in Table 1
  • NaCl manufactured by Nacalai Tesque, osmotic pressure inducer
  • Example 1 A mixture was prepared by mixing PEO-A as an excipient, PEG4000 as a binder, and acetaminophen (AAP) as an active ingredient in a mass ratio of 40:7.5:52.5 (excipient:binder:active ingredient) as shown in Table 1. 0.1 mass% of Aerosil (manufactured by Evonik) was added to this mixture, and the mixture was mixed for 150 minutes or more using a blender (Misugi Co., Ltd., Mazemazeman SKH-40CA: 0.7 revolutions/second) to obtain a raw material for twin-screw extrusion.
  • the obtained raw material was fed into a twin-screw extruder (TEM-18SS-10/2V: Toshiba Machine) equipped with the screw shown in Figure 3 at a feed rate of 0.9 kg/h using a gravimetric feeder (Kubota Instruments, model CE-W-OE-MP), and granulation was performed under conditions of a temperature of 25°C in heating zone 1, a temperature inside the barrel (temperature of heating zones 2 to 5) of 55°C, and a screw rotation speed of 100 rpm to obtain a granulated material.
  • the twin-screw extruder used was composed of 10 barrels, each of which was 75 mm long.
  • the area 0 to 75 mm away from the feed port was designated as zone 0, the area 75 to 225 mm away as heating zone 1, the area 225 to 375 mm away as heating zone 2, the area 375 to 525 mm away as heating zone 3, the area 525 to 675 mm away as heating zone 4, and the area 675 to 750 mm away as heating zone 5, and the heating temperature was controlled independently for each heating zone.
  • the kneading sections were located in heating zone 3 and heating zone 4 (shaded areas in Figure 3). The obtained granules were used as a granulated composition.
  • Example 2 A granulated composition was prepared in the same manner as in Example 1, except that the conditions were changed as shown in Table 1.
  • Example 12 A granulated composition was prepared in the same manner as in Example 1, except that a mixture was prepared by mixing PEO-A, PEG 4000, and sodium chloride as an osmotic pressure inducer in the mass ratios shown in Table 1.
  • ⁇ Dimensional stability> The granulated composition was crushed (10 s/time, performed a total of three times) with a food processor (ZOJIRUSHI Co., Ltd., "BM-RT08"), and then passed through a 32 mesh sieve. After this, 500 mg of the granulated composition after this treatment was pressed at a tableting pressure of 10 kN (Shimadzu Autograph AGS-J) to produce flat tablets (10.7 mm ⁇ , flat tablets). Four tablets were prepared and placed on a flat surface (in a blower dryer described below) so that they were placed at the vertices of a 5 cm x 5 cm rectangle. A 5 kg weight plate was placed and pressed so that all four tablets placed in this manner were covered.
  • the weight plate was placed so that the four tablets were evenly loaded.
  • the tablets were placed on the weight plate and pressed, and then allowed to stand in a blower dryer (Advantec FV-320) adjusted to a 70 ° C. atmosphere to heat them.
  • the thickness of the tablet was measured 1 hour after the start of heating, and this was defined as the tablet thickness after compression.
  • the dimensional stability of the tablet was evaluated based on the change in the tablet thickness before and after compression.
  • Thickness reduction rate (%) ⁇ (tablet thickness before compression - tablet thickness after compression) / tablet thickness before compression ⁇ x 100
  • the thickness reduction rate of the four tablets was calculated, and the average value was defined as the "average thickness reduction rate.”
  • a tablet with an average thickness reduction rate of 35% or less was evaluated as having "excellent dimensional stability.”
  • the tablets were placed in a dissolution tester (Toyama Sangyo Co., Ltd., dissolution tester NTR-6100AT), and 900 g of ion-exchanged water was further added to prepare samples, which were then subjected to a dissolution test at a water temperature of 37°C and a rotation speed of 100 rpm (paddle method).
  • the eluate was collected 3 hours and 24 hours after the addition of ion-exchanged water, and the absorbance at 243 nm was measured using a UV measuring device (Shimadzu Corporation, "UV-1800 100V").
  • Dissolution rate (%) (absorbance after 3 hours/absorbance after 24 hours) ⁇ 100
  • the dissolution rate was calculated by the above formula, and a dissolution rate of 90% or less was evaluated as "excellent sustained release properties.”
  • the rotors used were as follows, depending on the type of polyethylene oxide contained in the excipient. PEO-A rotor No. 4, 2 rpm PEO-B rotor No. 3, 10 rpm PEO-C rotor No. 3, 10 rpm PEO-D rotor No. 2, 10 rpm PEO-E rotor No. 1, 10 rpm
  • Table 1 shows the preparation conditions of the granulated compositions prepared in the Examples and Comparative Examples, as well as the evaluation results of the dusting evaluation, dimensional stability, and dissolution rate described above.
  • the values in the dusting evaluation column indicate the mass ratio (mass%) of the granulated material that passed through a 100 mesh (150 ⁇ m opening) sieve, and the values in the dimensional stability column indicate the average thickness reduction rate (%).
  • a granulated material containing an excipient containing polyethylene oxide with a 2% aqueous solution viscosity of 200 mPa ⁇ s or more, a binder, and having a T2-T1 value of 0.5 or less and a passing rate of 100% is suitable for producing a preparation with excellent dimensional stability and easy control of dissolution rate, and also has excellent granulation properties.
  • the granulated product of the present invention is suitable for producing preparations with excellent dimensional stability, and also has excellent granulation properties. Therefore, the granulated product of the present invention is considered to be suitable as a raw material for preparing various preparations, such as tablets and osmotic pump-type preparations. Since the granulated product of the present invention can be obtained without using organic solvents, it is also useful from the standpoint of environmental protection, as it can contribute to reducing the consumption of fossil-derived raw materials.

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne : un matériau granulé qui est approprié pour produire des préparations ayant une excellente stabilité dimensionnelle, et qui présente également d'excellentes propriétés de granulation ; un procédé de production du matériau granulé ; une composition granulée ; et une composition pour préparations.　Un matériau granulé selon la présente invention est un matériau granulé contenant un excipient et un liant, et a un taux de passage de 100% par rapport à un tamis à 5 mailles (ouverture 4000 µm). L'excipient contient un oxyde de polyéthylène pour lequel la viscosité de la solution aqueuse à 2% est d'au moins 200 mPa•s. En utilisant T2 (°C) pour la température de début de fusion du liant et en utilisant T1 (°C) pour la température de début de fusion de l'excipient, la valeur de la différence T2-T1 n'est pas supérieure à 0,5.
PCT/JP2024/016156 2023-04-27 2024-04-24 Matériau granulé et son procédé de production, composition granulée et composition pour préparations WO2024225348A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005232185A (ja) * 2003-03-06 2005-09-02 Astellas Pharma Inc 放出制御用医薬組成物およびその製造方法
JP2007517062A (ja) * 2003-12-29 2007-06-28 アルザ・コーポレーシヨン 機械的圧縮中に付着抵抗を与える薬物顆粒のコーティング
JP2009531453A (ja) * 2006-03-24 2009-09-03 オクシリウム インターナショナル ホールディングス，インコーポレイティド アルカリ不安定ドラッグを含む安定化された組成物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005232185A (ja) * 2003-03-06 2005-09-02 Astellas Pharma Inc 放出制御用医薬組成物およびその製造方法
JP2007517062A (ja) * 2003-12-29 2007-06-28 アルザ・コーポレーシヨン 機械的圧縮中に付着抵抗を与える薬物顆粒のコーティング
JP2009531453A (ja) * 2006-03-24 2009-09-03 オクシリウム インターナショナル ホールディングス，インコーポレイティド アルカリ不安定ドラッグを含む安定化された組成物

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