Pharmaceutical composition for oral administration of edaravone and method of administering the same

Abstract

To provide a pharmaceutical composition for oral administration or similar administration containing edaravone as an active ingredient, and to provide a method of administering the same in oral administration or similar administration.SOLUTION: A pharmaceutical composition of the present invention contains edaravone represented by the following formula as an active ingredient, and is orally or intragastrically administered at a first-time interval selected from the group consisting of 1) to 3): 1) 8 hours or more after ingestion of a high-fat meal; 2) 4 hours or more after ingestion of a normal meal; and 3) 2 hours or more after ingestion of a light meal.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition for oral or intragastric administration, which contains edaravone as an active ingredient, and a method for administering the same. [Background technology]

[0002] Edaravone is 3-methyl-1-phenyl-2-pyrazolin-5-one represented by the following formula, and is known to have medicinal uses as a therapeutic agent for oxidative stress diseases such as amyotrophic lateral sclerosis (ALS) and as an agent for normalizing brain function (Patent Documents 1 and 2). [ka]

[0003] ALS is an intractable disease that begins with initial symptoms such as weakness of the hands, motor impairment of the fingers, and fascicle spasms of the upper limbs, and progresses to muscle atrophy, muscle weakness, bulbar paralysis, and muscle fascicle spasms, eventually leading to respiratory failure. ALS is classified into upper limb type, bulbar type, lower limb type, and mixed type depending on the site of onset, and in all types, the muscles of the entire body are affected as the symptoms progress. The etiology of ALS has not yet been fully elucidated, but the main hypotheses proposed as causes of the disease include (1) autoimmune hypothesis (appearance of autoantibodies against Ca channels), (2) excitatory amino acid excess and intoxication hypothesis (increase in extracellular glutamate and impaired transport of glutamate), (3) oxidative stress disorder hypothesis (neuronal cell damage caused by Cu / Zn superoxide dismutase (SOD) gene abnormalities and free radicals), (4) cytoskeletal disorder hypothesis (accumulation of neurofilament in motor neurons and appearance of inclusion bodies), and (5) deficiency of neurotrophic factors.

[0004] Currently, edaravone is used as a representative example of an ALS treatment, but for this purpose, it is only available in the form of an injection. For this reason, there is a demand for an oral formulation that places less of a burden on patients and caregivers and is favorable in terms of QOL. Thus, the development of an oral formulation of edaravone is being advanced through clinical trials, etc. (Patent Document 3). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Special Publication No. 5-31523 [Patent Document 2] Patent No. 3758164 [Patent Document 3] WO2020 / 091036 issue [Non-patent literature]

[0006] [Non-Patent Document 1] Pharmaceutical Research, Vol. 22, No. 1, 11-23, 2005 Summary of the Invention [Problem to be solved by the invention]

[0007] On the other hand, in general, when it comes to therapeutic agents for oxidative stress diseases, even if the same drug is used, the conditions under which the drug can effectively exert its effects may differ depending on the administration method. As for the oral formulation of edaravone, it is still under development, and the conditions under which it can exert the same effect as the injection formulation have not yet been clarified.

[0008] Therefore, an object of the present invention is to provide a pharmaceutical composition containing edaravone as an active ingredient for oral administration or administration equivalent thereto. [Means for solving the problem]

[0009] The pharmaceutical composition of the present invention contains edaravone as an active ingredient, and is administered at a first time interval selected from the group consisting of 1) to 3) below: 1) If you have consumed a high-fat meal, wait at least 8 hours after ingestion. 2) If you have eaten regular food, it should be taken at least 4 hours after ingestion. 3) If you have consumed light meals, wait at least 2 hours after ingestion. The present invention is characterized in that the drug is administered orally or intragastricly with a gap therebetween.

[0010] The method for administering the pharmaceutical composition containing edaravone of the present invention comprises administering the pharmaceutical composition containing edaravone as an active ingredient at a first time interval selected from the group consisting of 1) to 3) below: 1) If you have consumed a high-fat meal, wait at least 8 hours after ingestion. 2) If you have eaten regular food, it should be taken at least 4 hours after ingestion. 3) If you have consumed light meals, wait at least 2 hours after ingestion. The present invention is characterized in that the drug is administered orally or intragastricly with a gap therebetween.

[0011] The present inventors have discovered the present invention through the following circumstances. However, these descriptions are not intended to particularly limit the present invention.

[0012] Food-drug interactions can have a significant impact on drug safety and efficacy. For example, administering a drug with food can increase systemic absorption of the drug, altering its pharmacokinetics and improving efficacy or increasing the incidence of side effects. It can also decrease systemic absorption and therefore efficacy.

[0013] On the other hand, Wu et al. reported that when drugs showing high solubility and high permeability, classified as BCS class 1, are orally administered, food intake has little effect on pharmacokinetics, such as bioavailability (Non-Patent Document 1).

[0014] The inventors have confirmed that edaravone is classified as a high solubility compound because the amount of water required to dissolve 1 g of edaravone is 500 mL (Radicut Pharmaceutical Interview Form (revised in June 2017 (20th edition)) and the amount of water required to dissolve 105 mg of edaravone is calculated to be 52.5 mL. Furthermore, the inventors have confirmed that edaravone is classified as a high permeability compound based on the results of a membrane permeability test using Caco-2 cells shown in Example 3 below. Therefore, edaravone is considered to be a BCS Class 1 drug classified as high solubility and high permeability in the above report by Wu et al. For this reason, it has been speculated that edaravone is a compound whose pharmacokinetics are not affected by food intake.

[0015] However, despite this, it has become clear that the ingestion of a meal before administration affects the pharmacokinetics of edaravone, as shown in the Examples described below. As a result of further intensive research, the present inventors have newly found that the effects on the pharmacokinetics of edaravone differ not only depending on the presence or absence of a meal, but also depending on the type of meal, and further that there is an appropriate administration timing for each type of meal, which has led to the completion of the present invention. Effect of the Invention

[0016] According to the present invention, the first time interval from after a meal to administration can be optimized for each type of meal, so that whether edaravone is administered orally or intragastricly, the influence of food on pharmacokinetics such as bioavailability can be avoided. Therefore, similar to the conventional administration method of intravenous injection, the pharmaceutical composition of the present invention can exhibit excellent therapeutic effects against oxidative stress diseases as an agent for oral administration (hereinafter also referred to as oral agent) or an agent for intragastric administration (hereinafter also referred to as intragastric agent). In addition, since the pharmaceutical composition of the present invention can be administered orally or intragastricly, the burden on patients and caregivers can be further reduced. [Brief description of the drawings]

[0017] [Figure 1] The spaghetti plot shows the Cmax after oral administration of edaravone in a fasting group, a group administered 8 hours after ingestion of a high-fat meal, a group administered 4 hours after ingestion of a normal meal, and a group administered 2 hours after ingestion of a light meal. The circles and solid lines indicate individual values, and the crosses and dotted lines indicate the average values. [Diagram 2] A spaghetti plot comparing AUC0-1h and AUC1h-∞ after oral administration of edaravone between the high-fat meal intake group and the fasting administration group at 1 hour after administration is shown. Circles and solid lines indicate individual values, and crosses and dotted lines indicate average values. [Diagram 3] Box plot (Study #9) and individual plots (Studies #5, #6, #9) of AUC0-∞ and Cmax after oral administration of edaravone are shown. Circles indicate individual values, and crosses indicate average values. In the box plot, the top and bottom of the whiskers indicate the maximum and minimum values, and the upper, middle, and lower limits of the box indicate the 25th, 50th, and 75th percentile values, respectively. [Figure 4] Individual value plots of AUC0-∞ versus edaravone dose and curves regressed by a four-parameter logistic model are shown. Individual values ​​in Study #7 are shown as circles, and individual values ​​in Study #8 are shown as squares. The AUC0-∞ of edaravone administered intravenously is shown as a dotted line using the value at 60 mg / 60 min administration. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] An aspect of the present invention is as follows.

[0019] In the pharmaceutical composition of the present invention, for example, the second time interval from administration of edaravone to ingestion of the next meal is 30 minutes or longer.

[0020] In the pharmaceutical composition of the present invention, for example, the second time interval from administration of edaravone to ingestion of the next meal is 1 hour or longer.

[0021] The pharmaceutical composition of the present invention is, for example, for oral administration.

[0022] The pharmaceutical composition of the present invention is, for example, for intragastric administration.

[0023] In the pharmaceutical composition of the present invention, for example, the intragastric administration is administration via a tube.

[0024] In the pharmaceutical composition of the present invention, for example, the tube is a gastrostomy catheter or a nasogastric catheter.

[0025] The pharmaceutical composition of the present invention is, for example, a pharmaceutical composition for treating an oxidative stress disease.

[0026] In the pharmaceutical composition of the present invention, for example, the oxidative stress disease is any one disease selected from the group consisting of amyotrophic lateral sclerosis, Parkinson's disease, spinocerebellar degeneration, muscular dystrophy, Alzheimer's disease, cerebral infarction, multiple sclerosis, systemic sclerosis, and stomatitis.

[0027] In the pharmaceutical composition of the present invention, for example, the oxidative stress disease is amyotrophic lateral sclerosis.

[0028] In the pharmaceutical composition of the present invention, for example, the first time interval is a time interval during a dosing period of intermittent administration or daily administration.

[0029] The pharmaceutical composition of the present invention contains 90 to 120 mg of edaravone per dose, for example.

[0030] The pharmaceutical composition of the present invention contains edaravone in a single dose of 90 to 105 mg, for example.

[0031] The pharmaceutical composition of the present invention is administered once a day, for example, with a single dose of 105 mg of edaravone.

[0032] In the method of administering the pharmaceutical composition of the present invention, for example, the second time interval from administration of the pharmaceutical composition to the intake of the next meal is 30 minutes or more.

[0033] In the method of administering the pharmaceutical composition of the present invention, for example, the second time interval from administration of edaravone to intake of the next meal is 1 hour or longer.

[0034] The method for administering the pharmaceutical composition of the present invention includes, for example, orally administering the pharmaceutical composition.

[0035] The method for administering the pharmaceutical composition of the present invention is, for example, administering the pharmaceutical composition intragastrically.

[0036] In a method for administering the pharmaceutical composition of the present invention, for example, the intragastric administration is administration by a tube.

[0037] The pharmaceutical composition of the present invention is administered, for example, through a gastrostomy catheter or a nasogastric catheter.

[0038] The method for administering the pharmaceutical composition of the present invention involves, for example, administering the pharmaceutical composition for the purpose of treating an oxidative stress disease.

[0039] The method of administering the pharmaceutical composition of the present invention is, for example, when the oxidative stress disease is any one disease selected from the group consisting of amyotrophic lateral sclerosis, Parkinson's disease, spinocerebellar degeneration, muscular dystrophy, Alzheimer's disease, cerebral infarction, multiple sclerosis, systemic sclerosis, and stomatitis.

[0040] In the method of administering the pharmaceutical composition of the present invention, for example, the oxidative stress disease is amyotrophic lateral sclerosis.

[0041] In the method of administering the pharmaceutical composition of the present invention, for example, administration of the pharmaceutical composition includes intermittent administration or daily administration, and the pharmaceutical composition is administered at the first time interval during the dosing period of the intermittent administration or daily administration.

[0042] In the method of administering the pharmaceutical composition of the present invention, for example, the dosage of the pharmaceutical composition per administration is 90 to 120 mg of edaravone.

[0043] In the method of administering the pharmaceutical composition of the present invention, for example, the dosage of the pharmaceutical composition per administration is 90 to 105 mg of edaravone.

[0044] The method for administering the pharmaceutical composition of the present invention is, for example, such that the pharmaceutical composition is administered once per day and the dosage of the pharmaceutical composition per administration is 105 mg of edaravone.

[0045] The present invention will be described below with reference to specific examples, but is not limited to these examples. The pharmaceutical composition of the present invention can be used in the administration method of the present invention, and the descriptions of the pharmaceutical composition of the present invention and the descriptions of the administration method of the present invention can be mutually incorporated.

[0046] In the present invention, the "first time interval" means the time from ingestion of a meal to administration, and can be rephrased as, for example, a "pre-administration time interval" or a "post-prandial / pre-administration time interval," and the "second time interval" means the time from administration to ingestion of a meal, and can be rephrased as, for example, a "post-administration time interval" or a "post-administration / pre-prandial time interval." The notations "1" and "2" in the "first time interval" and "second time interval" are used to formally distinguish two types of time intervals, pre-administration and post-administration, and do not, for example, limit the order.

[0047] As described above, the pharmaceutical composition of the present invention and the administration method of the present invention are characterized by the administration timing condition of administration after a meal at a first time interval of any one of 1) to 3) according to the type of meal, and other conditions and steps are not particularly limited. Specifically, the effect of the present invention, that is, the excellent effect of avoiding the influence of meals on the pharmacokinetics of edaravone, is due to the administration timing. Therefore, for example, the content and composition of edaravone in the pharmaceutical composition of the present invention are not particularly limited. In the present invention, the type of meal can be classified, for example, based on calories.

[0048] In this specification, "oral administration" means administering a drug through the mouth, and "intragastric administration" means administering a drug directly to the stomach. The pharmaceutical composition of the present invention is a pharmaceutical composition used for such oral administration or intragastric administration. In the use of the pharmaceutical composition of the present invention and in the drug administration method of the present invention, for example, when an apparatus or device is used for oral administration or intragastric administration, the type is not particularly limited. In the case of intragastric administration, for example, a tube such as a feeding tube (hereinafter sometimes referred to as a tube for feeding, nutrition, or feed tube) can be used, and the tube is also called, for example, a catheter. Intragastric administration using the tube is also called, for example, tube administration or intragastric tube administration. Examples of intragastric administration include administration via a gastrostomy tube and nasogastric administration. The administration via a gastrostomy tube is, for example, a method in which a hole is made on the surface of the abdomen to directly feed nutrition to the stomach (a gastrostomy tube is constructed), the tube is passed through the hole (gastrostomy tube), and the drug is directly administered into the stomach. Examples of the tube used for administration via the gastrostomy include a gastrostomy catheter (hereinafter, may be referred to as a gastrostomy tube, a feeding tube, a feeding connection tube, a connection tube, a Percutaneous Endoscopic Gastrostomy (PEG) catheter, or a Percutaneous Endoscopic Gastrostomy (PEG) tube). The nasogastric administration is, for example, a method of passing a tube from the nose into the stomach and administering a drug directly into the stomach. Examples of the tube used for the nasogastric administration include a nasogastric catheter (hereinafter, may be referred to as a nasogastric tube, a nasogastric feeding tube, a nasogastric tube, a nasogastric tube, a feeding catheter, a nasogastric feeding catheter, a gastric tube catheter, a gastric catheter, or a Nasopharyngeal Gastric (NG) tube). When used for intragastric administration via the tube, the pharmaceutical composition of the present invention is also referred to as, for example, a "tube-feeding agent".

[0049] As described above, the pharmaceutical composition of the present invention contains edaravone as an active ingredient, and is characterized in that it is administered orally or intragastricly at an optimal first time interval selected from the group consisting of 1) to 3) for each type of meal.

[0050] The composition of the pharmaceutical composition of the present invention may contain edaravone as an active ingredient, and other components are not particularly limited. The pharmaceutical composition of the present invention may contain, for example, only the active ingredient, or may contain the active ingredient and other additives. The active ingredient may be, for example, only edaravone, or may be a combination of edaravone and other drugs. In the pharmaceutical composition of the present invention, the form of edaravone is not particularly limited, and examples thereof include particulates (hereinafter also referred to as edaravone particles). The other additives are not particularly limited, and examples thereof include dispersants such as polyvinyl alcohol and sucrose fatty acid esters, thickeners such as xanthan gum and powdered tragacanth, sweeteners such as sorbitol, stabilizers such as sodium hydrogen sulfite and L-cysteine ​​hydrochloride, pH regulators such as phosphoric acid, acetic acid, and sodium hydroxide, antifoaming agents such as simethicone emulsion, excipients such as glucose and starch, solvents, flavors, etc. The solvents include, for example, aqueous solvents such as water, buffer solutions, and saline, and oily solvents such as olive oil, etc.

[0051] Specific examples of the pharmaceutical composition of the present invention include a suspension containing edaravone particles, a dispersant, and water. The suspension is also referred to as an edaravone suspension for oral administration (hereinafter, sometimes referred to as "edaravone oral agent") or an edaravone suspension for intragastric administration (hereinafter, sometimes referred to as "edaravone intragastric agent"). Hereinafter, with respect to the pharmaceutical composition of the present invention, the oral agent can be read as an intragastric agent, and the intragastric agent can be read as an oral agent. As described above, the pharmaceutical composition of the present invention is characterized by the administration timing, and its composition is not limited. For this reason, the details of the composition of the pharmaceutical composition of the present invention can be cited, for example, in the contents described in WO2020 / 091036, and can be produced by the method described in WO2020 / 091036. The subject to which the pharmaceutical composition of the present invention is administered is, for example, a human or a non-human animal, and preferably a human. Non-human animals include, for example, mice, rats, rabbits, horses, etc.

[0052] The form of the pharmaceutical composition of the present invention is not particularly limited, and can be, for example, a form suitable for oral administration, a form suitable for intragastric administration, or a form applicable to both oral administration and intragastric administration.The form is, for example, liquid, gel, solid, etc.In the case of liquid, for example, liquid agent, suspension agent, etc., in the case of gel, for example, jelly agent, etc., in the case of solid, for example, tablet, capsule, powder, fine granule, granule, etc. can be exemplified.In the present invention, the preferred form is liquid, and among them, suspension agent is preferred.

[0053] Examples of embodiments of the pharmaceutical composition of the present invention include compositions (1) to (5) exemplified below, with composition (1) being preferred, but 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), powdered tragacanth (thickening agent), sorbitol (sweetener), sodium hydrogen sulfite (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 hydrogen sulfite (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.

[0054] More specifically, the composition of (1) above may be, for example, a suspension having the following composition. The suspension having the following composition has a total volume of 5 mL, an edaravone content of 105 mg, and is, for example, in the form of a liquid. However, the present invention is not limited thereto. 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 bisulfite (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 pH: 2.5~6.0

[0055] As described above, the pharmaceutical composition of the present invention can avoid the influence of food intake on the pharmacokinetics of edaravone when edaravone is administered orally or intragastricly by changing the administration timing according to the type of food, i.e., by setting the first time interval from food intake to administration to the condition 1), 2), or 3). In the present invention, "avoiding the influence of food intake on the pharmacokinetics of edaravone" means, for example, maintaining the same pharmacokinetics as when a pharmaceutical composition containing edaravone is administered under fasting conditions (for example, fasting for 10 hours or more). Specifically, for example, when the same pharmaceutical composition containing edaravone is administered by the same administration method, oral or intragastric administration, the pharmacokinetics when administered under the condition 1), 2), or 3) according to food maintains the same pharmacokinetics as when administered under the fasting condition. In addition, "the same pharmacokinetics" means, for example, that the pharmacokinetics of the target is completely the same or in a range without significant difference. As a specific example, for example, the edaravone concentration in the plasma of a subject is measured for a predetermined period before and after administration of a pharmaceutical composition containing edaravone. The maximum plasma concentration (Cmax) and area under the curve (AUC) of edaravone are compared with Cmax and AUC when fasted for 10 hours or more, and the distribution of individual values ​​is not significantly changed, or the statistical level is the same as the general bioequivalence standard (for example, the least squares mean ratio and its 90% confidence interval are in the range of 0.8-1.25). Therefore, according to the present invention, by orally or intragastricly administering a pharmaceutical composition containing edaravone at the optimal administration interval of 1) to 3) for each type of meal, the same pharmacokinetics as when the pharmaceutical composition is administered under fasting conditions can be maintained, regardless of the formulation of the pharmaceutical composition.

[0056] The pharmaceutical composition of the present invention can be administered orally or intragastricly when a meal is ingested, for example, at a first time interval selected from the group consisting of 1) to 3) below, depending on the type of meal, as described above. 1) If you have consumed a high-fat meal, wait at least 8 hours after ingestion. 2) If you have eaten regular food, it should be taken at least 4 hours after ingestion. 3) If you have consumed light meals, wait at least 2 hours after ingestion.

[0057] In certain embodiments, the pharmaceutical composition of the present invention can be administered orally or intragastricly, for example, when a meal is ingested, at a first time interval selected from 2) or 3) above, depending on the type of meal.

[0058] Furthermore, the pharmaceutical composition of the present invention can further effectively maintain the pharmacokinetics of edaravone by, for example, adjusting the second time interval from administration to the next meal intake. The pharmaceutical composition of the present invention may be administered with, for example, a second time interval of 30 minutes or more, preferably 1 hour or more or 2 hours or more between administration of the composition and the next meal intake. Specifically, the pharmaceutical composition of the present invention may be administered with, for example, a time interval of 30 minutes or more, 1 hour or more or 2 hours or more between administration and the next meal intake. Note that, in the present invention, the length of the second time interval after administration is not limited, for example, by the type of the next meal.

[0059] In certain embodiments, the pharmaceutical composition of the present invention can be administered orally or intragastricly, for example, when a meal is ingested, after a first time interval of any one of the group consisting of 1) to 3) above depending on the type of meal, and after a second time interval of 30 minutes or more until the next meal is ingested.

[0060] In a certain embodiment, the pharmaceutical composition of the present invention is orally administered orally after a first time interval selected from the group consisting of 1) to 3) depending on the type of meal, for example, when a meal is ingested, and after a second time interval of at least one hour until the next meal is ingested. stomach It can be administered by oral administration.

[0061] In certain embodiments, the pharmaceutical composition of the present invention can be administered orally or intragastricly, for example, when a meal is ingested, after a first time interval of any one of the group consisting of 1) to 3) above depending on the type of meal, and after a second time interval of 2 hours or more until the next meal is ingested.

[0062] In certain embodiments, the pharmaceutical composition of the present invention can be administered orally or intragastricly, for example, when a meal is consumed, after a first time interval selected from 2) or 3) above depending on the type of meal, and after a second time interval of 30 minutes or more until the next meal is consumed.

[0063] In certain embodiments, the pharmaceutical composition of the present invention can be administered orally or intragastricly, for example, when a meal is consumed, after a first time interval selected from 2) or 3) above depending on the type of meal, and after a second time interval of at least one hour until the next meal is consumed.

[0064] In certain embodiments, the pharmaceutical composition of the present invention can be administered orally or intragastricly, for example, when a meal is consumed, after a first time interval selected from 2) or 3) above depending on the type of meal, and after a second time interval of 2 hours or more until the next meal is consumed.

[0065] In the present invention, high-fat meals, normal meals, and light meals can be classified based on, for example, the general classification criteria in the medical field. Specifically, for example, they can be classified according to the total calories of one meal, and more specifically, for example, they can be classified according to the total calories and the percentage (%) of the calories from lipids in the total calories.

[0066] The high-fat diet is a diet that is mainly classified as a high-fat diet, and may include, for example, a diet with a calorie content close to the upper and lower limits of the general standard value for classification as a high-fat diet. Specifically, the high-fat diet of the present invention may include, for example, a diet that is less than the standard calorie content of a high-fat diet and exceeds the standard calorie content of a normal diet in the general classification standard, in addition to a high-fat diet, or may include a diet that exceeds the standard calorie content of a high-fat diet. In this way, by applying the condition of the first time interval in 1) above to not only a high-fat diet but also a diet that exceeds the standard calorie content of a normal diet, the pharmacokinetics of orally or intragastrically administered edaravone can be effectively maintained even when a meal that falls between a high-fat meal and a normal meal is ingested. The same applies to a meal that exceeds the standard calorie content of a high-fat meal.

[0067] A general standard for a high-fat diet is, for example, a total calorie intake of 800-1000 kcal per meal, and examples thereof include a diet with a total calorie intake of 800-1000 kcal and 50% of the calorie intake from lipids, or a diet with a total calorie intake of 800-1000 kcal and 500-600 kcal of the calorie intake from lipids and 250 kcal of the calorie intake from carbohydrates. In addition to the high-fat diets described above, a diet with a total calorie intake of more than 500 kcal and less than 800 kcal can also be classified as a high-fat diet. In addition, a diet with a total calorie intake of more than 1000 kcal can also be classified as a high-fat diet. Furthermore, in the present invention, the high-fat diet may be, for example, a diet described as a high-fat meal in the FDA guideline (Assessing the Effects of Food on Drugs in INDs and NDAs - Clinical Pharmacology Considerations) or a diet described as a high-fat meal in the EMA guideline (Guideline on the investigation of drug interactions).

[0068] In the present invention, the unit of total calories, "kilocalorie", is defined as the energy required to raise the temperature of 1 liter of water by 1°C. Furthermore, as described on the website of the United States Department of Agriculture (USDA) (https: / / www.nutrition.gov / expert-qa), the kilocalorie in this specification is synonymous with the "calories" used in meals (see the section "What is the difference between calories and kilocalories?"). As described above, in this specification, the unit "kilocalorie" based on the former definition is used. For example, 800 to 1000 kilocalories described in this specification means 800 to 1000 calories according to the explanation of the United States Department of Agriculture (USDA).

[0069] Regular meals are meals that are mainly classified as regular meals, and may include, for example, meals with calories that are close to the lower limit of the general standard value classified as regular meals. In this specification, regular meals may also be referred to as low-fat meals or standard meals. Specifically, regular meals in the present invention may include, for example, meals that are less than the standard calorie of regular meals and exceed the standard calorie of snacks in general classification standards, in addition to regular meals. In this way, by applying the condition of the first time interval in 2) above to not only regular meals but also meals that exceed the standard calorie of snacks, the pharmacokinetics of orally or intragastrically administered edaravone can be effectively maintained even when a meal that falls between a regular meal and a snack is ingested.

[0070] A general standard for a normal diet is, for example, a total calorie of 400 to 500 kcal per meal, and examples thereof include a diet with a total calorie of 400 to 500 kcal and 25% of the calorie intake from fat, or a diet with a total calorie of 400 to 500 kcal and 150 kcal of the calorie intake from fat. In addition to the normal diet, a diet with a total calorie of more than 250 kcal and less than 400 kcal can also be classified as a normal diet in the present invention. Furthermore, in the present invention, the normal diet may be, for example, a diet described as a low-fat meal in the FDA guideline (Assessing the Effects of Food on Drugs in INDs and NDAs - Clinical Pharmacology Considerations) or a diet described as a moderate meal in the EMA guideline (Guideline on the investigation of drug interactions).

[0071] Snacks are meals mainly classified as snacks, and may include meals with calories close to the lower limit of the general standard value classified as snacks. In this specification, snacks may be referred to as calorie supplements, calorie supplement foods, calorie supplements, nutritional supplements, nutritional supplements, nutritional foods, enteral nutrients, protein amino acid preparations, elemental nutrients, digested enteral nutrients, digested nutrients, semi-digested enteral nutrients, semi-digested nutrients, nutritional supplements, nutritional supplement drinks, nutritional foods, or nutritional functional foods. Specifically, snacks in the present invention may include, in addition to snacks, meals with calories less than the standard calorie of snacks in general classification standards. In this way, by applying the condition of the first time interval in 3) above to not only snacks but also meals with calories less than the standard calorie of snacks, the pharmacokinetics of orally or intragastrically administered edaravone can be effectively maintained even when a meal with calories less than the standard calorie of snacks is ingested.

[0072] A general standard for snacks is, for example, a meal with a total calorie content of 250 kcal per meal. A specific example of a snack is a liquid type nutritional supplement (enteral nutritional supplement: Ensure Liquid (registered trademark)) with a total calorie content of about 250 kcal. This is used, for example, to maintain nutrition in patients after surgery and to provide tube feeding to patients who have difficulty in taking food for a long period of time. In addition to the snacks with a total calorie content of about 250 kcal, meals with a total calorie content of less than 250 kcal can also be classified as snacks in the present invention.

[0073] The method of administration of the pharmaceutical composition of the present invention may be either oral administration or intragastric administration. When the pharmaceutical composition of the present invention is administered to a patient multiple times, it may be only intragastric administration, only oral administration, a combination of intragastric administration and oral administration, or a change from oral administration to intragastric administration, or a change from intragastric administration to oral administration. In general, intragastric administration is used as a measure when necessary nutrients cannot be taken orally due to swallowing disorders, etc. For this reason, for example, in order to perform more effective treatment depending on the symptoms, oral administration may be changed to intragastric administration. In addition, in the case of intragastric administration, for example, as described above, intragastric administration by a tube (also called tube administration or tube intragastric administration) may be used, and as a specific example, administration by a gastrostomy catheter or administration by a nasogastric catheter may be used, or a combination of both may be used, or one may be changed to the other.

[0074] The material of the catheter is not particularly limited, and examples thereof include silicone, polyvinyl chloride, polyurethane, etc. In the catheter, the material of the button is, for example, silicone, polyurethane, silicone rubber, etc., and the material of the tubing is, for example, polyvinyl chloride, silicone rubber / polyacetal, etc. In the catheter, examples of the combination of the material of the button and the tubing include a combination of a button of silicone and a tubing of polyvinyl chloride, a button of polyurethane and a tubing of polyvinyl chloride, or a button of silicone rubber and a tubing of silicone rubber / polyacetal, etc.

[0075] In a preferred embodiment of the present invention, edaravone, an active ingredient of the present invention, is administered orally or through a feeding tube in the form of the pharmaceutical composition of the present invention. As the feeding tube, for example, a nasopharyngeal gastric catheter (sometimes called a nasopharyngeal gastric (NG) tube) or a gastrostomy catheter (sometimes called a percutaneous endoscopic gastronomy (PEG) tube) can be used, and the pharmaceutical composition is administered through this feeding tube. As the feeding tube, for example, one made of silicone, polyvinyl chloride (PVC) and / or polyurethane is used.

[0076] In a preferred embodiment of the present invention, when edaravone, an active ingredient of the present invention, is administered in the form of a pharmaceutical composition of the present invention, the pharmaceutical composition is taken on an empty stomach. In this form, it is preferable to avoid eating for 1 hour after administration, and it is also preferable to avoid high-fat meals (800-1000 calories (synonymous with 800-1000 kcal as defined herein), 50% fat) for 8 hours before administration, low-fat meals (400-500 calories (synonymous with 400-500 kcal as defined herein), 25% fat) for 4 hours before administration, or calorie supplements (250 calories (synonymous with 250 kcal as defined herein), e.g., ENSURE LIQUID®) for 2 hours before administration.

[0077] In another preferred embodiment of the present invention, when administering the active ingredient edaravone of the present invention in the form of the pharmaceutical composition of the present invention, the patient is informed that edaravone must be taken on an empty stomach in the morning, and it is preferable to stop eating at bedtime the night before each administration, and not eat for 1 hour after administration. In addition, for administration after a meal, it is preferable to fast for 8 hours before administration if a high-fat meal (1000 calories (synonymous with 1000 kcal as defined herein), 50% fat) is consumed, and for 4 hours before administration if a low-fat meal (normal meal) (400 calories (synonymous with 400 kcal as defined herein), 25% fat) is consumed. An alternative option for the patient may be, for example, calorie supplementation (250 calories (synonymous with 250 kcal as defined herein) (e.g., protein drink)) 2 hours before administration.

[0078] In the administration of the pharmaceutical composition of the present invention, the intake of water is not particularly limited.In the oral administration, when the pharmaceutical composition of the present invention is solid, for example, it is preferable to administer it with water, and when the pharmaceutical composition of the present invention is liquid or gel, for example, it may be administered without water or with water.In the case of intragastric administration by the tube, for example, water is preferably injected from the tube (for example, gastrostomy catheter, nasogastric catheter) for washing after administration of the pharmaceutical composition of the present invention.

[0079] As described above, the pharmaceutical composition of the present invention is intended to avoid the influence of food on the pharmacokinetics of edaravone when edaravone is orally or intragastricly administered. Therefore, the use of the pharmaceutical composition of the present invention may be any use for oral or intragastric administration of edaravone, and the target disease or symptom may be any disease or symptom that edaravone can directly or indirectly act on, and is not particularly limited. Specifically, for example, the target disease or symptom may be a disease or symptom that can be treated by scavenging free radicals with edaravone.

[0080] The disease is, for example, an oxidative stress disease, and specifically includes, for example, neurodegenerative diseases accompanied by motor dysfunction such as ALS, Parkinson's disease, and spinocerebellar degeneration; muscle diseases such as muscular dystrophy; intracerebral neurodegenerative diseases presenting cognitive dysfunction such as Alzheimer's disease; vascular disorders such as cerebral infarction; systemic inflammatory diseases such as multiple sclerosis and systemic sclerosis; or local inflammatory diseases such as stomatitis, and among them, ALS is preferable. In the present invention, the treatment of a disease includes, for example, alleviation of disease progression, cure of a disease, prevention of morbidity, prevention of recurrence, and the like, and may also mean treatment of symptoms caused by the disease. In the present invention, the treatment of a symptom includes, for example, inhibition of symptom progression, alleviation of symptoms, cure of symptoms, prevention of symptom occurrence, prevention of symptom recurrence, and the like. The symptom is, for example, a functional disorder in the oxidative stress disease, and specific examples thereof include, for example, motor dysfunction, cognitive dysfunction, and the like. In the present invention, the treatment of a disease can be read as, for example, treatment of a disease or treatment of a symptom associated with a disease, and the therapeutic agent can be read as, for example, a therapeutic agent for a disease or a therapeutic agent for a symptom associated with a disease (specific examples include, for example, a symptom progression inhibitor, etc.). In the present invention, with regard to the treatment of a disease or a symptom, the pharmaceutical composition of the present invention can be used for, for example, any one of the purposes or for two or more purposes.

[0081] The method of administering the pharmaceutical composition of the present invention can be, for example, a method of treating a disease on which edaravone acts directly or indirectly, and a specific example is a method of treating the above-mentioned oxidative stress diseases.

[0082] As described above, the administration of the pharmaceutical composition of the present invention is not particularly limited except that oral administration or intragastric administration is performed under the condition 1), 2) or 3) according to the type of meal, and for example, the administration conditions using an injection containing edaravone can be referred to. Specifically, when used for the treatment of oxidative stress disease (preferably ALS), the pharmaceutical composition of the present invention can be, for example, the administration method described in WO2020 / 091036 or the administration method using an injection of edaravone currently used in clinical practice. The administration method may be, for example, daily administration or intermittent administration, and a specific example is the intermittent administration method used in the treatment of ALS. That is, in the present invention, the first time interval and the second time interval may be, for example, a time interval during the administration period of intermittent administration or daily administration. The intermittent administration method is intermittent administration, that is, for example, an administration method in which a dosing period and a withdrawal period are taken as one unit and this is repeated two or more times. When a dosing period and a withdrawal period are repeated two or more times as one unit, the last one is a withdrawal period, but a final withdrawal period may or may not be provided. That is, for example, when a dosing period and a withdrawal period are repeated twice as one unit, it may be, for example, "dosing period, withdrawal period, dosing period, withdrawal period", or it may be "dosing period, withdrawal period, dosing period" without a final withdrawal period.

[0083] In the present invention, the drug holiday period refers to, for example, a period during which no drug is administered for several consecutive days or more, and is preferably 7 days or 14 days. The drug administration period is, for example, 14 days, and in this case, during the drug administration period, the drug may be administered for 14 consecutive days, or may be administered for 10 days out of the 14 days. The 10 days out of the 14 days means, for example, any 10 days out of 14 consecutive days, and the 10 days during which the drug is administered may be 10 consecutive days, or may be 10 discontinuous days separated by one or more periods (for example, 1 to 4 days) during which the drug is not administered. The drug administration period can be, for example, a preferred period while observing the condition of the patient. More specifically, for example, a method in which a 14-day initial drug administration period is followed by a 14-day initial drug holiday period, and then a 10-day drug administration period and a 14-day drug holiday period are repeated out of the 14 days. The number of times that the 10-day medication period and the 14-day drug holiday period are repeated during the 14 days is not particularly limited, and may be, for example, once or more.

[0084] When the pharmaceutical composition of the present invention is used for the treatment of an oxidative stress disease (preferably ALS), it may be repeatedly administered to a patient, for example, every day or almost every day during the administration period (also referred to as the daily administration). The dosage of the pharmaceutical composition of the present invention per administration can be appropriately selected depending on, for example, the age and condition (for example, the severity of the disease) of the patient. The dosage of the pharmaceutical composition of the present invention can be determined, for example, as the dosage of edaravone contained in the pharmaceutical composition. As a general specific example, the single dose of the pharmaceutical composition of the present invention, as the dose of edaravone for an adult, has a lower limit of, for example, 60 mg or 90 mg, and an upper limit of, for example, 400 mg, 140 mg, 120 mg, or 105 mg, and is in the range of, for example, 60 mg to 400 mg, preferably 90 to 140 mg, more preferably 90 to 120 mg, even more preferably 90 mg to 105 mg, particularly preferably 90 mg, 100 mg, 105 mg, or 120 mg, with 100 mg or 105 mg being preferred, and most preferably 105 mg.

[0085] Furthermore, when the pharmaceutical composition of the present invention is used to treat an oxidative stress disease (preferably ALS), for example, the dosage per administration during the administration period of the intermittent administration method is the same as the dosage described above.

[0086] Edaravone injection (trademark in Japan "Radicut", registered trademark) currently used in clinical settings as an ALS therapeutic agent is set to have a single dose of 60 mg of edaravone. For the pharmaceutical composition of the present invention for oral or intragastric administration, when the effect is to be the same as that when the edaravone injection (60 mg of edaravone per dose) is intravenously injected, for example, the single dose is preferably set to 90 to 105 mg of edaravone, more specifically, it is preferably set to 105 mg of edaravone.

[0087] The number of times of administration of the pharmaceutical composition of the present invention is not particularly limited, for example, whether it is oral administration or intragastric administration, and is also not particularly limited, whether it is daily administration or intermittent administration.The number of times of administration can be selected as a preferred number, for example, while observing the condition of the patient.Specifically, for example, taking into consideration the burden on the patient, etc., once or twice a day is preferred, and once is more preferred. EXAMPLES

[0088] The present invention will now be described in detail with reference to examples and test examples, but the present invention is not limited thereto. As the pharmaceutical composition of the present invention, an oral preparation of edaravone was used and evaluated by oral administration or intragastric administration using a tube. When the oral preparation of edaravone is used for intragastric administration, it is also called an intragastric preparation of edaravone.

[0089] [Example 1] Effect of food intake before oral administration of edaravone on the pharmacokinetics of edaravone

[0090] The effect of food intake before administration of edaravone oral preparation on the pharmacokinetics of edaravone was evaluated. Specifically, clinical trials #1, #2, and #3, which will be described later, were conducted on different days with healthy adult male Japanese subjects. Each of clinical trials #1, #2, and #3 used a single dose of edaravone oral preparation (edaravone suspension) of formulations #1, #2, and #3, respectively, shown in Table 1 below, and administration during the test period was a single oral administration. The number of subjects in each clinical trial is shown in Table 2, which will be described later. For each clinical trial, a reference test was conducted in which edaravone oral preparation was administered in a fasting state (reference example), as will be described later, and the same subjects were administered in each clinical trial and the corresponding reference test.

[0091] [Table 1]

[0092] The high-fat diet was a diet with a total calorie intake of 800-1000 kcal per meal and 50% of the calories coming from fat. The normal diet was a diet with a total calorie intake of 400-500 kcal per meal and 25% of the calories coming from fat. The snack was a liquid-type nutritional supplement (enteral nutritional supplement: Ensure Liquid (registered trademark)) with a total calorie intake of 250 kcal per meal.

[0093] Clinical Trial #1: Comparative Example for the First Time Interval Condition 1) The subjects were orally administered with edaravone oral preparation (formulation #1) 30 minutes after ingestion of a high-fat meal. Blood samples were taken before administration, and 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 36 hours, and 48 hours after administration, and the plasma concentration of unchanged edaravone was measured. On the other hand, as a reference example, the same subjects in a fasting state were orally administered with the edaravone oral preparation, and blood samples were taken and the plasma concentration of unchanged edaravone was measured in the same manner. The administration in the fasting state was oral administration at a time when 10 hours or more had passed since the previous meal intake (hereinafter the same). None of the subjects ingested the next meal until blood collection 4 hours after administration was completed. The obtained PK profile is shown in Table 2 below.

[0094] Clinical Trial #2: Comparative Example to the First Time Interval Condition 1) The oral preparation of edaravone (#2) was orally administered to the subjects 4 hours after ingestion of a high-fat meal. Blood samples were taken before administration, and 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 36 hours, and 48 hours after administration, and the plasma concentration of unchanged edaravone was measured. On the other hand, as a reference example, the oral preparation of edaravone was orally administered to the same subjects in a fasting state, and blood samples were taken and the plasma concentration of unchanged edaravone was measured in the same manner. The administration in the fasting state was oral administration at a time when 10 hours or more had passed since the previous meal intake. None of the subjects ingested the next meal until blood collection 4 hours after administration was completed. The obtained PK profile is shown in Table 2 below.

[0095] Clinical Trial #3: Examples of first time interval conditions 1), 2) and 3), and comparative examples for first time interval condition 2) As an example, the edaravone oral preparation (#3) was orally administered to each subject 8 hours after ingestion of a high-fat meal, 4 hours after ingestion of a normal meal, and 2 hours after ingestion of a light meal. Blood samples were taken before administration, and 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, and 48 hours after administration, and the plasma concentration of unchanged edaravone was measured. In addition, as a comparative example, the edaravone oral preparation was orally administered to the same subject 2 hours after ingestion of a normal meal, and blood samples were taken and the plasma concentration of unchanged edaravone was measured in the same manner. Meanwhile, as a reference example, the edaravone oral preparation was orally administered to the same subject in a fasting state, and blood samples were taken and the plasma concentration of unchanged edaravone was measured in the same manner. The administration in the fasting state was orally administered at a time when 10 hours or more had passed since the previous meal intake. All subjects were not allowed to eat a meal until blood sampling was completed 4 hours after administration. The PK parameters obtained are shown in Table 2 below.

[0096] [Table 2]

[0097] The following results were obtained regarding the influence of high-fat meal intake. First, a comparison example #2 (#2: 4-h after high-fat meal) in which an oral preparation of edaravone was administered 4 hours after ingestion of a high-fat meal was compared with an example #3 (#3: 8-h after high-fat meal) in which an oral preparation of edaravone was administered 8 hours after ingestion of a high-fat meal. As shown in Table 2 above, in the comparative example #2 (#2: 4-h after high-fat meal), administration was performed 4 hours after ingestion of a high-fat meal, and as a result, a 44% decrease in Cmax (percentage of decrease, the same applies below) and a 24% decrease in AUC were observed compared with the fasting state (#2: Fasted). In contrast, in the example of test #3 (#3: 8-h after high-fat meal), as shown in Table 2 above, administration was performed 8 hours after ingestion of a high-fat meal, which satisfies the condition 1) of the first time interval, and thus no decrease in Cmax and AUC was observed compared with the fasting state (#3: Fasted). In the comparative example #2 and the example #3, the formulation of the oral preparation of edaravone used is almost the same, and therefore, according to the present invention, it was found that the pharmacokinetics of edaravone can be maintained similar to that of administration in a fasting state by timing administration after meal intake. In the comparative example #1 (#1: 30-min after high-fat meal), the time from meal intake to administration of the oral preparation of edaravone was further shortened to 30 minutes after high-fat meal intake. As a result, compared to the fasting state (#1: Fasted), Cmax decreased by 82% and AUC decreased by 61%, and the rate of decrease was greater than that of the comparative example #2. The oral preparation of edaravone with the formulation of #1 used in the comparative example #1 contains almost twice as much edaravone as the comparative example #2 and the example #3. This also shows that the effect of the present invention is not compensated for by, for example, an increase in the edaravone content in the edaravone oral preparation, but is obtained by the first time interval from meal intake to administration of the edaravone oral preparation according to the type of meal.

[0098] The following results were obtained regarding the effects of normal meal intake and light meal intake. That is, as shown in Table 2, in the example of Test #3 (#3: 4-h after standard meal), administration was performed 4 hours after normal meal intake, which satisfies the condition 2) of the first time interval, and in the example of Test 3 (#3: 2-h after light meal), administration was performed 2 hours after light meal intake, which satisfies the condition 3) of the first time interval, and no decrease in Cmax and AUC was observed compared to the fasting state (#3: Fasted). Thus, the fact that no decrease in Cmax and AUC was observed in the example of Test #3 was also supported by the results of the analysis of variance shown below.

[0099] That is, from the results of the edaravone PK parameters, an analysis of variance was performed on AUC and Cmax taking into account the food condition. The results are shown in Table 3 below. The results of summary statistics regarding Cmax are shown in Table 4 below, and a spaghetti plot is shown in Figure 1. The spaghetti plot in Figure 1 shows the results of an individual subject, and the results of fasting administration and the results of postprandial administration of the same subject are connected by a line.

[0100] [Table 3] [Table 4]

[0101] As shown in Table 3, the least squares mean ratio of the AUC of the Examples administered at each first time interval after meal to the AUC of the Reference Example administered in a fasted state (Fasted) by the analysis of variance showed that the 90% confidence interval was in the range of 0.8-1.25, which is the general equivalence standard. This result shows that when an oral preparation of edaravone is administered 8 hours after a high-fat meal, 4 hours after a normal meal, and 2 hours after a light meal, food has no effect on the AUC, and the same pharmacokinetic maintenance effect as administration in a fasted state can be achieved. Furthermore, as shown in Table 3, the coefficient of variation (the ratio of SD to the mean value) of Cmax was large, and the 90% confidence interval of the ratio (the value in brackets in the Ratio column) did not fall within the range of 0.8-1.25, which is the standard, but the point estimate of the ratio (the value outside the brackets in the Ratio column) did not show any significant change and was within the range of the standard. Furthermore, as shown in the summary statistics of Cmax in Table 4 and the spaghetti plot in Figure 1, the values ​​for each subject were distributed between approximately 1000 and approximately 5000 for both fasting and postprandial administration, regardless of the conditions of postprandial administration, with the median being approximately 2000, which was unchanged compared to the fasting state.

[0102] As described above, the Examples of Test #3 demonstrated that administration of an oral preparation of edaravone 8 hours after ingestion of a high-fat meal that satisfies condition 1), 4 hours after ingestion of a regular meal that satisfies condition 2), and 2 hours after ingestion of a light meal that satisfies condition 3) can achieve Cmax and AUC similar to those achieved by oral administration in a fasted state, thereby avoiding the effect of food on the pharmacokinetics of edaravone.

[0103] As described above, in the examples, it was confirmed that the same pharmacokinetics as when the same edaravone oral preparation was administered in a fasting state can be maintained by setting the timing of administration after meal intake to the first time interval conditions 1), 2), and 3). Furthermore, from these results, it was confirmed that the pharmaceutical composition of the present invention only needs to contain edaravone as an active ingredient, and the composition itself is not particularly limited, and even when a pharmaceutical composition of the same composition is used, the effect of the present invention can be obtained by setting the administration conditions as described above according to the type of meal.

[0104] [Example 2] Effect of food intake after oral administration of edaravone on the pharmacokinetics of edaravone 1

[0105] The effect of food intake on the pharmacokinetics of edaravone 1 hour after administration of the oral preparation was evaluated. Specifically, the subjects were Japanese healthy adult male subjects, and the clinical trial #4 described below was conducted on the same subjects. In the clinical trial #4, the oral preparation of edaravone with the formulation #2 in Table 1 was used, and the administration during the test period was a single oral administration. The high-fat diet was the same as that used in Example 1.

[0106] Clinical Trial #4 As a post-administration intake group, the same subjects in a fasting state after 10 hours or more had passed since eating were orally administered the edaravone oral preparation, and 1 hour after administration, they were made to eat a high-fat meal. Blood was collected before administration, and 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 36 hours, and 48 hours after administration, and the plasma concentration of unchanged edaravone was measured. The high-fat meal was eaten 1 hour after administration, after blood was collected 1 hour after administration, and no meals were eaten thereafter until blood was collected 4 hours after administration. On the other hand, as a reference fasting group, the same subjects in a fasting state were orally administered the edaravone oral preparation, and blood was collected and the plasma concentration of unchanged edaravone was measured in the same manner. The subjects in the fasting group also did not eat until blood was collected 4 hours after administration. The PK parameters obtained are shown in Table 5 below.

[0107] [Table 5]

[0108] The post-administration group, which was given a high-fat meal 1 hour after the oral administration of edaravone, was compared with the fasting group, which was given the oral administration in a fasting state and was not allowed to eat for 4 hours or more. As a result, as shown in Table 5, the post-administration group showed only a slight decrease in Cmax of about 17.0% and AUC of about 10.4% compared to the fasting group, and no significant difference was observed. Therefore, it was found that the intake of food 1 hour after oral administration does not affect the pharmacokinetics of edaravone.

[0109] In addition, AUC 0-∞ The results from 0 hours to 1 hour after administration (0-1h, before resuming food intake after administration) (AUC 0-1h ) and the results after 1 hour (1h-∞h, after resuming food intake after administration) (AUC 1h-∞ ), and the post-administration intake group (1-h before high-fat meal) and the fasted group (Fasted) were evaluated. These results are shown in Table 6 below and the spaghetti plot in Figure 2. As shown in Table 6 below and Figure 2, the post-administration intake group (1-h before high-fat meal) had a higher AUC 0-1h Although there was a slight decrease in AUC 1h-∞ There was no change in AUC 0-1h The slight decrease in Cmax and AUC is not due to the effect of food, but is rather due to intraindividual variability, i.e., variation within the same subject (i.e., variation from day to day due to fasting and fed data being obtained on different days for the same subject).

[0110] [Table 6]

[0111] From the above results, even when a high-fat meal was consumed one hour after administration of oral edaravone, there was no change in the pharmacokinetics of edaravone compared to administration in a fasting state, indicating that meals after administration do not affect the pharmacokinetics. Thus, the evaluation results using a high-fat meal showed that there was no effect on the pharmacokinetics of edaravone. Therefore, regardless of whether a high-fat meal was consumed, there was no change in the pharmacokinetics of edaravone when a normal meal or a light meal was consumed one hour after administration of oral edaravone compared to a fasting state, and it is considered that there is no effect of food.

[0112] [Example 3] Evaluation of Edaravone in Caco-2 Cell Membrane Permeability Assay

[0113] Caco-2 cells were seeded in a 24-well plate and cultured at 37°C for 21 to 23 days in a CO2 incubator, after which a Caco-2 cell monolayer membrane permeability test was carried out. After confirming the membrane resistance value of the cultured cell layer, the culture medium in the plate was replaced with HBSS (pH 7.4) and pre-incubated at 37°C for 1 hour, after which edaravone and a control compound at a given concentration were added to the apical side and incubated at 37°C for 2 hours. The control compound was used as a high membrane permeability control [ 3 H]propranolol, as a low membrane permeability control, 14 The concentrations of edaravone and the control compound on the basal side were measured, and the permeability coefficient (P app The results are shown in Table 7 below. app The data are shown as Mean±SD. As shown in Table 7 below, edaravone exhibited membrane permeability equal to or greater than that of propranolol, a control compound with high membrane permeability.

[0114] [Table 7]

[0115] It is known that cell membrane permeability is constant regardless of the concentration of a substance when a transporter is not involved. The control compounds propranolol and mannitol are not substrates of the transporters P-gp and BCRP expressed in Caco-2 cells, so it is considered that the permeability coefficient value will not change depending on the concentration used in the test. Therefore, the following test was conducted to confirm that edaravone is also not a substrate of the transporters P-gp and BCRP.

[0116] Specifically, Caco-2 cells were seeded on a 96-well plate and cultured in a CO2 incubator at 37°C for 10 to 11 days, after which a transcellular transport test was performed. app P from the apical side to the basal side app The Efflux ratio was calculated using n=3. app The Efflux ratio was calculated as the ratio of the average values ​​of the Efflux ratio and the Efflux ratio. The results are shown in Table 8 below. As shown in Table 8 below, the Efflux ratio of edaravone was not more than 2, and the Efflux ratio was not affected by the addition of typical inhibitors of P-gp and / or BCRP. This indicates that edaravone is not a substrate of P-gp and BCRP.

[0117] [Table 8]

[0118] Sun et al. (Pharmaceutical Research, Vol. 19, No. 10, 2002) and Yamashita et al. (European Journal of Pharmaceutical Sciences 10 (2000) 195-204) have shown that the permeability coefficient of a drug determined by the Caco-2 cell membrane permeability test correlates with the drug absorption rate in humans. Paterson et al. (Pharmacologia Cliniea 2, 127-133 (1970)) and Borgstrom et al. (Journal of Pharmacokinetics and Biopharmaceutics, Vol 9 No. 4, 1981) have shown that propranolol is almost entirely absorbed in the intestine when administered orally to humans.

[0119] As described above, since edaravone showed a permeability coefficient equal to or higher than that of propranolol, it was found that when edaravone is orally administered to humans, the absorption rate of edaravone is considered to be high, and it was found to be positioned as a compound of high permeability. In addition, as described above in the report by Wu et al. (Non-Patent Document 1), it is described that a compound of high permeability is less susceptible to the pharmacokinetics caused by food. However, in contrast to this, although edaravone is highly permeable, its pharmacokinetics was affected by food as described in the above-mentioned Examples 1 and 2. In this way, the present inventors have found for the first time that the pharmacokinetics of edaravone is affected by food, that the effect differs depending on the type of food, and that the effect on the pharmacokinetics can be avoided by setting the administration timing to the above conditions 1), 2), and 3) depending on the type of food.

[0120] [Example 4] Pharmacokinetics of edaravone in patients with ALS

[0121] In order to evaluate the pharmacokinetics of edaravone in ALS patients, Clinical Trial #5 shown below was conducted on ALS patients who are able to live independently and carry out daily activities (patient group).

[0122] Clinical Trial #5 The oral edaravone preparation was orally administered to the fasting patient group after 10 hours or more had passed since the intake of food. In addition, for the ALS patients who had already been administered the intravenous infusion preparation of edaravone, the oral edaravone preparation was orally administered after 48 hours or more had passed since the end of the previous intravenous infusion preparation. The oral edaravone preparation was the same as the formulation #3 in Table 1. Then, blood was collected before administration, and 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, and 24 hours after administration, and the plasma concentration of unchanged edaravone was measured. The patient group did not take food after administration until the blood collection 4 hours after administration was completed.

[0123] Clinical Trial #9 On the other hand, the following clinical trial #9 was carried out on healthy adult males and females (42 subjects in total) (reference group). That is, the reference group, which was in a fasting state after 10 hours or more, was orally administered with the edaravone oral preparation of the formulation #3. Blood samples were taken before administration, and 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, and 48 hours after administration, and the plasma concentration of unchanged edaravone was measured. The reference group also did not eat food after administration until blood collection 4 hours after administration was completed.

[0124] The obtained PK parameters were corrected for each of the patient group and the reference group by proportional calculation with the body weight of each subject being 70 kg. The results of the PK parameters before correction for the patient group and the reference group are shown in Table 9 below. The results of the PK parameters after correction for the patient group are shown in Figure 3 as a box plot for #9 (reference group) and individual plots for #5 (patient group) and #9 (reference group). In Figure 3, x is the average value. As shown in Table 9 below, there was a 15% difference in Cmax before body weight correction between the patient group and the reference group, and a 1.5% difference in AUC before body weight correction, but as shown in Figure 3, the difference in Cmax after body weight correction and the difference in AUC after body weight correction were 9.8% and 5.8%, respectively, both of which were within 10%. On the other hand, the mean value ± standard error of Cmax after weight correction in the patient group was 1607 ± 231, and the mean value ± standard error of AUC after weight correction in the patient group was 1461 ± 166, both of which had large standard errors. Therefore, the difference in Cmax and AUC before weight correction between the patient group and the reference group seen in Table 9 below is due to the difference in weight between the patient group and the reference group, and the difference in Cmax and AUC after weight correction between the patient group and the reference group seen in Figure 3 are each considered to be within the range of error.

[0125] [Table 9]

[0126] As described above, the comparison of Cmax and AUC of edaravone after oral administration between ALS patients and healthy adults showed that the pharmacokinetics of edaravone was similar between ALS patients and healthy adults, and sufficient plasma concentrations of edaravone were secured in ALS patients as in healthy adults. From this, it can be said that oral administration of edaravone itself does not affect the plasma concentration, regardless of whether the patient is a patient or not.

[0127] [Example 5] Pharmacokinetics of Edaravone Administered via a Gastrostomy Catheter 1

[0128] The pharmacokinetics of edaravone oral preparations administered via a gastrostomy catheter was evaluated. Specifically, clinical trial #6, which will be described later, was conducted on ALS patients with gastrostomy catheters. In clinical trial #6, the oral preparation of edaravone with formulation #3 shown in Table 1 was used.

[0129] Clinical Trial #6 The oral edaravone preparation was administered through a gastrostomy catheter to a group of patients in a fasting state after 10 hours or more had passed since the intake of a meal. That is, first, 100 mL of lukewarm water was injected through the gastrostomy catheter 1 hour before the administration of the oral edaravone preparation, and 10 mL of lukewarm water was injected through the gastrostomy catheter immediately before the administration. Next, the oral edaravone preparation was administered through the gastrostomy catheter, and 10 mL of water was injected through the gastrostomy catheter three times to wash the oral edaravone preparation. In addition, for ALS patients who had already been administered an intravenous infusion preparation of edaravone, the oral edaravone preparation was administered through the gastrostomy catheter 48 hours or more after the end of the administration of the previous intravenous infusion preparation. Blood samples were taken before administration, and 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration, and the plasma concentration of unchanged edaravone was measured. The patient group did not eat any food until the blood sampling was completed 4 hours after administration of the gastrostomy catheter. The reference example utilized the results of the reference group in which the same edaravone oral preparation of Formulation #3 as in Example 4 was orally administered and blood was sampled.

[0130] The obtained PK parameters were corrected by proportional calculation assuming that the body weight of each subject in the patient group was 70 kg. The results of the PK parameters before correction for the patient group are shown in Table 10 below. The results of the PK parameters after correction for the patient group are shown in an individual plot as #6 in FIG. 3. The patient group administered via gastrostomy catheter in Table 10 below was compared with the reference group administered via oral administration in Table 9 above. As a result, between the patient group administered via gastrostomy catheter and the reference group administered via oral administration, there was a 30% difference in Cmax before body weight correction and a 33% difference in AUC before body weight correction, but as shown in FIG. 3, the difference in Cmax after body weight correction and the difference in AUC after body weight correction were 8.3% and 9.5%, respectively, both of which were within 10%. On the other hand, as shown in Figure 3, the mean value ± standard error of Cmax after weight correction in the patient group administered with a gastrostomy catheter was 1585 ± 251, and the mean value ± standard error of AUC after weight correction in the patient group was 1698 ± 228, both of which had large standard errors. Therefore, the difference in Cmax and AUC before weight correction between the patient group administered with a gastrostomy catheter and the reference group administered with an oral administration shown in Table 10 below is due to the difference in weight between the patient group administered with a gastrostomy catheter and the reference group administered with an oral administration, and the difference in Cmax and AUC after weight correction between the patient group administered with a gastrostomy catheter and the reference group administered with an oral administration shown in Figure 3 are each considered to be within the range of error.

[0131] [Table 10]

[0132] From the results of oral administration in Example 4 and the results of gastrostomy catheter administration in Example 5, it was shown that the Cmax and AUC of edaravone after gastrostomy catheter administration of an oral formulation of edaravone were similar to those after oral administration of the same oral formulation of edaravone. This shows that there is no difference in the pharmacokinetics of edaravone between gastrostomy catheter administration and oral administration, and that a sufficient plasma concentration of edaravone is ensured by gastrostomy catheter administration, as well as oral administration.

[0133] [Example 6] Doses of oral edaravone that show equivalent bioavailability to intravenous edaravone

[0134] The dose of edaravone in an oral formulation that shows the same bioavailability as the already approved 60 mg edaravone intravenous (IV) administration was examined. Specifically, the subjects were healthy adult male subjects, and clinical trials #7 and #8, which will be described later, were conducted on each subject group. Clinical trials #7 and #8 used a single dose of edaravone oral formulation (edaravone suspension) of formulations #7 and #8, respectively, shown in Table 11 below, and administration during the study period was a single oral administration.

[0135] [Table 11]

[0136] Clinical Trial #7 The subjects in a fasting state after 10 hours or more had passed since eating were orally administered with the oral preparations of edaravone (formulation #7) containing 30 mg, 60 mg, 120 mg, 200 mg or 300 mg of edaravone. Each oral preparation of edaravone with each content was orally administered to six subjects. Blood samples were taken before administration, and 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 36 hours and 48 hours after administration, and the concentration of unchanged edaravone was measured, and the AUC was calculated. The subjects did not eat after administration until blood collection was completed 4 hours after administration.

[0137] Clinical Trial #8 The edaravone oral preparation (formulation #8) containing 100 mg of edaravone was orally administered to nine subjects in a fasting state after 10 hours or more had passed since eating. Blood was collected before administration, and 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 36 hours, and 48 hours after administration, and the plasma concentration of unchanged edaravone was measured, and the AUC was calculated. The subjects also did not eat after administration until blood collection was completed 4 hours after administration.

[0138] These results are shown in FIG. 4 as individual value plots of the dose of edaravone and the AUC and a four-parameter logistic model showing the relationship between them. In the figure, the horizontal axis is the dose of edaravone, and the vertical axis is the AUC. Also, in FIG. 4, the AUC value (1738 ng·h / mL) of the already approved 60 mg edaravone intravenous formulation is shown by a dotted line. As shown in FIG. 4, the amount of edaravone showing the same AUC as that of the 60 mg edaravone intravenous formulation was calculated to be in the range of 100 to 105 mg. From this result, for the edaravone oral formulation (including the meaning of the edaravone intravenous formulation), for example, by setting the amount of edaravone contained in one administration to 100 to 105 mg and administering it orally or via a gastrostomy catheter at the administration timing in the present invention described above, it becomes possible to provide medical care that maintains the same effect as the approved 60 mg edaravone intravenous formulation and reduces the burden on patients and caregivers.

[0139] [Example 7] Effect of food intake after oral administration of edaravone on the pharmacokinetics of edaravone 2

[0140] The effect of food intake 30 minutes after administration of an oral preparation of edaravone on the pharmacokinetics of edaravone was evaluated. Specifically, clinical trial #10 described below was conducted on healthy adult male Japanese subjects. In clinical trial #10, an oral preparation of edaravone with formulation #7 (containing 120 mg of edaravone) in Table 11 was used, and the administration during the test period was a single oral administration. The normal food was the same as that used in Example 1.

[0141] Clinical Trial #10 For the post-administration group, subjects in a fasting state 10 hours or more after meal ingestion were orally administered the edaravone oral preparation, and 30 minutes after administration, they were made to eat a normal meal. Blood samples were taken before administration, and 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration, and the plasma concentration of unchanged edaravone was measured. The normal meal was taken 30 minutes after administration, after the blood sample was taken 30 minutes after administration, and no further meals were taken until the blood sample was taken 4 hours after administration.

[0142] On the other hand, as a fasting group for reference, the oral preparation of edaravone was orally administered to another subject in a fasting state, and blood was collected and the plasma concentration of unchanged edaravone was measured in the same manner. The subjects in the fasting group also did not take any food until blood collection 4 hours after administration was completed. The obtained PK parameters are shown in Table 12 below.

[0143] [Table 12]

[0144] The post-administration group, which was given a normal meal 30 minutes after the oral administration of edaravone, was compared with the fasting group, which was given the oral administration in a fasting state and was not allowed to eat for 4 hours or more. As a result, as shown in Table 12, the post-administration group showed a slight increase of about 12.6% in Cmax and a slight decrease of about 14.5% in AUC compared to the fasting group, and no significant difference was observed. Therefore, it was found that eating 30 minutes after oral administration does not affect the pharmacokinetics of edaravone.

[0145] From the above results, it is believed that when a normal meal is consumed 30 minutes after administration of oral edaravone, no significant changes occur compared to the fasting state. Also, because edaravone is administered as a suspension, it is quickly excreted from the stomach and it is presumed that 30 minutes after administration most of it has reached the upper part of the small intestine, which is thought to be the site of absorption, so it is believed that there is no effect depending on the type of food consumed 30 minutes after administration. This suggests that when oral administration of edaravone is administered, it is not affected by food after 30 minutes has passed, regardless of the type of food.

[0146] [Example 8] Pharmacokinetics of Edaravone Administered via a Gastrostomy Catheter 2 The pharmacokinetics of edaravone oral preparation administered via a gastrostomy catheter was evaluated in 36 healthy adults. Specifically, since it is difficult to create a gastrostomy in healthy adults, a nasogastric catheter, which is the same feeding tube used for administration into the stomach, was used as a model for gastrostomy catheter administration, and clinical trial #11, which will be described later, was conducted. In clinical trial #11, the oral preparation of edaravone with formulation #3 shown in Table 1 above was used.

[0147] Clinical Trial #11 The oral preparation of edaravone (#3) was administered to a group of subjects in a fasting state after 10 hours or more had passed since the intake of a meal through a nasogastric catheter. In the administration through the nasogastric catheter, first, 100 mL of lukewarm water was injected through the nasogastric catheter 1 hour before the administration of the oral preparation of edaravone, and 10 mL of lukewarm water was injected through the nasogastric catheter immediately before the administration. Next, the oral preparation of edaravone was administered through the nasogastric catheter, and 30 mL of water was further injected through the nasogastric catheter for washing. Blood samples were taken before administration, and 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, and 48 hours after administration, and the plasma concentration of unchanged edaravone was measured. As a reference example, the same subjects were orally administered the same edaravone oral preparation, and blood samples were taken and plasma concentrations of unchanged edaravone were measured in the same manner. Oral administration was performed at least 10 hours after the previous meal. None of the subjects took their next meal until blood samples were taken 4 hours after administration. The obtained PK parameters are shown in Table 13 below. In addition, the results of an analysis of variance of AUC and Cmax taking into account the administration route are shown in Table 14 below.

[0148] [Table 13]

[0149] [Table 14]

[0150] As shown in Table 13, the PK parameters were very similar regardless of the administration route, indicating that the pharmacokinetics was maintained regardless of the administration route. As shown in Table 14, the least squares mean ratio of the AUC and Cmax of the Example administered via a nasogastric catheter to the AUC and Cmax of the Reference Example administered orally by the variance analysis showed that the 90% confidence interval was in the range of 0.8-1.25, which is the general equivalence standard. This result indicates that when edaravone is administered into the stomach via a catheter, there is no effect on the pharmacokinetic parameters AUC and Cmax, and it can exhibit the same effect of maintaining pharmacokinetics as when administered orally.

[0151] From the results of oral administration in this Example 8 and the results of gastrostomy catheter administration in the above Example 5, it was shown that the Cmax and AUC of edaravone after intragastric administration of the above edaravone oral preparation through a nasogastric catheter are equivalent to those after oral administration of the same edaravone oral preparation. From this, it was found that there was no difference in the pharmacokinetics of edaravone between intragastric administration through a catheter and oral administration, and that sufficient plasma concentration of edaravone was ensured in intragastric administration through a catheter as in oral administration. This result supports the fact that the plasma concentration of edaravone administered to ALS patients through a gastrostomy catheter in Example 5 is maintained similarly to oral administration, using a larger number of subjects.

[0152] [Example 9] In vitro study of edaravone adsorption onto catheters In the medical field, catheters made of various materials are used for administration using catheters. Therefore, whether administration is possible using catheters made of any material was examined by evaluating adsorption. That is, after the oral preparation of edaravone (#3) was passed through a catheter, the percentage of edaravone recovered by washing with water was evaluated. The types of gastrostomy catheters No. 1 to 3 used in the evaluation are shown in Table 15.

[0153] [Table 15]

[0154] Specifically, the oral edaravone preparation was filled in a catheter administration syringe so that the amount of edaravone was 105 mg, and the oral edaravone preparation was passed from the syringe into each of the catheters. Then, water at a predetermined temperature was injected into the catheters to wash them out. The oral edaravone preparation and the washing liquid that passed through the catheters were collected and mixed, and the amount of edaravone contained in the mixed liquid was measured. The washing conditions were 10 mL of water three times, 30 mL of water at 25°C or 40°C once, or 50 mL of water at 25°C or 40°C once. Three measurements were performed for each catheter, and the average and SD of the recovery rate % were calculated. These results are shown in Table 16.

[0155] [Table 16]

[0156] As shown in Table 16, regardless of the catheter material used, almost the entire amount of edaravone was recovered by washing with water of the specified amount. As described above, no adsorption of edaravone was observed in any catheter material, demonstrating that oral formulations of edaravone can be administered via catheter regardless of the catheter material.

[0157] Although the present invention has been described above with reference to the embodiment and examples, the present invention is not limited to the above embodiment. Various modifications that can be understood by those skilled in the art can be made to the configuration and details of the present invention within the scope of the present invention.

[0158] This application claims priority based on Japanese Patent Application No. 2020-188514, filed on November 12, 2020, the disclosure of which is incorporated herein in its entirety. [Industrial Applicability]

[0159] The pharmaceutical composition containing edaravone of the present invention can be administered at optimal administration intervals for each type of meal to avoid the influence of food intake on pharmacokinetics and can exhibit excellent effects as an oral or intragastric administration preparation of edaravone, and is therefore useful, for example, in the treatment of oxidative stress diseases.

Claims

1. The present invention relates to a method for administering a medicament containing edaravone as an active ingredient, the method comprising administering to said patient a first time interval selected from the group consisting of 1) to 3) below: 1) If you have consumed a high-fat meal, wait at least 8 hours after ingestion. 2) If regular food is consumed, it must be consumed for at least 4 hours. 3) If you have eaten a light meal, wait at least 2 hours after ingestion. The pharmaceutical composition is administered orally or intragastricly with a gap therebetween.

2. 2. The pharmaceutical composition according to claim 1, wherein the second time interval between administration of edaravone and ingestion of the next meal is 30 minutes or longer.

3. 3. The pharmaceutical composition according to claim 1, wherein the second time interval between administration of edaravone and the next meal intake is 1 hour or longer.

4. The pharmaceutical composition according to any one of claims 1 to 3, which is for oral administration.

5. The pharmaceutical composition according to any one of claims 1 to 3, which is for intragastric administration.

6. The pharmaceutical composition according to claim 1 , wherein the intragastric administration is by tube administration.

7. The pharmaceutical composition according to claim 6 , wherein the tube is a gastrostomy catheter.

8. The pharmaceutical composition of claim 6 , wherein the tube is a nasogastric catheter.

9. The pharmaceutical composition according to any one of claims 1 to 8 for treating an oxidative stress disease.

10. The pharmaceutical composition according to claim 9, wherein the oxidative stress disease is any one disease selected from the group consisting of amyotrophic lateral sclerosis, Parkinson's disease, spinocerebellar degeneration, muscular dystrophy, Alzheimer's disease, cerebral infarction, multiple sclerosis, systemic sclerosis and stomatitis.

11. The pharmaceutical composition according to claim 9 or 10, wherein the oxidative stress disease is amyotrophic lateral sclerosis.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the first time interval is a time interval during a dosing period of intermittent or daily administration.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the dosage per administration is 90 to 120 mg of edaravone.

14. The pharmaceutical composition according to any one of claims 1 to 12, wherein the dosage per administration is 90 to 105 mg of edaravone.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the number of times of administration per day is one and the dosage per day is 105 mg of edaravone.

16. A pharmaceutical composition comprising edaravone as an active ingredient, the composition being administered at a first time interval selected from the group consisting of 1) to 3) below: 1) If you have consumed a high-fat meal, wait at least 8 hours after ingestion. 2) If regular food is consumed, it must be consumed for at least 4 hours. 3) If you have eaten a light meal, wait at least 2 hours after ingestion.

2. A method for administering a pharmaceutical composition containing edaravone, comprising administering the same orally or intragastricly with an interval therebetween.

17. 17. The method of claim 16, wherein the second time interval between administration of the pharmaceutical composition and ingestion of the next meal is greater than or equal to 30 minutes.

18. 18. The method of claim 16 or 17, wherein the second time interval between administration of the pharmaceutical composition and the next meal intake is at least 1 hour.

19. The method according to any one of claims 16 to 18, wherein the pharmaceutical composition is administered orally.

20. The method according to any one of claims 16 to 18, wherein the pharmaceutical composition is administered intragastrically.

21. 21. The method of claim 20, wherein the intragastric administration is by tube.

22. 22. The method of claim 21, wherein the tube is a gastrostomy catheter.

23. 22. The method of claim 21, wherein the tube is a nasogastric catheter.

24. The method according to any one of claims 16 to 23, wherein the pharmaceutical composition is administered to treat an oxidative stress disease.

25. The method according to claim 24, wherein the oxidative stress disease is any one disease selected from the group consisting of amyotrophic lateral sclerosis, Parkinson's disease, spinocerebellar degeneration, muscular dystrophy, Alzheimer's disease, cerebral infarction, multiple sclerosis, systemic sclerosis and stomatitis.

26. The method according to claim 24 or 25, wherein the oxidative stress disease is amyotrophic lateral sclerosis.

27. administration of the pharmaceutical composition comprises intermittent or daily administration; 27. The method of any one of claims 16 to 26, wherein the pharmaceutical composition is administered at said first time intervals during said intermittent or daily dosing period.

28. The method according to any one of claims 16 to 27, wherein the pharmaceutical composition is administered in a single dose of 90 to 120 mg of edaravone.

29. The method according to any one of claims 16 to 27, wherein the pharmaceutical composition is administered in a single dose of 90 to 105 mg of edaravone.

30. The method according to any one of claims 16 to 29, wherein the pharmaceutical composition is administered once per day, and the dosage of the pharmaceutical composition per administration is 105 mg of edaravone.

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