WO2024024865A1 - Levodopa sustained release formulation - Google Patents

Levodopa sustained release formulation Download PDF

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Publication number
WO2024024865A1
WO2024024865A1 PCT/JP2023/027466 JP2023027466W WO2024024865A1 WO 2024024865 A1 WO2024024865 A1 WO 2024024865A1 JP 2023027466 W JP2023027466 W JP 2023027466W WO 2024024865 A1 WO2024024865 A1 WO 2024024865A1
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WIPO (PCT)
Prior art keywords
levodopa
dissolution
pharmaceutical composition
dissolution test
minutes
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PCT/JP2023/027466
Other languages
French (fr)
Japanese (ja)
Inventor
浩人 寺田
崇弘 松本
沙耶 下原
智彦 村上
南 岸本
直樹 森田
和城 宮崎
和人 小野
Original Assignee
大原薬品工業株式会社
株式会社PARKINSON Laboratories
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Priority to JP2024537209A priority Critical patent/JPWO2024024865A1/ja
Publication of WO2024024865A1 publication Critical patent/WO2024024865A1/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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

Definitions

  • the present disclosure relates to granules containing levodopa and carbidopa as pharmaceutically active ingredients, an oral pharmaceutical composition containing the granules, and a therapeutic agent for Parkinson's disease containing the oral pharmaceutical composition.
  • Levodopa (chemical name: 3-Hydroxy-L-tyrosine) is a compound (pharmaceutically active ingredient) used for the treatment of Parkinson's disease and Parkinson's syndrome.
  • Combination therapy with levodopa and carbidopa hydrate (chemical name: (2S)-2-(3,4-Dihydroxybenzyl)-2-hydrazinopropanoic acid monohydrate), a decarboxylase inhibitor, is also known.
  • Dopastone registered trademark
  • neodopastone registered trademark
  • Stalevo registered trademark
  • Patent Document 1 As an oral solid preparation with controlled release of levodopa, a miniaturized tablet containing levodopa with good sustained release properties has been reported (Patent Document 1). Furthermore, a preparation has been reported in which four or more types of granules containing levodopa, a decarboxylase inhibitor, and a carboxylic acid and having different compositions are filled into the same capsule (Patent Document 2).
  • Patent No. 7066351 Special table 2011-507956
  • the present inventors have conducted extensive studies on important formulation characteristics for the oral pharmaceutical composition containing levodopa and carbidopa of the present disclosure to exhibit a blood kinetic profile of a drug that has both immediate effect and long-lasting effect.
  • the paddle method using a pH 1.2 dissolution test solution is generally conducted for a maximum of 2 hours.
  • the dissolution test was carried out over an extended period of time, and the target formulation characteristics were set as the dissolution behavior so that the drug would be released gradually even in the stomach.
  • the flow-through cell method which allows the dissolution test solution to be seamlessly changed.
  • the dissolution behavior was set as a target formulation characteristic such that the drug gradually elutes into the body no matter where the oral pharmaceutical composition of the present disclosure is present in the gastrointestinal tract.
  • the present disclosure includes the following features.
  • the dissolution test first solution (pH 1.2) specified in the 18th revised Japanese Pharmacopoeia/General Test Methods was used.
  • the dissolution rate of levodopa at 30 minutes after the start of the dissolution test was 18% or more. 43%, the dissolution rate of levodopa at 180 minutes after the start of the dissolution test is 20% to 80%, and the dissolution rate of levodopa at 360 minutes after the start of the dissolution test is 30% or more.
  • the dissolution rate of levodopa at 30 minutes after the start of the dissolution test was 20% to 40%, and the dissolution rate of levodopa at 180 minutes after the start of the dissolution test was 25% to 70%, and the dissolution rate was 25% to 70% after the start of the dissolution test.
  • Pharmaceutical composition characterized by a levodopa dissolution behavior in which the dissolution rate of levodopa is 35% or more at 360 minutes after the start of the dissolution test, and the dissolution rate of levodopa is 75% or more at 960 minutes after the start of the dissolution test.
  • the second dissolution test liquid (pH 6.8) specified in the 18th revised Japanese Pharmacopoeia/General Test Methods was used at a liquid temperature of 37°C (37 ⁇ 0.5°C range).
  • the dissolution rate of levodopa at 45 minutes after the start of the dissolution test was 15% to 45%
  • the dissolution rate of levodopa at 180 minutes after the start of the dissolution test. is 40% to 80%
  • the dissolution rate of levodopa at 540 minutes after the start of a dissolution test is 80% or more.
  • the dissolution rate of levodopa at 45 minutes after the start of the dissolution test was 20% to 40%, and the dissolution rate of levodopa at 180 minutes after the start of the dissolution test was 50% to 75%, and the dissolution rate at 180 minutes after the start of the dissolution test was 50% to 75%.
  • the dissolution rate of levodopa at 180 minutes after the start of the dissolution test is 25% to 70%
  • the dissolution rate of levodopa at 360 minutes after the start of the dissolution test is 35% or more
  • the dissolution rate is 960% after the start of the dissolution test.
  • the first dissolution test solution (pH 1.2) specified in the 18th revised Japanese Pharmacopoeia/General Test Methods was applied to the dissolution test using a liquid pump with pulsating flow until 45 minutes after the start of the dissolution test. From 180 to 180 minutes, use diluted McIlvaine buffer (pH 5.5), and from 180 to 540 minutes, use the second dissolution test solution (pH 6.8) specified in the 18th revised Japanese Pharmacopoeia/General Test Methods.
  • the dissolution rate of levodopa at 45 minutes after the start of the dissolution test was 20% to 40%.
  • the sustained release portion and the immediate release portion each independently form granules or form the same granule, according to any one of [1] to [5].
  • Oral pharmaceutical composition is independently form granules or form the same granule, according to any one of [1] to [5].
  • the lubricant is one or more lubricants selected from magnesium stearate and calcium stearate.
  • the granules are characterized in that they pass through Japanese Pharmacopoeia Sieve No. 4.7 and remain in Japanese Pharmacopoeia Sieve No. 12, as described in the Particle Size Measurement Method of the 18th Edition of the Japanese Pharmacopoeia/General Tests.
  • the granules forming the sustained release portion and the immediate release portion are each selected from the group consisting of crystalline cellulose, ammonioalkyl methacrylate copolymer, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, partially pregelatinized starch, and silicon dioxide.
  • the oral pharmaceutical composition according to [14] which contains one or more selected additives.
  • the enteric polymer is selected from the group consisting of methacrylic acid copolymer LD, dry methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, hypromellose acetate succinate, hypromellose phthalate ester, and carboxymethylethylcellulose.
  • the disintegrant is one selected from the group consisting of partially pregelatinized starch, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, hydroxypropyl starch, starch, sodium starch glycolate, croscarmellose sodium, and crospovidone.
  • the granules forming the sustained release portion are made of one or more selected from the group consisting of crystalline cellulose, ammonioalkyl methacrylate copolymer, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, partially pregelatinized starch, and silicon dioxide.
  • the oral pharmaceutical composition according to [18] which contains an additive.
  • the enteric polymer is selected from the group consisting of methacrylic acid copolymer LD, dry methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, hypromellose acetate succinate, hypromellose phthalate ester, and carboxymethylethylcellulose.
  • the water-soluble polymer is one or more selected from the group consisting of polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, polyvinyl alcohol, hydroxypropylcellulose, hypromellose, methylcellulose, povidone, carmellose sodium, and pregelatinized starch.
  • a therapeutic agent for Parkinson's disease or Parkinson's syndrome comprising the oral pharmaceutical composition according to any one of [7] to [22].
  • a therapeutic agent for Parkinson's disease comprising the oral pharmaceutical composition according to any one of [7] to [22].
  • [25] Use of the formulation characteristics related to levodopa dissolution behavior described in any one of [1] to [5] as an evaluation criterion for designing an oral pharmaceutical composition containing levodopa and carbidopa.
  • the present disclosure provides an oral pharmaceutical composition containing levodopa and carbidopa (in the present disclosure, a "controlled release preparation") that exhibits a levodopa blood dynamics profile that is both immediate and sustained, and is miniaturized and has improved convenience. ” or “levodopa/carbidopa hydrate combination long-acting preparation”).
  • one type or two types of granules with controlled drug release are combined.
  • the present disclosure makes it possible to provide an oral pharmaceutical composition containing levodopa and carbidopa that contains a higher content of levodopa and carbidopa, that can be made smaller, and that reduces the burden on patients when taking it.
  • the present disclosure makes it possible to provide an oral pharmaceutical composition containing levodopa and carbidopa that exhibits a levodopa blood dynamics profile that is both immediate and long-lasting, without containing an acid component such as a carboxylic acid as an essential component. Ru.
  • the present disclosure can provide formulation characteristics related to levodopa dissolution behavior that are used as evaluation criteria for formulation design of oral pharmaceutical compositions containing levodopa and carbidopa.
  • FIG. 2 is a diagram showing the average plasma levodopa concentration over time after conducting a comparative pharmacokinetic study.
  • the formulation obtained in Example 12 of the present disclosure is administered orally in a single dose to 17 healthy adult males under fasting conditions, with 1 capsule to 6 males, 2 capsules to 5 males, and 4 capsules to the remaining 6 males.
  • FIG. 2 is a diagram showing the results of a pharmacokinetic comparison test and the changes in average plasma levodopa concentration for each preparation.
  • the oral pharmaceutical composition of the present disclosure contains levodopa and carbidopa as pharmaceutically active ingredients. Any pharmacologically equivalent molecular species of levodopa and carbidopa, such as anhydride, hydrate, salt, etc., can be used.
  • the oral pharmaceutical composition of the present disclosure contains levodopa and carbidopa hydrate as pharmaceutically active ingredients.
  • Levodopa and carbidopa can be adjusted to any particle size by dry or wet pulverization as necessary. Note that the median diameter can be measured (based on volume) by laser diffraction/scattering method.
  • the median diameter (d 50 ) of levodopa and carbidopa is between 1.0 ⁇ m and 100.0 ⁇ m.
  • the median diameter (d 50 ) of levodopa and carbidopa is between 3.0 ⁇ m and 75 ⁇ m.
  • the oral pharmaceutical composition of the present disclosure contains levodopa and carbidopa (as anhydrous) in a mass ratio of 4:1.
  • carbidopa when calculating the mass ratio of levodopa to carbidopa is calculated based on the mass of carbidopa anhydride.
  • the present disclosure provides an oral pharmaceutical composition comprising levodopa and carbidopa, wherein the weight ratio of levodopa to carbidopa is 4:1,
  • the dissolution test first solution (pH 1.2) specified in the 18th revised Japanese Pharmacopoeia/General Test Methods was used.
  • the dissolution rate of levodopa at 30 minutes after the start of the dissolution test was 18% or more. 43%, the dissolution rate of levodopa at 180 minutes after the start of the dissolution test is 20% to 80%, and the dissolution rate of levodopa at 360 minutes after the start of the dissolution test is 30% or more.
  • An oral pharmaceutical composition is provided.
  • the present disclosure provides, in the dissolution test, the dissolution rate of levodopa at 30 minutes after the start of the dissolution test is 20% to 40%, and the dissolution rate of levodopa at 180 minutes after the start of the dissolution test is 20% to 40%. 25% to 70%, the dissolution rate of levodopa is 35% or more at 360 minutes after the start of the dissolution test, and the dissolution rate of levodopa is 75% or more at 960 minutes after the start of the dissolution test.
  • An oral pharmaceutical composition is provided.
  • the present disclosure provides an oral pharmaceutical composition comprising levodopa and carbidopa, wherein the weight ratio of levodopa to carbidopa is 4:1,
  • the open-loop method was performed using a small flow-through cell, and a liquid delivery pump with pulsating flow was used.
  • the first dissolution test solution pH 1.2
  • McIlvaine buffer pH 5.5
  • the second dissolution test liquid (pH 6.8) specified in the 18th revised Japanese Pharmacopoeia/General Test Methods was used at a liquid temperature of 37°C (37 ⁇ 0.5°C range).
  • the dissolution rate of levodopa at 45 minutes after the start of the dissolution test was 15% to 45%
  • the dissolution rate of levodopa at 180 minutes after the start of the dissolution test. is 40% to 80%
  • the dissolution rate of levodopa at 540 minutes after the start of a dissolution test is 80% or more.
  • the present disclosure provides that in the dissolution test, the dissolution rate of levodopa at 45 minutes after the start of the dissolution test is 20% to 40%, and the dissolution rate of levodopa at 180 minutes after the start of the dissolution test is 20% to 40%.
  • the present invention provides an oral pharmaceutical composition characterized by a levodopa dissolution behavior of 50% to 75% and a levodopa dissolution rate of 80% or more at 540 minutes after the start of a dissolution test.
  • the present disclosure provides an oral pharmaceutical composition comprising levodopa and carbidopa, wherein the weight ratio of levodopa to carbidopa is 4:1,
  • the dissolution test first solution (pH 1.2) specified in the 18th revised Japanese Pharmacopoeia/General Test Methods was used.
  • the dissolution rate of levodopa at 30 minutes after the start of the dissolution test is 20% or more. 40%, the dissolution rate of levodopa at 180 minutes after the start of the dissolution test is 25% to 70%, the dissolution rate of levodopa at 360 minutes after the start of the dissolution test is 35% or more, and the dissolution rate is 960% after the start of the dissolution test.
  • the present disclosure provides an oral pharmaceutical composition comprising levodopa and carbidopa, wherein the weight ratio of levodopa and carbidopa is 4:1, the composition comprising: ) and a sustained release part containing a pharmaceutically active ingredient and an enteric polymer; comprising a pharmaceutically active ingredient containing levodopa and carbidopa (mass ratio 4:1) and an immediate release part containing a disintegrant or a water-soluble polymer;
  • the sustained release part and the immediate release part are characterized in that they each form granules independently or form the same granule, and the levodopa elution behavior shown in the paddle method and/or flow-through cell method is Provided is an oral pharmaceutical composition characterized by:
  • an oral pharmaceutical composition containing levodopa and carbidopa was exemplified from the viewpoint of formulation characteristics based on levodopa dissolution behavior.
  • the oral pharmaceutical composition containing levodopa and carbidopa may be any pharmaceutical composition that satisfies the levodopa elution behavior shown in Embodiment 1, and the composition of the pharmaceutical composition (formulation components, content, blending ratio, etc.) ) are not particularly limited.
  • Embodiment 2-4 embodiments of an oral pharmaceutical composition containing levodopa and carbidopa will be exemplified from the viewpoint of the composition of the pharmaceutical composition (formulation components, content, blending ratio, etc.), but are limited to these. It is not something that will be done.
  • the present disclosure provides an oral pharmaceutical composition containing levodopa and carbidopa, comprising a pharmaceutically active ingredient comprising levodopa and carbidopa (4:1 weight ratio) and an enteric polymer.
  • an oral pharmaceutical composition characterized by comprising a sustained release part and an immediate release part containing a water-soluble polymer and a pharmaceutically active ingredient containing levodopa and carbidopa (mass ratio 4:1).
  • the sustained release part and the immediate release part each form granules independently, or form the same granule.
  • a "sustained release part” is a part constituting an oral pharmaceutical composition, and is a part that is used in vivo for a long period of time after administration of the oral pharmaceutical composition to a subject (including a patient). This refers to the area where the elution of pharmaceutically active ingredients is controlled so that the blood concentration of pharmaceutically active ingredients can be maintained.
  • blood concentration refers to effective blood concentration or plasma concentration.
  • the sustained release portion may be granules (including coated granules) containing a pharmaceutically active ingredient and an enteric polymer including levodopa and carbidopa (in a mass ratio of 4:1).
  • the "sustained release part” may have a structure covered with an elementary granule part containing levodopa and carbidopa (mass ratio 4:1) and a coating layer containing an enteric polymer.
  • the "elementary granule part” refers to levodopa and carbidopa (mass ratio 4:1) as pharmaceutically active ingredients and additives that may be optionally added (for example, excipients, binders, disintegrants, (lubricating agent, fluidizing agent).
  • the "coating layer” may be a layer containing an enteric polymer, a coating agent, and optional additives (for example, a fluidizing agent, a plasticizer, a coloring agent, etc.).
  • the "enteric polymer” is substantially insoluble in an aqueous solvent (pH 1.2 to pH 5.4) having an acidic pH value assuming the gastric environment (i.e., its 1.
  • the amount of solvent required at 25°C to dissolve .0 g is 10,000 mL or more), and it dissolves well in an aqueous solvent with a neutral to alkaline pH value (pH 5.5 or more) assuming the intestinal environment (i.e. , the amount of solvent at 25°C required to dissolve 1.0 g of it is less than 10,000 mL).
  • the enteric polymer includes, for example, methacrylic acid copolymers (e.g., methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, dry methacrylic acid copolymer LD, etc.), hydroxyalkyl alkyl cellulose phthalate, etc.
  • methacrylic acid copolymers e.g., methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, dry methacrylic acid copolymer LD, etc.
  • hydroxyalkyl alkyl cellulose phthalate examples include acid esters (e.g., hypromellose phthalate), hydroxyalkylalkylcellulose acetate succinate (e.g., hypromellose acetate succinate), carboxyalkylalkylcellulose (e.g., carboxymethylethyl cellulose), etc. , but not
  • enteric polymers include, but are not limited to, methacrylic acid copolymers, hypromellose phthalate, hypromellose acetate succinate, carboxymethylethylcellulose, and the like.
  • the enteric polymer includes, for example, methacrylic acid copolymer LD, dry methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, hypromellose acetate succinate, hypromellose phthalate ester. and carboxymethylethylcellulose, but are not limited to these.
  • the enteric polymer is contained in the granules in an amount of 0.5% by weight or more based on the total weight of the granules.
  • the enteric polymer is contained in the granules in an amount ranging from 1.0% to 10.0% by weight based on the total weight of the granules.
  • the coating agent includes, for example, D-mannitol, lactose, trehalose, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, hypromellose, hydroxypropylcellulose, methylcellulose, etc. Not limited.
  • the coating agent is contained in the granules in an amount ranging from 0.5% to 10.0% by weight based on the total weight of the granules.
  • an "immediate release part” is a component of an oral pharmaceutical composition that promptly releases a pharmaceutically active ingredient into the body after administration of the oral pharmaceutical composition to a patient, i.e., An area where the release of pharmaceutically active ingredients is not controlled.
  • the immediate release portion comprises a pharmaceutically active ingredient comprising levodopa and carbidopa (4:1 mass ratio), a disintegrant or a water-soluble polymer, and optional additives. It may also be granules containing.
  • disintegrants include, for example, partially pregelatinized starch, low substituted hydroxypropyl cellulose, carmellose, carmellose calcium, hydroxypropyl starch, starch, sodium starch glycolate, croscarmellose sodium, crospovidone. etc., but are not limited to these.
  • water-soluble polymers include, for example, alkylcelluloses (e.g., methylcellulose), hydroxyalkylcelluloses (e.g., hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose), hydroxyalkylalkylcelluloses (e.g., hydroxy ethyl methylcellulose, hypromellose), carboxyvinyl polymer, polyvinyl alcohol, polyvinyl alcohol copolymer (copolymer in which polyvinyl alcohol is one of the monomers, such as polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, Examples include, but are not limited to, polyvinyl alcohol/polyethylene glycol/graft copolymer), polyvinylpyrrolidone, carmellose sodium, pregelatinized starch, and the like.
  • alkylcelluloses e.g., methylcellulose
  • hydroxyalkylcelluloses e.g., hydroxymethylcellulose, hydroxy
  • the water-soluble polymer includes, for example, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, hydroxypropylcellulose, hypromellose, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, carmellose sodium, pregelatinized starch. etc., but are not limited to these.
  • the sustained release part and the immediate release part may each independently form granules.
  • the granules may be raw granules or coated granules.
  • the sustained release portion and the immediate release portion may be combined to form the same granule.
  • a granule can be exemplified in which a sustained release part containing an enteric polymer forms granules, and the granules are coated with an immediate release part containing a water-soluble polymer.
  • the mass ratio of levodopa contained in the sustained release portion to levodopa contained in the immediate release portion is 4:1 to 3:2.
  • the total mass of levodopa and carbidopa in the granules is 70% or more based on the mass of the granules.
  • the combined weight of levodopa and carbidopa in the granules is 70% to 95% of the granule weight.
  • the combined weight of levodopa and carbidopa in the granules is 75% to 90% of the granule weight.
  • the present disclosure provides an oral pharmaceutical composition, wherein the granules contain a lubricant from 0.6% to 10% based on the granule weight.
  • the content of lubricant in the granules is between 0.6% and 10% based on the granule mass.
  • the content of lubricant in the granules is between 0.6% and 5% relative to the granule mass.
  • the content of lubricant in the granules is between 1% and 5% relative to the granule mass.
  • the present disclosure provides an oral pharmaceutical composition containing levodopa and carbidopa, comprising: a sustained release part containing a pharmaceutically active ingredient containing levodopa and carbidopa (mass ratio 4:1) and an enteric polymer;
  • the sustained release part and the immediate release part independently form granules, which contain a pharmaceutically active ingredient containing levodopa and carbidopa (mass ratio 4:1) and an immediate release part containing a disintegrant or a water-soluble polymer.
  • an oral pharmaceutical composition characterized in that the granules forming the release part are granules coated with an enteric polymer, and the granules forming the immediate release part are granules containing a disintegrant.
  • the elementary granule part of the granule forming the sustained release part and the granule forming the immediate release part are made of crystalline cellulose, ammonioalkyl methacrylate copolymer, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer. Contains one or more additives selected from coalesced, partially pregelatinized starch and silicon dioxide.
  • the elementary granules of the granules forming the sustained release portion include methacrylic acid copolymer LD, dry methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, hypromellose acetate succinate, hypromellose acetate succinate, It is coated with one or more enteric polymers selected from promellose phthalate and carboxymethylethyl cellulose.
  • the granules forming the immediate release portion are partially pregelatinized starch, low substituted hydroxypropyl cellulose, carmellose, carmellose calcium, hydroxypropyl starch, starch, sodium starch glycolate, croscarmellose sodium. , crospovidone.
  • the present disclosure provides an oral pharmaceutical composition containing levodopa and carbidopa in granules, the pharmaceutically active ingredients comprising levodopa and carbidopa (4:1 weight ratio) and an enteric polymer. and an immediate release part containing a water-soluble polymer and a pharmaceutically active ingredient containing levodopa and carbidopa (mass ratio 4:1),
  • the oral pharmaceutical composition is an oral pharmaceutical composition in which the sustained release part and the immediate release part form the same granules, wherein the sustained release part forms granules coated with an enteric polymer.
  • the present invention further provides an oral pharmaceutical composition characterized in that the granules are surrounded by an immediate-release region containing a water-soluble polymer.
  • the elementary granules of the granules forming the sustained release portion include crystalline cellulose, ammonioalkyl methacrylate copolymer, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, partially pregelatinized starch, and silicon dioxide. Contains one or more additives selected from.
  • the enteric polymer that coats the elementary granule portion of the sustained release portion is methacrylic acid copolymer LD, dry methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, hypromellose acetate succinate. It is one or more enteric polymers selected from ester, hypromellose phthalate, and carboxymethylethyl cellulose.
  • the water-soluble polymer of the immediate release portion is polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, polyvinyl alcohol, hydroxypropylcellulose, hypromellose, methylcellulose, polyvinylpyrrolidone, carmellose sodium, alpha One or more water-soluble polymers selected from modified starches.
  • the particle size measurement of the granules of the present disclosure is carried out under an appropriately controlled room temperature and humidity environment that does not easily cause significant moisture absorption or dehumidification or aggregates due to changes in humidity.
  • the granules of the present disclosure pass Japanese Pharmacopoeia Sieve No. 4.7 as described in the Particle Size Measurement Method of the Japanese Pharmacopoeia, 18th Edition General Testing Methods.
  • the granules of the present disclosure remain in Japanese Pharmacopoeia Sieve No. 12 as described in the Particle Size Measurement Method of the Japanese Pharmacopoeia, 18th Edition General Test Methods.
  • the granules of the present disclosure pass through Japanese Pharmacopoeia Sieve No. 4.7 and remain in No. 12 as described in the Particle Size Measurement Method of the 18th Edition of the Japanese Pharmacopoeia General Test Methods.
  • the shape of the granules of the present disclosure is cylindrical.
  • the diameter of the cylindrical granules is 1.5 mm to 3.0 mm ( ⁇ 10%) as measured using a digital micrometer (manufactured by Mitutoyo: Model PK-1012APX).
  • the diameter of the cylindrical granules measured using a digital micrometer is 1.5 mm to 2.5 mm ( ⁇ 10%).
  • the diameter of the cylindrical granules measured using a digital micrometer is 1.5 mm to 2.1 mm ( ⁇ 10%).
  • additives commonly used in the technical field can be used as additives.
  • additives include, but are not limited to, excipients, binders, disintegrants, lubricants, flow agents, lubricants, plasticizers, colorants, etc. Not done.
  • the blending amount of the additive is not particularly limited as long as it does not impair the effects of the present invention.
  • excipients include, for example, lactose hydrate, anhydrous lactose, crystalline cellulose, D-mannitol, erythritol, xylitol, sorbitol, isomalt, maltitol, maltose, sucrose, sucrose, glucose, starch (corn starch, potato starch, rice starch, wheat starch, etc.), hydroxypropyl starch, pregelatinized starch, partially pregelatinized starch, sodium carboxymethyl starch, dextrin, powdered reduced maltose starch syrup, ammonioalkyl methacrylate copolymer, ethyl cellulose, hydrogen phosphate
  • examples include, but are not limited to, calcium.
  • binders include, for example, alkylcelluloses (e.g., methylcellulose), hydroxyalkylcelluloses (e.g., hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose), hydroxyalkylalkylcelluloses (e.g., hydroxyethylmethylcellulose, hypromellose).
  • alkylcelluloses e.g., methylcellulose
  • hydroxyalkylcelluloses e.g., hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose
  • hydroxyalkylalkylcelluloses e.g., hydroxyethylmethylcellulose, hypromellose
  • carboxyvinyl polymer polyvinyl alcohol, polyvinyl alcohol copolymer (a copolymer in which polyvinyl alcohol is one of the monomers, such as polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, polyvinyl alcohol/polyethylene glycol) - graft copolymer), polyvinylpyrrolidone, carmellose sodium, pregelatinized starch, etc., but are not limited to these.
  • examples of the disintegrant include partially pregelatinized starch, low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, hydroxypropyl starch, starch, sodium starch glycolate, croscarmellose sodium, crospovidone, and the like. but not limited to.
  • examples of the fluidizing agent include, but are not limited to, light anhydrous silicic acid, hydrated silicon dioxide, talc, magnesium aluminate metasilicate, and the like.
  • examples of lubricants include, but are not limited to, magnesium stearate, calcium stearate, sodium stearyl fumarate, and hydrogenated oil.
  • lubricants include, but are not limited to, magnesium stearate and/or calcium stearate.
  • plasticizer examples include, but are not limited to, triethyl citrate, triacetin, polyethylene glycol, diethyl phthalate, dibutyl phthalate, and the like.
  • examples of the coloring agent include, but are not limited to, yellow iron sesquioxide, iron sesquioxide, titanium oxide, and the like.
  • the present disclosure provides a therapeutic agent for Parkinson's disease or Parkinson's syndrome, which includes the oral pharmaceutical composition of the present disclosure.
  • the present disclosure provides a treatment for Parkinson's disease comprising an oral pharmaceutical composition of the present disclosure.
  • Examples of the dosage form of the pharmaceutical composition of the present disclosure include, but are not limited to, granules, capsules containing granules, sticks containing granules, tablets containing granules, and the like.
  • the pharmaceutical composition of the present disclosure can be manufactured by common manufacturing methods in the technical field depending on its dosage form.
  • the granules of the present disclosure can be produced, for example, by the following steps.
  • Granules are produced by gradually dropping a solution (granulation liquid) while mixing levodopa, carbidopa, and additives (e.g., excipients, binders, disintegrants, lubricants, fluidizers, etc.) (agitation granulation method).
  • the granules obtained above are dried and sized, mixed with a lubricant, etc., and then compressed into granules (primary granules) using a tablet machine.
  • the compression pressure when compression molding the granules obtained above is within the range of 200 to 3000 N per granule.
  • the granules obtained above can also be produced as coated granules by coating them with a coating agent or the like by a known method.
  • a method for producing elementary granules for example, a direct granulation method in which a liquid containing levodopa, carbidopa, and a binder is sprayed onto levodopa and carbidopa fluidized in a fluidized bed to obtain high-content granules.
  • a layering method in which granules are obtained by spraying a liquid containing levodopa, carbidopa, and a binder onto core particles made of crystalline cellulose or saccharides
  • a layering method in which granules are obtained by mixing levodopa, carbidopa, and additives and then kneading them with water or a solvent.
  • Examples include, but are not limited to, an extrusion granulation method in which granules are produced by mixing and extruding the kneaded product through a mesh.
  • Capsules of the present disclosure can be produced by filling capsules with the above-mentioned elementary granules or coated granules by a general filling method in the technical field.
  • a capsule commonly used in the technical field can be used as the capsule.
  • gelatin capsules hydroxypropyl methylcellulose (HPMC) capsules, pullulan capsules, etc. (e.g., hydroxypropyl methylcellulose (HPMC) capsules), Licaps(TM) capsules, Vcaps(TM) capsules, Coni-Snap(TM) capsules, Press- Examples include, but are not limited to, fit(TM) capsules and Xpress-fit(TM) capsules.
  • the size of the capsule includes, for example, a No. 1 capsule, a No. 2 capsule, a No. 3 capsule, a No. 4 capsule, etc., but is not limited to these.
  • No. 3 capsules or No. 4 capsules are selected from the viewpoint of compliance.
  • the stick preparation of the present disclosure can be manufactured by using the above-mentioned granules or coated granules and filling them into stick packaging, which is common in the technical field.
  • the tablet of the present disclosure can be manufactured by a common tablet manufacturing method in the technical field using the above-mentioned granules or coated granules.
  • the formulation characteristics related to levodopa dissolution behavior obtained from the dissolution test of the present disclosure are useful for evaluation for formulation design of an oral pharmaceutical composition containing levodopa and carbidopa and exhibiting a levodopa blood dynamics profile that has both immediate and sustained action. Can be used as a reference.
  • formulation characteristics regarding levodopa dissolution behavior are evaluated as the results of a levodopa dissolution test using the paddle method described in Test Example 1 and the flow-through cell method described in Test Example 2.
  • the evaluation criteria for designing oral pharmaceutical compositions are the levodopa elution behavior of a pharmaceutical composition (preparation) that achieves a levodopa blood dynamics profile that is both immediate and long-lasting in healthy adults.
  • the range of formulation characteristics related to levodopa dissolution behavior described in Embodiment 1 can be mentioned.
  • Levodopa (median diameter: 55 ⁇ m) 500.0 g, carbidopa hydrate (median diameter: 7.4 ⁇ m) 135.0 g, crystalline cellulose 64.6 g, ammonioalkyl methacrylate copolymer 48.0 g, polyvinyl alcohol/acrylic acid/methacrylic acid After premixing 6.0 g of methyl copolymer and 6.0 g of light anhydrous silicic acid into a high-speed stirring granulator (Model FM-VG-10, manufactured by Powrex), 100 g of ethanol and 85 g of water were added. Granulated.
  • Model FM-VG-10 Model FM-VG-10, manufactured by Powrex
  • the obtained granulated product was dried in a fluidized bed dryer (manufactured by Powrex Co., Ltd.: Model MP-01), and then sized with a sieving machine (manufactured by Powrex Co., Ltd.: QC-197S model) to obtain a sized product.
  • a fluidized bed dryer manufactured by Powrex Co., Ltd.: Model MP-01
  • a sieving machine manufactured by Powrex Co., Ltd.: QC-197S model
  • Example 2 120.6 mg of coated granules obtained in Example 2 and 39.6 mg of elementary granules obtained in Example 3 were filled into a No. 3 capsule containing 100 mg of levodopa and 27 mg of carbidopa hydrate (25 mg as carbidopa). A long-acting formulation containing levodopa/carbidopa hydrate was obtained.
  • Levodopa 500.0 (median diameter: 55 ⁇ m) g, carbidopa hydrate (median diameter: 7.4 ⁇ m) 135.0 g, crystalline cellulose 76.6 g, ammonioalkyl methacrylate copolymer 24.0 g, polyvinyl alcohol/acrylic acid/methacrylate After premixing 18.0 g of acid methyl copolymer and 6.0 g of light anhydrous silicic acid into a high-speed stirring granulator (Model FM-VG-10, manufactured by Powrex), 95 g of ethanol and 85 g of water were added. and granulated.
  • Model FM-VG-10 Model FM-VG-10, manufactured by Powrex
  • the obtained granulated product was dried in a fluidized bed dryer (manufactured by Powrex Co., Ltd.: Model MP-01), and then sized with a sieving machine (manufactured by Powrex Co., Ltd.: QC-197S model) to obtain a sized product.
  • a fluidized bed dryer manufactured by Powrex Co., Ltd.: Model MP-01
  • a sieving machine manufactured by Powrex Co., Ltd.: QC-197S model
  • Example 122.4 mg of coated granules obtained in Example 6 and 39.6 mg of elementary granules obtained in Example 7 were filled into a No. 3 capsule containing 100 mg of levodopa and 27 mg of carbidopa hydrate (25 mg as carbidopa).
  • a long-acting formulation containing levodopa/carbidopa hydrate was obtained.
  • Levodopa (median diameter: 16 ⁇ m) 3400.0 g, carbidopa hydrate (median diameter: 4.5 ⁇ m) 918.0 g, crystalline cellulose 357.4 g, ammonioalkyl methacrylate copolymer 244.8 g, polyvinyl alcohol/acrylic acid/methacrylic acid 81.6 g of methyl copolymer and 81.6 g of light anhydrous silicic acid were premixed in a high-speed stirring granulator (Model FM-VG-25, manufactured by Powrex), and then 1100 g of water was added and granulated. .
  • a high-speed stirring granulator Model FM-VG-25, manufactured by Powrex
  • the obtained granulated product was dried in a fluidized bed dryer (manufactured by Powrex Co., Ltd.: FD-GPCG-5SPC type), and then sized with a sieving machine (manufactured by Powrex Co., Ltd.: QC-197S type) to obtain a sized product. I got it.
  • 1170 g of the obtained elementary granules were put into a ventilation coating machine (manufactured by Freund Sangyo: HC-FZ-LABO type), and 90.0 g of methacrylic acid copolymer LD (27.0 g as solid content), 13.5 g of talc, and D-mannitol were added.
  • a suspension of 10.8 g of triethyl citrate, 2.3 g of triethyl citrate, and 0.5 g of yellow iron sesquioxide in 480 g of purified water was sprayed to obtain coated granules each weighing 6.8 mg.
  • Example 122.4 mg of coated granules obtained in Example 10 and 39.6 mg of elementary granules obtained in Example 11 were filled into a No. 3 capsule containing 100 mg of levodopa and 27 mg of carbidopa hydrate (25 mg as carbidopa).
  • a long-acting formulation containing levodopa/carbidopa hydrate was obtained.
  • Example 10 979.2 g of the coated granules obtained in Example 10 were put into a ventilation coating machine (manufactured by Freund Sangyo: HC-FZ-LABO type), and 200.0 g of levodopa, 54.0 g of carbidopa hydrate, and polyvinyl alcohol/acrylic were added. A suspension of 13.7 g of acid/methyl methacrylate copolymer in 2,700 g of purified water was sprayed to obtain levodopa/carbidopa hydrate-containing long-lasting granules each containing 8.7 mg.
  • a ventilation coating machine manufactured by Freund Sangyo: HC-FZ-LABO type
  • Levodopa (median diameter: 16 ⁇ m) 4500.0 g, carbidopa hydrate (median diameter: 4.5 ⁇ m) 1215.0 g, crystalline cellulose 473.0 g, ammonioalkyl methacrylate copolymer 324.0 g, polyvinyl alcohol/acrylic acid/methacrylic acid 108.0 g of methyl copolymer and 108.0 g of light anhydrous silicic acid were premixed in a high-speed stirring granulator (Model FM-VG-25, manufactured by Powrex), and then 1500 g of water was added and granulated. .
  • a high-speed stirring granulator Model FM-VG-25, manufactured by Powrex
  • the obtained granulated product was dried in a fluidized bed dryer (manufactured by Powrex Co., Ltd.: FD-GPCG-5SPC type), and then sized with a sieving machine (manufactured by Powrex Co., Ltd.: QC-197S type) to obtain a sized product. I got it.
  • Example 15 129.2 mg of coated granules obtained in Example 15 and 39.6 mg of elementary granules obtained in Example 16 were filled into a No. 3 capsule containing 100 mg of levodopa and 27 mg of carbidopa hydrate (25 mg as carbidopa). A long-acting formulation containing levodopa/carbidopa hydrate was obtained.
  • Example 18 119.4 mg of coated granules obtained in Example 18 and 39.6 mg of elementary granules obtained in Example 19 were filled into a No. 3 capsule containing 100 mg of levodopa and 27 mg of carbidopa hydrate (25 mg as carbidopa). A long-acting formulation containing levodopa/carbidopa hydrate was obtained.
  • Example 21 234 g of the coated granules obtained in Example 21 were put into an aeration-type coating machine (manufactured by Freund Sangyo: HC-FZ-LABO type), and 72.0 g of levodopa, 19.4 g of carbidopa hydrate, and polyvinyl alcohol, acrylic acid, A suspension of 5.0 g of methyl methacrylate copolymer in 555 g of purified water was sprayed until the mass of one granule was 8.5 mg to obtain long-lasting granules containing levodopa/carbidopa hydrate.
  • an aeration-type coating machine manufactured by Freund Sangyo: HC-FZ-LABO type
  • Example 22 153.0 mg of the coated granules obtained in Example 22 were filled into No. 3 capsules to obtain a long-acting levodopa/carbidopa hydrate combination formulation containing 100 mg of levodopa and 27 mg of carbidopa hydrate (25 mg as carbidopa). .
  • Example 122.4 mg of coated granules obtained in Example 10 and 39.6 mg of elementary granules obtained in Example 24 were filled into a No. 3 capsule containing 100 mg of levodopa and 27 mg of carbidopa hydrate (25 mg as carbidopa).
  • a long-acting formulation containing levodopa/carbidopa hydrate was obtained.
  • Example 122.4 mg of coated granules obtained in Example 10 and 39.6 mg of elementary granules obtained in Example 26 were filled into a No. 3 capsule containing 100 mg of levodopa and 27 mg of carbidopa hydrate (25 mg as carbidopa).
  • a long-acting formulation containing levodopa/carbidopa hydrate was obtained.
  • Example 121.1 mg of the coated granules obtained in Example 28 and 39.6 mg of the elementary granules obtained in Example 11 were filled into No. 3 capsules, and levodopa containing 100 mg of levodopa and 27 mg of carbidopa hydrate (25 mg as carbidopa) was prepared. / Obtain a long-acting preparation containing carbidopa hydrate.
  • Neodopastone registered trademark
  • combination tablet L100 manufactured by Ohara Pharmaceutical Co., Ltd.
  • 1 tablet contains 100 mg of levodopa and 10.8 mg of carbidopa hydrate.
  • This levodopa elution behavior is because when each formulation is actually administered to a subject, levodopa in the formulation of Comparative Example 1 is expected to be rapidly eluted in the stomach and immediately absorbed in the gastrointestinal tract.
  • Example 8 Example 12, Example 17, Example 20, Example 23, Example 25, and Example 27 about 30% of levodopa was quickly absorbed in the stomach.
  • the levodopa blood concentration immediately rises to a certain level, and after that, even if the preparation remains in the subject's stomach, it gradually dissolves and maintains a constant levodopa blood concentration. It is suggested.
  • the first solution (pH 1.2) was diluted with McIlvaine buffer (pH 5.5) (manufactured by Kanto Kagaku) from 45 to 180 minutes, and the 18th revised Japanese Pharmacopoeia General Test Method was used from 180 to 540 minutes.
  • the prescribed elution test second solution (pH 6.8) was fed at a liquid temperature of 37° C. (range of 37 ⁇ 0.5° C.) and a liquid feeding rate of 16 mL/min.
  • Example 4 the pH 1.2 test About 30% of the indicated amount of the solution was eluted at 45 minutes after starting the dissolution test, and when the test solution with pH 5.5 and then the test solution with pH 6.8 were sent, levodopa was released regardless of the pH of the test solution. It was confirmed that eluted continuously.
  • Example 8 Example 12, Example 17, Example 20, Example 23, Example 25, and Example 27
  • levodopa blood concentration immediately increases to a certain level by eluting into the levodopa.
  • Example 4 and Example 8 when each of the formulations of Example 4 and Example 8 was administered to subjects, the plasma levodopa concentration quickly rose to a certain level, and the plasma levodopa concentration remained at the same level for about 4 hours thereafter. is made of.
  • the levodopa dissolution behavior of the presently disclosed formulation shown herein shows that an oral pharmaceutical composition containing levodopa and carbidopa as pharmaceutically active ingredients can achieve a levodopa blood dynamics profile that is both immediate and long-lasting. This suggests that this is a particularly important formulation characteristic.
  • Example 4 Sieving test Coated granules of Example 2, Example 6, Example 10, Example 15, Example 18, and Example 21, and Example 3, Example 7, Example 11, and Example 16 , the elementary granules of Examples 19, 24, and 26, and the levodopa/carbidopa hydrate combination long-lasting granules of Examples 13 and 22, all of which comply with the 18th revised Japanese Pharmacopoeia/General Test Methods. It passed through Japanese Pharmacopoeia Sieve No. 4.7 and remained on Japanese Pharmacopoeia Sieve No. 12, which is described in the particle size measurement method.
  • Example 5 Pharmacokinetic comparative study of levodopa depending on dosage in healthy adults Regarding the formulation obtained in Example 12 (levodopa 100 mg/carbidopa hydrate 27 mg), 17 healthy adult males were tested. capsules (levodopa 100 mg/carbidopa hydrate 27 mg), 2 capsules (levodopa 200 mg/carbidopa hydrate 54 mg) to 5 people, and 4 capsules (levodopa 400 mg/carbidopa hydrate 108 mg) to the remaining 6 people, each under fasting. A comparative pharmacokinetic study using oral administration was conducted. The results of the average plasma levodopa concentration over time for each preparation are shown in FIG. 2.
  • Example 12 When the formulation of Example 12 was administered to subjects at varying doses, the plasma levodopa concentration quickly rose to a certain level without being affected by the dose, and then remained at the same level for about 4 hours. Plasma levodopa concentration can be maintained. As described above, the formulation exhibiting the dissolution behavior shown in the present disclosure exhibits sustained pharmacokinetics without being affected by dosage, suggesting that it is possible to provide a clinically extremely meaningful formulation. .

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Abstract

The present disclosure provides an oral pharmaceutical composition containing levodopa and carbidopa as pharmaceutical active ingredients.

Description

レボドパ持続性製剤Levodopa long-acting formulation
　本開示は、薬学的活性成分としてレボドパとカルビドパを含有する顆粒、該顆粒を含む経口用医薬組成物、該経口用医薬組成物を含むパーキンソン病の治療剤に関する。 The present disclosure relates to granules containing levodopa and carbidopa as pharmaceutically active ingredients, an oral pharmaceutical composition containing the granules, and a therapeutic agent for Parkinson's disease containing the oral pharmaceutical composition.
　レボドパ（化学名：３－Ｈｙｄｒｏｘｙ－Ｌ－ｔｙｒｏｓｉｎｅ）は、パーキンソン病、パーキンソン症候群の治療に用いられる化合物（薬学的活性成分）である。レボドパとデカルボキシラーゼ阻害剤であるカルビドパ水和物（化学名：（２Ｓ)－２－(３，４－Ｄｉｈｙｄｒｏｘｙｂｅｎｚｙｌ)－２－ｈｙｄｒａｚｉｎｏｐｒｏｐａｎｏｉｃ　ａｃｉｄ　ｍｏｎｏｈｙｄｒａｔｅ）との併用療法も知られている。 Levodopa (chemical name: 3-Hydroxy-L-tyrosine) is a compound (pharmaceutically active ingredient) used for the treatment of Parkinson's disease and Parkinson's syndrome. Combination therapy with levodopa and carbidopa hydrate (chemical name: (2S)-2-(3,4-Dihydroxybenzyl)-2-hydrazinopropanoic acid monohydrate), a decarboxylase inhibitor, is also known.
　レボドパを含有する医薬品として、ドパストン（登録商標）、ネオドパストン（登録商標）、スタレボ（登録商標）等が市販されている。しかしながら、レボドパの血中半減期が１時間程度であることから、ウェアリングオフ現象やジスキネジア等の運動合併症が発現し、長期治療の際に大きな課題となっている。 Dopastone (registered trademark), neodopastone (registered trademark), Stalevo (registered trademark), etc. are commercially available as pharmaceuticals containing levodopa. However, since the blood half-life of levodopa is about 1 hour, motor complications such as wearing-off phenomenon and dyskinesia occur, which is a major problem in long-term treatment.
　レボドパの放出が制御された経口固形製剤として、良好な徐放性を有する、レボドパ含有小型化錠剤が報告されている（特許文献１）。また、レボドパ、デカルボキシラーゼ阻害剤、及びカルボン酸を含む、組成の異なる４種類以上の顆粒を同一カプセルに充填した製剤が報告されている（特許文献２）。 As an oral solid preparation with controlled release of levodopa, a miniaturized tablet containing levodopa with good sustained release properties has been reported (Patent Document 1). Furthermore, a preparation has been reported in which four or more types of granules containing levodopa, a decarboxylase inhibitor, and a carboxylic acid and having different compositions are filled into the same capsule (Patent Document 2).
　しかしながら、薬学的活性成分としてレボドパとカルビドパを含有し、即効性と持続性を併せ持つレボドパ血中動態プロファイルを示す経口用医薬組成物であって、その構成及び製造方法が複雑でなく、生産性の面で課題が少なく、更に服薬性にも優れた経口用医薬組成物は報告されていない。 However, it is an oral pharmaceutical composition that contains levodopa and carbidopa as pharmaceutically active ingredients and exhibits a levodopa blood dynamics profile that is both immediate and long-lasting. No oral pharmaceutical compositions have been reported that have fewer problems in terms of efficacy and are also excellent in takeability.
特許第７０６６３５１号Patent No. 7066351 特表２０１１－５０７９５６Special table 2011-507956
　放出制御製剤の設計においては、目標とする薬学的活性成分（本開示において、「薬物」とも呼ばれる。）の血中動態プロファイルを実現するために、どのような製剤特性が求められるかを明確にすることが必要である。その評価基準の開発は、製剤の設計時のみならず、実生産規模の製造における確実な品質コントロールにおいても重要である。 When designing a controlled-release formulation, it is important to clarify what formulation properties are required to achieve the targeted blood kinetic profile of the pharmaceutically active ingredient (also referred to as “drug” in this disclosure). It is necessary to. The development of evaluation criteria is important not only when designing pharmaceuticals, but also for reliable quality control during commercial-scale manufacturing.
　しかしながら、ｉｎ　ｖｉｖｏ試験における薬物の血中濃度とｉｎ　ｖｉｔｒｏ試験における製剤特性との相関を明確にした事例は少ない。特に、放出制御製剤においては、医薬組成物の胃排出時間や消化管ｐＨの違い等の影響を強く受けることから、目標とする製剤特性を見出すことは非常に困難である。 However, there are few cases in which the correlation between the blood concentration of a drug in an in-vivo test and the formulation characteristics in an in-vitro test has been clarified. In particular, it is very difficult to find target formulation characteristics for controlled release formulations because they are strongly influenced by the gastric emptying time of the pharmaceutical composition and differences in gastrointestinal pH.
　本発明者らは、本開示のレボドパとカルビドパを含有する経口用医薬組成物が、即効性と持続性を併せ持つ薬物の血中動態プロファイルを示すための重要な製剤特性について鋭意検討を行った。 The present inventors have conducted extensive studies on important formulation characteristics for the oral pharmaceutical composition containing levodopa and carbidopa of the present disclosure to exhibit a blood kinetic profile of a drug that has both immediate effect and long-lasting effect.
　その結果、胃排出時間や消化管内ｐＨの違いといった生体内における薬物動態の変動要因を考慮したｉｎ　ｖｉｔｒｏ試験における目標製剤特性を溶出試験法による薬物の溶出挙動として設定することで本開示の経口用医薬組成物の設計に成功した。 As a result, by setting the target formulation characteristics in in vitro tests as the dissolution behavior of the drug in the dissolution test method, which takes into account factors that fluctuate pharmacokinetics in vivo, such as differences in gastric emptying time and gastrointestinal pH, A pharmaceutical composition was successfully designed.
　具体的には、本開示の経口用医薬組成物が胃内に長時間滞留する可能性については、一般的には最長２時間の試験であるｐＨ１．２の溶出試験液を用いたパドル法の溶出試験を長時間延長して実施し、胃内でも薬物が徐々に放出するように目標製剤特性を溶出挙動として設定した。 Specifically, regarding the possibility that the oral pharmaceutical composition of the present disclosure will remain in the stomach for a long time, the paddle method using a pH 1.2 dissolution test solution is generally conducted for a maximum of 2 hours. The dissolution test was carried out over an extended period of time, and the target formulation characteristics were set as the dissolution behavior so that the drug would be released gradually even in the stomach.
　また、消化管内ｐＨの違いに対しては、溶出試験液をシームレスに変更可能なフロースルーセル法を、溶出試験液のｐＨをｐＨ１．２、ｐＨ５．５、ｐＨ６．８と試験時間の経過と共に変化させて実施し、本開示の経口用医薬組成物が消化管のどの部分に存在しても薬物が徐々に生体内に溶出するような目標製剤特性を溶出挙動として設定した。 In addition, in order to deal with differences in the pH within the gastrointestinal tract, we used the flow-through cell method, which allows the dissolution test solution to be seamlessly changed. The dissolution behavior was set as a target formulation characteristic such that the drug gradually elutes into the body no matter where the oral pharmaceutical composition of the present disclosure is present in the gastrointestinal tract.
　さらに、上記製剤特性を満たす経口用医薬組成物の構成（製剤成分、含量、配合比率等）について鋭意検討を重ねた結果、薬物放出を制御した顆粒を１種又は２種を組合わせることにより、上記製剤特性を満足しうる本開示の経口用医薬組成物の設計に成功した。 Furthermore, as a result of intensive studies on the composition of an oral pharmaceutical composition (formulation components, content, blending ratio, etc.) that satisfies the above formulation characteristics, we found that by combining one or two types of granules with controlled drug release, We have succeeded in designing an oral pharmaceutical composition of the present disclosure that can satisfy the above formulation characteristics.
　そのうえで、本開示の経口用医薬組成物を健康成人に投与した薬物動態比較試験を実施した結果、即効性と持続性を併せ持つレボドパ血中動態プロファイルを示すことが確認できたことから、本発明を完成させるに至った。 In addition, as a result of conducting a pharmacokinetic comparative study in which the oral pharmaceutical composition of the present disclosure was administered to healthy adults, it was confirmed that the oral pharmaceutical composition of the present disclosure exhibited a levodopa blood dynamics profile that had both immediate and long-lasting effects. I ended up completing it.
　本開示は、以下の特徴を包含する。
[１]
　レボドパとカルビドパを含有し、レボドパとカルビドパとの質量比率が、４：１である経口用医薬組成物であって、
第１８改正日本薬局方・一般試験法の溶出試験第２法（パドル法）に基づく溶出試験において、第１８改正日本薬局方・一般試験法に規定される溶出試験第１液（ｐＨ１．２）を９００ｍＬ用い、パドル回転数１００回転／分、液温３７℃（３７±０．５℃の範囲）による溶出試験を実施するとき、溶出試験開始後３０分時点におけるレボドパの溶出率が１８％～４３％であり、溶出試験開始後１８０分時点におけるレボドパの溶出率が２０％～８０％であり、溶出試験開始後３６０分時点におけるレボドパの溶出率が３０％以上であるレボドパ溶出挙動を特徴とする、経口用医薬組成物。
[２]
　前記溶出試験において、溶出試験開始後３０分時点におけるレボドパの溶出率が２０％～４０％であり、溶出試験開始後１８０分時点におけるレボドパの溶出率が２５％～７０％であり、溶出試験開始後３６０分時点におけるレボドパの溶出率が３５％以上であり、溶出試験開始後９６０分時点におけるレボドパの溶出率が７５％以上であるレボドパ溶出挙動を特徴とする、[１]に記載の経口用医薬組成物。
[３]
　レボドパとカルビドパを含有し、レボドパとカルビドパとの質量比率が、４：１である経口用医薬組成物であって、
第１８改正日本薬局方・一般試験法の溶出試験第３法（フロースルーセル法）に基づく溶出試験において、オープンループ法で小型フロースルーセルを用いて行い、脈流のある送液ポンプで、溶出試験開始から４５分までは第１８改正日本薬局方・一般試験法に規定される溶出試験第１液（ｐＨ１．２）を、４５分から１８０分までは薄めたＭｃＩｌｖａｉｎｅ緩衝液（ｐＨ５．５）を、１８０分から５４０分までは第１８改正日本薬局方・一般試験法に規定される溶出試験第２液（ｐＨ６．８）をいずれも液温３７℃（３７±０．５℃の範囲）、送液速度１６ｍＬ／分で送液した溶出試験を実施するとき、溶出試験開始後４５分時点におけるレボドパの溶出率が１５％～４５％であり、溶出試験開始後１８０分時点におけるレボドパの溶出率が４０％～８０％であり、溶出試験開始後５４０分時点におけるレボドパの溶出率が８０％以上であるレボドパ溶出挙動を特徴とする、経口用医薬組成物。
[４]
　前記溶出試験において、溶出試験開始後４５分時点におけるレボドパの溶出率が２０％～４０％であり、溶出試験開始後１８０分時点におけるレボドパの溶出率が５０％～７５％であり、溶出試験開始後５４０分時点におけるレボドパの溶出率が８０％以上であるレボドパ溶出挙動を特徴とする、[３]に記載の経口用医薬組成物。
[５]
　レボドパとカルビドパを含有し、レボドパとカルビドパとの質量比率が、４：１である経口用医薬組成物であって、
第１８改正日本薬局方・一般試験法の溶出試験第２法（パドル法）に基づく溶出試験において、第１８改正日本薬局方・一般試験法に規定される溶出試験第１液（ｐＨ１．２）を９００ｍＬ用い、パドル回転数１００回転／分、液温３７℃（３７±０．５℃の範囲）による溶出試験を実施するとき、溶出試験開始後３０分時点におけるレボドパの溶出率が２０％～４０％であり、溶出試験開始後１８０分時点におけるレボドパの溶出率が２５％～７０％であり、溶出試験開始後３６０分時点におけるレボドパの溶出率が３５％以上であり、溶出試験開始後９６０分時点におけるレボドパの溶出率が７５％以上であり、かつ
第１８改正日本薬局方・一般試験法の溶出試験第３法（フロースルーセル法）に基づく溶出試験において、オープンループ法で小型フロースルーセルを用いて行い、脈流のある送液ポンプで、溶出試験開始から４５分までは第１８改正日本薬局方・一般試験法に規定される溶出試験第１液（ｐＨ１．２）を、４５分から１８０分までは薄めたＭｃＩｌｖａｉｎｅ緩衝液（ｐＨ５．５）を、１８０分から５４０分までは第１８改正日本薬局方・一般試験法に規定される溶出試験第２液（ｐＨ６．８）をいずれも液温３７℃（３７±０．５℃の範囲）、送液速度１６ｍＬ／分で送液した溶出試験を実施するとき、溶出試験開始後４５分時点におけるレボドパの溶出率が２０％～４０％であり、溶出試験開始後１８０分時点におけるレボドパの溶出率が５０％～７５％であり、溶出試験開始後５４０分時点におけるレボドパの溶出率が８０％以上であるレボドパ溶出挙動を特徴とする、経口用医薬組成物。
[６]   
　レボドパとカルビドパ（質量比率４：１）を含む薬学的活性成分及び腸溶性高分子を含有する徐放部と、
レボドパとカルビドパ（質量比率４：１）を含む薬学的活性成分及び崩壊剤又は水溶性高分子を含有する速放部とを含み、
前記徐放部及び前記速放部は、それぞれ独立して顆粒を形成するか、又は、同一の顆粒を形成することを特徴とする、[１]～[５]のいずれか１つに記載の経口用医薬組成物。
[７] 
　レボドパとカルビドパを含有する経口用医薬組成物であって、
レボドパとカルビドパ（質量比率４：１）を含む薬学的活性成分及び腸溶性高分子を含有する徐放部と、
レボドパとカルビドパ（質量比率４：１）を含む薬学的活性成分及び崩壊剤又は水溶性高分子を含有する速放部とを含み、
前記徐放部及び前記速放部は、それぞれ独立して顆粒を形成するか、又は、同一の顆粒を形成することを特徴とする、経口用医薬組成物。
[８]
　前記徐放部に含まれるレボドパと前記速放部に含まれるレボドパの質量の比率が、４：１～３：２であることを特徴とする、[７]に記載の経口用医薬組成物。
[９]
　前記顆粒中のレボドパとカルビドパの合計質量が顆粒質量に対して７０％以上であることを特徴とする、[７]又は[８]に記載の経口用医薬組成物。
[１０]
　前記顆粒は、滑沢剤を顆粒質量に対して０．６％～１０％含有することを特徴とする、[７]～[９]のいずれか１つに記載の経口用医薬組成物。
[１１]
　前記滑沢剤が、ステアリン酸マグネシウム、ステアリン酸カルシウム、フマル酸ステアリルナトリウム、及び硬化油からなる群から選ばれる１種以上の滑沢剤である、[１０]に記載の経口用医薬組成物。
[１２]
　前記滑沢剤が、ステアリン酸マグネシウム及びステアリン酸カルシウムから選ばれる１種以上の滑沢剤である、[１０]に記載の経口用医薬組成物。
[１３]
　前記顆粒が、第１８改正日本薬局方・一般試験法の粒度測定法に記載される、日本薬局方ふるい番号４．７号を通過し、日本薬局方ふるい番号１２号に残留することを特徴とする、[７]～[１２]のいずれか１つに記載の経口用医薬組成物。
[１４]
　前記徐放部及び前記速放部が独立して顆粒を形成する経口用医薬組成物であって、前記徐放部を形成する顆粒が腸溶性高分子で被覆された顆粒であり、前記速放部を形成する顆粒が崩壊剤を含有する顆粒であることを特徴とする、[７]～[１３]のいずれか１つに記載の経口用医薬組成物。
[１５]
　前記徐放部及び前記速放部を形成する顆粒が、それぞれ結晶セルロース、アンモニオアルキルメタクリレートコポリマー、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、部分アルファー化デンプン、及び二酸化ケイ素からなる群から選ばれる１種以上の添加剤を含有する、[１４]に記載の経口用医薬組成物。
[１６]
　前記腸溶性高分子が、メタクリル酸コポリマーＬＤ、乾燥メタクリル酸コポリマーＬＤ、メタクリル酸コポリマーＬ、メタクリル酸コポリマーＳ、ヒプロメロース酢酸エステルコハク酸エステル、ヒプロメロースフタル酸エステル、及びカルボキシメチルエチルセルロースからなる群から選ばれる１種以上の腸溶性高分子である、[１４]に記載の経口用医薬組成物。
[１７]
　前記崩壊剤が、部分アルファー化デンプン、低置換度ヒドロキシプロピルセルロース、カルメロース、カルメロースカルシウム、ヒドロキシプロピルスターチ、デンプン、デンプングリコール酸ナトリウム、クロスカルメロースナトリウム、及びクロスポビドンからなる群から選ばれる１種以上の崩壊剤である、[１４]に記載の経口用医薬組成物。
[１８]
　前記徐放部及び前記速放部が同一の顆粒を形成する経口用医薬組成物であって、前記徐放部が腸溶性高分子で被覆された顆粒を形成し、更に該顆粒の周囲が水溶性高分子を含有する速放部により被覆された顆粒であることを特徴とする、[７]～[１３]のいずれか１つに記載の経口用医薬組成物。
[１９]
　前記徐放部を形成する顆粒が、結晶セルロース、アンモニオアルキルメタクリレートコポリマー、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、部分アルファー化デンプン、及び二酸化ケイ素からなる群から選ばれる１種以上の添加剤を含有する、[１８]に記載の経口用医薬組成物。
[２０]
　前記腸溶性高分子が、メタクリル酸コポリマーＬＤ、乾燥メタクリル酸コポリマーＬＤ、メタクリル酸コポリマーＬ、メタクリル酸コポリマーＳ、ヒプロメロース酢酸エステルコハク酸エステル、ヒプロメロースフタル酸エステル、及びカルボキシメチルエチルセルロースからなる群から選ばれる１種以上の腸溶性高分子である、[１８]に記載の経口用医薬組成物。
[２１]
　前記水溶性高分子が、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、ポリビニルアルコール、ヒドロキシプロピルセルロース、ヒプロメロース、メチルセルロース、ポビドン、カルメロースナトリウム、及びアルファー化デンプンからなる群から選ばれる１種以上の水溶性高分子である、[１８]に記載の経口用医薬組成物。
[２２]
　前記経口用医薬組成物が、顆粒剤、カプセル剤、スティック剤、又は錠剤である、[７]～[２１]のいずれか１つに記載の経口用医薬組成物。
[２３]
　[７]～[２２]のいずれか１つに記載の経口用医薬組成物を含む、パーキンソン病又はパーキンソン症候群の治療剤。
[２４]
　[７]～[２２]のいずれか１つに記載の経口用医薬組成物を含む、パーキンソン病の治療剤。
[２５]
　レボドパとカルビドパを含有する経口用医薬組成物を製剤設計するための評価基準としての、[１]～[５]のいずれかに１つ記載されたレボドパ溶出挙動に関する製剤特性の使用。 The present disclosure includes the following features.
[1]
An oral pharmaceutical composition containing levodopa and carbidopa, the mass ratio of levodopa and carbidopa being 4:1,
In the dissolution test based on the dissolution test method 2 (paddle method) of the 18th revised Japanese Pharmacopoeia/General Test Methods, the dissolution test first solution (pH 1.2) specified in the 18th revised Japanese Pharmacopoeia/General Test Methods was used. When conducting a dissolution test using 900 mL of levodopa at a paddle rotation speed of 100 revolutions/min and a liquid temperature of 37°C (range of 37 ± 0.5°C), the dissolution rate of levodopa at 30 minutes after the start of the dissolution test was 18% or more. 43%, the dissolution rate of levodopa at 180 minutes after the start of the dissolution test is 20% to 80%, and the dissolution rate of levodopa at 360 minutes after the start of the dissolution test is 30% or more. An oral pharmaceutical composition.
[2]
In the dissolution test, the dissolution rate of levodopa at 30 minutes after the start of the dissolution test was 20% to 40%, and the dissolution rate of levodopa at 180 minutes after the start of the dissolution test was 25% to 70%, and the dissolution rate was 25% to 70% after the start of the dissolution test. The oral use according to [1], characterized by a levodopa dissolution behavior in which the dissolution rate of levodopa is 35% or more at 360 minutes after the start of the dissolution test, and the dissolution rate of levodopa is 75% or more at 960 minutes after the start of the dissolution test. Pharmaceutical composition.
[3]
An oral pharmaceutical composition containing levodopa and carbidopa, the mass ratio of levodopa and carbidopa being 4:1,
In the dissolution test based on the dissolution test method 3 (flow-through cell method) of the 18th revised Japanese Pharmacopoeia/General Tests, the dissolution test was performed using a small flow-through cell using the open loop method, and a liquid delivery pump with pulsating flow was used. For 45 minutes from the start of the dissolution test, use the first dissolution test solution (pH 1.2) specified in the 18th revised Japanese Pharmacopoeia/General Test Methods, and from 45 minutes to 180 minutes, use diluted McIlvaine buffer (pH 5.5). From 180 to 540 minutes, the second dissolution test liquid (pH 6.8) specified in the 18th revised Japanese Pharmacopoeia/General Test Methods was used at a liquid temperature of 37°C (37 ± 0.5°C range). When performing a dissolution test at a rate of 16 mL/min, the dissolution rate of levodopa at 45 minutes after the start of the dissolution test was 15% to 45%, and the dissolution rate of levodopa at 180 minutes after the start of the dissolution test. is 40% to 80%, and the dissolution rate of levodopa at 540 minutes after the start of a dissolution test is 80% or more.
[4]
In the dissolution test, the dissolution rate of levodopa at 45 minutes after the start of the dissolution test was 20% to 40%, and the dissolution rate of levodopa at 180 minutes after the start of the dissolution test was 50% to 75%, and the dissolution rate at 180 minutes after the start of the dissolution test was 50% to 75%. The oral pharmaceutical composition according to [3], characterized by a levodopa dissolution behavior in which the levodopa dissolution rate at 540 minutes is 80% or more.
[5]
An oral pharmaceutical composition containing levodopa and carbidopa, the mass ratio of levodopa and carbidopa being 4:1,
In the dissolution test based on the dissolution test method 2 (paddle method) of the 18th revised Japanese Pharmacopoeia/General Test Methods, the dissolution test first solution (pH 1.2) specified in the 18th revised Japanese Pharmacopoeia/General Test Methods was used. When performing a dissolution test using 900 mL of levodopa at a paddle rotation speed of 100 revolutions/min and a liquid temperature of 37°C (range of 37 ± 0.5°C), the dissolution rate of levodopa at 30 minutes after the start of the dissolution test is 20% or more. 40%, the dissolution rate of levodopa at 180 minutes after the start of the dissolution test is 25% to 70%, the dissolution rate of levodopa at 360 minutes after the start of the dissolution test is 35% or more, and the dissolution rate is 960% after the start of the dissolution test. The dissolution rate of levodopa at the time point of 75% or more, and in the dissolution test based on the dissolution test method 3 (flow-through cell method) of the 18th revised Japanese Pharmacopoeia/General Tests, the small flow-through cell was tested using the open-loop method. The first dissolution test solution (pH 1.2) specified in the 18th revised Japanese Pharmacopoeia/General Test Methods was applied to the dissolution test using a liquid pump with pulsating flow until 45 minutes after the start of the dissolution test. From 180 to 180 minutes, use diluted McIlvaine buffer (pH 5.5), and from 180 to 540 minutes, use the second dissolution test solution (pH 6.8) specified in the 18th revised Japanese Pharmacopoeia/General Test Methods. When performing a dissolution test at a liquid temperature of 37°C (37 ± 0.5°C range) and a liquid delivery rate of 16 mL/min, the dissolution rate of levodopa at 45 minutes after the start of the dissolution test was 20% to 40%. and is characterized by a levodopa dissolution behavior in which the dissolution rate of levodopa at 180 minutes after the start of the dissolution test is 50% to 75%, and the dissolution rate of levodopa at 540 minutes after the start of the dissolution test is 80% or more, Oral pharmaceutical composition.
[6]
a sustained release part containing a pharmaceutically active ingredient containing levodopa and carbidopa (mass ratio 4:1) and an enteric polymer;
comprising a pharmaceutically active ingredient containing levodopa and carbidopa (mass ratio 4:1) and an immediate release part containing a disintegrant or a water-soluble polymer;
The sustained release portion and the immediate release portion each independently form granules or form the same granule, according to any one of [1] to [5]. Oral pharmaceutical composition.
[7]
An oral pharmaceutical composition containing levodopa and carbidopa,
a sustained release part containing a pharmaceutically active ingredient containing levodopa and carbidopa (mass ratio 4:1) and an enteric polymer;
comprising a pharmaceutically active ingredient containing levodopa and carbidopa (mass ratio 4:1) and an immediate release part containing a disintegrant or a water-soluble polymer;
An oral pharmaceutical composition, wherein the sustained release part and the immediate release part each form granules independently or form the same granule.
[8]
The oral pharmaceutical composition according to [7], wherein the mass ratio of levodopa contained in the sustained release part to levodopa contained in the immediate release part is 4:1 to 3:2.
[9]
The oral pharmaceutical composition according to [7] or [8], wherein the total mass of levodopa and carbidopa in the granules is 70% or more based on the mass of the granules.
[10]
The oral pharmaceutical composition according to any one of [7] to [9], wherein the granules contain a lubricant in an amount of 0.6% to 10% based on the mass of the granules.
[11]
The oral pharmaceutical composition according to [10], wherein the lubricant is one or more lubricants selected from the group consisting of magnesium stearate, calcium stearate, sodium stearyl fumarate, and hydrogenated oil.
[12]
The oral pharmaceutical composition according to [10], wherein the lubricant is one or more lubricants selected from magnesium stearate and calcium stearate.
[13]
The granules are characterized in that they pass through Japanese Pharmacopoeia Sieve No. 4.7 and remain in Japanese Pharmacopoeia Sieve No. 12, as described in the Particle Size Measurement Method of the 18th Edition of the Japanese Pharmacopoeia/General Tests. The oral pharmaceutical composition according to any one of [7] to [12].
[14]
An oral pharmaceutical composition in which the sustained release portion and the immediate release portion independently form granules, wherein the granules forming the sustained release portion are coated with an enteric polymer; The oral pharmaceutical composition according to any one of [7] to [13], wherein the granules forming the part are granules containing a disintegrant.
[15]
The granules forming the sustained release portion and the immediate release portion are each selected from the group consisting of crystalline cellulose, ammonioalkyl methacrylate copolymer, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, partially pregelatinized starch, and silicon dioxide. The oral pharmaceutical composition according to [14], which contains one or more selected additives.
[16]
The enteric polymer is selected from the group consisting of methacrylic acid copolymer LD, dry methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, hypromellose acetate succinate, hypromellose phthalate ester, and carboxymethylethylcellulose. The oral pharmaceutical composition according to [14], which is one or more selected enteric polymers.
[17]
The disintegrant is one selected from the group consisting of partially pregelatinized starch, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, hydroxypropyl starch, starch, sodium starch glycolate, croscarmellose sodium, and crospovidone. The oral pharmaceutical composition according to [14], which is the above disintegrant.
[18]
An oral pharmaceutical composition in which the sustained release part and the immediate release part form the same granule, wherein the sustained release part forms granules coated with an enteric polymer, and the surroundings of the granules are water-soluble. The oral pharmaceutical composition according to any one of [7] to [13], characterized in that it is a granule coated with an immediate release part containing a sex polymer.
[19]
The granules forming the sustained release portion are made of one or more selected from the group consisting of crystalline cellulose, ammonioalkyl methacrylate copolymer, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, partially pregelatinized starch, and silicon dioxide. The oral pharmaceutical composition according to [18], which contains an additive.
[20]
The enteric polymer is selected from the group consisting of methacrylic acid copolymer LD, dry methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, hypromellose acetate succinate, hypromellose phthalate ester, and carboxymethylethylcellulose. The oral pharmaceutical composition according to [18], which is one or more selected enteric polymers.
[21]
The water-soluble polymer is one or more selected from the group consisting of polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, polyvinyl alcohol, hydroxypropylcellulose, hypromellose, methylcellulose, povidone, carmellose sodium, and pregelatinized starch. The oral pharmaceutical composition according to [18], which is a water-soluble polymer.
[22]
The oral pharmaceutical composition according to any one of [7] to [21], wherein the oral pharmaceutical composition is a granule, a capsule, a stick, or a tablet.
[23]
A therapeutic agent for Parkinson's disease or Parkinson's syndrome, comprising the oral pharmaceutical composition according to any one of [7] to [22].
[24]
A therapeutic agent for Parkinson's disease, comprising the oral pharmaceutical composition according to any one of [7] to [22].
[25]
Use of the formulation characteristics related to levodopa dissolution behavior described in any one of [1] to [5] as an evaluation criterion for designing an oral pharmaceutical composition containing levodopa and carbidopa.
　本開示により、即効性と持続性を併せ持つレボドパ血中動態プロファイルを示し、且つ小型化されて利便性が向上した、レボドパとカルビドパを含有する経口用医薬組成物（本開示において、「放出制御製剤」又は「レボドパ／カルビドパ水和物配合持続性製剤」とも呼ばれる。）を提供できることが示唆される。 The present disclosure provides an oral pharmaceutical composition containing levodopa and carbidopa (in the present disclosure, a "controlled release preparation") that exhibits a levodopa blood dynamics profile that is both immediate and sustained, and is miniaturized and has improved convenience. ” or “levodopa/carbidopa hydrate combination long-acting preparation”).
　本開示により、薬物放出を制御した顆粒（本開示において、「素顆粒」、「コーティング顆粒」又は「レボドパ／カルビドパ水和物配合持続性顆粒」とも呼ばれる。）を１種又は２種を組合わせることで、レボドパとカルビドパを含有する経口用医薬組成物の製造工程を省力化することができ、生産性が大幅に向上できることが示唆される。 According to the present disclosure, one type or two types of granules with controlled drug release (also referred to as "plain granules", "coated granules", or "levodopa/carbidopa hydrate blended long-lasting granules" in the present disclosure) are combined. This suggests that it is possible to save labor in the manufacturing process of an oral pharmaceutical composition containing levodopa and carbidopa, and that productivity can be significantly improved.
　本開示により、レボドパとカルビドパをより高含有量含み、且つ小型化が可能となり、患者の服用時の負担が軽減されたレボドパとカルビドパを含有する経口用医薬組成物を提供できることが示唆される。 It is suggested that the present disclosure makes it possible to provide an oral pharmaceutical composition containing levodopa and carbidopa that contains a higher content of levodopa and carbidopa, that can be made smaller, and that reduces the burden on patients when taking it.
　本開示により、カルボン酸のような酸成分を必須の成分として含むことなく、即効性と持続性を併せ持つレボドパ血中動態プロファイル示すレボドパとカルビドパを含有する経口用医薬組成物を提供できることが示唆される。 It is suggested that the present disclosure makes it possible to provide an oral pharmaceutical composition containing levodopa and carbidopa that exhibits a levodopa blood dynamics profile that is both immediate and long-lasting, without containing an acid component such as a carboxylic acid as an essential component. Ru.
　本開示により、レボドパとカルビドパを含有する経口用医薬組成物を製剤設計するための評価基準として使用される、レボドパ溶出挙動に関する製剤特性を提供できることが示唆される。 It is suggested that the present disclosure can provide formulation characteristics related to levodopa dissolution behavior that are used as evaluation criteria for formulation design of oral pharmaceutical compositions containing levodopa and carbidopa.
本開示の実施例４及び実施例８で得られたレボドパとカルビドパを含有するそれぞれの経口用医薬組成物、並びに比較例１のレボドパとカルビドパを含有する製剤を用いて、健康成人男性を対象とした薬物動態比較試験を実施し、その平均血漿中レボドパ濃度推移を示す図である。Using the oral pharmaceutical compositions containing levodopa and carbidopa obtained in Examples 4 and 8 of the present disclosure, and the formulation containing levodopa and carbidopa of Comparative Example 1, healthy adult males were administered. FIG. 2 is a diagram showing the average plasma levodopa concentration over time after conducting a comparative pharmacokinetic study. 本開示の実施例１２で得られた製剤について、健康成人男性１７人を対象とし、６人に１カプセル、５人に２カプセルおよび残り６人に４カプセルをそれぞれ絶食下で単回経口投与する薬物動態比較試験を実施し、それぞれの製剤の平均血漿中レボドパ濃度推移の結果を示す図である。The formulation obtained in Example 12 of the present disclosure is administered orally in a single dose to 17 healthy adult males under fasting conditions, with 1 capsule to 6 males, 2 capsules to 5 males, and 4 capsules to the remaining 6 males. FIG. 2 is a diagram showing the results of a pharmacokinetic comparison test and the changes in average plasma levodopa concentration for each preparation.
  以下、本開示の経口用医薬組成物等を詳細に説明する。但し、以下の記載は本開示を説明するための例示であり、本開示をこの記載範囲にのみ限定する趣旨ではない。 Hereinafter, the oral pharmaceutical composition and the like of the present disclosure will be explained in detail. However, the following description is an example for explaining the present disclosure, and is not intended to limit the present disclosure only to the scope of this description.
  本開示の経口用医薬組成物は、薬学的活性成分としてレボドパとカルビドパを含有する。レボドパとカルビドパは、無水物、水和物、塩等、薬理学的に等価な分子種であれば、いずれも使用することができる。 The oral pharmaceutical composition of the present disclosure contains levodopa and carbidopa as pharmaceutically active ingredients. Any pharmacologically equivalent molecular species of levodopa and carbidopa, such as anhydride, hydrate, salt, etc., can be used.
　一部の実施形態において、本開示の経口用医薬組成物は、薬学的活性成分としてレボドパとカルビドパ水和物を含有する。 In some embodiments, the oral pharmaceutical composition of the present disclosure contains levodopa and carbidopa hydrate as pharmaceutically active ingredients.
　レボドパとカルビドパは、必要に応じて適宜乾式又は湿式粉砕を行い、任意の粒子径に調整することも可能である。尚、メディアン径は、レーザー回析・散乱法によって測定（体積基準）することが可能である。 Levodopa and carbidopa can be adjusted to any particle size by dry or wet pulverization as necessary. Note that the median diameter can be measured (based on volume) by laser diffraction/scattering method.
　一部の実施形態において、レボドパとカルビドパのメディアン径（ｄ５０）は、１．０μｍ～１００．０μｍである。 In some embodiments, the median diameter (d 50 ) of levodopa and carbidopa is between 1.0 μm and 100.0 μm.
　別の実施形態において、レボドパとカルビドパのメディアン径（ｄ５０）は、３．０μｍ～７５μｍである。　 In another embodiment, the median diameter (d 50 ) of levodopa and carbidopa is between 3.0 μm and 75 μm.
　本開示の経口用医薬組成物は、レボドパとカルビドパ（無水物として）を質量比率４：１で含有する。尚、本開示において、特に説明がない限り、レボドパとカルビドパとの質量比率を算出する際のカルビドパは、カルビドパ無水物としての質量で算出される。 The oral pharmaceutical composition of the present disclosure contains levodopa and carbidopa (as anhydrous) in a mass ratio of 4:1. In the present disclosure, unless otherwise specified, carbidopa when calculating the mass ratio of levodopa to carbidopa is calculated based on the mass of carbidopa anhydride.
実施形態１ Embodiment 1
　一部の実施形態において、本開示は、レボドパとカルビドパを含有し、レボドパとカルビドパとの質量比率が、４：１である経口用医薬組成物であって、
第１８改正日本薬局方・一般試験法の溶出試験第２法（パドル法）に基づく溶出試験において、第１８改正日本薬局方・一般試験法に規定される溶出試験第１液（ｐＨ１．２）を９００ｍＬ用い、パドル回転数１００回転／分、液温３７℃（３７±０．５℃の範囲）による溶出試験を実施するとき、溶出試験開始後３０分時点におけるレボドパの溶出率が１８％～４３％であり、溶出試験開始後１８０分時点におけるレボドパの溶出率が２０％～８０％であり、溶出試験開始後３６０分時点におけるレボドパの溶出率が３０％以上であるレボドパ溶出挙動を特徴とする、経口用医薬組成物を提供する。 In some embodiments, the present disclosure provides an oral pharmaceutical composition comprising levodopa and carbidopa, wherein the weight ratio of levodopa to carbidopa is 4:1,
In the dissolution test based on the dissolution test method 2 (paddle method) of the 18th revised Japanese Pharmacopoeia/General Test Methods, the dissolution test first solution (pH 1.2) specified in the 18th revised Japanese Pharmacopoeia/General Test Methods was used. When conducting a dissolution test using 900 mL of levodopa at a paddle rotation speed of 100 revolutions/min and a liquid temperature of 37°C (range of 37 ± 0.5°C), the dissolution rate of levodopa at 30 minutes after the start of the dissolution test was 18% or more. 43%, the dissolution rate of levodopa at 180 minutes after the start of the dissolution test is 20% to 80%, and the dissolution rate of levodopa at 360 minutes after the start of the dissolution test is 30% or more. An oral pharmaceutical composition is provided.
　一部の実施形態において、本開示は、前記溶出試験において、溶出試験開始後３０分時点におけるレボドパの溶出率が２０％～４０％であり、溶出試験開始後１８０分時点におけるレボドパの溶出率が２５％～７０％であり、溶出試験開始後３６０分時点におけるレボドパの溶出率が３５％以上であり、溶出試験開始後９６０分時点におけるレボドパの溶出率が７５％以上であるレボドパ溶出挙動を特徴とする経口用医薬組成物を提供する。 In some embodiments, the present disclosure provides, in the dissolution test, the dissolution rate of levodopa at 30 minutes after the start of the dissolution test is 20% to 40%, and the dissolution rate of levodopa at 180 minutes after the start of the dissolution test is 20% to 40%. 25% to 70%, the dissolution rate of levodopa is 35% or more at 360 minutes after the start of the dissolution test, and the dissolution rate of levodopa is 75% or more at 960 minutes after the start of the dissolution test. An oral pharmaceutical composition is provided.
　一部の実施形態において、本開示はレボドパとカルビドパを含有し、レボドパとカルビドパとの質量比率が、４：１である経口用医薬組成物であって、
第１８改正日本薬局方・一般試験法の溶出試験第３法（フロースルーセル法）に基づく溶出試験において、オープンループ法で小型フロースルーセルを用いて行い、脈流のある送液ポンプで、溶出試験開始から４５分までは第１８改正日本薬局方・一般試験法に規定される溶出試験第１液（ｐＨ１．２）を、４５分から１８０分までは薄めたＭｃＩｌｖａｉｎｅ緩衝液（ｐＨ５．５）を、１８０分から５４０分までは第１８改正日本薬局方・一般試験法に規定される溶出試験第２液（ｐＨ６．８）をいずれも液温３７℃（３７±０．５℃の範囲）、送液速度１６ｍＬ／分で送液した溶出試験を実施するとき、溶出試験開始後４５分時点におけるレボドパの溶出率が１５％～４５％であり、溶出試験開始後１８０分時点におけるレボドパの溶出率が４０％～８０％であり、溶出試験開始後５４０分時点におけるレボドパの溶出率が８０％以上であるレボドパ溶出挙動を特徴とする、経口用医薬組成物を提供する。 In some embodiments, the present disclosure provides an oral pharmaceutical composition comprising levodopa and carbidopa, wherein the weight ratio of levodopa to carbidopa is 4:1,
In the dissolution test based on the dissolution test method 3 (flow-through cell method) of the 18th revised Japanese Pharmacopoeia/General Tests, the open-loop method was performed using a small flow-through cell, and a liquid delivery pump with pulsating flow was used. For 45 minutes from the start of the dissolution test, use the first dissolution test solution (pH 1.2) specified in the 18th revised Japanese Pharmacopoeia/General Test Methods, and from 45 minutes to 180 minutes, use diluted McIlvaine buffer (pH 5.5). From 180 to 540 minutes, the second dissolution test liquid (pH 6.8) specified in the 18th revised Japanese Pharmacopoeia/General Test Methods was used at a liquid temperature of 37°C (37 ± 0.5°C range). When performing a dissolution test in which the liquid was delivered at a delivery rate of 16 mL/min, the dissolution rate of levodopa at 45 minutes after the start of the dissolution test was 15% to 45%, and the dissolution rate of levodopa at 180 minutes after the start of the dissolution test. is 40% to 80%, and the dissolution rate of levodopa at 540 minutes after the start of a dissolution test is 80% or more.
　一部の実施形態において、本開示は、前記溶出試験において、溶出試験開始後４５分時点におけるレボドパの溶出率が２０％～４０％であり、溶出試験開始後１８０分時点におけるレボドパの溶出率が５０％～７５％であり、溶出試験開始後５４０分時点におけるレボドパの溶出率が８０％以上であるレボドパ溶出挙動を特徴とする、経口用医薬組成物を提供する。 In some embodiments, the present disclosure provides that in the dissolution test, the dissolution rate of levodopa at 45 minutes after the start of the dissolution test is 20% to 40%, and the dissolution rate of levodopa at 180 minutes after the start of the dissolution test is 20% to 40%. The present invention provides an oral pharmaceutical composition characterized by a levodopa dissolution behavior of 50% to 75% and a levodopa dissolution rate of 80% or more at 540 minutes after the start of a dissolution test.
　一部の実施形態において、本開示は、レボドパとカルビドパを含有し、レボドパとカルビドパとの質量比率が、４：１である経口用医薬組成物であって、
第１８改正日本薬局方・一般試験法の溶出試験第２法（パドル法）に基づく溶出試験において、第１８改正日本薬局方・一般試験法に規定される溶出試験第１液（ｐＨ１．２）を９００ｍＬ用い、パドル回転数１００回転／分、液温３７℃（３７±０．５℃の範囲）による溶出試験を実施するとき、溶出試験開始後３０分時点におけるレボドパの溶出率が２０％～４０％であり、溶出試験開始後１８０分時点におけるレボドパの溶出率が２５％～７０％であり、溶出試験開始後３６０分時点におけるレボドパの溶出率が３５％以上であり、溶出試験開始後９６０分時点におけるレボドパの溶出率が７５％以上であり、かつ
第１８改正日本薬局方・一般試験法の溶出試験第３法（フロースルーセル法）に基づく溶出試験において、オープンループ法で小型フロースルーセルを用いて行い、脈流のある送液ポンプで、溶出試験開始から４５分までは第１８改正日本薬局方・一般試験法に規定される溶出試験第１液（ｐＨ１．２）を、４５分から１８０分までは薄めたＭｃＩｌｖａｉｎｅ緩衝液（ｐＨ５．５）を、１８０分から５４０分までは第１８改正日本薬局方・一般試験法に規定される溶出試験第２液（ｐＨ６．８）をいずれも液温３７℃（３７±０．５℃の範囲）、送液速度１６ｍＬ／分で送液した溶出試験を実施するとき、溶出試験開始後４５分時点におけるレボドパの溶出率が２０％～４０％であり、溶出試験開始後１８０分時点におけるレボドパの溶出率が５０％～７５％であり、溶出試験開始後５４０分時点におけるレボドパの溶出率が８０％以上であるレボドパ溶出挙動を特徴とする、経口用医薬組成物を提供する。 In some embodiments, the present disclosure provides an oral pharmaceutical composition comprising levodopa and carbidopa, wherein the weight ratio of levodopa to carbidopa is 4:1,
In the dissolution test based on the dissolution test method 2 (paddle method) of the 18th revised Japanese Pharmacopoeia/General Test Methods, the dissolution test first solution (pH 1.2) specified in the 18th revised Japanese Pharmacopoeia/General Test Methods was used. When performing a dissolution test using 900 mL of levodopa at a paddle rotation speed of 100 revolutions/min and a liquid temperature of 37°C (range of 37 ± 0.5°C), the dissolution rate of levodopa at 30 minutes after the start of the dissolution test is 20% or more. 40%, the dissolution rate of levodopa at 180 minutes after the start of the dissolution test is 25% to 70%, the dissolution rate of levodopa at 360 minutes after the start of the dissolution test is 35% or more, and the dissolution rate is 960% after the start of the dissolution test. The dissolution rate of levodopa at the time point of 75% or more, and in the dissolution test based on the dissolution test method 3 (flow-through cell method) of the 18th revised Japanese Pharmacopoeia/General Tests, the small flow-through cell was tested using the open-loop method. The first dissolution test solution (pH 1.2) specified in the 18th revised Japanese Pharmacopoeia/General Test Methods was applied to the dissolution test using a liquid pump with pulsating flow until 45 minutes after the start of the dissolution test. From 180 to 180 minutes, use diluted McIlvaine buffer (pH 5.5), and from 180 to 540 minutes, use the second dissolution test solution (pH 6.8) specified in the 18th revised Japanese Pharmacopoeia/General Test Methods. When performing a dissolution test at a liquid temperature of 37°C (37 ± 0.5°C range) and a liquid delivery rate of 16 mL/min, the dissolution rate of levodopa at 45 minutes after the start of the dissolution test was 20% to 40%. and is characterized by a levodopa dissolution behavior in which the dissolution rate of levodopa at 180 minutes after the start of the dissolution test is 50% to 75%, and the dissolution rate of levodopa at 540 minutes after the start of the dissolution test is 80% or more, Oral pharmaceutical compositions are provided.
　一部の実施形態において、本開示は、レボドパとカルビドパを含有し、レボドパとカルビドパとの質量比率が、４：１である経口用医薬組成物であって、レボドパとカルビドパ（質量比率４：１）を含む薬学的活性成分及び腸溶性高分子を含有する徐放部と、
レボドパとカルビドパ（質量比率４：１）を含む薬学的活性成分及び崩壊剤又は水溶性高分子を含有する速放部とを含み、
前記徐放部及び前記速放部は、それぞれ独立して顆粒を形成するか、又は、同一の顆粒を形成することを特徴とし、かつ前記パドル法及び／又はフロースルーセル法で示すレボドパ溶出挙動を特徴とする、経口用医薬組成物を提供する。 In some embodiments, the present disclosure provides an oral pharmaceutical composition comprising levodopa and carbidopa, wherein the weight ratio of levodopa and carbidopa is 4:1, the composition comprising: ) and a sustained release part containing a pharmaceutically active ingredient and an enteric polymer;
comprising a pharmaceutically active ingredient containing levodopa and carbidopa (mass ratio 4:1) and an immediate release part containing a disintegrant or a water-soluble polymer;
The sustained release part and the immediate release part are characterized in that they each form granules independently or form the same granule, and the levodopa elution behavior shown in the paddle method and/or flow-through cell method is Provided is an oral pharmaceutical composition characterized by:
　実施形態１では、レボドパとカルビドパを含有する経口用医薬組成物について、レボドパ溶出挙動に基づく製剤特性の観点から実施形態を例示した。ここで、レボドパとカルビドパを含有する経口用医薬組成物は、実施形態１に示されるレボドパ溶出挙動を満足する医薬組成物であればよく、医薬組成物の構成（製剤成分、含量、配合比率等）については特に制限されるものではない。 In Embodiment 1, an oral pharmaceutical composition containing levodopa and carbidopa was exemplified from the viewpoint of formulation characteristics based on levodopa dissolution behavior. Here, the oral pharmaceutical composition containing levodopa and carbidopa may be any pharmaceutical composition that satisfies the levodopa elution behavior shown in Embodiment 1, and the composition of the pharmaceutical composition (formulation components, content, blending ratio, etc.) ) are not particularly limited.
　以下の実施形態２－４では、レボドパとカルビドパを含有する経口用医薬組成物について、医薬組成物の構成（製剤成分、含量、配合比率等）の観点から実施形態を例示するが、これらに限定されるものではない。 In Embodiment 2-4 below, embodiments of an oral pharmaceutical composition containing levodopa and carbidopa will be exemplified from the viewpoint of the composition of the pharmaceutical composition (formulation components, content, blending ratio, etc.), but are limited to these. It is not something that will be done.
実施形態２ Embodiment 2
　一部の実施形態において、本開示は、レボドパとカルビドパを含有する経口用医薬組成物であって、レボドパとカルビドパ（質量比率４：１）を含む薬学的活性成分及び腸溶性高分子を含有する徐放部と、レボドパとカルビドパ（質量比率４：１）を含む薬学的活性成分及び水溶性高分子を含有する速放部とを含むことを特徴とする、経口用医薬組成物を提供する。前記徐放部及び前記速放部は、それぞれ独立して顆粒を形成するか、又は、同一の顆粒を形成する。 In some embodiments, the present disclosure provides an oral pharmaceutical composition containing levodopa and carbidopa, comprising a pharmaceutically active ingredient comprising levodopa and carbidopa (4:1 weight ratio) and an enteric polymer. Provided is an oral pharmaceutical composition characterized by comprising a sustained release part and an immediate release part containing a water-soluble polymer and a pharmaceutically active ingredient containing levodopa and carbidopa (mass ratio 4:1). The sustained release part and the immediate release part each form granules independently, or form the same granule.
　本開示において、「徐放部」とは経口用医薬組成物を構成する部分であって、経口用医薬組成物の対象者（患者を含む。）への投与後長時間にわたって、生体内で薬学的活性成分の血中濃度が維持できるように薬学的活性成分の溶出が制御されている部分をいう。ここで「血中濃度」とは、有効血中濃度又は血漿中濃度をいう。 In the present disclosure, a "sustained release part" is a part constituting an oral pharmaceutical composition, and is a part that is used in vivo for a long period of time after administration of the oral pharmaceutical composition to a subject (including a patient). This refers to the area where the elution of pharmaceutically active ingredients is controlled so that the blood concentration of pharmaceutically active ingredients can be maintained. Here, "blood concentration" refers to effective blood concentration or plasma concentration.
　一部の実施形態において、該徐放部は、レボドパとカルビドパ（質量比率４：１を含む薬学的活性成分及び腸溶性高分子を含有する顆粒（コーティング顆粒含む）であってもよい。 In some embodiments, the sustained release portion may be granules (including coated granules) containing a pharmaceutically active ingredient and an enteric polymer including levodopa and carbidopa (in a mass ratio of 4:1).
　本開示において、「徐放部」は、レボドパとカルビドパ（質量比率４：１）を含む素顆粒部及び腸溶性高分子を含むコーティング層で被覆された構造を有していてもよい。 In the present disclosure, the "sustained release part" may have a structure covered with an elementary granule part containing levodopa and carbidopa (mass ratio 4:1) and a coating layer containing an enteric polymer.
　本開示において、「素顆粒部」は、薬学的活性成分としてのレボドパとカルビドパ（質量比率４：１）及び任意に添加してもよい添加剤（例えば、賦形剤、結合剤、崩壊剤、滑沢剤、流動化剤）を含むことができる。 In the present disclosure, the "elementary granule part" refers to levodopa and carbidopa (mass ratio 4:1) as pharmaceutically active ingredients and additives that may be optionally added (for example, excipients, binders, disintegrants, (lubricating agent, fluidizing agent).
　本開示において、「コーティング層」は、腸溶性高分子、コーティング剤及び任意に添加してもよい添加剤（例えば、流動化剤、可塑剤、着色剤等）を含む層であってもよい。 In the present disclosure, the "coating layer" may be a layer containing an enteric polymer, a coating agent, and optional additives (for example, a fluidizing agent, a plasticizer, a coloring agent, etc.).
  本開示において、「腸溶性高分子」は、胃内環境を想定した酸性のｐＨ値をもつ水溶液溶媒（ｐＨ１．２～ｐＨ５．４）に対して実質的に溶解せず（即ち、其の１．０ｇを溶かすに要する２５℃の溶媒量が１００００ｍＬ以上である）、腸内環境を想定した中性～アルカリ性のｐＨ値（ｐＨ５．５以上）をもつ水溶液溶媒に対して良好に溶解する（即ち、其の１．０ｇを溶かすのに要する２５℃の溶媒量が１００００ｍＬ未満である。）。 In the present disclosure, the "enteric polymer" is substantially insoluble in an aqueous solvent (pH 1.2 to pH 5.4) having an acidic pH value assuming the gastric environment (i.e., its 1. The amount of solvent required at 25°C to dissolve .0 g is 10,000 mL or more), and it dissolves well in an aqueous solvent with a neutral to alkaline pH value (pH 5.5 or more) assuming the intestinal environment (i.e. , the amount of solvent at 25°C required to dissolve 1.0 g of it is less than 10,000 mL).
  一部の実施形態において、腸溶性高分子としては、例えば、メタクリル酸コポリマー（例えば、メタクリル酸コポリマーＬ、メタクリル酸コポリマーＬＤ、メタクリル酸コポリマーＳ、乾燥メタクリル酸コポリマーＬＤ等）、 ヒドロキシアルキルアルキルセルロースフタル酸エステル（例えば、ヒプロメロースフタル酸エステル）、ヒドロキシアルキルアルキルセルロース酢酸エステルコハク酸エステル（例えば、ヒプロメロース酢酸エステルコハク酸エステル）、カルボキシアルキルアルキルセ ルロース（例えば、カルボキシメチルエチルセルロース）等が挙げられるが、これらに限定されない。 In some embodiments, the enteric polymer includes, for example, methacrylic acid copolymers (e.g., methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, dry methacrylic acid copolymer LD, etc.), hydroxyalkyl alkyl cellulose phthalate, etc. Examples include acid esters (e.g., hypromellose phthalate), hydroxyalkylalkylcellulose acetate succinate (e.g., hypromellose acetate succinate), carboxyalkylalkylcellulose (e.g., carboxymethylethyl cellulose), etc. , but not limited to.
  一部の実施形態において、腸溶性高分子としては、例えば、メタクリル酸コポリマー、ヒプロメロースフタル酸エステル、ヒプロメロース酢酸エステルコハク酸エステル、カルボキシメチルエチルセルロース等が挙げられるが、これらに限定されない。 In some embodiments, enteric polymers include, but are not limited to, methacrylic acid copolymers, hypromellose phthalate, hypromellose acetate succinate, carboxymethylethylcellulose, and the like.
  一部の実施形態において、腸溶性高分子としては、例えば、メタクリル酸コポリマーＬＤ、乾燥メタクリル酸コポリマーＬＤ、メタクリル酸コポリマーＬ、メタクリル酸コポリマーＳ、ヒプロメロース酢酸エステルコハク酸エステル、ヒプロメロースフタル酸エステル及びカルボキシメチルエチルセルロース等が挙げられるが、これらに限定されない。 In some embodiments, the enteric polymer includes, for example, methacrylic acid copolymer LD, dry methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, hypromellose acetate succinate, hypromellose phthalate ester. and carboxymethylethylcellulose, but are not limited to these.
  一部の実施形態において、腸溶性高分子は、顆粒全重量に対して０．５重量％以上顆粒中に含有される。 In some embodiments, the enteric polymer is contained in the granules in an amount of 0.5% by weight or more based on the total weight of the granules.
  別の実施形態において、腸溶性高分子は、顆粒全重量に対して１．０重量％～１０．０重量％の範囲で、顆粒中に含有される。 In another embodiment, the enteric polymer is contained in the granules in an amount ranging from 1.0% to 10.0% by weight based on the total weight of the granules.
  一部の実施形態において、コーティング剤としては、例えば、Ｄ-マンニトール、乳糖、トレハロース、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、ヒプロメロース、ヒドロキシプロピルセルロース、メチルセルロース等が挙げられるが、これらに限定されない。 In some embodiments, the coating agent includes, for example, D-mannitol, lactose, trehalose, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, hypromellose, hydroxypropylcellulose, methylcellulose, etc. Not limited.
　一部の実施形態において、コーティング剤は、顆粒全重量に対して、０．５重量％～１０．０重量％の範囲で顆粒中に含有される。 In some embodiments, the coating agent is contained in the granules in an amount ranging from 0.5% to 10.0% by weight based on the total weight of the granules.
　本開示において、「速放部」とは経口用医薬組成物の構成部分であって、経口用医薬組成物の患者への投与後、速やかに薬学的活性成分を生体内に放出する、即ち、薬学的活性成分の放出が制御されていない部分をいう。 In the present disclosure, an "immediate release part" is a component of an oral pharmaceutical composition that promptly releases a pharmaceutically active ingredient into the body after administration of the oral pharmaceutical composition to a patient, i.e., An area where the release of pharmaceutically active ingredients is not controlled.
　一部の実施形態において、該速放部は、レボドパとカルビドパ（質量比率４：１）を含む薬学的活性成分、崩壊剤又は水溶性高分子、及び、任意に添加してもよい添加剤を含有する顆粒であってもよい。 In some embodiments, the immediate release portion comprises a pharmaceutically active ingredient comprising levodopa and carbidopa (4:1 mass ratio), a disintegrant or a water-soluble polymer, and optional additives. It may also be granules containing.
  一部の実施形態において、崩壊剤としては、例えば、部分アルファー化デンプン、低置換度ヒドロキシプロピルセルロース、カルメロース、カルメロースカルシウム、ヒドロキシプロピルスターチ、デンプン、デンプングリコール酸ナトリウム、クロスカルメロースナトリウム、クロスポビドン等が挙げられるが、これらに限定されない。 In some embodiments, disintegrants include, for example, partially pregelatinized starch, low substituted hydroxypropyl cellulose, carmellose, carmellose calcium, hydroxypropyl starch, starch, sodium starch glycolate, croscarmellose sodium, crospovidone. etc., but are not limited to these.
  一部の実施形態において、水溶性高分子としては、例えば、アルキルセルロース（例えばメチルセルロース）、ヒドロキシアルキルセルロース（例えばヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシブチルセルロース）、ヒドロキシアルキルアルキルセルロース（例えばヒドロキシエチルメチルセルロース、ヒプロメロース）、カルボキシビニルポリマー、ポリビニルアルコール、ポリビニルアルコール系共重合体（ポリビニルアルコールがモノマーの一つである共重合体であって、例えばポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、 ポリビニルアルコール・ポリエチレングリコール・グラフトコポリマー）、ポリビニルピロリドン、カルメロースナトリウム、アルファー化デンプン等が挙げられるが、これらに限定されない。 In some embodiments, water-soluble polymers include, for example, alkylcelluloses (e.g., methylcellulose), hydroxyalkylcelluloses (e.g., hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose), hydroxyalkylalkylcelluloses (e.g., hydroxy ethyl methylcellulose, hypromellose), carboxyvinyl polymer, polyvinyl alcohol, polyvinyl alcohol copolymer (copolymer in which polyvinyl alcohol is one of the monomers, such as polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, Examples include, but are not limited to, polyvinyl alcohol/polyethylene glycol/graft copolymer), polyvinylpyrrolidone, carmellose sodium, pregelatinized starch, and the like.
　別の実施形態において、メチルセルロース、ヒドロキシプロピルセルロース、カルボキシビニルポリマー、ポリビニルアルコール等が挙げられるが、これらに限定されない。 Other embodiments include, but are not limited to, methylcellulose, hydroxypropylcellulose, carboxyvinyl polymer, polyvinyl alcohol, and the like.
  一部の実施形態において、水溶性高分子としては、例えば、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、ヒドロキシプロピルセルロース、ヒプロメロース、メチルセルロース、ポリビニルアルコール、ポリビニルピロリドン、カルメロースナトリウム、アルファー化デンプン等が挙げられるが、これらに限定されない。 In some embodiments, the water-soluble polymer includes, for example, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, hydroxypropylcellulose, hypromellose, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, carmellose sodium, pregelatinized starch. etc., but are not limited to these.
  一部の実施形態において、徐放部及び速放部は、それぞれ独立して顆粒を形成してもよい。該顆粒は、素顆粒でもよく、コーティング顆粒であってもよい。 In some embodiments, the sustained release part and the immediate release part may each independently form granules. The granules may be raw granules or coated granules.
  一部の実施形態において、徐放部及び速放部は、一体となって同一の顆粒を形成してもよい。例えば、腸溶性高分子を含有する徐放部が顆粒を形成し、該顆粒が水溶性高分子を含有する速放部により被覆された顆粒を例示することができる。 In some embodiments, the sustained release portion and the immediate release portion may be combined to form the same granule. For example, a granule can be exemplified in which a sustained release part containing an enteric polymer forms granules, and the granules are coated with an immediate release part containing a water-soluble polymer.
  一部の実施形態において、徐放部に含まれるレボドパと速放部に含まれるレボドパの質量の比率が、４：１～３：２である。 In some embodiments, the mass ratio of levodopa contained in the sustained release portion to levodopa contained in the immediate release portion is 4:1 to 3:2.
　一部の実施形態において、顆粒中のレボドパとカルビドパの合計質量が顆粒質量に対して７０％以上である。 In some embodiments, the total mass of levodopa and carbidopa in the granules is 70% or more based on the mass of the granules.
　別の実施形態において、顆粒中のレボドパとカルビドパの合計質量が顆粒質量に対して７０％～９５％である。 In another embodiment, the combined weight of levodopa and carbidopa in the granules is 70% to 95% of the granule weight.
　別の実施形態において、顆粒中のレボドパとカルビドパの合計質量が顆粒質量に対して７５％～９０％である。 In another embodiment, the combined weight of levodopa and carbidopa in the granules is 75% to 90% of the granule weight.
　一部の実施形態において、本開示は、顆粒が滑沢剤を顆粒質量に対して０．６％～１０％含有することを特徴とする、経口用医薬組成物を提供する。 In some embodiments, the present disclosure provides an oral pharmaceutical composition, wherein the granules contain a lubricant from 0.6% to 10% based on the granule weight.
　一部の実施形態において、顆粒中における滑沢剤の含量は、顆粒質量に対して０．６％～１０％である。 In some embodiments, the content of lubricant in the granules is between 0.6% and 10% based on the granule mass.
　別の実施形態において、顆粒中における滑沢剤の含量は、顆粒質量に対して０．６％～５％である。 In another embodiment, the content of lubricant in the granules is between 0.6% and 5% relative to the granule mass.
　別の実施形態において、顆粒中における滑沢剤の含量は、顆粒質量に対して１％～５％である。 In another embodiment, the content of lubricant in the granules is between 1% and 5% relative to the granule mass.
実施形態３ Embodiment 3
　一部の実施形態において、本開示は、レボドパとカルビドパを含有する経口用医薬組成物であって、
レボドパとカルビドパ（質量比率４：１）を含む薬学的活性成分及び腸溶性高分子を含有する徐放部と、
レボドパとカルビドパ（質量比率４：１）を含む薬学的活性成分及び崩壊剤又は水溶性高分子を含有する速放部とを含み徐放部及び速放部が独立して顆粒を形成し、徐放部を形成する顆粒が腸溶性高分子で被覆された顆粒であり、速放部を形成する顆粒が崩壊剤を含有する顆粒であることを特徴とする経口用医薬組成物を提供する。 In some embodiments, the present disclosure provides an oral pharmaceutical composition containing levodopa and carbidopa, comprising:
a sustained release part containing a pharmaceutically active ingredient containing levodopa and carbidopa (mass ratio 4:1) and an enteric polymer;
The sustained release part and the immediate release part independently form granules, which contain a pharmaceutically active ingredient containing levodopa and carbidopa (mass ratio 4:1) and an immediate release part containing a disintegrant or a water-soluble polymer. Provided is an oral pharmaceutical composition characterized in that the granules forming the release part are granules coated with an enteric polymer, and the granules forming the immediate release part are granules containing a disintegrant.
　一部の実施形態において、前記徐放部を形成する顆粒の素顆粒部及び前記速放部を形成する顆粒は、結晶セルロース、アンモニオアルキルメタクリレートコポリマー、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、部分アルファー化デンプン及び二酸化ケイ素から選ばれる１種以上の添加剤を含有する。 In some embodiments, the elementary granule part of the granule forming the sustained release part and the granule forming the immediate release part are made of crystalline cellulose, ammonioalkyl methacrylate copolymer, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer. Contains one or more additives selected from coalesced, partially pregelatinized starch and silicon dioxide.
　一部の実施形態において、前記徐放部を形成する顆粒の素顆粒部が、メタクリル酸コポリマーＬＤ、乾燥メタクリル酸コポリマーＬＤ、メタクリル酸コポリマーＬ、メタクリル酸コポリマーＳ、ヒプロメロース酢酸エステルコハク酸エステル、ヒプロメロースフタル酸エステル及びカルボキシメチルエチルセルロースから選ばれる１種以上の腸溶性高分子で被覆される。 In some embodiments, the elementary granules of the granules forming the sustained release portion include methacrylic acid copolymer LD, dry methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, hypromellose acetate succinate, hypromellose acetate succinate, It is coated with one or more enteric polymers selected from promellose phthalate and carboxymethylethyl cellulose.
　一部の実施形態において、前記速放部を形成する顆粒が、部分アルファー化デンプン、低置換度ヒドロキシプロピルセルロース、カルメロース、カルメロースカルシウム、ヒドロキシプロピルスターチ、デンプン、デンプングリコール酸ナトリウム、クロスカルメロースナトリウム、クロスポビドンから選ばれる１種以上の水溶性高分子（崩壊剤）を含有する。 In some embodiments, the granules forming the immediate release portion are partially pregelatinized starch, low substituted hydroxypropyl cellulose, carmellose, carmellose calcium, hydroxypropyl starch, starch, sodium starch glycolate, croscarmellose sodium. , crospovidone.
実施形態４ Embodiment 4
　一部の実施形態において、本開示は、顆粒中にレボドパとカルビドパを含有する経口用医薬組成物であって、レボドパとカルビドパ（質量比率４：１）を含む薬学的活性成分及び腸溶性高分子を含有する徐放部と、レボドパとカルビドパ（質量比率４：１）を含む薬学的活性成分及び水溶性高分子を含有する速放部とを含み、
前記経口用医薬組成物経口用医薬組成物徐放部及び速放部が同一の顆粒を形成する経口用医薬組成物であって、前記徐放部が腸溶性高分子で被覆された顆粒を形成し、更に該顆粒の周囲が水溶性高分子を含有する速放部により被覆された顆粒であることを特徴とする経口用医薬組成物を提供する。 In some embodiments, the present disclosure provides an oral pharmaceutical composition containing levodopa and carbidopa in granules, the pharmaceutically active ingredients comprising levodopa and carbidopa (4:1 weight ratio) and an enteric polymer. and an immediate release part containing a water-soluble polymer and a pharmaceutically active ingredient containing levodopa and carbidopa (mass ratio 4:1),
The oral pharmaceutical composition is an oral pharmaceutical composition in which the sustained release part and the immediate release part form the same granules, wherein the sustained release part forms granules coated with an enteric polymer. The present invention further provides an oral pharmaceutical composition characterized in that the granules are surrounded by an immediate-release region containing a water-soluble polymer.
　一部の実施形態において、前記徐放部を形成する顆粒の素顆粒部が、結晶セルロース、アンモニオアルキルメタクリレートコポリマー、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、部分アルファー化デンプン及び二酸化ケイ素から選ばれる１種以上の添加剤を含有する。 In some embodiments, the elementary granules of the granules forming the sustained release portion include crystalline cellulose, ammonioalkyl methacrylate copolymer, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, partially pregelatinized starch, and silicon dioxide. Contains one or more additives selected from.
　一部の実施形態において、前記徐放部の素顆粒部を被覆する腸溶性高分子が、メタクリル酸コポリマーＬＤ、乾燥メタクリル酸コポリマーＬＤ、メタクリル酸コポリマーＬ、メタクリル酸コポリマーＳ、ヒプロメロース酢酸エステルコハク酸エステル、ヒプロメロースフタル酸エステル及びカルボキシメチルエチルセルロースから選ばれる１種以上の腸溶性高分子である。 In some embodiments, the enteric polymer that coats the elementary granule portion of the sustained release portion is methacrylic acid copolymer LD, dry methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, hypromellose acetate succinate. It is one or more enteric polymers selected from ester, hypromellose phthalate, and carboxymethylethyl cellulose.
　一部の実施形態において、前記速放部の水溶性高分子が、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、ポリビニルアルコール、ヒドロキシプロピルセルロース、ヒプロメロース、メチルセルロース、ポリビニルピロリドン、カルメロースナトリウム、アルファー化デンプンから選ばれる１種以上の水溶性高分子である。 In some embodiments, the water-soluble polymer of the immediate release portion is polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, polyvinyl alcohol, hydroxypropylcellulose, hypromellose, methylcellulose, polyvinylpyrrolidone, carmellose sodium, alpha One or more water-soluble polymers selected from modified starches.
　本開示において、本開示の顆粒の粒度測定は、湿度変化によって著しい吸湿又は脱湿を起こしやすい又は凝集体が生じないような、適度に調整された室温及び湿度環境下で実施される。 In the present disclosure, the particle size measurement of the granules of the present disclosure is carried out under an appropriately controlled room temperature and humidity environment that does not easily cause significant moisture absorption or dehumidification or aggregates due to changes in humidity.
　一部の実施形態において、本開示の顆粒は、第１８改正日本薬局方・一般試験法の粒度測定法に記載される、日本薬局方ふるい番号４．７号を通過する。 In some embodiments, the granules of the present disclosure pass Japanese Pharmacopoeia Sieve No. 4.7 as described in the Particle Size Measurement Method of the Japanese Pharmacopoeia, 18th Edition General Testing Methods.
　別の実施形態において、本開示の顆粒は、第１８改正日本薬局方・一般試験法の粒度測定法に記載される、日本薬局方ふるい番号１２号に残留する。 In another embodiment, the granules of the present disclosure remain in Japanese Pharmacopoeia Sieve No. 12 as described in the Particle Size Measurement Method of the Japanese Pharmacopoeia, 18th Edition General Test Methods.
　別の実施形態において、本開示の顆粒は、第１８改正日本薬局方・一般試験法の粒度測定法に記載される、日本薬局方ふるい番号４．７号を通過し、１２号に残留する。 In another embodiment, the granules of the present disclosure pass through Japanese Pharmacopoeia Sieve No. 4.7 and remain in No. 12 as described in the Particle Size Measurement Method of the 18th Edition of the Japanese Pharmacopoeia General Test Methods.
　一部の実施形態において、本開示の顆粒の形状は、円柱状である。 In some embodiments, the shape of the granules of the present disclosure is cylindrical.
　一部の実施形態において、デジタルマイクロメーター（ミツトヨ製：ＰＫ－１０１２ＡＰＸ型）を用いて測定した円柱状の顆粒の直径は、１.５ｍｍ～３.０ｍｍ（±１０％）である。 In some embodiments, the diameter of the cylindrical granules is 1.5 mm to 3.0 mm (±10%) as measured using a digital micrometer (manufactured by Mitutoyo: Model PK-1012APX).
　別の実施形態において、デジタルマイクロメーター（ミツトヨ製：ＰＫ－１０１２ＡＰＸ型）を用いて測定した円柱状の顆粒の直径は、１．５ｍｍ～２．５ｍｍ（±１０％）である。 In another embodiment, the diameter of the cylindrical granules measured using a digital micrometer (manufactured by Mitutoyo: PK-1012APX type) is 1.5 mm to 2.5 mm (±10%).
　別の実施形態において、デジタルマイクロメーター（ミツトヨ製：ＰＫ－１０１２ＡＰＸ型）を用いて測定した円柱状の顆粒の直径は、１．５ｍｍ～２．１ｍｍ（±１０％）である。 In another embodiment, the diameter of the cylindrical granules measured using a digital micrometer (manufactured by Mitutoyo: PK-1012APX type) is 1.5 mm to 2.1 mm (±10%).
　本開示において、添加剤は、当該技術分野における慣用の添加剤を用いることができる。一部の実施形態において、添加剤としては、例えば、賦形剤、結合剤、崩壊剤、滑沢剤、流動化剤、滑沢剤、可塑剤、着色剤等が挙げられるが、これらに限定されない。 In the present disclosure, additives commonly used in the technical field can be used as additives. In some embodiments, additives include, but are not limited to, excipients, binders, disintegrants, lubricants, flow agents, lubricants, plasticizers, colorants, etc. Not done.
　本開示において、添加剤の配合量は、本発明の効果を損なわない範囲であれば特に限定されない。 In the present disclosure, the blending amount of the additive is not particularly limited as long as it does not impair the effects of the present invention.
　本開示において、賦形剤としては、例えば、乳糖水和物、無水乳糖、結晶セルロース、Ｄ-マンニトール、エリスリトール、キシリトール、ソルビトール、イソマルト、マルチトール、マルトース、白糖、ショ糖、ブドウ糖、デンプン（トウモロコシデンプン、バレイショデンプン、コメデンプン、コムギデンプン等）、ヒドロキシプロピルスターチ、アルファー化デンプン、部分アルファー化デンプン、カルボキシメチルスターチナトリウム、デキストリン、粉末還元麦芽糖水アメ、アンモニオアルキルメタクリレートコポリマー、エチルセルロース、リン酸水素カルシウム等が挙げられるが、これらに限定されない。 In the present disclosure, excipients include, for example, lactose hydrate, anhydrous lactose, crystalline cellulose, D-mannitol, erythritol, xylitol, sorbitol, isomalt, maltitol, maltose, sucrose, sucrose, glucose, starch (corn starch, potato starch, rice starch, wheat starch, etc.), hydroxypropyl starch, pregelatinized starch, partially pregelatinized starch, sodium carboxymethyl starch, dextrin, powdered reduced maltose starch syrup, ammonioalkyl methacrylate copolymer, ethyl cellulose, hydrogen phosphate Examples include, but are not limited to, calcium.
  本開示において、結合剤としては、例えば、アルキルセルロース（例えばメチルセルロース）、ヒドロキシアルキルセルロース（例えばヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシブチルセルロース）、ヒドロキシアルキルアルキルセルロース（例えばヒドロキシエチルメチルセルロース、ヒプロメロース）、カルボキシビニルポリマー、ポリビニルアルコール、ポリビニルアルコール系共重合体（ポリビニルアルコールがモノマーの一つである共重合体であって、例えばポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、ポリビニルアルコール・ポリエチレングリコール・グラフトコポリマー）、ポリビニルピロリドン、カルメロースナトリウム、アルファー化デンプン等が挙げられるが、これらに限定されない。 In the present disclosure, binders include, for example, alkylcelluloses (e.g., methylcellulose), hydroxyalkylcelluloses (e.g., hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose), hydroxyalkylalkylcelluloses (e.g., hydroxyethylmethylcellulose, hypromellose). , carboxyvinyl polymer, polyvinyl alcohol, polyvinyl alcohol copolymer (a copolymer in which polyvinyl alcohol is one of the monomers, such as polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, polyvinyl alcohol/polyethylene glycol) - graft copolymer), polyvinylpyrrolidone, carmellose sodium, pregelatinized starch, etc., but are not limited to these.
  本開示において、崩壊剤としては、例えば、部分アルファー化デンプン、低置換度ヒドロキシプロピルセルロース、カルメロース、カルメロースカルシウム、ヒドロキシプロピルスターチ、デンプン、デンプングリコール酸ナトリウム、クロスカルメロースナトリウム、クロスポビドン等が挙げられるが、これらに限定されない。 In the present disclosure, examples of the disintegrant include partially pregelatinized starch, low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, hydroxypropyl starch, starch, sodium starch glycolate, croscarmellose sodium, crospovidone, and the like. but not limited to.
  本開示において、流動化剤としては、例えば、軽質無水ケイ酸、含水二酸化ケイ素、タルク、メタケイ酸アルミン酸マグネシウム等が挙げられるが、これらに限定されない。 In the present disclosure, examples of the fluidizing agent include, but are not limited to, light anhydrous silicic acid, hydrated silicon dioxide, talc, magnesium aluminate metasilicate, and the like.
　本開示において、滑沢剤としては、例えば、ステアリン酸マグネシウム、ステアリン酸カルシウム、フマル酸ステアリルナトリウム、及び硬化油等が挙げられるが、これらに限定されない。 In the present disclosure, examples of lubricants include, but are not limited to, magnesium stearate, calcium stearate, sodium stearyl fumarate, and hydrogenated oil.
　一部の実施形態において、滑沢剤としては、例えば、ステアリン酸マグネシウム又は/及びステアリン酸カルシウム等が挙げられるが、これらに限定されない。  In some embodiments, lubricants include, but are not limited to, magnesium stearate and/or calcium stearate.​
  本開示において、可塑剤としては、例えば、クエン酸トリエチル、トリアセチン、ポリエチレングリコール、フタル酸ジエチル、フタル酸ジブチル等が挙げられるが、これらに限定されない。 In the present disclosure, examples of the plasticizer include, but are not limited to, triethyl citrate, triacetin, polyethylene glycol, diethyl phthalate, dibutyl phthalate, and the like.
  本開示において、着色剤としては、例えば、黄色三二酸化鉄、三二酸化鉄、酸化チタン等が挙げられるが、これらに限定されない。 In the present disclosure, examples of the coloring agent include, but are not limited to, yellow iron sesquioxide, iron sesquioxide, titanium oxide, and the like.
　本開示において、本開示の経口用医薬組成物を含む、パーキンソン病又はパーキンソン症候群の治療剤を提供する。 The present disclosure provides a therapeutic agent for Parkinson's disease or Parkinson's syndrome, which includes the oral pharmaceutical composition of the present disclosure.
　一部の実施形態において、本開示は、本開示の経口用医薬組成物を含む、パーキンソン病の治療剤を提供する。 In some embodiments, the present disclosure provides a treatment for Parkinson's disease comprising an oral pharmaceutical composition of the present disclosure.
　本開示の医薬組成物の剤型としては、例えば、顆粒剤、顆粒を封入したカプセル剤、顆粒を封入したスティック剤、顆粒を包含する錠剤等が挙げられるが、これらに限定されない。 Examples of the dosage form of the pharmaceutical composition of the present disclosure include, but are not limited to, granules, capsules containing granules, sticks containing granules, tablets containing granules, and the like.
　本開示の医薬組成物は、その剤形に応じて当該技術分野における一般的な製造方法によって製造することができる。 The pharmaceutical composition of the present disclosure can be manufactured by common manufacturing methods in the technical field depending on its dosage form.
　本開示の顆粒は、例えば以下の工程により製造することができる。レボドパ、カルビドパ及び添加剤（例えば、賦形剤、結合剤、崩壊剤、滑沢剤、流動化剤等）を混合させながら溶液（造粒液）を徐々に滴下することで造粒物を製造する（攪拌造粒法）。前記で得られた造粒物は、乾燥及び整粒された後、滑沢剤等と混合した後に打錠機によって圧縮成形されて顆粒（素顆粒）とされる。前記で得られた顆粒を圧縮成形する際の圧縮圧力は、１顆粒当たり２００～３０００Ｎの範囲内である。前記で得られた顆粒は、公知の方法によりコーティング剤等で被覆することにより、コーティング顆粒としても製造することもできる。 The granules of the present disclosure can be produced, for example, by the following steps. Granules are produced by gradually dropping a solution (granulation liquid) while mixing levodopa, carbidopa, and additives (e.g., excipients, binders, disintegrants, lubricants, fluidizers, etc.) (agitation granulation method). The granules obtained above are dried and sized, mixed with a lubricant, etc., and then compressed into granules (primary granules) using a tablet machine. The compression pressure when compression molding the granules obtained above is within the range of 200 to 3000 N per granule. The granules obtained above can also be produced as coated granules by coating them with a coating agent or the like by a known method.
　また、素顆粒の製造方法としては、例えば、流動層中で流動させたレボドパとカルビドパに、レボドパとカルビドパ及び結合剤を含む液をスプレーして高含量の顆粒を得ることができる直接顆粒化法、結晶セルロースや糖類等からなる核粒子にレボドパとカルビドパ及び結合剤を含む液をスプレーして顆粒を得ることができるレイアリング法、及びレボドパとカルビドパ及び添加剤を混合したのち水や溶媒で練合し、練合物をメッシュから押し出すことで顆粒を製造する押し出し造粒法等が挙げられるが、これらに限定されない。 In addition, as a method for producing elementary granules, for example, a direct granulation method in which a liquid containing levodopa, carbidopa, and a binder is sprayed onto levodopa and carbidopa fluidized in a fluidized bed to obtain high-content granules. , a layering method in which granules are obtained by spraying a liquid containing levodopa, carbidopa, and a binder onto core particles made of crystalline cellulose or saccharides, and a layering method in which granules are obtained by mixing levodopa, carbidopa, and additives and then kneading them with water or a solvent. Examples include, but are not limited to, an extrusion granulation method in which granules are produced by mixing and extruding the kneaded product through a mesh.
  本開示のカプセル剤は、上記の素顆粒やコーティングした顆粒剤を、当該技術分野における一般的な充填方法によりカプセルに充填することにより製造することができる。 Capsules of the present disclosure can be produced by filling capsules with the above-mentioned elementary granules or coated granules by a general filling method in the technical field.
　本開示において、カプセルとしては、当該技術分野における慣用のカプセルを用いることができる。例えば、ゼラチンカプセル、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）カプセル、プルランカプセル等（例えば、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）カプセル）、Ｌｉｃａｐｓ（商標）カプセル、Ｖｃａｐｓ（商標）カプセル、Ｃｏｎｉ－Ｓｎａｐ（商標）カプセル、Ｐｒｅｓｓ－ｆｉｔ（商標）カプセル及びＸｐｒｅｓｓ－ｆｉｔ（商標）カプセル等が挙げられるが、これらに限定されない。 In the present disclosure, a capsule commonly used in the technical field can be used as the capsule. For example, gelatin capsules, hydroxypropyl methylcellulose (HPMC) capsules, pullulan capsules, etc. (e.g., hydroxypropyl methylcellulose (HPMC) capsules), Licaps(TM) capsules, Vcaps(TM) capsules, Coni-Snap(TM) capsules, Press- Examples include, but are not limited to, fit(TM) capsules and Xpress-fit(TM) capsules.
　本開示において、カプセルの大きさとしては、例えば、１号カプセル、２号カプセル、３号カプセル及び４号カプセル等が挙げられるが、これらに限定されない。一部の実施形態において、服薬性の観点から、３号カプセル又は４号カプセルが選択される。 In the present disclosure, the size of the capsule includes, for example, a No. 1 capsule, a No. 2 capsule, a No. 3 capsule, a No. 4 capsule, etc., but is not limited to these. In some embodiments, No. 3 capsules or No. 4 capsules are selected from the viewpoint of compliance.
  本開示のスティック剤は、上記の顆粒やコーティング顆粒を用いて、当該技術分野における一般的なスティック包装に充填する方法により製造することができる。 The stick preparation of the present disclosure can be manufactured by using the above-mentioned granules or coated granules and filling them into stick packaging, which is common in the technical field.
　本開示の錠剤は、上記の顆粒やコーティング顆粒を用いて、当該技術分野における一般的な錠剤の製造方法により製造することができる。 The tablet of the present disclosure can be manufactured by a common tablet manufacturing method in the technical field using the above-mentioned granules or coated granules.
実施形態５ Embodiment 5
　本開示の溶出試験から得られたレボドパ溶出挙動に関する製剤特性は、レボドパとカルビドパを含有し、即効性と持続性を併せ持つレボドパ血中動態プロファイルを示す経口用医薬組成物を製剤設計するための評価基準として使用することができる。 The formulation characteristics related to levodopa dissolution behavior obtained from the dissolution test of the present disclosure are useful for evaluation for formulation design of an oral pharmaceutical composition containing levodopa and carbidopa and exhibiting a levodopa blood dynamics profile that has both immediate and sustained action. Can be used as a reference.
　本開示において、レボドパ溶出挙動に関する製剤特性は、試験例１に記載されたパドル法及び試験例２に記載されたフロースルーセル法を用いたレボドパ溶出試験の結果として評価される。 In the present disclosure, formulation characteristics regarding levodopa dissolution behavior are evaluated as the results of a levodopa dissolution test using the paddle method described in Test Example 1 and the flow-through cell method described in Test Example 2.
　本開示において、経口用医薬組成物を製剤設計するための評価基準は、健康成人において即効性と持続性を併せ持つレボドパ血中動態プロファイルが達成された医薬組成物（製剤）に係るレボドパ溶出挙動の範囲として設定され、具体的には、実施形態１に記載されたレボドパ溶出挙動に関する製剤特性の範囲を挙げることができる。 In the present disclosure, the evaluation criteria for designing oral pharmaceutical compositions are the levodopa elution behavior of a pharmaceutical composition (preparation) that achieves a levodopa blood dynamics profile that is both immediate and long-lasting in healthy adults. Specifically, the range of formulation characteristics related to levodopa dissolution behavior described in Embodiment 1 can be mentioned.
　本開示において、任意に処方された製剤について上記の溶出試験を実施し、レボドパ溶出挙動に関する製剤特性が前記の評価基準を満たすかどうかを確認することにより、即効性と持続性を併せ持つレボドパ血中動態プロファイルを示す経口用医薬組成物を簡便に製剤設計することが可能となる。 In the present disclosure, by conducting the above dissolution test on arbitrarily prescribed formulations and confirming whether the formulation characteristics related to levodopa dissolution behavior satisfy the above evaluation criteria, we have determined that levodopa that has both immediate and long-lasting effects can be obtained in the blood. It becomes possible to easily formulate an oral pharmaceutical composition that exhibits a kinetic profile.
　以下、実施例により本発明を説明するが、本発明は以下の実施例に限定されるものではない。 Hereinafter, the present invention will be explained with reference to examples, but the present invention is not limited to the following examples.
　レボドパ（メディアン径：５５μｍ）５００．０ｇ、カルビドパ水和物（メディアン径：７．４μｍ）１３５．０ｇ、結晶セルロース６４．６ｇ、アンモニオアルキルメタクリレートコポリマー４８．０ｇ、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体６．０ｇ及び軽質無水ケイ酸６．０ｇを高速攪拌造粒機（パウレック社製：ＦＭ－ＶＧ－１０型）に投入して予混合した後、エタノール１００ｇ及び水８５ｇを加えて造粒した。得られた造粒品を流動層乾燥機（パウレック社製：ＭＰ－０１型）にて乾燥したのち、整粒機（パウレック社製：ＱＣ－１９７Ｓ型）で整粒し、整粒品を得た。 Levodopa (median diameter: 55 μm) 500.0 g, carbidopa hydrate (median diameter: 7.4 μm) 135.0 g, crystalline cellulose 64.6 g, ammonioalkyl methacrylate copolymer 48.0 g, polyvinyl alcohol/acrylic acid/methacrylic acid After premixing 6.0 g of methyl copolymer and 6.0 g of light anhydrous silicic acid into a high-speed stirring granulator (Model FM-VG-10, manufactured by Powrex), 100 g of ethanol and 85 g of water were added. Granulated. The obtained granulated product was dried in a fluidized bed dryer (manufactured by Powrex Co., Ltd.: Model MP-01), and then sized with a sieving machine (manufactured by Powrex Co., Ltd.: QC-197S model) to obtain a sized product. Ta.
　実施例１で得られた整粒品６０７．７ｇに軽質無水ケイ酸１．９ｇ及びステアリン酸マグネシウム４．８ｇを加え、ポリエチレン製の袋にて混合した。得られた混合品をロータリー式打錠機（菊水製作所製：ＶＩＲＧＯ型）で打錠し、１顆粒質量６．４ｍｇの素顆粒を得た。得られた素顆粒３５０ｇを通気式コーティング機（フロイント産業製：ＨＣ－ＦＺ－ＬＡＢＯ型）に投入し、メタクリル酸コポリマーＬＤ２２．８ｇ（固形分として６．８ｇ）、タルク７．５ｇ、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体０．７ｇ及びクエン酸トリエチル０．７ｇを精製水２７０．０ｇに懸濁した液をスプレーし、１顆粒質量６．７ｍｇのコーティング顆粒を得た。 1.9 g of light anhydrous silicic acid and 4.8 g of magnesium stearate were added to 607.7 g of the sized product obtained in Example 1, and mixed in a polyethylene bag. The obtained mixture was tableted using a rotary tabletting machine (VIRGO type, manufactured by Kikusui Seisakusho) to obtain elementary granules each having a mass of 6.4 mg. 350 g of the obtained elementary granules were put into a ventilation coating machine (manufactured by Freund Sangyo, HC-FZ-LABO type), and 22.8 g of methacrylic acid copolymer LD (6.8 g as solid content), 7.5 g of talc, polyvinyl alcohol, A suspension of 0.7 g of acrylic acid/methyl methacrylate copolymer and 0.7 g of triethyl citrate in 270.0 g of purified water was sprayed to obtain coated granules each weighing 6.7 mg.
　実施例１で得られた整粒品６０７．７ｇに部分アルファー化デンプン１９．２ｇ、軽質無水ケイ酸１．９ｇ及びステアリン酸マグネシウム４．８ｇを加え、ポリエチレン製の袋にて混合した。得られた混合品をロータリー式打錠機（菊水製作所製：ＶＩＲＧＯ型）で打錠し、１顆粒質量６．６ｍｇの素顆粒を得た。 19.2 g of partially pregelatinized starch, 1.9 g of light anhydrous silicic acid, and 4.8 g of magnesium stearate were added to 607.7 g of the sized product obtained in Example 1, and mixed in a polyethylene bag. The obtained mixture was tableted using a rotary tabletting machine (VIRGO type, manufactured by Kikusui Seisakusho) to obtain elementary granules each having a mass of 6.6 mg.
　実施例２で得られたコーティング顆粒１２０．６ｍｇと実施例３で得られた素顆粒３９．６ｍｇを、３号カプセルに充填し、レボドパ１００ｍｇ及びカルビドパ水和物２７ｍｇ（カルビドパとして２５ｍｇ）を含有するレボドパ／カルビドパ水和物配合持続性製剤を得た。 120.6 mg of coated granules obtained in Example 2 and 39.6 mg of elementary granules obtained in Example 3 were filled into a No. 3 capsule containing 100 mg of levodopa and 27 mg of carbidopa hydrate (25 mg as carbidopa). A long-acting formulation containing levodopa/carbidopa hydrate was obtained.
　レボドパ５００．０（メディアン径：５５μｍ）ｇ、カルビドパ水和物（メディアン径：７．４μｍ）１３５．０ｇ、結晶セルロース７６．６ｇ、アンモニオアルキルメタクリレートコポリマー２４．０ｇ、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体１８．０ｇ及び軽質無水ケイ酸６．０ｇを高速攪拌造粒機（ パウレック社製：ＦＭ－ＶＧ－１０型）に投入して予混合した後、エタノール９５ｇ及び水８５ｇを加えて造粒した。得られた造粒品を流動層乾燥機（パウレック社製：ＭＰ－０１型）にて乾燥したのち、整粒機（パウレック社製：ＱＣ－１９７Ｓ型）で整粒し、整粒品を得た。 Levodopa 500.0 (median diameter: 55 μm) g, carbidopa hydrate (median diameter: 7.4 μm) 135.0 g, crystalline cellulose 76.6 g, ammonioalkyl methacrylate copolymer 24.0 g, polyvinyl alcohol/acrylic acid/methacrylate After premixing 18.0 g of acid methyl copolymer and 6.0 g of light anhydrous silicic acid into a high-speed stirring granulator (Model FM-VG-10, manufactured by Powrex), 95 g of ethanol and 85 g of water were added. and granulated. The obtained granulated product was dried in a fluidized bed dryer (manufactured by Powrex Co., Ltd.: Model MP-01), and then sized with a sieving machine (manufactured by Powrex Co., Ltd.: QC-197S model) to obtain a sized product. Ta.
　実施例５で得られた整粒品６０７．７ｇに軽質無水ケイ酸１．９ｇ及びステアリン酸マグネシウム４．８ｇを加え、ポリエチレン製の袋にて混合した。得られた混合品をロータリー式打錠機（菊水製作所製：ＶＩＲＧＯ型）で打錠し、１顆粒質量６．４ｍｇの素顆粒を得た。得られた素顆粒３５０ｇを通気式コーティング機（フロイント産業製：ＨＣ－ＦＺ－ＬＡＢＯ型）に投入し、メタクリル酸コポリマーＬＤ２７．３ｇ（固形分として８．２ｇ）、タルク３．３ｇ、Ｄ－マンニトール８．２ｇ及びクエン酸トリエチル０．８ｇを精製水６４０ｇ に懸濁した液をスプレーし、１顆粒が６．８ｍｇのコーティング顆粒を得た。 1.9 g of light anhydrous silicic acid and 4.8 g of magnesium stearate were added to 607.7 g of the sized product obtained in Example 5, and mixed in a polyethylene bag. The obtained mixture was tableted using a rotary tabletting machine (VIRGO type, manufactured by Kikusui Seisakusho) to obtain elementary granules each having a mass of 6.4 mg. 350 g of the obtained elementary granules were put into a ventilation coating machine (manufactured by Freund Sangyo: HC-FZ-LABO type), and 27.3 g of methacrylic acid copolymer LD (8.2 g as solid content), 3.3 g of talc, and D-mannitol were added. A suspension of 8.2 g and 0.8 g of triethyl citrate in 640 g of purified water was sprayed to obtain coated granules each weighing 6.8 mg.
　実施例５で得られた整粒品６０７．７ｇに部分アルファー化デンプン１９．２ｇ、軽質無水ケイ酸１．９ｇ及びステアリン酸マグネシウム４．８ｇを加え、ポリエチレン製の袋にて混合した。得られた混合品をロータリー式打錠機（菊水製作所製：ＶＩＲＧＯ型）で打錠し、１顆粒質量６．６ｍｇの素顆粒を得た。 19.2 g of partially pregelatinized starch, 1.9 g of light anhydrous silicic acid, and 4.8 g of magnesium stearate were added to 607.7 g of the sized product obtained in Example 5, and mixed in a polyethylene bag. The obtained mixture was tableted using a rotary tabletting machine (VIRGO type, manufactured by Kikusui Seisakusho) to obtain elementary granules each having a mass of 6.6 mg.
　実施例６で得られたコーティング顆粒１２２．４ｍｇと実施例７で得られた素顆粒３９．６ｍｇを、３号カプセルに充填し、レボドパ１００ｍｇ及びカルビドパ水和物２７ｍｇ（カルビドパとして２５ｍｇ）を含有するレボドパ／カルビドパ水和物配合持続性製剤を得た。 122.4 mg of coated granules obtained in Example 6 and 39.6 mg of elementary granules obtained in Example 7 were filled into a No. 3 capsule containing 100 mg of levodopa and 27 mg of carbidopa hydrate (25 mg as carbidopa). A long-acting formulation containing levodopa/carbidopa hydrate was obtained.
　レボドパ（メディアン径：１６μｍ）３４００．０ｇ、カルビドパ水和物（メディアン径：４．５μｍ）９１８．０ｇ、結晶セルロース３５７．４ｇ、アンモニオアルキルメタクリレートコポリマー２４４．８ｇ、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体８１．６ｇ及び軽質無水ケイ酸８１．６ｇを高速攪拌造粒機（ パウレック社製：ＦＭ－ＶＧ－２５型）に投入して予混合した後、水１１００ｇを加えて造粒した。得られた造粒品を流動層乾燥機（パウレック社製：ＦＤ－ＧＰＣＧ－５ＳＰＣ型）にて乾燥したのち、整粒機（パウレック社製：ＱＣ－１９７Ｓ型）で整粒し、整粒品を得た。 Levodopa (median diameter: 16 μm) 3400.0 g, carbidopa hydrate (median diameter: 4.5 μm) 918.0 g, crystalline cellulose 357.4 g, ammonioalkyl methacrylate copolymer 244.8 g, polyvinyl alcohol/acrylic acid/methacrylic acid 81.6 g of methyl copolymer and 81.6 g of light anhydrous silicic acid were premixed in a high-speed stirring granulator (Model FM-VG-25, manufactured by Powrex), and then 1100 g of water was added and granulated. . The obtained granulated product was dried in a fluidized bed dryer (manufactured by Powrex Co., Ltd.: FD-GPCG-5SPC type), and then sized with a sieving machine (manufactured by Powrex Co., Ltd.: QC-197S type) to obtain a sized product. I got it.
　実施例９で得られた整粒品２９９０．０ｇに軽質無水ケイ酸９．６ｇ及びステアリン酸マグネシウム１２０．０ｇを加え、回転式混合機（愛知電機社製：ＲＭ－１０－３型）で混合した。得られた混合品をロータリー式打錠機（菊水製作所製：ＶＩＲＧＯ型）で打錠し、１顆粒質量６．５ｍｇの素顆粒を得た。得られた素顆粒１１７０ｇを通気式コーティング機（フロイント産業製：ＨＣ－ＦＺ－ＬＡＢＯ型）に投入し、メタクリル酸コポリマーＬＤ９０．０ｇ（固形分として２７．０ｇ）、タルク１３．５ｇ、Ｄ－マンニトール１０．８ｇ、クエン酸トリエチル２．３ｇ及び黄色三二酸化鉄０．５ｇを精製水４８０ｇに懸濁した液をスプレーし、１顆粒が６．８ｍｇのコーティング顆粒を得た。 9.6 g of light anhydrous silicic acid and 120.0 g of magnesium stearate were added to 2990.0 g of the sized product obtained in Example 9, and mixed with a rotary mixer (manufactured by Aichi Electric Co., Ltd.: RM-10-3 type). did. The obtained mixture was tableted using a rotary tabletting machine (VIRGO type, manufactured by Kikusui Seisakusho) to obtain elementary granules each having a mass of 6.5 mg. 1170 g of the obtained elementary granules were put into a ventilation coating machine (manufactured by Freund Sangyo: HC-FZ-LABO type), and 90.0 g of methacrylic acid copolymer LD (27.0 g as solid content), 13.5 g of talc, and D-mannitol were added. A suspension of 10.8 g of triethyl citrate, 2.3 g of triethyl citrate, and 0.5 g of yellow iron sesquioxide in 480 g of purified water was sprayed to obtain coated granules each weighing 6.8 mg.
　実施例９で得られた整粒品９９６．８ｇに部分アルファー化デンプン３２．０ｇ、軽質無水ケイ酸３．２ｇ及びステアリン酸マグネシウム２４．０ｇを加え、回転式混合機（愛知電機社製：ＲＭ－１０－３型）で混合した。得られた混合品をロータリー式打錠機（菊水製作所製：ＶＩＲＧＯ型）で打錠し、１顆粒質量６．６ｍｇの素顆粒を得た。 32.0 g of partially pregelatinized starch, 3.2 g of light anhydrous silicic acid, and 24.0 g of magnesium stearate were added to 996.8 g of the sized product obtained in Example 9, and a rotary mixer (manufactured by Aichi Denki Co., Ltd.: RM) was added. -10-3 type). The obtained mixture was tableted using a rotary tabletting machine (manufactured by Kikusui Manufacturing Co., Ltd.: VIRGO type) to obtain elementary granules each having a mass of 6.6 mg.
　実施例１０で得られたコーティング顆粒１２２．４ｍｇと実施例１１で得られた素顆粒３９．６ｍｇを、３号カプセルに充填し、レボドパ１００ｍｇ及びカルビドパ水和物２７ｍｇ（カルビドパとして２５ｍｇ）を含有するレボドパ／カルビドパ水和物配合持続性製剤を得た。 122.4 mg of coated granules obtained in Example 10 and 39.6 mg of elementary granules obtained in Example 11 were filled into a No. 3 capsule containing 100 mg of levodopa and 27 mg of carbidopa hydrate (25 mg as carbidopa). A long-acting formulation containing levodopa/carbidopa hydrate was obtained.
　実施例１０で得られたコーティング顆粒９７９．２ｇを通気式コーティング機（フロイント産業製：ＨＣ－ＦＺ－ＬＡＢＯ型）に投入し、レボドパ２００．０ｇ、カルビドパ水和物５４．０ｇ及びポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体１３．７ｇを精製水２７００ｇに懸濁した液をスプレーし、１顆粒が８．７ｍｇのレボドパ／カルビドパ水和物配合持続性顆粒を得た。 979.2 g of the coated granules obtained in Example 10 were put into a ventilation coating machine (manufactured by Freund Sangyo: HC-FZ-LABO type), and 200.0 g of levodopa, 54.0 g of carbidopa hydrate, and polyvinyl alcohol/acrylic were added. A suspension of 13.7 g of acid/methyl methacrylate copolymer in 2,700 g of purified water was sprayed to obtain levodopa/carbidopa hydrate-containing long-lasting granules each containing 8.7 mg.
　レボドパ（メディアン径：１６μｍ）４５００．０ｇ、カルビドパ水和物（メディアン径：４．５μｍ）１２１５．０ｇ、結晶セルロース４７３．０ｇ、アンモニオアルキルメタクリレートコポリマー３２４．０ｇ、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体１０８．０ｇ及び軽質無水ケイ酸１０８．０ｇを高速攪拌造粒機（パウレック社製：ＦＭ－ＶＧ－２５型）に投入して予混合した後、水１５００ｇを加えて造粒した。得られた造粒品を流動層乾燥機（パウレック社製：ＦＤ－ＧＰＣＧ－５ＳＰＣ型）にて乾燥したのち、整粒機（パウレック社製：ＱＣ－１９７Ｓ型）で整粒し、整粒品を得た。 Levodopa (median diameter: 16 μm) 4500.0 g, carbidopa hydrate (median diameter: 4.5 μm) 1215.0 g, crystalline cellulose 473.0 g, ammonioalkyl methacrylate copolymer 324.0 g, polyvinyl alcohol/acrylic acid/methacrylic acid 108.0 g of methyl copolymer and 108.0 g of light anhydrous silicic acid were premixed in a high-speed stirring granulator (Model FM-VG-25, manufactured by Powrex), and then 1500 g of water was added and granulated. . The obtained granulated product was dried in a fluidized bed dryer (manufactured by Powrex Co., Ltd.: FD-GPCG-5SPC type), and then sized with a sieving machine (manufactured by Powrex Co., Ltd.: QC-197S type) to obtain a sized product. I got it.
　実施例１４で得られた整粒品３３６４．０ｇに軽質無水ケイ酸１０．８ｇ及びステアリン酸マグネシウム１３５．０ｇを加え、回転式混合機（愛知電機社製：ＲＭ－１０－３型）で混合した。得られた混合品をロータリー式打錠機（菊水製作所製：ＶＩＲＧＯ型）で打錠し、１顆粒質量３．２５ｍｇの素顆粒を得た。得られた素顆粒２５０ｇを通気式コーティング機（フロイント産業製：ＨＣ－ＦＺ－ＬＡＢＯ型）に投入し、メタクリル酸コポリマーＬＤ４３．３ｇ（固形分として１３．０ｇ）、タルク６．５ｇ、Ｄ－マンニトール５．２ｇ、クエン酸トリエチル１．１ｇ及び黄色三二酸化鉄０．３ｇを精製水２３２ｇに懸濁した液をスプレーし、１顆粒が３．５８ｍｇのコーティング顆粒を得た。 10.8 g of light anhydrous silicic acid and 135.0 g of magnesium stearate were added to 3364.0 g of the sized product obtained in Example 14, and mixed with a rotary mixer (manufactured by Aichi Electric Co., Ltd.: RM-10-3 type). did. The obtained mixture was tableted using a rotary tabletting machine (VIRGO type, manufactured by Kikusui Seisakusho) to obtain elementary granules each having a mass of 3.25 mg. 250 g of the obtained elementary granules were put into a ventilation coating machine (manufactured by Freund Sangyo: HC-FZ-LABO type), and 43.3 g of methacrylic acid copolymer LD (13.0 g as solid content), 6.5 g of talc, and D-mannitol were added. A suspension of 5.2 g of triethyl citrate, 1.1 g of triethyl citrate, and 0.3 g of yellow iron sesquioxide in 232 g of purified water was sprayed to obtain coated granules each weighing 3.58 mg.
　実施例１４で得られた整粒品１１２１．０ｇに部分アルファー化デンプン３６．０ｇ、軽質無水ケイ酸３．６ｇ及びステアリン酸マグネシウム２７．０ｇを加え、回転式混合機（愛知電機社製：ＲＭ－１０－３型）で混合した。得られた混合品をロータリー式打錠機（菊水製作所製：ＶＩＲＧＯ型）で打錠し、１顆粒質量３．３ｍｇの素顆粒を得た。 36.0 g of partially pregelatinized starch, 3.6 g of light anhydrous silicic acid, and 27.0 g of magnesium stearate were added to 1121.0 g of the sized product obtained in Example 14, and a rotary mixer (manufactured by Aichi Denki Co., Ltd.: RM) was added. -10-3 type). The obtained mixture was tableted using a rotary tabletting machine (VIRGO type, manufactured by Kikusui Seisakusho) to obtain elementary granules each having a mass of 3.3 mg.
　実施例１５で得られたコーティング顆粒１２９．２ｍｇと実施例１６で得られた素顆粒３９．６ｍｇを、３号カプセルに充填し、レボドパ１００ｍｇ及びカルビドパ水和物２７ｍｇ（カルビドパとして２５ｍｇ）を含有するレボドパ／カルビドパ水和物配合持続性製剤を得た。 129.2 mg of coated granules obtained in Example 15 and 39.6 mg of elementary granules obtained in Example 16 were filled into a No. 3 capsule containing 100 mg of levodopa and 27 mg of carbidopa hydrate (25 mg as carbidopa). A long-acting formulation containing levodopa/carbidopa hydrate was obtained.
　実施例１４で得られた整粒品３３６４．０ｇに軽質無水ケイ酸１０．８ｇ及びステアリン酸マグネシウム１３５．０ｇを加え、回転式混合機（愛知電機社製：ＲＭ－１０－３型）で混合した。得られた混合品をロータリー式打錠機（菊水製作所製：ＶＩＲＧＯ型）で打錠し、１顆粒質量１９．５０ｍｇの素顆粒を得た。得られた素顆粒２５０ｇを通気式コーティング機（フロイント産業製：ＨＣ－ＦＺ－ＬＡＢＯ型）に投入し、メタクリル酸コポリマーＬＤ９．０ｇ（固形分として）２．７ｇ）、タルク１．３５ｇ、Ｄ－マンニトール１．０８ｇ、クエン酸トリエチル０．２３ｇ及び黄色三二酸化鉄０．０５ｇを精製水４８ｇに懸濁した液をスプレーし、１顆粒が１９．９ｍｇのコーティング顆粒を得た。 10.8 g of light anhydrous silicic acid and 135.0 g of magnesium stearate were added to 3364.0 g of the sized product obtained in Example 14, and mixed with a rotary mixer (manufactured by Aichi Electric Co., Ltd.: RM-10-3 type). did. The obtained mixture was tableted using a rotary tabletting machine (VIRGO type, manufactured by Kikusui Seisakusho) to obtain elementary granules each having a mass of 19.50 mg. 250 g of the obtained elementary granules were put into a ventilation coating machine (manufactured by Freund Sangyo: HC-FZ-LABO type), and methacrylic acid copolymer LD 9.0 g (as solid content) 2.7 g), talc 1.35 g, D- A suspension of 1.08 g of mannitol, 0.23 g of triethyl citrate, and 0.05 g of yellow iron sesquioxide in 48 g of purified water was sprayed to obtain coated granules each weighing 19.9 mg.
　実施例１４で得られた整粒品１１２１．０ｇに部分アルファー化デンプン３６．０ｇ、軽質無水ケイ酸３．６ｇ及びステアリン酸マグネシウム２７．０ｇを加え、回転式混合機（愛知電機社製：ＲＭ－１０－３型）で混合した。得られた混合品をロータリー式打錠機（菊水製作所製：ＶＩＲＧＯ型）で打錠し、１顆粒質量１９．８ｍｇの素顆粒を得た。 36.0 g of partially pregelatinized starch, 3.6 g of light anhydrous silicic acid, and 27.0 g of magnesium stearate were added to 1121.0 g of the sized product obtained in Example 14, and a rotary mixer (manufactured by Aichi Denki Co., Ltd.: RM) was added. -10-3 type). The obtained mixture was tableted using a rotary tabletting machine (manufactured by Kikusui Manufacturing Co., Ltd.: VIRGO type) to obtain elementary granules each having a mass of 19.8 mg.
　実施例１８で得られたコーティング顆粒１１９．４ｍｇと実施例１９で得られた素顆粒３９．６ｍｇを、３号カプセルに充填し、レボドパ１００ｍｇ及びカルビドパ水和物２７ｍｇ（カルビドパとして２５ｍｇ）を含有するレボドパ／カルビドパ水和物配合持続性製剤を得た。 119.4 mg of coated granules obtained in Example 18 and 39.6 mg of elementary granules obtained in Example 19 were filled into a No. 3 capsule containing 100 mg of levodopa and 27 mg of carbidopa hydrate (25 mg as carbidopa). A long-acting formulation containing levodopa/carbidopa hydrate was obtained.
　実施例１４で得られた整粒品３３６４．０ｇに軽質無水ケイ酸１０．８ｇ及びステアリン酸マグネシウム１３５．０ｇを加え、回転式混合機（愛知電機社製：ＲＭ－１０－３型）で混合した。得られた混合品をロータリー式打錠機（菊水製作所製：ＶＩＲＧＯ型）で打錠し、１顆粒質量６．５ｍｇの素顆粒を得た。得られた素顆粒２５０ｇを通気式コーティング機（フロイント産業製：ＨＣ－ＦＺ－ＬＡＢＯ型）に投入し、メタクリル酸コポリマーＬＤ１１．６ｇ（固形分として３．５ｇ）、タルク１．７４ｇ、Ｄ－マンニトール１．３９ｇ、クエン酸トリエチル０．３０ｇ及び黄色三二酸化鉄０．０７ｇを精製水６０ｇに懸濁した液をスプレーし、１顆粒が６．６ｍｇのコーティング顆粒を得た。 10.8 g of light anhydrous silicic acid and 135.0 g of magnesium stearate were added to 3364.0 g of the sized product obtained in Example 14, and mixed with a rotary mixer (manufactured by Aichi Electric Co., Ltd.: RM-10-3 type). did. The obtained mixture was tableted using a rotary tabletting machine (VIRGO type, manufactured by Kikusui Seisakusho) to obtain elementary granules each having a mass of 6.5 mg. 250 g of the obtained elementary granules were put into a ventilation coating machine (manufactured by Freund Sangyo: HC-FZ-LABO type), and 11.6 g of methacrylic acid copolymer LD (3.5 g as solid content), 1.74 g of talc, and D-mannitol were added. A suspension of 1.39 g of triethyl citrate, 0.30 g of triethyl citrate, and 0.07 g of yellow iron sesquioxide in 60 g of purified water was sprayed to obtain coated granules each weighing 6.6 mg.
　実施例２１で得られたコーティング顆粒２３４ｇを通気式コーティング機（フロイント産業製：ＨＣ－ＦＺ－ＬＡＢＯ型）に投入し、レボドパ７２．０ｇ、カルビドパ水和物１９．４ｇ及びポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体５．０ｇを精製水５５５ｇに懸濁した液を、１顆粒の質量が８．５ｍｇとなるまでスプレーし，レボドパ／カルビドパ水和物配合持続性顆粒を得た。 234 g of the coated granules obtained in Example 21 were put into an aeration-type coating machine (manufactured by Freund Sangyo: HC-FZ-LABO type), and 72.0 g of levodopa, 19.4 g of carbidopa hydrate, and polyvinyl alcohol, acrylic acid, A suspension of 5.0 g of methyl methacrylate copolymer in 555 g of purified water was sprayed until the mass of one granule was 8.5 mg to obtain long-lasting granules containing levodopa/carbidopa hydrate.
　実施例２２で得られたコーティング顆粒１５３．０ｍｇを、３号カプセルに充填し、レボドパ１００ｍｇ及びカルビドパ水和物２７ｍｇ（カルビドパとして２５ｍｇ）を含有するレボドパ／カルビドパ水和物配合持続性製剤を得た。 153.0 mg of the coated granules obtained in Example 22 were filled into No. 3 capsules to obtain a long-acting levodopa/carbidopa hydrate combination formulation containing 100 mg of levodopa and 27 mg of carbidopa hydrate (25 mg as carbidopa). .
　実施例１４で得られた整粒品９９６．８ｇに低置換度ヒドロキシプロピルセルロース３２．０ｇ、軽質無水ケイ酸３．２ｇ及びステアリン酸カルシウム２４．０ｇを加え、回転式混合機（愛知電機社製：ＲＭ－１０－３型）で混合した。得られた混合品をロータリー式打錠機（菊水製作所製：ＶＩＲＧＯ型）で打錠し、１顆粒質量６．６ｍｇの素顆粒を得た。 32.0 g of low-substituted hydroxypropyl cellulose, 3.2 g of light anhydrous silicic acid, and 24.0 g of calcium stearate were added to 996.8 g of the sized product obtained in Example 14, and the mixture was mixed with a rotary mixer (manufactured by Aichi Denki Co., Ltd.: RM-10-3 type). The obtained mixture was tableted using a rotary tabletting machine (VIRGO type, manufactured by Kikusui Seisakusho) to obtain elementary granules each having a mass of 6.6 mg.
　実施例１０で得られたコーティング顆粒１２２．４ｍｇと実施例２４で得られた素顆粒３９．６ｍｇを、３号カプセルに充填し、レボドパ１００ｍｇ及びカルビドパ水和物２７ｍｇ（カルビドパとして２５ｍｇ）を含有するレボドパ／カルビドパ水和物配合持続性製剤を得た。 122.4 mg of coated granules obtained in Example 10 and 39.6 mg of elementary granules obtained in Example 24 were filled into a No. 3 capsule containing 100 mg of levodopa and 27 mg of carbidopa hydrate (25 mg as carbidopa). A long-acting formulation containing levodopa/carbidopa hydrate was obtained.
　実施例１４で得られた整粒品９９６．８ｇにカルメロースカルシウム３２．０ｇ、軽質無水ケイ酸３．２ｇ及びステアリン酸カルシウム２４．０ｇを加え、回転式混合機（愛知電機社製：ＲＭ－１０－３型）で混合した。得られた混合品をロータリー式打錠機（菊水製作所製：ＶＩＲＧＯ型）で打錠し、１顆粒質量６．６ｍｇの素顆粒を得た。 32.0 g of carmellose calcium, 3.2 g of light anhydrous silicic acid, and 24.0 g of calcium stearate were added to 996.8 g of the sized product obtained in Example 14, and a rotary mixer (manufactured by Aichi Denki Co., Ltd.: RM-10) was added. -3 type). The obtained mixture was tableted using a rotary tabletting machine (VIRGO type, manufactured by Kikusui Seisakusho) to obtain elementary granules each having a mass of 6.6 mg.
　実施例１０で得られたコーティング顆粒１２２．４ｍｇと実施例２６で得られた素顆粒３９．６ｍｇを、３号カプセルに充填し、レボドパ１００ｍｇ及びカルビドパ水和物２７ｍｇ（カルビドパとして２５ｍｇ）を含有するレボドパ／カルビドパ水和物配合持続性製剤を得た。 122.4 mg of coated granules obtained in Example 10 and 39.6 mg of elementary granules obtained in Example 26 were filled into a No. 3 capsule containing 100 mg of levodopa and 27 mg of carbidopa hydrate (25 mg as carbidopa). A long-acting formulation containing levodopa/carbidopa hydrate was obtained.
　実施例１４で得られた整粒品３３６４．０ｇに軽質無水ケイ酸１０．８ｇ及びステアリン酸カルシウム１３５．０ｇを加え、回転式混合機（愛知電機社製：ＲＭ－１０－３型）で混合する。得られる混合品をロータリー式打錠機（菊水製作所製：ＶＩＲＧＯ型）で打錠し、１顆粒質量６．５ｍｇの素顆粒を得る。得られる素顆粒２５０ｇを通気式コーティング機（フロイント産業製：ＨＣ－ＦＺ－ＬＡＢＯ型）に投入し、メタクリル酸コポリマーＬＤ１４．５ｇ（固形分として４．３ｇ）、タルク２．１８ｇ、Ｄ－マンニトール１．７４ｇ、クエン酸トリエチル０．３８ｇ及び黄色三二酸化鉄０．０９ｇを精製水７５ｇに懸濁した液をスプレーし、１顆粒が６．７ｍｇのコーティング顆粒を得る。 Add 10.8 g of light anhydrous silicic acid and 135.0 g of calcium stearate to 3364.0 g of the sized product obtained in Example 14, and mix with a rotary mixer (manufactured by Aichi Electric Co., Ltd.: RM-10-3 type). . The resulting mixture is tableted using a rotary tabletting machine (VIRGO type, manufactured by Kikusui Seisakusho) to obtain elementary granules each having a mass of 6.5 mg. 250 g of the obtained elementary granules were put into a ventilation coating machine (manufactured by Freund Sangyo: HC-FZ-LABO type), and 14.5 g of methacrylic acid copolymer LD (4.3 g as solid content), 2.18 g of talc, and 1 part of D-mannitol were added. A suspension of 0.74 g of triethyl citrate, 0.38 g of triethyl citrate, and 0.09 g of yellow iron sesquioxide in 75 g of purified water was sprayed to obtain coated granules each weighing 6.7 mg.
　実施例２８で得られるコーティング顆粒１２１．１ｍｇと実施例１１で得られた素顆粒３９．６ｍｇを、３号カプセルに充填し、レボドパ１００ｍｇ及びカルビドパ水和物２７ｍｇ（カルビドパとして２５ｍｇ）を含有するレボドパ／カルビドパ水和物配合持続性製剤を得る。 121.1 mg of the coated granules obtained in Example 28 and 39.6 mg of the elementary granules obtained in Example 11 were filled into No. 3 capsules, and levodopa containing 100 mg of levodopa and 27 mg of carbidopa hydrate (25 mg as carbidopa) was prepared. / Obtain a long-acting preparation containing carbidopa hydrate.
　本開示の製剤１カプセル中の成分を下記の表１に示した。
表１
 The ingredients in one capsule of the formulation of the present disclosure are shown in Table 1 below.
Table 1
［比較例１］
　ネオドパストン（登録商標）配合錠Ｌ１００（大原薬品工業製）：１錠中レボドパ１００ｍｇ及びカルビドパ水和物１０．８ｍｇを含有する。 [Comparative example 1]
Neodopastone (registered trademark) combination tablet L100 (manufactured by Ohara Pharmaceutical Co., Ltd.): 1 tablet contains 100 mg of levodopa and 10.8 mg of carbidopa hydrate.
〔試験例１〕レボドパの溶出試験（パドル法）
　実施例４、実施例８、実施例１２、実施例１７、実施例２０、実施例２３、実施例２５及び実施例２７で得られたそれぞれの製剤、並びに比較例１の製剤について、第１８改正日本薬局方・一般試験法の溶出試験第２法（パドル法）を実施した。溶出試験液には第１８改正日本薬局方・一般試験法に規定される溶出試験第１液（ｐＨ１．２）を９００ｍＬ用い、パドル回転数１００回転／分、液温３７℃（３７±０．５℃の範囲）の条件下で溶出試験を行い、各サンプリング時点でのレボドパの溶出量を高速液体クロマトグラフ法で求め、表示量に対するレボドパの溶出率（ｎ＝６）を下記の表２に示した。
　＜使用した装置＞
・溶出試験機　／ＲＴＪ－２０００（大日本精機製）
・高速液体クロマトグラフ　／ＮＥＸＥＲＡシステム（島津製作所製） [Test Example 1] Levodopa dissolution test (paddle method)
Regarding each of the formulations obtained in Example 4, Example 8, Example 12, Example 17, Example 20, Example 23, Example 25, and Example 27, and the formulation of Comparative Example 1, the 18th Amendment Dissolution test method 2 (paddle method) of the Japanese Pharmacopoeia/General Test Methods was conducted. As the dissolution test solution, 900 mL of the dissolution test first solution (pH 1.2) specified in the 18th revised Japanese Pharmacopoeia/General Test Methods was used, the paddle rotation speed was 100 revolutions/min, and the liquid temperature was 37 °C (37 ± 0.5 °C). A dissolution test was carried out under conditions (in the range of 5°C), and the elution amount of levodopa at each sampling point was determined using high performance liquid chromatography. The dissolution rate of levodopa (n = 6) relative to the indicated amount is shown in Table 2 below. Indicated.
<Equipment used>
・Dissolution tester /RTJ-2000 (manufactured by Dainippon Seiki)
・High-performance liquid chromatograph/NEXERA system (manufactured by Shimadzu Corporation)
表２　試験例１ パドル法でのレボドパの溶出試験結果（ｎ＝６）
 Table 2 Test Example 1 Levodopa dissolution test results using the paddle method (n=6)
　比較例１の製剤を用いた溶出試験結果では、溶出試験開始後３０分時点で表示量の１００％が溶出しているのに対し、実施例４、実施例８、実施例１２、実施例１７、実施例２０、実施例２３、実施例２５及び実施例２７のそれぞれの製剤を用いた溶出試験結果では、溶出試験開始後３０分時点では表示量の３０％程度が溶出し、その後は３時間以上かけてレボドパが徐々に溶出していることが確認された。 In the dissolution test results using the formulation of Comparative Example 1, 100% of the labeled amount was eluted 30 minutes after the start of the dissolution test, whereas Examples 4, 8, 12, and 17 The dissolution test results using the formulations of Example 20, Example 23, Example 25, and Example 27 show that approximately 30% of the labeled amount was eluted at 30 minutes after the start of the dissolution test, and after that for 3 hours. It was confirmed that levodopa was gradually eluted over the above steps.
　このレボドパ溶出挙動は、実際にそれぞれの製剤を対象者に投与した際に、比較例１の製剤は胃内で速やかにレボドパが溶出して直ちに消化管で吸収されることが予想されるのに対して、実施例４、実施例８、実施例１２、実施例１７、実施例２０、実施例２３、実施例２５及び実施例２７のそれぞれの製剤では胃内で３０％程度のレボドパが速やかに溶出することで直ちにレボドパ血中濃度が一定水準まで上昇し、その後、たとえ製剤が対象者の胃内で滞留していたとしても徐々に溶け出して一定のレボドパ血中濃度が維持されることが示唆される。 This levodopa elution behavior is because when each formulation is actually administered to a subject, levodopa in the formulation of Comparative Example 1 is expected to be rapidly eluted in the stomach and immediately absorbed in the gastrointestinal tract. On the other hand, in each of the formulations of Example 4, Example 8, Example 12, Example 17, Example 20, Example 23, Example 25, and Example 27, about 30% of levodopa was quickly absorbed in the stomach. By dissolving, the levodopa blood concentration immediately rises to a certain level, and after that, even if the preparation remains in the subject's stomach, it gradually dissolves and maintains a constant levodopa blood concentration. It is suggested.
〔試験例２〕レボドパの溶出試験（フロースルーセル法）
　実施例４、実施例８、実施例１２、実施例１７、実施例２０、実施例２３、実施例２５及び実施例２７で得られたそれぞれの製剤、並びに比較例１の製剤について、第１８改正日本薬局方・一般試験法の溶出試験第３法（フロースルーセル法）を実施した。溶出試験は、オープンループ法で小型フロースルーセルを用いて行い、脈流のある送液ポンプで、溶出試験開始から４５分までは第１８改正日本薬局方・一般試験法に規定される溶出試験第１液（ｐＨ１．２）を、４５分から１８０分までは薄めたＭｃＩｌｖａｉｎｅ緩衝液（ｐＨ５．５）（関東化学製）を、１８０分から５４０分までは第１８改正日本薬局方・一般試験法に規定される溶出試験第２液（ｐＨ６．８）をいずれも液温３７℃（３７±０．５℃の範囲）、送液速度１６ｍＬ／分で送液した。溶出試験開始後２分、５分、１０分、１５分、２０分、３０分、４５分、６０分、７５分、９０分、１２０分、１５０分、１８０分、２１０分、２４０分、３００分、３６０分、４２０分、４８０分及び５４０分時点でのレボドパの溶出量を高速液体クロマトグラフで求め、レボドパの溶出量の積算値から算出した各時点での表示量に対するレボドパの溶出率（ｎ＝７）を下記の表３に示した。
　＜使用した装置＞
・溶出試験機　／フロースルーセル法溶出試験機ＤＦ－７（大日本精機製）
・高速液体クロマトグラフ　／ＮＥＸＥＲＡシステム（島津製作所製） [Test Example 2] Levodopa dissolution test (flow-through cell method)
Regarding each of the formulations obtained in Example 4, Example 8, Example 12, Example 17, Example 20, Example 23, Example 25, and Example 27, and the formulation of Comparative Example 1, the 18th Amendment The third dissolution test method (flow-through cell method) of the Japanese Pharmacopoeia/General Test Methods was conducted. The dissolution test was conducted using a small flow-through cell using an open-loop method, using a pump with a pulsating flow, and for up to 45 minutes from the start of the dissolution test, the dissolution test specified in the 18th revised Japanese Pharmacopoeia/General Test Methods was carried out. The first solution (pH 1.2) was diluted with McIlvaine buffer (pH 5.5) (manufactured by Kanto Kagaku) from 45 to 180 minutes, and the 18th revised Japanese Pharmacopoeia General Test Method was used from 180 to 540 minutes. The prescribed elution test second solution (pH 6.8) was fed at a liquid temperature of 37° C. (range of 37±0.5° C.) and a liquid feeding rate of 16 mL/min. 2 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, 75 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes, 210 minutes, 240 minutes, 300 minutes after starting the elution test The elution amount of levodopa at minutes, 360 minutes, 420 minutes, 480 minutes, and 540 minutes was determined using a high-performance liquid chromatograph, and the elution rate of levodopa relative to the indicated amount at each time point was calculated from the integrated value of the elution amount of levodopa ( n=7) are shown in Table 3 below.
<Equipment used>
・Dissolution tester / Flow-through cell method dissolution tester DF-7 (manufactured by Dainippon Seiki)
・High-performance liquid chromatograph/NEXERA system (manufactured by Shimadzu Corporation)
表３　試験例２ フロースルーセル法でのレボドパの溶出試験結果（ｎ＝７）
 Table 3 Test Example 2 Levodopa dissolution test results using flow-through cell method (n=7)
　比較例１の製剤を用いた溶出試験結果では、ｐＨ１．２の溶出試験液を送液すると速やかにレボドパが溶出し、溶出試験開始後１５分時点ですでにほぼすべてのレボドパが溶出した。 In the results of the dissolution test using the formulation of Comparative Example 1, when the dissolution test solution at pH 1.2 was delivered, levodopa was quickly eluted, and almost all of the levodopa was already eluted 15 minutes after the start of the dissolution test.
　一方、実施例４、実施例８、実施例１２、実施例１７、実施例２０、実施例２３、実施例２５及び実施例２７のそれぞれの製剤を用いた溶出試験結果では、ｐＨ１．２の試験液を溶出試験開始後４５分時点では表示量の３０％程度が溶出し、その後ｐＨ５．５の試験液、続いてｐＨ６．８の試験液を送液した時、試験液のｐＨに依らずレボドパが持続的に溶出していることが確認された。 On the other hand, in the dissolution test results using the respective formulations of Example 4, Example 8, Example 12, Example 17, Example 20, Example 23, Example 25, and Example 27, the pH 1.2 test About 30% of the indicated amount of the solution was eluted at 45 minutes after starting the dissolution test, and when the test solution with pH 5.5 and then the test solution with pH 6.8 were sent, levodopa was released regardless of the pH of the test solution. It was confirmed that eluted continuously.
　この溶出挙動は、実際にそれぞれの製剤を対象者に投与した際に、比較例１の製剤は試験例１と同様に胃内で速やかにレボドパが溶出して直ちに消化管で吸収されることが示唆される。 This dissolution behavior shows that when each formulation was actually administered to a subject, levodopa in the formulation of Comparative Example 1 was rapidly eluted in the stomach and absorbed immediately in the gastrointestinal tract, similar to Test Example 1. It is suggested.
　一方、実施例４、実施例８、実施例１２、実施例１７、実施例２０、実施例２３、実施例２５及び実施例２７のそれぞれの製剤では、やはり胃内で３０％程度のレボドパが速やかに溶出することで、直ちにレボドパ血中濃度を一定水準まで上昇させることが示唆される。 On the other hand, in each of the formulations of Example 4, Example 8, Example 12, Example 17, Example 20, Example 23, Example 25, and Example 27, about 30% of levodopa was absorbed quickly in the stomach. It is suggested that levodopa blood concentration immediately increases to a certain level by eluting into the levodopa.
　これらの結果から、たとえ生体内における消化管内ｐＨに個体間差があったとしても、その影響を受けることなく製剤が徐々に溶け出して、一定のレボドパ血中濃度が維持されることが示唆される。 These results suggest that even if there are interindividual differences in the pH in the gastrointestinal tract in vivo, the formulation gradually dissolves without being affected by this, and a constant blood concentration of levodopa is maintained. Ru.
〔試験例３〕健康成人におけるレボドパの薬物動態比較試験
　健康成人男性１２人に実施例４、実施例８で得られたそれぞれの製剤（レボドパ１００ｍｇ／カルビドパ水和物２７ｍｇ）及び比較例１の製剤（レボドパ１００ｍｇ／カルビドパ水和物１０．８ｍｇ）をそれぞれ絶食下で単回経口投与する薬物動態比較試験を実施した。それぞれの製剤の平均血漿中レボドパ濃度推移の結果を図１に示す。 [Test Example 3] Comparative pharmacokinetic study of levodopa in healthy adults Each of the formulations obtained in Examples 4 and 8 (levodopa 100 mg/carbidopa hydrate 27 mg) and the formulation of Comparative Example 1 were administered to 12 healthy adult males. A comparative pharmacokinetic study was conducted in which a single dose of (levodopa 100 mg/carbidopa hydrate 10.8 mg) was orally administered under fasting conditions. The results of the average plasma levodopa concentration over time for each preparation are shown in Figure 1.
　比較例１の製剤を被験者に投与した直後から、血漿中レボドパ濃度は速やかに上昇しているが、該製剤の投与１時間後には血漿中レボドパ濃度は半分程度まで低下しており、レボドパの薬理作用の効果の持続が難しいことが示唆される。 Immediately after administering the formulation of Comparative Example 1 to the subject, the plasma levodopa concentration rose rapidly, but one hour after the administration of the formulation, the plasma levodopa concentration decreased to about half, indicating that the pharmacology of levodopa was low. This suggests that it is difficult to maintain the effect of the action.
　一方、実施例４及び実施例８のそれぞれの製剤を被験者に投与した場合には、速やかに血漿中レボドパ濃度が一定の水準まで上昇し、その後約４時間、同程度の血漿中レボドパ濃度を維持できている。この結果から、一回の投与で即効性と持続性を併せ持つレボドパ血中動態プロファイルを示すことで、長時間レボドパの薬理作用の効果が持続することが示唆される。 On the other hand, when each of the formulations of Example 4 and Example 8 was administered to subjects, the plasma levodopa concentration quickly rose to a certain level, and the plasma levodopa concentration remained at the same level for about 4 hours thereafter. is made of. These results suggest that the pharmacological effects of levodopa are sustained over a long period of time by showing a blood dynamics profile of levodopa that is both immediate and long-lasting after a single administration.
　この結果は、放出制御製剤を設計するうえで重要なｉｎ　ｖｉｔｒｏでの製剤特性の評価基準として、試験例１及び試験例２で示した溶出試験が極めて有効な評価方法であることを示している。 This result shows that the dissolution test shown in Test Examples 1 and 2 is an extremely effective evaluation method as an evaluation criterion for in vitro drug properties, which is important in designing controlled release preparations. .
　本明細書で示した本開示の製剤のレボドパ溶出挙動は、薬学的活性成分としてレボドパとカルビドパを含有する経口用医薬組成物が、即効性と持続性を併せ持つレボドパ血中動態プロファイルを達成するうえで特に重要な製剤特性であることが示唆される。 The levodopa dissolution behavior of the presently disclosed formulation shown herein shows that an oral pharmaceutical composition containing levodopa and carbidopa as pharmaceutically active ingredients can achieve a levodopa blood dynamics profile that is both immediate and long-lasting. This suggests that this is a particularly important formulation characteristic.
〔試験例４〕ふるい分け試験
　実施例２、実施例６、実施例１０、実施例１５、実施例１８及び実施例２１のコーティング顆粒、並びに実施例３、実施例７、実施例１１，実施例１６，実施例１９、実施例２４及び実施例２６の素顆粒、さらに実施例１３及び実施例２２のレボドパ／カルビドパ水和物配合持続性顆粒は、いずれも第１８改正日本薬局方・一般試験法の粒度測定法に記載される、日本薬局方ふるい番号４．７号を通過し、日本薬局方ふるい番号１２号に残留した。 [Test Example 4] Sieving test Coated granules of Example 2, Example 6, Example 10, Example 15, Example 18, and Example 21, and Example 3, Example 7, Example 11, and Example 16 , the elementary granules of Examples 19, 24, and 26, and the levodopa/carbidopa hydrate combination long-lasting granules of Examples 13 and 22, all of which comply with the 18th revised Japanese Pharmacopoeia/General Test Methods. It passed through Japanese Pharmacopoeia Sieve No. 4.7 and remained on Japanese Pharmacopoeia Sieve No. 12, which is described in the particle size measurement method.
〔試験例５〕健康成人における投与量によるレボドパの薬物動態比較試験
　実施例１２で得られた製剤（レボドパ１００ｍｇ／カルビドパ水和物２７ｍｇ）について、健康成人男性１７人を対象とし、６人に１カプセル（レボドパ１００ｍｇ／カルビドパ水和物２７ｍｇ）、５人に２カプセル（レボドパ２００ｍｇ／カルビドパ水和物５４ｍｇ）および残り６人に４カプセル（レボドパ４００ｍｇ／カルビドパ水和物１０８ｍｇ）をそれぞれ絶食下で単回経口投与する薬物動態比較試験を実施した。それぞれの製剤の平均血漿中レボドパ濃度推移の結果を図２に示す。 [Test Example 5] Pharmacokinetic comparative study of levodopa depending on dosage in healthy adults Regarding the formulation obtained in Example 12 (levodopa 100 mg/carbidopa hydrate 27 mg), 17 healthy adult males were tested. capsules (levodopa 100 mg/carbidopa hydrate 27 mg), 2 capsules (levodopa 200 mg/carbidopa hydrate 54 mg) to 5 people, and 4 capsules (levodopa 400 mg/carbidopa hydrate 108 mg) to the remaining 6 people, each under fasting. A comparative pharmacokinetic study using oral administration was conducted. The results of the average plasma levodopa concentration over time for each preparation are shown in FIG. 2.
　実施例１２の製剤について、投与量を変化させて被験者に投与した場合において、投与量の影響を受けることなく速やかに血漿中レボドパ濃度が一定の水準まで上昇し、その後約４時間、同程度の血漿中レボドパ濃度を維持できている。このように、本開示で示した溶出挙動を示す製剤は、投与量の影響を受けずに持続的な薬物動態を示しており、臨床上極めて有意義な製剤を提供可能であることが示唆される。 When the formulation of Example 12 was administered to subjects at varying doses, the plasma levodopa concentration quickly rose to a certain level without being affected by the dose, and then remained at the same level for about 4 hours. Plasma levodopa concentration can be maintained. As described above, the formulation exhibiting the dissolution behavior shown in the present disclosure exhibits sustained pharmacokinetics without being affected by dosage, suggesting that it is possible to provide a clinically extremely meaningful formulation. .
　以上例示的な実施形態及び実施例を参照しながら、本発明を説明してきたが、この説明は限定する意味で解釈されることを意図したものではない。したがって、本発明の例示的な実施形態の様々な変更形態及び他の実施形態は、この説明を参照すれば当業者に自明であろう。したがって、添付の特許請求の範囲は、そのようないずれの変更形態又は実施形態も包含すると考えられる。 Although the invention has been described with reference to illustrative embodiments and examples, this description is not intended to be construed in a limiting sense. Accordingly, various modifications and other embodiments of the exemplary embodiments of the invention will be apparent to those skilled in the art upon reference to this description. It is therefore intended that the appended claims cover any such modifications or embodiments.
  本明細書で参照されるすべての刊行物、特許及び特許出願は、個々の刊行物、特許又は特許出願がそれぞれ、参照により全体として組み込まれているように具体的にかつ個別に示されているのと同じ程度に、参照により全体として組み込まれている。 All publications, patents and patent applications referenced herein are specifically and individually indicated to indicate that each individual publication, patent or patent application is specifically and individually indicated to be incorporated by reference in its entirety. Incorporated by reference in its entirety to the same extent as.

Claims (25)

  1. 　レボドパとカルビドパを含有し、レボドパとカルビドパとの質量比率が、４：１である経口用医薬組成物であって、
    第１８改正日本薬局方・一般試験法の溶出試験第２法（パドル法）に基づく溶出試験において、第１８改正日本薬局方・一般試験法に規定される溶出試験第１液（ｐＨ１．２）を９００ｍＬ用い、パドル回転数１００回転／分、液温３７℃（３７±０．５℃の範囲）による溶出試験を実施するとき、
    溶出試験開始後３０分時点におけるレボドパの溶出率が１８％～４３％であり、溶出試験開始後１８０分時点におけるレボドパの溶出率が２０％～８０％であり、溶出試験開始後３６０分時点におけるレボドパの溶出率が３０％以上であるレボドパ溶出挙動を特徴とする、経口用医薬組成物。     An oral pharmaceutical composition containing levodopa and carbidopa, the mass ratio of levodopa and carbidopa being 4:1,
    In the dissolution test based on the dissolution test method 2 (paddle method) of the 18th revised Japanese Pharmacopoeia/General Test Methods, the dissolution test first solution (pH 1.2) specified in the 18th revised Japanese Pharmacopoeia/General Test Methods was used. When conducting a dissolution test using 900 mL of , paddle rotation speed 100 revolutions/min, liquid temperature 37 °C (37 ± 0.5 °C range),
    The dissolution rate of levodopa at 30 minutes after the start of the dissolution test was 18% to 43%, the dissolution rate of levodopa at 180 minutes after the start of the dissolution test was 20% to 80%, and the dissolution rate at 360 minutes after the start of the dissolution test was 18% to 43%. An oral pharmaceutical composition characterized by levodopa dissolution behavior in which the levodopa dissolution rate is 30% or more.
  2. 　前記溶出試験において、溶出試験開始後３０分時点におけるレボドパの溶出率が２０％～４０％であり、溶出試験開始後１８０分時点におけるレボドパの溶出率が２５％～７０％であり、溶出試験開始後３６０分時点におけるレボドパの溶出率が３５％以上であり、溶出試験開始後９６０分時点におけるレボドパの溶出率が７５％以上であるレボドパ溶出挙動を特徴とする、請求項１に記載の経口用医薬組成物。 In the dissolution test, the dissolution rate of levodopa at 30 minutes after the start of the dissolution test was 20% to 40%, and the dissolution rate of levodopa at 180 minutes after the start of the dissolution test was 25% to 70%, and the dissolution rate was 25% to 70% after the start of the dissolution test. The oral use according to claim 1, characterized by a levodopa dissolution behavior in which the dissolution rate of levodopa is 35% or more at 360 minutes after the start of the dissolution test, and the dissolution rate of levodopa is 75% or more at 960 minutes after the start of the dissolution test. Pharmaceutical composition.
  3. 　レボドパとカルビドパを含有し、レボドパとカルビドパとの質量比率が、４：１である経口用医薬組成物であって、
    第１８改正日本薬局方・一般試験法の溶出試験第３法（フロースルーセル法）に基づく溶出試験において、オープンループ法で小型フロースルーセルを用いて行い、脈流のある送液ポンプで、溶出試験開始から４５分までは第１８改正日本薬局方・一般試験法に規定される溶出試験第１液（ｐＨ１．２）を、４５分から１８０分までは薄めたＭｃＩｌｖａｉｎｅ緩衝液（ｐＨ５．５）を、１８０分から５４０分までは第１８改正日本薬局方・一般試験法に規定される溶出試験第２液（ｐＨ６．８）をいずれも液温３７℃（３７±０．５℃の範囲）、送液速度１６ｍＬ／分で送液した溶出試験を実施するとき、
    溶出試験開始後４５分時点におけるレボドパの溶出率が１５％～４５％であり、溶出試験開始後１８０分時点におけるレボドパの溶出率が４０％～８０％であり、溶出試験開始後５４０分時点におけるレボドパの溶出率が８０％以上であるレボドパ溶出挙動を特徴とする、経口用医薬組成物。     An oral pharmaceutical composition containing levodopa and carbidopa, the mass ratio of levodopa and carbidopa being 4:1,
    In the dissolution test based on the dissolution test method 3 (flow-through cell method) of the 18th revised Japanese Pharmacopoeia/General Tests, the dissolution test was performed using a small flow-through cell using the open loop method, and a liquid delivery pump with pulsating flow was used. For 45 minutes from the start of the dissolution test, use the first dissolution test solution (pH 1.2) specified in the 18th revised Japanese Pharmacopoeia/General Test Methods, and from 45 minutes to 180 minutes, use diluted McIlvaine buffer (pH 5.5). From 180 to 540 minutes, the second dissolution test liquid (pH 6.8) specified in the 18th revised Japanese Pharmacopoeia/General Test Methods was used at a liquid temperature of 37°C (37 ± 0.5°C range). When conducting a dissolution test using a liquid feeding rate of 16 mL/min,
    The dissolution rate of levodopa at 45 minutes after the start of the dissolution test is 15% to 45%, the dissolution rate of levodopa at 180 minutes after the start of the dissolution test is 40% to 80%, and the dissolution rate at 540 minutes after the start of the dissolution test. An oral pharmaceutical composition characterized by levodopa dissolution behavior with a levodopa dissolution rate of 80% or more.
  4. 　前記溶出試験において、溶出試験開始後４５分時点におけるレボドパの溶出率が２０％～４０％であり、溶出試験開始後１８０分時点におけるレボドパの溶出率が５０％～７５％であり、溶出試験開始後５４０分時点におけるレボドパの溶出率が８０％以上であるレボドパ溶出挙動を特徴とする、請求項３に記載の経口用医薬組成物。 In the dissolution test, the dissolution rate of levodopa at 45 minutes after the start of the dissolution test was 20% to 40%, and the dissolution rate of levodopa at 180 minutes after the start of the dissolution test was 50% to 75%, and the dissolution rate at 180 minutes after the start of the dissolution test was 50% to 75%. 4. The oral pharmaceutical composition according to claim 3, characterized by a levodopa dissolution behavior in which the dissolution rate of levodopa at 540 minutes is 80% or more.
  5. 　レボドパとカルビドパを含有し、レボドパとカルビドパとの質量比率が、４：１である経口用医薬組成物であって、
    第１８改正日本薬局方・一般試験法の溶出試験第２法（パドル法）に基づく溶出試験において、第１８改正日本薬局方・一般試験法に規定される溶出試験第１液（ｐＨ１．２）を９００ｍＬ用い、パドル回転数１００回転／分、液温３７℃（３７±０．５℃の範囲）による溶出試験を実施するとき、
    溶出試験開始後３０分時点におけるレボドパの溶出率が２０％～４０％であり、溶出試験開始後１８０分時点におけるレボドパの溶出率が２５％～７０％であり、溶出試験開始後３６０分時点におけるレボドパの溶出率が３５％以上であり、溶出試験開始後９６０分時点におけるレボドパの溶出率が７５％以上であり、かつ
    第１８改正日本薬局方・一般試験法の溶出試験第３法（フロースルーセル法）に基づく溶出試験において、オープンループ法で小型フロースルーセルを用いて行い、脈流のある送液ポンプで、溶出試験開始から４５分までは第１８改正日本薬局方・一般試験法に規定される溶出試験第１液（ｐＨ１．２）を、４５分から１８０分までは薄めたＭｃＩｌｖａｉｎｅ緩衝液（ｐＨ５．５）を、１８０分から５４０分までは第１８改正日本薬局方・一般試験法に規定される溶出試験第２液（ｐＨ６．８）をいずれも液温３７℃（３７±０．５℃の範囲）、送液速度１６ｍＬ／分で送液した溶出試験を実施するとき、
    溶出試験開始後４５分時点におけるレボドパの溶出率が２０％～４０％であり、溶出試験開始後１８０分時点におけるレボドパの溶出率が５０％～７５％であり、溶出試験開始後５４０分時点におけるレボドパの溶出率が８０％以上であるレボドパ溶出挙動を特徴とする、経口用医薬組成物。     An oral pharmaceutical composition containing levodopa and carbidopa, the mass ratio of levodopa and carbidopa being 4:1,
    In the dissolution test based on the dissolution test method 2 (paddle method) of the 18th revised Japanese Pharmacopoeia/General Test Methods, the dissolution test first solution (pH 1.2) specified in the 18th revised Japanese Pharmacopoeia/General Test Methods was used. When conducting a dissolution test using 900 mL of , paddle rotation speed 100 revolutions/min, liquid temperature 37 °C (37 ± 0.5 °C range),
    The dissolution rate of levodopa at 30 minutes after the start of the dissolution test is 20% to 40%, the dissolution rate of levodopa at 180 minutes after the start of the dissolution test is 25% to 70%, and the dissolution rate at 360 minutes after the start of the dissolution test. The dissolution rate of levodopa is 35% or more, the dissolution rate of levodopa at 960 minutes from the start of the dissolution test is 75% or more, and the dissolution test method 3 of the 18th revised Japanese Pharmacopoeia/General Tests (Flow-through In the dissolution test based on the 18th revised Japanese Pharmacopoeia (Japanese Pharmacopoeia, General Test Method), the dissolution test was performed using a small flow-through cell using the open-loop method, using a liquid pump with pulsating flow, and from the start of the dissolution test until 45 minutes. Specified dissolution test first solution (pH 1.2), diluted McIlvaine buffer (pH 5.5) from 45 to 180 minutes, and from 180 to 540 minutes according to the 18th revised Japanese Pharmacopoeia General Test Method. When carrying out an elution test in which the specified second solution (pH 6.8) was delivered at a liquid temperature of 37°C (range of 37 ± 0.5°C) and a delivery rate of 16 mL/min,
    The dissolution rate of levodopa at 45 minutes after the start of the dissolution test is 20% to 40%, the dissolution rate of levodopa at 180 minutes after the start of the dissolution test is 50% to 75%, and the dissolution rate at 540 minutes after the start of the dissolution test. An oral pharmaceutical composition characterized by levodopa dissolution behavior with a levodopa dissolution rate of 80% or more.
  6. 　レボドパとカルビドパ（質量比率４：１）を含む薬学的活性成分及び腸溶性高分子を含有する徐放部と、
    レボドパとカルビドパ（質量比率４：１）を含む薬学的活性成分及び崩壊剤又は水溶性高分子を含有する速放部とを含み、
    前記徐放部及び前記速放部は、それぞれ独立して顆粒を形成するか、又は、同一の顆粒を形成することを特徴とする、請求項１～５のいずれか１項に記載の経口用医薬組成物。     a sustained release part containing a pharmaceutically active ingredient containing levodopa and carbidopa (mass ratio 4:1) and an enteric polymer;
    comprising a pharmaceutically active ingredient containing levodopa and carbidopa (mass ratio 4:1) and an immediate release part containing a disintegrant or a water-soluble polymer;
    The oral drug according to any one of claims 1 to 5, wherein the sustained release part and the immediate release part form granules independently or form the same granule. Pharmaceutical composition.
  7. 　レボドパとカルビドパを含有する経口用医薬組成物であって、
    レボドパとカルビドパ（質量比率４：１）を含む薬学的活性成分及び腸溶性高分子を含有する徐放部と、
    レボドパとカルビドパ（質量比率４：１）を含む薬学的活性成分及び崩壊剤又は水溶性高分子を含有する速放部とを含み、
    前記徐放部及び前記速放部は、それぞれ独立して顆粒を形成するか、又は、同一の顆粒を形成することを特徴とする、経口用医薬組成物。     An oral pharmaceutical composition containing levodopa and carbidopa,
    a sustained release part containing a pharmaceutically active ingredient containing levodopa and carbidopa (mass ratio 4:1) and an enteric polymer;
    comprising a pharmaceutically active ingredient containing levodopa and carbidopa (mass ratio 4:1) and an immediate release part containing a disintegrant or a water-soluble polymer;
    An oral pharmaceutical composition, wherein the sustained release part and the immediate release part each form granules independently or form the same granule.
  8. 　前記徐放部に含まれるレボドパと前記速放部に含まれるレボドパの質量の比率が、４：１～３：２であることを特徴とする、請求項７に記載の経口用医薬組成物。 The oral pharmaceutical composition according to claim 7, characterized in that the mass ratio of levodopa contained in the sustained release part and levodopa contained in the immediate release part is 4:1 to 3:2.
  9. 　前記顆粒中のレボドパとカルビドパの合計質量が顆粒質量に対して７０％以上であることを特徴とする、請求項７又は８に記載の経口用医薬組成物。 The oral pharmaceutical composition according to claim 7 or 8, wherein the total mass of levodopa and carbidopa in the granules is 70% or more based on the mass of the granules.
  10. 　前記顆粒は、滑沢剤を顆粒質量に対して０．６％～１０％含有することを特徴とする、請求項７～９のいずれか１項に記載の経口用医薬組成物。 The oral pharmaceutical composition according to any one of claims 7 to 9, wherein the granules contain a lubricant in an amount of 0.6% to 10% based on the mass of the granules.
  11. 　前記滑沢剤が、ステアリン酸マグネシウム、ステアリン酸カルシウム、フマル酸ステアリルナトリウム、及び硬化油からなる群から選ばれる１種以上の滑沢剤である、請求項１０に記載の経口用医薬組成物。 The oral pharmaceutical composition according to claim 10, wherein the lubricant is one or more lubricants selected from the group consisting of magnesium stearate, calcium stearate, sodium stearyl fumarate, and hydrogenated oil.
  12. 　前記滑沢剤が、ステアリン酸マグネシウム及びステアリン酸カルシウムからなる群から選ばれる１種以上の滑沢剤である、請求項１０に記載の経口用医薬組成物。 The oral pharmaceutical composition according to claim 10, wherein the lubricant is one or more lubricants selected from the group consisting of magnesium stearate and calcium stearate.
  13. 　前記顆粒が、第１８改正日本薬局方・一般試験法の粒度測定法に記載される、日本薬局方ふるい番号４．７号を通過し、日本薬局方ふるい番号１２号に残留することを特徴とする、請求項７～１２のいずれか１項に記載の経口用医薬組成物。 The granules are characterized in that they pass through Japanese Pharmacopoeia Sieve No. 4.7 and remain in Japanese Pharmacopoeia Sieve No. 12, as described in the Particle Size Measurement Method of the 18th Edition of the Japanese Pharmacopoeia/General Tests. The oral pharmaceutical composition according to any one of claims 7 to 12.
  14. 　前記徐放部及び前記速放部が独立して顆粒を形成する経口用医薬組成物であって、前記徐放部を形成する顆粒が腸溶性高分子で被覆された顆粒であり、前記速放部を形成する顆粒が崩壊剤を含有する顆粒であることを特徴とする、請求項７～１３のいずれか１項に記載の経口用医薬組成物。 An oral pharmaceutical composition in which the sustained release portion and the immediate release portion independently form granules, wherein the granules forming the sustained release portion are coated with an enteric polymer; The oral pharmaceutical composition according to any one of claims 7 to 13, characterized in that the granules forming the part are granules containing a disintegrant.
  15. 　前記徐放部及び前記速放部を形成する顆粒が、それぞれ結晶セルロース、アンモニオアルキルメタクリレートコポリマー、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、部分アルファー化デンプン、及び二酸化ケイ素からなる群から選ばれる１種以上の添加剤を含有する、請求項１４に記載の経口用医薬組成物。 The granules forming the sustained release portion and the immediate release portion are each selected from the group consisting of crystalline cellulose, ammonioalkyl methacrylate copolymer, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, partially pregelatinized starch, and silicon dioxide. The oral pharmaceutical composition according to claim 14, containing one or more selected additives.
  16. 　前記腸溶性高分子が、メタクリル酸コポリマーＬＤ、乾燥メタクリル酸コポリマーＬＤ、メタクリル酸コポリマーＬ、メタクリル酸コポリマーＳ、ヒプロメロース酢酸エステルコハク酸エステル、ヒプロメロースフタル酸エステル、及びカルボキシメチルエチルセルロースからなる群から選ばれる１種以上の腸溶性高分子である、請求項１４に記載の経口用医薬組成物。 The enteric polymer is selected from the group consisting of methacrylic acid copolymer LD, dry methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, hypromellose acetate succinate, hypromellose phthalate ester, and carboxymethylethylcellulose. The oral pharmaceutical composition according to claim 14, which is one or more selected enteric polymers.
  17. 　前記崩壊剤が、部分アルファー化デンプン、低置換度ヒドロキシプロピルセルロース、カルメロース、カルメロースカルシウム、ヒドロキシプロピルスターチ、デンプン、デンプングリコール酸ナトリウム、クロスカルメロースナトリウム、及びクロスポビドンからなる群から選ばれる１種以上の崩壊剤である、請求項１４に記載の経口用医薬組成物。 The disintegrant is one selected from the group consisting of partially pregelatinized starch, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, hydroxypropyl starch, starch, sodium starch glycolate, croscarmellose sodium, and crospovidone. The oral pharmaceutical composition according to claim 14, which is the above disintegrant.
  18. 　前記徐放部及び前記速放部が同一の顆粒を形成する経口用医薬組成物であって、前記徐放部が腸溶性高分子で被覆された顆粒を形成し、更に該顆粒の周囲が水溶性高分子を含有する速放部により被覆された顆粒であることを特徴とする、請求項７～１３のいずれか１項に記載の経口用医薬組成物。 An oral pharmaceutical composition in which the sustained release part and the immediate release part form the same granule, wherein the sustained release part forms granules coated with an enteric polymer, and the surroundings of the granules are water-soluble. The oral pharmaceutical composition according to any one of claims 7 to 13, characterized in that it is a granule coated with an immediate release part containing a sexual polymer.
  19. 　前記徐放部を形成する顆粒が、結晶セルロース、アンモニオアルキルメタクリレートコポリマー、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、部分アルファー化デンプン、及び二酸化ケイ素からなる群から選ばれる１種以上の添加剤を含有する、請求項１８に記載の経口用医薬組成物。 The granules forming the sustained release portion are made of one or more selected from the group consisting of crystalline cellulose, ammonioalkyl methacrylate copolymer, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, partially pregelatinized starch, and silicon dioxide. The oral pharmaceutical composition according to claim 18, containing an additive.
  20. 　前記腸溶性高分子が、メタクリル酸コポリマーＬＤ、乾燥メタクリル酸コポリマーＬＤ、メタクリル酸コポリマーＬ、メタクリル酸コポリマーＳ、ヒプロメロース酢酸エステルコハク酸エステル、ヒプロメロースフタル酸エステル、及びカルボキシメチルエチルセルロースからなる群から選ばれる１種以上の腸溶性高分子である、請求項１８に記載の経口用医薬組成物。 The enteric polymer is selected from the group consisting of methacrylic acid copolymer LD, dry methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, hypromellose acetate succinate, hypromellose phthalate ester, and carboxymethylethylcellulose. The oral pharmaceutical composition according to claim 18, which is one or more selected enteric polymers.
  21. 　前記水溶性高分子が、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、ポリビニルアルコール、ヒドロキシプロピルセルロース、ヒプロメロース、メチルセルロース、ポビドン、カルメロースナトリウム、及びアルファー化デンプンからなる群から選ばれる１種以上の水溶性高分子である、請求項１８に記載の経口用医薬組成物。 The water-soluble polymer is one or more selected from the group consisting of polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, polyvinyl alcohol, hydroxypropylcellulose, hypromellose, methylcellulose, povidone, carmellose sodium, and pregelatinized starch. The oral pharmaceutical composition according to claim 18, which is a water-soluble polymer.
  22. 　前記経口用医薬組成物が、顆粒剤、カプセル剤、スティック剤、又は錠剤である、請求項７～２１のいずれか１項に記載の経口用医薬組成物。 The oral pharmaceutical composition according to any one of claims 7 to 21, wherein the oral pharmaceutical composition is a granule, a capsule, a stick, or a tablet.
  23. 　請求項７～２２のいずれか１項に記載の経口用医薬組成物を含む、パーキンソン病又はパーキンソン症候群の治療剤。 A therapeutic agent for Parkinson's disease or Parkinson's syndrome, comprising the oral pharmaceutical composition according to any one of claims 7 to 22.
  24. 　請求項７～２２のいずれか１項に記載の経口用医薬組成物を含む、パーキンソン病の治療剤。 A therapeutic agent for Parkinson's disease, comprising the oral pharmaceutical composition according to any one of claims 7 to 22.
  25. 　レボドパとカルビドパを含有する経口用医薬組成物を製剤設計するための評価基準としての、請求項１～５のいずれか１項に記載されたレボドパ溶出挙動に関する製剤特性の使用。 Use of the formulation characteristics related to levodopa dissolution behavior according to any one of claims 1 to 5 as an evaluation criterion for formulation design of an oral pharmaceutical composition containing levodopa and carbidopa.
PCT/JP2023/027466 2022-07-28 2023-07-26 Levodopa sustained release formulation WO2024024865A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005528430A (en) * 2002-05-29 2005-09-22 インパックス ラボラトリーズ、 インコーポレイテッド Combined immediate release and controlled release levodopa / carbidopa dosage form
JP2011518148A (en) * 2008-04-18 2011-06-23 インテック ファーマ リミテッド Carbidopa / levodopa gastric retentive drug supply
JP2012500221A (en) * 2008-08-15 2012-01-05 ディポメド，インコーポレイティド Gastric retentive pharmaceutical composition for treatment and prevention of CNS disorders
JP2016532655A (en) * 2013-10-07 2016-10-20 インパックス ラボラトリーズ、 インコーポレイテッドＩｍｐａｘ Ｌａｂｏｒａｔｏｒｉｅｓ， Ｉｎｃ． Mucoadhesive controlled release formulation of levodopa and / or levodopa ester and use thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005528430A (en) * 2002-05-29 2005-09-22 インパックス ラボラトリーズ、 インコーポレイテッド Combined immediate release and controlled release levodopa / carbidopa dosage form
JP2011518148A (en) * 2008-04-18 2011-06-23 インテック ファーマ リミテッド Carbidopa / levodopa gastric retentive drug supply
JP2012500221A (en) * 2008-08-15 2012-01-05 ディポメド，インコーポレイティド Gastric retentive pharmaceutical composition for treatment and prevention of CNS disorders
JP2016532655A (en) * 2013-10-07 2016-10-20 インパックス ラボラトリーズ、 インコーポレイテッドＩｍｐａｘ Ｌａｂｏｒａｔｏｒｉｅｓ， Ｉｎｃ． Mucoadhesive controlled release formulation of levodopa and / or levodopa ester and use thereof

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