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WO2024024865A1 - Formulation à libération prolongée de lévodopa - Google Patents

Formulation à libération prolongée de lévodopa 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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WO
WIPO (PCT)
Prior art keywords
levodopa
dissolution
pharmaceutical composition
dissolution test
minutes
Prior art date
Application number
PCT/JP2023/027466
Other languages
English (en)
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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Filing date
Publication date
Application filed by 大原薬品工業株式会社, 株式会社PARKINSON Laboratories filed Critical 大原薬品工業株式会社
Priority to JP2024537209A priority Critical patent/JPWO2024024865A1/ja
Publication of WO2024024865A1 publication Critical patent/WO2024024865A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—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

La présente divulgation concerne une composition pharmaceutique orale contenant de la lévodopa et de la carbidopa en tant que principes actifs pharmaceutiques.
PCT/JP2023/027466 2022-07-28 2023-07-26 Formulation à libération prolongée de lévodopa WO2024024865A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005528430A (ja) * 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 組合せ即時放出および制御放出レボドーパ／カルビドーパ剤型
JP2011518148A (ja) * 2008-04-18 2011-06-23 インテック ファーマ リミテッド カルビドパ／レボドパ胃内滞留性薬物供給
JP2012500221A (ja) * 2008-08-15 2012-01-05 ディポメド，インコーポレイティド Ｃｎｓ障害の処理及び予防のための胃保持性医薬組成物
JP2016532655A (ja) * 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． レボドパ及び／又はレボドパのエステルの粘膜付着性制御放出配合物、並びにその使用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005528430A (ja) * 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 組合せ即時放出および制御放出レボドーパ／カルビドーパ剤型
JP2011518148A (ja) * 2008-04-18 2011-06-23 インテック ファーマ リミテッド カルビドパ／レボドパ胃内滞留性薬物供給
JP2012500221A (ja) * 2008-08-15 2012-01-05 ディポメド，インコーポレイティド Ｃｎｓ障害の処理及び予防のための胃保持性医薬組成物
JP2016532655A (ja) * 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． レボドパ及び／又はレボドパのエステルの粘膜付着性制御放出配合物、並びにその使用

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