Levodopa sustained release formulation

Abstract

To provide an oral pharmaceutical composition containing levodopa and carbidopa, which exhibits a levodopa blood kinetic profile that combines immediacy of effect with sustained release.SOLUTION: An oral pharmaceutical composition contains levodopa and carbidopa, in which a mass ratio of levodopa to carbidopa is 4:1, the composition being characterized by a levodopa dissolution behavior such that, in a dissolution test based on Dissolution Test Method 2 (paddle method) of the Japanese Pharmacopoeia, 18th Revision, General Tests, using 900 mL of the dissolution test first fluid (pH 1.2) defined therein, with a paddle rotation speed of 100 rpm and a liquid temperature of 37°C (within 37±0.5°C), the dissolution rate of levodopa is 18% to 43% at 30 minutes after start of the dissolution test, 20% to 80% at 180 minutes after start, and 30% or more at 360 minutes after start.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present disclosure relates to granules containing levodopa and carbidopa as pharmaceutically active ingredients, an oral pharmaceutical composition comprising the granules, and a therapeutic agent for Parkinson's disease comprising the oral pharmaceutical composition. [Background technology]

[0002] Levodopa (chemical name: 3-hydroxy-L-tyrosine) is a compound (active pharmaceutical ingredient) used to treat Parkinson's disease and Parkinsonian syndrome. Combination therapy with levodopa and the decarboxylase inhibitor carbidopa hydrate (chemical name: (2S)-2-(3,4-Dihydroxybenzyl)-2-hydrazinopropanoic acid monohydrate) is also known.

[0003] Pharmaceuticals containing levodopa are commercially available, including Dopaston (registered trademark), Neodopaston (registered trademark), and Stalevo (registered trademark). However, because the half-life of levodopa in the blood is approximately one hour, motor complications such as wearing-off and dyskinesia occur, posing a major challenge during long-term treatment.

[0004] A miniaturized tablet containing levodopa with good sustained-release properties has been reported as an oral solid formulation for controlled release of levodopa (Patent Document 1). Also, a formulation has been reported in which four or more types of granules with different compositions containing levodopa, a decarboxylase inhibitor, and a carboxylic acid are filled in the same capsule (Patent Document 2).

[0005] However, no oral pharmaceutical composition has been reported that contains levodopa and carbidopa as pharmaceutically active ingredients, exhibits a levodopa blood kinetic profile that is both rapid-acting and sustained-acting, has a simple structure and manufacturing method, has few productivity issues, and is easy to take. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Patent No. 7066351 [Patent Document 2] Special Publication 2011-507956 Summary of the Invention [Problem to be solved by the invention]

[0007] In the design of controlled-release formulations, it is necessary to clarify the formulation characteristics required to achieve the target blood kinetic profile of the pharmaceutically active ingredient (also referred to as "drug" in this disclosure). The development of evaluation criteria is important not only during formulation design but also for reliable quality control during commercial-scale manufacturing.

[0008] However, there are few cases where the correlation between the blood concentration of a drug in vivo and the formulation characteristics in in vitro tests has been clearly demonstrated. In particular, for controlled-release formulations, it is extremely difficult to identify the target formulation characteristics because they are strongly affected by differences in gastric emptying time and gastrointestinal pH of the pharmaceutical composition. [Means for solving the problem]

[0009] The present inventors have conducted extensive research into important formulation characteristics that enable the oral pharmaceutical composition containing levodopa and carbidopa of the present disclosure to exhibit a drug blood kinetic profile that is both rapid-acting and sustained-acting.

[0010] As a result, the oral pharmaceutical composition of the present disclosure was successfully designed by setting the target formulation characteristics in in vitro tests, which take into account factors that affect pharmacokinetics in the body, such as differences in gastric emptying time and pH in the digestive tract, as the dissolution behavior of the drug using a dissolution test method.

[0011] Specifically, to investigate the possibility that the oral pharmaceutical composition of the present disclosure may remain in the stomach for a long period of time, a paddle method dissolution test using a dissolution test solution of pH 1.2, which is generally a test lasting up to 2 hours, was extended for a long period of time, and the target formulation characteristics were set as the dissolution behavior so that the drug would be gradually released even in the stomach.

[0012] Furthermore, to address differences in pH within the gastrointestinal tract, a flow-through cell method, which allows for seamless change of dissolution test liquid, was performed by changing the pH of the dissolution test liquid from pH 1.2 to pH 5.5 to pH 6.8 over the course of the test time, and the target formulation characteristics were set as dissolution behavior, such that the drug would gradually dissolve in the body regardless of the location of the oral pharmaceutical composition of the present disclosure in the gastrointestinal tract.

[0013] Furthermore, as a result of extensive research into the composition (formulation components, content, blending ratio, etc.) of an oral pharmaceutical composition that satisfies the above-mentioned formulation characteristics, the inventors have succeeded in designing an oral pharmaceutical composition of the present disclosure that can satisfy the above-mentioned formulation characteristics by combining one or two types of granules with controlled drug release.

[0014] Furthermore, a comparative pharmacokinetic study was conducted in which the oral pharmaceutical composition of the present disclosure was administered to healthy adults, and it was confirmed that the composition exhibited a levodopa blood kinetic profile that was both rapid-acting and sustained. This led to the completion of the present invention.

[0015] The present disclosure includes the following features. [1] An oral pharmaceutical composition containing levodopa and carbidopa, wherein the mass ratio of levodopa to carbidopa is 4:1, A pharmaceutical composition for oral administration characterized by a levodopa dissolution profile in which, when a dissolution test based on Dissolution Test Method 2 (paddle method) of the General Testing Methods of the Japanese Pharmacopoeia, 18th Edition, is conducted using 900 mL of Dissolution Test Fluid 1 (pH 1.2) specified in the General Testing Methods of the Japanese Pharmacopoeia, 18th Edition, at a paddle rotation speed of 100 rpm and a fluid temperature of 37°C (within a range of 37±0.5°C), the dissolution rate of levodopa at 30 minutes after the start of the dissolution test is 18% to 43%, at 180 minutes after the start of the dissolution test is 20% to 80%, and at 360 minutes after the start of the dissolution test is 30% or more. [2] The pharmaceutical composition for oral administration according to [1], characterized by a levodopa dissolution profile in which, in the dissolution test, the dissolution rate of levodopa is 20% to 40% at 30 minutes after the start of the dissolution test, 25% to 70% at 180 minutes after the start of the dissolution test, 35% or more at 360 minutes after the start of the dissolution test, and 75% or more at 960 minutes after the start of the dissolution test. [3] An oral pharmaceutical composition containing levodopa and carbidopa, wherein the mass ratio of levodopa to carbidopa is 4:1, The dissolution test was conducted using a small flow-through cell in an open-loop manner based on the 3rd method (flow-through cell method) of the general test method of the Japanese Pharmacopoeia, 18th Edition. A pulsating pump was used to deliver the first solution (pH 1.2) specified in the general test method of the Japanese Pharmacopoeia, 18th Edition, for 45 minutes from the start of the test, diluted McIlvaine buffer solution (pH 5.5) from 45 minutes to 180 minutes, and the first solution (pH 5.5) specified in the general test method of the Japanese Pharmacopoeia, 18th Edition, for 180 minutes to 540 minutes. The pharmaceutical composition for oral administration is characterized by a levodopa dissolution profile in which, when a dissolution test is conducted using the second dissolution test fluid (pH 6.8) specified in the Act at a fluid temperature of 37°C (within a range of 37±0.5°C) and a fluid delivery rate of 16 mL / min, the dissolution rate of levodopa at 45 minutes after the start of the dissolution test is 15% to 45%, at 180 minutes after the start of the dissolution test is 40% to 80%, and at 540 minutes after the start of the dissolution test is 80% or more. [4] The pharmaceutical composition for oral administration according to [3], characterized by a levodopa dissolution profile in which, in the dissolution test, the dissolution rate of levodopa is 20% to 40% at 45 minutes after the start of the dissolution test, the dissolution rate of levodopa is 50% to 75% at 180 minutes after the start of the dissolution test, and the dissolution rate of levodopa is 80% or more at 540 minutes after the start of the dissolution test. [5] An oral pharmaceutical composition containing levodopa and carbidopa, wherein the mass ratio of levodopa to carbidopa is 4:1, In a dissolution test based on Dissolution Test Method 2 (paddle method) of the General Testing Methods of the Japanese Pharmacopoeia, 18th Edition, when a dissolution test is conducted using 900 mL of dissolution test fluid 1 (pH 1.2) specified in the General Testing Methods of the Japanese Pharmacopoeia, 18th Edition, at a paddle rotation speed of 100 rpm and a fluid temperature of 37°C (within the range of 37±0.5°C), the dissolution rate of levodopa at 30 minutes after the start of the dissolution test is 20% to 40%, at 180 minutes after the start of the dissolution test is 25% to 70%, at 360 minutes after the start of the dissolution test is 35% or more, and at 960 minutes after the start of the dissolution test is 75% or more, and The dissolution test was conducted using a small flow-through cell in an open-loop manner based on the 3rd method (flow-through cell method) of the general test method of the Japanese Pharmacopoeia, 18th Edition. A pulsating pump was used to deliver the first solution (pH 1.2) specified in the general test method of the Japanese Pharmacopoeia, 18th Edition, for 45 minutes from the start of the test, diluted McIlvaine buffer solution (pH 5.5) from 45 minutes to 180 minutes, and the first solution (pH 5.5) specified in the general test method of the Japanese Pharmacopoeia, 18th Edition, for 180 minutes to 540 minutes. The pharmaceutical composition for oral administration is characterized by a levodopa dissolution profile in which, when a dissolution test is conducted using the second dissolution test fluid (pH 6.8) specified in the Act at a fluid temperature of 37°C (within a range of 37±0.5°C) and a fluid 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%, at 180 minutes after the start of the dissolution test is 50% to 75%, and at 540 minutes after the start of the dissolution test is 80% or more. [6] a sustained-release portion containing a pharmaceutically active ingredient including levodopa and carbidopa (mass ratio 4:1) and an enteric polymer; and an immediate-release portion containing a pharmaceutically active ingredient including levodopa and carbidopa (mass ratio 4:1) and a disintegrant or a water-soluble polymer, The oral pharmaceutical composition according to any one of [1] to [5], wherein the sustained-release portion and the immediate-release portion each form independent granules, or form the same granules. [7] An oral pharmaceutical composition containing levodopa and carbidopa, a sustained-release portion containing a pharmaceutically active ingredient including levodopa and carbidopa (mass ratio 4:1) and an enteric polymer; and an immediate-release portion containing a pharmaceutically active ingredient including levodopa and carbidopa (mass ratio 4:1) and a disintegrant or a water-soluble polymer, 10. The oral pharmaceutical composition, wherein the sustained-release portion and the immediate-release portion each independently form granules, or form the same granules. [8] The oral pharmaceutical composition according to [7], wherein 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. [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 of the mass of the granules.

[10] The pharmaceutical composition for oral administration 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 oils.

[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 oral pharmaceutical composition according to any one of [7] to

[12] , characterized in that the granules pass through Japanese Pharmacopoeia sieve number 4.7 and remain on Japanese Pharmacopoeia sieve number 12, as described in the particle size measurement method of the Japanese Pharmacopoeia, 18th Edition, General Test Methods.

[14] The oral pharmaceutical composition according to any one of [7] to

[13] , wherein the sustained-release portion and the immediate-release portion independently form granules, the granules forming the sustained-release portion being granules coated with an enteric polymer, and the granules forming the immediate-release portion being granules containing a disintegrant.

[15] The oral pharmaceutical composition according to

[14] , wherein the granules forming the sustained-release portion and the immediate-release portion each contain one or more additives selected from the group consisting of crystalline cellulose, ammonioalkyl methacrylate copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, partially pregelatinized starch, and silicon dioxide.

[16] The oral pharmaceutical composition according to

[14] , wherein the enteric polymer is one or more enteric polymers 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, and carboxymethylethylcellulose.

[17] The pharmaceutical composition for oral administration according to

[14] , wherein the disintegrant is one or more 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.

[18] The oral pharmaceutical composition according to any one of [7] to

[13] , wherein the sustained-release portion and the immediate-release portion form the same granules, and the sustained-release portion forms granules coated with an enteric polymer, and the granules are further coated with the immediate-release portion containing a water-soluble polymer.

[19] The oral pharmaceutical composition according to

[18] , wherein the granules forming the sustained-release portion contain one or more additives selected from the group consisting of crystalline cellulose, ammonioalkyl methacrylate copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, partially pregelatinized starch, and silicon dioxide.

[20] The oral pharmaceutical composition according to

[18] , wherein the enteric polymer is one or more enteric polymers 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, and carboxymethylethylcellulose. [twenty one] The oral pharmaceutical composition according to

[18] , wherein the water-soluble polymer is one or more water-soluble polymers selected from the group consisting of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyvinyl alcohol, hydroxypropyl cellulose, hypromellose, methylcellulose, povidone, carmellose sodium, and pregelatinized starch. [twenty two] The oral pharmaceutical composition according to any one of [7] to

[21] , which is in the form of granules, capsules, sticks, or tablets. [twenty three] A therapeutic agent for Parkinson's disease or Parkinson's syndrome, comprising the oral pharmaceutical composition according to any one of [7] to

[22] . [twenty four] A therapeutic agent for Parkinson's disease, comprising the oral pharmaceutical composition according to any one of [7] to

[22] . [twenty five] Use of formulation characteristics relating to levodopa dissolution behavior described in any one of [1] to [5] as an evaluation criterion for designing a formulation of an oral pharmaceutical composition containing levodopa and carbidopa. [Effects of the Invention]

[0016] The present disclosure suggests that it is possible to provide an oral pharmaceutical composition containing levodopa and carbidopa (also referred to in the present disclosure as a "controlled-release formulation" or a "levodopa / carbidopa hydrate sustained-release formulation") that exhibits a levodopa blood kinetic profile that is both rapid-acting and sustained, and that is miniaturized for improved convenience.

[0017] The present disclosure suggests that by combining one or two types of granules with controlled drug release (also referred to in the present disclosure as "plain granules," "coated granules," or "levodopa / carbidopa hydrate sustained-release granules"), it is possible to reduce the labor required for the production of oral pharmaceutical compositions containing levodopa and carbidopa, and to significantly improve productivity.

[0018] The present disclosure suggests that it is possible to provide an oral pharmaceutical composition containing levodopa and carbidopa that contains higher amounts of levodopa and carbidopa, can be made smaller, and reduces the burden on patients when taking it.

[0019] The present disclosure suggests that it is possible to provide an oral pharmaceutical composition containing levodopa and carbidopa that exhibits a levodopa blood kinetic profile that is both rapid-acting and sustained-acting, without including an acid component such as a carboxylic acid as an essential component.

[0020] It is suggested that the present disclosure can provide formulation characteristics relating to the dissolution behavior of levodopa, which can be used as an evaluation criterion for formulating an oral pharmaceutical composition containing levodopa and carbidopa. [Brief explanation of the drawings]

[0021] [Figure 1]FIG. 1 shows the time course of mean plasma levodopa concentration in a comparative pharmacokinetic study conducted on healthy adult males using the oral pharmaceutical compositions containing levodopa and carbidopa obtained in Example 4 and Example 8 of the present disclosure, and the formulation containing levodopa and carbidopa in Comparative Example 1. [Figure 2] A comparative pharmacokinetic study was conducted on the formulation obtained in Example 12 of the present disclosure, in which 17 healthy adult male subjects were given a single oral dose of 1 capsule to 6 subjects, 2 capsules to 5 subjects, and 4 capsules to the remaining 6 subjects under fasting conditions. The graph shows the results of the changes in the average plasma levodopa concentration for each formulation. DETAILED DESCRIPTION OF THE INVENTION

[0022] The oral pharmaceutical composition and the like of the present disclosure will be described in detail below. However, the following description is merely an example for explaining the present disclosure, and is not intended to limit the present disclosure to the scope of the description.

[0023] 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 anhydrous forms, hydrates, salts, etc., can be used.

[0024] In some embodiments, oral pharmaceutical compositions of the present disclosure contain levodopa and carbidopa hydrate as the pharmaceutically active ingredients.

[0025] Levodopa and carbidopa can be adjusted to any particle size by dry or wet milling as needed. The median size can be measured (volume basis) by laser diffraction / scattering.

[0026] In some embodiments, the median diameter (d 50 ) is 1.0 μm to 100.0 μm.

[0027] In another embodiment, the median diameter (d 50) is 3.0 μm to 75 μm.

[0028] The oral pharmaceutical composition of the present disclosure contains levodopa and carbidopa (as anhydrous) in a mass ratio of 4: 1. In addition, unless otherwise specified in the present disclosure, when calculating the mass ratio of levodopa to carbidopa, carbidopa is calculated as the mass of carbidopa anhydrous.

[0029] Embodiment 1

[0030] In some embodiments, the present disclosure provides an oral pharmaceutical composition comprising levodopa and carbidopa, wherein the mass ratio of levodopa to carbidopa is 4:1, Provided is a pharmaceutical composition for oral administration, characterized by a levodopa dissolution profile in which, when a dissolution test based on Dissolution Test Method 2 (paddle method) of the General Testing Methods of the Japanese Pharmacopoeia, 18th Edition, is conducted using 900 mL of Dissolution Test Fluid 1 (pH 1.2) specified in the General Testing Methods of the Japanese Pharmacopoeia, 18th Edition, at a paddle rotation speed of 100 rpm and a fluid temperature of 37°C (within a range of 37±0.5°C), the dissolution rate of levodopa at 30 minutes after the start of the dissolution test is 18% to 43%, at 180 minutes after the start of the dissolution test is 20% to 80%, and at 360 minutes after the start of the dissolution test is 30% or more.

[0031] In some embodiments, the present disclosure provides an oral pharmaceutical composition characterized by a levodopa dissolution profile in which, in the dissolution test, the dissolution rate of levodopa is 20% to 40% at 30 minutes after the start of the dissolution test, 25% to 70% at 180 minutes after the start of the dissolution test, 35% or more at 360 minutes after the start of the dissolution test, and 75% or more at 960 minutes after the start of the dissolution test.

[0032] In some embodiments, the present disclosure provides an oral pharmaceutical composition comprising levodopa and carbidopa, wherein the mass ratio of levodopa to carbidopa is 4:1, The dissolution test was conducted using a small flow-through cell in an open-loop manner based on the 3rd method (flow-through cell method) of the general test method of the Japanese Pharmacopoeia, 18th Edition. A pulsating pump was used to deliver the first solution (pH 1.2) specified in the general test method of the Japanese Pharmacopoeia, 18th Edition, from the start of the test to 45 minutes, diluted McIlvaine buffer solution (pH 5.5) from 45 minutes to 180 minutes, and the second solution (pH 5.5) specified in the general test method of the Japanese Pharmacopoeia, 18th Edition, from 180 minutes to 540 minutes. Provided is a pharmaceutical composition for oral administration, characterized by a levodopa dissolution profile in which, when a dissolution test is conducted using a specified second dissolution test fluid (pH 6.8) at a fluid temperature of 37°C (within a range of 37±0.5°C) and a fluid delivery rate of 16 mL / min, the dissolution rate of levodopa at 45 minutes after the start of the dissolution test is 15% to 45%, at 180 minutes after the start of the dissolution test is 40% to 80%, and at 540 minutes after the start of the dissolution test is 80% or more.

[0033] In some embodiments, the present disclosure provides an oral pharmaceutical composition characterized by a levodopa dissolution profile in which, in the dissolution test, the dissolution rate of levodopa is 20% to 40% at 45 minutes after the start of the dissolution test, the dissolution rate of levodopa is 50% to 75% at 180 minutes after the start of the dissolution test, and the dissolution rate of levodopa is 80% or more at 540 minutes after the start of the dissolution test.

[0034] In some embodiments, the present disclosure provides an oral pharmaceutical composition comprising levodopa and carbidopa, wherein the mass ratio of levodopa to carbidopa is 4:1, In a dissolution test based on Dissolution Test Method 2 (paddle method) of the General Testing Methods of the Japanese Pharmacopoeia, 18th Edition, when a dissolution test is conducted using 900 mL of dissolution test fluid 1 (pH 1.2) specified in the General Testing Methods of the Japanese Pharmacopoeia, 18th Edition, at a paddle rotation speed of 100 rpm and a fluid temperature of 37°C (within the range of 37±0.5°C), the dissolution rate of levodopa at 30 minutes after the start of the dissolution test is 20% to 40%, at 180 minutes after the start of the dissolution test is 25% to 70%, at 360 minutes after the start of the dissolution test is 35% or more, and at 960 minutes after the start of the dissolution test is 75% or more, and The dissolution test was conducted using a small flow-through cell in an open-loop manner based on the 3rd method (flow-through cell method) of the general test method of the Japanese Pharmacopoeia, 18th Edition. A pulsating pump was used to deliver the first solution (pH 1.2) specified in the general test method of the Japanese Pharmacopoeia, 18th Edition, from the start of the test to 45 minutes, diluted McIlvaine buffer solution (pH 5.5) from 45 minutes to 180 minutes, and the second solution (pH 5.5) specified in the general test method of the Japanese Pharmacopoeia, 18th Edition, from 180 minutes to 540 minutes. Provided is a pharmaceutical composition for oral administration, characterized by a levodopa dissolution profile in which, when a dissolution test is conducted using a specified second dissolution test fluid (pH 6.8) at a fluid temperature of 37°C (within a range of 37±0.5°C) and a fluid 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%, at 180 minutes after the start of the dissolution test is 50% to 75%, and at 540 minutes after the start of the dissolution test is 80% or more.

[0035] In some embodiments, the present disclosure provides an oral pharmaceutical composition comprising levodopa and carbidopa, wherein the mass ratio of levodopa to carbidopa is 4:1, the composition comprising a sustained-release portion containing a pharmaceutically active ingredient comprising levodopa and carbidopa (mass ratio 4:1) and an enteric polymer; and an immediate-release portion containing a pharmaceutically active ingredient including levodopa and carbidopa (mass ratio 4:1) and a disintegrant or a water-soluble polymer, The sustained-release portion and the immediate-release portion each independently form granules or form the same granules, and the oral pharmaceutical composition is characterized by the levodopa dissolution behavior exhibited by the paddle method and / or the flow-through cell method.

[0036] In Embodiment 1, an oral pharmaceutical composition containing levodopa and carbidopa is illustrated from the viewpoint of formulation properties based on the dissolution behavior of levodopa. Here, the oral pharmaceutical composition containing levodopa and carbidopa may be any pharmaceutical composition that satisfies the dissolution behavior of levodopa shown in Embodiment 1, and there are no particular limitations on the constitution of the pharmaceutical composition (formulation components, contents, blending ratios, etc.).

[0037] In the following embodiments 2-4, examples of oral pharmaceutical compositions containing levodopa and carbidopa are illustrated from the viewpoint of the composition of the pharmaceutical composition (formulation components, content, blending ratio, etc.), but the present invention is not limited to these.

[0038] Embodiment 2

[0039] In some embodiments, the present disclosure provides an oral pharmaceutical composition containing levodopa and carbidopa, comprising: a sustained-release portion containing a pharmaceutically active ingredient comprising levodopa and carbidopa (mass ratio 4:1) and an enteric polymer; and an immediate-release portion containing a pharmaceutically active ingredient comprising levodopa and carbidopa (mass ratio 4:1) and a water-soluble polymer. The sustained-release portion and the immediate-release portion each independently form granules, or form the same granules.

[0040] In the present disclosure, the term "sustained-release portion" refers to a portion constituting an oral pharmaceutical composition in which the release of the pharmaceutically active ingredient is controlled so that the blood concentration of the pharmaceutically active ingredient can be maintained in the body for a long period of time after administration of the oral pharmaceutical composition to a subject (including a patient). Here, "blood concentration" refers to the effective blood concentration or plasma concentration.

[0041] In some embodiments, the sustained-release portion may be granules (including coated granules) containing a pharmaceutically active ingredient comprising levodopa and carbidopa (mass ratio of 4:1) and an enteric polymer.

[0042] In the present disclosure, the "sustained-release portion" may have a structure in which an elementary granule portion containing levodopa and carbidopa (mass ratio 4:1) is coated with a coating layer containing an enteric polymer.

[0043] In the present disclosure, the "elementary granule portion" can contain levodopa and carbidopa (mass ratio 4:1) as pharmaceutically active ingredients, and optional additives (e.g., excipients, binders, disintegrants, lubricants, and flow agents).

[0044] 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 colorant, etc.).

[0045] In the present disclosure, an "enteric polymer" is substantially insoluble in aqueous solvents having an acidic pH value (pH 1.2 to pH 5.4) simulating the gastric environment (i.e., the amount of solvent at 25°C required to dissolve 1.0 g of the polymer is 10,000 mL or more), and is highly soluble in aqueous solvents having a neutral to alkaline pH value (pH 5.5 or higher) simulating the intestinal environment (i.e., the amount of solvent at 25°C required to dissolve 1.0 g of the polymer is less than 10,000 mL).

[0046] In some embodiments, examples of enteric polymers include, but are not limited to, 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 esters (e.g., hypromellose phthalate), hydroxyalkyl alkyl cellulose acetate succinate esters (e.g., hypromellose acetate succinate), carboxyalkyl alkyl celluloses (e.g., carboxymethyl ethyl cellulose), and the like.

[0047] In some embodiments, enteric polymers include, but are not limited to, methacrylic acid copolymers, hypromellose phthalate, hypromellose acetate succinate, carboxymethylethylcellulose, and the like.

[0048] In some embodiments, enteric polymers include, but are not limited to, methacrylic acid copolymer LD, dry methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, hypromellose acetate succinate, hypromellose phthalate, and carboxymethylethylcellulose.

[0049] 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.

[0050] In another embodiment, the enteric polymer is contained in the granules in an amount ranging from 1.0% by weight to 10.0% by weight based on the total weight of the granules.

[0051] In some embodiments, examples of coating agents include, but are not limited to, D-mannitol, lactose, trehalose, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, hypromellose, hydroxypropyl cellulose, and methyl cellulose.

[0052] In some embodiments, the coating agent is contained in the granules in an amount ranging from 0.5% by weight to 10.0% by weight based on the total weight of the granules.

[0053] In the present disclosure, the "immediate-release portion" refers to a component of an oral pharmaceutical composition that rapidly releases the pharmaceutically active ingredient in the body after administration of the oral pharmaceutical composition to a patient, i.e., the portion in which the release of the pharmaceutically active ingredient is not controlled.

[0054] In some embodiments, the immediate-release portion may be a granule containing pharmaceutically active ingredients including levodopa and carbidopa (mass ratio 4:1), a disintegrant or a water-soluble polymer, and optionally added additives.

[0055] In some embodiments, examples of disintegrants include, but are not limited to, partially pregelatinized starch, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, hydroxypropyl starch, starch, sodium starch glycolate, croscarmellose sodium, crospovidone, and the like.

[0056] In some embodiments, examples of water-soluble polymers include, but are not limited to, alkyl celluloses (e.g., methyl cellulose), hydroxyalkyl celluloses (e.g., hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose), hydroxyalkyl alkyl celluloses (e.g., hydroxyethyl methyl cellulose, hypromellose), carboxyvinyl polymers, polyvinyl alcohol, polyvinyl alcohol-based copolymers (copolymers in which polyvinyl alcohol is one of the monomers, such as polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer and polyvinyl alcohol-polyethylene glycol graft copolymer), polyvinylpyrrolidone, carmellose sodium, and pregelatinized starch.

[0057] In other embodiments, the additives include, but are not limited to, methyl cellulose, hydroxypropyl cellulose, carboxyvinyl polymers, polyvinyl alcohol, and the like.

[0058] In some embodiments, examples of water-soluble polymers include, but are not limited to, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, hydroxypropyl cellulose, hypromellose, methyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, carmellose sodium, and pregelatinized starch.

[0059] In some embodiments, the sustained-release portion and the immediate-release portion may each independently form granules, which may be uncoated granules or coated granules.

[0060] In some embodiments, the sustained-release portion and the immediate-release portion may be integrated to form the same granules, for example, a granule formed by the sustained-release portion containing an enteric polymer, and the granules are coated with the immediate-release portion containing a water-soluble polymer.

[0061] 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.

[0062] In some embodiments, the combined mass of levodopa and carbidopa in the granules is 70% or more of the granule mass.

[0063] In another embodiment, the total mass of levodopa and carbidopa in the granules is 70% to 95% of the granule mass.

[0064] In another embodiment, the total mass of levodopa and carbidopa in the granules is 75% to 90% of the granule mass.

[0065] In some embodiments, the present disclosure provides an oral pharmaceutical composition, wherein the granules contain 0.6% to 10% of a lubricant based on the mass of the granules.

[0066] In some embodiments, the content of the lubricant in the granules is 0.6% to 10% based on the granule mass.

[0067] In another embodiment, the content of the lubricant in the granules is 0.6% to 5% based on the mass of the granules.

[0068] In another embodiment, the content of the lubricant in the granules is 1% to 5% based on the mass of the granules.

[0069] Embodiment 3

[0070] In some embodiments, the present disclosure provides an oral pharmaceutical composition comprising levodopa and carbidopa, a sustained-release portion containing a pharmaceutically active ingredient including levodopa and carbidopa (mass ratio 4:1) and an enteric polymer; Provided is an oral pharmaceutical composition comprising a pharmaceutically active ingredient containing levodopa and carbidopa (mass ratio 4:1) and an immediate-release portion containing a disintegrant or a water-soluble polymer, wherein the sustained-release portion and the immediate-release portion independently form granules, the granules forming the sustained-release portion are granules coated with an enteric polymer, and the granules forming the immediate-release portion are granules containing a disintegrant.

[0071] In some embodiments, the elementary granule portion of the granules forming the sustained-release portion and the granules forming the immediate-release portion contain one or more additives selected from crystalline cellulose, ammonioalkyl methacrylate copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, partially pregelatinized starch, and silicon dioxide.

[0072] In some embodiments, the base granule portion of the granules forming the sustained-release portion is coated with one or more enteric polymers selected from methacrylic acid copolymer LD, dry methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, hypromellose acetate succinate, hypromellose phthalate, and carboxymethylethylcellulose.

[0073] In some embodiments, the granules forming the immediate-release portion contain one or more water-soluble polymers (disintegrants) selected from partially pregelatinized starch, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, hydroxypropyl starch, starch, sodium starch glycolate, croscarmellose sodium, and crospovidone.

[0074] Embodiment 4

[0075] In some embodiments, the present disclosure provides an oral pharmaceutical composition comprising levodopa and carbidopa in granules, the composition comprising: a sustained-release portion comprising pharmaceutically active ingredients comprising levodopa and carbidopa (mass ratio 4:1) and an enteric polymer; and an immediate-release portion comprising pharmaceutically active ingredients comprising levodopa and carbidopa (mass ratio 4:1) and a water-soluble polymer; The oral pharmaceutical composition provides an oral pharmaceutical composition in which the sustained-release portion and the immediate-release portion form the same granules, characterized in that the sustained-release portion forms granules coated with an enteric polymer, and the granules are further surrounded by an immediate-release portion containing a water-soluble polymer.

[0076] In some embodiments, the elementary granule portion of the granules forming the sustained-release portion contains one or more additives selected from crystalline cellulose, ammonioalkyl methacrylate copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, partially pregelatinized starch, and silicon dioxide.

[0077] In some embodiments, the enteric polymer coating the elementary granule portion of the sustained-release portion is one or more enteric polymers selected from methacrylic acid copolymer LD, dry methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, hypromellose acetate succinate, hypromellose phthalate, and carboxymethylethylcellulose.

[0078] In some embodiments, the water-soluble polymer of the immediate-release portion is one or more water-soluble polymers selected from polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyvinyl alcohol, hydroxypropyl cellulose, hypromellose, methyl cellulose, polyvinylpyrrolidone, carmellose sodium, and pregelatinized starch.

[0079] In the present disclosure, particle size measurement of the granules of the present disclosure is carried out in an environment of appropriately controlled room temperature and humidity, where significant moisture absorption or desorption due to humidity changes or agglomeration is not likely to occur.

[0080] In some embodiments, the granules of the present disclosure pass through Japanese Pharmacopoeia sieve number 4.7, as described in the Particle Size Measurement Method of the Japanese Pharmacopoeia, 18th Edition, General Test Methods.

[0081] In another embodiment, the granules of the present disclosure remain on Japanese Pharmacopoeia sieve number 12 as described in the Particle Size Measurement Method of the Japanese Pharmacopoeia, 18th Edition, General Test Methods.

[0082] In another embodiment, the granules of the present disclosure pass through a Japanese Pharmacopoeia sieve number 4.7 and remain on a Japanese Pharmacopoeia sieve number 12, as described in the particle size measurement method of the Japanese Pharmacopoeia, 18th Edition, General Test Methods.

[0083] In some embodiments, the shape of the granules of the present disclosure is cylindrical.

[0084] 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: PK-1012APX type).

[0085] 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%).

[0086] 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%).

[0087] In the present disclosure, additives may be conventional additives used in the art. In some embodiments, examples of additives include, but are not limited to, excipients, binders, disintegrants, lubricants, flow agents, glidants, plasticizers, colorants, etc.

[0088] In the present disclosure, the amount of the additives to be added is not particularly limited as long as it is within a range that does not impair the effects of the present invention.

[0089] In the present disclosure, examples of excipients include, but are not limited to, lactose hydrate, anhydrous lactose, crystalline cellulose, D-mannitol, erythritol, xylitol, sorbitol, isomalt, maltitol, maltose, white sugar, 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 syrup, ammonioalkyl methacrylate copolymer, ethyl cellulose, calcium hydrogen phosphate, and the like.

[0090] In the present disclosure, examples of binders include, but are not limited to, alkyl celluloses (e.g., methyl cellulose), hydroxyalkyl celluloses (e.g., hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose), hydroxyalkyl alkyl celluloses (e.g., hydroxyethyl methyl cellulose, hypromellose), carboxyvinyl polymers, polyvinyl alcohol, polyvinyl alcohol-based copolymers (copolymers in which polyvinyl alcohol is one of the monomers, such as polyvinyl alcohol-acrylic acid-methyl methacrylate copolymers and polyvinyl alcohol-polyethylene glycol graft copolymers), polyvinylpyrrolidone, carmellose sodium, and pregelatinized starch.

[0091] In the present disclosure, examples of disintegrants include, but are not limited to, partially pregelatinized starch, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, hydroxypropyl starch, starch, sodium starch glycolate, croscarmellose sodium, crospovidone, and the like.

[0092] In the present disclosure, examples of fluidizing agents include, but are not limited to, light anhydrous silicic acid, hydrous silicon dioxide, talc, magnesium aluminometasilicate, and the like.

[0093] In the present disclosure, examples of lubricants include, but are not limited to, magnesium stearate, calcium stearate, sodium stearyl fumarate, and hardened oils.

[0094] In some embodiments, lubricants include, but are not limited to, magnesium stearate and / or calcium stearate.

[0095] In the present disclosure, examples of plasticizers include, but are not limited to, triethyl citrate, triacetin, polyethylene glycol, diethyl phthalate, dibutyl phthalate, and the like.

[0096] In the present disclosure, examples of colorants include, but are not limited to, yellow ferric oxide, ferric oxide, titanium oxide, and the like.

[0097] The present disclosure provides a therapeutic agent for Parkinson's disease or Parkinson's syndrome, comprising the oral pharmaceutical composition of the present disclosure.

[0098] In some embodiments, the present disclosure provides a therapeutic agent for Parkinson's disease, comprising an oral pharmaceutical composition of the present disclosure.

[0099] Dosage forms of the pharmaceutical composition of the present disclosure include, for example, granules, capsules containing granules, sticks containing granules, tablets containing granules, and the like, but are not limited to these.

[0100] The pharmaceutical composition of the present disclosure can be manufactured by a general manufacturing method in the art depending on the dosage form.

[0101] The granules of the present disclosure can be produced, for example, by the following process. A solution (granulation liquid) is gradually added dropwise while mixing levodopa, carbidopa, and additives (e.g., excipients, binders, disintegrants, lubricants, glidants, etc.) to produce a granule (stirring granulation method). The granules obtained above are dried and sized, then mixed with lubricants, etc., and compressed in a tablet press to produce granules (raw granules). The compression pressure when compressing 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, etc., using a known method.

[0102] Furthermore, examples of methods for producing elementary granules include, but are not limited to, 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 a liquid containing levodopa, carbidopa, and a binder is sprayed onto core particles made of crystalline cellulose, sugars, or the like to obtain granules; and an extrusion granulation method in which levodopa, carbidopa, and additives are mixed, kneaded with water or a solvent, and the kneaded mixture is extruded through a mesh to produce granules.

[0103] The capsules of the present disclosure can be produced by filling the above-mentioned raw granules or coated granules into capsules by a filling method generally used in the art.

[0104] In the present disclosure, capsules that are commonly used in the art can be used, including, but not limited to, gelatin capsules, hydroxypropyl methylcellulose (HPMC) capsules, pullulan capsules (e.g., hydroxypropyl methylcellulose (HPMC) capsules), Licaps™ capsules, Vcaps™ capsules, Coni-Snap™ capsules, Press-fit™ capsules, and Xpress-fit™ capsules.

[0105] In the present disclosure, capsule sizes include, but are not limited to, No. 1 capsule, No. 2 capsule, No. 3 capsule, and No. 4 capsule. In some embodiments, No. 3 capsule or No. 4 capsule is selected from the viewpoint of medication ease.

[0106] The stick formulation of the present disclosure can be produced by filling the above-mentioned granules or coated granules into a stick package as is common in the art.

[0107] The tablets of the present disclosure can be manufactured using the above-mentioned granules and coated granules by a general tablet manufacturing method in the art.

[0108] Embodiment 5

[0109] The formulation characteristics regarding the levodopa dissolution behavior obtained from the dissolution test of the present disclosure can be used as evaluation criteria for designing a formulation of an oral pharmaceutical composition containing levodopa and carbidopa and exhibiting a levodopa blood kinetic profile that is both rapid-acting and sustained-acting.

[0110] In the present disclosure, the formulation characteristics regarding the 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.

[0111] In the present disclosure, the evaluation criteria for formulating an oral pharmaceutical composition are set as the range of levodopa dissolution behavior for a pharmaceutical composition (formulation) that achieves a levodopa blood kinetic profile that is both fast-acting and sustained in healthy adults, and specifically include the range of formulation characteristics related to levodopa dissolution behavior described in embodiment 1.

[0112] In the present disclosure, by performing the above-mentioned dissolution test on an arbitrarily formulated formulation and confirming whether the formulation properties related to levodopa dissolution behavior satisfy the above-mentioned evaluation criteria, it becomes possible to simply and easily design a formulation of an oral pharmaceutical composition that exhibits a levodopa blood kinetic profile that is both rapid-acting and sustained-acting.

[0113] The present invention will be described below with reference to examples, but the present invention is not limited to the following examples. [Example]

[0114] 500.0 g of levodopa (median diameter: 55 μm), 135.0 g of carbidopa hydrate (median diameter: 7.4 μm), 64.6 g of microcrystalline cellulose, 48.0 g of ammonioalkyl methacrylate copolymer, 6.0 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and 6.0 g of light anhydrous silicic acid were premixed in a high-speed agitation granulator (Powrex Corporation, Model FM-VG-10) and granulated with 100 g of ethanol and 85 g of water. The resulting granules were dried in a fluidized-bed dryer (Powrex Corporation, Model MP-01) and then sized in a sieving machine (Powrex Corporation, Model QC-197S) to obtain a sized product. [Example]

[0115] 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 resulting mixture was compressed using a rotary tablet press (Kikusui Seisakusho: VIRGO type) to obtain unrefined granules weighing 6.4 mg per granule. 350 g of the unrefined granules were placed in a ventilated coating machine (Freund Corporation: HC-FZ-LABO type) and sprayed with a suspension of 22.8 g of methacrylic acid copolymer LD (6.8 g as solids), 7.5 g of talc, 0.7 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and 0.7 g of triethyl citrate in 270.0 g of purified water, to obtain coated granules weighing 6.7 mg per granule. [Example]

[0116] 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 resulting mixture was compressed into tablets using a rotary tablet press (VIRGO type, manufactured by Kikusui Seisakusho) to obtain core granules with a mass of 6.6 mg per granule. [Example]

[0117] 120.6 mg of the coated granules obtained in Example 2 and 39.6 mg of the uncoated granules obtained in Example 3 were filled into No. 3 capsules to obtain a levodopa / carbidopa hydrate sustained-release formulation containing 100 mg of levodopa and 27 mg of carbidopa hydrate (25 mg as carbidopa). [Example]

[0118] 500.0 g of levodopa (median diameter: 55 μm), 135.0 g of carbidopa hydrate (median diameter: 7.4 μm), 76.6 g of microcrystalline cellulose, 24.0 g of ammonioalkyl methacrylate copolymer, 18.0 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and 6.0 g of light anhydrous silicic acid were premixed in a high-speed agitator granulator (Powrex Corporation, Model FM-VG-10) and granulated with 95 g of ethanol and 85 g of water. The resulting granules were dried in a fluidized-bed dryer (Powrex Corporation, Model MP-01) and then sized in a sieving machine (Powrex Corporation, Model QC-197S) to obtain a sized product. [Example]

[0119] 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 resulting mixture was compressed using a rotary tablet press (Kikusui Seisakusho: VIRGO type) to obtain unrefined granules weighing 6.4 mg per granule. 350 g of the unrefined granules were placed in a ventilated coating machine (Freund Corporation: HC-FZ-LABO type) and sprayed with a suspension of 27.3 g of methacrylic acid copolymer LD (8.2 g as solids), 3.3 g of talc, 8.2 g of D-mannitol, and 0.8 g of triethyl citrate in 640 g of purified water to obtain coated granules weighing 6.8 mg per granule. [Example]

[0120] 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 resulting mixture was compressed into tablets using a rotary tablet press (VIRGO type, manufactured by Kikusui Seisakusho) to obtain core granules with a mass of 6.6 mg per granule. [Example]

[0121] 122.4 mg of the coated granules obtained in Example 6 and 39.6 mg of the uncoated granules obtained in Example 7 were filled into No. 3 capsules to obtain a levodopa / carbidopa hydrate sustained-release formulation containing 100 mg of levodopa and 27 mg of carbidopa hydrate (25 mg as carbidopa). [Example]

[0122] 3400.0 g of levodopa (median diameter: 16 μm), 918.0 g of carbidopa hydrate (median diameter: 4.5 μm), 357.4 g of microcrystalline cellulose, 244.8 g of ammonioalkyl methacrylate copolymer, 81.6 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and 81.6 g of light anhydrous silicic acid were premixed in a high-speed agitator granulator (Powrex Corporation, Model FM-VG-25) and granulated with 1100 g of water. The resulting granules were dried in a fluidized-bed dryer (Powrex Corporation, Model FD-GPCG-5SPC) and then sized in a sieving machine (Powrex Corporation, Model QC-197S) to obtain a sized product. [Example]

[0123] 2990.0 g of the sized product obtained in Example 9 was mixed with 9.6 g of light anhydrous silicic acid and 120.0 g of magnesium stearate in a rotary mixer (Aichi Electric Co., Ltd.: Model RM-10-3) and blended. The resulting mixture was compressed into tablets using a rotary tablet press (Kikusui Seisakusho: Model VIRGO) to obtain unrefined granules weighing 6.5 mg per granule. 1170 g of the unrefined granules were placed in a ventilated coating machine (Freund Corporation: Model HC-FZ-LABO) and sprayed with a suspension of 90.0 g of methacrylic acid copolymer LD (27.0 g as solids), 13.5 g of talc, 10.8 g of D-mannitol, 2.3 g of triethyl citrate, and 0.5 g of yellow ferric oxide in 480 g of purified water, to obtain coated granules weighing 6.8 mg per granule. [Example]

[0124] 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 mixed in a rotary mixer (Model RM-10-3, manufactured by Aichi Electric Co., Ltd.) The resulting mixture was compressed into tablets in a rotary tablet press (Model VIRGO, manufactured by Kikusui Seisakusho) to obtain core granules with a mass of 6.6 mg per granule. [Example]

[0125] 122.4 mg of the coated granules obtained in Example 10 and 39.6 mg of the uncoated granules obtained in Example 11 were filled into No. 3 capsules to obtain a levodopa / carbidopa hydrate sustained-release formulation containing 100 mg of levodopa and 27 mg of carbidopa hydrate (25 mg as carbidopa). [Example]

[0126] 979.2 g of the coated granules obtained in Example 10 were placed in a ventilation coating machine (HC-FZ-LABO model, manufactured by Freund Corporation), and a suspension of 200.0 g of levodopa, 54.0 g of carbidopa hydrate, and 13.7 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer in 2700 g of purified water was sprayed onto the granules to obtain sustained-release granules containing 8.7 mg of levodopa / carbidopa hydrate. [Example]

[0127] 4500.0 g of levodopa (median diameter: 16 μm), 1215.0 g of carbidopa hydrate (median diameter: 4.5 μm), 473.0 g of microcrystalline cellulose, 324.0 g of ammonioalkyl methacrylate copolymer, 108.0 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and 108.0 g of light anhydrous silicic acid were premixed in a high-speed agitator granulator (Powrex Corporation, Model FM-VG-25) and granulated with 1500 g of water. The resulting granules were dried in a fluidized-bed dryer (Powrex Corporation, Model FD-GPCG-5SPC) and then sized in a sieving machine (Powrex Corporation, Model QC-197S) to obtain a sized product. [Example]

[0128] 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 in a rotary mixer (Aichi Electric Co., Ltd.: Model RM-10-3). The resulting mixture was compressed into tablets using a rotary tablet press (Kikusui Seisakusho: Model VIRGO) to obtain unrefined granules weighing 3.25 mg per granule. 250 g of the unrefined granules were placed in a ventilated coating machine (Freund Corporation: Model HC-FZ-LABO) and sprayed with a suspension of 43.3 g of methacrylic acid copolymer LD (13.0 g as solids), 6.5 g of talc, 5.2 g of D-mannitol, 1.1 g of triethyl citrate, and 0.3 g of yellow ferric oxide in 232 g of purified water, to obtain coated granules weighing 3.58 mg per granule. [Example]

[0129] 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 mixed in a rotary mixer (Model RM-10-3, manufactured by Aichi Electric Co., Ltd.) The resulting mixture was compressed into tablets in a rotary tablet press (Model VIRGO, manufactured by Kikusui Seisakusho) to obtain core granules with a mass of 3.3 mg per granule. [Example]

[0130] 129.2 mg of the coated granules obtained in Example 15 and 39.6 mg of the uncoated granules obtained in Example 16 were filled into No. 3 capsules to obtain a levodopa / carbidopa hydrate sustained-release formulation containing 100 mg of levodopa and 27 mg of carbidopa hydrate (25 mg as carbidopa). [Example]

[0131] 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 in a rotary mixer (Aichi Electric Co., Ltd.: Model RM-10-3). The resulting mixture was compressed into tablets using a rotary tablet press (Kikusui Seisakusho: Model VIRGO) to obtain unrefined granules weighing 19.50 mg per granule. 250 g of the unrefined granules were placed in a ventilated coating machine (Freund Corporation: Model HC-FZ-LABO) and sprayed with a suspension of 9.0 g of methacrylic acid copolymer LD (2.7 g as solids), 1.35 g of talc, 1.08 g of D-mannitol, 0.23 g of triethyl citrate, and 0.05 g of yellow ferric oxide in 48 g of purified water to obtain coated granules weighing 19.9 mg per granule. [Example]

[0132] 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 1,121.0 g of the sized product obtained in Example 14 and mixed in a rotary mixer (RM-10-3, manufactured by Aichi Electric Co., Ltd.) The resulting mixture was compressed into tablets in a rotary tablet press (VIRGO, manufactured by Kikusui Seisakusho) to obtain core granules with a mass of 19.8 mg per granule. [Example]

[0133] 119.4 mg of the coated granules obtained in Example 18 and 39.6 mg of the uncoated granules obtained in Example 19 were filled into No. 3 capsules to obtain a levodopa / carbidopa hydrate sustained-release formulation containing 100 mg of levodopa and 27 mg of carbidopa hydrate (25 mg as carbidopa). [Example]

[0134] 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 in a rotary mixer (Aichi Electric Co., Ltd.: Model RM-10-3). The resulting mixture was compressed into tablets using a rotary tablet press (Kikusui Seisakusho: Model VIRGO) to obtain unrefined granules weighing 6.5 mg per granule. 250 g of the unrefined granules were placed in a ventilated coating machine (Freund Corporation: Model HC-FZ-LABO) and sprayed with a suspension of 11.6 g of methacrylic acid copolymer LD (3.5 g as solids), 1.74 g of talc, 1.39 g of D-mannitol, 0.30 g of triethyl citrate, and 0.07 g of yellow ferric oxide in 60 g of purified water to obtain coated granules weighing 6.6 mg per granule. [Example]

[0135] 234 g of the coated granules obtained in Example 21 were placed in a ventilated coating machine (HC-FZ-LABO model, manufactured by Freund Corporation), and a suspension of 72.0 g of levodopa, 19.4 g of carbidopa hydrate, and 5.0 g of polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer in 555 g of purified water was sprayed onto the granules until the mass of each granule reached 8.5 mg, yielding sustained-release granules containing levodopa and carbidopa hydrate. [Example]

[0136] 153.0 mg of the coated granules obtained in Example 22 were filled into a No. 3 capsule to obtain a levodopa / carbidopa hydrate sustained-release preparation containing 100 mg of levodopa and 27 mg of carbidopa hydrate (25 mg as carbidopa). [Example]

[0137] 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 mixed in a rotary mixer (RM-10-3 model, manufactured by Aichi Electric Co., Ltd.) The resulting mixture was compressed into tablets in a rotary tablet press (VIRGO model, manufactured by Kikusui Seisakusho) to obtain core granules with a mass of 6.6 mg per granule. [Example]

[0138] 122.4 mg of the coated granules obtained in Example 10 and 39.6 mg of the uncoated granules obtained in Example 24 were filled into No. 3 capsules to obtain a levodopa / carbidopa hydrate sustained-release formulation containing 100 mg of levodopa and 27 mg of carbidopa hydrate (25 mg as carbidopa). [Example]

[0139] 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 mixed in a rotary mixer (RM-10-3, manufactured by Aichi Denki Co., Ltd.) The resulting mixture was compressed into tablets in a rotary tablet press (VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.) to obtain core granules with a mass of 6.6 mg per granule. [Example]

[0140] 122.4 mg of the coated granules obtained in Example 10 and 39.6 mg of the uncoated granules obtained in Example 26 were filled into No. 3 capsules to obtain a levodopa / carbidopa hydrate sustained-release formulation containing 100 mg of levodopa and 27 mg of carbidopa hydrate (25 mg as carbidopa). [Example]

[0141] 10.8 g of light anhydrous silicic acid and 135.0 g of calcium stearate were added to 3364.0 g of the sized product obtained in Example 14 and mixed in a rotary mixer (Aichi Electric Co., Ltd.: Model RM-10-3). The resulting mixture was compressed into tablets using a rotary tablet press (Kikusui Seisakusho: Model VIRGO) to obtain raw granules weighing 6.5 mg per granule. 250 g of the resulting raw granules were placed in a ventilated coating machine (Freund Corporation: Model HC-FZ-LABO) and sprayed with a suspension of 14.5 g of methacrylic acid copolymer LD (4.3 g as solids), 2.18 g of talc, 1.74 g of D-mannitol, 0.38 g of triethyl citrate, and 0.09 g of yellow ferric oxide in 75 g of purified water to obtain coated granules weighing 6.7 mg per granule. [Example]

[0142] 121.1 mg of the coated granules obtained in Example 28 and 39.6 mg of the raw granules obtained in Example 11 are filled into a No. 3 capsule to obtain a levodopa / carbidopa hydrate sustained-release formulation containing 100 mg of levodopa and 27 mg of carbidopa hydrate (25 mg as carbidopa).

[0143] The ingredients in one capsule of the formulation of the present disclosure are shown in Table 1 below. Table 1 JPEG2025122084000002.jpg156143

[0144] [Comparative Example 1] Neodopaston (registered trademark) combination tablets L100 (manufactured by Ohara Pharmaceutical Co., Ltd.): Each tablet contains 100 mg of levodopa and 10.8 mg of carbidopa hydrate.

[0145] [Test Example 1] Dissolution test of levodopa (paddle method) The formulations obtained in Examples 4, 8, 12, 17, 20, 23, 25, and 27, as well as the formulation of Comparative Example 1, were subjected to the dissolution test Method 2 (paddle method) of the General Testing Methods of the Japanese Pharmacopoeia, 18th Edition. The dissolution test was carried out using 900 mL of the Dissolution Test Fluid 1 (pH 1.2) specified in the General Testing Methods of the Japanese Pharmacopoeia, 18th Edition, at a paddle rotation speed of 100 rpm and a fluid temperature of 37°C (within a range of 37±0.5°C). The amount of levodopa dissolved at each sampling point was determined by high-performance liquid chromatography, and the dissolution rates of levodopa relative to the labeled amount (n=6) are shown in Table 2 below. <Equipment used> Dissolution tester / RTJ-2000 (manufactured by Dai Nippon Seiki) High-performance liquid chromatograph / NEXERA system (Shimadzu Corporation)

[0146] Table 2. Test Example 1: Results of levodopa dissolution test using the paddle method (n=6) JPEG2025122084000003.jpg55143

[0147] In the dissolution test using the formulation of Comparative Example 1, 100% of the labeled amount was dissolved 30 minutes after the start of the dissolution test, whereas in the dissolution test using each of the formulations of Examples 4, 8, 12, 17, 20, 23, 25, and 27, it was confirmed that approximately 30% of the labeled amount was dissolved 30 minutes after the start of the dissolution test, and that levodopa was then gradually dissolved over a period of 3 hours or more.

[0148] This levodopa dissolution behavior suggests that when each formulation is actually administered to a subject, it is expected that levodopa will dissolve quickly in the stomach with the formulation of Comparative Example 1 and be immediately absorbed in the digestive tract, whereas in each of the formulations of Examples 4, 8, 12, 17, 20, 23, 25, and 27, approximately 30% of levodopa will dissolve quickly in the stomach, causing the levodopa blood concentration to immediately rise to a certain level, and thereafter, even if the formulation remains in the stomach of the subject, it will gradually dissolve and a certain levodopa blood concentration will be maintained.

[0149] [Test Example 2] Dissolution test of levodopa (flow-through cell method) The formulations obtained in Examples 4, 8, 12, 17, 20, 23, 25, and 27, as well as the formulation of Comparative Example 1, were subjected to the third method of dissolution testing (flow-through cell method) of the General Testing Methods of the Japanese Pharmacopoeia, 18th Edition. The dissolution tests were performed using a small flow-through cell by the open-loop method. A pulsating pump was used to deliver the following fluids at a temperature of 37°C (within a range of 37±0.5°C) and a delivery rate of 16 mL / min: Fluid 1 (pH 1.2) specified in the General Testing Methods of the Japanese Pharmacopoeia, 18th Edition, from the start of the test until 45 minutes; diluted McIlvaine buffer (pH 5.5) (Kanto Chemical) from 45 minutes to 180 minutes; and Fluid 2 (pH 6.8) specified in the General Testing Methods of the Japanese Pharmacopoeia, 18th Edition, from 180 minutes to 540 minutes. The amounts of levodopa dissolved at 2, 5, 10, 15, 20, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, 480, and 540 minutes after the start of the dissolution test were determined by high-performance liquid chromatography, and the dissolution rates of levodopa (n=7) relative to the labeled amount at each time point calculated from the integrated values of the amounts of levodopa dissolved are shown in Table 3 below. <Equipment used> Dissolution tester / Flow-through cell method dissolution tester DF-7 (manufactured by Dai Nippon Seiki) High-performance liquid chromatograph / NEXERA system (Shimadzu Corporation)

[0150] Table 3. Test Example 2: Results of levodopa dissolution test using the flow-through cell method (n=7) JPEG2025122084000004.jpg133143

[0151] In the dissolution test results using the formulation of Comparative Example 1, levodopa was rapidly dissolved when a dissolution test solution of pH 1.2 was fed, and almost all of the levodopa had already been dissolved 15 minutes after the start of the dissolution test.

[0152] On the other hand, in the results of the dissolution test using each of the formulations of Example 4, Example 8, Example 12, Example 17, Example 20, Example 23, Example 25, and Example 27, it was confirmed that approximately 30% of the labeled amount was dissolved in the test solution of pH 1.2 45 minutes after the start of the dissolution test, and when the test solution of pH 5.5 and then the test solution of pH 6.8 were then delivered, levodopa was continuously dissolved regardless of the pH of the test solution.

[0153] This dissolution behavior suggests that when each formulation is actually administered to a subject, levodopa will be rapidly dissolved in the stomach in the formulation of Comparative Example 1, as in Test Example 1, and will be immediately absorbed in the digestive tract.

[0154] On the other hand, in the preparations of Examples 4, 8, 12, 17, 20, 23, 25, and 27, about 30% of levodopa is rapidly dissolved in the stomach, suggesting that the levodopa blood concentration is immediately increased to a certain level.

[0155] These results suggest that even if there are individual differences in gastrointestinal pH in the body, the formulation gradually dissolves without being affected by this, and a constant blood levodopa concentration is maintained.

[0156] [Test Example 3] Comparative pharmacokinetic study of levodopa in healthy adults A comparative pharmacokinetic study was conducted in which 12 healthy adult males were orally administered a single dose of each of the formulations obtained in Examples 4 and 8 (100 mg levodopa / 27 mg carbidopa hydrate) and the formulation of Comparative Example 1 (100 mg levodopa / 10.8 mg carbidopa hydrate) under fasting conditions. The results of the mean plasma levodopa concentration over time for each formulation are shown in Figure 1.

[0157] Immediately after the administration of the formulation of Comparative Example 1 to the subject, the plasma levodopa concentration rose rapidly, but one hour after administration of the formulation, the plasma levodopa concentration fell to about half, suggesting that it is difficult to sustain the pharmacological effects of levodopa.

[0158] On the other hand, when the formulations of Examples 4 and 8 were administered to subjects, the plasma levodopa concentration quickly rose to a certain level and was maintained at the same level for approximately four hours thereafter. These results suggest that a single administration of the formulations exhibits a levodopa blood kinetic profile that is both rapid and sustained, thereby allowing the pharmacological effects of levodopa to be sustained for a long period of time.

[0159] These results demonstrate that the dissolution tests shown in Test Examples 1 and 2 are extremely effective evaluation methods as criteria for evaluating in vitro formulation properties, which are important in designing controlled-release formulations.

[0160] The levodopa dissolution behavior of the formulations of the present disclosure shown herein suggests that this is a particularly important formulation characteristic for an oral pharmaceutical composition containing levodopa and carbidopa as pharmaceutically active ingredients to achieve a levodopa blood kinetic profile that is both rapid and sustained.

[0161] [Test Example 4] Sieving test The coated granules of Examples 2, 6, 10, 15, 18, and 21, the uncoated granules of Examples 3, 7, 11, 16, 19, 24, and 26, and the levodopa / carbidopa hydrate sustained-release granules of Examples 13 and 22 all passed through Japanese Pharmacopoeia Sieve No. 4.7 and remained on Japanese Pharmacopoeia Sieve No. 12, as described in the particle size measurement method of the Japanese Pharmacopoeia, 18th Edition, General Test Methods.

[0162] [Test Example 5] Comparative study of levodopa pharmacokinetics by dose in healthy adults A comparative pharmacokinetic study was conducted on 17 healthy adult male subjects, in which one capsule (100 mg levodopa / 27 mg carbidopa hydrate) obtained in Example 12 was orally administered in a single dose under fasting conditions to six subjects (1 capsule (100 mg levodopa / 27 mg carbidopa hydrate), 5 subjects (2 capsules (200 mg levodopa / 54 mg carbidopa hydrate), and the remaining 6 subjects (4 capsules (400 mg levodopa / 108 mg carbidopa hydrate)). The results over time of the mean plasma levodopa concentration for each formulation are shown in Figure 2.

[0163] When the formulation of Example 12 was administered to subjects at different doses, the plasma levodopa concentration quickly rose to a certain level without being affected by the dose, and the same plasma levodopa concentration was maintained for approximately 4 hours thereafter. Thus, the formulations exhibiting the dissolution profile shown in the present disclosure exhibit sustained pharmacokinetics without being affected by the dose, suggesting that they can provide clinically significant formulations.

[0164] While the present invention has been described with reference to exemplary embodiments and examples, this description is not intended to be construed in a limiting sense. Accordingly, various modifications of the exemplary embodiments and other 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.

[0165] All publications, patents, and patent applications referenced in this specification are incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

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