Edaravone suspension for oral administration

Abstract

Provided is an edaravone suspension for oral administration that can reduce the burden on ALS patients and caregivers and exhibit an ALS treatment effect equivalent to that of an injection.SOLUTION: An edaravone suspension for human oral administration including edaravone particles, a dispersant, and water is provided.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an edaravone suspension for oral administration and a kit for preparing an edaravone suspension for oral administration. [Background technology]

[0002] Edaravone is 3-methyl-1-phenyl-2-pyrazolin-5-one (see formula below): [ka] It is known to have medicinal uses as a brain function normalizer as well as a therapeutic agent for ALS (amyotrophic lateral sclerosis) (Patent Documents 1 and 2).

[0003] ALS, a motor neuron disease, is an intractable disease that initially manifests with hand weakness, motor impairment, and upper limb fasciculations. It progresses through muscle atrophy, weakness, bulbar paralysis, and muscle fasciculations, eventually leading to respiratory failure. ALS is classified as upper limb, bulbar, lower limb, or mixed type depending on the site of onset. In all types, the entire body's muscles are affected as the disease progresses. The etiology of ALS is still unclear, but several hypotheses have been proposed, including (1) autoimmune disease (the appearance of autoantibodies against calcium channels), (2) excitatory amino acid excess / toxicity (increased extracellular glutamate and impaired glutamate transport), (3) oxidative stress disorder (neuronal damage caused by Cu / Zn superoxide dismutase (SOD) gene abnormalities and free radicals), (4) cytoskeletal dysfunction (accumulation of neurofilament and the appearance of inclusion bodies in motor neurons), and (5) neurotrophic factor deficiency.

[0004] Edaravone is currently used as a treatment for ALS, but it is only available as an injectable drug. Therefore, there is a need for an orally administered formulation that places less burden on patients and caregivers and is more favorable in terms of quality of life. However, unlike injectable drugs, which are administered directly into the bloodstream, various factors such as gastrointestinal absorption and the first-pass effect affect the bioavailability of oral formulations, making it extremely difficult to obtain a formulation that is bioequivalent to an injectable drug. Oral administration formulations are generally solid formulations such as tablets and capsules, but these formulations can be difficult for ALS patients who are expected to have a reduced ability to swallow to take the medication directly. For these patients, oral administration forms such as liquids and suspensions are preferable. Non-Patent Documents 1 to 3 describe CMC-Na suspensions of edaravone, but when these were administered to animals, they all showed low bioavailability. Patent Document 3 describes an oral solution of edaravone using an aqueous solution of gum tragacanth, and states that a sufficient blood concentration was obtained in rats. However, the blood concentration was lower than the results of the CMC-Na suspension described in the above Non-Patent Documents 1 to 3, and the formulation described in this document does not have bioavailability comparable to that of an injection. In order to overcome the low bioavailability of suspensions, Patent Document 4 describes an edaravone solution with excellent absorbability. However, this solution requires a dosage of as much as 100 mL due to the low solubility of edaravone in water, which is undesirable in terms of patient adherence. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Special Publication No. 5-31523 [Patent Document 2] Patent No. 3758164 [Patent Document 3] Japanese Patent Application Laid-Open No. 2004-91441 [Patent Document 4] WO2018 / 134243 publication [Non-patent literature]

[0006] [Non-Patent Document 1] JOURNAL OF PHARMACEUTICAL SCIENCES 103:730-742, 2014 [Non-patent document 2] International Journal of Pharmaceutics 515 (2016) 490-500 [Non-patent document 3] Drug Delivery, 24:1, 962-978 Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present invention is to provide an orally administered edaravone suspension that reduces the burden on ALS patients and their caregivers and that can provide an ALS therapeutic effect equivalent to that of an injection. [Means for solving the problem]

[0008] As a result of extensive research, the present inventors have found that by incorporating a dispersant, edaravone particles can be uniformly dispersed in water and the dispersed state can be maintained, and even if the edaravone particles settle after storage, they can be quickly redispersed by gentle shaking, thereby making it possible to prepare a pharmaceutical-friendly edaravone suspension for oral administration.Furthermore, based on the findings of Non-Patent Documents 1 to 3, the prepared edaravone suspension for oral administration was found to exhibit unexpectedly excellent bioavailability when administered to humans, despite being a suspension that has been considered to be disadvantageous in terms of bioavailability based on the results of previous animal experiments, and have thus completed the present invention. The means to solve the problem are as follows: <1> ~ <23> The present invention relates to, but is by no means limited to,

[0009] <1> An edaravone suspension for oral administration to humans, comprising edaravone particles, a dispersant and water. <2> The dispersant is a dispersant that exhibits a transmitted scattered light intensity of 1% or more. <1> Suspension agent. <3> The dispersant has a contact angle of 80° or less. <1> Suspension agent. <4> The dispersing agent is one or two selected from polyvinyl alcohol, methylcellulose, hypromellose, sucrose fatty acid esters, and polysorbates. <1> Suspension agent. <5> The dispersing agent is one or two selected from polyvinyl alcohol and methyl cellulose; <4> Suspension agent. <6> The dispersant is polyvinyl alcohol. <4> or <5> Suspension agent. <7> The polyvinyl alcohol has a saponification degree of 86.5 to 89.0 and a kinematic viscosity of a 4% aqueous solution at 20°C of 3 mm 2 / s~55.7mm 2 / s, <4> ~ <6> Any one of the suspensions. <8> The amount of dispersant blended is 0.001% (w / v) to 1.0% (w / v), <1> ~ <7> Any one of the suspensions.

[0010] <9> Further comprising a thickener, <1> ~ <8> Any one of the suspensions. <10> The thickener is one or two selected from xanthan gum and powdered tragacanth; <9> Suspension agent. <11> The thickener is xanthan gum. <9> or <10> Suspension agent. <12> The amount of thickener is 0.1% (w / v) to 1.2% (w / v), <9> ~ <11> Any one of the suspensions. <13> The D50 particle size of the edaravone particles in the suspension is 10 μm to 100 μm, and the D90 particle size is 50 μm to 300 μm. <1> ~ <12> A suspension of any one of the following: <14> The amount of edaravone particles is 0.06% (w / v) to 36% (w / v). <1> ~ <13> Any one of the suspensions. <15> Further containing one or more additives selected from sweeteners, stabilizers and pH adjusters, <1> ~ <14> Any one of the suspensions. <16> The viscosity of the suspension is 50 mPa·s to 1750 mPa·s. <1> ~ <15> Any one of the suspensions. <17> The density of the suspension is 1g / mL to 1.5g / mL. <1> ~ <16> Any one of the suspensions. <18> When a dissolution test is conducted in accordance with the Japanese Pharmacopoeia (test solution: first solution, paddle rotation speed: 50 rpm), the dissolution rate of edaravone is 80% or more 30 minutes after the start of the test. <1> ~ <17> The suspension according to any one of the preceding claims. <19> (A) a solid composition containing edaravone particles, and (B) a dispersant solution A kit for preparing an edaravone suspension for oral administration to humans, comprising: <20> When 90 to 120 mg of edaravone was orally administered to humans, the mean Cmax of edaravone in plasma was 500 to 2500 ng / mL, and the mean AUC 0-∞ Edaravone suspension for oral administration to humans showing a concentration of 1000 to 2500 h*ng / mL. <21> In a crossover study in which a suspension containing 90-120 mg of edaravone was orally administered to humans using edaravone injection as a control, the 90% confidence interval lower limit of the ratio of the geometric mean Cmax to the control formulation and the AUC 0-∞ Edaravone suspension for oral administration to humans, for which the lower limits of the 90% confidence intervals of the ratios of the geometric means are all greater than 0.8. <22> In a crossover study in which a suspension containing 90-120 mg of edaravone was orally administered to humans using edaravone injection as a control, the geometric mean Cmax ratio and AUC 0-∞ An edaravone suspension for oral administration to humans, wherein all of the geometric mean value ratios are between 0.8 and 1.25. <23> A therapeutic agent for ALS, characterized in that the dosage of the formulation for oral administration per dose is 1 to 20 mL, and the dosage contains 50 to 210 mg of edaravone. [Effects of the Invention]

[0011] According to the present invention, it is possible to provide an orally administered edaravone suspension that reduces the burden on ALS patients and their caregivers and that can provide an ALS therapeutic effect equivalent to that of an injection. [Brief explanation of the drawings]

[0012] [Figure 1] 1 shows the PK profiles of unchanged edaravone in plasma after oral administration of the suspension of the present invention (Example 26) or intravenous injection of edaravone. In the figure, the symbol ● represents the suspension of the present invention, and the symbol ▲ represents the edaravone injection. DETAILED DESCRIPTION OF THE INVENTION

[0013] The edaravone suspension for oral administration and the kit for preparing the edaravone suspension for oral administration of the present invention are described in detail below. All publications cited in this specification are incorporated herein by reference. Furthermore, in this specification, unless otherwise specified, "% (w / v)" means % by mass relative to the volume of the suspension, and a numerical range indicated using "to" indicates a range that includes the numerical values ​​before and after "to" as the minimum and maximum values, respectively.

[0014] The suspension for oral administration to humans of the present invention contains edaravone particles, a dispersant, and water. As a result, the suspension of the present invention reduces the burden on ALS patients and their caregivers and exhibits ALS therapeutic effects equivalent to those of injections.

[0015] Furthermore, the suspension of the present invention may further contain a thickener, if necessary. This makes it easier for patients with swallowing disorders to swallow without the risk of aspiration, and enables the edaravone particles to remain dispersed for an even longer period of time. Furthermore, the inclusion of a thickener greatly reduces the variability in drug blood concentrations between patients when administered to humans, and more stable medicinal effects can be expected.

[0016] Edaravone in the present invention is a known compound and can be easily synthesized by those skilled in the art by the method described in, for example, Japanese Patent Publication No. 5-31523.

[0017] The edaravone particles contained in the suspension of the present invention are solid particles containing edaravone, and may be composed of only edaravone or may contain other components, and edaravone may be in either a crystalline state or an amorphous state. The particle size of the edaravone particles in the suspension is not particularly limited, but from the viewpoints of maintaining a stable dispersion state in the suspension, rapid absorption in the body, and no rough feeling when taken, it is preferable that the D50 particle size (cumulative 50% particle size on a volume basis) is in the range of 10 μm to 100 μm and the D90 particle size (cumulative 90% particle size on a volume basis) is in the range of 50 μm to 300 μm, and more preferably the D50 particle size is in the range of 20 μm to 80 μm and the D90 particle size is in the range of 100 μm to 250 μm. In the present invention, the cumulative 50% particle size and cumulative 90% particle size respectively refer to particle sizes on a volume basis. The particle size distribution of edaravone particles in the suspension is measured by dispersing a portion of the suspension in a dispersion medium for measurement (aqueous solution saturated with edaravone) and using a laser diffraction particle size distribution analyzer (Sympatec / HELOS&CUVETTE).

[0018] The concentration (amount) of edaravone particles incorporated into the suspension of the present invention can be adjusted as appropriate depending on the optimal dose of edaravone and the amount of suspension provided to ALS patients (e.g., single dose, daily dose, weekly dose, 10-day dose), but an amount that allows the suspension to maintain its form is appropriate. When the edaravone particles are composed solely of edaravone, the concentration of the edaravone particles should be 2 mg / mL or more, which is equal to or greater than the saturated solubility of edaravone in a dispersion medium (e.g., water), and is preferably 0.06% (w / v) to 36% (w / v), more preferably 0.5% (w / v) to 36% (w / v), or 0.5% (w / v) to 20% (w / v), even more preferably 1% (w / v) to 20% (w / v), or 1% (w / v) to 10% (w / v), and most preferably 1% (w / v) to 5% (w / v).

[0019] The suspension of the present invention contains a dispersant. This allows the edaravone particles to maintain a good dispersion state in the suspension of the present invention, and even if the edaravone particles settle after long-term storage, they can be quickly redispersed by shaking (e.g., manual or mechanical shaking). The redispersion behavior can be confirmed visually or by a spectroscopic method (e.g., using a laser diffraction particle size analyzer).

[0020] The dispersant may be any dispersant that can disperse edaravone particles well in water without forming secondary aggregation, etc. For example, such a dispersant may be a dispersant with a transmitted scattered light intensity of 1% or more. Here, 1% or more means a range of 1% to 100%. A dispersant with a transmitted scattered light intensity of X% or more means a dispersant that, when 40 mL of a 0.1% (w / v) aqueous dispersant solution is mixed with 840 mg of edaravone and the transmitted scattered light intensity (ΔT%) is measured just below the liquid surface, is X% or more. For example, a dispersant with a transmitted scattered light intensity of 1% or more means a dispersant that, when 40 mL of a 0.1% (w / v) aqueous dispersant solution is mixed with 840 mg of edaravone (D50: 37 μm, D90: 143 μm) and stirred for 30 minutes or more, the transmitted scattered light intensity (ΔT%) just below the liquid surface is measured and is 1% or more. Furthermore, the transmitted scattered light intensity here refers to the value measured 10 minutes after filling 20 mL of the above liquid into a cylindrical sample bottle (inner diameter 25 mm x outer diameter 27.5 mm x height 72 mm) and starting measurement of the transmitted scattered light intensity at a height of 39 to 40 mm in the sample bottle at 25°C using a TURBISCAN Tower (manufactured by Formulaction). Examples of dispersants with a transmitted scattered light intensity of 1% or more include polyvinyl alcohol, sucrose fatty acid esters, polysorbate, methylcellulose, and hypromellose.

[0021] Furthermore, dispersants with a contact angle of 80° or less can also be suitably used. Here, 80° or less means 0° to 80°. A dispersant with a contact angle of 80° or less means a dispersant that, when a droplet of a saturated aqueous edaravone solution in which 0.1% (w / v) of the dispersant is dissolved is dropped onto an edaravone tablet, the angle (contact angle) formed between the tangent of the droplet and the surface of the edaravone tablet is 80° or less. Here, the edaravone tablet refers to a tablet obtained by compression molding 120 mg of edaravone (D50: 37 μm, D90: 143 μm) using an 8 mm diameter flat punch at a tableting pressure of 800 kg, and the contact angle is measured using a contact angle measuring device (Kyowa Interface Science, CAX-150) under the following conditions: Syringe used: glass, 1 mL Needle: 23 gauge Liquid volume: 1 μL Measurement time: after 3.1 seconds Examples of dispersants with a contact angle of 80° or less include polyvinyl alcohol, sucrose fatty acid esters, polysorbates, and hypromellose.

[0022] Specific examples of preferred dispersants include one or more selected from the group consisting of polyvinyl alcohol, sucrose fatty acid esters, polysorbates, methylcellulose, and hypromellose, particularly preferably one or two selected from the group consisting of polyvinyl alcohol and methylcellulose, and most preferably polyvinyl alcohol.

[0023] The polyvinyl alcohol has a saponification degree of 86.5 to 89.0, and a kinematic viscosity range of 3 mm at 20 ° C. in a 4% aqueous solution. 2 / s~55.7mm 2 Preferred are those which are recommended as pharmaceutical additives, but are not limited to these. Examples include Gohsenol EG-03P, EG-05P, EG-05PW, EG-18P, EG-22P, EG-30P, EG-30PW, EG-40P, EG-40PW, and EG-48P, all of which are sold by Nippon Synthetic Chemical Industry Co., Ltd. Any of the dispersants may be used alone or in combination of two or more.

[0024] The amount of the dispersant to be added may be selected within a range that disperses the edaravone particles and does not adversely affect manufacturability, and is generally 0.001% (w / v) to 1.0% (w / v), preferably 0.005% (w / v) to 0.5% (w / v), and most preferably 0.01% (w / v) to 0.1% (w / v).

[0025] The suspension of the present invention may contain a thickener to maintain the dispersion state of the edaravone particles in a good condition for a long period of time. The inclusion of a thickener makes the suspension easy to swallow even for patients with dysphagia without the risk of aspiration, and also significantly reduces the variation in blood drug concentration among patients when administered to humans, thereby enabling the expectation of more stable medicinal effects. As the thickener, any thickener known in pharmaceutical formulations can be used. Specific examples include carmellose sodium, dextrin, powdered tragacanth, and xanthan gum. From the viewpoint of the storage stability of edaravone, powdered tragacanth and xanthan gum are preferred, and xanthan gum is most preferred. Any of the thickeners may be used alone or in combination of two or more.

[0026] The higher the amount of thickener used, the longer the dispersed state can be maintained, but too much is undesirable because it increases viscosity, reduces manufacturability, makes the formulation difficult to swallow, and reduces redispersibility when particles settle after long-term storage. For example, in the case of xanthan gum, the amount of thickener used may be 0.1% (w / v) to 1.2% (w / v), preferably 0.2% (w / v) to 1.0% (w / v), and most preferably 0.3% (w / v) to 0.5% (w / v).

[0027] The incorporation of a thickener can impart viscosity to the suspension, making it easier for patients with swallowing disorders to swallow and preventing aspiration, which is advantageous. The viscosity of such a suspension may be within a range not exceeding 1750 mPa·s, preferably within a range of 50 mPa·s to 1750 mPa·s, and most preferably within a range of 150 mPa·s to 900 mPa·s. The amount of thickener blended is not limited to the above, and can be adjusted appropriately to achieve the above viscosity. Furthermore, the incorporation of a thickener has the unexpected effect of minimizing the variation in blood concentration of edaravone over time among patients when administered to them, so stable efficacy can be expected for all patients.

[0028] The suspension for oral administration of the present invention can be blended with a sweetener for the purpose of adjusting the taste of the preparation for oral administration and increasing the density of the suspension solution to delay the sedimentation of edaravone particles. Among sweeteners, sugars can be blended in at a higher ratio than other additives, and can contribute to increasing the density of the solution. Furthermore, dissolving sugars can make the density of the solution closer to that of the particles, and can also contribute to suppressing the sedimentation rate of the particles.

[0029] The density of the suspension is desirably close to that of edaravone particles, and is greater than the density of water, preferably within the range of 1 g / mL to 1.5 g / mL, and most preferably within the range of 1.05 g / mL to 1.2 g / mL. Examples of sweeteners include sugars, artificial sweeteners, non-sugar sweeteners, etc. Specific examples of sugars include mannitol, sorbitol, xylitol, maltitol, erythritol, sucrose, trehalose, lactose, maltose, glucose, glycerin, etc. Specific examples of artificial sweeteners include sucralose, aspartame, acesulfame potassium, saccharin, etc. Specific examples of non-sugar sweeteners include thaumatin, stevia extract, etc. Among these, sorbitol, xylitol, or sucrose is preferred, sorbitol or sucrose is more preferred, and sorbitol is most preferred.

[0030] The sweeteners may be used alone or in combination of two or more. The amount of sweetener to be added can be adjusted as appropriate taking into consideration the user's preference and the need to suppress particle sedimentation. For example, the amount of sorbitol to be added is 5% (w / v) to 70% (w / v), preferably 10% (w / v) to 60% (w / v), and more preferably 20% (w / v) to 50% (w / v).

[0031] Since the pharmaceutical ingredient edaravone in the suspension of the present invention is susceptible to oxidation by dissolved oxygen in the liquid, it is preferable to incorporate a known stabilizer. Such stabilizers include antioxidants such as sulfites, bisulfites, and pyrosulfites, cysteines, methionines, polyethylene glycol, polyoxyethylene polyoxypropylene glycol, and EDTA. Particularly preferred are the stabilizers described in JP-B-7-121861. That is, stabilizers selected from one or more antioxidants selected from sulfites, bisulfites, and pyrosulfites and cysteines.

[0032] Examples of sulfites include sodium sulfite (NaSO), potassium sulfite (KSO), and calcium sulfite (CaSO). Examples of bisulfites include sodium bisulfite (NaHSO), potassium bisulfite (KHSO), and ammonium bisulfite (NHHSO). Examples of pyrosulfites include sodium pyrosulfite (NaSO) and potassium pyrosulfite (KSO). Examples of cysteines include L-cysteine, DL-cysteine, N-acetylcysteine, and their hydrochlorides. Most preferred examples of the antioxidant include sodium bisulfite, and the most preferred example of the cysteine ​​is L-cysteine ​​hydrochloride.

[0033] The amount of antioxidant and cysteine ​​derivatives added is preferably 0.001% (w / v) to 0.5% (w / v), particularly 0.01% (w / v) to 0.2% (w / v), for antioxidants, and 0.005% (w / v) to 0.5% (w / v), particularly 0.01% (w / v) to 0.2% (w / v) for cysteines.

[0034] Furthermore, since the oxidation of edaravone is known to be accelerated at pH 2.5 or below and pH 6.0 or above, it is preferable that a pH adjuster be incorporated into the suspension of the present invention. The pH adjuster can be used in an amount that adjusts the pH of the suspension to a range of 2.5 to 6.0, preferably 3.0 to 4.5. Either a base or an acid can be used to adjust the pH to the desired level. When it is necessary to lower the pH, an acidic pH adjuster (e.g., hydrochloric acid, phosphoric acid, acetic acid, citric acid, tartaric acid, etc., preferably phosphoric acid) can be used. When it is necessary to raise the pH, a basic pH adjuster (e.g., sodium hydroxide, potassium hydroxide, calcium carbonate, magnesium oxide, magnesium hydroxide, etc., preferably sodium hydroxide) can be used.

[0035] The suspension of the present invention may further contain pharmaceutically acceptable additives such as flavorings, preservatives, and antifoaming agents, if necessary. Flavorings include various flavors such as citrus flavors (orange, lemon, grapefruit, etc.), peach, grape, vanilla, soda, and berry flavors (strawberry, cranberry, blueberry, etc.), and a preferred blending amount of flavoring is, for example, 0.05% (w / v) to 0.2% (w / v). Examples of antifoaming agents include simethicone emulsion, fatty acid esters, polysorbates, and ethanol, and the amount of antifoaming agent blended is, for example, 0.01% (w / v) to 0.05% (w / v).

[0036] Examples of preservatives include methylparaben, ethylparaben, propylparaben, butylparaben, benzoic acid, sorbic acid, sodium benzoate, benzyl alcohol, phenylethanol, etc., and the amount of preservative to be added is, for example, 0.01% (w / v) to 0.5% (w / v). However, surprisingly, the suspension of the present invention does not allow bacterial growth even without a preservative, so the addition of a preservative is unnecessary.

[0037] The liquid medium (dispersion medium) used in the oral suspension of the present invention is preferably water, and may contain a pharmaceutically acceptable organic solvent, such as propylene glycol (1,2-propanediol), polyethylene glycol 300, polyethylene glycol 400, or ethanol.

[0038] Preferred embodiments of the combination of components in the suspension of the present invention are exemplified below, but are not limited thereto. (1) Edaravone particles, polyvinyl alcohol (dispersant), xanthan gum (thickener), sorbitol (sweetener), sodium bisulfite (stabilizer), L-cysteine ​​hydrochloride (stabilizer), phosphoric acid (pH adjuster), sodium hydroxide (pH adjuster), simethicone emulsion (antifoaming agent), and water. (2) Edaravone particles, polyvinyl alcohol (dispersant), tragacanth powder (thickener), sorbitol (sweetener), sodium bisulfite (stabilizer), L-cysteine ​​hydrochloride (stabilizer), phosphoric acid (pH adjuster), sodium hydroxide (pH adjuster), simethicone emulsion (antifoaming agent), and water. (3) Edaravone particles, sucrose fatty acid ester (dispersant), xanthan gum (thickener), sucrose (sweetener), sodium bisulfite (stabilizer), L-cysteine ​​hydrochloride (stabilizer), acetic acid (pH adjuster), sodium hydroxide (pH adjuster), simethicone emulsion (antifoaming agent), and water. (4) Edaravone particles, polyvinyl alcohol (dispersant), xanthan gum (thickener), sorbitol (sweetener), sodium bisulfite (stabilizer), phosphoric acid (pH adjuster), sodium hydroxide (pH adjuster), simethicone emulsion (antifoaming agent), and water. (5) Edaravone particles, polyvinyl alcohol (dispersant), xanthan gum (thickener), sorbitol (sweetener), sodium bisulfite (stabilizer), L-cysteine ​​hydrochloride (stabilizer), phosphoric acid (pH adjuster), sodium hydroxide (pH adjuster), simethicone emulsion (antifoaming agent), fragrance, and water.

[0039] In the suspension of the present invention, the edaravone particles maintain a well-dispersed state for a long period of time, so that uniformity of the drug content can be always ensured even when a fixed amount is taken from the whole solution and administered. Furthermore, even if the edaravone particles settle after long-term storage, they can be quickly redispersed by shaking, and the chemical stability of edaravone is not impaired during such long-term storage, and bacterial growth does not occur even without the addition of a preservative.

[0040] Furthermore, by further blending a thickener into the formulation of the present invention, appropriate viscosity is imparted, making it easy for patients with swallowing disorders to take and reducing the risk of aspiration. In addition, when administered to humans, the variation in drug blood concentration between patients is reduced, allowing for the expectation of stable medicinal efficacy.

[0041] The suspension of the present invention exhibits excellent bioavailability, and therefore, it is possible to achieve a blood concentration profile equivalent to that obtained when an injection of edaravone, which is currently used in clinical settings as a therapeutic agent for ALS, such as Radicut (registered trademark) in Japan, is administered (60 mg of edaravone is administered intravenously over one hour), with a very small oral dose of edaravone, specifically 90 to 120 mg, more specifically 100 to 110 mg, and most specifically 105 mg.

[0042] Specifically, when a crossover study was conducted in humans using the suspension of the present invention as a control with Edaravone injection, the lower limit of the 90% confidence interval for the ratio of the geometric mean Cmax to the control formulation and the AUC 0-∞ The lower limit of the 90% confidence interval of the ratio of the geometric mean values ​​can exceed 0.8. In the above test, the oral dose of edaravone in the suspension of the present invention is 90 to 120 mg, preferably 100 to 110 mg, and most preferably 105 mg, and 60 mg of edaravone in the control formulation for edaravone injection is intravenously injected over one hour. In the above test, the suspension of the present invention has a lower limit of the 90% confidence interval of the ratio of the geometric mean values ​​of Cmax to the control formulation that exceeds 0.8, and the AUC 0-∞The 90% confidence interval for the ratio of geometric means can fall within the range of 0.8 to 1.25. In the above test, the suspension of the present invention had a 90% confidence interval of the ratio of the geometric mean Cmax to the control formulation within the range of 0.8 to 2.0, and the AUC 0-∞ The 90% confidence interval for the ratio of geometric means can fall within the range of 0.8 to 1.25. Furthermore, in the suspension of the present invention, the 90% confidence interval of the ratio of the geometric mean Cmax to the control formulation is within the range of 0.8 to 1.5, and the AUC 0-∞ The 90% confidence interval for the ratio of geometric means can fall within the range of 0.8 to 1.25. In addition, the suspension of the present invention was evaluated for the ratio of Cmax geometric mean value to that of the control preparation and the AUC 0-∞ The ratio of the geometric mean values ​​can be in the range of 0.8 to 1.25.

[0043] When the suspension of the present invention (for example, 90 to 120 mg, more specifically 100 to 110 mg, and even more specifically 105 mg of edaravone) is orally administered to humans, the mean Cmax is in the range of 500 to 2500 ng / mL, the mean AUC 0-∞ In more detail, the average Cmax is in the range of 1000 to 2000 ng / mL, the average AUC 0-∞ The mean Cmax and mean AUC 0-∞ may be either an arithmetic mean value or a geometric mean value.

[0044] Examples of suspensions equivalent to the above-mentioned edaravone injection include, but are not limited to, suspensions having the following compositions. Edaravone particles: 2.1% (w / v) Polyvinyl alcohol (dispersant): 0.1% (w / v) Xanthan gum (thickener): 0.3% (w / v) Sorbitol (sweetener): 40% (w / v) Sodium sulfite (stabilizer): 0.1% (w / v) L-cysteine ​​hydrochloride (stabilizer): 0.05% (w / v) Sodium hydroxide (pH adjuster): appropriate amount Phosphoric acid (pH adjuster): appropriate amount Simethicone emulsion (antifoaming agent): 0.05% (w / v) Dispersion medium: water Oral administration of 5 mL of the above suspension (105 mg of edaravone) results in a plasma concentration profile equivalent to that obtained when the above edaravone injection (60 mg of edaravone) is intravenously administered over 60 minutes.

[0045] The suspension for oral administration of the present invention can be prepared by mixing the above-mentioned edaravone particles, a dispersant, and other ingredients (thickener, sweetener, etc.) as needed, and water. The edaravone particles used preferably have a D50 particle size (cumulative 50% particle size on a volume basis) of 2 μm to 50 μm and a D90 particle size (cumulative 90% particle size on a volume basis) of 100 μm to 250 μm. To prepare edaravone particles with the above particle sizes, for example, when the edaravone particles are composed solely of edaravone, bulk edaravone powder obtained by the method described in JP-B-5-31523 can be milled using a known mill, such as a jet mill, hammer mill, pin mill, or ball mill, to prepare edaravone particles with the desired particle size. The particle size of the edaravone particles can be measured by a dry method using a laser diffraction particle size analyzer (Sympatec / HELOS&CUVETTE). The dissolution rate of edaravone from the obtained formulation can be changed by changing the particle size of the edaravone particles used. Specifically, the smaller the particle size, the faster the dissolution. For example, when the edaravone particles are a pulverized product of edaravone bulk powder obtained by the above method, by setting the D50 particle size within the range of 10 μm to 50 μm and the D90 particle size within the range of 50 μm to 200 μm, preferably within the range of 20 μm to 40 μm and the D90 particle size within 70 μm to 150 μm, a formulation can be obtained in which the edaravone dissolution rate is 80% or more 30 minutes after the start of the test when a dissolution test is conducted according to the Japanese Pharmacopoeia (test solution: first solution, second solution, 0.05 mol / L acetic acid-sodium acetate buffer solution (pH 4.0), etc., paddle rotation speed: 50 rpm to 75 rpm), and thus rapid efficacy can be expected.

[0046] The suspension of the present invention can be prepared by blending the components and then using a known mixing method such as stirring, shaking, or ultrasonic irradiation to prepare a homogeneous suspension. A suitable preparation method includes, for example, a method of uniformly dispersing (suspending) edaravone particles in water (dispersant solution) in which a dispersant has been dissolved, which may involve either adding edaravone particles to the dispersant solution or adding the dispersant solution to edaravone particles. Other components such as a thickener and a sweetener may be added to the dispersant solution before dispersing the edaravone particles, or may be added simultaneously with dispersing the edaravone particles, or may be added after dispersing the edaravone particles. The timing of adding these components may differ depending on the component.

[0047] The suspension for oral administration of the present invention is preferably provided in a state in which the edaravone particles are suspended, as this reduces the number of operations required during administration. However, it may also be provided as a kit for preparation when used, in which the edaravone particles and water are separated. Such a form includes a kit for preparation of an edaravone suspension, which includes (A) a solid composition containing edaravone particles and (B) a dispersant solution. A kit for preparation when used can be expected to have longer storage stability than a pre-prepared suspension.

[0048] The solid composition containing (A) edaravone particles may be edaravone particles alone or may be a mixture with other components. The edaravone particles may be those used for preparing the suspension. Furthermore, the solid composition containing edaravone particles may be granulated by a known method to form fine granules or granules, or may be compressed and molded into tablets. The (B) dispersant solution may contain not only the dispersant used in the present invention but also other ingredients such as a thickener, a sweetener, etc. The suspension of the present invention is obtained by a medical professional mixing (A) and (B) and shaking them.

[0049] Furthermore, the suspension for oral administration of the present invention may be provided in the form of a solid composition that can be prepared immediately by simply adding water, i.e., a solid composition containing edaravone particles and a dispersing agent. Of course, this solid composition may contain other ingredients used in the suspension of the present invention, such as a thickener and a sweetener, and further, this solid composition may be granulated by a known method to form fine granules or granules, or may be compressed and formed into tablets. In this form, the suspension of the present invention can also be obtained by a healthcare professional mixing a solid composition containing edaravone particles and a dispersing agent with water and shaking the mixture.

[0050] The suspension of the present invention is administered by the intermittent administration method described in WO2005 / 75434 and currently used in clinical settings for the treatment of ALS using edaravone injections, i.e., an administration method in which an administration period and a withdrawal period are repeated two or more times as one unit. When the administration period and withdrawal period are repeated two or more times, the last period is always a withdrawal period, but it is not necessary to provide a final withdrawal period. That is, for example, when the administration period and withdrawal period are repeated twice, the system will be "administration period, withdrawal period, administration period, withdrawal period," but it may also be "administration period, withdrawal period, administration period" without a final withdrawal period.

[0051] The drug holiday period refers to a period of 7 or more consecutive days during which no drug is administered, and is preferably 14 days. The dosing period can be 14 days or 10 days out of 14 days. "10 days out of 14 days" means any 10 days out of 14 consecutive days, and these 10 days of dosing may be consecutive, or may be non-consecutive days separated by one or more periods of 1 to 4 days without dosing. A preferred dosing period can be selected while observing the patient's condition. More specifically, an example of such a method is to provide an initial 14-day drug-withdrawal period after an initial 14-day drug-withdrawal period, and then repeat a 10-day drug-withdrawal period during the 14 days. The number of times that the 10-day drug-withdrawal period and the 14-day drug-withdrawal period are repeated during the 14 days is not particularly limited, as long as it is at least once.

[0052] The daily dose during the dosing period of intermittent administration can be selected as appropriate depending on conditions such as the age and condition of the patient (e.g., severity of the disease), and generally, the dose of edaravone for an adult is 60 mg to 400 mg, preferably 60 mg to 300 mg, more preferably 90 mg to 210 mg, particularly preferably 90 mg, 100 mg, 105 mg, 180 mg, 200 mg or 210 mg, even more preferably 105 mg or 210 mg, and most preferably 105 mg.

[0053] Alternatively, the suspension of the present invention may be administered to a patient daily or repeatedly almost daily during the administration period. The daily dose can be appropriately selected depending on conditions such as the age and condition of the patient (e.g., severity of the disease), and generally, the dose of edaravone for an adult is 60 mg to 400 mg, preferably 60 mg to 300 mg, more preferably 90 mg to 210 mg, particularly preferably 90 mg, 100 mg, 105 mg, 180 mg, 200 mg, or 210 mg, even more preferably 105 mg or 210 mg, and most preferably 105 mg. Whether administered daily or intermittently, there is no limit to the number of doses per day, and a preferred number can be selected while observing the patient's condition. However, taking into consideration the burden on the patient, three, two, or one dose is preferred, with one dose being more preferred. Furthermore, since the suspension of the present invention can contain a high content of edaravone, the dosage of edaravone can be reduced to a small amount, which is advantageous for ALS patients with dysphagia. For example, the suspension of the present invention can be used to prepare a therapeutic agent for ALS in which the dosage per oral administration is 1 to 20 mL and the dosage contains 50 to 210 mg of edaravone.

[0054] Furthermore, the suspension of the present invention can also be used for diseases other than ALS that have been reported to be associated with oxidative stress, such as neurodegenerative diseases accompanied by motor dysfunction, such as Parkinson's disease and spinocerebellar degeneration, muscle diseases such as muscular dystrophy, intracerebral neurodegenerative diseases presenting with cognitive dysfunction, such as Alzheimer's disease, vascular disorders such as cerebral infarction, systemic inflammatory diseases such as multiple sclerosis and systemic sclerosis, and local inflammatory diseases such as stomatitis. [Example]

[0055] Next, the present invention will be specifically explained using examples and test examples, but the present invention is not limited thereto.

[0056] Example 1 200 mg of polyvinyl alcohol (Nippon Synthetic Chemical Industry, EG-05P) was dissolved in 200 mL of water to prepare a 0.1% (w / v) aqueous polyvinyl alcohol solution. 100 mg of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm) was dispersed in 10 mL of the aqueous polyvinyl alcohol solution to obtain an edaravone suspension for oral administration.

[0057] Example 2 200 mg of polyvinyl alcohol (Nippon Synthetic Chemicals, EG-05P) was dissolved in 200 mL of water, and 1000 mg of xanthan gum (Sansho, KELTROL-CG) was further dissolved in the resulting polyvinyl alcohol aqueous solution to prepare a 0.1% (w / v) polyvinyl alcohol / 0.5% (w / v) xanthan gum aqueous solution. 100 mg of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm) were dispersed in 10 mL of the polyvinyl alcohol / xanthan gum aqueous solution to obtain an edaravone suspension.

[0058] Example 3 200 mg of polyvinyl alcohol (Nippon Synthetic Chemicals, EG-05P) was dissolved in 200 mL of water, and 1000 mg of tragacanth powder (Suzu Powder Pharmaceuticals) was further dissolved in the resulting polyvinyl alcohol aqueous solution to prepare a 0.1% (w / v) polyvinyl alcohol / 0.5% (w / v) tragacanth powder aqueous solution. 100 mg of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm) were dispersed in 10 mL of the polyvinyl alcohol / tragacanth powder aqueous solution to obtain an edaravone suspension.

[0059] Example 4 200 mg of methylcellulose (Shin-Etsu Chemical, SM-25) was dissolved in 200 mL of water to prepare a 0.1% (w / v) aqueous methylcellulose solution. 100 mg of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm) was dispersed in 10 mL of the aqueous methylcellulose solution to obtain an edaravone suspension.

[0060] Example 5 200 mg of methylcellulose (Shin-Etsu Chemical, SM-25) was dissolved in 200 mL of water, and 1000 mg of xanthan gum (Tansho, KELTROL-CG) was further dissolved in the resulting methylcellulose solution to prepare a 0.1% (w / v) methylcellulose / 0.5% (w / v) xanthan gum solution. 100 mg of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm) were dispersed in 10 mL of the methylcellulose / xanthan gum solution to obtain an edaravone suspension.

[0061] Example 6 200 mg of methylcellulose (Shin-Etsu Chemical, SM-25) was dissolved in 200 mL of water, and 1000 mg of powdered tragacanth (Suzu Powder Pharmaceuticals) was further dissolved in the resulting methylcellulose solution to prepare a 0.1% (w / v) methylcellulose / 0.5% (w / v) aqueous solution of powdered tragacanth. 100 mg of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm) was dispersed in 10 mL of the methylcellulose / powdery tragacanth solution to obtain an edaravone suspension.

[0062] Example 7 200 mg of polyvinyl alcohol (Nippon Synthetic Chemical Industry, EG-05P) was dissolved in 200 mL of water, and 1600 mg of carmellose sodium (Daicel FineChem, CMC Daicel 1150) was further dissolved in the resulting polyvinyl alcohol aqueous solution to prepare a 0.1% (w / v) polyvinyl alcohol / 0.5% (w / v) carmellose sodium aqueous solution. 100 mg of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm) was dispersed in 10 mL of the polyvinyl alcohol / carmellose sodium aqueous solution to obtain an edaravone suspension.

[0063] Example 8 200 mg of polyvinyl alcohol (Nippon Synthetic Chemicals, EG-05P) was dissolved in 200 mL of water, and 160 g of dextrin (Nippon Sterilization Chemicals, Akadama No. 3) was further dissolved in the resulting polyvinyl alcohol aqueous solution to prepare a 0.1% (w / v) polyvinyl alcohol / 0.5% (w / v) dextrin aqueous solution. 100 mg of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm) was dispersed in 10 mL of the polyvinyl alcohol / dextrin aqueous solution to obtain an edaravone suspension.

[0064] Example 9 200 mg of methylcellulose (Shin-Etsu Chemical, SM-25) was dissolved in 200 mL of water, and 1600 mg of carmellose sodium (Daicel FineChem, CMC Daicel 1150) was further dissolved in the resulting methylcellulose solution to prepare a 0.1% (w / v) methylcellulose / 0.5% (w / v) carmellose sodium aqueous solution. 100 mg of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm) was dispersed in 10 mL of the methylcellulose / carmellose sodium aqueous solution to obtain an edaravone suspension.

[0065] Example 10 200 mg of methylcellulose (Shin-Etsu Chemical, SM-25) was dissolved in 200 mL of water, and 160 g of dextrin (Nitto Chemical, Akadama No. 3) was further dissolved in the resulting methylcellulose solution to prepare a 0.1% (w / v) methylcellulose / 0.5% (w / v) dextrin solution. 100 mg of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm) was dispersed in 10 mL of the methylcellulose / dextrin solution to obtain an edaravone suspension.

[0066] Example 11 40 mg of polyvinyl alcohol (Nippon Synthetic Chemical Industry, EG-05P), 20 mg of simethicone emulsion (Basildon, PD30S), and 800 mg of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm) were dissolved and dispersed in water to a volume of 40 mL to obtain an edaravone suspension for oral administration.

[0067] Example 12 An edaravone suspension for oral administration was prepared by dissolving and dispersing 40 mg of polyvinyl alcohol (Nippon Synthetic Chemical Industry, EG-05P), 20 mg of simethicone emulsion (Basildon, PD30S), 80 mg of xanthan gum (Sansho, KELTROL-CG), and 800 mg of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm) in water to a volume of 40 mL.

[0068] Example 13 An edaravone suspension for oral administration was obtained by dissolving and dispersing 40 mg of polyvinyl alcohol (Nippon Synthetic Chemical Industry, EG-05P), 20 mg of simethicone emulsion (Basildon, PD30S), 120 mg of xanthan gum (Sansho, KELTROL-CG), and 800 mg of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm) in water to a volume of 40 mL.

[0069] Example 14 An edaravone suspension for oral administration was prepared by dissolving and dispersing 40 mg of polyvinyl alcohol (Nippon Synthetic Chemical Industry, EG-05P), 20 mg of simethicone emulsion (Basildon, PD30S), 200 mg of xanthan gum (Sansho, KELTROL-CG), and 800 mg of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm) in water to a volume of 40 mL.

[0070] Example 15 An edaravone suspension for oral administration was obtained by dissolving and dispersing 40 mg of polyvinyl alcohol (Nippon Synthetic Chemical Industry, EG-05P), 20 mg of simethicone emulsion (Basildon, PD30S), 4 g of D-sorbitol, 40 mg of xanthan gum (Sansho, KELTROL-CG), and 800 mg of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm) in water to a volume of 40 mL.

[0071] Example 16 An edaravone suspension for oral administration was obtained by dissolving and dispersing 40 mg of polyvinyl alcohol (Nippon Synthetic Chemical Industry, EG-05P), 20 mg of simethicone emulsion (Basildon, PD30S), 4 g of D-sorbitol, 120 mg of xanthan gum (Sansho, KELTROL-CG), and 800 mg of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm) in water to a volume of 40 mL.

[0072] Example 17 An edaravone suspension for oral administration was obtained by dissolving and dispersing 40 mg of polyvinyl alcohol (Nippon Synthetic Chemical Industry, EG-05P), 20 mg of simethicone emulsion (Basildon, PD30S), 4 g of D-sorbitol, 200 mg of xanthan gum (Sansho, KELTROL-CG), and 800 mg of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm) in water to a volume of 40 mL.

[0073] Example 18 40 mg of polyvinyl alcohol (Nippon Synthetic Chemical Industry, EG-05P), 40 mg of sodium bisulfite, 20 mg of L-cysteine ​​hydrochloride hydrate, 20 mg of simethicone emulsion (Basildon, PD30S), 4 g of D-sorbitol, 120 mg of xanthan gum (Sansho, KELTROL-CG), and 800 mg of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm) were dissolved and dispersed in water to a volume of 40 mL, and appropriate amounts of sodium hydroxide and phosphoric acid were added to the resulting suspension to adjust the pH to 4.20, thereby obtaining an edaravone suspension.

[0074] Example 19 A preservative solution was prepared by dissolving 40 mg of benzoic acid, 2 mg of propylparaben, and 2 mg of butylparaben in 40 mg of ethanol. 40 mg of polyvinyl alcohol (Nippon Synthetic Chemical Industry, EG-05P), 40 mg of sodium bisulfite, 20 mg of L-cysteine ​​hydrochloride hydrate, 20 mg of simethicone emulsion (Basildon, PD30S), 4 g of D-sorbitol, 120 mg of xanthan gum (Sansho, KELTROL-CG), and 800 mg of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm) were dissolved and dispersed in water to a volume of 40 mL, followed by the addition of the preservative solution. The pH of the resulting suspension was adjusted to 4.20 with the addition of appropriate amounts of sodium hydroxide and phosphoric acid to obtain an edaravone suspension.

[0075] Example 20 200 mg of polyvinyl alcohol (EG-05P, Nippon Synthetic Chemical Industry Co., Ltd.) was dissolved in 200 mL of purified water to obtain a 0.1% (w / v) polyvinyl alcohol solution. 120 mg of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm) were dispersed in 10 mL of the polyvinyl alcohol solution to obtain an edaravone suspension.

[0076] Example 21 300 mg of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm) were dispersed in 10 mL of the 0.1% (w / v) polyvinyl alcohol solution obtained in Example 20 to obtain an edaravone suspension.

[0077] Example 22 200 mg of polyvinyl alcohol (Nippon Synthetic Chemical Industry, EG-05P) and 1,000 mg of xanthan gum (Sansho, KELTROL-CG) were dissolved in 200 mL of purified water to obtain a 0.1% (w / v) polyvinyl alcohol / 0.5% (w / v) xanthan gum solution. 300 mg of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm) were dispersed in 10 mL of the polyvinyl alcohol / xanthan gum solution to obtain an edaravone suspension.

[0078] Example 23 In Example 19, edaravone particles (edaravone powder, D50: 19 μm, D90: 73 μm) were used instead of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm), to obtain an edaravone suspension.

[0079] Example 24 In Example 19, edaravone particles (edaravone powder, D50: 32 μm, D90: 110 μm) were used instead of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm), to obtain an edaravone suspension.

[0080] Example 25 In Example 19, edaravone particles (edaravone powder, D50: 44 μm, D90: 204 μm) were used instead of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm), to obtain an edaravone suspension.

[0081] Example 26 Polyvinyl alcohol (Nippon Synthetic Chemical Industry, EG-05P) 40 mg, sodium bisulfite 40 mg, L-cysteine ​​hydrochloride hydrate 20 mg, simethicone emulsion (Basildon, PD30S) 20 mg, D-sorbitol 16 g, xanthan gum (Sansho, KELTROL-CG) 120 mg, and 840 mg of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm) were dissolved and dispersed in water to a volume of 40 mL, and appropriate amounts of sodium hydroxide and phosphoric acid were added to the resulting suspension to adjust the pH to 4.20, thereby obtaining an edaravone suspension.

[0082] Example 27 In Example 26, edaravone particles (edaravone powder, D50: 17 μm, D90: 64 μm) were used instead of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm) to obtain an edaravone suspension.

[0083] Example 28 In Example 26, edaravone particles (edaravone powder, D50: 21 μm, D90: 79 μm) were used instead of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm), to obtain an edaravone suspension.

[0084] Example 29 In Example 26, edaravone particles (edaravone powder, D50: 31 μm, D90: 124 μm) were used instead of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm), to obtain an edaravone suspension.

[0085] Example 30 In Example 26, edaravone particles (edaravone powder, D50: 46 μm, D90: 185 μm) were used instead of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm) to obtain an edaravone suspension.

[0086] Example 31 In Example 26, 200 mg of powdered tragacanth (Suzu Powdered Pharmaceuticals) was used instead of 120 mg of xanthan gum (Tansho, KELTROL-CG) to obtain an edaravone suspension.

[0087] Test Example 1 (Selection of Dispersant) A 0.1% (w / v) aqueous solution of each of the formulation additives listed in the table below, which are generally known as substances capable of dispersing solid particles in a liquid, was prepared at room temperature. 50 mL of each aqueous solution of the additives was added to 3600 mg of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm), and the mixture was stirred with a stirrer. The results are shown in the table below. [Table 1] The results in the above table show that only polyvinyl alcohol, methyl cellulose, sucrose fatty acid ester, and hypromellose can disperse edaravone particles favorably in water.

[0088] Test Example 2 (Transmitted Scattered Light Intensity Test) A 0.1% (w / v) aqueous solution of each of the formulation additives listed in the table below, which are generally known as substances capable of dispersing solid particles in a liquid, was prepared at room temperature. To 840 mg of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm), 40 mL of each of the aqueous additive solutions was added and stirred with a stirrer for 30 minutes or more, and the dispersion state of the edaravone particles was confirmed. Furthermore, 20 mL of the dispersion obtained above was filled into a sample bottle (inner diameter 25 mm x outer diameter 27.5 mm x height 72 mm), and measurement of the transmitted scattered light intensity ΔT% at a sample bottle height of 39 to 40 mm was started using a TURBISCAN Tower (manufactured by Formulaction) (set at 25°C), and the value 10 minutes after the start of measurement was taken as the transmitted scattered light intensity ΔT% of each additive. The transmitted scattered light intensity ΔT% of each additive and the dispersion state of edaravone particles in each additive solution are shown in the table below. [Table 2] The results in the above table show that dispersants that can suitably disperse edaravone particles have a transmitted scattered light intensity ΔT% of 1% or more.

[0089] Test Example 3 (Contact Angle Test) 120 mg of edaravone bulk drug (D50: 37 μm, D90: 143 μm) was compression molded (punch: 8 mm diameter flat punch, tableting pressure: 800 kgf) using a single punch tableting machine (compaction analyzer) to obtain edaravone tablets for contact angle measurement. A saturated aqueous solution of edaravone was prepared at room temperature by dissolving 0.1% (w / v) of the formulation additives shown in the table below, which are generally known as substances capable of dispersing solid particles in a liquid, and the contact angle of the edaravone tablet prepared above was measured using a contact angle measuring device (Kyowa Interface Science, CAX-150). The results are shown in the table below. Syringe used: glass, 1 mL Needle: 23 gauge Liquid volume: 1 μL Measurement time: after 3.1 seconds [Table 3] From the above results and the results of Test Example 1 or 2, it can be seen that edaravone can be suitably dispersed in water if the substance exhibits a contact angle of 80° or less with an edaravone tablet when saturated with an aqueous edaravone solution containing 0.1% (w / v) of an additive.

[0090] Test Example 4 (Stability) 5 mL of each of the edaravone suspensions prepared in Examples 1 to 10 was placed in a glass bottle, sealed, and stored at 60°C for 4 weeks. After 4 weeks, the amount of edaravone related substances in each suspension was measured according to the Purity Test Related Substances (i) described in the Japanese Pharmacopoeia for Edaravone Injection. The results are shown in the table below. [Table 4] The above results show that, although the production of edaravone analogues was small in any of Examples 1 to 10, the production of analogues was particularly small in the suspensions of Examples 1 to 6, which used xanthan gum or tragacanth powder as a thickener.

[0091] Test Example 5 (Content Uniformity Test) From each of the edaravone suspensions (40 mL) obtained in Examples 11 to 14, 5 mL of suspension was extracted seven times using a syringe, and the edaravone content in each 5 mL of the extracted suspension was measured. The results are shown below (the values ​​in the table are relative values ​​(%) to the original amount of edaravone contained in 5 mL, 100 mg). [Table 5] Although content uniformity was ensured in all suspensions, the suspensions of Examples 12 to 14, which contained a thickener, showed particularly favorable content uniformity.

[0092] Test Example 6 (Redispersibility Test) The suspensions obtained in Examples 15 to 17 were centrifuged and subjected to a gravity of 4000 g for 6.6 hours to forcibly sediment the edaravone particles. After centrifugation, the suspensions were gently shaken by hand. The edaravone particles were redispersed within 10 seconds for the suspensions of Examples 15 and 16, and within 40 seconds for the preparation of Example 17. The gravity conditions were equivalent to those observed when the suspensions were stored for 3 years.

[0093] Test Example 7 (Preservative Effectiveness Test) A preservative effectiveness test was carried out according to the Japanese Pharmacopoeia using the suspensions obtained in Examples 18 and 19. Although the suspension of Example 18 did not contain a preservative, it exhibited preservative effectiveness equivalent to that of the suspension of Example 19, which contained a preservative. [Table 6]

[0094] Test Example 8 The edaravone suspensions (10 mL) obtained in Examples 20, 21, and 22 were orally administered to six healthy adult males in a fasting state. Blood samples were taken before administration and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, and 48 hours after administration, and the plasma concentration of unchanged edaravone was measured. The obtained PK profiles are shown in the following table. [Table 7] Cmax and AUC of Example 20 (Edaravone 120 mg) 0-24h The Cmax (1049 ng / mL) and AUC of edaravone injection (60 mg) were reported in Amyotroph Lateral Scler Frontotemporal Degener. 2017;18(suppl 1):80-87. 0-24h This significantly exceeds the bioavailability (1374 h*ng / mL), demonstrating that the suspension of the present invention has excellent bioavailability as a formulation for oral administration. Furthermore, a comparison of the PK profiles of Examples 21 and 22 shows that the addition of a thickener reduces the variability in plasma concentrations of edaravone among subjects, meaning that stable efficacy can be expected.

[0095] Test Example 9 (1) (Dissolution test) The suspensions prepared in Examples 19, 23, 24, and 25 were subjected to a dissolution test in accordance with Method 2 (paddle method) of the Japanese Pharmacopoeia Dissolution Test. Dissolution medium: Japanese Pharmacopoeia Dissolution Test Solution 1 (pH 1.2) or Solution 2 (pH 6.8), 900 ml Measurement method: Absorbance at a wavelength of 240 nm Paddle rotation speed: 50 rpm Sample size: n=3 The dissolution rate of edaravone 30 minutes after the start of the test and the similarity of the dissolution profile between the formulation of Example 19, which was used as the reference formulation, and the other Examples were calculated using the F2 function at 15, 30, and 45 minutes in accordance with the generic drug bioequivalence guidelines. The results are shown in the table below. The smaller the particle size of edaravone used in preparing the edaravone suspension, the faster the dissolution, indicating that the dissolution rate can be controlled by changing the particle size of the edaravone particles. On the other hand, the F2 function values ​​show that in the first fluid (pH 1.2), the formulations of Examples 23 to 25 exhibited dissolution profiles bioequivalent to the formulation of Example 19, and in the second fluid (pH 6.8), the formulations of Examples 23 and 24 exhibited dissolution profiles bioequivalent to the formulation of Example 19.

[0096] [Table 8]

[0097] Test Example 9 (2) (Dissolution test) The suspensions prepared in Examples 27 to 30 were subjected to a dissolution test in accordance with Method 2 (paddle method) of the Japanese Pharmacopoeia Dissolution Test. Eluent: 0.05 mol / L acetic acid / sodium acetate buffer (pH 4.0), 900 ml Measurement method: Absorbance at a wavelength of 240 nm Paddle rotation speed: 50 rpm Sample size: n=3 The dissolution rate of edaravone 30 minutes after the start of the test and the similarity of the dissolution profile between the formulation of Example 29, which was used as the reference formulation, and the other Examples were calculated using the F2 function in accordance with the generic drug bioequivalence guidelines, with 15, 30, and 45 minutes as the dissolution rate comparison time points. The results are shown in the table below. The smaller the particle size of edaravone used in preparing the edaravone suspension, the faster the dissolution, and it can be seen that the dissolution rate can be controlled by changing the particle size of the edaravone particles. On the other hand, the F2 function values ​​show that the formulations of Examples 27, 28, and 30 exhibit dissolution profiles bioequivalent to the formulation of Example 29.

[0098] [Table 9]

[0099] Test Example 10 (Bioequivalence Test) An open-label, single-dose, randomized crossover study was conducted on the suspension obtained in Example 26 in 42 healthy Japanese subjects, using edaravone injection as the control drug. The edaravone suspension of Example 26 was administered by gently shaking the glass bottle containing the suspension, then drawing out 5 mL (105 mg of edaravone) with a syringe for oral administration, and orally administering this to the subject in a fasting state. Edaravone injection was administered by intravenously injecting 200 mL of edaravone injection (Radicut injection) (60 mg of edaravone) over one hour to subjects in a fasting state. The PK profiles of unchanged edaravone in plasma after administration of the suspension described in Example 26 and after administration of the edaravone injection are shown in the following table and FIG. [Table 10] Furthermore, the results of the bioequivalence evaluation of the formulation of Example 26 to the edaravone injection are shown in the table below. [Table 11] Cmax or AUC when administered with the Example 26 formulation compared to when administered with edaravone injection 0-∞ The ratio of the geometric mean values ​​of Cmax and AUC 0-∞ All were within the range of 0.8 to 1.25. The 90% confidence interval for the ratio of the geometric mean values ​​was AUC 0-∞ The lower limit of Cmax was within the range of 0.8 to 1.25, but the upper limit exceeded the range. [Industrial Applicability]

[0100] The edaravone suspension of the present invention is particularly useful as a therapeutic agent for ALS, and therefore the present invention has industrial applicability.

Claims

1. An edaravone suspension for oral administration to humans, comprising edaravone particles, a dispersant and water.

2. 2. The suspension according to claim 1, wherein the dispersant exhibits a transmitted scattered light intensity of 1% or more.

3. 2. The suspension according to claim 1, wherein the dispersant has a contact angle of 80° or less.

4. 2. The suspension according to claim 1, wherein the dispersing agent is one or two selected from polyvinyl alcohol, methylcellulose, hypromellose, sucrose fatty acid esters, and polysorbates.

5. 5. The suspension according to claim 4, wherein the dispersing agent is one or two selected from polyvinyl alcohol and methyl cellulose.

6. 6. A suspension according to claim 4 or 5, wherein the dispersing agent is polyvinyl alcohol.

7. The polyvinyl alcohol has a saponification degree of 86.5 to 89.0 and a kinematic viscosity of a 4% aqueous solution at 20°C of 3 mm ２ / s ~ 55.7 mm ２ The suspension according to any one of claims 4 to 6, wherein the suspending agent is / s.

8. 8. The suspension according to claim 1, wherein the amount of the dispersant is 0.001% (w / v) to 1.0% (w / v).

9. The suspension according to any one of claims 1 to 8, further comprising a thickener.

10. 10. The suspension according to claim 9, wherein the thickener is one or two selected from the group consisting of xanthan gum and powdered tragacanth.

11. 11. A suspension according to claim 9 or 10, wherein the thickening agent is xanthan gum.

12. The suspension according to any one of claims 9 to 11, wherein the amount of the thickener is 0.1% (w / v) to 1.2% (w / v).

13. The suspension according to any one of claims 1 to 12, wherein the edaravone particles in the suspension have a D50 particle size of 10 µm to 100 µm and a D90 particle size of 50 µm to 300 µm.

14. The suspension according to any one of claims 1 to 13, wherein the amount of edaravone particles blended is 0.06% (w / v) to 36% (w / v).

15. 15. The suspension according to any one of claims 1 to 14, further comprising one or more additives selected from sweeteners, stabilizers and pH adjusters.

16. 16. The suspension according to any one of claims 1 to 15, wherein the viscosity of the suspension is from 50 mPa·s to 1750 mPa·s.

17. 17. The suspension according to any one of claims 1 to 16, wherein the density of the suspension is 1 g / mL to 1.5 g / mL.

18. The suspension according to any one of claims 1 to 17, wherein when a dissolution test is performed in accordance with the Japanese Pharmacopoeia (test solution: first solution, paddle rotation speed: 50 rpm), the dissolution rate of edaravone is 80% or more 30 minutes after the start of the test.

19. The following (A) and (B): (A) Solid composition containing edaravone particles (B) Dispersant solution A kit for preparing an edaravone suspension for oral administration to humans, comprising:

20. When 90 to 120 mg of edaravone was orally administered to humans, the mean Cmax of edaravone in plasma was 500 to 2500 ng / mL, and the mean AUC ０－∞ An edaravone suspension for oral administration to humans, which exhibits a serotonin concentration of 1000 to 2500 h*ng / mL.

21. In a crossover study in which a suspension containing 90-120 mg of edaravone was orally administered to humans using edaravone injection as a control, the 90% confidence interval lower limit of the ratio of the geometric mean Cmax to the control formulation and the AUC ０－∞ An edaravone suspension for oral administration to humans, in which all of the lower limits of the 90% confidence intervals of the ratios of the geometric means exceed 0.

8.

22. In a crossover study in which a suspension containing 90-120 mg of edaravone was orally administered to humans using edaravone injection as a control, the geometric mean Cmax ratio and AUC ratio were compared. ０－∞ An edaravone suspension for oral administration to humans, wherein all of the geometric mean value ratios are between 0.8 and 1.

25.

23. A therapeutic agent for ALS, characterized in that the dosage of the formulation per oral administration is 1 to 20 mL, and the dosage contains 50 to 210 mg of edaravone.

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